Julie Mclellan, Clare Bankhead, Jeff Aronson, Boby Mihaylova, Jan Verbakel, Chris O Callaghan, Rafael Perera

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1 Systematic review and meta-analysis to identify and evaluate drug interventions that modify the progression of patients with chronic kidney disease in stages 3 and 4 Julie Mclellan, Clare Bankhead, Jeff Aronson, Boby Mihaylova, Jan Verbakel, Chris O Callaghan, Rafael Perera Background Description of the condition Chronic kidney disease (CKD) is long term loss of renal function and continues to be a major health problem worldwide. In the UK in 2010, the Quality and Outcomes Framework reported a 4.2% prevalence in adults for stages 3-5 CKD (though research has suggested this is an underestimate and it is more likely to be 8.5% (Stevens, 2008)). In the USA kidney disease was the ninth leading cause of mortality in 2011 (Hoyert and Xu, 2012) and it is estimated that more that 20 million adults (10%) have CKD (CDC, 2010). The overall mean prevalence of CKD worldwide is estimated at 7.2% (Zhang, 2008). Historically, CKD was categorised by its cause: predominantly diabetes, hypertension, glomerulonephritis and polycystic kidney disease. Treatment could be recommended, but often opportunities were missed for early detection of the disease or prevention of clinical complications. The National Kidney Foundation (NKF) addressed this in its development of a staging system, which was adopted internationally in The NKF provide a five-stage system, from normal renal failure to complete renal failure, which allowed CKD to be defined, with a key set of recommendations for practice. Stages were defined by reduced glomerular filtration rates estimated from serum creatinine (egfr) (see appendix A). Stages can further be determined by taking into account proteinuria (albumin:creatinine ratio (ACR)), which increases with disease severity. The latest clinical practice guideline from Kidney Disease Improving Global outcomes (KDIGO) 2012 suggested using both measures to classify CKD (see appendix B). This classification was adopted in the UK in the most recent NICE CKD clinical guideline in July 2014 (CG182). The rate of CKD progression depends on the cause of the disease, but rates can also vary between patients. Four types of treatments have been suggested to slow disease progression: Blood pressure control (Peterson, 1995) Reduction of proteinuria (Peterson, 1995) Glycaemic control in patients with diabetes (Wang, 1993) Regulating lipid concentrations (Sandhu 2006)

2 Recent early research has further suggested that sodium bicarbonate may delay the progression of CKD (De Brito-Ashurst, 2009, Phisitkul, 2010, Mahajan, 2010). This treatment addresses metabolic acidosis, a prevalent complication, in moderate and late stage CKD, and may offer a simple and low cost treatment to slow CKD progression. Many drugs cannot be used or need dose adjustment in patients with CKD (Shastri, 2012). CKD is also associated with increased cardiovascular risk and all-cause mortality (Go, 2004; Rifkin, 2008; Wen, 2008). Lack of CKD control and its complications will ultimately lead to complete kidney failure and/or death. Existing research Several reviews have considered how these four types of treatment reduce CKD progression: Lv et al, 2013 investigated how intensive blood pressure lowering affects renal and cardiovascular outcomes. They concluded that it appears to provide protection in patients with a high degree of proteinuria, but that further research was needed in patients without proteinuria. They did not consider non intensive treatments. The Blood Pressure Lowering Treatment Trialists Collaboration, 2013 also concluded that blood pressure lowering is 'an effective strategy for preventing cardiovascular events among people with moderately reduced egfr', but found little evidence for which drug interventions to use. Lowering proteinuria is frequently linked with interventions to lower blood pressure, and proteinuria is considered an effect modifier rather than a potential target of intervention itself (Upadhyay, 2011). Bakris (2008), in a narrative review, concluded that several trials suggest that blood pressure lowering drugs can reduce proteinuria and provide benefits in patients with CKD besides those obtained by lowering blood pressure alone. Wang et al, 1993 in their review concluded that intensive blood glucose management can reduce the progression of CKD in patients with type I diabetes, but they only looked at changes in degrees of proteinuria. Cummings et al (2011) reported this in a retrospective cohort study, but noted that blood glucose reduction was only moderately significant in changing egfr, and demographic and clinical risk factors, such as ethnicity, were significantly associated with these changes. Sandhu et al, 2006 assessed the effect of lipid regulating drugs (statins) on the rate of kidney function loss. They concluded that statins produce a small reduction in the progression of CKD, in patients with cardiovascular disease, but did not comment on other patient groups. This review is the closest methodological match to the proposed review, but it searched only up to Lewis et al, 2012 are currently considering the effect of lowering low density lipoprotein cholesterol with statins on kidney function. Their preliminary findings suggest that for patients receiving statins there was a highly significant reduction in the annual rate of CKD progression compared to control groups (based on annual

3 rate of change in egfr). This review s strength is that it uses individual patient data from most large statin trials, but full publication is awaited. These reviews have made conclusions about the rate of progression of CKD, renal failure, cardiovascular events or all-cause mortality. However, none of them has presented results by stage 3 and 4 CKD. All of the reviews considered one strategy to reduce CKD progression, but none compared and evaluated the benefits of different strategies in reducing the rate of CKD progression. Apart from Sandhu et al, 2006 and Lewis et al, 2012 none of the reviews considered egfr levels as the outcome measure. Why it is important to do this research This research is important because no similar review has been conducted. No review has exclusively identified, evaluated and compared all drug interventions to reduce the rate of CKD progression, especially subdivided by CKD stage. Furthermore, the summary of evidence for effects of different interventions will allow effectiveness and cost-effectiveness analyses of the optimal drug regimen for different categories of CKD patients. This will contribute to addressing the research need identified in the NICE clinical guidelines on CKD (CG73, 4.1), which recommends that 'research is undertaken to identify more accurate and cost effective methods of monitoring kidney function, especially in patients with GFR (glomerular filtration rate) 60 ml/min/1.73m2 or more' (NCCCC, 2008). Objective To systematically identify and review randomised control trials about effects of drug interventions that could modify the progression of chronic kidney disease in patients with stages 3 and 4 chronic kidney disease. Methods A systematic review will be conducted in line with recommendations made in the Preferred reporting items for systematic reviews and meta-analyses statement (PRISMA) (Liberati et al, 2009). Search methods for identification of studies The search strategy will be designed with advice from an invited panel including an information specialist and experts in this medical field. MeSH terms to be considered by the panel will include terms for population (chronic kidney disease, renal, reduced glomerular filtration rate and proteinuria), outcomes (change in in GFR, creatinine clearance) and intervention terms (drug classes).

4 Searches will be conducted in CENTRAL, MEDLINE, EMBASE and clinical trials registers to identify relevant studies, regardless of their publication type. No language restriction will apply. All publications from 2001 onwards will be considered; this is consistent with the introduction of the CKD staging process in Reviews of relevant studies published prior to 2001 will also be reviewed. Current researchers in the field will be approached to identify other previous or unpublished relevant work. A review of references will be performed for all eligible studies retrieved and relevant existing reviews. The title and abstract of each paper will be reviewed by two reviewers and potentially relevant references will be identified. The full text of potentially relevant studies will be obtained, and two reviewers will independently select studies to be included in the review by using predetermined inclusion criteria. In all cases disagreements about study inclusion will be resolved by consensus and a third reviewer will be consulted if disagreements persist. A flowchart will summarise the selection process. Inclusion criteria This review will include all randomised controlled trials of drug interventions intended to modify the progression of chronic kidney disease in humans and provide a quantitative summary of effects on the specified outcomes. Studies will be excluded when there are fewer than forty participants and/or follow-up is less than two years. Participants: Intervention: Patients with stage 3 and 4 chronic kidney disease, aged 18 years or older. No gender restriction. Four drug classes that have been hypothesised to affect the progression of chronic kidney disease (antihypertensive, glycaemic control, lipid regulating drugs, bicarbonates) Control/comparator: Placebo, no drug intervention or a comparator drug. Outcome(s): Primary outcome: renal function as a change in GFR (glomerular filtration rate), estimated as change in GFR, creatinine clearance rate (CrCl) or estimated CrCl from baseline to end of follow-up and/or change in GFR/CrCl per annum. Secondary outcomes: change in proteinuria from baseline to end of follow-up and/or change per annum (e.g. ACR, albumin, creatinine, total protein); commencement of maintenance dialysis or transplantation among people not in end stage renal disease at baseline; cardiovascular events; cardiovascular mortality; all-cause mortality. Data extraction and management For included randomised control trials data will be extracted by two reviewers independently.

5 A data extraction form will be used; this will be piloted initially on a sample of five studies and refined if needed before use on all studies. Extracted data will include participant details (age, gender, ethnicity, smoking status), study details (setting, intervention dose and frequency, follow-up period, control group, source of funding, author conflicts), baseline characteristics (blood pressure, CKD stage, serum creatinine concentrations, amounts of proteinuria, GFR, egfr, CRCL, ecrcl measurements, existing comorbidities and existing drug regimens), follow-up data (proteinuria, GFR, egfr, CrCl, ecrcl, adverse events, commencement of dialysis, transplantation, cardiovascular events, mortality), and effect sizes on comorbid conditions. The methodological quality of studies will be assessed independently by two reviewers. Forming part of the data extraction form, a quality assessment will be undertaken based on the Cochrane Risk of Bias tool (Higgins 2011). This covers potential biases in the studies owing to selection bias (randomisation, allocation), blinding (participants and/or outcomes), attrition, and selective reporting. Disagreements about extracted data will be resolved by consensus: a third reviewer will be consulted if needed. When data are missing or insufficiently reported, the study authors will be contacted for clarification. Data analysis For studies identified in this systematic review a table will be constructed to show the number and characteristics of included studies by drug or drug class. All studies will be included in the table, but not all will necessarily contribute to the analysis if data are missing. The primary analysis will summarise the effect on (rate of) change in renal function (GFR, egfr, CrCl, ecrcl for each drug or drug class. Secondary analysis will be considered for change in proteinuria. Analyses will be completed for short term, medium term and long term follow-up periods (to capture both outcome data for patients with high degrees of proteinuria, and those without proteinuria (Lv et al, 2013)). Data will be summarised for comparison as standardised mean differences. Where possible fixed effects meta-analysis of data will be completed using standard methods for metaanalysis in Review Manager. Results will be displayed in forest plots. Heterogeneity will be assessed using I 2 and chi-squared. The potential sources of any heterogeneity (clinical or statistical) will be explored. Where the heterogeneity is very high and any pooling of data would be considered to be misleading, the results will be presented in a narrative form. Subgroup analysis, where possible, will be conducted by: Separately in CKD stage 3 and stage 4 Ethnicity Measure of renal function including method of egfr measurement

6 Proteinuria within the change renal function analysis Blood pressure (high/low) and /or the presence of intensive blood pressure lowering therapy Age (<65 years versus 65 years (O'Hare et al, 2006)) Smoker status Intensity of intervention (dose, dosage regimen) Sensitivity analyses will be conducted to determine the impact of study quality on the outcome. Focus will be placed on better quality studies. If there are sufficient studies sensitivity analyses will be completed by omitting: Low quality studies particularly in respect of attrition bias and allocation concealment Studies without intention to treat analysis Publication bias will be explored using a funnel plot analysis. Any future changes to the protocol will be documented with reasons. The protocol will be registered with PROSPERO. Dissemination The full review will be published as part of a larger project in a Health Technology Assessment report (RP-PG ). Conflicts of interest There are no conflicts of interest. Funding This article presents independent research funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (RP-PG ).

7 Appendix Appendix A: Kidney Disease Outcomes Quality Initiative classification (Levy 2003) Stages of CKD egfr (ml/min/1.73m 2 ) Description 1 90 Normal or increased GFR, with other evidence of kidney damage Slight decrease in GFR, with other evidence of kidney damage 3A Moderate decrease in GFR, 3B with or without other evidence of kidney damage Severe decrease in GFR, with or without other evidence of kidney damage 5 < 15 Established renal failure Appendix B: Kidney Disease Improving Global outcomes (KDIGO) 2012

8 Albuminuria = proteinuria. Green: low risk (if no other markers of disease, no CKD); yellow moderately increased risk; orange: high risk; red: very high risk References Bakris, G.L. (2008) Slowing Nephropathy Progression: Focus on Proteinuria Reduction. Clinical Journal of the American Society of Nephrology, 3 (suppl 1): S3 - S10. Blood Pressure Lowering Treatment Trialists Collaboration (2013) Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. British Medical Journal 347: f5680. Center for disease control and prevention CDC (2014) National chronic kidney disease fact sheet 2014 [online] Available from: (accessed 27th January 2014). Go, A.S., Chertow, G.M., Fan, D., McCulloch, C.E. and C Hsu (2004) Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization. The New England Journal of Medicine 351: Cummings, D.M., Larsen, L.C., Doherty, L., Lea, C.S., Holbert, D (2011). Glycemic control patterns and kidney disease progression among Primary Care patients with diabetes Mellitus. Journal of American Board Family Medicine 24:

9 De Brito-Ashurst I, Varagunam, M., Raftery, M.J., Yaqoob, M.M. (2009). Bicarbonate supplementation slows progression of CKD and improves nutritional status. Journal American Society Nephrology 20: Higgins, J.P.T., Altman, D.G., Gøtzsche, P.C., Jüni, P., Moher, D., Oxman, A.D., Savović, J. and K.F. Schulz (2011). The Cochrane Collaboration s tool for assessing risk of bias in randomised trials. British Medical Journal 343: d5928 Hoyert, D. and J. Xu (2012) Deaths: preliminary data for National Vital Statistics Reports 61: 6 Kidney Disease Improving Global Outcomes KDIGO (2012) Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements 3(1) Levey, A.S., Coresh, J., Balk, E., Kausz, A.T., Levin, A., Steffes, M.W., Hogg, R.J., Perrone, R.D. and J Lau (2003) National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Annals of Internal Medicine 139: Lewis, A., Emberson, J.R., Blackwell, L.J., Collins, R., Baigent, C (2012) Effect of Lowering LDL-Cholesterol on Kidney Function: Meta-Analysis of Data from 120,000 Participants in 21 Randomized Trials. Journal of the American Society of Nephrology Abstract supplement 23: 685A Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gøtzsche, P.C, Ioannidis, J.P.A., Clarke, M., Devereaux, P.J., Kleijnen, J. and D Moher (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. British Medical Journal 339: b2700. Lv, J., Ehteshami, P., Sarnak, M.J., Tighiouart, H., Jun, M., Ninomiya, T., Foote, C., Rodgers, A., Zhang, H., Wang, H., Strippoli, G.F., and V Perkovic (2013) Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis Canadian Medical Asscociation Journal, 185(11): Mahajan, A., Simoni, J., Sheather, S.J., Broglio, K.R., Rajab, H,. Wesson, D.E. (2010) Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney International 78: National Collaborating Centre for Chronic Conditions NCCCC (2008). CG73 Chronic kidney disease: NICE guideline [online] Available from (accessed 27th January 2014). National Institute for Health Care and Excellence (2014). CG182 Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care (accessed 10th February 2015).

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