Multidisciplinary or multifaceted renal care in early chronic kidney disease

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1 Multidisciplinary or multifaceted renal care in early chronic kidney disease Date written: July 2012 Author: Maria Chan, David Johnson GUIDELINES a. We recommend an individualised, structured care plan with appropriate prescription of medications and interventions targeting cardiovascular and renal risk modification, for all patients with early chronic kidney disease (1D). b. We suggest the involvement of a multidisciplinary healthcare team (eg doctor, practice nurse, dietician, social worker, etc.) in the management of patients with early chronic kidney disease as this results in improved clinical outcomes compared with care provided by a health practitioner working in isolation (2C). UNGRADED SUGGESTIONS FOR CLINICAL CARE Patients with diabetes should be referred to other professionals specialising in diabetes (eg diabetologist, diabetes educator and dietician) as soon as practicable. IMPLEMENTATION AND AUDIT Multidisciplinary chronic kidney disease (CKD) programs currently being rolled out in renal units in Australia should audit the impact of these programs on achievement of guideline recommended targets (blood pressure, cholesterol, HbA 1c, use of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB)), as well as clinical outcomes (GFR decline, cardiovascular events, time to dialysis, etc). BACKGROUND Chronic kidney disease (CKD) has become a major public health problem in Australia[1] and throughout the world. Early CKD patients (stages 1, 2 and 3) are managed principally in the primary health care setting. In the literature, a number of observational cohort studies [2-13] have demonstrated that timely referral of patients with advanced CKD (stages 4-5) to a multidisciplinary renal unit is associated with reduced rates of decline of kidney function, hospitalisation rate and decreased patient morbidity and mortality. Clinical practice guidelines that recommend earlier referral (CKD stages 1-3) to multidisciplinary care are mostly based on expert opinions as there is no high level clinical evidence to support such practice. It is difficult to distinguish the magnitude of intervention effects from individual disciplines on the global outcomes such as rates of kidney function decline, hospitalisation and cardiovascular events. Perhaps, specific referrals should be made based on targeting intermediate outcomes, such as (1) weight reduction for overweight and obese subjects to control blood pressure and proteinuria by a dietician, (2) counselling of smoking cessation by a clinical psychologist. From the literature and in Australia, renal multidisciplinary specialist care in primary or community settings is uncommon. A number of questions are yet to be answered to support multidisciplinary care: Early Chronic Kidney Disease July 2012 Page 1 of 11

2 a. Definitions of multidisciplinary vs multifaceted vs multifactorial care b. Generalist vs specialist care c. Provision of services provided by independent practitioners vs team setting d. Optimal timing of intervention e. Generic advice vs prescriptive intervention f. Intervention prescription and strategy g. Frequency and duration of intervention and monitoring In addition, the potential benefits must be weighed against the potential disadvantages of multidisciplinary referral: a. Inefficient and costly health care utilisation b. Additional burden of interventions that may be perceived to reduce quality of life, especially in older patients with limited life expectancy who may not realise the potential long term benefits of multidisciplinary management SEARCH STRATEGY Databases searched: Text words for chronic kidney disease were combined with MeSH terms and text words for multidisciplinary, multifaceted, multifactorial, multi- targeted, intervention and education. The search was carried out in Medline (1966 January 2010). Searches were limited to adult human studies and to studies published in English. An updated search was conducted in Medline (2010 June 2012). Text words and MeSH terms for chronic kidney disease were combined with text words and MeSH terms for patient care team. Date of search/es: 25 January 2010 and June WHAT IS THE EVIDENCE? Few studies on the multidisciplinary, multifaceted, multifactorial chronic kidney disease management and intervention have been published for CKD stages 1 to 3. Harris et al [14] reported the findings of a randomised, controlled clinical trial of an intensive, multidisciplinary case management program for 5 years in 437 primary-care patients (73% of those eligible) with early CKD (estimated creatinine clearance consistently < 50 ml/min with the last serum creatinine level >1.4 mg/dl) who were attending an urban academic general internal medicine practice. Approximately 44% of patients were diabetic. For this study, two of the four general medicine practices were randomly assigned to intervention status. Once enrolled, control patients were returned to the general medicine practice to receive primary care from their usual physicians. These physicians were free to refer patients to the regular renal clinic, located in the same multi-specialty outpatient centre. Patients in the intensive case management group received consultations in a nephrology case management clinic staffed by nephrologists, a renal nurse, a renal dietitian and a social worker. A total of 381 (87%) patients completed the fifth-year follow-up. After every nephrology case management clinic visit, the study nephrologists wrote a standardized letter to the patient s primary care physician that included a summary of all actions taken, suggestions for further care, and a summary of the clinic visit. Despite significantly more outpatient visits by the intervention group, there were no significant differences in the primary outcome measurements i.e. renal function, health services use or mortality. There were also no significant differences in the use of renal sparing or selected potentially nephrotoxic drugs. The authors concluded that this intensive, intrusive and expensive multidisciplinary casemanagement intervention had no effect on the outcomes of care among primary-care patients with established CKD. Despite representing state-of-the-art care, it should be further tested before being accepted into standard practice. The study was limited by small sample size (leading to a possible type 2 statistical error), limited centre comparisons, ascertainment bias, open label design (raising the possibility of observer bias), limited costings analyses, and the possibility of a Hawthorn effect. Chan et al. [15] randomly assigned 205 Chinese type 2 diabetic CKD patients (plasma creatinine levels µmol/l) aged years from nine public hospitals to receive structured care (n = 104) or usual care (n = 101) for 2 years. The structured care group was managed by a diabetes team including diabetologists, endocrine trainees, dietician and diabetes nurses using a preprinted case report book Early Chronic Kidney Disease July 2012 Page 2 of 11

3 containing predefined scheduled visits (every 3 months and more frequently if needed), assessment items, and treatment targets defined as follows: I) blood pressure < 130/80 mmhg, 2) HbA lc <7%, 3) calculated LDL cholesterol <2.6 mmol/l, 4) fasting plasma triglyceride <2 mmol/l, and 5) treatment with ACEi and/or ARBs unless patients developed persistent hyperkalemia (& 5.5 mmol/1) or an acute rise in plasma creatinine (e.g. 30%) upon drug introduction or dose titration. The usual care group was managed according to the usual clinic practice as defined by the respective hospital with no modification. All usual care participants had access to laboratory tests, investigations, and counseling from a pharmacist, educator, or dietitian, but these were ordered at the doctor's discretion. A total of 167 (81%) participants completed the 2-year study (84 structured care and 83 usual care). The primary composite end point of death, creatinine >500 µmol/l or dialysis was not significantly different between the structured versus usual care groups on an intention-to-treat basis (23.1% vs 23.8%, p = NS, RR 0.96, 95% CI: ). Using per protocol analysis, patients who attained 3 treatment goals (n = 91) had a 60% risk reduction in reaching the primary end point compared with those who did not attain 3 treatment goals (n = 1 14) (14 vs. 34; RR 0.43, 95% CI: ). At 2 years and after adjustment for age, sex, and study sites, the structured care group had lower diastolic blood pressure and A lc levels and were more likely to attain 3 treatment goals (61% [n = 63] vs. 28% [n = 28]). Nevertheless, the primary outcome analysis of this study was negative. The trial was limited by small sample size (leading to a possible type 2 statistical error), limited centre comparisons, heterogeneity of different care systems, open label design (raising the possibility of observer bias), lack of costings analyses, and the possibility of a Hawthorn effect limiting contrast between the 2 groups. In the Steno-2 Study, Gaede et al. [16] randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy for a mean treatment period of 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until 31 December Patients receiving conventional multifactorial treatment were treated according to the guidelines of the Danish Medical Association. In contrast, the intensified, target-driven therapy received a combination of medications and focused behaviour modification. The intensivetherapy group had defined targets consistent with the latest guidelines of the American Diabetes Association. These targets included a HbA 1c level < 6.5%, a fasting serum total cholesterol level < 175 mg/dl (4.5 mmol/l), a fasting serum triglyceride level <150 mg/dl (1.7 mmol/l), a systolic blood pressure < 130 mmhg, and a diastolic blood pressure < 80 mmhg. Patients were treated with blockers of the renin angiotensin system because of their microalbuminuria, regardless of blood pressure, and received low-dose aspirin as primary prevention. A total of 130 (81%) patients completed the study. The two study groups were similar at baseline but differed significantly at the end of the intervention period, indicating that intensive therapy was superior to conventional therapy in controlling the level of HbA 1c ; fasting serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; systolic and diastolic blood pressures; and rate of urinary albumin excretion. Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (HR 0.54, 95% CI: ; P = 0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (HR 0.43, 95% CI: ; P = 0.04) and of cardiovascular events (HR, 0.41, 95% CI: ; P < 0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P = 0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45, 95% CI: ; P = 0.02). Few major side effects were reported. The results of this study were limited by its single centre design (raising questions about generalisability) and uncertain allocation concealment. Gandjour and Lauterbach [17] (conducted a systematic search of studies published between January 1966 and December 2001 investigating the relationship between disease management tools and clinical and economic outcomes of patients with diabetic nephropathy. They concluded that high-quality studies on the use of many disease management tools were lacking, particularly with respect to the roles of case managers and primary care physicians in non-dialysis CKD patients. A number of subsequent pre-/post-intervention and non-randomised controlled trials have reported conflicting results regarding whether multidisciplinary CKD care is associated with beneficial outcomes [4, 18-24]. The results of these studies were further limited by ascertainment, selection, indication and co-intervention biases. Barrett et al [25] recently published the results of a randomized, unblinded, pilot clinical trial of care coordinated by a general practitioner (controls) with care by a nurse-coordinated team including a nephrologist (intervention) in 474 CKD patients aged years with an estimated GFR (egfr) between 25 and 60 ml/min/1.73 m 2 in five urban centres (nephrology and community clinics) in Canada. The participants were followed for a median (IQR) follow-up period of 742 days (614 to 854 days). 310 Early Chronic Kidney Disease July 2012 Page 3 of 11

4 (65%) patients had at least 20 months of follow-up with egfr estimates every 4 months. egfr declined by 4 ml/min per 1.73 m 2 from baseline to 20 months in 28 (17%) of the intervention group compared with 23 (13.9%) of controls (p=0.43). The achievement of blood pressure, lipid, iron, anaemia and smoking cessation targets were comparable between the 2 groups, as were the use of reninangiotensin system blockers and anti-platelet agents. Patient satisfaction was high in the intervention group with a consistent median (IQR) score of 31 (29,30) at 8, 16, and 24 months (maximum attainable score 32). Patient satisfaction scores were not reported for controls. The authors concluded that patients with stage 3 or 4 CKD identified through community laboratories had largely non-progressive kidney disease and that the rate of egfr decline and control of risk factors in this group was not significantly affected by care co-ordinated by general practitioners versus nephrology nurses. The limitations of the study included targeting of CKD patients not referred to nephrologists and who had largely stable renal disease, potential ascertainment bias, Hawthorne effect, inadequate statistical power and lack of evaluation of patient-level outcomes., SUMMARY OF EVIDENCE There are currently only 4 small randomised controlled trials of intensive, multidisciplinary versus usual care of patients with early CKD. The smallest and longest-running of these trials demonstrated a significant mortality benefit of multidisciplinary care in diabetic patients with early CKD, whilst 3 larger but shorter-term trials (32%, 43% and 100% diabetic patients) did not show any benefit of multidisciplinary care on surrogate or patient-level outcomes. There is a clear need for improved definition of CKD populations and individuals, review and refinement of proposed care pathways, and improved definition of the essential elements models of care for patients with early CKD. Models of care for CKD patients have not been subjected to the same rigorous scrutiny that other interventions (eg pharmacologic treatments) have been. Moreover, it is important that such models of care are also subjected to cost-effectiveness analyses before they can be recommended for routine clinical care. WHAT DO THE OTHER GUIDELINES SAY? Kidney Disease Outcomes Quality Initiative:[26] No clear recommendations for non- diabetic CKD patients Clinical practice recommendation 2: multifaceted approach to intervention in diabetes and chronic kidney disease Multiple risk factors are managed concurrently in patients with diabetes and CKD, and the incremental effects of treating each of these risk factors appear to add up to substantial clinical benefits. 2.1 The care of people with diabetes and CKD should incorporate a multifaceted approach to intervention that includes instruction in healthy behaviors and treatments to reduce risk factors. (C) 2.2 Target BMI for people with diabetes and CKD should be within the normal range ( kg/m 2 ). (C) UK Renal Association: No recommendation. Canadian Society of Nephrology: No recommendation. European Best Practice Guidelines: No recommendation. International Guidelines: Kidney Health Australia: Kidney Check Australia Taskforce [27] Multidisciplinary Care: The management of CKD is always a collaborative effort, involving at least the patient and their general practitioner. As kidney function declines, and as complications and co-morbidities increase, it becomes increasingly likely that the contribution of others will be needed for optimal care. These may include: Family members or other lay carers, practice nurse, nephrologist, renal nurse/nurse practitioner, pharmacist, endocrinologist and other professionals specialising in diabetes, cardiologist, dietitian, vascular and transplant surgeons, mental health professionals, community health professionals, social worker, Aboriginal health worker. The efficient integration of their various contributions becomes more challenging as the numbers of professionals involved in the patient s care increases. The general practitioner plays a crucial role, sustaining an ongoing relationship with the patient and their family, coordinating the care provided by others and ensuring that this care remains focused on the patient s own goals and priorities. At times the general practitioner may be required to advocate for the patient with other professionals. In addition, he or she has continuing responsibility for primary care of the patient, including: supporting and assisting the patient in the management of their kidney disease and other chronic health problems, responding appropriately to new symptoms screening for developing Early Chronic Kidney Disease July 2012 Page 4 of 11

5 problems and co-morbidities, provision of health promotion and disease prevention advice and interventions assistance with addressing psychosocial issues. National Institute for Clinical Excellence (NICE): Despite the recommendation of multifactorial interventions for CKD, there is no clear recommendation for CKD stages 1-3 SUGGESTIONS FOR FUTURE RESEARCH A clustered randomised control trial of the impact of intensive, multidisciplinary case management versus usual care of patients with early CKD on renal failure progression and cardiovascular mortality in the primary care setting CONFLICT OF INTEREST Maria Chan has no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by CARI. David Johnson has a level II b. conflict of interest for receiving speaker honoraria and advisor s fees from several companies related to anaemia, CKD-MBD, hypertension and cardiovascular disease between 2008 and Early Chronic Kidney Disease July 2012 Page 5 of 11

6 REFERENCES 1. Chadban SJ, Briganti EM, Kerr PG et al. Prevalence of kidney damage in Australian adults: The AusDiab kidney study. Journal of the American Society of Nephrology. 2003; 14: S Churchill DN. An evidence-based approach to earlier initiation of dialysis. American Journal of Kidney Diseases. 1997; 30: Binik YM, Devins GM, Barre PE et al. Live and learn: patient education delays the need to initiate renal replacement therapy in end-stage renal disease. Journal of Nervous & Mental Disease. 1993; 181: Curtis BM, Ravani P, Malberti F et al. The short- and long-term impact of muti-disciplinary clinics in addition to standard nephrology care on patient outcomes. Nephrol. Dial. Transplant. 2005; 20: Ratcliffe PJ, Phillips RE, and Oliver DO. Late referral for maintenance dialysis. British Medical Journal Clinical Research Ed. 1984; 288: Sesso R and Belasco AG. Late diagnosis of chronic renal failure and mortality on maintenance dialysis. Nephrology Dialysis Transplantation. 1996; 11: Chan MR, Dall AT, Fletcher KE et al. Outcomes in patients with chronic kidney disease referred late to nephrologists: a meta-analysis. American Journal of Medicine. 2007; 120: Jungers P, Zingraff J, Page B et al. Detrimental effects of late referral in patients with chronic renal failure: a case-control study. Kidney International - Supplement. 1993; 41: S Jungers P, Zingraff J, Albouze G et al. Late referral to maintenance dialysis: detrimental consequences. Nephrology Dialysis Transplantation. 1993; 8: Levinsky NG. Specialist evaluation in chronic kidney disease: too little, too late. Annals of Internal Medicine. 2002; 137: Jungers P, Joly D, Nguyen-Khoa T et al. [Continued late referral of patients with chronic kidney disease. Causes, consequences, and approaches to improvement]. Presse Medicale. 2006; 35: Collister D, Rigatto C, Hildebrand A et al. Creating a model for improved chronic kidney disease care: designing parameters in quality, efficiency and accountability. Nephrology Dialysis Transplantation. 2010; 25: Wei S-Y, Chang Y-Y, Mau L-W et al. Chronic kidney disease care program improves quality of pre-end-stage renal disease care and reduces medical costs. Nephrology. 2010; 15: Harris LE, Luft FC, Rudy DW et al. Effects of multidisciplinary case management in patients with chronic renal insufficiency. The American Journal of Medicine. 1998; 105: Chan JC, So WY, Yeung CY et al. Effects of structured versus usual care on renal endpoint in type 2 diabetes: The SURE Study. Diabetes Care. 2009; Gaede P, Lund-Andersen H, Parving HH et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. New England Journal of Medicine. 2008; Gandjour A and Lauterbach KW. An evidence-based disease-management program for patients with diabetic nephropathy. Journal of Nephrology. 2003; 16: Martinez-Ramirez HR, Jalomo-Martinez B, Cortes-Sanabria L et al. Renal function preservation in type 2 diabetes mellitus patients with early nephropathy: a comparative prospective cohort study between primary health care doctors and a nephrologist. American Journal of Kidney Diseases. 2006; 47: St Peter WL, Schoolwerth AC, McGowan T et al. Chronic kidney disease: Issues and establishing programs and clinics for improved patient outcomes. American Journal of Kidney Diseases. 2003; 41: Hemmelgarn BR, Manns BJ, Zhang J et al. Association between multidisciplinary care and survival for elderly patients with chronic kidney disease. Journal of the American Society of Nephrology. 2007; 18: Jones C, Roderick P, Harris S et al. An evaluation of a shared primary and secondary care nephrology service for managing patients with moderate to advanced CKD. American Journal of Kidney Diseases. 2006; 47: Early Chronic Kidney Disease July 2012 Page 6 of 11

7 22. Hoy WE, Wang Z, Baker PRA et al. Secondary prevention of renal and cardiovascular disease: results of a renal and cardiovascular treatment program in an Australian aboriginal community. Journal of the American Society of Nephrology. 2003a; 14: S Goldstein M, Yassa T, Dacouris N et al. Multidisciplinary predialysis care and morbidity and mortality of patients on dialysis. American Journal of Kidney Diseases. 2004; 44: Leung WYS, So WY, Tong PCY et al. The renoprotective effects of structured care in a clinical trial setting in type 2 diabetic patients with nephropathy. Nephrol. Dial. Transplant. 2004; 19: Barrett BJ, Garg AX, Goeree R et al. A nurse-coordinated model of care versus usual care for stage 3/4 chronic kidney disease in the community: a randomized controlled trial. Clinical Journal of The American Society of Nephrology: CJASN. 2011; 6: National Kidney Foundation. K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. American Journal of Kidney Diseases. 2007; 49 (suppl 2): S1-S Chronic Kidney Disease (CKD) Management in General Practice. 2007, Melbourne Australia: Kidney Health Australia Early Chronic Kidney Disease July 2012 Page 7 of 11

8 [Type text] APPENDICES Table 1. Characteristics of included studies Study ID N Study design Participants Harris et al (1998) [14] 437 RCT Patients with chronic kidney disease attending an urban academic general internal medicine practice. 206 (intervention group) 231 (control group) Chan et al (2009) [15] 205 RCT year old, Chinese, type 2 diabetic patients from nine public hospitals. 104 (intervention group) 101 (control group) Gaede et al (2008) [16] 160 RCT Patients with type 2 diabetes and persistent microalbuminuria. 80 (intervention group) 80 (conventional therapy) Follow up Comments and results 5 years There were no differences in renal function; health services use; mortality; or use of renal sparing or selected potentially nephrotoxic drugs, between the two groups The intervention group had more outpatient visits to the nephrology case management clinic. This added to the annual cost of $484 per intervention patient No effect on the outcomes of care 2 years The intervention group (structured care) achieved better results compared to the control group for: diastolic blood pressure 68 ± 12 vs 71 ± 12 mmhg, P=0.02 and HbA1c 7.3 ± 1.3 vs 8.0 ±1.6%, P <0.01, and achieving 3 treatment goals [61%, (n=63), vs 28%, (n=28), P<0.001], respectively Patients who achieved 3 treatment goals (n=91) had 60% risk reduction of the primary end point (end stage renal disease and death) compared to those who attained 2 treatment goals (14 vs 34 relative risk 0.43 [95% CI: 0.21 to 0.86] Overall the groups had similar end points Audits and feedback are needed to improve outcomes years Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI: 0.19 to 0.94, P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI: 0.25 to 0.67, P<0.001) 24 patients in the treatment group died compared to 40 patients in the control group (hazard ratio, 0.54; 95% CI: 0.32 to 0.89, P=0.02) One patient in the treatment group progressed to end-stage renal disease compared to six patients in the control group (P=0.04) Fewer patients in the intervention group required retinal photocoagulation (relative risk, 0.45; 95% CI: 0.23 to 0.86; P=0.02) Early Chronic Kidney Disease July 2012 Page 8 of 11

9 [Type text] Study ID N Study design Barrett et al (2011)[25] 474 RCT (nonblinded) Participants Adult patients with chronic kidney disease were randomised to receive care by a general practitioner (control) or receive care by a nursecoordinated team including a nephrologist (intervention). Multicentre, Canada. Follow up Comments and results 24 months (median) 28 (17%) of patients in the intervention group had a decline in egfr of 4 ml/min/1.73m 2 within 20 months of the study compared with 23 (13.9%) patients in the control group, (P = 0.43). Cardiovascular outcomes were not significantly different between the two groups There was an increased use of renin-angiotensin blockers 78% of patients in the intervention group compared with 66% in the control (P = 0.06) Patient satisfaction was high in the intervention group with a median score of 31 out of 32 (IQR: 29,30) at 8, 16 and 24 months. Patient satisfaction was not reported in the control group. There were 24 clinical endpoints in the intervention group and 24 in the control group. Table 1a. Characteristics of included randomised trials Study ID (author, year) Harris et al (1998) [14] 437 Randomised Chan et al (2009) [15] 205 Randomised controlled trial Gaede et al (2008) [16] 160 Randomised controlled trial Barrett et al (2011)[25] 474 Randomised controlled trial N Study Design Setting Participants Intervention (experimental group) Multicentre Participants with chronic Intensive case controlled trial centre, US kidney disease management Multicentre, Participants with type 2 China Multicentre, Denmark Multicentre, Canada diabetes Participants with type 2 diabetes and persistent microalbuminuria Patients with chronic kidney disease Intervention (control group) Follow up (months) Usual care from 60 - primary physician Structured care Usual care 24 - Intensified target driven therapy Care by a nurse coordinated team Conventional multifactorial treatment Care by general practitioner Comments Early Chronic Kidney Disease July 2012 Page 9 of 11

10 [Type text] Table 2a. Methodological quality of randomised trials Study ID (author, Method of allocation concealment * Blinding Intention-totreat Loss to Comments year) (participants) (investigators) (outcome assessors) analysis follow up (%) Harris et al (1998) [14] Not specified No No No Yes No - Chan et al (2009) [15] Sequentially labelled sealed envelopes No No No Yes Gaede et al (2008) [16] Sealed envelopes No No No Yes No - Barrett et al (2011)[25] Not specified No No Yes Yes * Choose between: central; third party (e.g. pharmacy); sequentially labelled opaque sealed envelopes; alternation; not specified. Choose between: yes; no; unclear. Quality score How successfully do you think the study minimised bias? Choose between: very well (+); okay (Ø); poorly ( ). Table 3a. Results and quality rating for dichotomous outcomes Outcomes Study ID (author, year) Intervention group (no. of patients with events/no. of patients exposed) Control group (no. of patients with events/no. of patients exposed) Relative risk (RR) [95% CI] Risk difference (RD) [95% CI] Death from any cause Gaede et al (2008) [16] 24 / / [0.40, 0.90] [-0.35, -0.05] Critical Barrett et al (2011)[25] 5 / / [0.61, ] 0.02 [0.00, 0.04] Death from cardiovascular causes Gaede et al (2008) [16] 9 / / [0.23, 0.98] [-0.24, -0.01] Critical Barrett et al (2011)[25] 2 / / [0.14, 6.98] [-0.02, 0.02] Importance** Diabetic nephropathy Gaede et al (2008) [16] 20 / / [0.35, 0.85] [-0.36, -0.07] Important End stage renal disease Gaede et al (2008) [16] 1 / 80 6 / [0.02, 1.35] [-0.13, 0.00] Critical Barrett et al (2011)[25] 2 / / [0.18, 21.72] 0.00 [-0.01, 0.02] Myocardial infarction Barrett et al (2011)[25] 5 / / [0.34, 4.56] 0.00 [-0.02, 0.03] Important Stroke Barrett et al (2011)[25] 1 / / [0.06, 15.76] [-0.01, 0.01] Important * Methodological quality, consistency across studies and directness of the evidence (generalisability/applicability). ** The GRADE system uses the following 3 categories to rank the importance of end points: critical for decision making important but not critical for decision making not important for decision making (of lower importance to patients) Early Chronic Kidney Disease July 2012 Page 10 of 11

11 [Type text] Table 3b. Results and quality rating for continuous outcomes Outcomes Study ID (author, year) Intervention group (mean [SD]) Creatinine clearance (ml/min) Control group (mean [SD]) Difference in means (95% CI) Importance** Harris et al (1998) [14] 30 (16) n= (24) n= (-7.79, -0.21) Important Chan et al (2009) [15] 24 (10.2) n= (12.4) n= (-5.71, 0.51) Hospitalisations Harris et al (1998) [14] 1.3 (1.8) n= (2.1) n= (-0.37, 0.37) Important Systolic blood pressure Harris et al (1998) [14] 142 (17) n= (17) n= (-6.20, 0.20) Important Chan et al (2009) [15] 135 (25) n= (21) n = (-8.31, 4.31) Gaede et al (2008) [16] 140 (14) n= (18) n= (-12.81, 0.81) Diastolic blood pressure Harris et al (1998) [14] 79 (8) n= (9) n= (-0.60, 2.60) Important [Chan et al (2009) [15] 68 (12) n= (12) n= (-6.29, 0.29) Gaede et al (2008) [16] 74 (8) n=55 73 (7) n= (1.93, 8.07) Methodological quality, consistency across studies and directness of the evidence (generalisability/applicability). ** The GRADE system uses the following 3 categories to rank the importance of end points: critical for decision making important but not critical for decision making not important for decision making (of lower importance to patients) Early Chronic Kidney Disease July 2012 Page 11 of 11