Diabetic nephropathy is a common complication in patients with diabetes. It is currently the leading cause of end stage renal disease ESRD in Western societies and the main factor responsible for the increase in ESRD prevalence 1. Owing to the clinical and economic burden of diabetic nephropathy, considerable effort is made to identify ways to prevent it and delay its progression. In this review of press, we will focus on 3 recent publications that identified biomarkers of diabetic nephropathy: adiponectin, plasma connective tissue growth factors (CTGF) and inflammatory biomarkers.
Saraheimo et al who previously reported that adiponectin ADPN levels were high in type 1 patients with nephropathy (see the section adiponectin and diabetic nephropathy in a previous edition) stated in a recent publication that increased serum ADPN predict the progression from macroalbuminuria to ESRD in type 1 diabetic patients 2. The study, which was a prospective follow-up as a part of the Finnish Diabetic Nephropathy Study included 1,330 type 1 diabetic patients followed for a median of 5 years. Patients were divided at baseline into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: 818 patients with normoalbuminuria (AER <20 microg/min), 216 patients with microalbuminuria (20 microg/min <or= AER < 200 microg/min), and 296 patients with macroalbuminuria (AER > or =200 microg/min). The results showed that there were no difference in adiponectin concentrations between progressors and non-progressors in patients with normoalbuminuria or microalbuminuria. In the patients with macroalbuminuria, progression to ESRD was associated with higher adiponectin in the entire group (23.4±17.1 vs. 16.0±8.5 mg/L, P<0.001) and in men (P<0.001) and women (P<0.001) separately. Progression to ESRD was also associated with systolic blood pressure, insulin dose, HBA1c, serum cholesterol, serum triglycerides, AER, and glomerular filtration rate (GFR). When these covariates were inserted in a Cox regression analysis, HBA1c, triglycerides, GFR, and ADPN were significantly associated with progression from macroalbuminuria.
In a similar work done at the Steno Medical Diabetes Center in Denmark, Jorsal et al 3 reported in a prospective observational follow-up study that high serum ADPN levels predict mortality and progression to end stage renal disease in type 1 diabetes. The study consisted of 438 patients with type 1 diabetics and overt diabetic nephropathy and 440 type 1 patients with normal albumin excretion. These two groups were followed for about 8 years and generally matched for gender, age and duration of diabetes. The analysis showed significant relation between all-cause mortality and serum ADPN that also predicted end stage renal disease in a covariate-adjusted analysis. However there was no association with cardiovascular events; two of eight gene polymorphisms studied were associated with increased serum adiponectin levels but none of the polymorphisms were associated with a renal or cardiovascular outcome
Again at Steno Diabetes Medical Center, Astrup et al 4 evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in GFR in type 1 diabetic patients. They prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with normoalbuminuria. The investigators constructed two Z scores: the inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The results showed that Z score of inflammatory biomarkers was associated with mortality in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1-2.6]; P=0.025 ). The adjustment remained significant after adjusting for age and sex in patients with diabetic nephropathy (HR 1.6, 95% CI [1.0-2.3]; P=0.031). The Z score for endothelial dysfunction correlated with decline in GFR (r=-0.243; P=0.001); the correlation persisted after multivariate adjustment (coefficient -1.38 [95% CI -2.27 to -0.50]; P =0002).
The third work, published by Tri G et al 5 evaluated the predictive value of baseline plasma connective tissue growth factor (CTGF) in a prospective study of patients with type 1 diabetes. 198 type I diabetic patients with established diabetic nephropathy, and 188 type 1 diabetic patients with persistent normoalbuminuria were followed up for up-to 12 years. Plasma CTGF was higher in patients with nephropathy than in patients with normoalbuminuria (median 381 [270-630] vs. 235 [168-353] pmol/l). In patients with nephropathy, elevated plasma CTGF was an independent predictor of ESRD (adjusted hazard ratio [HR] 1.6 [95% CI 1.1-2.5]) and correlated with the rate of decline in glomerular filtration rate (GFR) (cumulative R = 0.46). Plasma CTGF above a cut-off level of 413 pmol/l predicted ESRD with a sensitivity of 73% and a specificity of 63% and was associated with a higher rate of decline in GFR (5.4±4.9 vs. 3.3±3.5 ml/min per 1.73 m2 per year). Moreover, in patients with nephrotic range albuminuria (>3 g/day), plasma CTGF was the only predictor of ESRD (covariate-adjusted HR 4.5 [2.0-10.4]). Plasma CTGF was an independent predictor also of overall mortality (covariate-adjusted HR 1.4 [1.1-1.7]). In contrast, in normoalbuminuric patients, plasma CTGF did not correlate with clinical parameters and did not predict outcome.
