Occurrence of Diabetic Nephropathy After Renal Transplantation Despite Intensive Glycemic Control: An Observational Cohort Study

Abstract

The kinetics and risk factors of diabetic nephropathy after kidney transplantation remain unclear. This study investigated the posttransplant occurrence of diabetic nephropathy and the contribution of posttransplant glycemic control. RESEARCH DESIGN AND METHODS We performed a single-center prospective cohort study of 953 renal allograft recipients and 3,458 protocol-specified renal allograft biopsy specimens up to 5 years after transplantation. The effects of pretransplant diabetes and glycemic control (glycated hemoglobin levels) on the posttransplant histology were studied. RESULTS Before transplantation, diabetes was present in 164 (17.2%) renal allograft recipients, primarily type 2 (n = 146 [89.0%]). Despite intensive glycemic control (glycated hemoglobin 7.00 6 1.34% [53 6 14.6 mmol/mol], 6.90 6 1.22% [52 6 13.3 mmol/mol], and 7.10 6 1.13% [54 6 12.4 mmol/mol], at 1, 2, and 5 years after transplantation), mesangial matrix expansion reached a cumulative incidence of 47.7% by 5 years in the pretransplant diabetes group versus 27.1% in patients without diabetes, corresponding to a hazard ratio of 1.55 (95% CI 1.07-2.26; P = 0.005). Mesangial matrix expansion was not specific for diabetic nephropathy and associated independently with increasing age. Pretransplant diabetes was associated with posttransplant proteinuria but not with estimated glomerular filtration rate, graft failure, or any other structural changes of the glomerular, vascular, or tubulointerstitial renal compartments. The occurrence of diabetic nephropathy was independent of posttransplant glycated hemoglobin levels. CONCLUSIONS Mesangial matrix expansion, an early indicator of diabetic nephropathy, can occur rapidly in patients with diabetes before transplantation, despite intensive glycemic control. Prevention of diabetic nephropathy requires more than pursuing low levels of glycated hemoglobin.

Mesangial matrix expansion in a novel mouse model of diabetic kidney disease associated with the metabolic syndrome

“…This effect was even demonstrated to be independent of its glucoselowering effect (41,42). In a previous study in kidney transplant recipients, we found apparent independence of glycemic control in developing mesangial matrix expansion (9). Reflecting these findings in humans, also in our novel mouse model, mesangial matrix expansion was not significantly correlated with glucose levels but rather with the metabolic measures of insulin resistance and inflammation.…”

“…Also, dyslipidemia, hemodynamic factors, insulin resistance and other metabolic features of the metabolic syndrome could play a role in the development of mesangial matrix expansion (13). Our previous study and other studies also showed mesangial matrix expansion to be related to ageing (9,(14)(15)(16). In the human setting, where many of these factors co-occur, especially in patients with type 2 diabetes and the metabolic syndrome, it remains unclear which factors are most contributing to the mesangial matrix changes.…”

“…Reflecting these findings in humans, also in our novel mouse model, mesangial matrix expansion was not significantly correlated with glucose levels but rather with the metabolic measures of insulin resistance and inflammation. Insulin might indeed be a more important determinant of mesangial matrix expansion than plasma glucose levels alone, as suggested by the higher mesangial matrix expansion incidence in insulin-dependent diabetic patients (9), and by the finding that insulin prevents diabetes-induced hyperfiltration and proteinuria, but could not prevent glomerular growth, and even induced mesangial expansion (43). This might reflect an effect of insulin treatment itself, with more hypoglycemic hyperinsulinemic episodes, a trophic effect of insulin, and more fluctuating glucose profiles.…”

“…In a previous study in renal allografts, with the unique opportunity to study the histological evolution of diabetic nephropathy in sequential protocol biopsies, mesangial matrix expansion occurred more frequently in patients with pre-transplant (primarily type 2) diabetes mellitus, but independently of glycated haemoglobin levels (9). We hypothesized that the rapid onset of mesangial matrix expansion could be due to effects of diabetes on advanced glycation end product formation, inflammation, hemodynamics, and oxidative stress (10)(11)(12).…”

Mesangial expansion at 5 years predicts death and death‐censored graft loss after renal transplantation

“…The incidence of both increased from 5 to 10 years. 5 Coemans et al 14 16 Similarly, the data from our center have previously shown that cardiovascular disease is a major cause of mortality within the first 5 years post-transplants and it is related to cardiovascular disease prior to the transplant. 17 Here, we identified patients who survived the first 5 years to evaluate whether ongoing post-transplant metabolic risks factors can additionally increase the risk of mortality.…”