Antiproteinuric effect of DPP-IV inhibitors in diabetic and non-diabetic kidney diseases

Abstract Diabetes Mellitus (DM) is a chronic and severe metabolic disease, characterized by chronic hyperglycemia due to insulin resistance and/or reduced insulin secretion. Concerning the non-insulin glucose-lowering therapy for diabetes, Dipeptidyl-peptidase-4 (DPP-4) inhibitors, members of the incretin family, represent new agents, capable of a glycemic control improvement with an advantageous safety profile, given the absence of weight gain, the low incidence of hypoglycemia and the good renal tolerance in patients suffering from chronic renal failure. In addition to demonstrating efficacy in glycemic control through inhibition of GLP-1 degradation, DPP-4 inhibitors (DPP-4is) seem to demonstrate pleiotropic effects, which also make them interesting in both diabetic and non-diabetic nephropathies, especially for their capacity of reducing proteinuria. Several studies about diabetic nephropathy on patients’ cohorts and murine models have demonstrated a solid direct relationship between DPP-4 activity and urinary albumin excretion (UAE), thus confirming the capacity of DPP-4is to reduce proteinuria; the mechanism responsible for that effect was studied to assess if it was the result of a direct action on renal impairment or a secondary consequence of the better glycemic control related to these agents. As a result of these more in-depth studies, DPP-4is have demonstrated an improvement of renal inflammation markers and consequent proteinuria reduction, regardless of glucose concentrations. Considering the nephroprotective effects of DPP-4is might be glycemic independent, several studies were conducted to prove the validity of the same effects in non-diabetic nephropathies. Among these studies, DPP-4is demonstrated an improvement of various renal inflammatory markers on several models of non-diabetes dependent renal impairment, confirming their capacity to reduce proteinuria, independently from the action on glucose metabolism. The objective of this review is to present and discuss the so far demonstrated antiproteinuric effect of DPP-4is and their effects on diabetic and non-diabetic nephropathies.