Rationale, objectives, and type of studies
The purpose of this systematic review is to synthesize available data from human and animal experiments, specifically examining the impact of exogenous C-peptide on markers of kidney function compared to control, without the limitation of a particular etiology of kidney disease.
Information sources and search strategy
The electronic databases MEDLINE, EMBASE, and the Cochrane Central databases will be searched using standard controlled vocabulary (MeSH or EMTREE), text words, and keywords. The search will be intentionally broad to be as sensitive as possible and not to miss any relevant studies (see Appendix 1 for the full search strategy). An information specialist with previous systematic review experience will be consulted regarding the search strategy.
All titles and abstracts resulting from our initial search will be screened independently by two reviewers. Titles without abstracts will have the full text reviewed unless the article can be clearly excluded based on the information provided. Following reconciliation of differences between reviewers, the full text of the selected articles will be completely screened by each reviewer independently. During this process, a final decision for inclusion or exclusion will be made according to the criteria below. Any discrepancies will be resolved by a third party.
Inclusion and exclusion criteria
Peer-reviewed published articles will be included if they meet all of the following criteria:
The experimental subjects are either humans or other mammals of any age;
The study intervention involves the administration of exogenous C-peptide to subjects;
The reported outcomes are related to relevant markers of kidney function, kidney disease, requirement for renal replacement therapy, or mortality; and
The manuscript must be written in English.
Studies using purified, artificial, recombinant, synthetic, or long acting formulations of C-peptide will be included for analysis. C-peptide from any species will be acceptable for inclusion.
Single case reports, narrative reviews, and studies reporting exclusively in vitro cell culture experiments, or ex vivo experiments will be excluded. We will also exclude studies in which animals or humans were given C-peptide, but the results contain only cellular or molecular endpoints such as change in gene expression profile, change in protein or enzyme concentration or activity, or cellular viability. There will be no limits on study publication date, other study design parameters, or sample size.
Data collection process
Full text of all included articles will be electronically saved and each article will be assigned a unique code. Reference lists will be manually reviewed for other potentially eligible articles. In each included article, we will use a standardized form to collect information pertaining to:
Study design, methods, and timing of C-peptide administration;
Characteristics of experimental subjects;
C-peptide type and dosing;
Relevant renal outcomes such as glomerular filtration rate (GFR), serum creatinine, proteinuria/albuminuria, hematuria, renal blood flow, urine electrolyte excretion, kidney size, requirements for renal replacement therapy, and kidney histologic parameters;
Pertinent non-renal outcomes such as HbA1c, hemodynamic parameters (including blood pressure), cardiovascular risk, stroke risk, and mortality;
Study funding sources; and
Information necessary for risk of bias assessment.
Any randomized controlled trials that are included will be assessed for bias using the Cochrane Collaboration’s tool for assessing risk of bias.
Data synthesis and analysis
Human and animal studies will be analyzed separately. Additionally, because it is anticipated that kidney function in diabetes will be the most well studied model among the search results, diabetic nephropathy studies will be analyzed separately from studies looking at other types of kidney disease.
We anticipate several sources of heterogeneity among our final dataset, particularly among the animal studies since we expect variation in disease model employed, methodology including experimental timing, and differences in chosen outcomes of interest. In particular, the C-peptide dose, route, and duration of administration may vary considerably between studies. For studies that have comparable methodology and outcomes, we will pool the results using a random-effects model for continuous or categorical variables as appropriate. In situations where data cannot be pooled, a narrative synthesis will be provided.
The current evidence for a therapeutic role of C-peptide in the context of kidney disease will be summarized based on the results of the search. The potential future clinical use of C-peptide will be discussed, along with suggested further research directions.