Citation for published version (APA): Schoenmaker, N. J. (2013). Management & monitoring of paediatric end-stage renal disease

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1 UvA-DARE (Digital Academic Repository) Management & monitoring of paediatric end-stage renal disease Schoenmaker, N.J. Link to publication Citation for published version (APA): Schoenmaker, N. J. (2013). Management & monitoring of paediatric end-stage renal disease General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 12 Dec 2018

2 2013 Management & Monitoring of Paediatric End-Stage Renal Disease Nikki Schoenmaker Management & Monitoring of Paediatric End-Stage Renal Disease Nikki Schoenmaker

3 Management & Monitoring of Paediatric End-Stage Renal Disease Nikki J. Schoenmaker

4 Management & Monitoring of Peadiatric End-stage renal disease, PhD thesis, University of Amsterdam, The Netherlands The studies presented in this thesis were financially supported by The Dutch Kidney Foundation. The printing of this thesis was financially supported by: The University of Amsterdam, Amgen B.V., Astellas Pharma B.V., Baxter B.V., Fresenius Medical Care, Novartis Pharma B.V., Novo Nordisk B.V., Phizer B.V., Roche Nederland B.V., Sanofi- Aventis Netherlands B.V., Stichting Kindernierziekten, Stichting WOKA, Department Paediatric Nephrology Emma Children s Hospital. Cover: Tim van Amerongen Layout and Printing: Print Service Ede ISBN: Copyright 2013 N.J.Schoenmaker. All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission from the author.

5 Management & Monitoring of Paediatric End-Stage Renal Disease ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op woensdag 19 juni 2013, te 14:00 uur door Nikki Johanna Schoenmaker geboren te Haarlem

6 Promotiecommissie Promotor: Prof. dr. M. Offringa Co-promotores: Dr. J.W. Groothoff Dr. J.H. van der Lee Overige leden: Prof. dr. N.A. Blom Prof. dr. A.P. Bos Prof. dr. F.W. Dekker Prof. dr. J.B. van Goudoever Prof. dr. J.J. Homan van der Heide Prof. dr. B. Hoppe Prof. dr. B.J.M. Mulder Faculteit der Geneeskunde

7 Table of contents Chapter 1. General introduction, aim and outline of the thesis Part I. Management policies Chapter 2. Important differences in management policies for children with End-stage renal disease in the Netherlands and Belgium - Report from the RICH-Q study Chapter 3. Policy variation in donor and recipient status in 11 paediatric renal transplantation centres Chapter 4. Quality and consistency of clinical practice guidelines for the management of children on chronic dialysis Part II. Children from non-western origin Chapter 5. Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents Chapter 6. Non-Western immigrant children with end-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health related quality of life compared to Western children Part III. Cardiac monitoring Chapter 7. Low agreement between cardiologists diagnosing left ventricular hypertrophy in children with End-stage renal disease Chapter 8. Diastolic dysfunction measured by Tissue Doppler Imaging in paediatric patients with End-stage renal disease - Report from the RICH-Q study Chapter 9. Impaired longitudinal deformation measured by Speckle Tracking Echocardiography in paediatric patients with End-stage renal disease Chapter 10. General discussion and recommendations Chapter 11. Summary & Nederlandse Samenvatting Portfolio & Publications Levensverhaal van een patiënt Curriculum vitae Dankwoord

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9 1General introduction, aim and outline of the thesis 1 7

10 Chapter 1 Introduction End-stage renal disease (ESRD) in children was a lethal condition until the 1960s. Since the early seventies of the last century, renal replacement therapy (RRT) for children with ESRD has become a routine therapy. Gradually, a group of ESRD survivors has reached adulthood, and it is becoming clear how these patients fare as adults. In 1999, a follow-up study on patients who started chronic RRT in their childhood, found a mortality rate of 25% before the age of 30. Forty percent of these patients died of cardiovascular disease 1;2. The same study shows that juvenile ESRD has an important impact on somatic and psychosocial functioning in adult life: at least 40% of the adult survivors of ESRD with childhood onset suffer from some form of somatic complications, and about 20% are severely disabled 2-4. Despite all progress that has been made with various different technical aspects of RRT, the most recent data on children treated with RRT suggest that most of the unfavourable longterm consequences may still be the fate of the current population 5;6. Even more disturbing is the fact that for children on dialysis, about 40% of the children on RRT, all cause mortality rates have not changed significantly since the 1980 s 7. The relative lack of progress in improving the health outcomes of the children with ESRD may be partly due to the small number of patients treated per dialysis centre and the lack of a common database for optimal treatment. Contrary to the situation in adults, ESRD in children is a rare disorder. In the western world, the yearly incidence of ESRD in patients < 19 years of age is about 6-8 per million age related population. In a population of 3.9 million people below the age of 20 years in the Netherlands 8 and 2.5 million in Belgium 9, this implies, about 30 new patients per year in the Netherlands and 20 in Belgium. In order to maintain acceptable travel distances to the dialysis centre, patients can choose between several, and consequently all very small RRT centres, of which there are 4 in the Netherlands and 6 in Belgium. Until the start of the RICH-Q project (Renal Insufficiency in Children- Quality assessment and improvement) in 2007 no information was available on the quality of care (QoC) delivered by these dialysis centres, nor on the association of the QoC with health outcomes. Before the RICH-Q project no structural collaboration existed between the paediatric RRT centres, and there was no consensus on medical management issues related to dialysis treatment. RICH-Q was started as a collaborative initiative of all 10 Dutch and Belgian paediatric dialysis and renal transplantation centres; in 2011 an 11 th centre in Cologne, Germany, joined the project. RICH-Q aims to improve the QoC for children with ESRD by peer review and plenary discussion of prospectively recorded data on treatment characteristics and physical and psychosocial health outcomes, applying the latest scientific evidence and guidelines on RRT in children. On March 1 st 2013, 327 children had been included in the RICH-Q registry. The first results of the RICH-Q project showed the efforts that were made to initiate a international collaboration: guiding principles were established and a Good Clinical Practice database on RRT characteristics and health outcomes was developed 10. At onset of the RICH-Q project, current local management policies on RRT were surveyed by an in depth questionnaire. Since 2009 all participating centres have online access to specific quality indicators (e.g. serum haemoglobin level) of the children of their own centre compared to the total RICH-Q population. Fourteen paediatric nephrologists participating in the RICH-Q 8

11 General introduction, aim and outline of the thesis study meet twice a year to compare the results of the RICH-Q database between their centres, to make guidelines and set quality indicators and benchmarks, and to discuss the agenda for further research. For this thesis three priority areas were chosen. The first area of interest is the current QoC for children with ESRD. Quality improvement research strives to bridge the gap between ideal and actual care 11. However, in the field of paediatric ESRD there is by far insufficient evidence to define ideal care. A tool to improve the QoC is adherence to clinical practice guidelines Yet, for users of guidelines it is often not clear how these guidelines were developed and whether the recommendations are robust. We therefore aimed to identify all current published guidelines for the management of children on chronic dialysis and assess the quality of their development. Furthermore we aimed to quanitfy the variation in treatment policies and its consequences in daily practice for children with ESRD in the 11 RICH-Q centres. 1 Second, in Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-western European origin (Non-Western). An earlier RICH-Q study by Tromp et al. showed that non Western children received less pre-emptive transplantations and after transplantation had more rejections than native Dutch and Belgian children 15. The unfavourable outcomes of transplantation in children of non- Western origin as compared to native children might be due to biological factors, such as pharmacokinetic, immunologic or other biogenetic differences, or to factors related to the cultural gap between doctor and patient. Very little data exist on this group of patients. We therefore decided to further explore aspects of health outcomes in these patients. We set out to investigate if similar less favourable treatment characteristics and health outcomes might also occur in non-western children on dialysis as in transplanted patients. First we analysed overall treatment characteristics and outcomes, such as choice of dialysis modality, co-morbidity and complications of treatment, of both native Dutch and Belgian children in comparison to children from non-western immigrants. So far, it is not known whether disparities in treatment characteristics and health outcomes between young non-western and native ESRD patients are associated with differences in Health Related Quality of Life (HRQoL). Previous studies indicate that, in general, HRQoL is low in children with ESRD compared to healthy children. For non-western children, who usually live in less favourable circumstances, the burden of ESRD may add up to that caused by their non-western status. Over the last twenty years, the number of children on RRT in the Netherlands and Belgium from non-western origin has increased to such an extent, that it warrants exploration of these differences in order to optimise RRT for all paediatric patients. As cardiovascular disease is the main cause of death in young patients with ESRD 2, the third aim was to focus on the detection and prevention of cardiovascular disease in children with ESRD. To evaluate the efficacy of adjustment of cardio-protective therapy, it is essential to have an accurate and reproducible clinical marker for cardiovascular function and tissue integrity. Although assessment of cardiovascular disease in ESRD children is widely 9

12 Chapter 1 recommended, few data exist on the validity for children of the existing tools. Earlier RICH Q studies from Tromp et al. showed that current devices for Pulse wave velocity measurement were too unreliable for clinical evaluation of vascular disease in children with ESRD. This thesis is focused on the assessment of cardiac disease. Studies in adults with ESRD have shown that left ventricular hypertrophy, diastolic and systolic dysfunction are early predictors of cardiovascular mortality 16. To date, conventional echocardiography is recommended in children with ESRD as the method of choice for detection of cardiac disease 17;18. First, we analysed the sensitivity and reproducibility of detecting left ventricular hypertrophy and left ventricular dysfunction by this technique. Secondly, we explored the validity of advanced echocardiographic imaging modalities, e.g. Tissue Doppler Imaging (TDI) and 2-dimensional Speckle Tracking Echocardiography (STE), for establishment of left ventricular function. TDI and STE appear to be promising methods for the detection and quantification of subtle abnormalities in diastolic 19 and systolic 20 ventricle function in adults. Contrary to the situation in adults with chronic kidney disease (CKD), systolic ventricle function is thought to be preserved in children with CKD However, this hypothesis is based on studies that have examined systolic performance with conventional echocardiography and TDI. It is possible that evaluation with STE may unmask more subtle changes in systolic function. No STE data existed on children with ESRD. We therefore perfomed analyses of all 3 techniques in a selection of patients and tested the reproducibility of both TDI and STE in these children. Aim of the thesis The aim of this thesis is to evaluate the current management of paediatric ESRD and monitoring of the patients health outcomes, and to present recommendations for improvement of this management and monitoring of paediatric ESRD. To address this aim the following questions are addressed: Is there relevant variability in management policies between the various centres that provide paediatric RRT for children in the Netherlands and Belgium? Which guidelines on the management of chronic dialysis in children currently exist, what is the quality of their development, and are there any inconsistencies between guidelines? Are there relevant disparities in dialysis treatment characteristics and health outcomes, in children from non-western European origin compared to native Dutch, Belgian and German children? Are there relevant disparities in Health related quality of life in children from non-western European origin compared to native Dutch, Belgian and German children? What is the the validity and reproducibility in terms of intra-and inter-observer agreement of left ventricular hypertrophy by conventional echocardiography in children with ESRD? Is Tissue Doppler imaging more reliable than conventinal echocardiography in detecting early diastolic dysfunction in children with ESRD? Is Speckle Traching Echocardiography more reliable than conventinal echocardiography and TDI in detecting early systolic dysfunction in children with ESRD? 10

13 General introduction, aim and outline of the thesis Outline Part I describes the results of the studies on the variation of management policies for children on dialysis (Chapter 2) and renal transplantation (Chapter 3) between the different RICH-Q centres. A comparison between stated treatment policies, the currently available guidelines and actually performed care between 2007 and 2012 is made. Chapter 4 presents a systematic overview of all current published guidelines for the management of chronic dialysis in children, with an assessment of their methodological quality. Part II describes the disparities in treatment and health outcomes, including HRQoL, of non- Western children with ESRD compared to native patients. Chapter 5 presents disparities in dialysis treatment and outcomes in children from non-western European origin compared to native Dutch and Belgian children. Chapter 6 compares the HRQoL between Non-Western and Western children with ESRD. 1 Part III decribes our search for a reliable tool for early detection of cardiovascular diasease that is suitable for use in children with ESRD. In Chapter 7 the (dis)agreements between cardiologists diagnosing left ventricular hypertrophy in the same children are quantified. Chapter 8 compares the prevalence of diastolic function measured by echocardiography and TDI in children with ESRD, and examines the reproducibility of these measurements. Chapter 9 compares the systolic function of children on dialysis and after renal transplantation, assessed with conventional echocardiography, TDI and STE, and assesses the reproducibility of STE measurements. Finally, a general discussion of all findings in the present thesis is presented in Chapter 10. Here, implications for clinical practice and directions for future research are given. 11

14 Chapter 1 Reference List 1. McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350: Groothoff JW, Gruppen MP, Offringa M et al. Mortality and causes of death of endstage renal disease in children: a Dutch cohort study. Kidney Int 2002; 61: Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112-S Groothoff JW, Offringa M, Van Eck-Smit BL et al. Severe bone disease and low bone mineral density after juvenile renal failure. Kidney Int 2003; 63: Bakkaloglu SA, Saygili A, Sever L et al. Assessment of cardiovascular risk in paediatric peritoneal dialysis patients: a Turkish Pediatric Peritoneal Dialysis Study Group (TUPEPD) report. Nephrol Dial Transplant 2009; 24: Rinat C, Becker-Cohen R, Nir A et al. A comprehensive study of cardiovascular risk factors, cardiac function and vascular disease in children with chronic renal failure. Nephrol Dial Transplant 2010; 25: Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012; 23: Centraal Bureau Statistiek Nederland Statistics Belgium. http// Tromp WF, van der Lee JH, Offringa M et al. Lessons learned from efforts to improve the quality of care in children with end-stage renal disease in the Netherlands and Belgium. Arch Dis Child 2011; 96: Ting HH, Shojania KG, Montori VM, Bradley EH. Quality improvement: science and action. Circulation 2009; 119: Boluyt N, Lincke CR, Offringa M. Quality of evidence-based pediatric guidelines. Pediatrics 2005; 115: Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet 1993; 342: Kuzma-O Reilly B, Duenas ML, Greecher C et al. Evaluation, development, and implementation of potentially better practices in neonatal intensive care nutrition. Pediatrics 2003; 111: e461-e470 12

15 General introduction, aim and outline of the thesis 15. Tromp WF, Cransberg K, van der Lee JH et al. Fewer pre-emptive renal transplantations and more rejections in immigrant children compared to native Dutch and Belgian children. Nephrol Dial Transplant 2012; 27: Mitsnefes MM, Kimball TR, Border WL et al. Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 2004; 65: Fujimoto S, Kagoshima T, Nakajima T, Dohi K. Doppler echocardiographic assessment of left ventricular diastolic function in patients with systemic lupus erythematosus. Cardiology 1994; 85: Leung DY, Boyd A, Ng AA, Chi C, Thomas L. Echocardiographic evaluation of left atrial size and function: current understanding, pathophysiologic correlates, and prognostic implications. Am Heart J 2008; 156: Ommen SR, Nishimura RA, Appleton CP et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 2000; 102: Liu YW, Su CT, Huang YY et al. Left ventricular systolic strain in chronic kidney disease and hemodialysis patients. Am J Nephrol 2011; 33: Johnstone LM, Jones CL, Grigg LE, Wilkinson JL, Walker RG, Powell HR. Left ventricular abnormalities in children, adolescents and young adults with renal disease. Kidney Int 1996; 50: Palcoux JB, Palcoux MC, Jouan JP, Gourgand JM, Cassagnes J, Malpuech G. Echocardiographic patterns in infants and children with chronic renal failure. Int J Pediatr Nephrol 1982; 3: Colan SD, Sanders SP, Ingelfinger JR, Harmon W. Left ventricular mechanics and contractile state in children and young adults with end-stage renal disease: effect of dialysis and renal transplantation. J Am Coll Cardiol 1987; 10:

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17 2Important differences in management policies for children with End-stage renal disease in the Netherlands and Belgium - Report from the RICH-Q study Wilma F. Tromp 1, Nikki J. Schoenmaker 1, Johanna H. van der Lee 2, Brigitte Adams 3, Antonia H. M. Bouts 1, Laure Collard 4, Karlien Cransberg 5, Rita Van Damme-Lombaerts 6, Nathalie Godefroid 3, Koenraad van Hoeck 7, Linda Koster-Kamphuis 8, Marc R. Lilien 9, Ann Raes 10, Martin Offringa 2, and Jaap W. Groothoff 1 Departments of Paediatric Nephrology: 1 Emma Children s Hospital Academic Medical Centre Amsterdam, the Netherlands, 3 Hospital Universitaire des Enfants Reine Fabiola Brussels, Belgium, 4 Centre Hospitalier Universitaire de Liege, Belgium, 5 Sophia Children s Hospital Erasmus MC Rotterdam, the Netherlands, 6 University Hospital Leuven, Belgium, 7 University Hospital Antwerp, Belgium, 8 Radboud University Nijmegen Medical Centre, the Netherlands, 9 Wilhelmina Children s Hospital University Medical Centre Utrecht, the Netherlands, 10 University Hospital Gent, Belgium 2 Department of Paediatric Clinical Epidemiology Emma Children s Hospital AMC Amsterdam, the Netherlands Nephrol Dial Transplant May;27(5):

18 Chapter 2 Abstract Background The low prevalence of childhood End-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence based guidelines for chronic Renal Replacement Therapy (crrt) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in 9 centres that deliver crrt for children. Methods We surveyed treatment policies in all 9 centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to Results Data on policies and actual patient care were obtained from all 9 centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated Glomerular Filtration Rate treshold as indication for initiation of crrt, preferred initial mode of crrt, peritoneal dialysis catheter care, haemodialysis frequency, and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies no evidence based guidelines are available. Conclusions Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing crrt for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking. 16

19 Management policies Introduction End-stage renal disease (ESRD) in children is a rare but serious disorder 1;2. In the western world, the yearly incidence rate of ESRD in patients younger than 19 years of age is about 6-8 per million age related population 3. On an age related population of 3.9 million people in the Netherlands 4 and 2.5 million in Belgium 5, this implies that there are about 30 new patients per year in the Netherlands and 20 in Belgium. In order to maintain acceptable travel distances to the dialysis centre, patients can choose between several, and consequently all very small, dialysis centres, of which there are 4 in the Netherlands and 5 in Belgium. The low prevalence of childhood ESRD and the overall small centre sizes both have been a barrier for large clinical studies and the development of evidence based guidelines for treatment of children with ESRD worldwide. The RICH-Q study (Renal Insufficiency in Children-Quality assessment and improvement) 6 started in 2007 as a collaborative initiative of all Dutch and Belgian centres for paediatric chronic Renal Replacement Therapy (crrt). It aims to improve the quality of care (QoC) for children with ESRD by peer review and plenary discussion of prospectively recorded data on treatment characteristics and physical and psychosocial health outcomes applying the latest scientific evidence and guidelines on crrt in children. 2 In this paper, we describe treatment policies for children with ESRD on dialysis in all treatment centres in the Netherlands and Belgium at the onset of RICH-Q and we compare stated treatment policies with currently available guidelines and with the actually performed care between 2007 and Materials and methods In this study, information was obtained from three sources. A survey was conducted on management policies, a literature search was performed to identify guidelines, and clinical data were collected prospectively as part of the RICH-Q project. Each of the three methods of data-collection are described in detail below. Survey on treatment policies At the start of RICH-Q in 2007 we asked one paediatric nephrologist per participating centre to complete a questionnaire on treatment policies. The questionnaire was developed with input from all participating paediatric nephrologists, to ensure content validity. The questionnaire included 30 questions on 16 topics (Table 1) divided in 4 main sections, i.e. initiation of crrt and peritoneal dialysis (PD) policies and haemodialysis (HD) policies and paramedical care. Literature search Existing guidelines were identified by a comprehensive search in PubMed and websites of organizations known to produce guidelines for patients with ESRD (KDIGO 7, KDOQI 8, CARI 9, UK Renal Association 10, CSN Canada 11, Renal Physicians Association 12, ISPD 13 and EBPG 14 ). Clinical data collection in the RICH-Q project. In RICH-Q, anonymous data on treatment characteristics and physical and psychosocial health outcomes are registered prospectively concerning all children with ESRD treated in 17

20 Chapter 2 Table 1. Overview of topics and items of the questionnaire on treatment policies Topics Initiation of crrt Estimated Glomerular Filtration Rate at start crrt Reasons to start crrt Choice of crrt modality Peritoneal Dialysis (PD) PD types Adequacy tests Consultation PD catheter care Haemodialyis (HD) Home haemodialyis Overnight haemodialysis (in centre) Adequacy measurements Frequency of HD Policy for preservation of vasculature upper extremity for future vascular access ArterioVenous Fistula (AVF) Central venous catheters Paramedical care Medical personnel in the dialysis centre Composition of paramedical team Items egfr at which crrt initiation should be considered, in the absence of signs of uremia and/or growth failure and/or malnutrition Reasons to start crrt Preferred type of crrt to start with Preferred second choice of crrt if first choice is not available Types of PD used (Continuous Cyclic PD / Continuous Ambulatory PD) Calculation of kt/v for PD patients Performance of Peritoneum Equilibrium - / Standard Permeability Tests Intra-abdominal pressure measurements Frequency of consultation in the outpatient clinic Mupirocin prophylaxis yes / no Swimming yes/no Bath or shower Possibility yes/no Number of children treated with home-hd Possibility yes/no Number of children treated with overnight centre HD Calculation of kt/v for HD patients Frequency and duration of HD sessions at start crrt in children < 3 years Frequency and duration of HD sessions at start crrt in children 3-12 years Policy present or not Time between AVF-creation and (scheduled) start HD Type of surgeon who creates AVF Minumum age for AVF creation Monitoring of AVF function Type of surgeon who performs surgery Preferred type of catheter Preferred catheter lock solution Paediatric nephrologist or adult nephrologist Type of nurses: Specialized (paediatric) dialysis nurses Social worker, dietician, psychologist, hospital teachers 18

21 Management policies 1 of the 9 hospitals in the Netherlands and Belgium that provide crrt for children. In the RICH-Q registry we included (1) all prevalent Dutch and Belgian patients aged < 19 years on chronic dialysis on September 1 st 2007, and (2) all Dutch and Belgian patients aged < 19 years who started crrt or were transplanted from September 1 st, 2007 to date. We obtained ethical approval from the ethical boards of all participating hospitals and written Informed Consent from all participants or their parents. Online data extraction forms (DEF) are filled in for each included patient four times a year. An independent research institute (the Hans Mak Institute 15 ) checks these data for missing values and irregularities and assures the quality of the data by monitoring 20% of all completed DEFs. The clinical data from the RICH-Q database that we used in this paper were data concerning initiation of crrt, PD catheter management and HD frequency. For the initiation of crrt the following variables were used: date, age, treatment modality, height and creatinine at initiation of crrt and reason for initiation of crrt (indicated by the health care professional). For the calculation of the estimated Glomerular Filtration Rate (egfr) at initiation of crrt we used the original Schwartz equation: GFR (ml/min/1.73m 2 ) = k (Height in cm) / serum creatinine in mg/dl), with k being an age-dependent variable 16. For the section on PD catheter management we used data on type of PD-catheter, number of cuffs, exit site direction, use of mupirocin prophylaxis and number of peritonitis. For the section on HD frequency we used data on HD prescription; number and duration of dialysis sessions per week. Descriptive statistics are used to report the results. 2 Results We received completed questionnaires from all participating centres. In panel 1 all existing guidelines with recommendations on the topics chosen by the paediatric nephrologists on initiation of crrt are presented Guidelines with recommendations on topics concerning PD and concerning HD 22;23 are presented in panels 2 and 3, respectively. Panel 4 shows the guidelines with recommendations on topics concerning paramedical care 18;20;22;24. Between September 1 st 2007 and December 1 st 2010, 201 children with ESRD were included of whom 59 % were boys. The first mode of crrt at initiation of therapy was HD in 38%, PD in 38% and pre-emptive transplantation (ptx) in 24%. Median [range] age at inclusion of the study was 10 [0-18] years and median [range] duration of renal replacement therapy (crrt) 11 [0-209] months; 107 patients (53 %) were prevalent patients on dialysis at the start of RICH-Q. Initiation of chronic renal replacement therapy Both the stated policies of the participating centres and the available guidelines showed variations with respect to the recommended lower limit of the egfr at which crrt should be initiated. Table 2 shows the stated policies with respect to the lower limit of egfr for initiation of crrt in comparison with the actual median egfr at onset of crrt. Centre policies varied between a recommended lower egfr limit of 15 and 10 ml/min/1.73m 2. In contrast, the median egfr levels at which patients actually started with crrt were almost equal for all centres. Both policies and guidelines agreed to start crrt at an egfr < 15 ml/ min/1.73m 2. However, in 22 % (37/166) of patients crrt was started at an egfr above 15 ml/min/1.73m 2 and in 11% (18/166) even at an egfr above 20 ml/min/1.73m 2. Pre-emptive 19

22 Chapter 2 Table 2. Estimated Glomerular Filtration Rate (egfr) at start of chronic Renal Replacement Therapy (crrt). Reported policy Registry data Centre egfr at start crrt (ml/min/1.73 m 2 ) egfr at start crrt Median [range] (n=166)* Patients that met reported policy / all patients that started crrt (%) < [ ] 10/25 (40) < [ ] 15/27 (56) < [ ] 10/31 (32) < [ ] 7/16 (44) < [ ] 5/6 (83) < [ ] 23/28 (82) < [ ] 4/6 (67) < [ ] 11/15 (73) 9 never starts solely based on egfr 11.8 [ ] 8/12 (67) *Data to calculate egfr (age, height and serum creatinine at start crrt) were available for 166 patients that started crrt between January 2007 and December 1 st

23 Management policies transplantations were performed at a median (range) egfr of 14.0 (0-28.5) ml/min/1.73m 2, compared to a median (range) of 10.6 (0-29.9) for starting dialysis (p=0,011). Reasons for initiation of crrt in these specific cases are presented in Table 3. All centres reported pre-emptive transplantation (ptx) as the preferred mode of crrt at initiation of crrt in a child above 3 years old, but this could only be realized in 23% (32/138) of the patients. No clear recommendation on this choice was found in the guidelines. If ptx was impossible, stated policies of hospitals varied between PD and HD as a second choice. The actually performed first mode of crrt if ptx was impossible, differed from these stated policies in 27% (29/106) of patients (Table 4). Table 3. Reasons to start chronic Renal Replacement Therapy (crrt) at estimated Glomerular Filtration Rate (egfr) above 20 ml/min/1.73 m 2, by modality 2 First crrt modality Transplantation (n = 6) Haemodialysis (n = 6) Peritoneal dialysis (n = 6) Reasons* egfr [ ] ml/min/1.73 m 2 (n=18) egfr high potassium high phosphate poor condition next year final exam for school anorexia increasing inability to focus at school egfr high potassium high phosphate hyponatremia poor condition hypervolemia with severe arterial hypertension end-stage renal disease egfr high potassium high phosphate acidosis HUS uremia non-compliance (medication and diet) * In some children, more than one reason was reported to start crrt. 21

24 Chapter 2 Table 4. First mode of Renal Replacement Therapy (crrt) in children of 3 years and older that started crrt between January 2007 and December 1 st 2010 Centre Reported policy Patient registry (n=138) Mode of first If Tx is not First mode of crrt Adherence to own policy (%) choice possible Tx* HD PD If Tx is not First mode possible 1 TX PD /24 (29) 12/17 (71) 2 TX HD /19 (21) 4/15 (27) 3 TX HD /26 (27) 13/19 (68) 4 TX HD /14 (14) 10/12 (83) 5 TX PD /5 (20) 3/4 (75) 6 TX PD/HD /24 (25) 18/18 (100) 7 TX PD /4 (0) 2/4 (50) 8 TX HD /12 (17) 8/10 (80) 9 TX PD /10 (30) 7/7 (100) Total /138 (23) 77/106 (73) * Only transplanted patients that are included in the RICH-Q study are reported. Transplanted patients were included in the study only when they were transplanted after September HD = Haemodialysis, PD = Peritoneal Dialysis, Tx = Transplantation. Peritoneal Dialysis All centres preferred Continuous Cyclic Peritoneal Dialysis over Continuous Ambulatory Peritoneal Dialysis in children. Intra-abdominal pressure measurements were routinely performed in 7/9 centres, adequacy measurement, by calculating Kt/V in 6/9 centres. Topics that did not vary between centres were frequency of consultation (once per month, which is also the recommended frequency in the KDOQI guideline) and performances of Peritoneum Equilibrium Tests or Standard Permeability Analysis tests (performed in all centres, conform the KDOQI guidelines, once or twice per year). We found differences in treatment policies and actual performed therapies concerning PD catheter care and prevention of peritonitis (Table 5). In summary, mupirocin prophylaxis, applied at the exit site, was included in standard treatment in 3 of 9 centres only and double cuff catheters were used in 69 % (66/95) of all PD patients above 3 kilograms. The direction of the exit-site of catheters points downwards in 27% (26/95) of all catheters. The peritonitis incidence rate varied from 0 to 2.26 per patient year per centre, but the numbers were too small to detect meaningful differences between centres. 22

25 Management policies Table 5. Peritoneal dialysis (PD) policies and policy-related patient information (n=95) Patient data Policy Patient data Patient data Patient data Policy Source Peritonitis incidence rate [95%CI] (per patient year on PD) mupirocin prophylaxis Exit site pointing downwards/ all exit sites (%) Double-cuff catheters in patients > 3 kg / all PD catheters (%) Lifestyle guidelines Topic Centre Adherence to own policy (%) Stated policy shower bath swimming 1 yes yes yes 13/17 (76) 1/17 (6) no 12/17 (71) 0.87 [ ] 0.63 [ ] (36) yes 13/14 (93) 5/14 4/14 (29) yes (with stoma bag) 2 yes no (0) yes 11/14 (79) 0.36 [ ] 0/14 3/14 (21) yes (with stoma bag) 3 yes yes 0 [0 0.82] (100) no 3/6 (50) 6/6 6/6 (100) yes (in private swimming pool) 4 yes no 5/5 (100) 4/5 (80) no 5/5 (100) 1.35 [ ] yes (with special swimming belt ) 5 yes no 6 yes yes yes 15/17 (88) 1/17 (6) yes 15/17 (88) 0.46 [ ] 7 yes no no 2/3 (67) 2/3 (67) no 3/3 (100) 2.26 [ ] 0 [0 1.14] (67) no 6/6 (100) 4/6 5/6 (83) yes (in private swimming pool) 8 yes no 9 yes no no 13/13 (100) 3/13 (23) no 13/13 (100) 0.76 [ ] 2 23

26 Chapter 2 Haemodialysis Haemodialysis was offered in all centres in the Netherlands and Belgium, but in 2 centres it was only performed if PD was absolutely contra-indicated or impossible. Three Dutch centres offered home haemodialysis and 1 Belgian centre overnight centre haemodialysis. Between 2007 and 2010, 93% of HD patients were treated in the dialysis unit during daytime (66 of 71 HD patients at baseline); 3 patients (4%) were treated overnight in the dialysis unit and 2 patients (3%) were treated with home haemodialysis. The policies with respect to recommended frequency of dialysis varied per centre and ranged from 3-7 sessions per week. Actually applied frequencies of dialysis varied from 2 to 7 dialysis sessions per week (Table 6). In 6/9 centres there was an explicit policy to preserve the vasculature of the upper extremity for future vascular access. There was variation in the minimum age for arteriovenous fistula (AVF) creation. In 6 centres this surgery was performed in children from 6 years on, in 3 centres AVF were created at a younger age (from 1-2 years). AVF function was monitored by regular physical examination and flow measurements in 5 centres, by physical examination only in 2 centres and in 2 centres regular check ups were not routinely performed. If central venous catheters were used, all centres stated the right internal jugular vein as preferred site. These catheters were inserted by paediatric surgeons in 5 centres and by a paediatric nephrologist, an adult nephrologist and a vascular surgeon in 1 centre each. In 1 centre central lines were inserted by a paediatric or adult nephrologist, whereas tunnelled catheters were inserted by a paediatric surgeon. Various types of catheters were used: single lumen Hickman or Broviac catheters in 4 centres, double lumen Hickman or Broviac in 3 centres and 2 centres used two single Tesio catheters. Preferences on catheter lock solutions also varied: 5 centres preferred heparin, 3 citrate and 1 preferred heparin or urokinase. Kt/V calculation as an indicator of dialysis adequacy was routinely performed in 6/9 centres. According to the RICH-Q data 35 of 73 HD patients who started haemodialysis between 2007 and 2010 had AVF ; 38 patients had central lines. Of these 38, 26 were placed in the right jugular vein, 4 in the left jugular vein, 5 in the right subclavian vein, 2 in the left subclavian vein and 1 in the left femoral vein. Of the 38 patients who received haemodialysis through a central line, heparin was used as catheter lock solution in 23 patients, urokinase in 6, citrate in 5, Danaparoid Sodium in 2, Actilyse and Taurolock in 1 patient each. Paramedical care In line with the guidelines, all children on dialysis in all treatment centres were not only treated by paediatric nephrologists but surrounded by a team of paramedical experts. The composition of this team varied between the different centres: in 7/9 centres a social worker was included in standard care for the patient, in 8/9 a dietician, in 6/9 a psychologist and in 6/9 centres hospital teachers were present on the dialysis ward. 24

27 Management policies Table 6. Policies and policy-related patient information on frequency and duration of dialysis sessions for patients on haemodialysis (HD) treatment (n = 73) Children < 3 years (n= 7) Children 3-18 years ( n= 66) Centre policy registry policy registry sessions / week sessions / week (n) hours / week frequency sessions / week hours / week (2) 9* 3 3 (1) 2 (1) (1) 4 (1) 3 (12) (1) 18* (14) 2 (2) (1) (6) 2 (1) 5 HD < 3 years not provided (1) (4) 4 (6) 3 (2) 2 (1) (3) 4 (1) (2) (6) 2 (1) 12 6* 18 16* 12* 9 9* 2, 12* 3,14, 15* 6* 12* 3 6* (2) 12 12*, 14, 15 8*, 11, 12* 1 9* 6* 24 # 20 12* 3 6* * patient(s) had residual renal function, * 1 1 of the patients had residual renal function, * 2 2 of the patients had residual renal function, * 3 3 of the patients had residual renal function, * 9 9 of the patients had residual renal function, # nocturnal dialysis 25

28 Chapter 2 Discussion In this paper we demonstrate important differences in treatment policies across the 9 hospitals providing crrt for children in the Netherlands and Belgium. We also found that the physicians often do not follow their own reported policies for the management of children with ESRD. Here we will discuss some of the most important policy variations. Indication of initiation of crrt Stated policies on initiation of crrt varied from a threshold egfr of 10 to 15 ml/min/1.73 m 2 at which crrt initiation should be considered, in the absence of signs of uremia and/or growth failure and/or malnutrition. A considerable proportion of patients (22%), however, started crrt at an egfr above 15 ml/ min. This is not in accordance with any stated policies or international recommendations. Pre-emptive transplantations are performed at a significantly higher egfr than onset of dialysis. The wish to avoid dialysis for patients that are candidate for pre-emptive transplantation and planning logistics may motivate physicians to choose for a safe egfr level at the time of transplantation. Clinical factors are presumably considered at least as important as egfr level in the decision to start RRT. One additional reason to start RRT even at a relatively high egfr level may be the lack of patient s compliance to diet and therapy prescription. Part of the discrepancy between egfr recommendations, policies and actual applied therapy could be explained by the use of different formulas to calculate the egfr. e.g. the updated or not-updated Schwartz formula 16;26 or the Counahan-formula 27. In this analysis, egfr calculation by original Schwartz formula was used, in concordance with all local policies. Recently, an updated version of this formula was published 28. However, we used the original formula in this analysis since decisions to start dialysis in this population were made in the past, and therefore based on the previous formula. Yet, the use of different formulas can not explain discrepancies of more than 5 ml/min/1.73 m 2. The findings of the present study are in line with data from the European registry for paediatric nephrology (ESPN), concerning 938 patients from 14 European countries 25. In that survey, the percentage of children who started crrt accordingly to the egfr levels recommended by two sets of guidelines 17:19 was also low; 22% started crrt at an egfr above 15. Pre-emptive transplantation as first crrt All centres reported that pre-emptive transplantation was their preferred first mode of crrt in children of 3 years and older, but this could only be realized in 23% (32/138) of all patients who started crrt during the study period. An explanation for this could be that some patients only presented shortly before onset or even at the time of end-stage renal disease, which made acute dialysis necessary. Also, the waiting list system of Eurotransplant favours dialysis patients to such an extent that pre-emptive post-mortem transplantation in children has been made virtually impossible. Nevertheless, these figures show that pre-emptive living donation is less easily achieved in the Netherlands and Belgium than desirable. 26

29 Management policies PD policies Treatment policies for PD patients varied considerably between the 9 treatment centres. Unfortunately, the follow up time of this cohort is yet insufficient to determine associations with clinical outcomes such as peritonitis incidence. We found considerable variation in lifestyle guidelines. These variations are important because extensive lifestyle related restrictions result in lower quality of life. As far as we know, there are several studies that address exit site care, but none of these studies investigated the association between lifestyle guidelines for bathing and swimming and peritonitis frequency 29;30;31. Double cuff catheters are used in 69% of all PD patients above 3 kilograms, which is in line with 2 guidelines that clearly recommend the use of double cuff catheters in these patients. Apparently, due to anatomical or practical reasons (surgical impossibility, availability of double cuff catheters), in 31% of these patients PD catheters cannot be inserted according to current recommendations. For exit-sites the need for improvement is even more important, because only 27% of all catheters is inserted according to the recommended direction ( downwards ). Surgical and anatomical reasons combined with practical reasons could be explanations why this guideline can not always be followed. For example, if a child needs to wear a diaper, the exit site direction will be upwards, as described previously by Rönnholm et al 32, but this could only explain some of the cases and can not be responsible for this low guideline adherence. The question is whether it is realistic to strive for more guideline adherence on all topics or whether the recommendations need adjustment because they are not feasible in all cases. Current guidelines for local mupirocin prophylaxis to prevent exit site infections and peritonitis in paediatric crrt are contradictory. Both stated and performed policies in our study varied. Recently large studies have proven the preventive effect of mupirocin Based on this new evidence the guidelines need to be updated by recommending the use of mupirocin, which should be implemented in clinical practice. 2 HD policies With respect to haemodialysis policy, we found remarkable differences between the centres. Some centres only offer a maximum of 3 sessions per week as standard policy, whereas others adapt to the patients specific needs and offer up to 6-7 sessions per week. Only 3 centres offer home haemodialysis and only 1 centre has facilities for overnight-haemodialysis. In 2 centres HD is offered only when PD is not possible. All these differences in policy may have a great impact on the life of the patients and their families. In most centres, for financial and/or practical reasons, haemodialysis is only possible on particular and restricted days. Organizational and financial reasons are weighed differently against patient preferences in different centres. High quality evidence needs to be generated to elicit the association of dialysis frequency and important outcomes such as quality of life and survival. The fact that there is only one paediatric guideline on vascular access and that this guideline does not deal with all topics requested by the paediatric nephrologists, may explain differences in vascular access policies. Also, vascular access policies might be influenced mainly by the paediatric or adult surgeons in the centres and to a lesser extent by the paediatric nephrologist. For example, the possibility of creation of an AVF in young children demands surgical expertise, which is not available in all centres. If consultation at the adult vascular access department will not help out, as recommended by the KDOQI guideline 21, collaboration with other paediatric dialysis centres should take place, and harmonization of 27

30 Chapter 2 patient care should make it possible that every small child on HD may obtain a functioning AVF. Paramedical care Four guidelines for management of children on dialysis 18;20;24;36 emphasize that a team of paramedical experts is an important requirement for children on crrt. In general, we found that in most centres at least 6 paramedical health professionals are involved in the treatment of the patients with ESRD in the Netherlands and Belgium, but also, that not all recommended paramedical disciplines are accessible to all patients. This could be due to the small number of patients treated in some of the centres. Again, centralization of care could be helpful to guarantee quality of paramedical care. Implications for practice Our observations imply that, given the same clinical condition, management depends on in which centre a child with ESRD is treated, e.g. at what egfr crrt is initiated, what crrt treatment modality is given to the patient, and how strict the lifestyle recommendations are. It means that optimal and suboptimal management strategies may be applied in children with otherwise similar conditions and clinical problems. This is remarkable in two highly organized countries with a highly qualified medical care system, and may jeopardize health outcomes for these children. If these disparities exist in these two countries, they may also exist in other European countries and around the world. Suboptimal management strategies may well deteriorate the course of disease as well as the quality of life in these children. Obviously, many of the differences in patient care that we found, such as the significant differences in choice of dialysis modality and lifestyle recommendations, have various different important psychosocial implications for patient and caretakers. To what extent these differences also affect patient outcomes is more difficult to assess as empirical research relating management choices to health outcomes in this field is scarce, demonstrated by our finding that over 95% of the existing guidelines for paediatric crrt are opinion derived and not based on clinical evidence. The lack of a solid scientific ground for the existing guidelines may also be an explanation for the remarkable deviations of the local policies from the recommendations as stated in these guidelines, and also for the deviations in daily practice in most units from their own stated treatment policies that we found. ESRD in children is a rare disease. Its treatment is highly sophisticated, complicated and, unfortunately, as a consequence of its rarity generally offered only by very small treatment units. National and international collaboration of paediatric crrt units, regular peer reviewing of treatments and outcomes, and analyses of data of a comprehensive Good Clinical Practice database on treatment aspects and outcomes may offer a method to generate more evidence for treatment, develop more evidence based guidelines and harmonize crrt in children. 28

31 Management policies Conclusion In conclusion, health care disparities exist due to large and unwanted variation in treatment policies between all hospitals providing crrt for children in the Netherlands and Belgium. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking. Disparities may deteriorate the course of disease as well as the quality of life in these children. 2 29

32 Chapter 2 Reference List 1. Groothoff JW, Gruppen MP, Offringa M et al. Mortality and causes of death of endstage renal disease in children: a Dutch cohort study. Kidney Int 2002; 61: McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350: Broyer M, Chantler C, Donckerwolcke R, Ehrich JH, Rizzoni G, Scharer K. The paediatric registry of the European Dialysis and Transplant Association: 20 years experience. Pediatr Nephrol 1993; 7: Centraal Bureau Statistiek Statistics Belgium Renal Insufficiency therapy in Children - Quality Assessment and Improvement Kidney Disease: Improving Global Outcome National Kidney Foundation. Kidney Disease: Outcomes Quality Initiative (KDOQI) Caring for Australasians with Renal Impairment The Renal Association - United Kingdom. GuidelinesSection/Guidelines.aspx Canadian Society of Nephrology (CSN). asp?s= Renal Physician s Association (RPA) International Society for Peritoneal Dialysis European Best Practice Guidelines (EBPG). asp Hans Mak Instituut Schwartz GJ, Haycock GB, Edelmann CM, Jr., Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976; 58: NKF KDOQI. Clinical Practice Guidelines for Hemodialysis Adequacy, Update American Journal of Kidney Diseases 2006; 48: S2-S90 30

33 Management policies 18. NKF KDOQI. Clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 2006; 48 Suppl 1: S White CT, Gowrishankar M, Feber J, Yiu V. Clinical practice guidelines for pediatric peritoneal dialysis. Pediatr Nephrol 2006; 21: Watson AR, Gartland C. Guidelines by an Ad Hoc European Committee for Elective Chronic Peritoneal Dialysis in Pediatric Patients. Perit Dial Int 2001; 21: Warady BA, Schaefer F, Holloway M et al. Consensus guidelines for the treatment of peritonitis in pediatric patients receiving peritoneal dialysis. Perit Dial Int 2000; 20: Fischbach M, Edefonti A, Schroder C, Watson A. Hemodialysis in children: general practical guidelines. Pediatr Nephrol 2005; 20: NKF KDOQI. Clinical practice recommendation 8: vascular access in pediatric patients. Am J Kidney Dis 2006; 48 Suppl 1: S274-S Coleman JE et al.on behalf of the European Paediatric Peritoneal Dialysis Working Group. Guideline by an ad hoc European Committee on the assessment of growth and nutritional status in children on chronic peritoneal dialysis van Stralen KJ, Tizard EJ, Jager KJ et al. Determinants of egfr at start of renal replacement therapy in paediatric patients. Nephrol Dial Transplant 2010; 25: Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in fullterm infants during the first year of life. J Pediatr 1984; 104: Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of glomerular filtration rate from plasma creatinine concentration in children. Arch Dis Child 1976; 51: Schwartz GJ, Munoz A, Schneider MF et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20: Kopriva-Altfahrt G, Konig P, Mundle M et al. Exit-site care in Austrian peritoneal dialysis centers -- a nationwide survey. Perit Dial Int 2009; 29: Prowant BF, Warady BA, Nolph KD. Peritoneal dialysis catheter exit-site care: results of an international survey. Perit Dial Int 1993; 13: Piraino B. Dialysis: The importance of peritoneal catheter exit-site care. Nat Rev 31

34 Chapter 2 Nephrol 2010; 6: Ronnholm KA, Holmberg C. Peritoneal dialysis in infants. Pediatr Nephrol 2006; 21: Piraino B. Mupirocin for preventing exit-site infection and peritonitis in patients undergoing peritoneal dialysis. Was it effective? Nephrol Dial Transplant 2010; 25: Xu G, Tu W, Xu C. Mupirocin for preventing exit-site infection and peritonitis in patients undergoing peritoneal dialysis. Nephrol Dial Transplant 2010; 25: Aykut S, Caner C, Ozkan G et al. Mupirocin application at the exit site in peritoneal dialysis patients: five years of experience. Ren Fail 2010; 32: Fischbach M, Stefanidis CJ, Watson AR. Guidelines by an ad hoc European committee on adequacy of the paediatric peritoneal dialysis prescription. Nephrol Dial Transplant 2002; 17:

35 Management policies Panel 1. Guidelines about the initiation of Renal Replacement Therapy (crrt) Guideline e GFR 1 at which crrt initiation should be considered. Exceptions GFR start KDOQI HD < 15 GFR > 15 if clinical course is complicated by the presence of signs and symptoms listed in table as well as malnutrition or growth failure KDOQI PD < consider or start earlier when malnutrition, fluid overload, hypertension, hyperkalemia, hyperphosphataemia, acidosis, growth failure or neurological consequences of uremia White, < 10 and / or signs of uremia and growth failure Watson, Unless the child remains asymptomatic and growth is well maintained 1. egfr = estimated Glomerular Filtration Rate in ml/min/1.73 m 2 Choice of crrt modality no clear recommendation, no discussion no clear recommendation Choice of crrt depends on variety of factors, e.g. patient / family choice, size, medical comorbidities, family support no clear recommendation, no discussion no clear recommendation Patient and family should be involved in choice 2 33

36 Chapter 2 Panel 2. Guidelines for peritoneal dialysis Guideline Number of cuffs Direction of exit site Mupirocin prophylaxis White, Double-cuff catheters can be used in children heavier than 3 kg where the external cuff can be placed 2-3 cm from the exit site Watson, Double-cuffed curled catheters are preferred in most children (8-10) (paediatric size in patients 3-10 kg of bodyweight, and adult catheter in patients > 10kg). A single-cuffed catheter may be needed in infants less than 3 kg. Downward or laterally In all but the smallest infants the exit site should be downward facing No clear recommendation, no discussion PD catheter care No clear recommendation, no discussion no convincing There is to be no data to suggest swimming during screening children or care givers for S. the initial 6 week period Aureus nasal carriage Due to danger or on the use of Pseudomonas of mupirocin cream infection, there around the exit site on a regular basis should be no prolonged immersion of the exit site in the bath but showering before the exit-site change is suggested. Swimming is not encouraged, especially in public pools, lakes, rivers and whirlpools or hot tubs. It can take place with good supervision and with occlusive dressings covering the exit site and catheter after the 6 week healing period. An immediate dressing change should take place after swimming Warady, No clear recommendation, no discus sion No clear recommendation, no discussion Prophylactic antibiotics for S.Aureus nasal carriage is recommended No clear recommendation, no discussion 34

37 Management policies Panel 3. Guidelines for haemodialysis Guideline Frequency and duration of dialysis sessions Fischbach, Dialysis session, prescription and moni toring: individual prescription is required: babies/infants/children and assessment and adjustment is needed regularly in small/growing children Vascular access No clear recommendation, no discussion 2 KDOQI Vascular access paediatric patients Permanent access in the form of a fistula or graft is the preferred form of vascular access for most paediatric patients on maintenance HD therapy Circumstances in which a central venous catheter may be acceptable for paediatric longterm access include lack of surgical expertise to place permanent vascular access in small children, patient size too small to support a permanent vascular access, bridging HD for PD training or PD catheter removal for peritonitis, and expectation of expeditious kidney transplantation If surgical expertise to place permanent access does not exist in the patient s paediatric setting, efforts should be made to consult vascular access expertise among local adult-oriented surgeons to either supervise or place permanent vascular access in children An AVG stenosis surveillance protocol should be established to detect venous anastomosis stenosis and direct patients for surgical revision or PTA 35

38 Chapter 2 Panel 4. Guidelines for paramedical care Guideline Recommendation KDOQI PD adequacy all disciplines involved in the care for the paediatric PD patient, including physicians, nurses, social workers, dietitians, play therapists, psychologists and teachers. Watson, The multidisciplinary team provides support for the child and family during training and should include a nephrologist, a renal nurse, a renal dietitian, and a renal social worker. Other staff that may be involved include play staff, school teachers, psychologists/psychiatrists and youth workers. Fischbach, Haemodialysis should be delivered in a paediatric dialysis centre with a multidisciplinary support team which supports individualized and integrated therapy. Coleman, As part of the overall nutritional assessment it is essential for the dietitian, as a key member of the multidisciplinary team, to become familiar with each child s psychosocial environment. 36

39 3Policy variation in donor and recipient status in 11 paediatric renal transplantation centres Nikki J. Schoenmaker - Maike van Huis 1#, Jaap W. Groothoff 1, Johanna H. van der Lee 2, and Karlien Cransberg 3, on behalf of the RICH-Q group # Both authors contributed equally to this paper. Departments of Paediatric Nephrology: 1 Emma Children s Hospital Academic Medical Centre Amsterdam, the Netherlands 3 University Hospital Leuven, Belgium 2 Clinical Research Unit, Division Woman-Child, Academic Medical Centre Amsterdam, the Netherlands Nephrol Dial Transplant May;27(5):

40 Chapter 3 Abstract Background Evidence based guidelines for paediatric renal transplantation (Tx) are lacking. This may lead to unwanted treatment variations. We aimed to quanitfy the variation in treatment policies and its consequences in daily practice in 11 centres that provide renal Tx for children in 3 European countries. Methods We surveyed Tx policies in all ten centres in the Netherlands and Belgium and one centre in Germany. We compared Tx policies with the actually provided therapies and with recommendations from available published guidelines and existing literature. Information on treatment policies was obtained by a questionnaire; information on actually provided care was registered prospectively from The clinical guidelines were identified by searches of MEDLINE and websites of paediatric nephrology organizations. Results Between centres, we found discrepancies in policies on: the minimum accepted recipient weight (8-12 kilograms), the maximum living and deceased donor age (50-75 and years, respectively). HLA-match policies varied between acceptation of all mismatches to at least 1A1B1DR match. Living donor transplantations amounted to 49% in the Netherlands versus 26% in Belgium (p=0.006). Conclusion Management policies for renal Tx in children vary considerably between centres and nations. This has a direct impact on the delivered care, and by extrapolation, on health outcome. 38

41 Management policies Introduction End-stage renal disease (ESRD) in children is a rare but serious disorder 1;2. In the Western world, the yearly incidence rate of ESRD in people younger than 19 years is about 6-8 per million age related population. Renal transplantation (Tx) is the preferred chronic renal replacement therapy (RRT) for children with ESRD. The management of patients pre-tx and following successful Tx is essential to maximize the chance of good long-term graft function 3. In order to maintain acceptable travel distances to the hospital, patients can choose between several, and consequently all very small, Tx centres, of which there are 4 in the Netherlands, 6 in Belgium and 14 in Germany. The low prevalence of childhood ESRD and the overall small centre sizes worldwide both have been a barrier for adequately sized randomized clinical trials necessary for the development of evidence based guidelines for treatment of children with ESRD worldwide. The Renal Insufficiency in CHildren - Quality assessment and improvement (RICH-Q) 4 project started in 2007 as a collaborative initiative of all four Dutch and six Belgian centres for paediatric RRT. In 2011 one German centre in a geographically adjacent area, joined RICH-Q, since then comprising eleven paediatric centres which offer RRT. RICH-Q aims to improve the quality of care (QoC) for children with ESRD by peer review and plenary discussion of prospectively recorded data on treatment characteristics and physical and psychosocial health outcomes, applying the latest scientific evidence and guidelines on RRT in children. In 2012, we reported on large variation in dialysis management policies between the RICH-Q centres 5. In this paper, we report on variation in policy of acceptance of donors and recipients in children within the 11 RICH-Q sites. We also compare the reported treatment policies with currently available guidelines and with the actually performed care between 2007 and Materials and methods In this study information was obtained from 3 sources. A survey was conducted on management policies, a literature search was performed to identify guidelines, and clinical data were collected prospectively as part of the RICH-Q project. Each of the 3 methods of data-collection are described below. Survey on treatment policies In October 2011, we asked one paediatric nephrologist per participating centre to complete a questionnaire on local Tx policies. The questionnaire was developed with input from all participating paediatric nephrologists, to ensure content validity. The questionnaire included 22 questions on 10 topics within the 2 main topics; pre-transplantation work-up and transplantation. The questionnaire included one question regarding altruistic donation, which we defined as a situation in which someone chooses to donate an organ to a recipient with whom the donor has neither genetic nor emotional relationship 6. Literature search Clinical guidelines on the management of children with renal Tx were retrieved by searching MEDLINE using the following MeSH terms and text words combined as either/or : renal transplantation, end-stage renal disease, guideline, child and children. There was 39

42 Chapter 3 no limit for publication date. Furthermore, we searched websites of organizations known to produce guidelines for patients with ESRD (KDIGO 7, KDOQI 8, CARI 9, UK Renal Association 10, CSN Canada 11, Renal Physicians Association 12, ISPD 13 and ESPN 14 ). Included were published clinical guidelines, written in English, which concerned children (0-18 years) with renal Tx. Clinical data collection in the RICH-Q project In RICH-Q anonymous data on treatment characteristics and physical and psychosocial health outcomes are registered prospectively concerning all children with ESRD treated in the 11 RICH-Q associated hospitals. In the RICH-Q registry we included all prevalent Dutch and Belgian patients aged < 19 years on chronic dialysis on October 1 st 2007, and all Dutch and Belgian patients aged < 19 years who started RRT or were transplanted from October 1 st, 2007 to date. Since 2011, all incident patients treated in the centre of Cologne aged < 19 years are included in the database. For this paper data regarding Tx from the centre of Cologne were collected retrospectively back to We obtained ethical approval from the ethical boards of all participating hospitals and written Informed Consent from all parents of all participants and the participant themselves if possible. An independent research institute (the Hans Mak Institute 15 ) assures the quality of the data by monitoring 10% of all data. Time on dialysis prior to the first non pre-emptive Tx, weight and age of the recipient at the time of Tx, age of both living donor (LD) and deceased donor (DD) and cold ischemia time (CIT) of the allograft were the variables used for the present analysis. Statistics Analyses were performed using SPSS 18. Values are presented as median [range] unless stated otherwise. Kruskal Wallis and Mann-Whitney tests were used for testing differences in waiting time on dialysis between the Netherland, Belgium, and Cologne and between the Netherlands and Cologne on the one hand and Belgium on the other. A P-value < 0.05 was considered statistically significant. Results Reported policies and information from the registry Paediatric nephrologists of all 11 centres completed the questionnaire. All centres reported to have a pre-transplantation protocol. For an overview of all pre-transplantation policies, consultations and imaging see table 1. All RICH-Q centres stated to strive for pre-emptive transplantation in paediatric ESRD. At all sites, patients are informed about the two donor sources of Tx (LD and DD). In the Belgian centres, living donation is not emphasized as being the first choice for Tx. In contrast, all Dutch centres and the centre of Cologne underline the superiority of LD, over DD Tx with respect to graft survival. Participating centres stated that there were no differences in providing information between different ethnic, cultural and religious groups of patients. From October 2007 up to December 2011, 197 transplantations were recorded in our registry. 44 out of the total of 197 Tx (22%) were pre-emptive and 85 out of 197 Tx (43%) were from living donors. In the Netherlands and Cologne the proportion of transplantations from LD (72/147, 48%) was significantly larger than in Belgium (13/51, 26%) (p=0.006). We did not find statistically significant differences in time on dialysis before their first non pre-emptive Tx in children 40

43 Management policies Table 1 Pre-transplantation policies Number of centres Policy Yes No Only on indication Pre-transplantation protocol Vaccination protocol Pre-transplantation consultations Surgeon Urologist Social worker Psychologist Dentist Pre-transplantation imaging Cardiac ultrasound Electrocardiogram X-hand X-thorax Kidney, Urinary tract ultrasound DEXA-scan Vascular ultrasound Cystography Pre-transplantation serology IgG Eppstein Bar Virus IgG Cytomegaly Virus IgG Herpes Simplex Virus IgG Hepatitis C IgG Toxoplasmosis IgG measles, mumps, rubella Pre-transplantation laboratory Activated Partial Tromboplastin Time, Prothrombin time Factor V leiden Pre-transplantation surgery Nephrectomy

44 Chapter 3 who had received a DD kidney transplant (p=0.81, Table 2a), nor a non pre-emptive Tx from a LD (p=0.56) (Table 2b) between patients from The Netherlands and Cologne on the one hand and from Belgium on the other. Table 3 shows the reported policies with respect to minimum accepted recipient weight and maximum accepted age in comparison with the actual median weight at Tx as reported in the registry over Centre policies varied between a recommended minimum weight of 8 and 12 kilograms. Two patients had a lower weight at the moment of Tx than what was accounted as minimal acceptable according to the centre policy. Nevertheless, both were considered suitable for Tx according to the performing surgeons. Table 2. Time on dialysis (months) before 1st non pre-emptive Transplantation Table 2a: Non pre-emptive deceased donor Tx (n=107) P value: between P value: the the 3 countries Netherlands & Cologne Median IQR N vs Belgium the Netherlands Belgium Cologne Table 2b: Non pre-emptive living donor Tx (n=46) P value: the Median IQR N P value: between the 3 countries Netherlands & Cologne vs Belgium the Netherlands Belgium Cologne IQR= Inter Quartile Range, N= Number of transplantations, * the Netherlands versus Belgium, In most sites (6/11) of the centres minimum weight prevailed over age. The minimum age for receiving a kidney (derived from either a juvenile or adult donor) as stated in the policies varied between 10 months and 3 years. Accepting an adult kidney in a very small child depended on individual assessment by the performing surgeon. The stated policies with respect to the maximum donor age varied from 50 to 75 years and from 45 to 65 years, for LD and DD, respectively. Table 3 shows the stated policies regarding maximum age of both LD and DD in comparison with the actual median and range of the donor age as recorded in the registry. In three centres the actual LD age had exceeded the maximum donor age as stated in the policy. Upon inquiry this was explained by two factors. First, the age limit was not maintained very strictly, and second, the physical condition of these particular donors was considered excellent. 42

45 Management policies Table 3. Minimum accepted weight of the recipient (kg) and maximum accepted donor age (years) according to policy, median [range] recipient weight reported in registry, and recommendations for recipient weight in guidelines Minimum accepted weight Maximum accepted donor age Recipient (n=197) Living Donor (n=85) Deceased donor (n=112) Reported Registry Reported Registry Reported Registry Centre Policy median [range] N Policy Median [range] N Policy Median [range] N [10-80] [30-68] [3-44] [13-74] [30-67] [9-58] 13 t h e Netherlands [13-55] 24 NS 46 [37-60] [9-35] [17-81] [22-60] [14-62] [13-44] 4 60 NA [9-38] [13-74] [19-51] 4 NS 30 [15-47] 10 Belgium [11-64] [40-47] 5 NS 23 [4-47] [9-47] [33-44] [2-44] [20-84] [11-41] NA 0 55 NA 0 45 NA [8-64] [35-51] [13-52] 22 Cologne Maximum age deceased donor according to guideline Guideline Minimum weight according to guideline Maximum age living donor according to guideline ESPN No recommendation No recommendation No recommendation N=Number of transplantations, NA= Not applicable, NS= Not specified 3 43

46 Chapter 3 The stated policies with respect to maximum accepted CIT varied between 18 hours (one centre), 24 hours (seven centres) and 36 hours (three centres). In only one case the actual CIT exceeded the centre policy with 3 hours, due to peri-operative complications. The composition of the transplantation surgery teams varied between centres. In 6 centres the actual procedure was performed by a specialized transplantation surgeon, in 2 by a paediatric surgeon and in 3 by a vascular surgeon. A paediatric urologist assisted the transplantation surgeons on a routine base in 5 centres, while this occurred only on the demand in the other centres. In 2 centres the Tx was performed by both a paediatric surgeon and a vascular surgeon. In all centres the performing paediatric surgeon also participated in the adult Tx program. Not all centres have the same policy with regard to ABO-incompatible Tx, non heart-beating Tx, minimum accepted HLA-match and non-related LD Tx. Four centres stated to perform ABO-incompatible transplantations. Transplantation of kidneys from non-heart beating donors is performed in 3 centres. With respect to minimal accepted HLA-matches, policies varied from acceptation of all mismatches to a minimal match of 1A1B1DR. Five centres reported to accept non-related LD. Altruistic non-related donation was accepted in these centres as well, provided that the donor would remain anonymous. Between October 2007 and December 2011, no ABO-incompatible transplantations were performed. Kidneys of non-related LD were used twice and of DD after cardiac death three times. Guidelines One (14) of the 19 potentially relevant guidelines identified by the search met the selection criteria. This guideline was developed by The European Society for Paediatric Nephrology (ESPN). The ESPN provides paediatric specific guidelines with respect to contra-indications for Tx in children, pre-transplant nephrectomy, pre-tx vaccination and paediatric recipient age (14). They recommend a minimum recipient age of 6 months and states that ABOincompatible Tx is contraindicated in the paediatric patient. None of the guidelines provide specific recommendations with regard to the expertise of the surgeon performing the Tx. The ESPN guidelines recommend performing the paediatric Tx in specialized paediatric centres in multidisciplinary teams. Discussion In this paper we demonstrate a considerable variation in Tx policies across the 11 hospitals providing Tx for children in the Netherlands, Belgium and part of Germany. This corresponds to what we previously found in dialysis management policies 5. This variation implies structural differences in patient care with possible consequences for patient outcome even in a small geographical area. Sometimes physicians deviate from their own reported policies for the management of Tx in children. These deviations may be based on conscious decisions to tailor the treatment to the individual patient, due to practical challenges in adhering to the guidelines, or to uncertainty about the validity of certain clinical recommendations. Here we will discuss some of the most important differences between the various centres as well as between centres and current guidelines and literature. 44

47 Management policies Differences between centres Belgian and Dutch centres reported different policies with respect to LD versus DD Tx, which was reflected by the actual number of living and post-mortem donation in both countries as reported in the registry. All Dutch centres actively recommended living donation, whereas the Belgian approach was to inform parents and patients as neutrally as possible on this subject. One of the arguments for not actively promoting living-related transplantation according to most Belgian centres was the advantage of having a LD donor in reserve, since children have a relatively long life expectancy and hence a high probability for the need of a second transplantation. The different approaches between the two countries may also have been influenced by the higher availability of organ donors in Belgium compared to the other 2 countries, as is reflected by data from Eurotransplant, the allocation authority of DD organs of all 3 countries 16. In 2011, organs of 29.3 DD per million population were used in Belgium, compared with 13.3 and 14.4 in the Netherlands and Germany, respectively 16. Both a different legislation on organ donation and different overall death rates are associated with the relatively high availability of organs in Belgium in comparison to the Netherlands and Germany. Since 1987 the Belgian law comprises a presumed consent system which authorizes the removal of the organs of a Belgian citizen or someone who has lived in Belgium for more than 6 months unless this person has declared that his/hers organs cannot be used for donation. This contrasts with the Dutch and German so-called active informed consent system, which is a voluntary system of organ donation whereby relatives give permission at the time of death, usually in the knowledge that the potential donor had expressed a wish to become a donor. As a result, in the Netherlands, 47% of the paediatric transplantations were kidneys originating from DD, whereas in Belgium 72% of all paediatric transplantations were from DD. Contrary to what would have been expected from the Eurotransplant reports on donor availability of both countries, we did not find a shorter stay on dialysis of Belgian as compared to Dutch children on dialysis. This accounted both for LD and DD transplantations. A Type II error caused by the small number of patients might be one explanation. Taken into account the overall better outcome of LD Tx versus DD 17-19, we think that under all circumstances, decisions on either LD or DD Tx should be taken together with parents and patients in an open discussion, independent from the availability of DD organs. This will give patients and parents the optimal opportunity to consider what is the best option in their particular situation, either to go immediately for the option with the best forecast or to keep an family organ in reserve. There were remarkable differences between the centres with regard to the minimum accepted weight of the recipient and the maximum accepted age of the donor. The reasons for these differences are not clear. A minimum threshold of recipient weight or age may be determined by the skills of the local surgeon or paediatric nephrology team. This may lead to a longer waiting time on dialysis for those children who are considered too small or too young for Tx in a particular centre. 3 Differences between centre policies and current guidelines There has been much discussion about the minimum accepted recipient age. To date, the ESPN recommends 6 months to be the minimum acceptable recipient age. A prospective cohort study in 321 transplanted children by Humar et al. 20 showed no difference in delayed graft function and graft survival after living related Tx in children in three different age groups 45

48 Chapter 3 (<1 year, 1 through 4 years, and 5 through 13 years). This may have been due to a type II error cases by the small number (n=30) of patients aged less than 1 year vs. n=122 and n=169 for 1 through 4 years and 5 through 13 years, respectively. In contrast, in a report of the North American Paediatric Renal Transplant Cooperative Study (NAPRTCS), Elshihabi et al. 21 reported a higher risk of graft failure in younger recipients of kidneys from DD, below the age of two years (RR 1.95). The comparability of these reports is limited due to the difference in study designs. However, a minimum accepted recipient age might depend on whether the child is receiving a kidney of either a LD or a DD. In transplanting small children, technical difficulties arise. Therefore, instead of age, body weight might be the decisive factor in accepting a child for Tx. In the RICH-Q centres, the decision about transplantability was more often determined by body weight than by age. The RICH-Q centres based their maximum accepted donor age on the availability of donor organs, local paediatric guidelines and guidelines used in adult Tx policies. Adult recipients receiving a kidney from older (deceased) donors (>50 years)) are reported to have a high incidence of delayed graft function 3;22;23. In contrast, some studies found an excellent outcome in adult recipients of DD even over 70 years 24;25. Thus, the available information about the maximum accepted age of the donor in adult Tx is not consistent. Moreover, it is not known to what extent these results can be extrapolated to paediatric Tx. Fact is that the mean age of the donors in the Eurotransplant area is increasing 16. Furthermore, until recently, organs from paediatric donors (aged < 18 years) were not preferentially allocated to children. A change in policy in December 2010 resulted in a higher number of paediatric grafts being allocated to children than before. There is much discussion in the literature regarding the optimal CIT in adult TX 26;27. As far as we know, no studies have been performed in paediatric kidney recipients from DD. Despite the fact that the ESPN guideline 14 states that ABO-incompatible Tx is contraindicated in paediatric practice, seven of the 11 centres do provide ABO-incompatible Tx. Not much information concerning ABO-incompatible Tx in children has been published yet. A Japanese study 28 in 52 consecutive ABO-incompatible Tx found no significant difference in long term (15 years) allograft and patient survival between ABO-incompatible and ABO-compatible Tx in children. Given the scarcity of donor organs, ABO-incompatible Tx may be a valid alternative in paediatric Tx in the future. The above shows that there are large variations in management policies, possibly due to a lack of evidence-based guidelines. Introduction of evidence based guidelines might improve patient outcome, as was shown in a systematic review by Grimshaw and Russel 29. Conclusions and recommendations for further research Our observations show that paediatric Tx management policies on the acceptability of donors and recipients vary within a relatively small geographic area. Analysis of the impact of this variation on patient outcome after Tx awaits larger patient numbers and longer followup. The differences may be explained by a lack of evidence based paediatric guidelines. Guideline development in this field is hampered by a profound lack of systematically gathered prognostic information that is clearly reported. This emphasizes the need for more multicentre prospective studies on determinants of health after Tx in children, enabling paediatric nephrologists to generate evidence-based guidelines. Eventually this may lead to better health outcome in paediatric ESRD. 46

49 Management policies Reference List 1. Groothoff JW, Gruppen MP, Offringa M, Hutten J, Lilien MR, Van De Kar NJ, Wolff ED, Davin JC, Heymans HS (2002) Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study. Kidney Int 61: McDonald SP, Craig JC (2004) Long-term survival of children with end-stage renal disease. N Engl J Med 350: Heidotting NA, Ahlenstiel T, Kreuzer M, Franke D, Pape L (2012) The influence of low donor age, living related donation and pre-emptive transplantation on end-organ damage based on arterial hypertension after paediatric kidney transplantation. Nephrol Dial Transplant 27: (2012) RICH-Q. Renal Insufficiency in Children - Quality assesment and improvement Tromp WF, Schoenmaker NJ, van der Lee JH, Adams B, Bouts AH, Collard L, Cransberg K, Van Damme-Lombaerts R, Godefroid N, van HK, Koster-Kamphuis L, Lilien MR, Raes A, Offringa M, Groothoff JW (2012) Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study. Nephrol Dial Transplant 27: Massey EK, Kranenburg LW, Zuidema WC, Hak G, Erdman RA, Hilhorst M, Ijzermans JN, Busschbach JJ, Weimar W (2010) Encouraging psychological outcomes after altruistic donation to a stranger. Am J Transplant 10: Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM, Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk EM (2010) KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 77: (2012) National Kidney Foundation. Kidney Disease: Outcome Quality Initiative (KDOQI) 9. (2010) Caring for australians with renal impairment (CARI) (2011) The Renal association. 11. Knoll GA, Blydt-Hansen TD, Campbell P, Cantarovich M, Cole E, Fairhead T, Gill JS, Gourishankar S, Hebert D, Hodsman A, House AA, Humar A, Karpinski M, Kim SJ, Mainra R, Prasad GV (2010) Canadian Society of Transplantation and Canadian Society of Nephrology commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Kidney Dis 56:

50 Chapter (2011) Renal physicians association (2011) International Society for Peritoneal Dialysis. 14. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient (2002) Nephrol Dial Transplant 17 Suppl 4: (2010). Hans Mak instituut (2011) Eurotransplant Annual Report (2011) 17. Binet I, Bock AH, Vogelbach P, Gasser T, Kiss A, Brunner F, Thiel G (1997) Outcome in emotionally related living kidney donor transplantation. Nephrol Dial Transplant 12: Chkhotua AB, Klein T, Shabtai E, Yussim A, Bar-Nathan N, Shaharabani E, Lustig S, Mor E (2003) Kidney transplantation from living-unrelated donors: comparison of outcome with living-related and cadaveric transplants under current immunosuppressive protocols. Urology 62: Dale-Shall AW, Smith JM, McBride MA, Hingorani SR, McDonald RA (2009) The relationship of donor source and age on short- and long-term allograft survival in pediatric renal transplantation. Pediatr Transplant 13: Humar A, Arrazola L, Mauer M, Matas AJ, Najarian JS (2001) Kidney transplantation in young children: should there be a minimum age? Pediatr Nephrol 16: Elshihabi I, Chavers B, Donaldson L, Emmett L, Tejani A (2000) Continuing improvement in cadaver donor graft survival in North American children: the 1998 annual report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 4: Oppenheimer F, Aljama P, Asensio PC, Bustamante BJ, Crespo Albiach JF, Guirado PL (2004) The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant 19 Suppl 3:iii11-iii Vivas CA, O Donovan RM, Jordan ML, Hickey DP, Hrebinko R, Shapiro R, Starzl TE, Hakala TR, Jordan ML (1992) Cadaveric renal transplantation using kidneys from donors greater than 60 years old. Clin Transplant 6: Cravedi P, Ruggenenti P, Remuzzi G (2011) Old donors for kidney transplantation: how old? Gerontology 57: Remuzzi G, Cravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, Rigotti P, Baldan 48

51 Management policies N, Beatini M, Valente U, Scalamogna M, Ruggenenti P (2006) Long-term outcome of renal transplantation from older donors. N Engl J Med 354: Barba J, Zudaire JJ, Robles JE, Tienza A, Rosell D, Berian JM, Pascual I (2011) Is there a safe cold ischemia time interval for the renal graft?. Actas Urol Esp 35: Quiroga I, McShane P, Koo DD, Gray D, Friend PJ, Fuggle S, Darby C (2006) Major effects of delayed graft function and cold ischaemia time on renal allograft survival. Nephrol Dial Transplant 21: Shishido S, Hyodo YY, Aoki Y, Takasu J, Kawamura T, Sakai KK, Aikawa AA, Satou H, Muramatsu MM, Matsui Z (2012) Outcomes of pediatric ABO-incompatible kidney transplantations are equivalent to ABO-compatible controls. Transplant Proc 44: Grimshaw JM, Russell IT (1993) Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet 342:

52 50

53 4Quality and consistency of clinical practice guidelines for the management of children on chronic dialysis Nikki J. Schoenmaker 1, Wilma F. Tromp 1, Johanna H. van der Lee 2, Martin Offringa 3, Jonathan C. Craig 4, and Jaap W. Groothoff 1. 1 Department of Paediatric Nephrology, Emma Children s Hospital AMC, Amsterdam, the Netherlands 2 Department of Paediatric Clinical Epidemiology, Emma Children s Hospital AMC, Amsterdam, the Netherlands 3 Child Health Evaluative Sciences (CHES), Hospital for Sick Children, University of Toronto, Canada 4 Centre for Kidney Research, The Children s Hospital at Westmead, School of Public Health, University of Sydney, NSW, Australia. Revision Nephrol. Dial. Transplant. 51

54 Chapter 4 Abstract Clinical practice guidelines aim to improve the quality of care, yet for users of guidelines it is often not clear how these guidelines were developed and whether the recommendations are robust. We aimed to identify all current published guidelines for the management of children on chronic dialysis, assess the quality of their development, and evaluate consistency among their recommendations. We searched Medline (1948 to January 2012), and relevant websites of guideline development programs. Three reviewers appraised all 17 identified guidelines with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. These guidelines were developed by 5 different professional associations. The overall mean AGREE II score from 7 Kidney Disease Outcomes Quality Initiatives (KDOQI) guidelines was considered sufficient (mean scores 64-75%), and from all other 10 guidelines poor (29-44%). Five out of 7 KDOQI guidelines scored weak on applicability. We found important inconsistencies between recommendations concerning initiation of renal replacement therapy, management of hemoglobin level, and the use of mupirocin to prevent exit-site infections. While the recently developed KDOQI guidelines, meet the modern quality standards, advice for implementation of these recommendations is lacking. There is an urgent need for international collaboration and coordination to ensure that guidelines for management of children on chronic dialysis are consistent and, where possible, evidence based to promote best possible outcomes. 52

55 Management policies Introduction End-stage kidney disease in children is a rare but serious disorder 1;2. In the western world, the yearly incidence rate of End-stage kidney disease in patients younger than 19 years of age is about 6-8 per million, with an overall mortality in young adults about 30 times greater than in healthy age matched controls 1;2. In survivors to adulthood, juvenile End-stage kidney disease has an important impact on somatic and psychosocial functioning in adult life: at least 40% of the adult survivors of End-stage kidney disease with childhood onset suffer daily from somatic co-morbidity and about 20% are severely disabled 2-4. Despite all the progress that has been made in the technical aspects of chronic renal replacement therapy (RRT), recent data on children on RRT suggest that most of the unfavourable long-term consequences still occur in today s population 5;6. Clinical practice guidelines aim to improve outcomes by optimising management policies. Several studies have shown that adherence to evidence-based guidelines may indeed improve quality of care 7;8, but for many health conditions, it appears that treatment differs considerably from what has shown to be effective practice 9. We recently reported large and unwanted variation in management policies between all units providing dialysis for children in the Netherlands and Belgium, despite the existence of comprehensive guidelines in this field 10. Previous literature showed that there are several barriers to physician adherence to clinical practice guidelines (e.g. lack of awareness, lack of familiarity, lack of agreement, lack of self-efficacy, lack of outcome expectancy, and external barriers 11. One of the reasons for not following a guideline might be that for most users it is often unclear how the existing guidelines are developed and whether the recommendations are robust. The aims of this study were to assess the quality of published guidelines for the management of chronic dialysis in children, and evaluate consistency among the recommendations, and possible sources of inconsistency such as the evidence retrieval and appraisal processes. 4 Methods Search for guidelines and selection criteria Clinical guidelines on the management of children on chronic dialysis were retrieved by searching MEDLINE using the following MeSH terms and text words combined as either/ or, chronic kidney failure, end-stage renal disease, guideline, child, and children. The detailed search strategy (1948 to January 2012) is shown in Appendix 1. There was no limit for publication date. Furthermore, we searched websites of organizations known to produce guidelines for patients with End-stage kidney disease (KDIGO 12, KDOQI 13, CARI 14, UK renal association 15, CSN-Canada 16, ISPD 16;17, and EBPG-Europe 18 ). Included were published clinical guidelines, written in English, which concerned children (0-18 years) on chronic dialysis. Guidelines about the management of transplanted children were not included. Appraisal of guidelines with the AGREE II Instrument Three reviewers (NS, JL, and JG) independently reviewed all full text guidelines. All recommendations were categorized according to clinical topics to identify possible overlap. For each guideline the reviewers reported the number of countries and the types of disciplines represented in the guideline development group, and assessed whether the developers 53

56 Chapter 4 reported their recommendations as based on evidence, consensus, clinical experience, opinion or a combination of these. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument was used to appraise the methodological quality of the guideline development process 19. The AGREE instrument is established in 2004 and is an internationally validated, rigorously developed 23-item tool comprising six domains of guideline development, i.e. scope and purpose (3 items), stakeholder involvement (3 items), rigour of development (8 items), clarity and presentation (3 items), applicability (4 items), and editorial independence (2 items). Appendix 2 gives a more detailed description of these domains. Each item is rated on a seven-point Likert scale ranging from strongly disagree (1) to strongly agree (7). The domain score is expressed as a percentage of the maximum possible score for that domain and is obtained by summing the scores of individual items. The final item of the AGREE instrument involves a recommendation regarding the use of the guideline in practice, as recommended, recommended with modifications not recommended,. Although there is no threshold score, a domain scoring <50% is usually considered to be of limited use and therefore scored as not recommended. According to AGREE, each guideline should be assessed by at least 2 appraisers to increase the reliability of the assessment. Disagreements between the 3 reviewers were resolved by discussion until consensus was reached. Furthermore, we analysed the different recommendations for inconsistencies in similar clinical topics carefully. We reported on all established inconsistencies that may lead to variation in management of children on dialysis with potentially important implications on outcomes. And finally we assessed the reported level of evidence. If the guideline developers reported that their recommendations were evidence-based, the reviewers assessed whether the reference to the evidence could be found in the guideline. Results Searching and characteristics of included studies The search yielded 152 articles. Of these, 127 were excluded after title and abstract review. Of the remaining 25 potentially eligible articles, 8 were excluded, either because they did not contain clinical practice guidelines, only described guidelines on the management of adult patients, or concerned the management of transplant recipients. Seventeen of the 25 potentially relevant guidelines identified by the search fulfilled the eligibility criteria A flow chart of the search and selection process is shown in Figure 1. These guidelines were developed by five different professional associations, with the Kidney Disease Outcomes Quality Initiatives (KDOQI) and the European (Paediatric ) Peritoneal Dialysis Working Group (E(P)PDWG), the predominant groups, who developed seven guidelines each. The KDOQI guidelines were published between 2005 and 2009, all other guidelines between 2000 and 2006, except the guidelines on PD solutions by the EPDWG, which was published in The guidelines included 369 recommendations covering seven different topics. The characteristics of the included guidelines are shown in Table 1. The number of disciplines represented in the guideline development groups ranged from one 22;32;36 to ten 30. In six guidelines no information was found on the types of disciplines. 54

57 Management policies Table 1. Characteristics of included guidelines, arranged by topic Guidelines Name of guideline Year # of countries # of disciplines Peritoneal dialysis Recommen- dations based on ISPD 34 Consensus guidelines for the treatment of perito-200nitis USA, Europe (3) 5 ND in paediatric patients receiving PD EPPDWG 35 Guidelines by an ad hoc European committee for 2001 Europe (12) 2 CL/O elective chronic PD in paediatric patients EPPDWG 21 Guidelines by an ad hoc European committee on 2002 Europe (9) 2 C/CL/O adequacy of paediatric PD prescription KDOQI 25 Clinical practice guidelines for PD adequacy 2006 USA, Canada, Europe ND E/C/O (4) CAPN 36 Clinical practice guidelines for Paediatric PD 2006 Canada 1 E/O EPDWG 32 Solutions for PD in children: recommendations by 2011 Europe (12) 1 E/C/O the European Paediatric Dialysis Working group Haemodialysis EPDWG 22 Haemodialysis in children; general practical 2005 Europe (12) 1 E/CL/O guidelines KDOQI 26 Clinical practice guidelines for HD adequacy 2006 USA ND E/C/O Renal Osteodystrophy 4 KDOQI 24 EPDWG 23 Bone metabolism and disease in children with CKD Prevention and treatment of renal osteodystrophy in children on chronic renal failure Nutrition and Growth 2005 USA 6 E/C/O 2006 Europe (12) ND C/CL/O CARI 46 Nutrition and growth in kidney disease 2005 Australia, New Zealand ND E KDOQI 29 Clinical practice guideline for nutrition in 2009 USA, Canada, Europe 3 E/C/O children with CKD (2) EPPDWG 20 Guidelines by an ad hoc European committee on 2001 Europe (10) 2 CL/O the assessment of growth and nutritional status in children on chronic PD Anaemia EPPDWG 33 The management of anaemia in paediatric PD patients 2003 Europe (11) ND C/CL/O KDOQI 27 Clinical practice guidelines for anaemia in CKD 2007 USA, Canada, Europe 7 E/C/O (5) Cardiovascular KDOQI 30 Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients Vascular Access 2005 USA, Canada, Europe (2) 10 E/C/O KDOQI 28 Vascular access in Paediatric patients 2006 USA, Ireland 5 E/C/O PD= Peritoneal dialysis; HD=Haemodialysis; CKD=Chronic Kidney Disease. KDOQI= the Kidney Disease Outcomes Quality Initiatives; EP(P)DWG = European Paediatric (Peritoneal) Dialysis Working Group; CAPN= Canadian association of Paediatric Nephrologists; ISPD= International Society of Peritoneal dialysis; CARI= Caring for Australasians with Renal Impairment. E= Evidence, CL= Clinical Experience, C=Consensus, O=opinion 55

58 Chapter 4 In the other eleven guideline development groups at least one paediatric nephrologist was involved. The guideline development group members originated from one 24;26;36 to twelve countries 22;23;35. In sixteen guidelines the developers reported whether the guidelines were based on evidence, clinical experience, consensus or opinion. Although in eleven of these sixteen guidelines the recommendations were reported as evidence-based, this was confirmed by the reviewers in only seven. Quality appraisal In approximately 10% of the items one of the reviewers scored the AGREE II instrument two points higher or lower than the other two reviewers. These items were discussed at the consensus meetings. The items that were discussed most frequently were whether the health question was specifically described, whether there was an explicit link between the recommendation and the supporting evidence, and whether the guideline has been externally reviewed before publication. The results of the methodological quality appraisal are shown in Table 2. Scope & purpose The mean score for this domain was 65% (range 33%-80), with only 2 guidelines scoring <50%. This means that nearly all guidelines met at least 50% of the criteria of this domain, despite the fact that a detailed description of the health question covered by the guideline was rarely provided and that in none of the guidelines the designated age group or Chronic Kidney Disease (CKD) stage was specified. Stakeholder involvement The overall score in this domain was poor with a mean of 45% (range 24%-69%). Eight of the 17 guidelines scored <50%. Seven of the 17 guideline development groups included members from all relevant disciplines and in four of the group members from an important discipline were absent; in the remaining 6 guidelines the description of the members was not clear. In none of the 17 guidelines the views and preferences of the target population were sought. Rigour of development The overall mean score for rigour of development was only 42% (5-88%), with 10 guidelines scoring <50%. Eight guidelines reported using systematic methods to search for evidence. The criteria for selecting evidence were shown in 5 of these guidelines, all being KDOQI guidelines. The strengths and limitations of the body of evidence were clearly described in seven guidelines. Five of these seven guidelines were from KDOQI. The methods used for formulating the recommendations were clearly described in only two (KDOQI) guidelines 27;30. The consideration of health benefits, side effects, and risks of the recommendation was reported in 6 guidelines. For the other eleven guidelines there was no evidence that these issues had been addressed. Two KDOQI guidelines 24;27 were the only guidelines in which an explicit link between recommendations and the supporting evidence was described. We assumed that all the guidelines had been externally reviewed before publication since they were all published in peer-reviewed journals. However, only KDOQI reported on this. The seven KDOQI and the CARI guidelines described a procedure for updating the guidelines. Clarity and presentation 56

59 Management policies Table 2. Domain mean scores and overall assessment according to the AGREE II instrument Domain Guidelines Scope & purpose (%) Stakeholder involvement (%) Rigour of development (%) Clarity & presentation (%) Applicability (%) Editorial independence (%) Overall assessment Overall score (%) PD ISPD [34] NR 34 EPPDWG NR 29 EPPDWG NR 32 KDOQI R* 69 CAPN NR 38 EPDWG [32] NR 41 HD EPDWG NR 29 KDOQI R* 64 Renal Osteodystrophy 4 KDOQI R* 71 EPDWG NR 32 Nutrition & growth CARI NR 40 KDOQI R* 72 EPPDWG NR 39 Anaemia EPPDWG NR 29 KDOQI R* 75 Cardiovascular KDOQI R* 67 Vascular access KDOQI R* 68 Overall mean score KDOQI= the Kidney Disease Outcomes Quality Initiatives; EP(P)DWG = European Paediatric (Peritoneal) Dialysis Working Group; CAPN= Canadian association of Paediatric Nephrologists; ISPD= International Society of Peritoneal dialysis; CARI= Caring for Australasians with Renal Impairment; NR= not recommended; R*= recommended with modifications; R= recommended according to AGREE II instrument methods 57

60 Chapter 4 The mean score was 64% (range 40-84%), with only three scoring < 50%. In thirteen guidelines, the recommendations were specific and unambiguous. The other four guidelines were not specific and precise in their recommendations, as is illustrated by the following examples: recommended number of exchanges per day: 4, sometimes 3 or 5 according to age and residual renal function 21 ], and pain prevention is essential 22. One guideline 34 provided a detailed description of the appropriate intervention in specific situations. In thirteen of the seventeen guidelines, the key recommendations were easily identifiable. However, in the KDOQI guideline about cardiovascular disease, the recommendations specific for children were difficult to find. Applicability The mean score for applicability was only 27% (5-63%), the lowest of all domains. Fifteen guidelines (88%), including five KDOQI guidelines, scored <50%. Six guidelines provided advice and/or tools (e.g. flow charts) to put the recommendations into practice. Facilitators and barriers to guideline application were discussed in only two guidelines 27;28 The potential resource implications of applying the recommendations were considered in two guidelines 29;30. Only one guideline 27 presented monitoring and/or auditing criteria. Editorial independence The mean score for editorial independence was 48% ( range 7-87%), with only seven guidelines scoring > 50%. Eleven groups disclosed their independence from the funding body. KDOQI stated that all group members had declared that they have no conflict of interest. The other ten development groups did not report on this. Three of these ten guidelines mentioned a pharmaceutical company in the acknowledgement section 21;34;35. Overall assessment After considering all domain scores of the AGREE II instrument, the seven KDOQI guidelines were recommended with modifications and all other guidelines were not recommended. The highest score was achieved by the KDOQI guideline for Anaemia 27 with a total score of 75% (range 56-87%). The overall mean score of the seven guidelines from KDOQI (69%) was significantly higher than the overall mean of the other ten guidelines (34%), (mean difference [95%CI]: 35% [31-40%], p<0.001). The data driven comparison of the mean quality score between the seven KDOQI guidelines and the 10 non-kdoqi guidelines for each AGREE II domain is presented in Figure 2. The KDOQI guidelines had significantly higher (p<0.01) quality scores for all of the AGREE domains except for clarity and presentation (p=0.09). Guideline consistency The seventeen guidelines dealt with seven different topics and several subtopics. There was generally little overlap in scope. However, in the overlapping subject areas we found three inconsistencies between guidelines concerning recommendations on the decision when to start the renal replacement therapy, management of hemoglobin level, and the use of mupirocin to prevent exit site or tunnel infections in peritoneal dialysis (PD) (Table 3). The level of evidence of these recommendations as assigned by the developers were low. Six of the recommendations were opinion based, one was based on level A evidence in adult studies 58

61 Management policies Table 3. Inconsistencies between guidelines Guideline Topic Recommendation Recommendation based on Initiation egfr 1 RRT EPPDWG PD initiation: Unless the child remains asymptomatic and growth is well maintained. Opinion KDOQI PD consider: 9-14 recommended: <8 or start earlier when malnutrition, fluid overload, hypertension, hyperkalemia, hyperphosphataemia, acidosis, growth failure or neurological consequences of uremia CAPN PD initiation <10 and/or when there are symptoms and signs of uremia and/or growth failure KDOQI HD consider: <15.GFR > 15 if clinical course is complicated by the presence of signs and symptoms listed in table as well as malnutrition or growth failure Anaemia Opinion Opinion Level A evidence in adult studies 4 EPPDWG Anaemia 2003 [33] Hemoglobin > 11 g/dl KDOQI Anaemia Hemoglobin g/dl Hemoglobin < 13.0 g/dl Mupirocin prophylaxis Normal Ht level should be aimed. Iron or erythropoietin therapy should be initiated to obtain a target hemoglobin concentration of at least 11 g/ dl although there is a tendency to increase this target the selected hemoblobin target should generally be in the range of 11.0 to 12.0 g/dl and not be greater than 13.0 g/dl Opinion Opinion ISPD PD Yes Prophylactic antibiotic therapy for S. aureus nasal carriage is recommended to decrease the risk of S. aureus catheter exit-site/tunnel infections EPPDWG PD No there are no convincing data to suggest screening children or care givers for S. Aureus nasal carriage or on the use of mupirocin cream around the exit site on a regular basis None reported Opinion 1 egfr = estimated Glomerular Filtration Rate in ml/min/1.73 m 2 ; PD= Peritoneal dialysis; HD=Haemodialysis; KDOQI= the Kidney Disease Outcomes Quality Initiatives; EP(P)DWG = European Paediatric (Peritoneal) Dialysis Working Group; CAPN= Canadian association of Paediatric Nephrologists; ISPD= International Society of Peritoneal dialysis. 59

62 Chapter 4 and for one recommendation the level of evidence was not reported. Initiation of renal replacement therapy In four guidelines 25;26;35;36 the recommended estimated Glomerular Filtration Rate (egfr) to start RRT varied from < 8 to <15 ml/ min per 1.73 m 2. According to 3 guidelines 25;26;36, RRT should be initiated earlier than at the recommended lower limit of egfr in case of additional clinical symptoms. In contrast, another guideline 35 recommends not to start RRT as long as there are no clinical indications, even at an egfr below 8 ml/min/1.73m 2. Hemoglobin levels We found inconsistencies between two guidelines 27;33 concerning the management of hemoglobin level, as follows. Guideline 1: In the opinion of the Work Group, in paediatric dialysis patients with CKD receiving ESA therapy, the selected hemoglobin target should generally be in the range of 11.0 to 12.0 g/dl and not be greater than 13.0 g/dl 27 ; guideline 2: Normal hematocrit level should be aimed for iron or erythropoietin therapy should be initiated to obtain a target hemoglobin concentration of at least 11 g/dl although there is a tendency to increase this target 33. The risks of a high hemoglobin target were not discussed in the second guideline. Mupirocin prophylaxis Two guidelines addressed the use of mupirocin prophylaxis to prevent tunnel or exit site infections 34;35. One of these guidelines 34 recommended topical mupirocin prophylaxis for Staphylococcus aureus nasal carriers based on one trial in adults 37 which compared mupirocin with oral rifampicin, and concluded that both were equally effective, and on one cohort study in children using oral rifampicin instead of local mupirocin 38. The other guideline 35 stated that there are no convincing data to suggest screening children or care givers for Staphylococcus aureus nasal carriage or on the use of mupirocin cream around the exit site on a regular basis. Discussion In this systematic review we identified seventeen current guidelines on the management of chronic dialysis in children of which only the KDOQI guidelines were considered of fair quality with regard to their development. All other guidelines scored low with the most important domains rigour of development and applicability scoring the lowest. These results raise several concerns with regard to their implementation which we will address below. Most guidelines scored low on domains that are essential for good guideline development, such as stakeholder involvement, rigour of development and applicability. For example, in six guideline development groups, members from an important discipline were absent, as for instance, a guideline about PD catheter insertion that was exclusively developed by paediatric nephrologists with no surgeons involved. It is less likely that a guideline on a surgical procedure that is developed without the explicit involvement of a surgeon will actually be carried out accordingly in daily practice 39. Many of the guidelines did not report the criteria for selecting evidence or the methods for formulating the recommendations. This information is required to determine whether recommendations are truly evidence based and to 60

63 Management policies understand how the evidence was analyzed and used in the formulations of recommendations. This may have important implications for daily practice. For example, according to the KDOQI guidelines, the upper limit of Hb for adult patients on dialysis is fully applicable to children. They also underline (in the adult part), that aiming at an Hb of 13 g/dl will easily lead to exceeding the upper limit in daily practice, implicating that the target Hb should be lower. Yet, for children this is actually based on very few case reports from the early nineties of thrombosis and hypertension due to an (over)dose of erythropoietin in children on dialysis. At the same time, they underline the special need for treatment of anaemia in children on dialysis in order to improve cognitive performance, overall fitness and cardiac function. Furthermore, guidelines should consider potential barriers to implementation and provide monitoring criteria to assess a guidelines impact. In our study, the domain applicability scored poorly in most guidelines. All these are important issues for clinicians to appraise the guideline quality and to evaluate if the recommendations can be implemented. The scores obtained from the AGREE evaluation were similar to those reported by Boluyt et al. 40 in a study on the quality of evidence based paediatric clinical practice guidelines for ten frequent conditions in paediatric s. Our main scores were slightly lower for some domains (scope and purpose 65% vs. 84%, rigour of development 42% vs. 54% and, clarity and presentation 64% vs. 78%) when compared with those reported by Boluyt et al. 40. The relatively lower rigour of development in the dialysis guidelines could be related to the inclusion of non evidence based guidelines in our study. Also the low scores of the guidelines other than KDOQI can partly be explained by the fact that the KDOQI guidelines were developed more recently. The first KDOQI guideline was published in 2005, while the other guidelines were published between 2000 and 2006, and one in Although there were only a few overlapping content related topics, we found relevant inconsistencies among recommendations, particularly for initiation of renal replacement therapy, management of hemoglobin level, and the use of mupirocin to prevent exit site infections. Al these recommendations were underpinned by expert opinion or sparse evidence. This phenomenon is well known from literature on adult care. Tong et al. found considerable inconsistencies in recommendations for screening and follow up of living kidney donors, which were all based on low level evidence 41. In a comparison of 5 adult KDIGO guidelines in 2007, v Belleghem found conflicting recommendations, in some cases even based on the same literature 42. The conclusion should be that in case of no evidence, no strict recommendation should be given at all and recommendations for further research, as KDOQI often but not always provide, should be given for all these topics. This might enhance the process of harmonization of therapy, benchmarking, and improvement of care. We are aware of the major challenges hampering the development of guidelines in this field. End-stage kidney disease in children is very rare. Over the last ten years, the growing number of pre-emptive transplantations has even further reduced the number of children on dialysis in the western world. The consequently small number of paediatric patients on chronic dialysis, scattered over many small centres has precluded the generation of paediatric -specific evidence and hampered the development of guidelines. At the same time, there are fewer paediatric nephrologists than adult nephrologists. Because of the small number of patients and paediatric nephrologists there is fewer financial resources and time available for research. The lack of evidence based guidelines leads to children being treated based on clinical experience or opinion of various different nephrologists in different centres, perhaps 4 61

64 Chapter 4 partly based on evidence from adult studies. It is not clear to what extent evidence generated in adult studies can be extrapolated to children. Because of these major challenges hampering the development of evidence based guidelines the need for improvement of the development of consensus or best available evidence based guidelines for the management of children on chronic dialysis is essential. Implications After considering all domain scores, we can currently only recommend the 7 KDOQI guidelines to be used in local practice. Although we are faced with major challenges hampering the development of guidelines, such as the small number of patients, few paediatric nephrologists, and lack of funding, we emphasize the need for improvement of the development of guidelines for the management of children on chronic dialysis. Guideline developers should report the underpinning evidence or other considerations for their recommendations i.e. describe how the recommendations have been developed, assess the strength of the recommendation, and the potential problems and barriers in clinical practice. Such guidelines should be available to all paediatric nephrologists and associated disciplines in the world. Furthermore, we suggest international collaboration to overcome the challenge of the small sample sizes. There are several examples of international collaborative groups that have succeeded to perform multi centre studies in rare diseases, e.g. PRINTO in juvenile rheumatism 43, and the European Vasculitis Study Group (EUVAS) 44. Limitations One limitation of this study is that by including published guidelines we may have missed guidelines that have not been published in indexed medical journals. Furthermore, we excluded non-english guidelines due to translation restrictions therefore the applicability of our findings in other contexts is unclear. We used the AGREE II instrument to assess the quality of paediatric guidelines, one of the few guideline assessment tools with demonstrated validity and reliability 45. A guideline that addresses the issues covered by the AGREE instrument is more likely to be a rigorously developed guideline. However, poor reporting of the development process that may not reflect flaws in the actual development process of the guidelines is a recognized limitation of the AGREE II instrument. To assess the validity of the recommendations, the rater must have both paediatric subject matter knowledge and skills in evidence-based medicine. Furthermore, when items are not reported specifically, they receive a low score (i.e. 1, strongly disagree), although in fact the developers might have met the criterion. It is therefore important that future guidelines report all different items specifically. Conclusion The development process of currently existing guidelines for the management of children on chronic dialysis varies largely. Although the KDOQI guidelines scored sufficient on the overall score of the domains, improvement of rigour of development and applicability is needed before wide application can be expected. It is clear that the current major need for more valid guidelines in the field of paediatric End-stage kidney disease calls for more international collaborative efforts. 62

65 Management policies Reference List 1. McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350: Groothoff JW, Gruppen MP, Offringa M et al. Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study. Kidney Int 2002; 61: Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112-S Groothoff JW, Offringa M, Van Eck-Smit BL et al. Severe bone disease and low bone mineral density after juvenile renal failure. Kidney Int 2003; 63: Bakkaloglu SA, Saygili A, Sever L et al. Assessment of cardiovascular risk in paediatric peritoneal dialysis patients: a Turkish Pediatric Peritoneal Dialysis Study Group (TU- PEPD) report. Nephrol Dial Transplant 2009; 24: Rinat C, Becker-Cohen R, Nir A et al. A comprehensive study of cardiovascular risk factors, cardiac function and vascular disease in children with chronic renal failure. Nephrol Dial Transplant 2010; 25: Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet 1993; 342: Kuzma-O Reilly B, Duenas ML, Greecher C et al. Evaluation, development, and implementation of potentially better practices in neonatal intensive care nutrition. Pediatrics 2003; 111: e461-e NICU study: best practices are not always followed. Healthcare Benchmarks Qual Improv 2003; 10: Tromp WF, Schoenmaker NJ, van der Lee JH et al. Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study. Nephrol Dial Transplant 2011; 11. Cabana MD, Rand CS, Powe NR et al. Why don t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999; 282: Kidney Disease: Improving Global Outcome National Kidney Foundation. Kidney Disease: Outcomes Quality Initiative (KDOQI) Caring for Australasians with Renal Impairment

66 Chapter The Renal Association - United Kingdom Canadian Society of Nephrology (CSN). asp?s= International Society for Peritoneal Dialysis European Best Practice Guidelines (EBPG). asp The Appraisal of Guidelines Research and Evaluation (AGREE) Coleman JE et al.on behalf of the European Paediatric Peritoneal Dialysis Working Group. Guideline by an ad hoc European Committee on the assessment of growth and nutritional status in children on chronic peritoneal dialysis Fischbach M, Stefanidis CJ, Watson AR. Guidelines by an ad hoc European committee on adequacy of the paediatric peritoneal dialysis prescription. Nephrol Dial Transplant 2002; 17: Fischbach M, Edefonti A, Schroder C, Watson A. Haemodialysis in children: general practical guidelines. Pediatr Nephrol 2005; 20: Klaus G, Watson A, Edefonti A et al. Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 2006; 21: NKF KDOQI. Clinical practice guidelines for Bone Metabolism and disease in children with Chronic Kidney Disease. Am J Kidney Dis 2005; 46 Suppl 1: 25. NKF KDOQI. Clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 2006; 48 Suppl 1: S NKF KDOQI. Clinical Practice Guidelines for Haemodialysis Adequacy, Update American Journal of Kidney Diseases 2006; 48: S2-S NKF KDOQI. III. Clinical practice recommendations for anemia in chronic kidney disease in children. Am J Kidney Dis 2006; 47: S NKF KDOQI. Clinical practice recommendation 8: vascular access in pediatric patients. Am J Kidney Dis 2006; 48 Suppl 1: S274-S NKF KDOQI. Clinical Practice Guideline for Nutrition in children with CKD: 2008 update

67 Management policies 30. NKF KDOQI. Clinical Practice Guidelines for Cardiovascular Disease in Dialysis patients Pollock C, Voss D, Hodson E, Crompton C. The CARI guidelines. Nutrition and growth in kidney disease. Nephrology (Carlton ) 2005; 10 Suppl 5: S177-S Schmitt CP, Bakkaloglu SA, Klaus G, Schroder C, Fischbach M. Solutions for peritoneal dialysis in children: recommendations by the European Pediatric Dialysis Working Group. Pediatr Nephrol 2011; 26: Schroder CH. The management of anemia in pediatric peritoneal dialysis patients. Guidelines by an ad hoc European committee. Pediatr Nephrol 2003; 18: Warady BA, Schaefer F, Holloway M et al. Consensus guidelines for the treatment of peritonitis in pediatric patients receiving peritoneal dialysis. Perit Dial Int 2000; 20: Watson AR, Gartland C. Guidelines by an Ad Hoc European Committee for Elective Chronic Peritoneal Dialysis in Pediatric Patients. Perit Dial Int 2001; 21: White CT, Gowrishankar M, Feber J, Yiu V. Clinical practice guidelines for pediatric peritoneal dialysis. Pediatr Nephrol 2006; 21: Bernardini J, Piraino B, Holley J, Johnston JR, Lutes R. A randomized trial of Staphylococcus aureus prophylaxis in peritoneal dialysis patients: mupirocin calcium ointment 2% applied to the exit site versus cyclic oral rifampin. Am J Kidney Dis 1996; 27: Blowey DL, Warady BA, McFarland KS. The treatment of Staphylococcus aureus nasal carriage in pediatric peritoneal dialysis patients. Adv Perit Dial 1994; 10: Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ 1999; 318: Boluyt N, Lincke CR, Offringa M. Quality of evidence-based pediatric guidelines. Pediatrics 2005; 115: Tong A, Chapman JR, Wong G, de BJ, Craig JC. Screening and follow-up of living kidney donors: a systematic review of clinical practice guidelines. Transplantation 2011; 92: Vanbelleghem H, Vanholder R, Levin NW et al. The Kidney Disease: improving Global Outcomes website: comparison of guidelines as a tool for harmonization. Kidney Int 2007; 71: Paediatric Rheumatology International Trials Organisation

68 44. Jayne D. Update on the European Vasculitis Study Group trials. Curr Opin Rheumatol 2001; 13: Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care 2003; 12: Voss D, Hodson E, Crompton C. Nutrition and growth in kidney disease: CARI guidelines. Aust Fam Physician 2007; 36:

69 5Disparities in Dialysis Treatment and Outcomes for Dutch and Belgian children with immigrant parents Nikki J. Schoenmaker 1, Wilma F. Tromp 1, Johanna H. van der Lee 2, Brigitte Adams 3, Antonia H. Bouts 1, Laure Collard 4, Karlien Cransberg 5, Rita Van Damme-Lombaerts 6, Nathalie Godefroid 7, Koenraad J. Van Hoeck 8, Linda Koster-Kamphuis 9, Marc R. Lilien 10, Ann Raes 11 and Jaap W. Groothoff 1 Departments of Paediatric Nephrology: 1 Emma Children s Hospital AMC Amsterdam, the Netherlands; 3 Hospital Universitaire des Enfants Reine Fabiola Brussels, Belgium; 4 Centre Hospitalier Universitaire de Liege, Belgium; 5 Sophia Children s Hospital Erasmus MC Rotterdam, the Netherlands; 6 University Hospital Leuven, Belgium; 7 Universitaire catholique de Louvain Brussels, Belgium; 8 University Hospital Antwerp, University of Antwerp, Belgium; 9 University Medical Centre St Radboud Nijmegen, the Netherlands; 10 Wilhelmina Children s Hospital University Medical Centre Utrecht, the Netherlands; 11 University Hospital Gent, Belgium; 2 Department of Paediatric Clinical Epidemiology Emma Children s Hospital AMC Amsterdam, the Netherlands Pediatr Nephrol Aug;27(8):

70 Chapter 5 Abstract Background In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-western European origin (Non-Western). Concerns exist regarding whether these Non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post initial treatment, and outcomes between Non-Western and Western patients on dialysis. Methods All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included. Non-Western patients were defined as children of whom one or both parents were born in Non-Western countries. Results 79 of the 179 included patients (44%) were non-western children. Compared to Western patients, Non-Western patients more often were treated with haemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52% vs. 37% p=0.046). Before renal transplantation, Non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p=0.007). Renal osteodystrophy was diagnosed in 34% of Non-Western vs. 18% of Western patients (p =0.028). The incidence rate ratio [95%confidence interval] for acute peritonitis was 2.44 [ ] (p=0.032) for Non-Western compared to Western patients. Conclusions There are important disparities between children on chronic dialysis with parents from Western European and those from non-western European origin in the choice of modality, duration, and outcomes of dialysis therapy. 68

71 Children from non-western origin Introduction In the Netherlands and Belgium, a considerable proportion of the children treated with chronic dialysis have immigrant parents from Non-Western European origin (Non-Western). Over the last decade, the proportion of Non-Western immigrants in the Netherlands has grown from 9% to 11% 1. Data on clinical management and outcomes of patients of ethnic minorities are scarce. Yet, there is a growing awareness that there are considerable healthcare disparities between immigrants and native American patients 2;3. Stronks et al. showed that in the Netherlands the use of general practitioner care and the use of prescribed drugs is increased among Non-Western adult patients as compared to adult patients from Western origin 4. Cultural misunderstandings between doctor and patient as well as language barriers may contribute to a different approach and subsequent disparities in quality of care. For example, a Dutch study on asthma in children showed ethnicity and limited Dutch proficiency to be important risk factors for uncontrolled asthma in children 5. Disparities for patients of Non-Western background may be even more important for highly complex modes of healthcare such as chronic renal replacement therapy in children, which makes great demands on the understanding and discipline of patient and caretakers. Little is known about the management and outcomes of children of Non-Western immigrant parents requiring chronic dialysis. We therefore compared the choice of initial dialysis modality, post initial treatment and outcomes between first and second generation children of non-western origin and those from Western origin on chronic dialysis treatment. Methods 5 Patients All children aged < 19 years who were treated with haemodialysis (HD) or peritoneal dialysis (PD) in the Netherlands and Belgium between September 1 st 2007 and May 1 st 2011 were included. Data were collected as part of the RICH-Q project (Renal Insufficiency therapy in Children - Quality assessment and improvement) 6. Follow-up data were available until May 1 st 2011, or until transplantation, transition to adult care or death. We obtained ethical approval from the ethical institutional review boards of all participating hospitals and written informed consent from the parents of all participants, and the participants themselves, if possible. Survey on preferred first dialysis therapy At the start of RICH-Q in 2007 we asked one paediatric nephrologist per participating centre to complete a questionnaire on treatment policies. The questionnaire was developed with input from all participating paediatric nephrologists, to ensure content validity. The questionnaire included the following question: What is your preferred first mode of renal replacement therapy, if pre emptive tranplantation is not possible, in children > 3 years old? Data collection procedures Data were collected from the medical records of the patients by trained local research nurses or by the participating paediatric nephrologists. The following data were used: age, gender, 69

72 Chapter 5 primary cause of end-stage renal disease (ESRD), date of first chronic Renal Replacement Therapy (crrt), first crrt modality, waiting time on dialysis, country of birth for the child and parents, race/ethnicity as reported by the parents, i.e. Caucasian, Black, Asian or other, and the educational attainment of the parents. Primary causes of ESRD were classified into 7 categories: glomerulopathy, hemolytic uremic syndrome, urinary tract malformation, dysplasia, primary interstitial nephritis, tubular necrosis or other. The following outcomes were recorded: blood values of hemoglobin, phosphate, calcium, immunoreactive parathyroid hormone (ipth), alkaline phosphatase, homocysteine, presence of hypertension, medication prescriptions, and presence of metabolic bone disease at inclusion of the patients from 2007 till Complications of the therapy, such as peritonitis incidence, HD infections, and hospitalizations were monitored during the four-year study period. Definitions Non-Western patients were defined as children of whom 1 or both parents were born in Non-Western European countries 1. Western patients were defined as children from parents born in Western Europe. The total number of months on dialysis was defined as the period between the first day of dialysis and May 1 st 2011 or the date of transplantation, the date of transition to adult care, or the date of death. For the calculation of the estimated Glomerular Filtration Rate (egfr), we used the updated version of the Schwartz formula: egfr (ml/min/1.73m 2 ) = 0.413*(Height in cm) / serum creatinine in mg/dl) 7. The mean was calculated of 3 systolic and 3 diastolic blood pressure measurements at the time of inclusion. Hypertension was defined as either a systolic or diastolic blood pressure > p95 of the Task Force Report normal values corrected for age and gender 8. Renal osteodystrophy (ROD) was diagnosed by an experienced radiologist based on a hand X-ray at the time of inclusion. We made a distinction between incident patients, who were included within 3 months after the start of dialysis, and prevalent patients defined as patients who had been treated with dialysis for at least 3 months before inclusion. Poor condition as reason to start dialysis was defined by the paediatric nephrologists. Parental educational attainment was defined as the highest educational level, as reported by the parents themselves. Statistical Analysis Chi-square test or, in case of small expected cell counts, Fisher s Exact test, was used to test comparisons of categorical variables between Non-Western and Western patients. Student s T-test and Mann-Whitney U test were used for continuous variables when appropriate. Kaplan-Meier survival analysis was used to analyze waiting time on dialysis until transplantation. To investigate the association between Non-Western status and number of peritonitis episodes per PD year at risk and ROD, respectively, linear and logistic regression analysis was performed. At first only the central determinant was entered in the model (model with one determinant); possible confounders were then entered one at a time (multivariable models). If the regression coefficient of the central determinant Non-Western status changed >10% after addition of one determinant to the regression model, this added determinant was considered to be a confounder and was kept in the final model. To evaluate the change in the regression coefficient the same population was included in the bivariable analysis as in the multivariable analysis, i.e. excluding any subjects with missing values. The following determinants were considered as possible confounders: the duration of dialy- 70

73 Children from non-western origin sis before inclusion, poor condition as the reason to start dialysis, the cause of ESRD, and educational attainment of parents. All analyses were performed using SPSS 18.0 for Windows statistical software. For the incidence rate of infection and hospitalization, the number of new episodes per patient year at risk was calculated. The incidence rate ratio (IRR) was calculated to compare Non-Western and Western patients. Hospitalization was analyzed separately in children < 4 years old, because the hospitalization rate is on average higher in young children. Results Characteristics and initial treatment We included 179 children, of whom 79 (44%) had parents from Non-Western origin (Table 1). In 4 patients (2%), only one parent was from Non-Western origin; we considered these patients as Non-Western according to the definition of Statistics Netherlands (CBS) 1. We found no statistically significant differences between non-western and Western patients with respect to primary cause of ESRD, gender, age at start dialysis (HD or PD), egfr at start of dialysis, poor condition as the reason to start dialysis, PD modality or percentage of patients already treated with dialysis at the time of inclusion. Compared with Western children, non-western children were significantly more often treated with HD as the first mode of crrt, 37% vs. 52%, respectively (p=0.046). The median duration of dialysis at the start of the RICH-Q project was 9 months longer in non-western patients; in patients treated with HD this difference was statistically significant (p=0.018). Parents from non-western European origin had a significantly lower level of educational attainment (Table 1). 5 Preferred first dialysis therapy Of the 10 centres, 6 (60%) preferred PD as first dialysis treatment if pre-emptive transplantation was not possible, for children > 3 years old. In the 4 centres preferring HD, this preferred mode of dialysis was more often followed in non-western children than in Western children (p=0.006). Post initial dialysis treatment Compared with Western patients, Non-Western patients had a significantly longer median duration of HD, the median difference exceeding 10 months (p=0.003) (Table 2). No significant disparities were found between the 2 groups for the median duration of PD, the number of switches in therapy, medication use, or the time on haemodialysis per week (Table 2). Relatively more Non-Western than Western patients on HD had a Cimino fistula instead of a central venous catheter (53% vs. 33%), although this difference was not statistically significant (p=0.080). During the follow-up period, 88 children (33 Non-Western and 55 Western) received a kidney transplant. Prior to transplantation, Non-Western patients spent a significantly longer time on dialysis than Western patients, with a median of 30 months versus 15 months, respectively (p=0.007) (Fig. 1). Dialysis outcomes The incidence rate of peritonitis was 1.0 per patient year at risk for Non-Western and 0.41 per patient year at risk for Western patients. The incidence rates of HD exit site/ tunnel infections were comparable in both groups (Table 3). 71

74 Chapter 5 Table 1. Demographics, cause of ESRD and initial treatment of children with immigrant parents of non-western European origin (non-western) and children with parents of western-european origin (Western). Non-Western n = 79 (44) Western n= 100 (56) Male 50 (63) 52 (52) a p Origin of parents Morocco: 15 Turkey: 15 Surinam: 9 Asia: 5 Dutch Antilles / Caribbean: 3 Russia: 2 Africa (other): 15 Middle East (other): 15 Country of birth Netherlands: 37 Belgium: 13 United Kingdom: 2 Morocco: 2 Turkey: 3 Surinam: 3 Asia: 2 Dutch Antilles /Caribbean: 2 Africa (other): 6 Middle East (other): 9 Ethnicity Caucasian Black Asian Mixed Primary cause of ESRD -Glomerulopathy -Hemolytic uremic syndrome -Urinary tract malformation -Dysplasia -Primary interstitial nephritis -Tubular necrosis Other 42 (53) 25 (32) 7 (9) 5 (6) 18 (23) 4 (5) 15 (19) 20 (26) 1 (1) 5 (6) 16 (20) Netherlands: 63 Belgium: 34 Germany: 1 Luxembourg: 1 United Kingdom: 1 Netherlands: 63 Belgium: 34 Germany: 1 Luxembourg: 1 United Kingdom: 1 97 (97) (3) 28 (28) 6 (6) 16 (16) 24 (24) 4 (4) 8 (8) 14 (14) c 72

75 Children from non-western origin Educational attainment of the parents -Elementary school -Secondary education -Post secondary education missing 15 (19) 8 (10) 9 (11) 47 (60) Initial treatment of ESRD Age at start dialysis, years* median (range) Total HD PD 6.4 (0-17.0) 10.0 (0-17.0) 2.1 (0-16.6) 12 (12) 28(28) 30 (30) 30 (30) 6.4 (0-18.5) 8.3 ( ) 4.9 (0-16.7) a b b b egfr (ml/1.73 m 2 ) at start dialysis* 7.4 ( ) 7.5 ( ) b Poor condition as reason to start dialysis 24 (30) 36 (36) a First dialysis modality HD PD PD modality CCPD/APD CAPD Missing Inclusion in RICH-Q 41 (52) 38 (48) 28 (78) 7 (19) 1 (3) 37 (37) 63 (63) 55 (82) 7 (11) 5 (7) a a 5 Prevalent patients 46 (58%) 63 (63%) a Duration of dialysis before inclusion months* 1 HD (n=42) PD (n=46) 17.5 ( ) 19.3 ( ) 8.2 (3.1-65,3) 10.6 ( ) b b Data are presented as n (percentage), * data are presented as median (range), a Chi 2 test, b Mann Whitney U test, c Fisher Exact test, 1 From start dialysis until inclusion for the prevalent patients), egfr = estimated Glomerular Filtration Rate Schwartz. (Ref.2009), HD= haemodialysis, PD= peritoneal dialysis. Prevalent defined as >3 months treated with dialysis before inclusion. 73

76 Chapter 5 Table 2. Comparison of modes of dialysis and medication use between children with immigrant parents of non-western European origin (non-western) and children with parents of western-european origin (Western). Dialysis characteristics Non-Western N=79 Western N=100 p Duration and mode of dialysis Total months on HD* 1 Total months on PD* ( ) 11.4 ( ) 6.5 ( ) 13.6 ( ) b b Duration of dialysis before first Tx* 2 (months) n= ( ) 15.0 ( ) b Number of switches HD to PD PD to HD a a Total hours on HD per week* 12 (3-24) 12 (3-24) b Vascular access - Cimino fistula - Central venous catheter 23 (53%) 20 (47%) 11 (33%) 22 (67%) a Medication prescription Anti hypertensive drugs 39 (52%) 61 (61%) a > 2 anti hypertensive drugs 14 (25%) 12 (29%) a Erytropoetin 68 (91%) 92 (92%) a Phosphate binder -Calcium based -Non calcium based 39 (52%) 39 (52%) 44 (44%) 51 (51%) a a Etalpha 60 (80%) 81 (81%) a Growth hormone 25 (33%) 33 (33%) a Prophylactic antibiotics exit site 17 (47%) 22 (35%) a Data are presented as n (percentage), * data are presented as median (range), a Chi 2 test, b Mann Whitney U test, 1 From start dialysis until May 1 st 2011 or until transplantation, transition to adult care or death. 2 From start dialysis till first transplantation before May 1 st 2011, HD = haemodialysis, PD = peritoneal Dialysis, Tx = transplantation 74

77 Children from non-western origin The hospitalization rate in children older than 4 years was lower in Non-Western than in Western patients. Children treated with PD were more often admitted to the hospital than children on HD. Within the subgroups of HD and PD treatment modalities the hospitalization rates of Non-Western and Western patients did not differ significantly. The number of days of hospitalization was not significantly different between the groups either above or below the age of 4 years. Compared to Western patients, Non-Western patients had more peritonitis episodes, the mean difference [95% CI] being 0.58 [ ] episodes per year at risk, adjusted for poor condition as the reason to start dialysis (Table 4a). Signs of ROD at inclusion were present in 22 Non-Western (34%) and 15 Western patients (18%) (p=0.028) (Table 3). ROD was present before start of dialysis in 27% and 11% of the Non-Western and Werstern patients, respectively. When adjusted for parental educational attainment the OR [95% CI] for ROD in Non-Western patients was 1.8 [ ] (table 5b). Six children (3%) died during the follow up period, 3 Non-Western and 3 Western patients. Four children (two in each group) died of intercurrent diseases, one of Wilms tumor, one of congenital heart disease and two due to withdrawal of treatment because of multiple comorbidities. Two children (one in each group) died of complications of the treatment of the underlying kidney disease, one of pulmonary hypertension, and one due to a complication of a central line. Discussion 5 We found less favorable health outcomes and important disparities in the management of children on dialysis treatment with parents from Non-Western European origin as compared to those from Western origin in the Netherlands and Belgium. We will discuss the possible reasons for these disparities and formulate areas for further research. In both countries, Non-Western patients received more often HD as first mode of crrt instead of PD as compared to Western children. Although kidney transplantation is considered to be the optimal mode of crrt for children with ESRD, in most circumstances dialysis treatment as first crrt is inevitable 9. There is no consensus on the optimal mode of dialysis treatment. Peritoneal dialysis (PD) is offered to the younger children, especially under the age of two years or weighing less than 10 kg. Some centres recommend PD instead of HD in children because of its social advantages 10. PD permits a relatively normal lifestyle by allowing children to attend school full time with less dietary and fluid restrictions compared to HD. In addition, obtaining vascular access for HD in children can be challenging 11. In some European countries, haemodialysis (HD) is preferred for children over the age of five years 12. Factors that are reported to influence the choice of therapy include the age of the child (30%), parent preference (27%), distance from the unit (14%), patient preference (11%), social condition (7%), and inability to do one particular mode (6%) 12;13. In our study 40% of the centres preferred HD for children > 3 years old. We found that in Western children, the preferred mode of dialysis according to the centre policy was less often followed than in Non-Western children. If the preferred mode of dialysis was not followed in Western 75

78 Chapter 5 Table 3. Comparison of the outcomes between children with immigrant parents of non-western European origin (non-western and children with parents of western-european origin (Western) with end-stage renal disease Blood values (at inclusion) Hemoglobin mmol/l -Incident -Prevalent Phosphate mmol/l -Incident -Prevalent Calcium mmol/l -Incident -Prevalent ipth pmol/l -Incident -Prevalent Non-Western Western P value IRR [95%CI] n Median n Median (range) (range) ( ) 6.9 ( ) 1.65 ( ) 1.68 ( ) 2.44 ( ) 2.45 ( ) 14.9 ( ) 17.6 ( ) ( ) 7.0 ( ) 1.58 ( ) 1.68 ( ) 2.40 ( ) 2.43 ( ) 11.6 ( ) 14.1 ( ) b b b b b b b b Alkaline phosphatase U/l -Incident -Prevalent Homocysteine umol/l -Incident -Prevalent (71-987) 408 ( ) 9.5 ( ) 10.6 ( ) ( 4-825) 201 ( ) 13.3 ( ) 12.1 ( ) b b b b Hypertension 1 (at inclusion) (43) 4 45 (47) Renal osteodystrophy (at inclusion) X -ray hand: Moderate or severe signs (34) (18) a 76

79 Children from non-western origin Total - incident - prevalent Infection (27) 16 (36) (11) 12 (22) IRR [95%CI] Number of Peritonitis episodes per patient year PD at risk Number of HD exit site or tunnel infection per patient year HD at risk Hospitalization Total number of hospitalizations per patient year at risk Age < 4 years Age > 4 years HD PD Days of hospitalization per year All ages <4 years >4 years [ ] [ ] (0-282) 35 (7-282) 12 (0-162) (0-196) 22 (0-196) 10 (0-158) [ ] 0.79 [ ] 0.73 [ ] 0.77 [ ] 1.00 [ ] b b b 5 Data are presented as n (percentage), * data are presented as median (range), a Chi 2 test, b Mann Whitney U test, HD = Haemodialysis, PD = Peitoneal Dialysis, IRR = incidence rate ratio, 95%CI = 95% Confidence interval. 1 Hypertension was defined as systolic or diastolic blood pressures > p95 of the Task Force Report normal values corrected for age and gender (8). Prevalent defined as >3 months treated with dialysis before inclusion. Incident defined as included within 3 months after start dialysis. 77

80 Chapter 5 Table 4. Results of linear regression analysis for episodes of peritonitis/ PD year at risk in 94 children treated with peritoneal dialysis in all PD patients (5a) and in all patients in whom also data on the parental educational attainment was obtained (5b). 4. a B 95 % CI Model with one determinant (n=94) Non-Western status Multivariable models 1. Non-Western status - Months on PD before inclusion 2. Non-Western status - Poor condition as reason to start b B 95 % CI Model with one determinant (n=60) Non-Western status Multivariable models 1. Non-Western status Poor condition as reason to start Non Western status - Poor condition as reason to start Parental educational attainment (reference category: post secondary ) -Elementary school -Secondary education

81 Children from non-western origin children, PD was chosen more often than HD. In Non-Western children HD prevailed if the preferred modality was not followed. It is not clear whether the deviations from the centre policy had merely been the physicians or the patients choice. It is possible that Western parents more often prefer a situation of having the child out of the hospital as much as possible, as with PD, despite the burden of home therapy, even in a situation where the physician advises differently. Physicians, on the other hand, may have been reluctant to offer a home dialysis program to some Non- Western patients. The preference for HD might even be due to a more systematic physician bias in the treatment of Non-Western patients. Our findings are consistent with race associated disparities in the dialysis treatment of children in the United States. Furth et al. found more use of HD instead of PD in children of African-American descent. Family, patient, and provider preferences all accounted for the difference in choice of therapy by race 14. In addition, they suggest that systematic racial bias specifically may have contributed to the difference in dialysis modality choice. The extent to which subtle or overt and systematic provider preconceptions about race have affected dialysis modality choice in the children in our study is unclear. Financial motives may also play a role in the choice for either HD or PD. In the United States, unequal access to optimal medical care is an important cause for disparities in care. For example, Young et al. describe that paediatricians are facing the dilemma of rationing care to uninsured, undocumented children, especially for expensive life-saving care such as renal transplantation and dialysis 15. However, unlike in the United States, the social system in both the Netherlands and Belgium provides few financial incentives for choosing a certain treatment modality. Health insurance is mandatory. All insured patients pay an income-dependent contribution. In return they receive all necessary medical and paramedical care for free, including dietary, psychological and educational support. In the Netherlands, patients with a chronic disease can apply for a personal budget for extra help at home, depending on income and family situation. Even immigrants or refugees who are staying in the Netherlands or Belgium undocumented receive all necessary medical and paramedical care, if necessary for free 16. In 2010 the Netherlands was ranked first in a study comparing the health care systems of the US, Australia, Canada, Great Britain, Germany, and New Zealand 17. The study assessed five measures of healthcare; quality, efficiency, access to care, equity and, the ability to lead long, healthy, productive lives. 5 Non-Western patients spent significantly more time on dialysis prior to transplantation. The transplantation process involves a series of steps related to medical suitability, pre-transplant work-up, the possibility of a family member to donate, or movement up the waiting list for deceased donor to eventual transplantation 18. Some of these steps have been examined individually in previous studies in the United States 19;20. The study of Ozminkowski et al. showed that in the United States blacks move up the waiting list at a slower rate than whites 19 Movement on the waiting list has been studied extensively, and appears to reflect both biological factors (eg, HLA-based tissue typing) and non-biological factors (eg. transplant centre characteristics 20. Furth et al. reported racial disparities regarding access to the renal transplant waiting list in paediatric units in the United States 21. Whether these disparities were attributable to differences in the timing of presentation to a nephrologist, physician bias in identification of transplant candidates, or patient preferences was not clear. 79

82 Chapter 5 Table 5. Results of logistic regression analysis for renal osteodystrophy in 148 children treated with dialysis (5a) and in a subgroup of 87 patients on dialysis of whom we obtained data on educational attainment of the parents (5b). 5. 5a OR 95 % CI Model with one determinant (n=148) Non-Western status Multivariable models 1. Non-Western status Months on dialysis before diagnosed with ROD 2. Non-Western status Cause of ESRD (reference category: other ) -Glomerulopathy -Hemolytic uremic syndrome -Urinary tract malformation -Dysplasia -Primary interstitial nephritis -Tubular necrosis 3. Non-Western status Poor condition as reason to start 5. b Model with one determinant (n=87) Non-Western status 2.41 ( ) Multivariable model 1. Non-Western status Educational attainment of parents (reference category: post secondary ) -Elementary school -Secondary education ( ) ( ) ( ) 80

83 Children from non-western origin The longer time on dialysis in our Non-Western children could partly be explained by a different mode of transplantation. In an earlier study on the same cohort on transplantation policy and outcomes in Non-Western children with end-stage renal disease, we found that Non-Western patients less often received donor kidneys from a living related donor than deceased donor (DD) transplantations 22, contrary to Western patients. Non-Western patients who were treated with PD more often had peritonitis episodes than Western patients. This is remarkable given the relatively small number of Non-Western patients on PD as compared to HD, which suggests a positive selection for this modality. The incidence rates of HD exit site/ tunnel infections were similar in both groups, but Non-Western patients more often had a Cimino fistula. This might be related to different policies followed in Non-Western and Western patients with respect to vascular access. As discussed before, Non-Western patients were less often scheduled for living related donor transplantation and consequently more often prepared for deceased donor transplantation with a longer expected time on HD. This may have motivated physicians to choose for a Cimino fistula more often in Non-Western patients. The hospitalization rate was lower in Non-Western patients > 4 years than in Western patients of the same age. This might be explained by the fact that relatively more Non-Western patients receive HD than Western patients. Children on HD are monitored regularly and intravenous antibiotics can be given during the HD treatment sessions, both circumstances that make admission less often necessary than in PD. Consistent with this, both Non-Western and Western patients on PD were equally more often admitted than patients on HD. We found that ROD was more prevalent in Non-Western children. Nevertheless, in a multivariable analysis of a smaller subgroup without missing values, the educational attainment of the parents turned out to be an confounder of this association. Renal Osteodystrophy (ROD), which is associated with long duration of chronic kidney disease, is a major clinical problem in young adults with paediatric ESRD 23. To detect ROD a bone biopsy remains the gold standard investigation. Its invasive nature and the need for specialized processing and interpretation limits the use of bone biopsy in clinical practice 24. Hand X-ray is not invasive and has a high specificity (92%) for the detection of ROD bone features 25. ROD was already present before the start of dialysis in 6 Non-Western and 3 Western children. We have no evidence that Non-Western patients were less compliant with therapy before they developed ESRD. We found no indication of non-adherence in surrogate outcome markers for prevention of ROD such as ipth, phosphate and medication dosage of phosphate binders and Vitamin D derivates. Therefore, genetic factors influencing for instance the Vitamin D status might have been involved. Prevention of ROD requires extreme discipline to strictly follow the dietary and medication regime. The combination of impaired schooling of the parents and cultural misunderstandings might have hampered compliance in some children of Non-Western background. These patients might profit from a culturally tailored approach from the treatment team 26. In the Netherlands, there has been a shift in the Non-Western population. Especially in children, we see a new generation from Non-Western origin. They were born in the Netherlands, and are mostly second generation of Non-Western descent whose behaviour differs from elderly first generation Non-Western adults.perhaps this might be one of the explanations for the difference between the results of the present study and those of a recent Dutch study in adult immigrants which showed increased survival for adult immigrant patients on 5 81

84 Chapter 5 dialysis in the Netherlands compared to native Dutch dialysis patients 27. Another explanation might be that ESRD in adult immigrant patients is due to different causes than in young patients. A limitation of this study is the exclusion of children who had been transplanted before the start of the RICH-Q registry. The inclusion of patients in the RICH-Q project started in September Only children that were treated with dialysis were included in the present study. Children who had been transplanted before this date were not included. This probably has resulted in an overrepresentation of children who are not suitable for (pre- emptive) transplantation, which may have resulted in a relatively large proportion of Non-Western patients in this study. Therefore the percentage of Non-Western patients in this study is higher than in the general population. Another limitation is that we did not collect information on language barriers, which have been shown to impact a wide variety of health and healthcare outcomes 28. The parental educational attainment seemed to be a confounder in the development of ROD. Unfortunately, information on the educational attainment of the parents was missing in the majority of Non-Western European children. In conclusion, children with end-stage renal disease with parents of Non-Western European origin more often receive HD instead of PD as first crrt modality, and stay on dialysis longer before transplantation. These Non-Western patients have less favorable outcomes, such as an increased risk for PD-associated peritonitis and renal osteodystrophy. This situation might be improved by education of treatment providers about these disparities and about the potential roles of conscious and unconscious bias, cultural misunderstandings, and language barriers. 82

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87 trasound in comparison with bone histology. Nephron 75: Rodrigue JR, Cornell DL, Lin JK, Kaplan B, Howard RJ (2007) Increasing live donor kidney transplantation: a randomized controlled trial of a home-based educational intervention. Am J Transplant 7: van den Beukel TO, Dekker FW, Siegert CE (2008) Increased survival of immigrant compared to native dialysis patients in an urban setting in the Netherlands. Nephrol Dial Transplant 23: Flores G (2005) The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev 62:

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89 Children from non-western origin 6 Non-Western immigrant children with End-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health related quality of life compared to Western children 6 Nikki J. Schoenmaker 1, Lotte Haverman 2, Wilma F.Tromp 1, Johanna H. van der Lee 3, Martin Offringa 4, Brigitte Adams 5, Antonia H. M. Bouts 1, Laure Collard 6, Karlien Cransberg 7, Maria van Dyck 8, Nathalie Godefroid 9, Koenraad van Hoeck 10, Linda Koster-Kamphuis 11, Marc R. Lilien 12, Ann Raes 13, Christina Taylan 14, M.A. Grootenhuis 2 and J.W. Groothoff 1 Departments of Paediatric Nephrology: 1 Emma Children s Hospital Academic Medical Centre Amsterdam, the Netherlands, 5 Hospital Universitaire des Enfants Reine Fabiola Brussels, Belgium, 6 Centre Hospitalier Universitaire de Liege, Belgium, 7 Sophia Children s Hospital Erasmus MC Rotterdam, the Netherlands, 8 University Hospitals Leuven, Belgium, 9 University Centre Louvain, Brussels, 10 University Hospital Antwerp, Belgium, 11 Radboud University Nijmegen Medical Centre, the Netherlands, 12 Wilhelmina Children s Hospital University Medical Centre Utrecht, the Netherlands, 13 University Hospital Gent, Belgium, 14 University Hospital Cologne, Germany 2 Psychosocial Department, Emma Children s Hospital AMC, Amsterdam, the Netherlands 3 Clinical Research Unit, Division Woman-Child, Academic Medical Centre Amsterdam, the Netherlands 4 Child Health Evaluative Sciences (CHES), Hospital for Sick Children, University of Toronto, Canada Submitted 87

90 Chapter 6 Abstract Background Many children with end-stage renal disease (ESRD) in Western Europe are from non-western European origin. They have unfavorable somatic outcomes compared to Western ESRD children. In this study we compared the Health Related Quality of Life (HRQoL) of both groups. Methods All children (5-18 years) with ESRD included in the RICH-Q project (Renal Insufficiency therapy in Children-Quality assessment and improvement) or their parents were asked to complete the generic version of the Paediatric Quality of Life Inventory 4.0 (PedsQL). RICH-Q comprises the Netherlands, Belgium and a part of Germany. Children were considered to be non-western if they or at least one parent was born outside Western-European countries. Impaired HRQoL for Western and non-western children with ESRD was defined as a PedsQL score <5th percentile for healthy Dutch Western and non-western children, respectively. Results Of the 259 eligible children, 230 agreed to participate. 174 children responded, 32% were of non-western origin. Overall, 56% of the non-western children and 49% of the Western children with ESRD had an impaired total HRQoL score. Total HRQoL scores of Westerns and non-westerns with ESRD were comparable, but scores on emotional functioning and school functioning were lower in non-western children (p=0.004 and p=0.01, respectively). The adjusted odds ratios [95% confidence interval] for non-western children to have impaired emotional functioning and school functioning were 3.3 [ ] and 2.2 [ ], respectively. Conclusion Children with ESRD of non-western origin were found to be particularly at risk for impaired HRQoL on emotional and school functioning in 3 Western countries. These children warrant special attention. 88

91 Children from non-western origin Introduction In the Netherlands and Belgium up to 40% of the children on chronic dialysis are children from parents of non-western European origin 1. In the Netherlands, the proportion of non- Western immigrants has increased from 9 to 11% of the total population in the last decade, which implies an expansion of this group with more than 0.5 million people on a total population of 16.6 million people 2. Therefore, the interest in the specific needs of and care for this group is rising. Recent data from the Dutch and Belgian collaborative RICH-Q project (Renal Insufficiency therapy in CHildren-Quality assessment and improvement) showed that non-western children with end-stage renal disease (ESRD) were less often transplanted preemptively and had a higher rejection risk after transplantation than Western Dutch and Belgian children 3. Similar unfavourable outcomes were found in a comparison of non-western and Western Dutch and Belgian children on dialysis 1. So far, it is not known whether these disparities in treatment characteristics and health outcomes lead to poorer Health Related Quality of Life (HRQoL) in non-western children. HRQoL is considered as an essential health outcome measure in clinical trials and health services research and evaluation 4;5. Previous studies indicate that, in general, HRQoL is low in children with ESRD compared to healthy children 6;7. Various factors related to the treatment of this serious condition, might contribute to this impaired HRQoL. For example, the time spent on dialysis and during hospital visits and admissions may cause considerable disruption of normal social activities and school attendance 8. This disruption appears to have a lasting impact as children grow up, since adult survivors of paediatric ESRD report relatively low self-esteem, two third do not live independently and one third are unemployed For first and second generation non-western immigrants, who generally live in less favourable circumstances, the burden of ESRD may add up to those caused by their social economic status. We hypothesized that non-western children with ESRD have a lower HRQoL compared to Western children with ESRD because of these disadvantages. We studied the HRQoL of all children (5-18 years) with ESRD within the RICH-Q project, which comprises all RRT centres for children in the Netherlands and Belgium and a geographically adjacent part of Germany. We compared the HRQoL between non-western and Western children with ESRD after standardization based on HRQoL data retrieved in healthy non-western and Western children. 6 Patients and methods This international HRQoL study was designed as a cross sectional study within the RICH-Q project (Renal Insufficiency therapy in Children -Quality assessment and improvement) 12. In RICH-Q anonymous data on treatment characteristics and physical and psychosocial health outcomes are registered prospectively concerning all children with ESRD treated in the 11 RICH-Q associated hospitals. In the RICH-Q registry we included all prevalent Dutch and Belgian patients aged <19 years on chronic dialysis on October 1 st 2007, and all Dutch and Belgian patients aged <19 years who started dialysis or were transplanted from October 1 st, 2007 to September Since 2011, all prevalent dialysis and all incident ESRD patients in a geographically adjacent part of Germany treated in the centre of Cologne aged <19 years are included in the database. We obtained ethical approval from the ethics boards of all participating hospitals and written Informed Consent from all parents of all participants. Children or their parents who 89

92 Chapter 6 completed the PedsQL are called participants, and children or parents who either did not give informed consent or did not fill in the PedsQL in spite of initial consent are called nonparticipants. Baseline variables In accordance with the definition of Statistics Netherlands 2, children were considered to be non-western immigrants if they themselves or one or both parents had been born outside Western Europe. Primary causes of ESRD were classified into two categories: 1) acute onset (e.g. dense deposit disease, hemolytic uremic syndrome (HUS), tubular necrosis, tumor and nephrotic syndrome) and 2) insidious onset (e.g. urinary tract malformation, chronic renal failure, renal vascular disease, congenital diseases). Parental educational attainment was defined as the highest educational level of any parent as reported by the parents themselves. PedsQL Generic Scale 4.0 In order to compare the HRQoL scores of children with ESRD to the healthy population, we used the generic version of the Paediatric Quality of Life Inventory 4.0 (PedsQL) 13, because of its broad age range (5 to 18 years), its inclusion of self-reports (8 to 18 years) as well as proxy-reports (5 to 7 years), its short completion time (approximately 5 to 10 minutes) and good feasibility, validity and reliability 6;14. The 23-item PedsQL, version 4.0 Generic Core Scales, are grouped into four HRQoL subscales: 1) physical health (8 items), 2) emotional functioning (5 items), 3) social functioning (5 items) and 4) school functioning (5 items). We used child self-report for children from 8 to 12 years old and 13 to 18 years old and parent proxy-report for children from 5 to 7. The child or parent is asked how much of a problem each item has been during the past month on a 5-point Likert scale (0 = never a problem; 1= almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem). Item scores are reversed and linearly transformed to a 0 to 100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate better HRQoL. Scale scores are computed as the sum of the items divided by the number of items. In addition to the four subscales, there are two summary scores (Psychosocial health and Total score). Previous research provided data on a healthy Dutch population consisting of 198 Western and 51 non-western children 15. Statistical analysis All analyses were performed using SPSS 18.0 for Windows statistical software. Mann- Whitney U tests, Chi 2 test, or Fisher s exact test, if necessary, were used to compare continuous and categorical variables, respectively in two groups. First, known baseline variables were compared between participants and non-participants, then between non-western and Western participants. PedsQL scores were compared between non-western and Western participants with ESRD and between non-western participants with ESRD and healthy non-western children. To report the magnitude of these differences, standardized mean differences (pooled effect size) were calculated by dividing the difference in mean scores between the non-western children with ESRD and the reference group (first the Western participants with ESRD, then the healthy non-western children) by the pooled standard deviation. Standardized mean differences of up to 0.2, 0.5, or more than 0.8 were considered to be small, moderate or 90

93 Children from non-western origin Table 1. Demographic and disease characteristics of participants and nonparticipants. Age (years) at inclusion RICH-Q Age at onset ESRD Duration of RRT (months) Participants n=174 Median (range) 12.3 ( ) 10.0 ( ) 43.5 ( ) Non-participants* N=85 Median (range) 13.2 ( ) 10.4 ( ) 20.2 ( ) 0.59 a 0.65 a <0.001 a P value N % N % Sex (male) b Ethnicity (Caucasian) b Non-Western b Country of residence - The Netherlands - Belgium - Germany Cause of ESRD Glomerulopathy Haemolytic uremic syndrome b 0.99 b 6 - Urinary-tract malformation Dysplasia Primary interstitialnephritis Tubular necrosis Other *The group of non-participants consists of patients/parents who did not give consent (n=29) and patients/ parents who did not complete the PedsQL (n=56), ESRD= End-stage renal disease, a= Mann Whitney U, b= Chi Square 91

94 Chapter 6 Table 2. Demographic and disease characteristics of non-western and Western participants. Non-Western participants N=55 Western participants N=119 N Median (range) N Median(range) P value Age at onset RRT (years) 9.4 ( ) 10.4 ( ) Age PedsQL (years) 12.0 ( ) 13.8 ( ) Duration of RRT (months) 22.6 ( ) 12.8 ( ) Duration of dialysis (months) 46* 18.9 ( ) 85* 11.5 ( ) PedsQL Age categories: -5-7 years (proxy report) years (self report) years (self report) N % N % a 0.34 a 0.08 a 0.02 a Sex (male) b Ethnicity (Caucasian) Country of Residence (Netherlands) <0.001 b 0.71 b Acute onset of ESRD Mode of RRT at time of PedsQL -HD -PD -Tx Comorbidity - Comorbidity present - No comorbidity - Information missing b b 0.56 c a Mann Whitney U, b Chi Square, c Chi Square, excluding missing values * Not all participants have undergone dialysis; some were only treated with renal transplantation 92

95 Children from non-western origin large, respectively 16. Furthermore, the HRQoL scores of children with ESRD were standardized based on the healthy norm population, for non-western and Western participants separately. The proportion of children with an impaired HRQoL was based on a PedsQL score <5 th percentile (i.e. Z-score <-1.65) of the healthy Dutch population. Scores below the 5 th percentile of the healthy non-western population and of the healthy Western population were considered as consistent with impaired HRQoL for both non-western and Western participants, respectively. The mean difference and 95% confidence interval of the proportions of non-western and Western participants with an impaired HRQoL was calculated using Confidence Interval Analysis 17. Finally, a logistic regression analysis was performed to quantify the association between Non-Western immigrant status and impaired HRQoL, adjusted for confounding. All possible confounders were added one at a time, in a pre-specified order, to a model containing only the central determinant (non-western status). If addition of a potential confounder to the model resulted in a change of > 10% in the regression coefficient b of the primary determinant (non-western status), this variable was kept in the model. The following potential confounders were investigated consecutively: age, gender, duration of renal replacement therapy (RRT), number of school days missed in the last 3 months, RRT modality, highest educational attainment of the parents, country of residence, co- morbidity, parental work situation, parental marital status, number of children and assistance with completing the PedsQL. Results Participants Between September 2007 and September 2012, 259 children (5-18 years) with ESRD and their parents were asked to participate in the study. Informed consent for the HRQoL was given by 230 children and their parents (89%). Twenty-nine children or their parents either chose not to participate in this study or were unable to participate because of language problems. 174 of 230 participants completed the PedsQL questionnaire (overall response rate 76%). The 29 children who chose not to participate and the 56 non-responders together are denoted as non-participants (n=85). The socio-demographic and disease characteristics of participants and non-participants are shown in Table 1. At the time of investigation 105 children were on dialysis and 69 had a functioning renal graft. The median [range] age of all the participants was 12.3 [ ] years. Participants and non-participants differed significantly on several characteristics: the non-participating children had been on RRT for a shorter duration, were more frequently male and from non-western background. The demographic and disease characteristics of non-western and Western participants are shown in Table 2 and more detailed in Appendix 2. Fifty-five of the 174 participants (32%) were from non-western background. One of these was a child born in India adopted by Belgian parents (Appendix 2). The non-western children were more frequently treated with haemodialysis, and had been treated with dialyses for a longer period compared to Western children (Table 2). Furthermore, non-western participants or their parents had had more assistance completing the PedsQL in general and more assistance from a doctor or a nurse than from other people compared to Western participants. The parents of the non-western children had a lower educational attainment and were more frequently unemployed than 6 93

96 Chapter 6 Figure 1. Percentages of non-western and Western children with ESRD with impaired HRQoL, defined as a PedsQL score < 5 th percentile (SD 1.65) of the non- Western norm population (n=51) and of the Western norm population (n=198), respectively. Mean diff. [95% CI] of percentage with impaired HRQoL The upper part shows the mean difference and 95% confidence interval of the percentages in the lower part. 94

97 Children from non-western origin Western parents. Furthermore, non-western participants or their parents received more assistance completing the PedsQL in general and more assistance from a doctor or a nurse than from other people compared to Western participants. No significant differences were found between participating non-western and Western children with respect to age, duration of RRT, gender, country of residence, co-morbidity, parental marital status, and number of school days missed in the three month preceding completion of the PedsQL. HRQoL The absolute PedsQL scores are shown in Appendix 3. Absolute and standardized mean differences between PedsQL scores of non-western and Western participants and of non- Western participants and healthy non-western children from the Dutch norm group are shown in Table 3. No significant differences were found in the absolute values of the subscales between non-western children with ESRD and Western children with ESRD (standardized mean differences ranged from to 0.13). Non-Western children with ESRD showed lower HRQoL scores compared to healthy non-western children in the Dutch norm group (standardized mean differences ranged from to ). Figure 1 shows the percentages of participants with impaired HRQoL and the differences [95% confidence interval] in percentages between Western and non-western participants. Fifty-six percent of the non- Western children with ESRD had an impaired HRQoL compared to healthy non-western children, and 49% of the Western children with ESRD had impaired HRQoL compared to healthy Western children. The proportion of non-western participants with impaired HRQoL was significantly larger than the proportion of Western participants on the subscales emotional and school functioning (mean difference [95% CI] 20.8 [ ]% and 20.4 [ ]%, respectively). The results of the logistic regression analysis are shown in Table 4. Non-Western children had an OR [95%CI] of 3.3 [ ] of having impaired emotional functioning, adjusted for assistance with completion of the PedsQL and RRT modality. Their OR [95%CI] for impaired school functioning was 2.2 [ ] adjusted for RRT modality. 6 Discussion To our knowledge this is the first study to compare HRQoL between non-western and Western children with ESRD. We found that both Western and non-western children with ESRD had significant impairment of HRQoL compared to their healthy counterparts from a Dutch norm group. Within the ESRD group, non-western patients had a higher risk for having impaired emotional and school functioning compared to Western children. Several studies have shown that children with ESRD have an impaired HRQoL compared to healthy controls 4;6;7;18. Our study shows that approximately half of children with ESRD have impaired HRQoL based on the 5 th percentile of the reference group. On top of the disadvantage of having ESRD, we assumed that the non-western status might be of extra disadvantage since it has been shown that healthy non-western adults and adolescents have an impaired HRQoL compared to healthy Westerns 19;20. The disadvantage of being from non-western origin was also described in Dutch children with other chronic diseases A Dutch study on children with asthma identified ethnicity as well as insufficient comprehension of the Dutch language as independent risk factors for uncontrolled asthma

98 Chapter 6 A double disadvantage was also described in children with sickle cell disease. These children reported lower HRQoL scores compared to healthy children but comparable to their healthy siblings, except for the disease specific domains, implying that at least part of the impaired HRQoL was related to specific problems of the immigrant community, such as financial and social problems 21. Studies on HRQoL in non-western ESRD patients are scarce. Lopes et al. described differences in HRQoL in adults on chronic dialysis between different ethnic groups in the United States 24. They found that native Americans reported lower HRQoL on social functioning and mental health than Caucasians. To our knowledge there are no previous studies conducted concerning HRQoL between non-western and Western children with ESRD. Several studies have shown that Western children with ESRD are at particularly high risk for underperforming academically, emotional and social problems, and adjustment difficulties and psychological stress in adult life 25;26. The combination of physical impairment and low educational attainment is supposed to be an important barrier for finding employment in adult life for these patients. The fact that non-western immigrant children with ESRD reported lower HRQoL than Western children with ESRD, especially on school functioning is therefore an alarming fact to their developmental trajectory. Non-Western children with ESRD were more frequently treated with centre haemodialysis. We know that haemodialysis treatment schedules are burdensome and interfere with school attendance and participation in peer-related activities. This may have a severe impact on school performance as was demonstrated in a longitudinal study on HRQoL of children on dialysis over a 2 years period 18. The parents reported their children as functioning increasingly worse at school over time 18. Non-western children with ESRD could have a double disadvantage since school is a multi-cultural setting where students need social, material, physical and mental skills to attain school achievements. In non-western immigrants these skills are often lacking, even in healthy children 27. Statistics Netherlands reported that healthy non-western children had low school performance, more grade repetition and higher school dropout compared to Dutch students 2. The results of a Dutch study from Driessen et al. showed that parental educational attainment plays a central role in the explanation of differences in the school performance of the children 28. The ethnic origin of the family, the use of Dutch language at home, and the parental level of mastery of the Dutch language were also found to be of influence 28. Three hypotheses have been constructed about factors that determine differences in health outcome among ethnic groups and migrants. Some authors attribute an essential role to socioeconomic inequalities, others emphasize the importance of genetic and cultural factors, and other authors think that intercultural difficulties between doctors and patients play an important part influencing health In this study we only had data on parental educational attainment as a surrogate for socio-economic inequality, but this was not shown to be a confounder, possibly due to a type II error. The influence of cultural factors is difficult to investigate and might play an important role. However, significant differences between groups of various ethnic backgrounds were not found within the immigrant population in this study, again possibly due to the small sample size. Finally, to what extent intercultural difficulties between doctors and patient families play a role in the Netherlands, Belgium and Germany is not clear. 96

99 Children from non-western origin Table 3. Absolute and standardized mean differences between PedsQL scores of non-western and Western participants (ESRD) and of non-western participants and healthy non-western children from the Dutch norm group. ESRD Non-western children Non-Western vs. Western participants ESRD vs. healthy non-western population Mean diff Standardized mean diff Mean Diff Standardized mean diff Total Score Psychosocial Health Physical health Emotional functioning Social functioning School functioning *Social functioning is missing in one Western child with ESRD, **School functioning is missing in two Western children with ESRD, ESRD= End-stage renal disease, mean diff= mean difference 6 97

100 Chapter 6 Table 4. Results of logistic regression (odds ratio OR [95%CI]) to investigate the association between non-western immigrant status and impaired PedsQL total and subscales scores adjusted for confounding. Total score Psychosocial Health Physical Health Emotional functioning Social functioning School functioning Unadjusted model Non-Western 1.4 [ ] 1.2 [ ] 1.3[ ] 2.7 [ ] 1.2 [ ] 2.3 [ ] Models adjusting for confounding 1. Non-Western 2. Assistance with completion of PedsQL 1. Non-Western 2. RRT modality (dialysis vs. transplantation) 1.Non-Western 2. RRT modality (dialysis vs. transplantation) 3. Assistance with completion of PedsQL 1.9 [ ] 0.3 [ ] 1.3 [ ] 1.5 [ ] 1.8 [ ] 1.4 [ ] 0.3 [ ] 1.9 [ ] 0.2 [ ] 1.0 [ ] 3.0 [ ] 1.6 [ ] 2.9 [ ] 0.2 [ ] 1.6 [ ] 0.4[ ] 1.2 [ ] 1.6 [ ] 1.5 [ ] 1.5 [ ] 0.5 [ ] 3.6 [ ] 0.4 [ ] 2.5 [ ] 2.0 [ ] 3.3 [ ] 1.8 [ ] 0.4 [ ] 1.6 [ ] 0.3 [ ] 1.0 [ ] 2.7 [ ] 1.4 [ ] 2.5 [ ] 0.3 [ ] 2.7 [ ] 0.5 [ ] 2.2 [ ] 1.7 [ ] 2.6 [ ] 1.6 [ ] 0.6 [ ] 98

101 Children from non-western origin Limitations Some limitations of the study should be emphasized. Not all eligible families participated, and the participants were not a random sample of the entire population. The fact that we used the PedsQL in Dutch, French, German or English led to the exclusion of those non- Western immigrants who were not able to understand one of these languages. It is likely that the participating non-western patients represent a relatively well educated group, and, as a consequence, our findings may be too optimistic as this selection may have led to underrepresentation of children with a worse HRQoL. From each participant the first completed questionnaire was used in this study. This is a possible explanation for the difference in duration of RRT between the participants and non-participants. The centre from Cologne (Germany) joined the RICH-Q study in 2011, this explains the relatively small number of participants from Germany. Implications ESRD and its treatment both have a severe impact on the psychosocial development of children as it affects school and emotional functioning. The fact that non-western patients reported a lower HRQoL than their Western counterparts, especially on emotional and school functioning is extremely worrying. We need to raise awareness of this problem and give non-western children with ESRD special attention. To systematically assess psychosocial functioning, and to monitor children over time Patient Reported Outcomes (PROs) can be used by professionals in paediatric health care. In the past decades there has been a growing interest in these PROs as a tool for the paediatricians to discuss psychosocial issues during medical consultation 32. For example, a recent study investigating the effectiveness of the use of Health Related Quality of life (HRQoL) assessments for children with JIA in clinical practice, showed that providing information to paediatricians on a child s HRQoL, leads to significantly more discussion of emotional and social functioning during consultation and improves the child s, parent s, and paediatrician s satisfaction with the provided care 33. When paediatric psychologists and paediatricians work together, PROs can be used to closely monitor children with chronic illnesses in a multidisciplinary context and referral to psychosocial interventions can be better facilitated 33. What type of special care these children and families need is a subject for further investigation. Additional psycho-educational support and more stimulation and opportunity to attend school could be a helpful to enhance successful development towards independency in adulthood. To stimulate school performance, dialysis units should emphasize school activities during dialysis and maybe more tailor made lessons for non-western children should be developed. However, attending a regular school would always be preferable because of the social advantages of being with peers. One way of facilitating school attendance, if rapid transplantation is unachievable, would be to promote peritoneal dialysis or haemodialysis at home instead of centre haemodialysis. In conclusion, the present study shows a double disadvantage for non-western children with ESRD in HRQoL for school en emotional functioning. We believe that paediatric nephrologists and members of the multi-disciplinary team need to pay more attention to the development of emotional en school functioning in order to create conditions for an optimal HRQoL. 6 99

102 Chapter 6 Reference List 1. Schoenmaker NJ, Tromp WF, van der Lee JH et al. Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents. Pediatr Nephrol 2012; 27: Centraal Bureau Statistiek Nederland Tromp WF, Cransberg K, van der Lee JH et al. Fewer pre-emptive renal transplantations and more rejections in immigrant children compared to native Dutch and Belgian children. Nephrol Dial Transplant 2012; 27: Goldstein SL, Graham N, Warady BA et al. Measuring health-related quality of life in children with ESRD: performance of the generic and ESRD-specific instrument of the Pediatric Quality of Life Inventory (PedsQL). Am J Kidney Dis 2008; 51: Gerson A, Hwang W, Fiorenza J et al. Anemia and health-related quality of life in adolescents with chronic kidney disease. Am J Kidney Dis 2004; 44: Goldstein SL, Graham N, Burwinkle T, Warady B, Farrah R, Varni JW. Health-related quality of life in pediatric patients with ESRD. Pediatr Nephrol 2006; 21: Park KS, Hwang YJ, Cho MH et al. Quality of life in children with end-stage renal disease based on a PedsQL ESRD module. Pediatr Nephrol 2012; 8. Fielding D, Brownbridge G. Factors related to psychosocial adjustment in children with end-stage renal failure. Pediatr Nephrol 1999; 13: Morton MJ, Reynolds JM, Garralda ME, Postlethwaite RJ, Goh D. Psychiatric adjustment in end-stage renal disease: a follow up study of former paediatric patients. J Psychosom Res 1994; 38: Henning P, Tomlinson L, Rigden SP, Haycock GB, Chantler C. Long term outcome of treatment of end stage renal failure. Arch Dis Child 1988; 63: Reynolds JM, Morton MJ, Garralda ME, Postlethwaite RJ, Goh D. Psychosocial adjustment of adult survivors of a paediatric dialysis and transplant programme. Arch Dis Child 1993; 68: Tromp WF, van der Lee JH, Offringa M et al. Lessons learned from efforts to improve the quality of care in children with end-stage renal disease in the Netherlands and Belgium. Arch Dis Child 2011; 96: Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001; 39:

103 Children from non-western origin 14. Goldstein SL, Rosburg NM, Warady BA et al. Pediatric end stage renal disease healthrelated quality of life differs by modality: a PedsQL ESRD analysis. Pediatr Nephrol 2009; 24: Engelen V, Haentjens MM, Detmar SB, Koopman HM, Grootenhuis MA. Health related quality of life of Dutch children: psychometric properties of the PedsQL in the Netherlands. BMC Pediatr 2009; 9: Cohen J. A power primer. Psychol Bull 1992; 112: Altman DG, Bland JM. Standard deviations and standard errors. BMJ 2005; 331: Neul SK, Minard CG, Currier H, Goldstein SL. Health-related quality of life functioning over a 2-year period in children with end-stage renal disease. Pediatr Nephrol 2012; 19. Pantzer K, Rajmil L, Tebe C et al. Health related quality of life in immigrants and native school aged adolescents in Spain. J Epidemiol Community Health 2006; 60: Nesterko Y, Braehler E, Grande G, Glaesmer H. Life satisfaction and health-related quality of life in immigrants and native-born Germans: the role of immigration-related factors. Qual Life Res 2012; 21. Hijmans CT, Fijnvandraat K, Oosterlaan J, Heijboer H, Peters M, Grootenhuis MA. Double disadvantage: a case control study on health-related quality of life in children with sickle cell disease. Health Qual Life Outcomes 2010; 8: van Dellen QM, Stronks K, Bindels PJ, Ory FG, Bruil J, van Aalderen WM. Predictors of asthma control in children from different ethnic origins living in Amsterdam. Respir Med 2007; 101: van Dellen QM, van Aalderen WM, Bindels PJ, Ory FG, Bruil J, Stronks K. Asthma beliefs among mothers and children from different ethnic origins living in Amsterdam, the Netherlands. BMC Public Health 2008; 8: Lopes AA, Bragg-Gresham JL, Satayathum S et al. Health-related quality of life and associated outcomes among hemodialysis patients of different ethnicities in the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2003; 41: Brownbridge G, Fielding DM. Psychosocial adjustment and adherence to dialysis treatment regimes. Pediatr Nephrol 1994; 8: Gerson AC, Butler R, Moxey-Mims M et al. Neurocognitive outcomes in children with chronic kidney disease: Current findings and contemporary endeavors. Ment Retard Dev Disabil Res Rev 2006; 12:

104 Chapter Chau K, Baumann M, Kabuth B, Chau N. School difficulties in immigrant adolescent students and roles of socioeconomic factors, unhealthy behaviours, and physical and mental health. BMC Public Health 2012; 12: Driessen G. Family and Child Characteristics, Child-Rearing Factors, and Cognitive Competence of Young Children. Early Child Development and Care, 2003; Volume 173, Numbers 2-3: Williams DR. Race/ethnicity and socioeconomic status: measurement and methodological issues. Int J Health Serv 1996; 26: Nazroo JY. The structuring of ethnic inequalities in health: economic position, racial discrimination, and racism. Am J Public Health 2003; 93: Reijneveld SA. Reported health, lifestyles, and use of health care of first generation immigrants in The Netherlands: do socioeconomic factors explain their adverse position? J Epidemiol Community Health 1998; 52: Haverman L, Engelen V, van Rossum MA, Heymans HS, Grootenhuis MA. Monitoring health-related quality of life in paediatric practice: development of an innovative webbased application. BMC Pediatr 2011; 11: Haverman L, Verhoof EJ, Maurice-Stam H et al. Health-related quality of life and psychosocial developmental trajectory in young female beneficiaries with JIA. Rheumatology (Oxford) 2012; 51:

105 Children from non-western origin Appendix 1: PedsQL 4.0 Generic Core Scales Child Self-Report Item Content. Physical Functioning Scale Never - almost never - sometimes - often - almost always 1. It is hard for me to walk more than one block 2. It is hard for me to run 3. It is hard for me to do sports activity or exercise 4. It is hard for me to lift something heavy 5. It is hard for me to take a bath or shower by myself 6. It is hard for me to do chores around the house 7. I hurt or ache 8. I have low energy Emotional Functioning Scale 1. I feel afraid or scared 2. I feel sad or blue 3. I feel angry 4. I have trouble sleeping 5. I worry about what will happen to me Social Functioning Scale 1. I have trouble getting along with other kids 2. Other kids do not want to be my friend 3. Other kids tease me 4. I cannot do things that other kids my age can do 5. It is hard to keep up when I play with other kids School Functioning Scale 1. It is hard to pay attention in class 2. I forget things 3. I have trouble keeping up with my schoolwork 4. I miss school because of not feeling well 5. I miss school to go to the doctor or hospital 6 PedsQL is available at website Varni and Burwinkle Health and Quality of Life Outcomes :26 doi: /

106 Chapter 6 Appendix 2: Demographic characteristics of non-westerns and Western participants and their parents. Origin of Parents Country of birth of the child Highest educational attainment of the parents: - Post secondary education - Other - Information missing Work situation: - Unemployed - Employed - Information missing Parental marital status: - Married/ living together - Not living together - Information missing Number of children - More than 2 children - 1 or 2 children -missing Non-Western participants N=55 Belgium: 1 (adoption) Morocco: 11 Turkey: 10 Surinam: 7 Dutch Antilles or Caribbean:3 Asia: 3 Africa (other): 10 Middle East (other):9 The Netherlands: 23 Belgium: 6 Germany: 0 Morocco: 3 Turkey: 1 Surinam: 3 Asia: 2 Dutch Antilles or Caribbean: 3 Africa (other): 7 Middle East (other):7 Western participants N=119 The Netherlands: 71 Belgium: 40 Germany: 6 Spain: 1 Greece: 1 The Netherlands: 73 Belgium: 40 Germany: 5 Greece: 1 N % N % P Value b b 0.22 b 0.56 b Parents/ patient had Assistance with completion of PedsQL b Assistance from: - Doctor/ nurse - Family/Friends - Other Number of school days missed in last 3 months (1-92) (1-92) a Mann Whitney U, b Chi Square, excluding missing values <0.001 b 0.64 a 104

107 Children from non-western origin Appendix 3. Mean (sd) and median [range] PedsQL score for all (non-western and Western) children with ESRD and the healthy non-western children from the Dutch norm population. ESRD group Healthy Dutch Norm group Non-Western children N=51 Western participants N=119 Non-Western participants N=55 Mean (SD) Median [range] Mean (SD) Median [range] Mean (SD) Median [range] Age 12.0 [ ] 13.8 [ ] 12.9 [ ] Total Score (17.0) 66.3 [21-99] 85.9 [57-100] 67.4 [32-92] 85.6 (9.4) (15.5) Psychosocial Health 65.7 (15.0) 66.7 [38-93] 67.1 (15.6) 66.7 [18-100] 84.2 (11.1) 85.0 [47-100] Physical health 67.4 (19.1) 68.8 [19-97] 64.4 (24.4) 65.6 [0-100] 88.1 (8.8) 87.5 [63-100] Emotional functioning 64.4 (17.5) 60.0 [25-100] 67.1 (19.1) 65.0 [10-100] 80.8 (15.5) 85.0 [40-100] Social functioning 73.9 (20.3) 80.0 [30-100] 73.4* (17.7) 75.0* [25-100] 91.0 (11.7) 95.0 [40-100] School functioning 58.7 (17.2) 60.0 [25-94] 61.7** (18.6) 60.0** [15-100] 80.7 (11.4) 80.0 [50-100] *Social functioning is missing in one Western child with ESRD, **School functioning is missing in two Western children with ESRD, data is presented in median [range], ESRD= end stage renal disease 6 105

108 106

109 7Low agreement between cardiologists diagnosing left ventricular hypertrophy in children with Endstage renal disease Nikki J. Schoenmaker 1, Johanna H. van der Lee 2, Jaap W. Groothoff 1, Gabrielle G. van Iperen 3, Ingrid M.E. Frohn-Mulder 4, Ronald B.Tanke 5, Jaap Ottenkamp 6, and Irene M. Kuipers 6 1 Department of Paediatric Nephrology, Emma Children s Hospital AMC Amsterdam, 2 Department of Paediatric Clinical Epidemiology, Emma Children s Hospital AMC Amsterdam, 3 Department of Paediatric Cardiology, Wilhelmina Children s Hospital UMCU, Utrecht, 4 Department of Paediatric Cardiology, Erasmus MC Sophia, Rotterdam, 5 Department of Paediatric Cardiology, UMC st. Radboud, Nijmegen, 6 Department of Paediatric Cardiology, Emma Children s Hospital AMC Amsterdam Revision BMC Nephrology 107

110 Chapter 7 Abstract Background Monitoring of the appearance of left ventricular hypertrophy (LVH) by echocardiography is currently recommended for the management of children with End-stage renal disease (ESRD). In order to investigate the validity of this method in ESRD children, we assessed the intra- and inter-observer reproducibility of the diagnosis LVH. Methods Echocardiographic measurements in 92 children (0-18 years) with ESRD, made by original analysists, were reassessed offline, twice, by 3 independent observers. Smallest detectable changes (SDC) were calculated for continuous measurements of diastolic interventricular septum (IVSd), Left ventricle posterior wall thickness (LVPWd), Left ventricle end-diastolic diameter (LVEDd), and Left ventricle mass index (LVMI). Cohen s kappa was calculated to assess the reproducibility of LVH defined in two different ways. LVH WT was defined as Z-value of IVSd and/or LVPWd>2 and LVH MI was defined as LVMI> 103 g/m 2 for boys and >84 g/m 2 for girls. Results The intra-observer SDCs ranged from 1.6 to 1.7 mm, 2.0 to 2.6 mm and 17.7 to 30.5 g/m 2 for IVSd, LVPWd and LVMI, respectively. The inter-observer SDCs were 2.6 mm, 2.9 mm and 24.6 g/m 2 for IVSd, LVPWd and LVMI, respectively. Depending on the observer, the prevalence of LVH WT and LVH MI ranged from 2 to 30% and from 8 to 25%, respectively. Kappas ranged from 0.4 to 1.0 and from 0.1 to 0.5, for intra-and inter- observer reproducibility, respectively. Conclusions Changes in diastolic wall thickness of less than 1.6 mm or LVMI less than 17.7 g/m 2 cannot be distinguished from measurement error in individual children, even when measured by the same observer. This limits the use of echocardiography to detect changes in wall thickness in children with ESRD in routine practice. 108

111 Cardiac monitoring Introduction Cardiovascular disease is the leading cause of death in patients with end-stage renal disease (ESRD) 1;2. In Juvenile ESRD, the mortality associated with cardiac disease is reported to be times higher than in the general age-matched population 3. Left ventricular hypertrophy (LVH) is an indicator of cardiovascular disease and is independently associated with an increased mortality in adults with ESRD 4. Echocardiography studies have shown that patients with ESRD have abnormalities of both left ventricular (LV) structure and function 5. Several factors may be responsible for cardiac disease in ESRD, such as hypertension, anaemia, hyperphosphatemia, and a high parathyroid hormone (PTH) 6. In adult-onset ESRD, therapeutic interventions, such as an increase of the dialysis frequency and a stricter control of hypertension, hyperphosphatemia and anaemia have been proven effective in reducing cardiac mortality after LVH is established 7. Recently, Mitsnefes et al. emphasized the importance of frequent dialysis in children 8. Small single-centre studies have shown clinical improvements in LVH and function when children receive dialysis more frequently than the traditional, thrice-weekly schedule 9;10. Timely detection of cardiovascular disease in children with ESRD would therefore give an opportunity for targeted intervention in the highrisk patients, thereby preventing cardiovascular morbidity and mortality in early adulthood. LVH, diagnosed with echocardiography, is considered to be a reliable surrogate outcome marker for cardiac disease in ESRD. Only recently, Chavers et al. have proposed the performance of periodic routine echocardiography in all children with ESRD, to detect cardiac disease at an early stage 11. In the Netherlands, Belgium and Germany, the most widely used definition of LVH in children is based on the M-mode echocardiographic measurement of the interventricular septum thickness (IVSd) and left ventricular posterior wall in diastole (LVPWd). In the Netherlands, there are normal values for Dutch healthy children according to weight 12. In many clinical trials and epidemiological studies LVH was defined based on the LV Mass (LVM) 13;14. The interpretation of the LVM in children is challenging because such values need to be appropriately indexed for body size. Various different methods of indexing LVM to body size have been reported, including adjustment for body surface area (BSA) 15 and height ;17. The definition of LVH is a matter of ongoing controversy 17;18, especially in possibly growth-retarded children 19;20. In a project on quality assessment in children with end-stage renal disease, the RICH-Q project (Renal Insufficiency Therapy in Children: Quality Assessment and Improvement) 21, in which all Dutch centres for paediatric renal replacement therapy participate, we observed an unexpectedly large variation in the prevalence of LVH, using one definition, among all the Dutch centres. This raised questions about the reliability of the measurements. We therefore decided to investigate the intra- and inter-observer reproducibility of the measurements of left ventricular wall thicknesses during echocardiography and of the diagnosis LVH. 7 Methods Study Participants We included all children (0-18 years) treated with renal replacement therapy (RRT) between August 1 st 2007 and January 1 st 2011 in the Netherlands in the study. Written informed consent from the parents and/or the participants and approval from the ethical boards of all 109

112 Chapter 7 participating hospitals were obtained. For patients whose parents have provided informed consent, data on the routinely performed paediatric echocardiography are registered centrally in the RICH-Q project 21. Data Collection We reviewed one echocardiogram per subject. The recording and analysis of the echocardiograms had been performed by paediatric cardiologists ( original analysts ) in all 4 Dutch centres using either Vivid 7 (GE Medical Systems, Wauwatosa, WI) or Philips Sonos 5500, (Medical Systems, Andouver) ultrasound systems. Two-dimensionally guided M-mode echocardiography was performed from a parasternal long- axis view. Interventricular septum thickness in diastole (IVSd) in mm, left ventricular posterior wall thickness in diastole (LVPWd) in mm and left ventricular end-diastolic diameter (LVEDd) in mm were measured at end-diastole at the level just below the mitral valve leaflets. A simultaneous electrocardiogram (ECG) was used for the timing of the measurements in the cardiac cycle. The diastolic wall thickness was measured at the onset of the QRS wave of the ECG 22. Digital images were stored and analyzed offline, using EchoPac (General Electric Medical Systems), by three independent observers. Observers 1 and 2 were paediatric cardiologists, each with more than 12 years of experience in interpreting paediatric echocardiograms. Observer 3 was a research physician specifically trained in echocardiography. Each variable, i.e. IVSd, LVPWd and LVEDd, was measured three times and the mean was calculated. LV mass was calculated using the following equation: LV mass (grams) = 0.8 (1.04 ([LVEDd + IVSd + LVPWd] 3 [LVEDd] 3 )) g 23. To account for body size, the LV mass index (LVMI) (g/m 2 ) was calculated by dividing LV mass by body surface area (BSA). Two definitions were used for diagnosing LVH, one is based on the wall thicknesses of IVSd and LVPWd (LVH WT ) and the other on LVMI (LVH ). LVH was defined as a Z-score of either IVSd or LVPWd > MI WT + 2 based on a set of normal values of healthy Dutch children, corrected for weight, from Overbeek et al. 12. LVH MI was defined as LVMI > 103 g/m 2 for boys and > 84 g/m 2 for girls 16. Observers 1, 2 and 3 reassessed all echocardiograms in a randomly different order after a period of at least two weeks to preclude recollection of the values. This was the first part of the study. Usually the echocardiographic measurements are made by a cardiologist who stores 3 images, each representing 3 heart cycles. Each image is accompanied by the corresponding ECG. The cardiologist chooses one of the 3 onsets of the QRS wave of the ECG in 1 of the 3 images for measurement of the diastolic wall thickness which he considers appropriate for measurement. This procedure is based on the presumption that the variation between the M-mode images is of no influence on the measurement of the wall thickness. If this presumption would not be true, exclusion of this source of variation might improve the reproducibility of the measurement. Therefore we designed the second part of the study, in which observers 1 and 2 assessed one specific pre-selected image from each of twenty echocardiograms twice with a period of at least two weeks in between. The 20 echocardiograms were selected based on the range of Z-scores of IVSd, LVPWd and LVEDd to represent the entire range of the wall thickness in the patient population. From each echocardiogram, observer 2 selected one exact point of one heartbeat cycle in 1 image. Both observers measured IVSd, LVPWd and LVEDd at exactly the same point in that specific image three times and the mean was calculated. 110

113 Cardiac monitoring Statistical Analysis Intra- and inter-observer reproducibility of the continuous measures IVSd, LVEDd, LVPWd and LVMI was assessed by the Bland Altman method. The limits of agreement (LoA) are calculated as the mean difference in scores of repeated measurements (mean) ± 2 standard deviation of these differences (SD diff ) 24. The variability of the measurement is also reported as Smallest Detectable Change (SDC), calculated as standard error of measurement (SEM). SEM is the square root of the error variance calculated by analysis of variance (ANOVA). SDC reflects the smallest within-person change in score that, with P < 0.05, can be interpreted as a real change, above measurement error, in one individual (SDC ind ) 24 Cohen s kappa was calculated to assess intra- and inter-observer agreement for dichotomous variables, i.e. presence or absence of LVH. The interpretation of kappa is arbitrary. A value of 0.70 is generally recommended as a minimum standard for reliability 25. Results Ninety-two children with ESRD (0-18 years old) were included. Fifty one (55%) were boys; the median (range) age, weight and BSA were 13.1 ( ) years, 37.8 ( ) kg and 1.2 ( ) m 2, respectively. The median (range) duration of RRT was 1.8 (0-6.8) years. At time of the echocardiography, 26 children (28%) were treated with haemodialysis, 24 (26%) with peritoneal dialysis and 42 (46%) were transplanted. The results of the intra- and inter-observer reproducibility are shown in Table 1. The IVSd and LVPWd measurements of observer 2 were consistently smaller than those of observers 1 and 3. The intra-observer SDCs ranged from 1.6 to 1.7 mm, from 2.0 to 2.6 mm, from 2.8 to 6.9 mm and from 17.7 to 30.5 g/m 2 for IVSd, LVPWd, LVEDd and LVMI, respectively. The intra-observer kappas for the 3 observers for LVH WT and LVH MI ranged from 0.4 to 1.0 and from 0.5 to 0.6, respectively. The inter-observer SDCs were 2.6 mm, 2.9 mm, 5.9 mm and 24.6 g/m 2 for IVSd, LVPWd, LVEDd and LVMI, respectively. The inter-observer kappas for LVM WT and LVH MI ranged from 0.1to 0.4 and from 0.3 to 0.5, respectively. 7 Selected image of 20 selected patients From the 20 children whose echocardiograms were selected for the second part of the study, 10 (50%) had been diagnosed with LVH WT by the original observer. The results of the intra- and inter-observer reproducibility study are shown in Table 2. None of the reproducibility results were superior to those of the first part of the study, in which each observer chose the images to be measured. The results of the assessment of diagnosing LVH by the original analyst, observers 1, 2 and 3 of all 92 echocardiograms are shown in Table 3. The prevalence of LVH WT and LVH MI ranged from 2 to 30% and from 8 to 25% of the 92 patients, respectively. All 4 observers (the original analyst, observers 1, 2 and 3) agreed in 46 patients and 56 patients by diagnosing non LVH WT and non LVH MI, respectively. All 4 observers agreed in 2 patients and in 6 patients by diagnosing LVH WT and LVH MI, respectively. Use of the LVH WT definition resulted in a higher prevalence for two observers and a lower prevalence for the other two observers and vice versa, indicating that there is not a simple relation between the two definitions. 111

114 Chapter 7 Table 1. Intra- and inter-observer reproducibility of echocardiographic measurements. Part 1 (n=92) Intra-observer Observer 1 Observer 2 Observer 3 IVSd (mm) Median (range) 7.0 ( ) 6.1 ( ) 6.9 ( ) Mean diff. [95%CI] 0.2 [ ] 0.1 [ ] 0.1 [ ] LoA SDC LVPWd (mm) Median (range) 7.0 ( ) 5.9 ( ) 7.9 ( ) Mean diff. [95%CI] 0.4 [ ] 0.3 [ ] 0.1 [ ] LoA SDC LVEDd (mm) Median (range) 41 (21-59) 44 (23-63) 41 (20-57) Mean diff. [95%CI] 0.9 [ ] 0.2 [ ] 0.2 [ ] LoA SDC LVMI Median (range) 76 (34-219) 70 (39-181) 80 (31-255) (g/m 2 ) Mean diff.[95%ci] 1.1 [ ] 0.7 [ ] 0.7 [ ] LoA SDC LVH WT Kappa [95%CI] 0.4 [ ] 1.0 [ ] 0.4 [ ] LVH MI Kappa [95%CI] 0.6 [ ] 0.6 [ ] 0.5 [ ] Inter-observer Observer 1 vs 2 Observer 1 vs 3 Observer 2 vs 3 IVSd (mm) Mean diff. [95%CI] 1.0 [ ] 0.1 [ ] 1.1 [ ] LoA SDC (3 observers) 2.6 LVPWd (mm) Mean diff. [95%CI] 1.0 [ ] 0.6 [ ] 1.6 [ ] LoA SDC (3 observers) 2.9 LVEDd (mm) Mean diff. [95%CI] 2.4 [ ] 0.3 [ ] 2.7 [ ] LoA SDC (3 observers) 5.9 LVMI (g/ m 2 ) Mean diff. [95%CI] 6.5 [ ] 4.0 [ ] 10.6 [ ] LoA SDC (3 observers) 24.6 LVH WT Kappa [95%CI] 0.1 [ ] 0.4 [ ] 0.1 [ ] LVH MI Kappa [95%CI] 0.3 [ ] 0.5 [ ] 0.4 [ ] IVSd: diastolic interventricular septum, LVEDd: left ventricular end-diastolic diameter, LVPWd: diastolic left ventricular posterior wall thickness, LVMI: left ventricular mass index, Mean diff: mean difference, CI: confidence interval, LoA : limits of agreement, SDC: smallest detectable change. LVH WT was defined as a Z-score of IVSd and\ or LVPWd > + 2 (according to normal values of healthy Dutch children). LVH MI was defined as LV mass index (g/m 2 ) > 103 g/m 2 for boys and > 84 g/m 2 for girls 112

115 Cardiac monitoring Table 2. Intra- and inter-observer reproducibility based on identical images. Part 2 (n=20) Intra-observer Observer 1 Observer 2 IVSd (mm) Median (range) 7.5 ( ) 7.4 ( ) Mean diff. (95%CI) 0.2 ( ) 0.4 ( ) LoA SDC LVPWd (mm) Median (range) 6.9 ( ) 7.1 ( ) Mean diff. (95%CI) 0.4( ) 0.5 ( ) LoA SDC LVEDd (mm) Median (range) 43.2 ( ) 43.9 ( ) Mean diff. (95%CI) 0.4 ( ) 0.6 ( ) LoA SDC LVMI Median (range) 79 (45-226) 82 (47-221) (g/m 2 ) Mean diff. (95%CI) 4.0 ( ) 4.7 ( ) LoA SDC Inter-observer Observer 1 vs 2 IVSd (mm) Mean diff (95%CI) 0.4 ( ) LoA SDC 1.6 LVPWd (mm) Mean diff. (95%CI) 0.3 ( ) LoA SDC 1.9 LVEDd (mm) Mean diff. (95%CI) 1.5 ( ) LoA SDC 3.4 LVMI Mean diff. (95%CI) 0.1 ( ) (g/m 2 ) LoA SDC IVSd: diastolic interventricular septum, LVEDd: left ventricular end-diastolic diameter, LVPWd: diastolic left ventricular posterior wall thickness, LVMI: Left ventricular mass index, Mean diff: mean difference, CI: confidence interval, LoA: limits of agreement, SDC: smallest detectable change. 113

116 Chapter 7 Table 3. Prevalence of Left ventricular hypertrophy according to different definitions and different observers Observer LVH WT^ (%) n=92 # LVH MI (%) n=92 Kappa between LVH WT and LVH MI Original 28 (30%) 22 (24%) 0.62 analyst* 1 20 (22%) 23 (25%) (2%) 7 (8%) (29%) 22 (24%) 0.42 *The treating cardiologist who made the echocardiogram, LVH=left ventricular hypertrophy, ^LVH WT was defined as a Z-score of IVSd and/or LVPWd > + 2 (according to normal values of healthy Dutch children), # LVH MI was defined as LV mass index >103 g/m 2 for boys and >84 g/m 2 for girls Discussion We found a low reproducibility of the measurement of ventricular wall thickness, and as a result low agreement within and between observers in diagnosing LVH using conventional echocardiography in children with ESRD. The inaccurateness of the wall thickness measurements affects LVH assessment for all different definitions of LVH. Our data demonstrate that in individual children, changes in diastolic wall thickness or LVMI as a result of ESRD which are expected over a period of a year cannot be distinguished from measurement error, even when measured by the same observer. With more than 30 years of clinical use, echocardiography has become one of the most important non-invasive imaging methods in the evaluation of cardiac morphology and dynamics. It is generally considered a valuable method for the detection of LVH, due to its wide availability, non-invasiveness, and relatively low cost. However, in children the interpretation of echocardiographic data is hampered by various problems. First, according to our study, the variability of outcomes even within one experienced observer is of such magnitude that expected changes in wall thickness can not be monitored reliably. The intra-and inter-observer SDCs of the echocardiographic measurement of the IVSd and the LVPWd ranged from 1.6 to 2.6 mm and 2.0 to 2.9 mm, respectively. In an individual child only changes in septum or wall thickness larger than the SDC can be considered as real change. Since in children the normal values of IVSd and LVPWd are small, ranging from 3 to 10 mm and from 3 to 13 mm respectively, changes over time in an individual child need to be as large as 16 to 100% of the normal value before they can be considered as real change, i.e., not due to measurement variability. The intra-and inter-observer SDC of the LVMI ranged from 17.7 to 30.5 g/m 2. Similarly, since in children the normal values of LVMI are 40 to 80 g/m2, changes over time in an individual child need to be as large as 30-60% of the normal value before they can be considered as real change. Secondly, there is little consensus about the definition of LVH in children. In adults LVH is 114

117 Cardiac monitoring usually defined as LVMI > 51 (g/m 2.7 ), which is associated with increased cardiovascular morbidity and mortality 26. In children, LVH is based on the normal distribution of LVMI or wall thickness in healthy children, because cardiovascular outcome studies in children are lacking due to the low incidence of cardiovascular events. Some physicians define LVH as LVM according to Devereux corrected for body size above a cutoff value (> 51 g/m 2.7 or 38.6 g/ m 2.7 ) or above the P95 of healthy children for age. Yet, different indexations with respect to body size are used. All these different indexes for LVM lead to important differences in LVH prevalence, varying from 18% to 55% in children with chronic kidney disease 20 and from 27% to 52% in children on peritoneal dialysis 19. In 2009 Khoury et al. reported normal values for LVM indexed for height in children between 0 and 18 years of age 18. As LVM indexed for weight or BSA had been found not to be accurate in children with obesity 27, it is conceivable that Khoury s normal values are not applicable in growth-retarded (ESRD) children either. Borzych et al. showed that when using the Khoury charts, LVH prevalence was significantly higher in growth-retarded children on peritoneal dialysis than in children on peritoneal dialysis of normal height 28. Another approach to the definition of LVH is using z-scores of only the septal and/or posterior wall thickness as measure for LVH. In this definition, the effect of changes in left ventricular end-diastolic volume is neglected. Since ventricular dilatation leads to wall thinning, LVH may be missed in dilated cardiomyopathy by this method. In the present study we used LVM indexed for BSA because in our opinion height and weight allow a better estimation of lean body mass, and therefore heart size, than height 2.7 in children with possible growth retardation 17. Our results are in line with other studies. In two studies in healthy children, intra-observer variance was found to be smaller than inter-observer variance, as is usually the case 29;30. In the study by Schieken et al. 29 the intra-observer SDC was 1.7 mm for both IVSd and LVP- Wd. An explanation for this relatively high reproducibility might be that the data from the Schieken et al. s study were derived from a selection of 20 out of 28 echocardiograms, which satisfied the criteria for technical acceptability. Inter-observer SDCs were comparable with our findings. In the study by Day et al. 30 the intra-observer mean differences were equal to those found in our study, but the inter-observer mean differences were considerably larger. Still, the authors concluded that the echocardiographic measurements taken from healthy children in a longitudinal study can be made accurately with acceptable reproducibility. The reproducibility of the LV mass is highly dependent on the reproducibility of IVSd and LVPWd. In M-mode measurements, differences of IVSd and LVPWd of approximately 5% may be translated into differences in LV mass between 8% and 15%, which may represent about 50 g in adults 31. Thus, measurement inaccuracies in individual adult patients limit the use of the Devereux formula to calculate LV mass 31. Test-retest studies in adults indeed found differences of up to 30 g between tests 32;33. Therefore the authors of the reliability of M-Mode echocardiography studies (the RES trial) concluded that the probability of a true change in LV mass over time is maximized for a single-reader difference greater than 18% of the initial value. 7 Theoretically there are several sources of variability that can influence echocardiographic measurements. In our study the following sources of variation were excluded by the design of offline assessment of the stored images: placing of the echocardiogram probe, the way the images are captured and obviously within-patient variability like day-to-day variability in 115

118 Chapter 7 fluid status (e.g. before or after dialysis) and blood pressure. To minimize other sources of variation, such as timing in the cardiac cycle, all measurements were made according to the Guidelines and Standards for Performance of a Paediatric Echocardiogram of the American Society of Echocardiography 7. In these guidelines, the exact choice of the images and heart cycles within one assessment on which the calculations are based is not defined. We therefore adjusted the protocol in part two of the study to exclude any potential variability due to the choice of the image and heart cycle. This did not lead to improvement of the reproducibility results, indicating that the variability is inherent in the measurement procedure, and not due to the choice of the particular image. To improve reproducibility the standard method is to measure multiple heart cycles and calculate the mean value, as was done in our study. In addition, some authors even advise interpretation by more than one cardiologist 34. Others, however, advise that the same cardiologist reads all the echocardiograms for an individual patient to reduce the variability of the longitudinal measurements 35. This is unfortunately not supported by the low intra-observer reproducibility that we found. In 2010 Lopez et al. developed recommendations for quantifications during the performance of a paediatric echocardiogram 36. However, these recommendations are based on 2D or 3D short axis imaging, while in Europe M-mode echocardiography is still the most used technique. To date, it has to be established if 2D or 3D echocardiography is indeed better reproducible than M-mode echocardiography. A limitation of this study is that the original echocardiograms were assessed retrospectively without the original observers knowing this would be a reproducibility study. The observers 1, 2 and 3 were aware of the fact this was a reproducibility study. This could be an explanation of the differences between the original observer and the other observers. Furthermore, Cohen s kappa gives a quantitative assessment of how well two raters agree corrected for chance agreement. The interpretation of kappa is arbitrary. Several difficulties have been described with the interpretation of kappa, however, one of which is related to the prevalence of the condition 37;38. If only the most severe cases are diagnosed as LVH as was done by observer 2, the intra-observer kappa is inflated. Conclusions Our study has important clear implications. The need for cardiovascular monitoring in children with ESRD is beyond discussion. Timely detection of left ventricular abnormalities may decrease the risk for early cardiac death by therapeutic adjustments such as more frequent dialysis, conversion from peritoneal dialysis to (frequent) haemodialysis, dietary measures or adjustment of medication. In this respect, routinely yearly echocardiography in children with ESRD has been promoted. Yet we believe that LVH assessment by conventional echocardiography in an individual child with ESRD may too easily result in either underreporting of LVH or in an spurious diagnosis of LVH. This may either lead to a potentially preventable deterioration of cardiac function or to unnecessary interventions with potential burdens for the patient. We therefore believe that new, more sensitive tools (e.g. 3D echocardiography, Tissue Doppler imaging and Speckle Tracking Echocardiography) need to be explored as reliable tools for longitudinal cardiac follow-up in these children. 116

119 Cardiac monitoring Reference List 1. Groothoff JW, Gruppen MP, Offringa M et al. Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study. Kidney Int 2002; 61: McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350: Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112-S Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322: Johnstone LM, Jones CL, Grigg LE, Wilkinson JL, Walker RG, Powell HR. Left ventricular abnormalities in children, adolescents and young adults with renal disease. Kidney Int 1996; 50: O Regan S, Matina D, Ducharme G, Davignon A. Echocardiographic assessment of cardiac function in children with chronic renal failure. Kidney Int Suppl 1983; 15: S77-S82 7. Mitsnefes MM, Daniels SR, Schwartz SM, Meyer RA, Khoury P, Strife CF. Severe left ventricular hypertrophy in pediatric dialysis: prevalence and predictors. Pediatr Nephrol 2000; 14: Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012; 23: Hoppe A, von PC, Linke U et al. A hospital-based intermittent nocturnal hemodialysis program for children and adolescents. J Pediatr 2011; 158: 95-9, Fischbach M, Terzic J, Laugel V et al. Daily on-line haemodiafiltration: a pilot trial in children. Nephrol Dial Transplant 2004; 19: Chavers BM, Solid CA, Sinaiko A et al. Diagnosis of cardiac disease in pediatric end-stage renal disease. Nephrol Dial Transplant 2011; 26: Overbeek LI, Kapusta L, Peer PG, de Korte CL, Thijssen JM, Daniels O. New reference values for echocardiographic dimensions of healthy Dutch children. Eur J Echocardiogr 2006; 7: Lang RM, Bierig M, Devereux RB et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiol- 117

120 Chapter 7 ogy. J Am Soc Echocardiogr 2005; 18: Gottdiener JS, Bednarz J, Devereux R et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004; 17: Sluysmans T, Colan SD. Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 2005; 99: Daniels SR, Kimball TR, Morrison JA, Khoury P, Meyer RA. Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease. Am J Cardiol 1995; 76: Foster BJ, Mackie AS, Mitsnefes M, Ali H, Mamber S, Colan SD. A novel method of expressing left ventricular mass relative to body size in children. Circulation 2008; 117: Khoury PR, Mitsnefes M, Daniels SR, Kimball TR. Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr 2009; 22: Borzych D, Bakkaloglu SA, Zaritsky J et al. Defining left ventricular hypertrophy in children on peritoneal dialysis. Clin J Am Soc Nephrol 2011; 6: Simpson JM, Savis A, Rawlins D, Qureshi S, Sinha MD. Incidence of left ventricular hypertrophy in children with kidney disease: impact of method of indexation of left ventricular mass. Eur J Echocardiogr 2010; 11: Tromp WF, van der Lee JH, Offringa M et al. Lessons learned from efforts to improve the quality of care in children with end-stage renal disease in the Netherlands and Belgium. Arch Dis Child 2011; 96: Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M- mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: Devereux RB, Alonso DR, Lutas EM et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: Terwee CB, Bot SD, de Boer MR et al. Quality criteria were proposed for measurement properties of health status questionnaires. J Clin Epidemiol 2007; 60: de SG, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995; 25:

121 Cardiac monitoring 27. de Simoni G, Daniels SR, Devereux RB et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992; 20: Borzych D, Bakkaloglu SA, Zaritsky J et al. Defining left ventricular hypertrophy in children on peritoneal dialysis. Clin J Am Soc Nephrol 2011; 6: Schieken RM, Clarke WR, Mahoney LT, Lauer RM. Measurement criteria for group echocardiographic studies. Am J Epidemiol 1979; 110: Dai S, Ayres NA, Harrist RB, Bricker JT, Labarthe DR. Validity of echocardiographic measurement in an epidemiological study. Project HeartBeat! Hypertension 1999; 34: Stollberger C, Hollander I, Dimitrov L, Slany J. Influence of measurement inaccuracies on determination of left ventricular mass by M mode echocardiography. Heart 1996; 75: Palmieri V, Dahlof B, DeQuattro V et al. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomized Study Evaluating Regression of Ventricular Enlargement. J Am Coll Cardiol 1999; 34: de SG, Muiesan ML, Ganau A et al. Reliability and limitations of echocardiographic measurement of left ventricular mass for risk stratification and follow-up in single patients: the RES trial. Working Group on Heart and Hypertension of the Italian Society of Hypertension. Reliability of M-mode Echocardiographic Studies. J Hypertens 1999; 17: Di BM, Pozzi C, Cavallini MC et al. The diagnosis of heart failure in the community. Comparative validation of four sets of criteria in unselected older adults: the ICARe Dicomano Study. J Am Coll Cardiol 2004; 44: Grandits GA, Liebson PR, Dianzumba S, Prineas RJ. Echocardiography in multicentre clinical trials: experience from the Treatment of Mild Hypertension Study. Control Clin Trials 1994; 15: Lopez L, Colan SD, Frommelt PC et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010; 23: Kwiecien R, Kopp-Schneider A, Blettner M. Concordance analysis: part 16 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2011; 108: Byrt T, Bishop J, Carlin JB. Bias, prevalence and kappa. J Clin Epidemiol 1993; 46:

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123 8Diastolic dysfunction measured by Tissue Doppler imaging in children with End-stage renal disease- A report of the RICH-Q study Nikki J. Schoenmaker 1, Irene M. Kuipers 2, Johanna H. van der Lee 3, Wilma F. Tromp 1, Maria van Dyck 4, Marc Gewillig 5, Nico A. Blom 2 and Jaap W. Groothoff 1. 1 Department of Paediatric Nephrology, Emma Children s Hospital AMC Amsterdam, the Netherlands, 2 Department of Paediatric Cardiology, Emma Children s Hospital AMC Amsterdam, the Netherlands, 3 Department of Paediatric Clinical Epidemiology, Emma Children s Hospital AMC Amsterdam, the Netherlands, 4Department of Paediatric Nephrology, University Hospital Leuven, Belgium, 5 Department of Paediatric Cardiology, University Hospital Leuven, Belgium. Cardiology in the Young March 5: 1-7,

124 Chapter 8 Abstract Introduction Early detection of cardiovascular disease in children with End-stage renal disease is essential in order to prevent cardiovascular morbidity and mortality in early adulthood. Tissue Doppler imaging has shown to be a promising method to detect and quantify subtle abnormalities in diastolic function. We therefore compared assessment of diastolic function by conventional echocardiography and Tissue Doppler imaging. Methods We performed conventional echocardiography and Tissue Doppler imaging in 38 children with End-stage renal disease and 76 healthy controls. We compared outcomes on parameters related to diastolic function (E/a ratio for conventional echocardiography and E/E ratio for Tissue Doppler imaging) for both groups using multiple linear regression analysis. Diastolic dysfunction was defined as E/a ratio<1 or E/E ratio> 95th percentile for age. To assess the intra observer reproducibility the coefficient of variation was calculated. Results Children with End-stage renal disease had on average a lower E/a ratio (p=0.004) and a higher mitral and septal E/E ratio (both p<0.001) compared to controls. Two children with End-stage renal disease (5%) had diastolic dysfunction according to the E/a ratio, 11 according to the mitral E/E ratio (29%) and 16 according to the septal E/E ratio (42%) compared to none of the controls (p=0.109, p<0.001, and p<0.001 respectively). The coefficients of variation of the mitral (7%) and septal E/E ratio (4%), were smaller than the coefficient of variations of the E/a ratio (11%). Conclusions Tissue Doppler imaging is a more sensitive and reliable method to detect diastolic dysfunction than conventional E/a ratio in children with End-stage renal disease. 122

125 Cardiac monitoring Introduction Cardiovascular disease is the main cause of death in patients with End-stage renal disease since childhood 1. Left ventricular hypertrophy is an adaptive response to chronic pressure and volume overload, as occurs in End-stage renal disease. Chronic overload in combination with metabolic, electrolytic, and hormonal changes leads to maladaptive left ventricular hypertrophy characterized by structural changes in the myocardium and diastolic dysfunction 2. Early detection of cardiovascular disease in children with End-stage renal disease would therefore give an opportunity for targeted intervention in patients at higher risk in order to prevent cardiovascular morbidity and mortality in early adulthood. As a consequence, conventional echocardiography of the heart is currently recommended in children with Endstage renal disease as the method of choice for early detection of cardiac disease 3. However, reports on the reproducibility and validity of this assessment in children are scarce. In an earlier study of the same cohort, we found conventional echocardiography to be insufficiently sensitive and accurate for a reliable diagnosis of left ventricular hypertrophy 4. Tissue Doppler imaging appears to be a promising method for the detection and quantification of subtle abnormalities in diastolic ventricle function in adults 5. In order to investigate whether this method would also be useful in children with End-stage renal disease, we compared the accuracy of 2 echocardiographic techniques, i.e. conventional echocardiography and Tissue Doppler imaging, to detect impairment of left ventricle diastolic function. The aims of this study were: to compare the prevalence of diastolic dysfunction in children on renal replacement therapy and healthy children using conventional echocardiography and Tissue Doppler imaging, to assess the intra-observer reproducibility of both types of measurement, and to identify potential treatment related risk factors of diastolic dysfunction in children with End-stage renal disease. Material and Methods Participants All children, 0-19 years old, who were treated with chronic renal replacement therapy in the Emma Children s Hospital AMC Amsterdam (the Netherlands) or the University Hospital Leuven (Belgium) between October 1, 2007 and January 1, 2012 were included. Children with congenital heart disease were excluded from the study. These two centres are involved in the RICH-Q project, in which all Dutch and Belgian centres that provide paediatric renal replacement therapy collaborate to improve the quality of care 6. We obtained ethical approval from the ethical institutional review boards of all participating hospitals and written informed consent from the parents of all participants and the participants themselves, if possible. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology 7. In this study, we reviewed 38 echocardiograms of patients included in RICH-Q in the two selected hospitals and 76 echocardiograms of healthy control subjects from one of the centres offline. Controls were selected from healthy Dutch children without any medical history, evaluated at the cardiology department for a benign murmur, a positive family history for structural cardiac abnormalities or miscellaneous complaints that proved to be non-cardiac

126 Chapter 8 The 2 groups were matched for body surface area or, if height was not known, as was the case in 9 healthy children, for weight. Echocardiographic measurements Vivid 7 (GE Medical System, Wauwatosa, WI) device equipped with Tissue Doppler imaging technology was used for the standard, and pulsed tissue Doppler echocardiograms. The echocardiograms were made by paediatric cardiologists in the 2 centres between 2008 and The two-dimensional directed M-mode echocardiograms were performed according to the Guidelines and Standards for Performance of a Paediatric Echocardiogram of the American Society of Echocardiography 8. Digital images were stored and analyzed offline, using EchoPac (General Electric Medical Systems), by one independent paediatric cardiologist with more than 15 years of experience. Conventional parameters included: interventricular septum thickness in diastole (IVSd) in mm, left ventricular posterior wall thickness in diastole (LVPWd) in mm, left ventricular end diastolic diameter (LVEDd), early mitral valve ventricular filling velocity (E) in m/s, late (atrial) ventricular filling velocity (a) in m/s, and E wave Deceleration Time in milliseconds. Tissue Doppler imaging parameter peak early diastolic annular velocity (E ) was obtained at the cardiac base in the apical fourchamber orientation from 2 locations: the lateral mitral annulus of the left ventricle (LV) and interventricular septum (IVS). Each variable was measured three times and the mean was calculated. Diastolic dysfunction is characterized by impaired relaxation of the left ventricle, which results in a decrease of the E/a ratio in conventional echocardiography due to an increased late filling (a) phase of end-diastolic volume relative to early filling (E). Diastolic dysfunction was defined as E/a ratio< In Tissue Doppler imaging an impaired left ventricle relaxation and reduced elastic recoil will lead to a reduced flow propagation to the apex, and a relative reduction of E 10. Diastolic dysfunction as measured by Tissue Doppler imaging (DD TDI ) was defined as either septal or mitral E/E ratio (i.e. E divided by IVS E or by LV E, respectively) > 95th percentile for age 11. LV mass was calculated using the following equation: LV mass (grams) = 0.8 (1.04 ([LVEDd + IVSd + LVPWd] 3 [LVEDd] 3 )) g 12. To account for body size, the LV mass index (LVMI) was calculated by dividing LV mass by height raised to the power of 2.7 (g/m 2.7 ). Severe left ventricular hypertrophy (LVH) was defined as LVMI > 51 g/m All statistical analyses were performed using SPSS 18.0 for Windows. Values are presented as mean ± SD unless stated otherwise. An independent samples sample t-test or Mann- Whitney U test was used to compare the means of continuous variables when appropriate. Categorical values were compared using the chi-square test or Fisher s exact test, where indicated. Parameters related to diastolic function, i.e. E/a ratio and E/E ratios were analysed for both End-stage renal disease and control group using multiple linear regression analysis to adjust for confounding. Potential confounders were; age, gender and weight. If the regression coefficient of the central determinant End-stage renal disease changed >10% after addition of a particular determinant to the regression model, this determinant was considered to be a confounder and was kept in the final model. Intra- observer reproducibility To assess the intra-observer reproducibility of the diastolic function measurements by Tissue Doppler imaging and conventional echocardiography, the paediatric cardiologist re-assessed 25 echocardiograms offline, 10 from End-stage renal disease patients and 15 from 124

127 Cardiac monitoring healthy controls, in a randomly different order after a period of at least two weeks to preclude recollection. To assess intra-observer reproducibility, we calculated the Coefficient of Variation as the ratio of the standard deviation of the differences of the repeated measurements to the mean of all measurements in all individuals (grand mean). The Coefficient of Variation gives an indication of the measurement error as a percentage of the mean value in the study population. Potential determinants of diastolic dysfunction Data registered in the RICH-Q project were used for the analysis of possible renal replacement therapy -related determinants of diastolic dysfunction. Data were collected from the medical records of the patients by trained local research nurses or by the participating paediatric nephrologists. The following data were used: duration of renal replacement therapy (years) current renal replacement therapy modality, primary cause of End-stage renal disease (acute or chronic onset), cardiovascular indicators (e.g. hypertension, calciumphosphate metabolism, anaemia and ipth), and LV mass index and LVH. For the plasma concentrations and blood pressure measurements we used the mean of all available values of one year preceding the date of the echocardiogram. Hypertension was defined as either a systolic or diastolic blood pressure > p95 of the Task Force Report normal values corrected for age, gender and height 14. Primary causes of End-stage renal disease were classified into 2 categories: acute (e.g. dense deposit disease, hemolytic uremic syndrome (HUS), tubular necrosis, tumor and nephrotic syndrome) and chronic onset (urine tract malformation, chronic renal failure, renal vascular disease, congenital diseases). Logistic regression analysis was performed to investigate the association of these risk factors with DD TDI (mitral E/E > 95th percentile for age). Predicting factors were entered into a multivariable model one at a time in a preset order to maximize the explained variance. Results The children s characteristics and results of the echocardiographic measurements are shown in Table 1. At time of the echocardiogram, 11 children with End-stage renal disease were treated with haemodialysis, 8 with peritoneal dialysis and 19 children were transplanted. The children with End-stage renal disease were significantly older than their healthy controls, matched for body surface area or weight, the mean difference [95% Confidence Interval (CI)] being 3.3 [ ] years (p=0.002). After adjustment for age, children with ESRD had a larger mean IVSd (mm) and LVPWd (mm). Severe LVH was diagnosed in 4 of the 38 children with ESRD (11%) and in none of the controls (p=0.03). Children with End-stage renal disease had a lower E/a ratio compared to control subjects (mean difference [95%CI]); 0.3 [ ], p= 0.004). Diastolic dysfunction was diagnosed in 2 children (5%) with End-stage renal disease according to the E/a ratio (p=0.11). Children with End-stage renal disease had a lower mean value of E of both the mitral annulus of the left ventricle (LV E ) and the interventricular septum (IVS E ), and consequently, a higher mitral and septal E/E ratio than the controls (both p< 0.001). According to the mitral and septal E/E ratio, 11 (29%) and 16 (42%) children with End-stage renal disease, respectively, and none of the controls were diagnosed with diastolic dysfunction measured by Tissue Doppler imaging (DD TDI ), both p< In 10 children with End-stage renal disease, both septal and mitral E/E ratios were > 95 th percentile for age. In 6 children only the septal E/E ratio was > 95th percentile for age and in 1 child only the mitral E/E ratio 8 125

128 Chapter 8 Table 1. Characteristics of the study population and results of measurements of conventional echocardiography and Tissue Doppler imaging ESRD n=38 Healthy controls n=76 Mean difference 95%CI P value Characteristics BSA (m 2 ) 1.24 (0.4) 1.26 (0.4)^ a Weight (kg) 39.3 (16.3) 36.5 (19.6) a Male # 25 (66%) 46 (61%) b Age (years) 12.4 (4.5) 9.1 (4.9) a Conventional echocardiography Adjusted for age IVSd (mm) 6.8 (1.3) 5.4 (1.1) <0.001 d LVPWd (mm) 6.9 (1.5) 5.7 (1.3) d LVEDd (mm) 43.6 (6.5) 41.3 (7.2) LVMI (g/m 2.7 ) 36.0 (11.8) 26.7 (7.8) <0.001 d LVH # 4 (11%) 0 (0%) c E (cm/s) 95.5 (19.5) 97.8 (16.1) d a (cm/s) 56.1 (15.0) 50.9 (12.2) d E/a ratio 1.8 (0.6) 2.0 (0.5) d E wave Deceleration (33.2) (30.0) Time (ms) Tissue Doppler Imaging Adjusted for age LV E (cm/s) 14.2 (4.0) 18.1 (3.3) <0.001 d Mitral E/E ratio 7.1 (2.1) 5.6 (1.3) <0.001 d IVS E (cm/s) 10.2 (2.0) 13.6 (2.1) <0.001 d Septal E/E ratio 9.6 (2.1) 7.3 (1.4) <0.001 d Prevalence of diastolic dysfunction DD conventional echo: E/a ratio < 1 # 2 (5%) 0 (0) 5% 0-10% 0.11 c DD TDI : mitral E/E ratio> 11 (29%) 0 (0) 29% 20-40% <0.001 c p95 # DD TDI : septal E/E ratio>p95 # 16 (42%) 0 (0) 42% 30-60% <0.001 c Data are presented as mean (sd), # Data are presented as n (percentage), ^Body surface area (BSA) and therefore LVMI is missing in 9 healthy controls, a independent samples T- test, b Chi 2 test, c Fisher s exact test, d adjusted for age by linear regression analysis, ESRD= end-stage renal disease, IVSd= diastolic intraventricular septum thickness, LVPWd= diastolic left ventricular posterior wall thickness, LVEDd= left ventricle end diastolic diameter, LVH= left ventricle hypertrophy, E= early mitral valve ventricular filling velocity, a= late ventricular filling velocity, IVS= interventricular septum, LV= left ventricle, E = peak early diastolic annular velocity, and DD= diastolic dysfunction, CI= confidence interval. 126

129 Cardiac monitoring Table 2. Intra- observer reproducibility (n=25) Measurement 1 Mean (SD) Measurement 2 Mean (SD) Mean difference 95% CI CV Conventional echocardiography E (cm/s) 97 (16.0) 97 (15.0) % a (cm/s) 52 (12.0) 53 (12.0) % E/a ratio 2.0 (0.5) 1.9 (0.5) % E wave Deceleration Time (ms) (19.2) (25.1) % Tissue Doppler Imaging LV E (cm/s) 15.9 (3.3) 16.1 (3.6) % Mitral E/E ratio 6.4 (1.7) 6.4 (1.9) % IVS E (cm/s) 12.1 (2.0) 12.4 (2.0) % Septal E/E ratio 8.3 (1.9) 8.0 (1.9) % E= early mitral valve ventricular filling velocity, a=late ventricular filling velocity, LV= left ventricle, E = peak early diastolic annular velocity, Mitral E/E ratio = E divided by LV E, IVS= interventricular septum, Septal E/E ratio= E divided by IVS E, SD= standard deviation, CI= Confidence interval, and CV= coefficient of variation was > 95 th percentile for age. From the 11 children diagnosed with DD TDI according to the mitral E/E ratio, only 2 children had severe LVH. Three examples of mitral E measurements in a) child with ESRD and diastolic dysfunction, b) child with ESRD without diastolic dysfunction and c) healthy control are given in Figure 1. Intra- observer reproducibility The results of the intra-observer reproducibility are shown in Table 2. There were no significant differences between the repeated measurements for the conventional measurement (E, a, E/a ratio, and E wave Deceleration Time) or for the Tissue Doppler imaging measurements (IVS E, LV E, mitral and septal E/E ratio).the Coefficients of Variation of the mitral and septal E/E ratio, 7% and 4% respectively, were smaller than the Coefficient of Variation of the E/a ratio (11%). 8 Risk factors for diastolic dysfunction Disease characteristics of ESRD children with and without diastolic dysfunction, defined as mitral E/E ratio > 95th percentile for age, are shown in table 3. The children with DD TDI (n=11) were on average [95%CI] 4.1 [ ] years older than the children without DD TDI (n=27), p= There was a not-significant towards more males in the group with DD TDI compared to those with no DD (91% vs 56%: p=0.06). The mean (standard deviation) mitral E/E ratio for boys was 7.6 (2.3) and for girls 6.4 (1.5), 95%CI: ; p=0.036). Boys and 127

130 Chapter 8 Figure 1. Examples of E = peak early diastolic annular velocity in Tissue Doppler Images of the mitral annulus from a) child with ESRD and diastolic dysfunction, b) child with ESRD without diastolic dysfunction and c) healthy control. 1a. Child with ESRD and diastolic dysfunction 1b. Child with ESRD without diastolic dysfunction 1c. Healthy control 128

131 Cardiac monitoring girls ages were comparable. The primary diagnoses and mode of renal replacement therapy did not differ significantly between children with or without DD TDI or between boys and girls. The results of the logistic regression analysis to identify risk factors for DD TDI, defined as mitral E/E ratio > 95th percentile for age are shown in table 4. The odds ratio [95%CI] for boys compared to girls to develop DD TDI was 14.5 [ ] corrected for age. The multivariable logistic regression model containing age and gender explained 46% of the variance. None of the other risk factors showed a statistically significant association with DD TDI when analyzed as a single determinant. Discussion Depending on the exact outcome measure, we found between 30 and 40% of the children with End-stage renal disease to have signs of diastolic dysfunction as measured by Tissue Doppler imaging, depending on the outcome measure. These findings are consistent with those of several other studies Early detection of cardiac disease in End-stage renal disease children is important, given the extremely high cardiac mortality rate in young adolescent patients with paediatric End-stage renal disease. In a follow-up study of patients with End-stage renal disease since childhood, a mortality rate of 25% before the age of 30 was reported. Forty percent of these patients died of cardiovascular disease 1;18. Children with End-stage renal disease and diastolic dysfunction are thought to have a particularly increased risk for ventricular systolic dysfunction, leading to congestive heart failure, and early cardiac death 16. Hypertension, anaemia, increased PTH secretion, hyperphosphatemia and hypercalciemia and prolonged dialysis have been recognized in adults with End-stage renal disease as potential risk factors for cardiovascular mortality 19. These factors can be influenced by intensifying the treatment. In adult onset End-stage renal disease therapeutic interventions, such as an increase of the dialysis frequency, a stricter control of hypertension, hyperphosphatemia and anaemia all have shown to be effective in reducing cardiac mortality after left ventricular hypertrophy is established 20. It is therefore important to detect cardiovascular disease in End-stage renal disease children at an early stage so that targeted interventions can be started in time to prevent cardiovascular morbidity and mortality in early adulthood. In contrast with the studies of Mitsnefes et al. 16 and ten Harkel et al. 17 the main objective of the present study was not only to assess the prevalence of diastolic dysfunction in children with ESRD, but also to assess accuracy and reproducibility of the different echocardiographic techniques. Just like Mitsnefes et al. and Ten Harkel et al., we found lower E/a ratios and higher E/E ratios in children with ESRD than in healthy children. In addition, we found that TDI is more reproducible than conventional echocardiography. Although 30-40% of these children were diagnosed with DD TDI, only 5% were diagnosed with severe LVH. This suggests that DD measured by TDI is detected earlier than LVH measured in these children. This finding is supported by those of Borges et al 19. They showed that diastolic dysfunction was already present in hypertensive adults whose left ventricular mass index was still within the clinically defined normal range. This suggests that both the contractile and relaxing myocardial function may already be hampered with normal LV mass values, and supports the potential value of using TDI velocities in the evaluation of cardiac function. However, the definition of LVH is a matter of ongoing controversy 21;22, especially in possibly growth-retarded children 23;24. A different definition of LVH will probably lead to a different prevalence of LVH. Furthermore, Tissue Doppler imaging measurements detected 8 129

132 Chapter 8 Table 3. Association between diastolic dysfunction and possible determinants ESRD with DD TDI (n= 11) ESRD without DD TDI (n=27) Mean difference [95%CI] Mean (sd) age in years 15.2 (2.4) 11.2 (4.6) 4.1 [ ] p value a Male n (%) 10 (91%) 15 (56%) b Primary cause of ESRD: chronic onset 7 (64%) 18 (67%) b Mode of RRT at time of echocardiography n (%) - Haemodialysis - Peritoneal dialysis - Transplantation Dialysis as mode of RRT at time of ultrasound n (%) Median (range) duration RRT in months Median (range) duration dialysis in months # More than 2 years of RRT n (%) More than 2 years of dialysis n (%) 4 (36%) 1 (9%) 6 (55%) 7 (26%) 7 (26%) 13 (48%) 0.49 b 5 (45%) 14 (52%) b 37.2 (0-97) 21.7 (0-192) c 11.3 (0-66) 5.6 (0-192) c 7 (64%) 12 (26%) b 4 (36%) 8 (30%) 0.71 b Mean (sd) LVMI in g/m (12.9) 36.1 (11.6) 5.4 [ d 14.2] LVH 2 (18%) 2 (7%) b Hypertension, before ultrasound n (%) 5 (31%) 10 (45%) b Mean (sd) haemoglobin (mmol/l) Mean (sd) phosphate (mmol/l) 6.8 (1.0) 7.1 (0.7) 0.4 ( ) 1.52 (0.4) 1.54 (0.3) 0.0 ( ) Mean (sd) calcium (mmol/l) 2.41 (0.3) 2.38 (0.2) 0.0 ( ) Median (range) ipth (pmol/l)* 0.16 d 0.85 d 0.66 d 11.4 ( ) 17.0 ( ) c DD TDI is defined as mitral E/E ratio> p95 for age. a = Independent samples t test, b =Chi square/ Fischer s exact test, c =Mann Withney-U test. d = adjusted for age by linear regression. ESRD= end-stage renal disease, RRT= chronic renal replacement therapy, LVMI= left ventricular mass index, LVH= left ventricular hypertrophy, CI=confidence interval, * ipth bloodvalue is missing for 6 children without DD (n=21) and 2 children with DD (n=9). 130

133 Cardiac monitoring 24 to 37% more diastolic dysfunction in our study population than conventional echocardiography, by which only 5% of these children were diagnosed. Our findings are consistent with a study in adults with chronic kidney disease, in which Tissue Doppler imaging demonstrated impaired diastolic function in patients with left ventricular hypertrophy that was not detected by conventional echocardiography 25. To date, the E/a ratio, measured by conventional echocardiography has generally been used to evaluate left ventricular diastolic function 26;27. However, this method has several limitations, since it is directly influenced by both the left atrial pressure and the preload. This is especially important for patients on dialysis because of their abnormal hydration status. Tissue Doppler imaging measurements are relatively independent of loading conditions, and thus may be superior to conventional echocardiography to detect diastolic dysfunction in Endstage renal disease patients [28]. Furthermore, in our study, the intra-observer reproducibility of the E/E ratio was better than of the (conventional) E/a ratio. Reproducibility studies for Tissue Doppler imaging measurements in children are scant. Eidem et al assessed the intra and inter observer reproducibility of Tissue Doppler imaging measurements in healthy children 11. The reproducibility was expressed as the mean absolute percentage difference between 2 observers. Intra- and inter-observer measurement error of E measured at interventricular septum, left and right ventricle ranged from 1.6% - 2% and from %, respectively. They concluded that Tissue Doppler imaging offers an easily obtained, quantitative, reproducible echocardiographic measure of left ventricular function in children 11. Whether early detection of diastolic dysfunction using Tissue Doppler imaging can be used as a specific predictor of cardiovascular morbidity and mortality in children remains to be established. Longitudinal studies in children on renal replacement therapy are necessary to evaluate the role of DD TDI in the risk assessment of developing heart failure later in life. In adults the prognostic significance of an increased mitral E/E ratio has been established in various studies In adults with heart failure the mitral E/E ratio was shown to be associated with cardiac mortality and hospitalization for heart failure (odds ratio 1.92 [ ] per unit increment of E/E ratio, p = 0.001) 30. Wang et al. recommend that mitral E/E ratio should be measured during echocardiographic examination for additional prognostication in patients with End-stage renal disease 32. The role of the septal E/E ratio is less clear. Although in this study children with DD TDI were older than children without DD TDI, we found no significant influence of disease and therapy characteristics on outcomes with respect to DD TD. From other studies it is known that diastolic dysfunction already develops at the time of mild to moderate chronic renal insufficiency and progresses as renal function deteriorates 16;33. Unfortunately, we have no echocardiographic information from before the start of renal replacement therapy in these children. The difference that we found between boys and girls may be a real signal, or it may have been due to chance. One explanation could be that these boys had chronic kidney disease for a longer period before developing End-stage renal disease than girls. An earlier study in healthy children found no gender differences in E/E ratio 11. Additional studies are needed to either confirm or refute this gender difference in End-stage renal disease children. Unfortunately, we did not find significant associations between mitral E/E ratio and other possible determinants (e.g. mean LVMI, LVH, phosphate, haemoglobin, ipth, blood pressure) in this small study population

134 Chapter 8 Table 4. Results of logistic regression to identify risk factors for diastolic dysfunction in 38 children with End-stage renal disease Models with one determinant Gender (male vs female) Age (years) Cause of ESRD (acute vs chronic) Duration RRT (years) Current RRT modality (transplantation vs dialysis) Mean LVMI (g/m 2.7 ) LVH Hypertension Mean haemoglobin (mmol/l) Mean phosphate (mmol/l) Mean calcium (mmol/l) Mean ipth (pmol/l)* Multivariable model OR % CI Gender (male vs female) Age (years) Diastolic dysfunction is defined as mitral E/E ratio > P95 for age. ESRD= end-stage renal disease, RRT= chronic renal replacement therapy, LVMI= left ventricular mass index, LVH= left ventricular hypertrophy,*intact Parathyroid hormone (ipth) blood value is missing for 8 children. OR= odds ratio, CI= confidence interval Limitations The results of this study are limited by the small sample size in the End-stage renal disease group. The study was limited to 2 hospitals because Tissue Doppler imaging measurements in these hospitals were assessed with the same echocardiography machine (Vivid 7), using comparable methods and therefore suitable for offline analysis. Furthermore, this was a cross-sectional study, including dialysis and transplanted patients. We decided not to distinguish between these 2 modalities because all children had End-stage renal disease and most of the transplant patients had been on dialysis before. Recommendations Early detection of cardiovascular disease in children with End-stage renal disease might give an opportunity for targeted intervention in patients at higher risk in order to prevent cardiovascular morbidity and mortality in early adulthood. Tissue Doppler imaging measurements could be of great value to detect diastolic dysfunction in children with End-stage renal disease at an early stage, therefore Tissue Doppler imaging should be performed in addition to the conventional echocardiography. Longitudinal studies are necessary to evaluate the progression of cardiac dysfunction in these children. 132

135 Cardiac monitoring In conclusion, diastolic dysfunction is found in many children with End-stage renal disease. TDI is more sensitive in the early detection of diastolic dysfunction than conventional echocardiography in children with End-stage renal disease. Furthermore, Tissue Doppler imaging has better intra-observer reproducibility than the conventional echocardiography. Provided that the specificity of this technique in children is confirmed, Tissue Doppler imaging could be of great value to detect early onset of diastolic dysfunction in children with End-stage renal disease

136 Chapter 8 Reference List 1. Groothoff JW, Gruppen MP, Offringa M et al. Mortality and causes of death of endstage renal disease in children: a Dutch cohort study. Kidney Int 2002; 61: Dyadyk OI, Bagriy AE, Yarovaya NF. Disorders of left ventricular structure and function in chronic uremia: how often, why and what to do with it? Eur J Heart Fail 1999; 1: Chavers BM, Solid CA, Sinaiko A et al. Diagnosis of cardiac disease in pediatric endstage renal disease. Nephrol Dial Transplant 2011; 26: Schoenmaker NJ, van der Lee JH, Groothoff J et al. Low agreement between cardiologists diagnosing left ventricular hypertrophy in children with ESRD. 2012; Submitted for publication Ommen SR, Nishimura RA, Appleton CP et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 2000; 102: Tromp WF, van der Lee JH, Offringa M et al. Lessons learned from efforts to improve the quality of care in children with end-stage renal disease in the Netherlands and Belgium. Arch Dis Child 2011; 96: Coats AJ, Shewan LG. Statement on authorship and publishing ethics in the international journal of cardiology. Int J Cardiol 2011; 153: Lai WW, Geva T, Shirali GS et al. Guidelines and standards for performance of a pediatric echocardiogram: a report from the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr 2006; 19: Satpathy C, Mishra TK, Satpathy R, Satpathy HK, Barone E. Diagnosis and management of diastolic dysfunction and heart failure. Am Fam Physician 2006; 73: Gaasch WH, Little WC. Assessment of left ventricular diastolic function and recognition of diastolic heart failure. Circulation 2007; 116: Eidem BW, McMahon CJ, Cohen RR et al. Impact of cardiac growth on Doppler tissue imaging velocities: a study in healthy children. J Am Soc Echocardiogr 2004; 17: Devereux RB, Alonso DR, Lutas EM et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of 134

137 Cardiac monitoring growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995; 25: Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics 1996; 98: Goren A, Glaser J, Drukker A. Diastolic function in children and adolescents on dialysis and after kidney transplantation: an echocardiographic assessment. Pediatr Nephrol 1993; 7: Mitsnefes MM, Kimball TR, Border WL et al. Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 2004; 65: Ten Harkel AD, Cransberg K, Van Osch-Gevers M, Nauta J. Diastolic dysfunction in paediatric patients on peritoneal dialysis and after renal transplantation. Nephrol Dial Transplant 2009; 24: Groothoff J, Gruppen M, de GE, Offringa M. Cardiovascular disease as a late complication of end-stage renal disease in children. Perit Dial Int 2005; 25 Suppl 3: S123-S O Regan S, Matina D, Ducharme G, Davignon A. Echocardiographic assessment of cardiac function in children with chronic renal failure. Kidney Int Suppl 1983; 15: S77-S Mitsnefes MM. Cardiovascular complications of pediatric chronic kidney disease. Pediatr Nephrol 2008; 23: Foster BJ, Mackie AS, Mitsnefes M, Ali H, Mamber S, Colan SD. A novel method of expressing left ventricular mass relative to body size in children. Circulation 2008; 117: Khoury PR, Mitsnefes M, Daniels SR, Kimball TR. Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr 2009; 22: Borzych D, Bakkaloglu SA, Zaritsky J et al. Defining left ventricular hypertrophy in children on peritoneal dialysis. Clin J Am Soc Nephrol 2011; 6: Simpson JM, Savis A, Rawlins D, Qureshi S, Sinha MD. Incidence of left ventricular hypertrophy in children with kidney disease: impact of method of indexation of left ventricular mass. Eur J Echocardiogr 2010; 11: Hayashi SY, Rohani M, Lindholm B et al. Left ventricular function in patients with chronic kidney disease evaluated by colour tissue Doppler velocity imaging. Nephrol Dial Transplant 2006; 21:

138 26. Fujimoto S, Kagoshima T, Nakajima T, Dohi K. Doppler echocardiographic assessment of left ventricular diastolic function in patients with systemic lupus erythematosus. Cardiology 1994; 85: Leung DY, Boyd A, Ng AA, Chi C, Thomas L. Echocardiographic evaluation of left atrial size and function: current understanding, pathophysiologic correlates, and prognostic implications. Am Heart J 2008; 156: Johnstone LM, Jones CL, Grigg LE, Wilkinson JL, Walker RG, Powell HR. Left ventricular abnormalities in children, adolescents and young adults with renal disease. Kidney Int 1996; 50: Bruch C, Klem I, Breithardt G, Wichter T, Gradaus R. Diagnostic usefulness and prognostic implications of the mitral E/E ratio in patients with heart failure and severe secondary mitral regurgitation. Am J Cardiol 2007; 100: Hamdan A, Shapira Y, Bengal T et al. Tissue Doppler imaging in patients with advanced heart failure: relation to functional class and prognosis. J Heart Lung Transplant 2006; 25: Hillis GS, Moller JE, Pellikka PA et al. Noninvasive estimation of left ventricular filling pressure by E/e is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004; 43: Wang AY, Wang M, Lam CW, Chan IH, Zhang Y, Sanderson JE. Left ventricular filling pressure by Doppler echocardiography in patients with end-stage renal disease. Hypertension 2008; 52: Bullington N, Kartel J, Khoury P, Mitsnefes M. Left ventricular hypertrophy in pediatric kidney transplant recipients: long-term follow-up study. Pediatr Transplant 2006; 10:

139 9Impaired longitudinal deformation measured by Speckle Tracking Echocardiography in children with End-stage renal disease Nikki J. Schoenmaker 1, Jaap W. Groothoff 1, Johanna H. van der Lee 2, Maria van Dyck 3, Marc Gewillig 4, Linda Koster 5, Ronald Tanke 6, Nico A. Blom 7, Luc Mertens 8 and Irene M. Kuipers 7 1 Department of Paediatric Nephrology, Emma Children s Hospital AMC Amsterdam, the Netherlands, 2 Department of Paediatric Clinical Epidemiology, Emma Children s Hospital AMC Amsterdam, the Netherlands, 3 Department of Paediatric Nephrology, University Hospital Leuven, Belgium, 4 Department of Paediatric Cardiology, University Hospital Leuven, Belgium, 5 Department of Paediatric Nephrology, Radboud University Nijmegen Medical Centre, the Netherlands, 6 Department of Paediatric Cardiology, Radboud University Nijmegen Medical Centre, the Netherlands, 7 Department of Paediatric Cardiology, Emma Children s Hospital AMC Amsterdam, the Netherlands, 8 Cardiology, The Hospital for Sick Children, The University of Toronto, Toronto, ON, Canada. Submitted 137

140 Chapter 9 Abstract Objective End-stage renal disease (ESRD) can cause left ventricular (LV) dysfunction. In adults this is associated with poor prognosis. In children with ESRD LV function generally seems better preserved but limited data are available on the effect of renal disease on early myocardial changes. The aim of this study was to evaluate LV function in paediatric patients with ESRD and trying to identify changes in myocardial mechanics prior to changes in shortening fraction. Study design 24 Children on dialysis, 23 transplant recipients and 29 matched healthy controls, were included. Echocardiographic data, including M-mode, Tissue Doppler and Speckle Tracking Echocardiography (STE) measurements, were acquired in each individual centre. Longitudinal strain (LS) and Radial strain (RS) measurements were performed from the apical fourchamber and the short axis view, respectively. Impaired longitudinal strain was defined as LS< 5th percentile for age. Results No differences were found in systolic function measured by M-mode and TDI (e.g. shortening fraction and LV S ) between ESRD patients and healthy children. Using STE, dialysis and transplant patients had an impaired mean LS compared to controls (mean difference [95%CI] 3.5 [ ] and 2.3 [ ], respectively, both p<0.001), adjusted for age and gender. There were no differences found for radial strain. Impaired LS was diagnosed in 31 (66%) children with ESRD. Conclusions Impaired longitudinal deformation was diagnosed by STE in two-thirds of children with ESRD who had preserved systolic function measured by M-Mode echocardiography and TDI. Prospective follow-up studies are necessary to evaluate the predictive value of decreased longitudinal myocardial function with ESRD. 138

141 Cardiac monitoring Introduction Cardiovascular disease (CVD) is the main cause of death in both children and adults with end-stage renal disease (ESRD) 1;2. In young adults with ESRD, left ventricular hypertrophy (LVH) and impaired systolic function are associated with a poor cardiovascular prognosis 3-5. In both paediatric and adult patients, left ventricular hypertrophy (LVH) and decreased diastolic function are found even at early stages of chronic kidney disease (CKD) 6-8. In adults progression of renal failure frequently leads to systolic dysfunction, which can lead to clinical signs of heart failure associated with high mortality 5. In adults this is often related to cardiac co-morbidities like diabetes, obesity, hypertension and lipid disorders increasing the risks for ischemic heart disease. In children with ESRD, systolic LV function generally seems better preserved as was described in observational cohort studies using two-dimensional (2-D) echocardiography and Tissue Doppler Imaging (TDI) measurements 3;9;10. Newer echocardiographic techniques like Speckle Tracking Echocardiography (STE) allows studying myocardial deformation and myocardial mechanics 11;12. These techniques might be used for the early detection of myocardial dysfunction. Studies in adults and children exposed to anthracyclines have shown that changes longitudinal strain can be observed prior to changes in ejection fraction This is also described in children Duchenne cardiomyopathy 16. In adults with CKD a deterioration in renal function has been shown to be associated with a decline in longitudinal strain measurements (egfr) 17;18. The aim of this study was to evaluate LV function in paediatric patients with ESRD and trying to identify whether changes in myocardial mechanics can be detected prior to changes in shortening fraction or LV S. Methods Subjects All children, 0-19 years old, who were treated with dialysis or were transplanted in the Emma Children s Hospital AMC Amsterdam, Radboud University Nijmegen Medical Centre (the Netherlands) or University Hospital Leuven (Belgium) between October 1, 2007 and February 31, 2012, were eligible for inclusion. Children with a congenital heart disease were excluded. The three centres are involved in the Renal Insufficiency therapy in Children- Quality assessment and improvement (RICH-Q) project, in which all Dutch and Belgian centres providing paediatric RRT collaborate to improve the quality of care 19. The research ethics boards of all participating hospitals approved the study. Written informed consent was obtained from the parents and/or the patients. In the RICH-Q project data are prospectively collected and submitted to a centralized database. Primary causes of ESRD were classified into 2 categories: acute (e.g. dense deposit disease, hemolytic uremic syndrome (HUS), tubular necrosis, Wilms tumor and nephrotic syndrome) and chronic onset (e.g. urinary tract malformation, chronic renal failure, renal vascular disease, congenital diseases). The following potential clinical parameters were used in the current study to look for their association with cardiac dysfunction: duration of RRT (years), current RRT modality, primary cause of ESRD (acute or chronic onset), cardiovascular risk factors (blood pressure, calciumphosphate metabolism, anaemia, intact Parathyroid Hormone (ipth)). For the plasma concentrations and blood pressure measurements we used the mean of all available values of one year preceding the date of the echocardiogram. Arterial hypertension was defined as 9 139

142 Chapter 9 a systolic and/or diastolic blood pressure > 95th percentile of the Task Force Report normal values corrected for age and gender 20. Controls were selected from a database of healthy Dutch children without any medical history, who had been evaluated at the cardiology department of the AMC for a benign murmur, a positive family history for structural cardiac abnormalities or miscellaneous complaints that proved to be non-cardiac. The 2 groups were matched for body surface area (BSA). Echocardiographic measurements All children were studied using the Vivid 7 ultrasound system (GE Medical Systems, USA) using a standardized protocol. Measurements of LV size and function were performed according to the guidelines published by the American Society of Echocardiography 21. M-mode echocardiography was performed from the parasternal long axis views. Assessment of LV dimensions included: end-diastolic interventricular septum thickness (IVSd), left ventricular end-diastolic and end-systolic diameter (LVEDd, LVEDs), and diastolic left ventricular posterior wall thickness (LVPWd). Fractional shortening (FS) (%) was calculated. Left ventricular mass was calculated according to the Devereux formula and was corrected for height indexed to LVH was defined as LVMI (g/m2.7) > 95th percentile according to normal values for age and gender by Khoury et.al 23. From the apical four-chamber views early and late mitral valve inflow velocities (E and A) were measured and the E/A-ratio was calculated. Each variable was measured three times and the mean was calculated. Also pulsed-doppler TDI images were obtained from the apical four-chamber view. Tissue Doppler tracings were measured in the basal interventricular septum (IVS) and the basal LV lateral wall. Peak systolic (S ) and early diastolic (E ) velocities were measured in three consecutive cycles and averaged. Septal E/E and mitral E/E -ratios were calculated. Not all participating centres routinely obtained Pulsed Tissue Doppler tracings. Two-dimensional gray scale images were acquired in parasternal apical four-chamber view at frame rates between frames per second 24. Three consecutive cardiac cycles were acquired. Off-line analysis was performed using the EchoPac workstation (GE Medical Systems, USA) according to previously described methods. Briefly, the endocardial border was manually traced at end systole (starting mid-septum for short axis and basal septum from the apical four chamber view). Tracking was automatically performed and the analysis was accepted after visual inspection and when the software indicated adequate tracking. If tracking was sub-optimal the endocardial border was retraced. Lagrangian radial ε and SR curves and circumferential ε curves from the short axis view (6 segments: anterior septum, anterior, lateral, posterior, inferior and septum) and longitudinal ε curves from the apical four chamber view (6 segments: basal septum, mid septum, apical septum, apical lateral, mid lateral and basal lateral) were obtained. The automated timing of aortic valve closure was used. End-systolic strain values were measured. Mean longitudinal strain (LS) and radial strain (RS) were obtained by calculating the average strain values measured in each myocardial region (Figure 1). LS is a negative value and thus represents shortening. A less negative, i.e. higher value indicates less shortening, indicative of worse systolic LV function. The echocardiographic data were interpreted later according to a set of normal values obtained from healthy Dutch children, corrected for age 25. Impaired longitudinal strain/deformation was defined as LS smaller than the 5th percentile for age

143 Cardiac monitoring Figure 1. Two-dimensional Speckle Tracking echocardiography for left ventricular longitudinal strain in a healthy control subject and a child with End-stage renal disease (ESRD) The mean longitudinal strain (white dotted line) is the mean of the 6 segments of the myocardium of the left ventricle, (e.g. yellow= basal septum, light blue = mid septum, green= apical septum, red= basal lateral, dark blue is mid lateral, and purple = apical lateral). The mean longitudinal strain is significant lower in a child with ESRD compared to a healthy control subject. To assess the intra-observer reproducibility of the offline STE measurements concerning systolic dysfunction, the same observer re-analyzed 25 echocardiograms, 10 from ESRD patients and 15 from healthy controls, after a period of at least two weeks. 9 Statistical Analysis All analyses were performed using SPSS 18.0 for Windows statistical software. Values are presented as mean ± standard deviation unless stated otherwise. An independent samples t-test or Mann-Whitney test was used to compare the means of continuous variables when appropriate. Categorical values were compared using the chi-square test or Fisher exact test, where indicated. Parameters related to systolic function were compared between the ESRD and the control group using multiple linear regression analysis to adjust for confounding. Potential confounders were: age, gender and weight. If the regression coefficient of the central determinant ESRD changed >10% after addition of a particular variable to the 141

144 Chapter 9 Table 1. Characteristics of the study population Characteristics Dialysis Transplant recipients Healthy controls Dialysis vs healthy controls Transplant vs healthy controls n=24 n=23 n=29 Mean diff. [95%CI] P value Mean diff. [95%CI] BSA^ m (0.3) 1.3 (0.4) 1.3 (0.4) 0.0 [ ] 0.85 a 0.0 [ ] 0.77 a p value Weight kilograms 41.7 (15.6) 43.0 (21.5) 40.8 (17.7) 0.9 [ ] 0.67 a 2.2 [ ] 0.70 a Male* 15 (63%) 16 (70%) 14 (48%) b b Age years 13.0 (4.1) 12.3 (4.8) 10.4 (4.4) 2.6 [ ] 0.03 a 1.9 [ ] 0.15 a Data are presented as mean (standard deviation), *Data are presented as n (percentage), a independent samples T- test, b Chi 2 test, ^Body surface area (BSA) is missing in 5 healthy children, CI= confidence interval, Mean diff.=mean difference. 142

145 Cardiac monitoring Table 2. Conventional echocardiographic measurements Characteristics Dialysis Transplant recipients Healthy controls Dialysis vs healthy controls Transplant vs healthy controls n=24 n =23 n=29 Mean diff. [95%CI] P value Mean diff. [95%CI] P value Adjusted for age and gender by linear regression IVSd (mm) 6.8 (1.6) 6.9 (1.3) 6.0 (1.4) 0.0 [ ] [ ] 0.15 LVEDd (mm) (5.6) [ ] [ ] 0.04 c (6.6) (6.5) LVPWd (mm) 7.0 (1.6) 7.6 (1.8) 5.8 (1.1) 0.5 [ ] [ ] c LVMI (g/m 2.7 ) (15.3) [ ] [ ] c (12.1) (7.6) LVH 6 (25%) 10 (43%) 0 (0%) d - <0.001 d FS (%) (4.8) [ ] [ ] 0.25 (5.8) (4.5) n=14 n=13 n=23 MV E [ [ (20.8) (12.8) (44.7) 34.5] 46.0] MV a (11.3) [ [ ] (18.3) (20.9) 29.3] MV E/a ratio 1.9 (0.8) 1.8 (0.4) 2.3 (0.5) 0.4 [ ] [ ] 0.25 Data are presented as mean (standard deviation), *Data are presented as n (percentage), d Fisher s exact test, CI= confidence interval, Mean diff.=mean difference. regression model, this variable was considered to be a confounder and was kept in the final model. We performed logistic regression analysis to identify risk factors for systolic dysfunction in the ESRD group. All determinants were analyzed separately. Significant determinants (p<0.05) were entered into a multivariable model one at a time in a preset order, and were kept in the model only if the explained variance changed more than 5%. To assess intra-observer reproducibility, we calculated the Coefficient of Variation (CV) as the ratio of the standard deviation of the differences of the repeated measurements and the mean of all measurements in all individuals (grand mean). The CV gives an indication of the measurement error as a percentage of the mean value in the study population. 9 Results Seventy-one children were treated with renal replacement therapy in one of the 3 hospitals during the study period. Six children were excluded because of associated congenital heart disease. Echocardiograms of 18 children could not be analyzed because of incomplete studies or because of poor image quality. Studies obtained in 47 children with ESRD and 29 healthy control subjects were analyzed. At the time of the echocardiography 24 children were on dialysis (19 on haemodialysis and 5 on peritoneal dialysis) and 23 were transplant 143

146 Chapter 9 Table 4. Speckle Tracking measurements Characteristics Dialysis Transplantrecipients Healthy controls Dialysis vs healthy controls Transplant vs healthy controls n=24 n=23 n=29 Mean diff. [95%CI] P value Mean diff. [95%CI] P value Longitudinal strain Adjusted for age and gender by linear regression - Basal septum % (3.5) (3.0) (2.9) 3.0 [ ] [ ] Mid septum % (3.5) (1.9) (2.4) 2.1 [ ] < [ ] Apical septum % (4.4) (3.2) (3.3) 4.1 [ ] < [ ] < Basal lateral % (5.3) (6.2) (6.1) 2.3 [ ] [ ] Mid lateral % (6.2) (5.2) (4.5) 3.9 [ ] [ ] Apical lateral % (4.6) (4.9) (5.1) 3.0 [ ] [ ] 0.09 Mean LS % (3.9) (3.0) (1.8) 3.5 [ ] < [ ] <0.001 Impaired LS* 17 (71%) 14 (61%) 2 (7%) - <0.001 d - <0.001 d Radial Strain n=16 n=17 n=16 - Basal septum % 44.9 (18.6) 50.4 (16.6) 46.5 (15.8) 0.2 [ ] [ ] Mid septum % 54.1 (18.3) 63.9 (21.1) 54.7 (19.8) 2.0 [ ] [ ] Apical septum % 62.1 (18.6) 70.9 (22.8) 57.1 (21.5) 7.7 [ ] [ ] Basal lateral % 43.0 (18.3) 44.4 (18.7) 44.2 (15.0) 0.5 [ ] [ ] Mid lateral % 63.7(18.9) 71.8 (21.6) 56.7 (20.5) 11.5 [ ] [ ] Apical lateral % 56.4 (19.5) 61.1 (21.0) 50.6 (20.3) 10.9 [ ] [ ] 0.16 Mean radial strain % 54.1 (16.2) 60.4 (16.4) 51.6 (15.9) 5.4 [ ] [ ] 0.18 Data are presented as mean (standard deviation), *Data are presented as n (percentage), d Fisher s exact test, CI= confidence interval, Mean diff.=mean difference, *Impaired LS was defined as mean longitudinal strain < 5th percentile for age. 144

147 Cardiac monitoring Table 5. Results of logistic regression to identify risk factors for impaired longitudinal strain in 47 children with ESRD OR 95 % CI P value Models with one determinant 1. Age (years) 2. Gender (male vs female) 3. Cause of ESRD (chronic vs acute) 4. Duration RRT (years) 5. Duration dialysis (years) 6. Current RRT modality (dialysis vs transplantation) 7. RRT modality (>1 year transplantation vs dialysis) 8. Hypertension 9. Mean hemoglobin (mmol/l) 10. Mean phosphate (mmol/l) 11. Mean calcium (mmol/l) 12. Mean ipth (pmol/l)* 13. Left ventricular hypertrophy 14. Mitral E/E ratio Systolic dysfunction was defined as mean longitudinal strain < 5 th percentile for age, ESRD= End-stage renal disease, RRT= renal replacement therapy, *intact Parathyroid hormone (ipth) bloodvalue is missing for 4 children, OR= odds ratio, LVH was defined as LVMI> 95th percentile for age and gender. Table 6. Intra-observer reproducibility n=25 Measurement 1 Mean (sd) Measurement 1 Mean (sd) Mean Difference [95%CI] Mean longitudinal strain (%) (3.1) (2.9) 0.2 [ ] 3% Mean radial strain (%) 54.6 (16.3) 53.6 (15.0) 0.9 [ ] 7% n=25; 15 children with End-stage renal disease and 10 healthy controls. Sd=standard deviation, CI= confidence interval, CV=coefficient of variation. CV 9 145

148 Chapter 9 recipients. Sixteen of the 23 transplant recipients (70%) had been on dialysis before. The median [range] time between transplantation and echocardiography was 14 months [0-56] months. The characteristics of the children on dialysis, the transplant recipients and the healthy controls are shown in Table 1. The children on dialysis were significantly older than the control children, matched for BSA or weight. Table 2 summarizes the results of the LV dimensions, LV FS, LV mass and mitral inflow measurements. After adjusting for age and gender, both children on dialysis and transplant recipients had a significant increased LVMI compared to healthy controls. LVH was diagnosed in 6 (25%) of the dialysis children and 10 (43%) of the transplant recipients compared to none of the controls. There were no significant differences found for shortening fraction and E/A ratio between the two groups. Unfortunately, the TDI measurements were assessed in only 14 dialysis children, 13 transplant recipients and 23 healthy controls (Table 3). After adjustment for age and gender, both children on dialysis and transplant recipients had significantly lower E values in the IVS and LV lateral basal segments. This resulted in increased E/E -ratios in both segments. The longitudinal systolic function, measured by S, was only significantly lower for IVS S in the dialysis group compared to controls. Table 4 summarizes the longitudinal and radial strain measurements. The mean LS was reduced in patients on dialysis and after renal transplant when compared with normal control patients. No significant differences between the transplant and the dialysis group were observed. The differences in longitudinal strain values were more important in the interventricular septum compared with the LV lateral wall, suggesting more septal involvement. Reduced longitudinal strain was diagnosed in 17 dialysis patients (71%) and in 14 children following renal transplant (61%). No significant differences could be found in radial strain measurements between the patient groups and the controls. Association between systolic dysfunction and determinants The logistic regression analysis to identify risk factors for impaired longitudinal function in children with ESRD are shown in Table 5. Children with impaired longitudinal function (n=31) were on average 5 [95%CI ] years older than children with a normal systolic function (n=16), p<0.001 (Appendix 1). None of the other risk factors showed a statistically significant association with systolic dysfunction. Intra- observer reproducibility The results of the intra-observer reproducibility are shown in Table 6. There were no significant differences between the repeated measurements for the LS and RS. The CV of LS and RS were 3% and 7% respectively. Discussion Our study demonstrates that in paediatric patients with ESRD, longitudinal LV function can be decreased while radial function, shortening fraction and LV S are preserved. These abnormalities are both present in patients on dialysis and after renal transplant. We found age to be the most important risk factor identified for decreased longitudinal deformation in our patients. This suggests that longitudinal shortening abnormalities become more pro- 146

149 Cardiac monitoring nounced with increasing age. Apart from systolic abnormalities, we also found diastolic abnormalities, consistent with deceased early relaxation and increased filling pressures. Our findings suggests that in paediatric patients with ESRD, LV systolic performance as measured by conventional echocardiography and TDI is generally preserved is in line with other studies 6;9. So far mainly diastolic abnormalities have been described in this population 7. In all of our patients systolic function (shortening fraction and LV S ) is preserved and within normal range. A reduction in shortening fraction represents significantly advanced cardiac dysfunction, occurring late in the disease process. Changes in longitudinal myocardial function with preserved ejection fraction have been described in other disease populations, mainly in patients with left ventricular hypertrophy 26. In hypertensive patients these changes are the most prominent in the basal part of the interventricular septum. A decrease in longitudinal function precedes changes in circumferential and radial function in patients with LVH. In 25% of the dialysis patients and 43% of the transplant patients LV mass was increased suggesting some degree of LVH. In our study however the presence of LVH did not seem to be a risk factor for the decrease in longitudinal strain, suggesting that the strain changes can be present in ESRD patients even in the absence of LVH. It could be related to intrinsic myocardial damage caused by renal failure induced metabolic changes, such as increased FGF-23 and ipth levels, or by change in loading conditions associated with ESRD. The longitudinal LV fibers seem more vulnerable as regional fiber stress is higher in the longitudinal fibers compared to the circumferential fibers. This is related to the walls being flatter in the longitudinal direction compared to the radial and circumferential direction resulting in higher local radii of curvature and higher local wall stress. This could become important in the context of increased afterload. Myocardial perfusion is also the most vulnerable in the subendocardial area causing possible damage in the subendocardial region with increasing hypertrophy. The hypertrophic response also mainly occurs in the thicker circumferentially organized fibers. This results in a preservation of radial function, largely reflecting the circumferential fiber contraction. The thicker walls will also result in an overestimation of LV contractile function when using dimensional parameters like wall thickening and fractional shortening. STE has been validated using magnetic resonance imaging (MRI) tagging of the heart This MRI technique has also been applied to children with ESRD 30. This study looked at circumferential strain and interestingly described this to be reduced in about 45% of patients studied. Dialysis patients had lower circumferential strain values than transplant patients and an inverse relationship with LV mass index was found. The authors interpreted the reduced strain values related to LVH as a sign of a maladaptive hypertrophic response. In our study we could not find an association between a reduction in longitudinal strain and LVH. However the echocardiographic methodology for calculating LV mass is less reliable and more variable than MRI measurements 9 The reduced longitudinal function can be considered as an early marker of systolic function and has been described to occur prior to changes in ejection fraction in patients after anthracycline toxicity 14;15. Changes in longitudinal strain values and tissue Doppler velocities have been detected prior to changes in ejection fraction in this population. Also, reduced longitudinal systolic function in CKD 17 and haemodialysis patients 31 has been described by STE in adults. LS has been shown to decrease with deteriorating renal function (egfr) 17;18. In hypertensive patients with heart failure, the progressive decline of LS was correlated with 147

150 Chapter 9 the increase in serological markers of cardiac fibrosis 32. Moreover, LS has been shown to be significantly associated with all-cause mortality (hazard ratio [95% CI] 1.69 [ ] per 5% increase, P<0.001) in adults with chronic ischemic cardiomyopathy 33. Whether a reduction in LS can be used as a specific predictor of cardiovascular morbidity and mortality in children remains to be established. The only way to validate this method is by longitudinal studies in children with ESRD assessing the association of impaired LS with heart failure later in life. Limitations One of the main limitations of this study is the relative small sample size. The study was limited to the three hospitals in the study using the same ultrasound equipment, as we wanted to avoid the effect of intermachine variability on the measurements. Despite having a prospective protocol, not all data could be acquired retrospectively on all patients further limiting the number of measurements. This particularly affected the regression analysis and the lack of associations found between certain parameters, might be an effect of lack of statistical power. A problem we found was the difficulty of normalizing echocardiographic measurements in this population. A lot of ESRD patients are shorter and have a smaller BSA compared to age matched controls. Choosing the right correction for body size and age for this population remains a matter of controversy. Conclusion We found a decreased longitudinal LV deformation, consistent with systolic dysfunction in paediatric ESRD patients in the presence of preserved fractional shortening and radial function. The long-term significance of these findings warrants further investigation and followup. 148

151 Cardiac monitoring Reference List 1. Groothoff J, Gruppen M, de GE, Offringa M. Cardiovascular disease as a late complication of end-stage renal disease in children. Perit Dial Int 2005; 25 Suppl 3: S123-S McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350: Johnstone LM, Jones CL, Grigg LE, Wilkinson JL, Walker RG, Powell HR. Left ventricular abnormalities in children, adolescents and young adults with renal disease. Kidney Int 1996; 50: Foley RN, Parfrey PS, Harnett JD et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 1995; 47: Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray DC, Barre PE. Outcome and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial Transplant 1996; 11: Mitsnefes MM, Kimball TR, Witt SA, Glascock BJ, Khoury PR, Daniels SR. Left ventricular mass and systolic performance in pediatric patients with chronic renal failure. Circulation 2003; 107: Mitsnefes MM, Kimball TR, Border WL et al. Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 2004; 65: Matteucci MC, Wuhl E, Picca S et al. Left ventricular geometry in children with mild to moderate chronic renal insufficiency. J Am Soc Nephrol 2006; 17: Palcoux JB, Palcoux MC, Jouan JP, Gourgand JM, Cassagnes J, Malpuech G. Echocardiographic patterns in infants and children with chronic renal failure. Int J Pediatr Nephrol 1982; 3: Colan SD, Sanders SP, Ingelfinger JR, Harmon W. Left ventricular mechanics and contractile state in children and young adults with end-stage renal disease: effect of dialysis and renal transplantation. J Am Coll Cardiol 1987; 10: Liu YW, Tsai WC, Su CT, Lin CC, Chen JH. Evidence of left ventricular systolic dysfunction detected by automated function imaging in patients with heart failure and preserved left ventricular ejection fraction. J Card Fail 2009; 15: Marwick TH, Leano RL, Brown J et al. Myocardial strain measurement with 2-dimensional speckle-tracking echocardiography: definition of normal range. JACC Cardiovasc Imaging 2009; 2: Poterucha JT, Kutty S, Lindquist RK, Li L, Eidem BW. Changes in left ventricular longitu- 149

152 Chapter 9 dinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction. J Am Soc Echocardiogr 2012; 25: Sawaya H, Sebag IA, Plana JC et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 2011; 107: Fallah-Rad N, Walker JR, Wassef A et al. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 2011; 57: Mertens L, Ganame J, Claus P et al. Early regional myocardial dysfunction in young patients with Duchenne muscular dystrophy. J Am Soc Echocardiogr 2008; 21: Liu YW, Su CT, Huang YY et al. Left ventricular systolic strain in chronic kidney disease and hemodialysis patients. Am J Nephrol 2011; 33: Yan P, Li H, Hao C et al. 2D-speckle tracking echocardiography contributes to early identification of impaired left ventricular myocardial function in patients with chronic kidney disease. Nephron Clin Pract 2011; 118: c232-c Tromp WF, van der Lee JH, Offringa M et al. Lessons learned from efforts to improve the quality of care in children with end-stage renal disease in the Netherlands and Belgium. Arch Dis Child 2011; 96: Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics 1996; 98: Lai WW, Geva T, Shirali GS et al. Guidelines and standards for performance of a pediatric echocardiogram: a report from the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr 2006; 19: de Simoni G, Daniels SR, Devereux RB et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992; 20: Khoury PR, Mitsnefes M, Daniels SR, Kimball TR. Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr 2009; 22: Korinek J, Wang J, Sengupta PP et al. Two-dimensional strain--a Doppler-independent ultrasound method for quantitation of regional deformation: validation in vitro and in vivo. J Am Soc Echocardiogr 2005; 18:

153 Cardiac monitoring 25. Marcus KA, Mavinkurve-Groothuis AM, Barends M et al. Reference values for myocardial two-dimensional strain echocardiography in a healthy pediatric and young adult cohort. J Am Soc Echocardiogr 2011; 24: Cikes M, Sutherland GR, Anderson LJ, Bijnens BH. The role of echocardiographic deformation imaging in hypertrophic myopathies. Nat Rev Cardiol 2010; 7: Cho GY, Chan J, Leano R, Strudwick M, Marwick TH. Comparison of two-dimensional speckle and tissue velocity based strain and validation with harmonic phase magnetic resonance imaging. Am J Cardiol 2006; 97: Amundsen BH, Helle-Valle T, Edvardsen T et al. Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol 2006; 47: Singh GK, Cupps B, Pasque M, Woodard PK, Holland MR, Ludomirsky A. Accuracy and reproducibility of strain by speckle tracking in pediatric subjects with normal heart and single ventricular physiology: a two-dimensional speckle-tracking echocardiography and magnetic resonance imaging correlative study. J Am Soc Echocardiogr 2010; 23: Malatesta-Muncher R, Wansapura J, Taylor M, Lindquist D, Hor K, Mitsnefes M. Early cardiac dysfunction in pediatric patients on maintenance dialysis and post kidney transplant. Pediatr Nephrol 2012; 27: Wang H, Liu J, Yao XD et al. Multidirectional myocardial systolic function in hemodialysis patients with preserved left ventricular ejection fraction and different left ventricular geometry. Nephrol Dial Transplant 2012; 32. Plaksej R, Kosmala W, Frantz S et al. Relation of circulating markers of fibrosis and progression of left and right ventricular dysfunction in hypertensive patients with heart failure. J Hypertens 2009; 27: Bertini M, Ng AC, Antoni ML et al. Global longitudinal strain predicts long-term survival in patients with chronic ischemic cardiomyopathy. Circ Cardiovasc Imaging 2012; 5:

154 Appendix 1. Comparison between children with ESRD with and without systolic dysfunction for treatment modality and outcomes ESRD with SD n=31 ESRD without SD n=16 Mean diff. (95%CI) p value Mean age (sd) in years 14.3 (3.3) 9.5 (4.6) 4.8 ( ) <0.001 a Male* 19 (61%) 12 (75%) b Acute onset of ESRD* 12 (39%) 9 (56%) b Modality at time of STE HD PD Tx 14 (45%) 3 (10%) 14 (45%) 5 (31%) 2 (13%) 9 (56%) b Median duration RRT(range) in months 29 (0-208) 23 (0-68) d Median duration dialysis (range) in 11 (0-123) 12 (0-42) d months Median duration Tx (range) in months 18 (3-82) 20 (10-56) d > 12 months after transplantation 14 (45%) 6 (38%) b LVH 8 (26%) 7 (44%) b Hypertension 12 (39%) 9 (56%) b Mean (sd) hemoglobin (mmol/l) 7.1 (0.9) 7.0 (0.7) 0.1 ( )* 0.83 e Mean (sd) phosphate (mmol/l) 1.6 (0.4) 1.5 (0.8) 0.2 ( )* 0.17 e Mean (sd) calcium (mmol/l) 2.4 (0.2) 2.5 (0.1) 0.1 ( )* 0.11 e Median (range) ipth (pmol/l) 26.7 ( ) 12.6 ( ) d Data is presented in median (range), data is presented in n (%), a = independent sample T test, b =Chi Square test, c =Mann Whithney U test, d =Log transformation (LN), e = linear regression adjusted for age. DD=diastolic dysfunction, ESRD= End-stage renal disease, RRT= chronic renal replacement therapy, Tx= transplantation, CI=confidence interval, *adjusted for age. 152

155 10 General Discussion 153

156 Chapter 10 The aim of this thesis is to evaluate quality aspects of the current management of paediatric End-stage renal disease (ESRD) in the Netherlands, Belgium and the region of Cologne (Germany). The aim of this thesis is to evaluate quality aspects of the current management of paediatric End-stage renal disease (ESRD) in the Netherlands, Belgium and the region of Cologne (Germany). The first part focuses on treatment policies and outcomes. We analyzed local management policies for all children with ESRD and actual delivered care and compared it with international guidelines recommendations. Additionally, we reviewed the content and methodological quality of the existing international guidelines for the management of children on chronic dialysis. In the second part, we assessed the disparities in dialysis treatment and outcomes, including Health-related Quality of care (HRQoL), in children from non-western European origin compared to native children. In the third part, we analysed the quality of currently applied tools for monitoring cardiovascular disease, the most important life-threatening complication of ESRD in children, and we explored the validity of new, potentially more sensitive techniques for detecting early cardiac disease. In this chapter we will discuss the impact of the most important results on clinical practice, and present our recommendations for the research agenda. First, the main results of the work presented in this thesis are summarized. Main results 1. Management policies in 11 Dutch, Belgian and German centres for chronic dialysis and renal transplantation in children vary considerably. This may have impact on treatment outcomes in these children. 2. Of all published guidelines only the 5 KDOQI guidelines have been developed in such a way that they may serve as guidance for paediatric chronic dialysis treatment in daily practice. However, the lack of applicability of some of these guidelines in children is an important limiting factor for implementation. 3. Children on chronic dialysis of non-western European origin, treated in the Netherlands or Belgium, receive a different treatment and have less favourable health outcomes compared to children of native parents. 4. Children with ESRD of non-western origin appear to be at risk for impaired HRQoL for emotional and school functioning. 5. Conventional echocardiography is not reliable to detect small changes in cardiac wall thickness in children with ESRD. 6. Tissue Doppler Imaging (TDI) is a more sensitive and reliable method to detect diastolic dysfunction than conventional echocardiography in children with ESRD. 7. Impaired longitudinal deformation is diagnosed by Speckle Tracking Echocardiography in two-thirds of children with ESRD despite preserved systolic function according to measurements by conventional echocardiography and TDI. 154

157 General Discussion Implications We found that in the Netherlands, Belgium and Germany, important therapeutic decisions such as the exact indication for initiating renal replacement therapy (RRT), the primary choice of RRT modality, the minimum accepted weight of the recipient and the maximum accepted age of the donor allowed for renal transplantation, are all highly dependent on the opinion of the local physicians and consequently vary considerably between centres. This means that, for instance, a child of 10 kilograms bodyweight can be eligible for transplantation in centre A but has to stay on dialysis for 1 or 2 years until he has gained 2 kilograms in weight in centre B. Also, the choice between starting dialysis at egfr 15 ml/min/1.73m 2 and starting dialysis only when the egfr is below 10 ml/min/1.73m 2 may imply a delay of 1 or 2 years before starting dialysis for some patients. These differences are remarkable in three highly organized countries with a highly qualified medical care system. If these disparities exist in these three countries, they are likely to exist in other European countries and the rest of the world too. Obviously, many of the differences in patient care that we found, such as the considerable differences in choice of dialysis modality and lifestyle recommendations, have important psychosocial implications for patients and their caretakers. To what extent these differences affect patient outcomes on the long run is difficult to estimate as empirical research relating management choices to health outcomes in this field is scarce. The lack of a solid scientific foundation for the existing clinical practice guidelines and the low applicability of these guidelines into practice may be an explanation for the remarkable deviations of the local policies from the recommendations as stated in these guidelines. In this thesis we also focused on a specific, until now neglected, area of treatment quality and outcome: the care for children of non-western European origin. We found adverse health outcomes as well as treatment differences in these patients. Immigrant children received more often haemodialysis (HD) as a first mode of RRT instead of peritoneal dialysis (PD) compared to Dutch and Belgian native children, and spent more time on dialysis prior to transplantation. Immigrant children more frequently suffered from PD-associated peritonitis and renal osteodystrophy. They also scored lower on the HRQoL subscales emotional functioning and school functioning than native ESRD children. End-stage renal disease at childhood has great impact on the psychosocial development, as late outcome studies have shown 1. The combination of physical impairment and low educational attainment has been found to be an important barrier for becoming an independent person and finding employment in adult life for these patients. The fact that non-western patients are performing even worse than Western patients, is therefore an alarming fact. It is not clear whether the treatment variation had merely been the physicians or the patients choice. Physicians may have been reluctant to offer a home (i.e. peritoneal) dialysis program to some non-western patients. The preference for HD might even be due to a conscious or subconscious physician bias in the treatment of non-western patients. There is evidence from the adult literature showing that avoidant coping strategies are prevalent among all patients with renal disease but particularly among racial minorities 2. General misunderstanding, a reduced trust in doctors and the health care system, cultural and language barriers may all be factors leading to this behaviour. Such attitude may hinder adequate decision making and stimulate therapy non-adherence. Tailor made educational programs outside the hospital, including the social environment of the patients have shown to be suc

158 Chapter 10 cessful in the African-Americans with renal disease 3. Such approach could also be beneficial for non-western children and their caretakers. The need for cardiovascular monitoring in children with ESRD is beyond discussion 4. Timely detection of left ventricular abnormalities may decrease the risk for early cardiac death by therapeutic adjustments such as more frequent dialysis, dietary measures or adjustment of medication. In this respect, routinely yearly echocardiography in children with ESRD is recommended by leading physicians in the field of paediatric ESRD management. Based on our findings, we think that assessment of left ventricular hypertrophy (LVH) by conventional echocardiography in an individual child with ESRD may too easily result in either underreporting of LVH or in an unjust diagnosis of LVH. This may either lead to a potentially preventable deterioration of cardiac function or to unnecessary interventions with potential burdens for the patient. Therefore we searched for a new, more sensitive tool for a reliable longitudinal cardiac follow-up in these children. We found that Tissue Doppler Imaging (TDI) is a more sensitive and reliable method to detect diastolic dysfunction than conventional echocardiography. Furthermore, Speckle Tracking Echocardiography (STE) is a new, reliable method to detect impaired longitudinal deformation despite preserved systolic function according to measurements by conventional echocardiography and TDI. As a consequence of these more sensitive methods we found that the prevalence of diastolic and systolic dysfunction was much higher than measured with conventional echocardiogram. TDI and STE are a valuable addition to conventional echocardiography in children with ESRD. However, prospective follow-up studies are necessary to evaluate the predictive value of myocardial deformation in children with ESRD. Recommendations for clinical practice 1. Collaborate to enhance the quality of care. The difficulty of the management of ESRD in children is that it is a rare but serious and life-threatening disorder with a high overall mortality and morbidity. Patients can choose between several, consequently all very small dialysis centres. Concentration of care to 1 or 2 centres per country would introduce the problem of long daily travelling for chronic dialysis patients and is therefore not an attractive option. The only solution to improve the Quality of care (QoC) in these patients is a close and structured collaboration between these units. One might question whether renal transplantation in such small countries as Belgium and the Netherlands should not be performed in one or two centres in each country, in order to optimise the experience and knowledge in the field of paediatric renal transplantation. Close international collaboration between treatment units for paediatric RRT on a continuous basis with structured and continued peer discussions on treatment protocols, and evaluation of patient outcomes is needed. In RICH-Q a group of clinicians who work in separate centres with very small numbers of seriously ill patients now collaborate on a continuous basis to improve the quality of care in the virtual absence of population-specific evidence. This cooperative way of working increases the shared professional experience, promotes exchange of experiences and at the same time offers an opportunity to generate more evidence for the management of rare diseases by increasing the number of study subjects. Evaluation of the project over the next years will show whether this method indeed has lead to a more harmonized treatment of RRT in children with a better outcome. 156

159 General Discussion 2. Create an agenda for clinical practice guideline development and modification of the existing KDOQI guidelines. The development process of the few currently existing guidelines for the management of children on chronic dialysis varies largely. Although we are faced with major challenges hampering the development of guidelines, such as the small number of patients, few paediatric nephrologists, and lack of funding for rare disease research, we emphasize the need for improvement of the development of guidelines for the management of children on chronic dialysis. The lack of evidence based guidelines leads to children being treated based on clinical experience or opinion of various different nephrologists in different centres, partly based on evidence from adult studies. It is not clear to what extent evidence generated in adult studies can be extrapolated to children. Although the KDOQI guidelines were the best developed clinical practice guidelines for children with ESRD, improvement of the methodological development and applicability of the guidelines in daily practice is necessary. The current major need for more valid guidelines in the field of paediatric ESRD calls for more international collaborative studies. When centres work together in setting the research agenda, perform these studies together, and subsequently implement their results into practice, the current unwanted practice variation will be reduced, and the quality of care for these children will be improved. To date there are seven study groups within the RICH-Q study that address different topics (e.g. Anaemia, Renal Osteodystrophy, Nutrition & growth etc.) to create evidence based or consensus based clinical practice guidelines. These study groups create guideline proposals by assessing the level of evidence of the current published guidelines. These guideline proposals will be discussed extensively in the entire group with regard to the level of evidence and, if there is no paediatric-specific evidence, the possibility of extrapolation of evidence from studies in adults to the paediatric population. The proposed guidelines are evaluated, benchmarks are set, and compared with the benchmarks used in daily practice. Finally, these benchmarks are compared with the actual patient outcomes from the RICH-Q database. The feasibility, relevance and desirability of attaining these guidelines will be discussed. 3. Special attention and adjusted care for children from non-western origin with ESRD. Up to 40% of the children on dialysis are children with immigrant parents of non-western European origin. Our findings imply that these children are at high risk for an adverse outcome in early adulthood with respect to overall physical health, independency, employment and social productivity. This situation might be improved by education of treatment providers about these disparities and about the potential roles of conscious and unconscious bias, cultural misunderstandings, and language barriers. A culturally tailored educational approach to inform patients and caretakers on kidney function, kidney disease and therapy outside the hospital in their own environment might enhance therapy adherence. The approach of the TALK initiative in the USA who use cultural sensitive interventions in order to encourage African-Americans to consider donation for a live kidney transplantation may serve as an example to improve adherence to care 3. In an attempt to improve the HRQoL for school functioning additional educational support and more stimulation and opportunity to attend school could be a helpful support to a successful development towards independency in adulthood. To stimulate school performance, dialysis units should emphasize school activities during dialysis and more tailor made lessons for non-western children should be developed. However, attending a regular school would be preferable because of the social

160 Chapter 10 advantages of being with peers. One way of facilitating school attendance is to promote peritoneal dialysis or haemodialysis at home instead of centre haemodialysis, if rapid transplantation is unachievable. 4. Use new echocardiographic methods to detect early cardiovascular disease. As was found in earlier studies cardiovascular disease is still the most important cause of death in young adults with paediatric ESRD 4. TDI and Speckle tracking could be promising in the early detection of diastolic and systolic dysfunction. Timely detection of left ventricular abnormalities may decrease the risk for early cardiac death by therapeutic adjustments such as more frequent dialysis, dietary measures or adjustment of medication. We recommend a complete echocardiographic follow up (including TDI and STE) in all children with ESRD. Recommendations for research Priority topics for further research based on the findings of this thesis are: Establish quality of care (QoC) indicators and benchmarks. To manage and monitor QoC in a valid way, we need to establish benchmarks and quality indicators. When all indicators have been set, the current QoC can be compared with the QoC at the start of the intervention program from the data captured. In the RICH-Q project the first quality indicators were established based on a systematic review of the literature followed by a consensus procedure involving all centres. The group of paediatric nephrologists collaborating in RICH-Q will continue this procedure. Validate the guidelines and quality indicators in a broader EU setting. Allow European centres that want to join RICH-Q to contribute clinical data and academic input, and explore the possibilities for validation and implementation of the guidelines and quality indicators. The main requirement for this to be achieved is funding. RICH-Q was started as a collaborative initiative of all 10 Dutch and Belgian paediatric dialysis and renal transplantation centres; in 2011 an 11 th centre in Cologne, Germany, joined the project. Foster add-on studies on aspects of ESRD in children. Recently add-on studies in the RICH-Q project were prepared to generate new knowledge on RRT in children by analysing therapeutic determinants and outcomes registered in the RICH-Q database. For example, an add-on study was designed to search for a diagnostic tool to detect metabolic bone disease. Apart from the cardiovascular disease, patient with ESRD suffer from metabolic bone disease (MBD), frequently referred to as Renal Osteodystrophy (ROD). The detection of early ROD is hampered by the absence of a non-invasive but accurate way of assessing bone quality and strength. A promising tool to detect ROD in children is the micro Magnetic Resonance Imaging (micro MRI). Micro MRI is an imaging technology that provides the ability to acquire high resolution images of both cortical and trabecular bone. MRI uses a strong magnetic field and a sequence of radiofrequency pulses to produce a three-dimensional image. An add-on study in the RICH-Q population is in preparation to evaluate the validity and reproducibility of the micro MRI in children with ESRD. If the micro MRI is reproducible, valid compared to the existing measurement methods, and correlates with clinical and biochemical parameters, a longitudinal study 158

161 General Discussion can be proposed. Explore the causal factors of adverse outcomes in non-western immigrants. Little is known about which factors contribute to poorer outcome of immigrant children with ESRD and this needs to be investigated further. Insufficient knowledge or possible cultural factors, like misunderstanding due to language difficulties, different awareness of illness, or non-effective communication between patient and doctor, should be taken in consideration. Potential biological (genetic profile, pharmacokinetics) as well as social and cultural aspects have to be investigated. An extensive questionnaire or qualitative research methods such as focus groups could be helpful to explore the influence of language proficiency, cultural and socioeconomic status and the educational attainment of the caretakers on outcome in immigrant and native children with ESRD. The outcome of this study may help to improve the quality of care and, most importantly, the outcomes for children of immigrant background. Establish the evidence basis to reduce cardiovascular disease in children with ESRD. Cardiovascular disease is the most important cause of death in young adults with paediatric ESRD. Until now, only conventional echocardiography is recommended in children with ESRD as the method of choice for detection of cardiac disease. However, our data show that conventional echocardiography is unreliable to detect small changes in ventricular wall thickness. Although TDI and STE are helpful to detect early impairment in cardiac function, we still have to continue the search for a more reliable tool to detect early LVH, or more precise, small changes in wall thickness of the left ventricle. Furthermore the predictive validity of TDI and STE in children with ESRD has to be established by longitudinal studies. Finally, a search for early cardiovascular indicators, such as FGF23 en KLOTHO can be helpful in the future to detect cardiovascular risk factors at an early stage and prevent cardiovascular disease before the development of LVH and cardiac dysfunction 5;6. Cardiac MRI techniques seem promising as more sensitive and reproducible methods for the detection of left ventricular hypertrophy and functional cardiac disease 7;8. All these techniques should be explored to find out which is most valid and feasible for monitoring cardiovascular disease in children with ESRD on a routine basis

162 Chapter 10 Reference List 1. Grootenhuis MA, Stam H, Last BF, Groothoff JW. The impact of delayed development on the quality of life of adults with end-stage renal disease since childhood. Pediatr Nephrol 2006; 21: Lunsford SL, Simpson KS, Chavin KD et al. Racial differences in coping with the need for kidney transplantation and willingness to ask for live organ donation. Am J Kidney Dis 2006; 47: Boulware LE, Hill-Briggs F, Kraus ES et al. Protocol of a randomized controlled trial of culturally sensitive interventions to improve African Americans and non-african Americans early, shared, and informed consideration of live kidney transplantation: the Talking About Live Kidney Donation (TALK) Study. BMC Nephrol 2011; 12: Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012; 23: Faul C, Amaral AP, Oskouei B et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121: Semba RD, Cappola AR, Sun K et al. Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 2011; 59: Stewart GA, Foster J, Cowan M et al. Echocardiography overestimates left ventricular mass in hemodialysis patients relative to magnetic resonance imaging. Kidney Int 1999; 56: Katz J, Milliken MC, Stray-Gundersen J et al. Estimation of human myocardial mass with MR imaging. Radiology 1988; 169:

163 11 Summary & Nederlandse Samenvatting Portfolio & Publications Levensverhaal van een patiënt Curriculum vitae Dankwoord 161

164 Summary This thesis focused on the current management and monitoring of children with End-stage renal disease (ESRD) in the Netherlands, Belgium and a part of Germany. The results are part of the Renal Insufficiency in Children- Quality assessment and improvement (RICH-Q) project. This project started in 2007 as a collaborative initiative of all Dutch and Belgian centres proving paediatric renal replacement therapy (RRT). In this international longitudinal study, we aimed to improve the quality of care (QoC) for children with ESRD by by peer review and plenary discussion of prospectively recorded data on treatment characteristics and physical and psychosocial health outcomes applying the latest scientific evidence and guidelines. In 2011 a German centre (Cologne) joined the RICH-Q project. On March 1 st 2013, 327 children on RRT had been included in the RICH-Q study. In Chapter 1, the general introduction on ESRD and the RICH-Q study is provided. The main scope of this thesis was to study the current management and monitoring of care for children with ESRD and to present a new approach for improvement of the management and monitoring of this specific group of children. Part I is concerned with variation in care of children on chronic dialysis (Chapter 2) and renal transplantation (Chapter 3) between various centres. Chapter 2 quantifies the variation in treatment policies between 10 Dutch and Belgian centres providing chronic dialysis. The reported treatment policies were compared with the actually provided therapies and with recommendations from available published guidelines and existing literature. There were considerable disparities in management policies for chronic dialysis across the centres. Disparities were found in various topics, e.g. estimated Glomerular Filtration Rate treshold as indication for initiation of RRT, preferred initial mode of RRT, peritoneal dialysis catheter care, haemodialysis frequency, and vascular access. Furthermore, discrepancies were seen between stated treatment policies and actual performed therapies. In Chapter 3, we used the exact same approach as in chapter 2 but now for the management policies for renal transplantation (Tx) in all Dutch, all Belgian and one German centre providing renal Tx in children. Between the 11 centres, we found discrepancies in treatment policies on various topics, e.g. variations in minimum accepted living and deceased donor age, maximum accepted Cold Ischemia Time, maximum number of accepted HLA-mismatches, and different policies with respect to living donation. For the majority of policies no evidence based guidelines were available. These observations imply that it matters in which centre a child with ESRD is treated. This is remarkable in 3 highly organized countries with a highly qualified medical care system, and may jeopardize heath outcomes for these children. Differences in policies may be explained by a lack of evidence based paediatric guidelines regarding renal replacement therapy (RRT). This emphasizes the need for national and international collaboration of paediatric nephrology centres in order to develop uniform guidelines. In Chapter 4, a systematic review is provided on all current clinical practice guidelines for the management of chronic dialysis in children. The clinical guidelines were identified by searches of MED- LINE and websites of pediatric nephrology organizations. Three reviewers independently assessed the methodological quality of 17 guidelines, containing 369 recommendations, on the management of children on chronic dialysis using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Collaboration instrument. The overall mean AGREE II score from 7 KDOQI guidelines was fair and from all other 10 guidelines poor. In general, only the KDOQI guidelines may serve as guidance in daily practice of pediatric chronic dialysis treat- 162

165 ment. However, the lack of applicability of some of these guidelines in children may still be an important limiting factor for implementation. Part II describes the disparities in treatment and health outcomes, including HRQoL, of non-western children with ESRD compared to native patients. Chapter 5 reports treatment disparities in the care for children from non-western European origin compared to native Dutch and Belgian children with ESRD. In this study, the choice of initial dialysis, post initial dialysis and outcomes between immigrant and native children on dialysis were compared. 79 of the 179 included children (44%) were from immigrant origin. Remarkably, immigrant children received more often haemodialysis (HD) as first mode of RRT instead of peritoneal dialysis (PD) compared to Dutch and Belgian native children, and spend a longer time on dialysis prior to transplantation. Despite the adverse clinical outcomes (i.e. relatively high peritonitis and renal osteodystrophy incidence) that were found for immigrant children with respect to dialysis treatment, no important differences in disease-related or socio-economic factors could be identified. It is not clear whether the treatment variation had merely been the physicians or the patients choice. This situation might be improved by education of treatment providers about these disparities and about the potential roles of conscious and unconscious bias, cultural misunderstandings, and language barriers. Chapter 6 compares the HRQoL between Non-Western and Western children with ESRD. We found that both Western and non-western children with ESRD had significant impairment of HRQoL compared to their healthy counterparts from a Dutch norm group. Within the ESRD group, non- Western patients had a higher risk for having impaired emotional and school functioning compared to Western children. We believe that paediatric nephrologists and members of the multi-disciplinary team need to pay more attention to the development of emotional en school functioning in order to create conditions for an optimal HRQoL Part III decribes our search for a reliable tool for the early detection of cardiac diasease and their suitability for use in children with ESRD. In Chapter 7, the results of a reproducibility study of the detection of left ventricle hypertrophy in 92 children with ESRD is reported. Agreement within and between 3 independent observers diagnosing LVH using echocardiography is low. In individual children changes in diastolic wall thickness of less than 1.6 mm or Left ventricular mass index of less than 17.7 g/m 2 cannot be distinguished from measurement error, even when measured by the same observer. This limits the use of echocardiography to detect changes in wall thickness in children with ESRD. A more sensitive tool for reliable longitudinal cardiac follow-up in these children is essential. Through the advent of echocardiographic techniques it is now possible to quantify subtle impairment of diastolic and systolic performance in adults by Tissue Doppler Imaging (TDI) and Speckle Tracking Echocardiography (STE), respectively. Therefore, chapter 8 compares the conventiontional echocardiography and TDI measurements in the assessement of diastolic function of children with and without ESRD, and examines the reproducibility (i.e. coefficient of varation) of the TDI measurements. The 38 ESRD children had lower diastolic function, measured by conventional echocardiography (p=0.004) and TDI (p<0.001) than the 78 healthy controls. Two ESRD patients (5%) had diastolic dysfunction according to the conventional echocardiography and 11 (29%) according to TDI, compared to none of the controls p=0.109 and p<0.001, respectively. The coefficients of variation (CV) of the TDI measurements (4% and 7%) were smaller than the CV of the E/a ratio (11%) measured by conventional echocardiography. We conclude that; TDI is a more sensitive and reliable method to detect diastolic 163

166 dysfunction than conventional E/a ratio in children with ESRD. Therefore, TDI should be performed in addition to the conventional echocardiography. Chapter 9 compares conventional echocardiography, TDI and STE assesment of systolic function of children with and without ESRD. Our study demonstrates that in paediatric patients with ESRD, longitudinal LV function can be decreased while radial function, shortening fraction and LV S are preserved. These abnormalities are both present in patients on dialysis and after renal transplant. We found age to be the most important risk factor identified for decreased longitudinal deformation in our patients. Apart from systolic abnormalities, we also found diastolic abnormalities, consistent with deceased early relaxation and increased filling pressures. We emphasized that longitudinal studies are necessary to evaluate the predictive validity of STE in children. Finally, in chapter 10, the main general discussion of all findings, the implications for clinical practice and directions for future research are outlined. 164

167 Nederlandse samenvatting Sinds de jaren zeventig is het mogelijk om kinderen met terminale nierinsufficiëntie in leven te houden met chronische nierfunctievervangende therapie. Ondanks verbeteringen in de behandeling van kinderen met nierfunctievervangende therapie is de kans op overlijden en andere bijkomende ziekten nog steeds sterk verhoogd. Terminale nierinsufficiëntie bij kinderen is zeldzaam. In Nederland en België zijn er ongeveer 50 nieuwe kinderen per jaar met terminale nierinsufficiëntie. Om reisafstanden te beperken zijn er 4 Nederlandse en 6 Belgische betrekkelijk kleine centra waar chronisch nierfunctievervangende therapie (dialyse of niertransplantatie) wordt aangeboden voor kinderen. Tot de komst van het RICH-Q project (Renal Insufficiënty therapy in Children- Quality assessment and improvement) in 2007, bestond er geen structureel inhoudelijk overleg over dialyse patiënten tussen deze centra. In dit project werken alle 10 Nederlandse en Belgische centra voor dialyse en transplantatie bij kinderen nauw samen. Het doel van het project is om de kwaliteit van behandeling van kinderen met een terminale nierinsufficiëntie te verbeteren. Het project beoogt dit door alle gegevens over behandeling en uitkomsten van behandeling centraal te registreren en iedere zes maanden bij elkaar te komen om over de behandelingskarakteristieken en uitkomsten te discussiëren. Sinds 2011 participeert een groot Duits centrum uit Keulen. Op 1 maart 2013 waren er 327 kinderen geïncludeerd in de studie. Er zijn diverse werkgroepen geformeerd die zich bezig houden met richtlijnen en onderzoeksvoorstellen om verder inzicht te krijgen in de beste therapie. Daarnaast zijn er zogenaamde add-on studies ontwikkeld, studies naar nieuwe diagnostische procedures. De resultaten van dit proefschrift maken deel uit van het RICH-Q project. Dit proefschrift heeft als doel om de huidige zorg in kaart te brengen en verbeteringen aan te brengen in deze kwaliteit van zorg voor kinderen met terminale nierinsufficiëntie. In hoofdstuk 1 wordt een algemene introductie gegeven over terminale nierinsufficiëntie en het doel van dit proefschrift. Deel I van het proefschrift gaat over de verschillen in behandelstrategieën en uitkomsten van dialyse (hoofdstuk 2) en niertransplantatie (hoofdstuk 3) tussen de verschillende RICH- Q centra. Hoofdstuk 2 beschrijft de verschillende behandelstrategieën voor dialyse tussen de 10 verschillende centra in Nederland en België. De behandelstrategieën werden vergeleken met de richtlijnen uit de literatuur en de daadwerkelijke uitgevoerde therapie. Er bleken grote verschillen te zijn tussen de centra. Bijvoorbeeld; wanneer een kind moet starten met dialyse, met welke therapie een kind start (hemodialyse of peritoneaal dialyse) en de frequentie van hemodialyse. Verder bleken de behandelstrategieën niet overeen te komen met de aanbevolen richtlijnen en zelfs niet met de uitgevoerde therapie. In hoofdstuk 3 werden vergelijkbare resultaten gevonden maar dan voor niertransplantatie in 10 centra uit Nederland en België en 1 centra uit Duitsland. Er bleken verschillen te zijn in de minimale vereisten waar een donor of ontvanger aan moet voldoen. Deze resultaten impliceren dat het wel degelijk uitmaakt in welk centrum een kind wordt behandeld. Een groot deel van deze variatie is te verklaren door het ontbreken van goede richtlijnen speciaal voor kinderen met terminale nierinsufficiëntie. Om deze richtlijnen in kaart te brengen hebben we in hoofdstuk 4 een systematische literatuuronderzoek gedaan naar alle bestaande richtlijnen voor kinderen die worden behandeld met chronische dialyse. Er zijn 17 richtlijnen gevonden bestaande uit 369 aanbevelingen. Slechts 7 van deze richtlijnen waren zo ontwikkeld dat ze 165

168 met wat aanpassingen te gebruiken zijn in de dagelijkse praktijk. Op dit gebied bestaat er dus grote behoefte aan verbetering. RICH-Q is momenteel bezig om in kleine werkgroepen richtlijnen te ontwikkelen voor verschillende onderwerpen. Deel II van dit proefschrift beschrijft de verschillende behandelstrategieën en uitkomsten tussen kinderen met terminale nierinsufficiëntie van westerse en niet-westerse achtergrond. Hoofdstuk 5 beschrijft de resultaten van de verschillende behandelstrategieën en uitkomsten tussen kinderen van westerse en niet-westerse achtergrond die behandeld worden met dialyse. 79 van de 179 geïncludeerde kinderen waren van niet-westerse achtergrond. Hierbij hebben we een kind als niet-westers gedefinieerd als minimaal een van beide ouders in een niet-west-europees land was geboren. Niet-westerse kinderen werden vaker met hemodialyse behandeld in plaats van peritoneaal dialyse, werden minder snel getransplanteerd en hadden vaker buikvliesontstekingen en botziekten dan westerse kinderen. Het is niet duidelijk waardoor deze verschillen precies worden veroorzaakt. Meer aandacht voor niet-westerse patiënten is nodig om zowel de arts als de patiënt en zijn familie hiervan bewust te maken. Hoofdstuk 6 beschrijft de kwaliteit van leven van kinderen met terminale nierinsufficiëntie van westerse en niet-westerse achtergrond. Kinderen van niet-westerse achtergrond rapporteerden een slechtere kwaliteit van leven te hebben wat betreft school en emotioneel functioneren. Dit is verontrustend omdat de kwaliteit van leven van kinderen met terminale nierinsufficiënt al laag is in vergelijking met gezonde westerse en nietwesterse kinderen. Om de kwaliteit van leven van deze kinderen te verbeteren moet de kindernefroloog en het multidisciplinaire team die betrokken is bij het kind meer aandacht hebben voor school en emotioneel functioneren. Deel III van het proefschrift beschrijft onze zoektocht naar een betrouwbaar meetinstrument voor het opsporen van hartziekten bij kinderen met terminale nierinsufficientie. Harten vaatziekten vormen de belangrijkste doodsoorzaak van terminale nierinsufficiëntie bij kinderen en uiten zich in linker ventrikel hypertrofie (LVH) en diastolische- en systolische dysfunctie. Bij volwassenen patiënten zijn niet-invasieve technieken ontwikkeld om harten vaatziekten op te sporen, die in maat en getal direct zijn geassocieerd met de kans op overlijden. Betrouwbare gegevens bij kinderen zijn vooralsnog schaars. Vroege detectie van hart- en vaatziekten en associatie met de verschillende behandelingmethoden zijn essentieel om de prognose van deze kinderen te verbeteren. Hoofdstuk 7 beschrijft de reproduceerbaarheidstudie van het opsporen van LVH door middel van conventionele echografie. Vooralsnog worden er bij kinderen met terminale nierinsufficiëntie alleen routinematig conventionele echo s gedaan. Onze resultaten laten zien dat de reproduceerbaarheid van het meten van LVH laag is. In individuele kinderen was een verschil in vaatwanddikte van 1.6 mm niet te onderscheiden van de meetfout, zelfs als het gemeten was door dezelfde cardioloog. Onze studie toont aan dat de conventionele echo geen goede methode is om LVH op te sporen bij kinderen met terminale nierinsufficientie. Uit andere studies bleken Tissue Doppler Imaging (TDI) en Speckle Tracking Echocardiografie (STE) een veel belovende techniek te zijn voor het opsporen van diastolische en systolische dysfunctie. Daarom hebben wij in hoofdstuk 7 en 8 de verschillende technieken vergeleken. Hoofdstuk 8 vergelijkt de conventionele echo met TDI in het opsporen van diastolische dysfunctie in kinderen met terminale nierinsuffiensientie vergeleken met gezonde kinderen en vergelijkt de reproduceerbaarheid van beide technieken. Kinderen met terminale nierinsuffiecient hadden een significant slechtere dialstolische functie vergeleken met de gezonde kinderen zowel met de conventionale echo als met TDI gemeten. Maar gemeten met TDI waren er meer kinderen 166

169 gediagnostiseerd met diastolische dysfunctie dan met de conventionale echo. De reproduceerbaarheid van de TDI meteingen waren beter dan de conventionele echo meting. Wij concluderen dat TDI gevoeliger en beter reproduceerbaar is dan conventionale echo in het opsporen van vroege diastolische dysfunctie bij kinderen met terminale nierinsufficientie. Wij raden dan ook aan om ook TDI metingen routinematig bij deze kinderen te laten maken. In Hoodstuk 9 vergelijken we STE met conventionale echo en TDI in het opsporen van systolische dysfunctie in kinderen met terminale nierinsufficientie in vergelijkig met gezonde kinderen. Gemeten met STE hadden kinderen met terminale nierinsufficientie een significant slechtere systolische functie dan gezonde kinderen. De conventionele echo en TDI spoorden geen verschillen op in systolische functie tussen de groepen maar gemeten met STE, bleken meer dan 60% van de kinderen met terminale nierinsufficientie systolische dysfunctie te hebben. Dit is opmerkelijk omdat tot nu toe gedacht werd dat systolische dysfunctie pas op de volwassen leeftijd zou optreden. Er zijn longitudinale studies nodig om de validiteit van STE te bepalen in kinderen met terminale nierinsufficientie. Tot slot wordt in hoofdstuk 10 de algemene discussie van alle resultaten van dit proefschrift beschreven en worden er aanbevelingen gedaan voor het verbeteren van de kwaliteit van de zorg voor kinderen met terminale nierinsufficiëntie. 167

170 168

171 Portfolio & Publications 169

172 AMC Graduate School for Medical Sciences PhD portfolio Summary of PhD training, teaching and parameters of esteem Name PhD student: Nikki Schoenmaker PhD period: June December 2012 Promotor: Co-promotores: Prof. dr. M. Offringa Dr. J.W. Groothoff & Dr. J.H. van der Lee I. PhD training Year Workload General courses (ECTS) - Basic course in legislation and organisation for clinical researches - Oral presentation in English - Clinical Epidemiology - Practical Biostatistics - Scientific Writing in English for Publication - PD university basic course, Division of Nephrology Amsterdam Course on Epidemiology, ERA-EDTA Salzburg Oostenrijk - Masterclass of prof. dr. Gordon Guyatt, Emma children s Hospital, Amsterdam Oral Presentations Echocardiography in children with ESRD. Nederlandse Vereniging voor Kindergeneeskunde, Veldhoven - RICH-Q ; Baseline results and Agreement in diagnosing LVH. Nederlandse Nefrologie Dagen, Veldhoven - Renal Insufficiency therapy in Children -Quality assessment and improvement. Hans Mak Instituut Symposium. Toekomst Muziek, Bussum - TDI gevoeliger voor vroege detectie diastolische dysfunctie. Nederlandse Vereniging voor Kindergeneeskunde, Veldhoven. - Agreement in diagnosing LVH. Nederlandse Nefrologie Dagen, Veldhoven

173 - Richtlijnen voor de behandeling van kinderen met terminale nierinsufficiëntie. Nierstichting symposium Uit de kinderschoenen, Driebergen Poster Presentations - Intra and Inter-observer reproducibility in echocardiography in children with ESRD. International Pediatric Nephrology association, New York USA - Peritoneal dialysis-associated complications in Dutch and Belgian children. International Pediatric Nephrology association, New York USA - Current guidelines for the management of chronic dialysis in children: a systematic review. European Society Pediatric Nephrology, Dubrovnik Croatia. - Low agreement between cardiologists in diagnosing LVH in children with ESRD (nominee best poster award). European Society Pediatric Nephrology, Dubrovnik Croatia. - Diastolic function measured by Tissue Doppler Imaging in children with End Stage Renal Disease. European Society Pediatric Nephrology, Dubrovnik Croatia. - Low agreement between cardiologists in diagnosing LVH in children with ESRD. Association of European Paediatric Cardiology, Malaga Spain - Diastolic function measured by Tissue Doppler Imaging in children with End Stage Renal Disease. Association of European Paediatric Cardiology, Malaga Spain International conferences - International Pediatric Nephrology association, New York USA - European Society Pediatric Nephrology, Dubrovnik Croatia. - RICH-Q Advisory Board Meetings, twice a year. Amsterdam, Rotterdam, Utrecht, Antwerp, Liege, Brussels (Belgium) and Cologne (Germany)

174 II. Teaching Year Workload (ECTS) Lecturing - Lecture: Cohort studies. Third year Medical students - Bijscholing Kindernefrologie for dialysis nurses Supervising - Barend Geverd Dynoot. Second year Medical student. The psychosocial background of children with End-stage renal disease. - Silvia Tiebout. Third year Medical student. Primary diagnosis of End-stage renal disease - Tamara den Harink. Third year Medical student. Primary failure of PD catheters - Jelske van den Burg. Masterthesis. Hypertension in non- Western and Western European children III. Parameters of esteem Year Prizes - Low agreement between cardiologists diagnosing left ventricular hypertrophy in children with end stage renal disease. Abstract award, best clinical science. Pediatric Clinics Amsterdam - AMC by night. Poster award, most original study. Pediatric Clinics Amsterdam

175 Publications This thesis Wilma F. Tromp, Nikki J. Schoenmaker, Johanna H. van der Lee, Brigitte Adams, Antonia H. Bouts, Laure Collard, Rita Van Damme-Lombaerts, Koenraad J. Van Hoeck, Nathalie Godefroid, Linda Koster-Kamphuis, Karlien Cransberg, Marc R. Lilien, Ann Raes and Jaap W. Groothoff. Important differences in management policies for children with ESRD in the Netherlands and Belgium. Nephrol Dial Transplant. Nephrol Dial Transplant May;27(5): Nikki J. Schoenmaker - Maike van Huis, Jaap W. Groothoff, Johanna H. van der Lee, and Karlien Cransberg,on behalf of the RICH-Q group. Policy variation in donor and recipient status in 11 paediatric renal transplantation centres. Pediatr. Nephrol January; Epub ahead of print Nikki J. Schoenmaker, Wilma F. Tromp, Johanna H. van der Lee, Brigitte Adams, Antonia H. Bouts, Laure Collard, Rita Van Damme-Lombaerts, Koenraad J. Van Hoeck, Nathalie Godefroid, Linda Koster-Kamphuis, Karlien Cransberg, Marc R. Lilien, Ann Raes and Jaap W. Groothoff. Disparities in Dialysis Treatment and Outcomes for non-western children in the Netherlands and Belgium. Pediatr Nephrol Aug;27(8): Nikki J. Schoenmaker, Irene M. Kuipers, Wilma F.Tromp, Johanna H. van der Lee, Marc Gewillig, Jaap Ottenkamp and Jaap W. Groothoff. Diastolic function measured by Tissue Doppler imaging in pediatric patients with ESRD Report of the RICH-Q study. Cardiol Young Mar 5; 1-9:Epub ahead of print Nikki J. Schoenmaker, Wilma F. Tromp, Johanna H. van der Lee, Martin Offringa, Jonathan C. Craig, and Jaap W. Groothoff. Quality and consistency of clinical practice guidelines for the management of children on chronic dialysis. Revision Nephrol Dial Transplant Nikki J. Schoenmaker, Lotte Haverman, Wilma F.Tromp, Johanna H. van der Lee, Martin Offringa, Brigitte Adams, Antonia H. M. Bouts, Laure Collard, Karlien Cransberg, Maria van Dyck, Nathalie Godefroid, Koenraad van Hoeck, Linda Koster-Kamphuis, Marc R. Lilien, Ann Raes, Christina Taylan, M.A. Grootenhuis and J.W. Groothoff. Non-Western immigrant children with end-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health related quality of life compared to Western children. Submitted Nikki J. Schoenmaker, J.H. van der Lee, J.W. Groothoff, G. van Iperen, I.M.E. Frohn-Mulder, R.B.Tanke, J. Ottenkamp and I.M.Kuipers. Low agreement between cardiologists diagnosing left ventricular hypertrophy in children with end stage renal disease. Revision BMC Nephrology 173

176 Nikki J. Schoenmaker, Jaap W. Groothoff, Johanna H. van der Lee, Maria van Dyck, Marc Gewillig, Linda Koster, Ronald Tanke, Nico A. Blom, Luc Mertens and Irene M. Kuipers. Impaired longitudinal deformation measured by Speckle Tracking Echocardiography in children with End-stage renal disease. Submitted Others: Nikki J. Schoenmaker, Jan J. Weening and Raymond T. Krediet. Ibuprofen-induced HUS: case report. Clinical Nephrology. 2007; volume 68-No3: Nikki J. Schoenmaker, Marianne D. van de Wetering and Dasja Pajkrt. Invasive fungal infections in paediatric patients with a haematological malignancy: a ten years retrospective survey in a Dutch tertiary hematologic centre. Pediatric Clinics Amsterdam. 2009; volume 20(4): 4-6. Jelske W van der Burg, Nikki J. Schoenmaker, Jaap W Groothoff, Johanna H van der Lee; on behalf of the RICH-Q group. Non-Western immigrant children with end-stage renal disease have higher blood pressures than Western European patients. In progress Maike van Huis, Nikki J. Schoenmaker, Johanna H van der Lee, Marc G. Vervloet, Jaap. W. Groothoff. Klotho in anephric children. E letter to Nephrol Dial Transplant. Accepted 174

177 Levensverhaal van een patiënt 175

178 Altijd positief blijven, het komt wel goed Roentley Saturnilia (17) is een nierpatiënt. Twee weken na zijn geboorte in Curaçao komen zijn ouders erachter dat hij ziek is. Hij spuugt al zijn voeding uit, plast niet goed en huilt heel veel. Na een bezoek aan de poli blijkt Roentley uitgedroogd te zijn. Hij wordt gelijk opgenomen. Dit is het begin van vele ziekenhuis bezoeken. De zorg in Curaçao blijkt niet toereikend en het hele gezin verhuist naar Nederland. Roentley vertelt over zijn leven als nierpatiënt. Wat weet je nog van vroeger? Door foto s weet ik dat ik heel veel infusen in mijn lichaam had, omdat ze mijn vochtpeil omhoog wilde krijgen. Maar verder weet ik er weinig van. Hoe is het voor jou om zoveel tijd in het ziekenhuis door te brengen? Je went eraan. Vroeger wist ik niet beter, het was voor mij normaal. Maar nu is het wel anders, ik realiseer me dat ik hier niet wil zijn. Op 6 jarige leeftijd krijg je jouw eerste niertransplantatie. Hoe was het om te horen dat er een nier beschikbaar was? Het was midden in de nacht, de telefoon ging, maar niemand nam op. Dokter Jaap Groothoff, die al zeventien jaar mijn dokter is, heeft toen de politie naar ons huis gestuurd om ons het nieuws te vertellen. Met zaklampen schenen ze ons huis binnen en ze bonkten op de deur. Toen we de deur openden vroegen ze: Is hier iemand van zes jaar met de naam Roentley Saturnilia? We moesten direct stoppen met dialyseren en zijn s ochtends direct naar het ziekenhuis gegaan. 176