The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: Protocol for a Systematic Review.

Background/Objectives: Fibrates reduce cardiovascular risk in the general population and in patients with chronic kidney disease (CKD). Although, they are commonly used as second-line agents in addition to statins for hypertriglyceridemia, their use in CKD is limited due to a decrease of glomerular ltration rate (GFR) at treatment initiation. This change in GFR is reversible with brate discontinuation. Importantly, randomised control trials with brate treatment have demonstrated reduction in proteinuria and benet for microvascular diabetic complications. In addition, a number of experimental studies have shown nephroprotective effects with brates through attenuation of renal brosis and inammation. Thus, the effect of brates on renal outcomes remains undetermined. The objective of this systematic review is to summarize the evidence from randomised controlled studies and provide pooled estimates on the effect of brates on short- and long-term renal outcomes. Methods/Design: The study will be contacted according to the Cochrane Collaboration principles for Systematic reviews. We will include randomised trials comparing brate to placebo or studies comparing the addition of brate on statin versus statin alone and reporting on the short- and long-term effects on renal function, CKD progression and proteinuria. We will examine studies including patients with established CKD and those studies including patients at risk of developing CKD, separately. A comprehensive summary of the evidence will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Data from included studies suitable for metanalysis will be analyses accordingly to provide quantitative estimates using a random effects model. The Cochrane Collaboration tool for assessing the risk of bias in randomized clinical trials will be utilised. The quality of the evidence from included studies will be addressed descriptively using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). Discussion: The results of this systematic review will be informative for clinicians. A summary of high-level evidence with robust estimates of the effect of brates on safety and renal outcomes may be used to inform clinical practice guideline development for dyslipidaemias and primary and secondary prevention of CVD.

prevention for CVD are of paramount importance in the care of patients with CKD. Lipid-lowering therapy was shown to reduce the risk of major CVD events and vascular mortality in non-dialysis CKD patients. 7,8 Patients with CKD have a distinct lipid pro le; most commonly characterised by elevated triglycerides, low HDL levels and variable LDL and total cholesterol levels. 9,10 Nonetheless, the qualitive changes in the lipid pro le of patients with CKD are considered the main driver of atherosclerosis. Triglyceride-rich lipoproteins are observed in elevated levels in CKD and have been associated with subclinical atherosclerosis, as well as, coronary artery disease and mortality. [11][12][13] Fibrate treatment reduces cardiovascular risk in the general population and patients with CKD and can be used as a second-line agent to control hypertriglyceridemia. Although brates are widely used in the general population, their use in CKD is limited due to safety concerns in view of moderate decrease in glomerular ltration rate (GFR) at treatment initiation. The decrease in eGFR is reversible upon brate discontinuation. In addition, proteinuria reduction has been observed in CKD studies with the use of brates 14,15 and a number of experimental studies have shown nephroprotective bene ts at the cellular level 16,17 . Thus, their effect on safety, long term renal disease and preventing CKD progression are unknown.

Objectives:
The purpose of this systematic review and metanalysis is to determine the short-term effects of brates on kidney function and the longer-term effects on proteinuria, renal disease progression to end stage kidney disease (ESKD) in patients with established CKD and patients at risk of developing renal disease.

Methods And Design:
The study will be contacted according to the Cochrane Collaboration principles for Systematic reviews 18 and will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (additional le 1). 19,20 The study is registered with the International Prospective Register of Systematic Reviews (PROSPERO, https://www.crd.york.ac.uk/PROSPERO) with the registration number CRD42020187764.

Eligibility criteria:
We have used the Population, Intervention, Comparator, Outcomes, Study design (PICOS) criteria 21 to formulate our research question and de ne clear study objectives.

Study population:
Adult patients (older than 18 years old) with chronic kidney disease or at risk of developing CKD will be included. The following inclusion and exclusion criteria for the examined studies were utilised (table): Inclusion criteria: We will use the following criteria to de ne patients with CKD or at risk for developing CKD: [1] patients with eGFR < 60 ml/min/1.73m 2 with or without proteinuria estimated with any of the following formulas: Cockcroft-Gault, MDRD or CKD-EPI.

Types of intervention:
We will include studies which examined the use of brate alone or brate in addition to any statin. The brate utilised may be any of the following: brate, clo brate, clo bric acid, beza brate, gem brozil, feno brate, procetofen.

Comparators:
The comparator group for patients receiving brate alone will be placebo or no intervention ( brate vs placebo/no intervention). The comparator group for patients receiving brate in addition to statin will be statin and placebo or statin alone (Fibrate + Statin vs Statin alone).

Outcomes:
The primary outcomes will be change in serum creatinine, change in renal function (using any GFR estimation formula or measured GFR), CKD progression, development of ESKD, change in proteinuria, development of proteinuria, proteinuria reduction, mortality.
The secondary outcomes will include adverse events and mortality.
Study Design/Setting: Randomized controlled trials Languages: We will not impose language restrictions Search Strategy: The electronic databases MEDLINE/SCOPUS/COCHRANE LIBRARY/ and Clinical Trial Registers (clinicaltrials.gov; clinicaltrialsregistry.eu) will be searched from inception until July 2020. We will use custom designed search algorithms consisting of Medical Subject Headings (MeSH) terms, relevant short terms and combinations of terms either in the title or abstract for the following: brate, clo brate, clo bric acid, beza brate, gem brozil, feno brate, procetofen, renal insu ciency, kidney failure, chronic kidney disease, albuminuria, serum creatinine, eGFR, glomerular ltration, creatinine clearance, proteinuria, renal impairment, dialysis, end stage renal disease, microalbuminuria, diabetes, hypertension, mortality, cardiovascular mortality, drug-related adverse events. The references of eligible studies will be checked for missing articles. We will not impose language restrictions, however, the nal analysis will include studies published in English (additional le 2).

Study screening and exclusions:
Systematic review and metanalysis will include randomized control trials of brate compared to placebo or brate+statin compared to statin alone, conducted in adults with chronic kidney disease or hypertension, diabetes or high cardiovascular risk and reporting data on proteinuria, renal disease progression, ESRD and (drug related adverse events). The summary of inclusion and exclusion criteria is provided in the eligibility criteria section of this document. Studies will be considered eligible if they describe the association with short term change of eGFR or creatinine or creatine clearance and at the end of follow-up change in eGFR, creatinine clearance or creatinine, kidney disease progression, ESKD or dialysis, proteinuria or proteinuria reduction in the form of Hazard Ratio or Relative Risk. Authors of studies that did not have data on renal function will be contacted. In the initial phase, all citations will be screened via the title and abstract. Two reviewers will screen independently all the studies identi ed in the initial electronic search results and thus screening will be performed in duplicate manner. A third researcher will resolve any discrepancies. Following the initial screen, all the identi ed studies by title and/or abstract will be retrieved for full-text review by two researchers independently. The inclusion and exclusion criteria will be applied for the nal selection of studies which will be analysed. Any discrepancies by the two independent reviewers will be resolved by a third independent reviewer in order to reach consensus. In the case that further information is needed before the nal decision the authors will be contacted.

Data extraction:
Data will be extracted on a pre-designed ms excel sheet and will include (a) study main characteristics, design and methodology, (b) sample characteristics, intervention and comparator group characteristics and (c) outcomes. Primary outcomes will include the effect of brates on proteinuria or albuminuria (new onset, progression or regression), effects of brates on kidney function (serum creatinine or eGFR or mGFR or 24-h urine creatinine clearance), effects of brates on rate of kidney function decline (i.e. mean annualized change in eGFR), effect of brates on incident chronic kidney disease, effect of brates on ESKD (de ned as starting any type of haemodialysis, peritoneal dialysis or transplantation).
The secondary outcomes will include change in serum creatinine at < 4 months or early after initiation of brates (timing as per individual study) and any reported side effects, biochemical abnormalities or deaths.

Analysis plan:
Characteristics of included studies will be summarized on tables and presented in the form of narrative synthesis in the text. Suitability for metanalysis of the studies will be based on clinical, methodological and statistical homogeneity. Where metanalysis is possible we will analysed data accordingly: a. For continuous outcomes (i.e. eGFR, creatinine), we will perform a generalised inverse variance analysis of mean difference between patients in intervention and control group, pre and post administration of intervention/treatment/placebo. b. For categorical outcomes, risk estimates from each study, reported as hazard ratio (HR) or relative risk (RR) will be synthesized.
When available, we will use adjusted estimates from multivariate model. Pooled estimates will be calculated with a random-effects model (DerSimonian-Laird method) to account for both within and between study variability. Heterogeneity between synthesized studies to be calculated using the I² statistic and the presence of publication bias will be investigated graphically by precision funnel plots. All statistical analyses will be performed using STATA (Version 12, StataCorp, College Station, TX, USA).

Risk of bias:
The risk of bias will be assessed using the Cochrane Collaboration tool for assessing the risk of bias in randomized clinical trials 23 and the quality of the evidence from the included studies will be addressed descriptively using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) 24 . Two reviewers will perform the risk of bias and quality assessment independently. The outcome will be reported in the form of a table and critical narrative review.

Subgroup analyses:
If possible, from available data, subgroup analysis will be performed in patients with diabetes compared to non-diabetic patients.

Discussion:
With the current systematic review, we aim to provide a comprehensive summary of the existing literature on an important clinical question, pertinent to general practitioners, nephrologists, cardiologists and clinicians who provide care for the primary and secondary CVD prevention and management in the general population and for patients with CKD. If the identi ed studies are suitable for metanalysis, we will provide robust quantitative estimates on the short-and long-term effects of brates on kidney function, proteinuria and kidney disease progression. We will only be including studies with high level of evidence, in the form of RCTs, and thus our analysis will be informative for clinical decision making and guideline development. A gap in the literature on this topic is evident. We anticipate underreporting of renal function and heterogeneity of the methods used to estimate and report eGFR and proteinuria. Authors will be contacted for all studies where this information is missing and heterogeneity will be assessed and reported utilising up-to-date guidelines and tools. The results of this study will be presented in the form of abstracts in conferences and will be submitted in peer-reviewed journals.