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Diabetic nephropathy (DN) is a progressive kidney disease, a well-known complication of long-standing diabetes. DN is the most frequent reason for dialysis in many Western countries. Early detection may enable development of specific drugs and early initiation of therapy, thereby postponing/preventing the need for renal replacement therapy. We evaluated urinary proteome analysis as a tool for prediction of DN. Capillary electrophoresis-coupled mass spectrometry was used to profile the low-molecular weight proteome in urine. We examined urine samples from a longitudinal cohort of type 1 and 2 diabetic patients (n = 35) using a previously generated chronic kidney disease (CKD) biomarker classifier to assess peptides of collected urines for signs of DN. The application of this classifier to samples of normoalbuminuric subjects up to 5 years prior to development of macroalbuminuria enabled early detection of subsequent progression to macroalbuminuria (area under the curve [AUC] 0.93) compared with urinary albumin routinely used to determine the diagnosis (AUC 0.67). Statistical analysis of each urinary CKD biomarker depicted its regulation with respect to diagnosis of DN over time. Collagen fragments were prominent biomarkers 3-5 years before onset of macroalbuminuria. Before albumin excretion starts to increase, there is a decrease in collagen fragments. Urinary proteomics enables noninvasive assessment of DN risk at an early stage via determination of specific collagen fragments. [ABSTRACT FROM AUTHOR]

Objective: Experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. Whether uric acid has a causal role in the development of diabetic nephropathy is not known. The objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria.Research Design and Methods: This prospective observational follow-up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes. Of these, 270 patients had blood samples taken at baseline. In seven cases, uric acid could not be determined; therefore, 263 patients (156 men) were available for analysis. Uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria.Results: During a median follow-up of 18.1 years (range 1.0-21.8), 23 of 263 patients developed persistent macroalbuminuria (urinary albumin excretion rate >300 mg/24 h in at least two of three consecutive samples). In patients with uric acid levels in the highest quartile (>249 micromol/l), the cumulative incidence of persistent macroalbumnuria was 22.3% (95% CI 10.3-34.3) compared with 9.5% (3.8-15.2) in patients with uric acid in the three lower quartiles (log-rank test, P = 0.006). In a Cox proportional hazards model with sex and age as fixed covariates, uric acid was associated with subsequent development of persistent macroalbuminuria (hazard ratio 2.37 [95% CI 1.04-5.37] per 100 micromol/l increase in uric acid level; P = 0.04). Adjustment for confounders did not change the estimate significantly.Conclusions: Uric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) versus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-beta, and AGE peptides were assessed. Irbesartan treatment yielded significant changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P < 0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo's 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo's 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro- and macrovascular disease. [ABSTRACT FROM AUTHOR]

Inflammation and complement activation via the mannose-binding lectin (MBL) pathway have been suggested to play a role in the pathogenesis of diabetic microvascular complications. The association between the complement-activating protein MBL and the development of persistent microalbuminuria was evaluated in an inception cohort of 286 newly diagnosed type 1 diabetic patients consecutively admitted to the Steno Diabetes Center between 1 September 1979 and 31 August 1984. Serum MBL was measured with an immunofluorometric assay in 270 of the patients (159 men) after 3 years of diabetes duration. During the median (range) follow-up period of 18.0 (1.0-21.8) years, 75 patients subsequently progressed to persistent micro- or macroalbuminuria (urinary albumin excretion rate >30 mg/24 h). In patients with MBL levels above the median (1,597 microg/l), the cumulative incidence of persistent micro- or macroalbuminuria was 41% (CI 31-50) as compared with 26% (CI 17-34) in patients with MBL levels below the median (log-rank test, P = 0.003). In a Cox proportional hazard model with sex and age as fixed covariates, MBL was independently associated with later development of persistent micro- or macroalbuminuria (hazard ratio 1.21 [CI 1.02-1.42] per 1,000 microg/l increase in MBL; P = 0.03) after adjusting for possible confounders. In our study, high levels of MBL early in the course of type 1 diabetes was significantly associated with later development of persistent micro- or macroalbuminuria, suggesting that complement activation initiated by MBL may be involved in the pathogenesis of diabetic microvascular complications.