The therapeutic potential of C-peptide in kidney disease: a protocol for a systematic review and meta-analysis

Chronic kidney disease (CKD) is a growing international healthcare problem. Approximately 13% of North Americans are estimated to have CKD, a prevalence that is higher than populations in Europe, Asia, and Australia [1, 2]. The presence of CKD is associated with increased morbidity, mortality, and healthcare costs [3]. Current clinical guidelines recommend a multifactorial approach to CKD, targeted towards risk factor and lifestyle modification, optimal control of blood pressure and blood sugar, reduction in proteinuria, and management of the metabolic sequelae of CKD [4, 5]. Although a major objective of this clinical management strategy is to slow or prevent progression to end-stage renal disease (ESRD), this is unavoidable in many cases and results in the requirement for renal replacement therapies, which are associated with adverse outcomes [6]. Thus, there is a need for additional therapies for the management of kidney diseases to not only reduce the risk of progression to ESRD, but improve patient outcomes overall.

A central and accepted paradigm for insulin biosynthesis is the transcription and translation of the INS gene from chromosome 11 that generates a 110 amino acid polypeptide termed preproinsulin [7]. The subsequent post-translational modification of this molecule results in an intermediate molecule called proinsulin, which is then processed and split into insulin and C-peptide that are both released into the circulation in equimolar amounts from pancreatic beta cells [8–10]. C-peptide was initially thought of as a necessary yet biologically inert by-product of this process, but has retained clinical utility as a semi-quantitative marker of insulin secretion [10]. As examples, measurement of circulating C-peptide levels is useful in the management of diabetic patients to determine residual beta cell function, in pancreas or islet cell transplant patients to determine graft function, and in the workup of patients with hypoglycemia.

In contrast to the clinical role of C-peptide as a marker of endogenous insulin secretion, there are studies that support biological activity of C-peptide [11]. Importantly, some studies have suggested that C-peptide has renoprotective properties. Observational studies of patients with diabetes mellitus type 1 or 2 have correlated higher C-peptide levels with decreased prevalence of microvascular complications including diabetic nephropathy [12–15], reviewed in [16]. Furthermore, patients with type 1 diabetes have shown improved renal function following pancreas transplant, a procedure that repletes both C-peptide and insulin from transplanted beta cells [17, 18]. Finally, small trials in which C-peptide was administered to experimental subjects with type 1 diabetes have also shown that C-peptide may improve renal function in these patients independent of any potential effect on glycemic control [19, 20]. However, the therapeutic potential of C-peptide for patients with diabetic kidney disease remains incompletely understood. Whether the potential benefit of C-peptide is limited to patients with diabetes, or is applicable to a broader group of patients is currently unknown.

The aim of this systematic review is to ascertain the current evidence for and against the notion that exogenous delivery of proinsulin C-peptide has a potential beneficial effect on parameters of renal function. The rigorous and systematic nature of our review will ensure that it includes the best available information. Effort will be made to identify and limit procedural sources of bias and data heterogeneity.

Because the therapeutic use of C-peptide is still in an early experimental stage we have purposely decided to keep the search strategy and study inclusion criteria relatively broad in order to capture a comprehensive understanding of the potential therapeutic use for C-peptide in patients with kidney disease of any etiology. Although it is anticipated that most included studies will focus on models of CKD, we will not exclude studies looking at the role of C-peptide in the treatment of acute kidney injury (AKI) if they exist, so long as they meet eligibility criteria.

Our review may be limited by the number of available studies in the literature. As such, we have intentionally included both human and other mammalian studies to determine if a biological effect or signal for C-peptide truly exists. The added benefit of this is that other mechanisms of kidney injury may be tested against C-peptide administration in animal models that have not been considered for human trial at present, and may identify further areas of research.

We have elected to exclude studies in which C-peptide was given to whole animals, but reported results pertain only to changes in gene or protein expression, enzyme activity, or other cellular or molecular endpoints. The rationale for this exclusion is two-fold. First, we only wish to include studies that directly examine gross organ structure and function per se, to facilitate clinical interpretation of the potential therapeutic utility of C-peptide. In the context of this review we view genetic and molecular-based endpoints as mechanistic in nature. Although these studies serve the important role of furthering our understanding of the underlying processes leading to changes in organ structure and function, that level of detail is outside the scope of our research question. Second, inclusion of these studies would increase the heterogeneity of the pooled results since we anticipate different investigators will be looking at different genes, proteins, and signal transduction pathways. Overall, our decision to look at only human and in vivo mammalian studies was made to make the results of our study applicable to clinical practice and future clinical research as much as possible.

All medical interventions carry some degree of risk. Accordingly, our data extraction will also include relevant non-renal endpoints pertaining to hemodynamics (for example, blood pressure), glycemic control, cardiovascular risk, stroke risk, and mortality, if reported, to assess for any evidence of adverse events with C-peptide administration.

The results of this study will determine the potential role of C-peptide as a therapeutic intervention for patients with kidney disease, which will help guide subsequent clinical trials. The study may also provide insight into which patients or disease states are likely to benefit the most from C-peptide.