The study will be contacted according to the Cochrane Collaboration principles for Systematic reviews18 and will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (additional file 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.
We have used the Population, Intervention, Comparator, Outcomes, Study design (PICOS) criteria21 to formulate our research question and define clear study objectives.
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):
We will use the following criteria to define patients with CKD or at risk for developing CKD:
 patients with eGFR < 60 ml/min/1.73m2 with or without proteinuria estimated with any of the following formulas: Cockcroft-Gault, MDRD or CKD-EPI.
 patients with CKD stage I, II, III and IV according to the CKD nomenclature used by the Kidney Disease: Improving Global Outcomes (KDIGO).22
 patients with measured GFR < 60 ml/min/1.73m2
 patients with proteinuria even if eGFR > 90ml/min/1.73m2
 patients with major risk factors for developing CKD or proteinuria; hypertension, diabetes, dyslipidaemias, obesity, cardiovascular disease (heart failure, stroke, ischemic heart disease, coronary revascularization).
 Paediatric patients (< 18 years of age)
 any form of renal replacement therapy (peritoneal dialysis or haemodialysis) transplantation or eGFR < 15ml/min/1.73m2
Types of intervention:
We will include studies which examined the use of fibrate alone or fibrate in addition to any statin. The fibrate utilised may be any of the following: fibrate, clofibrate, clofibric acid, bezafibrate, gemfibrozil, fenofibrate, procetofen.
The comparator group for patients receiving fibrate alone will be placebo or no intervention (fibrate vs placebo/no intervention). The comparator group for patients receiving fibrate in addition to statin will be statin and placebo or statin alone (Fibrate + Statin vs Statin alone).
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.
Randomized controlled trials
We will not impose language restrictions
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: fibrate, clofibrate, clofibric acid, bezafibrate, gemfibrozil, fenofibrate, procetofen, renal insufficiency, kidney failure, chronic kidney disease, albuminuria, serum creatinine, eGFR, glomerular filtration, 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 final analysis will include studies published in English (additional file 2).
Study screening and exclusions:
Systematic review and metanalysis will include randomized control trials of fibrate compared to placebo or fibrate+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 identified 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 identified 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 final 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 final decision the authors will be contacted.
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 fibrates on proteinuria or albuminuria (new onset, progression or regression), effects of fibrates on kidney function (serum creatinine or eGFR or mGFR or 24-h urine creatinine clearance), effects of fibrates on rate of kidney function decline (i.e. mean annualized change in eGFR), effect of fibrates on incident chronic kidney disease, effect of fibrates on ESKD (defined 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 fibrates (timing as per individual study) and any reported side effects, biochemical abnormalities or deaths.
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:
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.
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 trials23 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.
If possible, from available data, subgroup analysis will be performed in patients with diabetes compared to non-diabetic patients.