West Midlands guidelines for managing Chronic Kidney Disease related Mineral and Bone Disorders in Haemodialysis Patients

Transcription

1 West Midlands Renal Network West Midlands guidelines for managing Chronic Kidney Disease related Mineral and Bone Disorders in Haemodialysis Patients WMRN/Regional Bone Management Guidelines /1010/Final 1

2 West Midlands Bone Steering Group Members Co-chairs: Dr. Indranil Dasgupta and Joanne Martin Consultant Nephrologist and Renal Dietitian Heart of England NHS Foundation Trust West Midlands Renal Network Nanette Grant West Midlands Renal Network Manager Consultant Nephrologist Dr. Fouad Al-Baaj Dr. Dominic De-Takats Dr. Johann Nicholas Dr. Daniel Zehnder University Hospitals Birmingham NHS Foundation Trust University Hospital of North Staffordshire NHS Trust Royal Wolverhampton Hospitals NHS Trust University Hospitals Coventry and Warwickshire NHS Trust Renal Dietitian Beverley Beynon-Cobb Caroline Bird Emma Chapman Sylvia Grace Christine Morgan University Hospitals Coventry and Warwickshire NHS Trust University Hospitals Coventry and Warwickshire NHS Trust University Hospitals Birmingham NHS Foundation Trust Royal Shrewsbury Hospitals NHS Trust Dudley Group of Hospitals NHS Foundation Trust Pharmaceutical Advisor Clair Huckerby Pharmaceutical Adviser for Dudley PCT WMRN/Regional Bone Management Guidelines /1010/Final 2

3 Contents Page: 1. Background to guidelines Summary of guidelines Background of Chronic Kidney Disease related Mineral 11 and Bone Disorders 4. Guideline 1: Dietetic referral Guideline 2: Dialysis adequacy Guideline 3: Phosphate Guideline 4: Corrected Calcium Guideline 5: Parathyroid Hormone Guideline 6: Dialysis fluid calcium concentration Guideline 7: Phosphate binders Guideline 8a: Calcium containing phosphate binder Guideline 8b: Elemental calcium content of Phosphate binders 13. Guideline 8c: Non-calcium containing Phosphate binder 14. Guideline 8d: Aluminium hydroxide Guideline 9: Pharmacological treatment with active Vitamin D compounds 16. Guideline 10: Treatment of uncontrolled Secondary Hyperparathyroidism 17. Reference List Appendix 1: West Midlands calcium phosphate Management audit WMRN/Regional Bone Management Guidelines /1010/Final 3

4 19. Appendix 2: West Midlands dietetic renal dietetic staffing levels 20. Appendix 3: Phosphate Binder table WMRN/Regional Bone Management Guidelines /1010/Final 4

5 1. Background In 2002 the West Midlands Network Audit Group identified the need for a regional calcium and phosphate audit and recommended that it should be dietetic led. In the same year the Renal Nutrition Group highlighted the need for evidence of dietetic intervention in various areas of renal nutrition and proposed regional audits were conducted. West Midlands was assigned to do a calcium phosphate (Ca/Po4) audit as preparatory work was already in progress for a regional audit. Although work commenced on the audit back in 2002, it was put on hold for various reasons until January 2006 when Dr. Dasgupta took over as medical lead and in February 2006 Dr. Fallouh was assigned to the audit. The aims of the audit were to: Identify good practice regionally to support improved Ca/Po4 management Determine/promote the role of Renal Dietitian in Ca/Po4 management Identify any inadequacies in management of calcium and phosphate regionally against national standards. Provide evidence to support the development of regional calcium and phosphate guidelines The lead Clinician & Dietitian of each renal unit in the West Midlands were contacted to inform them of the audit and to request support. Data was collected for haemodialysis (HD) patients only who had been on dialysis for 3months. 7 base units and 19 satellite units within the West Midlands were included with a total number of 1919 patients. Questionnaires were developed and completed independently by the Clinician and Dietitian to collect data on current protocols in use within units, target ranges and standards used, dietetic involvement, phosphate binder and vitamin D use and dialysis calcium concentration. In addition to this a data spreadsheet was developed to collect demographic data, ethnicity and bone biochemical parameters for October A full analysis of the results can be referred to in Appendix 1. In summary, the main conclusions to come from the audit were that: There were discrepancies between dieticians and clinicians with target ranges, upper levels of intervention, 1 st line intervention, frequency in changes to medication and standard dialysis fluid used. Dieticians and clinicians agreed that dieticians lead or are heavily involved in Ca/Po4 management The majority of units followed standards PO4 <1.8mmol/l (RAS), Corrected Calcium mmol/l (RAS), PTH 4 times upper level of normal (RAS) and the most common target for CaxPO4 <4.7mmol/l There was a wide range in PO4 control across the units ranging between 52-76% There was no relationship between PO4 control and dialysis adequacy or phosphate binder used. WMRN/Regional Bone Management Guidelines /1010/Final 5

6 All units exceeded >1500mg elemental calcium from binders with a total of 22% of patients exceeding >1500mgs despite Sevelemar being the most used binder across units. The audit only provided a snapshot in time but highlighted the need to standardise our practice not only within units but across the West Midlands. In addition to this it highlighted the need for multidisciplinary protocols within units to promote uniformity of practice. The audit was presented at the West Midlands Audit Meeting in November Following on from this the West Midlands Renal Network Group endorsed the need to develop regional bone management guidelines. A steering group was set up. All nephrologists and renal dieticians who participated in the audit were invited to join as well as a pharmacist and Nanette Grant to represent the West Midlands Renal Network Group. The first meeting was in November 2008 with subsequent meetings in January 2009, May 2009, July 2009, September 2009 and March In April 2006, the group conducted a West Midlands Renal Dietetic staffing survey and compared current staffing levels to the national BRS Workforce Planning Recommendations The group also undertook an evidence review prior to the publication of the KDIGO guidelines in 2009 on calcium content of dialysis fluid, elemental calcium content of phosphate binders, PTH levels and starting dose of alfacalcidol, PTH assay, vascular calcification in diabetics, vitamin D 3 monitoring and supplementation. The Renal Association Guidelines, KDIQO guidelines, Renal Registry Data and KDIGO guidelines when they were published in 2009 were reviewed by the group. Dr. Alan Jones, Clinical Biochemist was invited as an external speaker to discuss PTH assay and Vitamin D monitoring at a group meeting. WMRN/Regional Bone Management Guidelines /1010/Final 6

7 2. Summary of guidelines Guideline 1: Dietetic Referral Good Practice Recommendation: It is important to detect and manage hyperphosphataemia at an early stage. All patients with CKD Stage 4 and with a serum phosphate level > 1.4mmol/l should be referred to a Renal Dietitian for a full dietary assessment. Good Practice Recommendation: Renal Dietetic staffing levels should be based on the BRS Renal Workforce Planning Recommendations 2002 as stated below. This is currently under review and therefore the recommendations may change in the future. 1WTE per 135 haemodialysis patients 1WTE per 180 low clearance patients 1 WTE per 270 peritoneal patients 2 WTE per 28 bedded ward Guideline 2: Dialysis Adequacy Good Practice Recommendation: Minimum haemodialysis hours should be based on 4hours x 3times per week In relation to phosphate control, urea reduction ratio (URR) should be maintained > 65% and/ or equilibrated Kt/V should be maintained >1.2 (RA standard) Guideline 3: Phosphate Good practice recommendation: Pre-dialysis serum phosphate measurements should be monitored monthly. Pre-dialysis blood samples should be taken in a shorter inter-dialytic interval. Effort should be made to lower serum phosphate levels to within normal laboratory reference range. It is recommended that patients with: A serum phosphate level > 1.4mmol/l should be referred to a Renal Dietitian All patients should have their serum phosphate levels maintained <1.6mmol/l with adequate dialysis, dietary modification and/or use of phosphate binders. Guideline 4: Corrected Calcium Good practice recommendation: Pre-dialysis serum corrected calcium measurements should be monitored monthly. Pre-dialysis samples should be taken in a shorter inter-dialytic interval Pre-dialysis serum calcium, adjusted for serum albumin, should be within the normal laboratory reference range. WMRN/Regional Bone Management Guidelines /1010/Final 7

8 Guideline 5: Parathyroid Hormone (PTH) Good practice recommendation: PTH should be monitored at least 3monthly and treatment changes should be based on trends of serum PTH rather than a single measurement. Changes in serum phosphate, corrected calcium and alkaline phosphatase levels should be taken into consideration when making treatment changes. Raised alkaline phosphatase levels in the absence of evidence of liver disease would suggest high bone turnover. PTH levels should be maintained within 2-9 times of upper limit of laboratory reference range. The group acknowledge that it is not logistically feasible to standardise PTH assay across the region. Laboratories should express PTH values in pmol/l to enable comparison between units for audit purposes. However, we need to recognise that there remains variability between assays. Patients on Paricalcitol and Cinacalcet need more frequent monitoring of PTH levels particularly following initiation or changes to treatment. Guideline 6: Dialysis fluid Calcium Concentration There is insufficient evidence to support the use of 1.25, 1.5 or 1.75mmol calcium concentration in standard dialysis fluid. Good Practice Recommendation: To use standard dialysis fluid calcium concentration of 1.5mmol To use dialysis fluid calcium concentration of 1.25mmol for patients with adynamic bone disease (ADBD), evidence of vascular calcification or hypercalcaemia To use dialysis fluid calcium concentration of 1.75mmol for patients with hypocalcaemia. Guideline 7: Phosphate Binders Good Practice Recommendation: Phosphate Binder should be started when phosphate levels 1.6mmol/l despite adequate dialysis and dietary modification. Guideline 8a: Calcium Containing Phosphate Binder Good Practice Recommendation: The choice of phosphate binder should be individualised, depending on clinical circumstances. In comparison to calcium carbonate, calcium acetate has a higher binder capacity per mg of elemental calcium and its action is less ph dependant. Calcium carbonate may be less effective when used with inhibitors of gastric acidity e.g. proton pump inhibitors WMRN/Regional Bone Management Guidelines /1010/Final 8

9 Guideline 8b: Elemental calcium content of Phosphate Binders. There is insufficient evidence to make a recommendation limiting the oral calcium from diet or binders. Good Practice Recommendation: An individualised strategy to limit the total calcium intake should be in place for patients: on higher dialysis fluid calcium concentration (>1.5mmol/l) with pre-existing vascular calcification or at risk of vascular calcification (e.g. diabetics). A lateral abdominal x-ray can be used to assess vascular calcification. with elevated serum calcium levels with low serum PTH levels. Calcium based binders should be synchronised with phosphate containing meals. Guideline 8c: Non-Calcium Containing Phosphate Binder There is insufficient evidence to recommend any one non-calcium binder over another Good Practice Recommendation: Starting any binder should be at the clinician s discretion and should take into account all relevant patient factors. Guideline 8d: Aluminium Hydroxide Good Practice Recommendation: Aluminium hydroxide should be used as last resort and for a limited period of 3 months; further use will be at the clinician s discretion. Guideline 9: Pharmacological treatment with active vitamin D compounds. There is insufficient evidence to recommend either calcitriol or alfacalcidol as the first line vitamin D therapy. The group felt that as alfacalcidol is a prodrug, calcitriol should be used in preference. There is insufficient evidence to make a recommendation on the starting dose of calcitriol or alfacalcidol based on PTH levels. Good Practice Recommendation: Commence calcitriol or alfacalcidol at the lowest dose and titrate according to serum calcium and subsequent PTH values. Aim to maintain corrected calcium within the normal laboratory reference range and phosphate levels 1.6mmol/l. Paricalcitol should be considered on patients with high serum PTH levels and a serum calcium level at the upper level of the normal reference range despite maximum oral or intravenous active vitamin D therapy. WMRN/Regional Bone Management Guidelines /1010/Final 9

10 Good Practice Recommendation: Monitoring and supplementing 25- hydroxyvitamin D (25(OH)D) to counteract vitamin D insufficiency. The group feels that, in view of the emerging evidence of pleiotropic effects of 25(OH)D in patients with CKD, it is perhaps reasonable to identify vitamin D deficiency among dialysis patients and give supplementation with vitamin D 3 (cholecalciferol) or vitamin D 2 (ergocalciferol) as a single substance not combined with calcium or other vitamins. Vitamin D supplementation should not be confused with calcitriol or alfacalcidol treatment. Guideline 10: Treatment of uncontrolled severe secondary hyperparathyroidism. Good Practice Recommendation: For patients who are fit for surgery, total parathyroidectomy without re-implantation should be considered as treatment for persistent severe secondary hyperparathyroidism (PTH levels > 9 times upper limit of normal reference range) despite maximum medical therapy and clinical evidence of morbidity in association with this. In the presence of calciphylaxis parathyroidectomy should be considered in patients with lower PTH levels. Cinacalcet should be considered in patients with persistent severe secondary hyperparathyroidism who are high surgical risk for parathyroidectomy in accordance with the NICE guidelines. Cinacalcet should also be considered in such patients who are fit for surgery but for whom surgery is not immediately available for whatever reason. WMRN/Regional Bone Management Guidelines /1010/Final 10

11 3. Chronic Kidney Disease related Mineral and Bone Disorders Chronic kidney disease mineral bone disorder can be defined as a systemic disorder of mineral and bone metabolism due to chronic kidney disease manifested by one or a combination of the following: Abnormalities of calcium, phosphorus, parathyroid hormone (PTH) or vitamin D metabolism Abnormalities in bone turnover, mineralisation, volume, linear growth or strength Vascular or other soft tissue calcification (KDIQO, 2009) Abnormalities in phosphate homeostasis is detected with a glomerular filtration rate (GFR) <30mls/min (CKD Stage 4) resulting in elevated serum phosphorus levels. Hyperphosphataemia inhibits calcitriol production which results in reduced calcium absorption and hence serum calcium levels fall. Hypocalcaemia and lower calcitriol production stimulates PTH synthesis and secretion causing an elevation in serum PTH levels. If hyperphosphataemia remains untreated, by the time most people progress to CKD stage 5 they are at higher risk of developing hyperparathyroidism, cardiovascular and soft tissue calcification all of which can contribute substantially to cardiovascular mortality. The most threatening localization of unwanted calcification is at vascular sites where it can manifest as medial (arteriosclerotic) and intimal (atherosclerotic) calcification of the arteries. Medial is the most common target of vascular calcification in end stage renal disease and diabetes. Intimal follows development of atherosclerosis plaques which cause narrowing of the vessels and is more common in elderly patients. It is associated with cardiovascular events such as myocardial infarction, angina and stroke. Medial calcification results in calcified blood vessels which cause arterial stiffness leading to an elevated pulse pressure and increased pulse wave velocity. This contributes to reduced coronary perfusion, left ventricular hypertrophy, dysfunction and failure. Advanced calcification of the heart valves may lead to heart failure and increased risk of endocarditis. Cardiovascular calcifications are usually progressive and their extent and severity are highest in patients with CKD. Experimental studies cited by KDIGO 2009, suggest that the vascular smooth muscle cell may be critical in the development of calcification by transforming into osteoblast-like phenotype. Elevated phosphate and calcium levels are thought to stimulate this transformation of smooth muscle cells into oesteoblast like-cells which can accelerate calcification process in CKD. Risk of vascular calcification is higher in patients with diabetes, increasing age, long history of haemodialysis and high calcium phosphate product. Early management of hyperphosphataemia to try and delay the progression of calcification prior to initiation of haemodialysis is therefore of prime importance in the management of mineral bone disorder. WMRN/Regional Bone Management Guidelines /1010/Final 11

12 Guideline 1: Dietetic Referral Good Practice Recommendation: It is important to detect and manage hyperphosphataemia at an early stage. All patients with CKD Stage 4 and above with a serum phosphate level > 1.4mmol/l should be referred to a Renal Dietitian for a full dietary assessment. Good Practice Recommendation: Renal Dietetic staffing levels should be based on the BRS Renal Workforce Planning Recommendations 2002 which state: o 1WTE per 135 haemodialysis patients o 1WTE per 180 low clearance patients o 1 WTE per 270 peritoneal patients o 2 WTE per 28 bedded ward As phosphorus levels begin to elevate above the normal reference range, dietary phosphate restriction should be considered as first line management as CKD stage 4. Earlier guidelines recommended that dietary phosphate should be restricted to between mgs/ day when dietary phosphate levels rise above normal target levels in CKD stage 4 (KDOQI 2003, ESPEN 2006). More recently the KDIGO guidelines did not advise on a daily phosphate dietary intake target, but suggested dietary phosphate restriction may be helpful in early stages of CKD. Dietary phosphorus is found in protein foods therefore achieving an adequate reduction in phosphate intake without compromising adequate protein intake can be difficult. Further symptoms evident in advanced CKD such as progressive worsening of appetite, reduced protein and calorie intake along with a spontaneous reduction in protein intake (Iklizer,1995) can increase the risk of protein-energy malnutrition. It is advisable therefore for patients with declining renal function, particularly CKD stage 3 and onwards, to receive specialist and individualised dietary advice from a Renal Dietitian. The Renal Association guidelines recommended that all units should have access to dedicated renal dietitians in line with the British Renal Society Workforce Planning Recommendations In addition to this, they recommend that intensive dietetic support is required to optimise compliance and the effectiveness of dietetic input. The KDOQI guidelines also endorsed the importance of appropriate education and counselling to ensure appropriate phosphate modification whilst maintaining an adequate protein intake. Once commenced on haemodialysis, current guidelines available suggest that patients should be advised on a dietary phosphate restriction of 1200mg per day. Achieving this level of phosphate restriction is very difficult due to the increased protein requirements secondary to dialysis protein losses. Dialysate losses of proteins, including amino acids, peptides and whole proteins are estimated to be approximately 10-12g per session. Haemodialysis patients are therefore advised to WMRN/Regional Bone Management Guidelines /1010/Final 12

13 maintain a protein intake between 1-1.2g/kg/ideal body weight (IBW) per day. There are various other dialysis and non-dialysis issues which can adversely affect nutritional intake making it difficult to achieve this protein intake. Imposing a dietary phosphate restriction can further compromise this. KDIGO 2009 reported that there was insufficient data to strongly endorse dietary phosphate restriction as the primary intervention in CKD stage 5, but suggested that dietary restriction as an adjunct to phosphate binders and dialytic removal may be beneficial. Due to the limitations of dietary phosphate modification and dialysis removal, the majority of dialysis patients will require phosphate binders to help control their phosphate levels. In order to work effectively, phosphate binders need to be adjusted according to the phosphate content of meals and snacks. The renal dietitian is recognised by the renal multi-professional team as being in the best position to assess these requirements and to facilitate patient concordance by finding a preparation most suited to the patient in terms of acceptability, dosage and maintaining phosphate and corrected calcium levels within target ranges (KDOQI,2003). A dietetic led approach to calcium phosphate management under an agreed protocol has been introduced in a number of renal units nationally and has been shown to be safe and effective (Wells, 2002, Howes, 2003). The West Midlands Regional Audit highlighted that both clinicians and dietitians agreed that Renal Dietitians should lead or at least be involved in the management of calcium and phosphate. At the time of our audit, the majority of units did not have dietetic protocols in place for commencing and adjusting phosphate binders. Despite this, the audit highlighted that 100% of clinicians within the West Midlands agreed dietitians were best placed to make recommendations to dosage of binders and changes to timings of binder and 92% felt dietitians made recommendations in adjustments to the type of binder used. Within our steering group, the overall agreement was that Renal Dietitians have a vital role in the management of mineral bone disorders but acknowledged the limitations of achieving this without adequate dietetic funding within units. In 2002, BRS developed workforce planning recommendations for dietetic time across all treatment modalities. Our group felt it would be useful to compare renal dietetic manpower within the West Midlands to these guidelines. In April 2006 a survey was conducted, which highlighted an overall deficit for all treatment modalities of 21.1WTE Dietitian. When subdivided, there was a 5.5 WTE deficit for haemodialysis and a 15.6 WTE deficit for all other treatment modalities in comparison to the recommendations. (Refer to appendix 2 for full results of the survey). These workforce planning recommendations are currently under review and will updated accordingly in our guidelines. More recently, results from the West Midlands Quality Peer Review (February 2010) highlighted that Allied Health Professionals (AHP) staffing was below the recommended level when compared to the BRS Workforce Planning Recommendations. They recommend that The Renal Network should review the expected contribution of AHP s to services for patients with end stage renal failure WMRN/Regional Bone Management Guidelines /1010/Final 13

14 and the staffing levels needed to achieve this, taking account of development of new roles and new ways of working. The working group all agreed that a Renal Dietitian should first be involved in the treatment of mineral bone disorders early at stage 4 when phosphate levels start to rise above the normal reference range to assess diet, educate on a low phosphate diet as required whilst ensuring that an adequate energy and protein intake is maintained. At present, due to the current deficit in dietetic staffing levels in the West Midlands this will not be achievable. Additional dietetic funding may be required within units to facilitate this therefore a recommendation on dietetic staffing levels from the Workforce Planning Recommendations has been included within the Protocol. WMRN/Regional Bone Management Guidelines /1010/Final 14

15 Guideline 2: Dialysis Adequacy Good Practice Recommendation: Minimum haemodialysis hours should be based on 4hours x 3times per week. In relation to phosphate control, urea reduction ratio (URR) should be maintained > 65% and/ or equilibrated Kt/V should be maintained >1.2 (,RA standard) Between 50-70% of dietary phosphate is absorbed, therefore a well nourished dialysis patient following the recommended dietary phosphate restriction would absorb between mgs per week. Serum phosphate levels drop rapidly in the first 1-2 hours of treatment then plateau. Dialysis removal decrease in the 2 nd half of dialysis and serum phosphate levels then rise relatively quickly in the first few hours after termination of dialysis so called the rebound phenomenon Conventional 4hours, thrice weekly haemodialysis treatment removes between mgs per session equating to 3000mgs per week, therefore even patients receiving adequate dialysis will not achieve adequate phosphate removal. Renal Association recommend that minimum haemodialysis hours should be 4hours x3 times per week and URR should be maintained >65% and/or Kt/V >1.2. Patients receiving less than these recommended dialysis hours or inadequate dialysis will have reduced phosphate removal which will further enhance hyperphosphataemia. Additionally, inadequate dialysis can induce uraemic symptoms which can compromise dietary intake thus making dietary phosphate restrictions more difficult to achieve. Striving to achieve minimum haemodialysis hours and dialysis adequacy targets should be considered an important part of phosphate management. Members of the steering group agreed that in relation to phosphate control, the recommendation for minimum haemodialysis hours and dialysis adequacy should be consistent with the Renal Association targets. WMRN/Regional Bone Management Guidelines /1010/Final 15

16 Guideline 3: Phosphate Good practice recommendation: Pre-dialysis serum phosphate measurements should be monitored monthly. Pre-dialysis blood samples should be taken in a shorter inter-dialytic interval. Effort should be made to lower serum phosphate levels to within normal laboratory reference range. It is recommended that patients with: A serum phosphate level > 1.4mmol/l should be referred to a Renal Dietitian All patients should have their serum phosphate levels maintained 1.6mmol/l with adequate dialysis, dietary modification and/or use of phosphate binder. No randomised control trials have been conducted to demonstrate outcome benefits at any level of phosphate control (KDIGO 2009) Epidemiological and observational data have demonstrated hyperphosphataemia to be an independent predictor of cardiovascular mortality in dialysis patients. (DOPPS, Block et al 2004) Block et al, 2004 found that serum PO4 levels > 1.6mmol/l were associated with a stepwise increase in all cause mortality and cardiovascular mortality. Observational data from DOPPS also found serum PO4 > 1.62 and > 1.94mmol/l were associated with increased cardiovascular mortality risk and all cause mortality risk respectively. DOPPS data also showed that if a facility had 10% more patients with phosphate levels between mmol/l and >2.26mmol/l mortality risk was 5.3% and 4.3% higher respectively. Block et al 2004 also found a serum PO4 level <0.96mmol/l to have a1.5 times mortality risk although this did not reach statistical significance. One plausible explanation for this observed risk could be that patients with low serum phosphate levels may reflect poor nutritional intake. Dietetic assessment and intervention in patients who have persistently low serum phosphate levels is essential. KDIGO 2009 recommended that in the absence of randomised control trials, phosphate control should be individualised. They did however, acknowledge that based on the positive correlation shown between higher serum phosphate levels and mortality in epidemiological studies that it would seen plausible to aim for serum phosphate levels to be lowered towards the normal reference range in stage CKD 5d. The steering group agreed that it was difficult to set a target for phosphate based on the limited and poor quality of evidence available, but agreed aiming for a phosphate level 1.6mmol/l would be sensible based on observational data suggesting phosphate levels >1.6mmol/l are associated with cardiovascular mortality and PO4 levels > 1.94mmol/l are associated with an all cause mortality risk. In order to achieve this target, the group agreed that patients should be referred to a Renal Dietitian when phosphate levels > 1.4mmol/l and initiation of treatment should be considered as phosphate levels start to rise > 1.6mmol/l. WMRN/Regional Bone Management Guidelines /1010/Final 16

17 The group recommend that phosphate measurements should be standardised to be taken during the shorter inter-dialytic interval and monitored on a monthly basis. Treatment changes should be made taking into considerations trends in phosphate levels rather than individual measurements. The group recommend that phosphate management should be a three tier approach encompassing dialysis adequacy, dietary modification and phosphate binder therapy. WMRN/Regional Bone Management Guidelines /1010/Final 17

18 Guideline 4: Corrected Calcium Good practice recommendation: Pre-dialysis serum corrected calcium measurements should be monitored monthly. Pre-dialysis samples should be taken in a shorter inter-dialytic interval Pre-dialysis serum calcium, adjusted for serum albumin, should be within the normal laboratory reference range No randomised control trials are available to demonstrate outcome benefits at any calcium level. Observational data from DOPPS demonstrated the highest risk of mortality with serum calcium >2.53mmol/l. Block et al 2004 associated this risk with serum levels > 2.38mmol/l. It is not clear from the available data, what level of low serum calcium levels is associated with mortality risk. The measurement of serum calcium, corrected for albumin, is susceptible to all the problems of inter-assay variation. In addition to this there are several formulae in use for correction of serum calcium for albumin concentration. Comparisons of standards of care between units, with regard to control of serum calcium will, therefore, remain difficult until these problems have been resolved. (RA) The group agreed it was difficult to set a target for calcium due to the limited data and poor quality available in addition to the problems with inter-assay variation. The group recommend that measurements of calcium, adjusted for serum albumin, should be standardised to be taken during the shorter inter-dialytic interval and monitored on a monthly basis. Treatment changes should be made taking into considerations trends in calcium levels rather than individual measurements but recommend aiming for calcium levels within the normal laboratory reference range. WMRN/Regional Bone Management Guidelines /1010/Final 18

19 Guideline 5: Parathyroid Hormone (PTH) Good practice recommendation: PTH should be monitored at least 3 monthly and treatment changes should be based on trends of serum PTH rather than a single measurement. Changes in serum phosphate, corrected calcium and alkaline phosphatase levels should also be taken into consideration when making treatment changes. Raised alkaline phosphatase levels in the absence of liver disease would suggest high bone turnover PTH levels should be maintained within 2-9 times of upper limit of laboratory reference range. The group acknowledge that it is not logistically feasible to standardise PTH assay across the region. Laboratories should express PTH values in pmol/l to enable comparison between units for audit purposes. We need to however recognise that there remains variability between assays. Patients on paricalcitol and Cinacalcet need more frequent monitoring of PTH levels particularly following initiation or changes to treatment. Reliable measurements of PTH are essential for the appropriate diagnosis and management of patients with CKD mineral bone disorder. The West Midlands audit found that the greatest discrepancy in biochemical markers across the region was in relation to PTH targets. There were eight different PTH target ranges reported across units, and two different concentration units for PTH (ng/l or pmol/l). In view of these discrepancies, the group investigated the possibility of standardising PTH assays across the region. Dr Alan Jones, Biochemist from Birmingham Heartlands Hospital was invited to attend one of the meetings. Dr Jones gave a thorough overview of PTH assays and clarified some of the terminology with regards to the different assays used. PTH metabolism PTH is a single polypeptide of 84 amino acids. Intact PTH is the form stored in the glands and the principal form secreted into the bloodstream. The intact PTH (1-84) molecule is metabolised within minutes to form an amino acid fragment of at least 34 amino acids (N terminal fragment), carboxy-terminal (C terminal fragments) and mid-regional PTH fragments of varying lengths. N-terminal fragments are metabolized in the liver. The main pathway for elimination of C-terminal PTH fragments is glomerular filtration, followed by tubular degradation. As a consequence of this C-terminal fragments are retained in patients with CKD. The biological activity of intact PTH resides in the first 34 amino acids in the N-terminal. C terminal fragments consist of amino acids which are biologically inactive. WMRN/Regional Bone Management Guidelines /1010/Final 19

20 PTH Assay The first assays used were known as competitive assays which are no longer used and utilised a radiolabelled antibody directed at the C terminal of PTH. Since the assay measured both intact PTH and C-terminal fragments, without biological activity, it over-estimated functional PTH and has been replaced with other tests which are likely to better represent functional PTH. 1 st generation immunometric assays used to measure intact PTH, used two antibodies directed against PTH, in a two site non-competitive immuno-metric assay. In these measurements the first antibody is detected at the N-terminal fragment (containing amino acids 1-37) and the second antibody at the C-terminal fragment (containing amino acids 38-84). There are currently a number of commercially available kits that measure intact PTH. Each kit comes with a specific antibody reagent therefore the antibody binding site on the N-terminal varies depending on the PTH assay used. For example the Allegro Assay (Nichols Institute Dianostics) binds between whereas the Elecsys Assay (Roche Diagnostics) and the Siemens assay bind between (Torres, 2006) The antibody reagent is specific to each kit and is not inter-changeable with analytical equipment from alternative manufacturers. The normal laboratory reference range for PTH within individual units will therefore be set according to the equipment used. To standardise PTH assay across the region each unit would need to purchase equipment from the same manufacturer. As this equipment is very expensive it is unfeasible to make a recommendation for each laboratory to change their equipment. In the KDOQI guidelines 2003, the recommendation for a PTH target of ng/l was based on the predictive ability of an assay (Nichols Allegro ipth assay) to identify low and high turnover bone diseases. This assay is no longer available and studies since then have shown PTH levels within this range are not predictive of underlying bone disease (KDIGO, 2009). It is therefore is no longer feasible to state KDOQI target PTH ranges for units to work towards that is based on this assay. Souberbielle et al, 2006 compared the PTH concentrations measured with 15 commercial kits in 47 serum pools from dialysis patients using the Allegro assay as reference. Although the assays were highly correlated, the PTH concentrations differed from one assay to another. The median bias between the tested assays and the Allegro assay ranged from to 123%. When the PTH concentrations were ng/l with the Allegro intact PTH assay, the concentrations with other assays ranged from 83 to323 ng/l and from 160 to638 ng/l. The authors associated this variability in results with the standardisation and antibody specificity of each kit. Different assays were found to measure different quantities of N and C-terminal fragments. WMRN/Regional Bone Management Guidelines /1010/Final 20

21 The steering group also reviewed the results of a study conducted in Dumfries and Galloway NHS Trust which compared different assays. This study included 21 haemodialysis patients. Five one ml plasma samples were taken. One sample was analysed in local laboratory and the other samples were analysed at 4 different centres on the same day. Each of the laboratories used different PTH assays (Diasorin, Beckman Access, Roche, Siemens Centaur, Siemens Immunolite). For one patient the PTH levels ranged from (a 3.4 fold differences). In the remaining patients there was fold difference in the levels. The authors concluded that the PTH variability caused by the nature of the assay is large enough to potentially influence clinical decision making. The study concluded that PTH concentration varied widely depending on the assay used. It was originally believed these assays could accurately measure whole molecule PTH (amino acids 1-84) as they did not detect the smaller molecular weight PTH fragments in the middle and C-terminal regions of PTH. More recent studies have noted that these two site ipth assays appeared to react with an additional molecular form of PTH. This was thought to be a large PTH fragment with a truncated N- terminus also known as non-(1-84) PTH. This fragment is positioned at PTH (7-84) thereby missing amino acids 1-6 in the N-terminus which are thought to be the most biologically active. It is thought this fragment of PTH contains large biologically inactive fragments of middle and C-terminal PTH which accumulate due to the inability of the kidneys to excrete them as normal. PTH (7-84) thought to account for 35 to 55% of intact PTH in haemodialysis patients. 2 nd generation assays have recently become available which only detect 1-84 aminoacid full length molecule. Dr Jones informed the group that currently no 2 nd generation assays are available. KDIGO have reported currently there is no supportive evidence which demonstrate these assays convincingly improve this predictive value in detecting underlying bone disease or other markers of bone turnover. KDIGO 2009 reported problems with sample collection and assay variability raise significant concerns with regard to the validity of absolute levels of PTH and their use as a clinically relevant biomarker for targeting specific values. Nevertheless the clinical consequences of not measuring PTH and treating secondary hyperparathyroidism are of equal concern. PTH Target Range Due to the variation in PTH assays used across the region and the inability to standardise these, it is difficult to make a recommendation on a set target range for PTH. If different assays are used within units across the region, this would lead to variations in PTH readings making it difficult to follow the same target range. To limit variability between PTH measurements, dialysis units should aim to ensure local standardisation in the methods of sample collection, processing and assay used. WMRN/Regional Bone Management Guidelines /1010/Final 21

22 Evidence from observational data, assessing association between PTH and patient level end points have found the range at which PTH becomes significantly associated with increased all-cause mortality risk varies between 400- > 600ng/L (Kalantar- Zadehr, 2006, Young et al 2005, DOPPS I& II, Kimata et al, 2007, Block et al 1998, Block et al 2004). DOPPS I, II and III (Tentori, 2008) found a non-significant increase in all-cause and cardiovascular mortality risk for patients with PTH level compared to patients with PTH ng/L. There was a significant 21% increase in all-cause mortality when PTH levels > 600ng/L compared to patients with PTH levels ng/L. Block et al, 2004 demonstrated that when results were multi-variable adjusted, the relative risk of mortality was greater in patients with PTH levels > 600 ng/l. Studies relating to PTH are complicated by the problems with assay methods and poor precision. Further limitation is that they only use single-base line figures or infrequent measurements. KDIGO highlighted that there are no randomised control trials to demonstrate that achieving a specific PTH level will result in improved outcomes. KDIGO 2009 recommend that PTH levels < 2 times upper or > 9 times upper level of normal for the PTH assay used represents extreme risk. PTH levels should not be interpreted in isolation. Consideration of other bone parameters such as calcium, phosphate, alkaline phosphatase in addition to PTH levels should guide therapy. The group agreed that large elevations in PTH levels are more likely to be of concern and agreed that trends in PTH levels overtime rather than precise measurements should be used to guide therapy. To facilitate this, PTH measurements should be taken more frequently and a recommendation of 3 monthly PTH measurements is recommended. WMRN/Regional Bone Management Guidelines /1010/Final 22

23 Guideline 6: Dialysis fluid Calcium Concentration There is insufficient evidence to support the use of 1.25, 1.5 or 1.75mmol calcium concentration in standard dialysis fluid. Good Practice Recommendation: To use standard dialysis fluid calcium concentration of 1.5mmol To use dialysis fluid calcium concentration of 1.25mmol for patients with adynamic bone disease (ADBD), evidence of vascular calcification or hypercalcaemia To use dialysis fluid calcium concentration of 1.75mmol for patients with hypocalcaemia. The KDOQI (2003) guidelines recommended a calcium concentration in dialysis fluid of 1.25mmol/l. This was however, based on opinion. As yet there is no evidence to suggest that low calcium concentrate is more beneficial than 1.5mmol/l or 1.75mmol/l concentrate in general. A prospective control study of 5 years of the effect of the 3 concentrates did not show any significant effect on serum ipth or overall survival. The only benefit noted was a lower serum calcium level in the low calcium concentrate group at the end of the study (Hwang et al, 2008). Another prospective study showed low calcium dialysis fluid caused improvement in bone turnover in patients with adynamic bone disease (Hemano et al, 2005). A systematic review observed that low calcium baths are useful in the setting of adynamic bone disease where an increase in bone turnover is required. Low calcium levels in the dialysate, however, may also predispose to cardiac arrhythmias and hemodynamically unstable dialysis sessions with intradialytic hypotension. Higher calcium dialysate is useful to sustain normal serum calcium levels where patients are not taking calcium-based binders or if calcium supplements are not able to normalize serum levels. Suppression of hyperparathyroidism is also effective with dialysate calcium of1.75 mmol/l, but hypercalcemia, metastatic calcification, and oversuppression of parathyroid hormone are risks. Dialysate calcium of 1.5mmol/L may be a compromise between bone protection and reduction in cardiovascular risk for conventional HD (Toussaint et al, 2006). The group agreed that 1.5mmol calcium should be used as the standard dialysis fluid. The group did agree however that within the guideline we need to be flexible with our recommendations regarding dialysis fluid calcium concentration based on individual clinical judgement. The group also agreed that this recommendation will be reviewed in line with new research. WMRN/Regional Bone Management Guidelines /1010/Final 23

24 Guideline 7: Phosphate Binders Good Practice Recommendation: Phosphate Binder should be started when phosphate levels 1.6mmol/l despite adequate dialysis and dietary modification. Due to the limitations of dietary phosphate modification and dialysis removal, the majority of dialysis patients will require phosphate binders to help control their phosphate levels. KDOQI Guidelines 2003 completed a systematic review of all randomised control trials examining phosphate binders and concluded that all phosphate binders were effective at lowering serum phosphate levels. KDIGO 2009 has followed this recommendation stating that for patients with CKD stage 5d, phosphate-binding agents should be used in the treatment of hyperphosphataemia. Despite many advances in the range of phosphate binders available for the treatment of hyperphosphataemia, phosphate control remains inadequate across renal unit. The latest Renal Registry Data (2009) indicates 55% of units achieved serum phosphate levels mmol/l. The West Midlands audit based on data for 2006, found that on average 65% units achieved serum phosphate levels < 1.8mmol/l (range 52-76%) Inadequate phosphate control could be attributed to poor concordance with dietary advice and phosphate binder therapy. It is feasible that this concordance issue may be in part, due to patients understanding of dietary phosphate, phosphate binders and the consequences of hyperphosphataemia. Several studies have suggested that focused education programmes from renal dietitians are effective in enhancing patients knowledge about dietary phosphate and phosphate binders and consequently improving serum phosphate levels in those with hyperphosphataemia (Reddy et al 2009, Nisio et al 2007, Ford et al 2004, Ashurst & Dobbie 2003). Stamatakis et al (1997) also found that patients awareness of the consequences of hyperphosphataemia and its treatment was associated with lower serum phosphate levels. In order to work effectively, phosphate binders need to be adjusted according to the phosphate content of meals and snacks. Additionally, further patient education could enhance their efficacy and potentially improve concordance in terms of timing of binder therapy and better understanding of how binders work. The renal dietitian is recognised by the renal multi-professional team as being in the best position to assess these requirements and to facilitate patient concordance by finding a preparation most suited to the patient in terms of acceptability, dosage and maintaining phosphate and corrected calcium levels within target ranges. (KDOQI, 2003). A dietetic led approach to calcium phosphate management under an agreed protocol has been introduced in a number of renal units nationally and has been shown to be safe and effective (Wells, 2002, Howes, 2003). WMRN/Regional Bone Management Guidelines /1010/Final 24

25 Another factor attributable to the poor concordance of phosphate binders is the number and size of tablets required to achieve target phosphate levels. Reducing the daily pill burden could be potentially advantageous for maintaining patient concordance with phosphate binder. The CARE study (2004) found the average dose of sevelamer was 6.9g/day (equivalent to mg tablets or mgs tablets). This is comparable to the findings of the Treat to Goal Study where 6.5mgs/day of sevelamer was required to maintain target phosphate levels. (Chertow et al 2002). The average dose of calcium acetate (Phoslo) required to control phosphate levels in the CARE study was 7g/day which is equivalent to 10.7 tablets per day. Chertow et al, found serum phosphate levels were maintained with calcium acetate at a daily dose of 4.6g per day which is equivalent to approximately x7 Phoslo or x5 Phosex tablets per day. Phase II and III trials assessing the efficacy of lanthanum carbonate found the daily dose required to maintain serum phosphate levels was mgs/day, equivalent to 3x500mg or 3x1000mg tablets per day. (Hutchison et al 2004, 2005, 2006, Al-Baaj et al 2005, Joy& Finn 2003 and Finn 2006). Vemuri et al (2006) showed that treatment with lanthanum carbonate allowed a reduction in the overall phosphate binder tablet burden of approximately 30 40% compared with the patients previous therapy, while maintaining target serum phosphate levels. When comparing specifically with combination therapy, the reduction in tablet burden was as high as 56%. Patient preference should also be taken into consideration when commencing phosphate binders. Kaplan et al (2002) evaluated patient preference of calcium acetate in tablet form compared with gelcap (Phoslo) formulation. They found 90% of patients preferred calcium acetate gelcaps to the tablet formulation. A study by Mehrotra et al, involving 509 patients with established renal failure, found patient and physician satisfaction and preference scores to be strongly in favour of lanthanum carbonate over sevelamer, calcium-based phosphate binders and other phosphate binders. The range of phosphate binders available are summarised in Appendix 2. When commencing a phosphate binder the choice of agent should be individualised taking into account all clinical circumstances including: Patient tolerance Size of tablets Number of tablets Side effects Effects of available agents on a range of clinical parameters (KDIGO 2009) WMRN/Regional Bone Management Guidelines /1010/Final 25

26 Guideline 8a: Calcium Containing Phosphate Binder Good Practice Recommendation: The choice of phosphate binder should be individualised, depending on clinical circumstances. In comparison to calcium carbonate, calcium acetate has a higher binder capacity per mg of elemental calcium and its action is less ph dependant (Sheikh et al, 1989) Calcium carbonate may be less effective when used with inhibitors of gastric acidity e.g. proton pump inhibitors The KDOQI guidelines particularly reviewed trials comparing calcium carbonate and calcium acetate and concluded that both were effective at lowering serum phosphorus. Both were associated with hypercalcaemia but reported calcium acetate to be less hypercalcaemic than calcium carbonate. Sheikh et al 1989 found that in comparison to calcium carbonate, calcium acetate has a higher binder capacity per mg of elemental calcium and its action is less ph dependant. The authors concluded that more calcium acetate can be administered to control phosphate levels with less effect on serum calcium levels in comparison to calcium carbonate. KDIGO 2009 endorsed KDOQI recommendations but found no further comparative studies between calcium acetate and calcium carbonate. Various trials since then have focused on comparison between calcium containing binders with either sevelamer or lanthanum carbonate. WMRN/Regional Bone Management Guidelines /1010/Final 26