Inflammation and Progressive Nephropathy in Type 1 Diabetes Mellitus in the Diabetes Control and Complications Trial (DCCT)

Abstract

Objective: Progressive nephropathy represents a substantial source of morbidity and mortality in type 1 diabetes. Increasing albuminuria is a strong predictor of progressive renal dysfunction and heightened cardiovascular risk. Early albuminuria likely reflects vascular endothelial dysfunction, which may be mediated in part by chronic inflammation.

Research Design and Methods: We measured baseline levels of four inflammatory biomarkers (high sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1], and soluble tumor necrosis factor alpha receptor-1 [sTNF-R1]) in stored blood samples from the 1441 participants of the Diabetes Control and Complication Trial (DCCT). We used mixed effects regression models to determine the average change in urinary albumin excretion (AER) by tertiles of each biomarker. We also used Cox proportional hazards models to estimate the relative risk of incident sustained microalbuminuria (MA) according to levels of each biomarker.

Results: After adjustment for baseline age, sex, duration of diabetes, hemoglobin A1c%, and randomized treatment assignment, we observed a significantly higher 5.9 mcg/min/year increase in AER among those in the highest compared to the lowest tertile of baseline sICAM-1 (p=0.04). Those in the highest tertile of sICAM-1 had an adjusted relative risk of 1.67 (95% CI, 0.96 to 2.92) of developing incident sustained MA (p-for-trend=0.03).

Conclusions: Higher baseline sICAM-1 levels predicted an increased risk of progressive nephropathy in type 1 diabetes and may represent an early risk marker that reflects the important role of vascular endothelial dysfunction in this long-term complication.