Urinary Adiponectin Excretion: A Novel Marker for Vascular Damage in Type 2 Diabetes

OBJECTIVE

Markers reliably identifying vascular damage and risk in diabetic patients are rare, and reports on associations of serum adiponectin with macrovascular disease have been inconsistent. In contrast to existing data on serum adiponectin, this study assesses whether urinary adiponectin excretion might represent a more consistent vascular damage marker in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Adiponectin distribution in human kidney biopsies was assessed by immunohistochemistry, and urinary adiponectin isoforms were characterized by Western blot analysis. Total urinary adiponectin excretion rate was measured in 156 patients with type 2 diabetes who had a history of diabetic nephropathy and 40 healthy control subjects using enzyme-linked immunosorbent assay. Atherosclerotic burden was assessed by common carotid artery intima-media-thickness (IMT).

RESULTS

A homogenous staining of adiponectin was found on the endothelial surface of glomerular capillaries and intrarenal arterioles in nondiabetic kidneys, whereas staining was decreased in diabetic nephropathy. Low-molecular adiponectin isoforms (∼30–70 kDa) were detected in urine by Western blot analysis. Urinary adiponectin was significantly increased in type 2 diabetes (7.68 ± 14.26 vs. control subjects: 2.91 ± 3.85 μg/g creatinine, P = 0.008). Among type 2 diabetic patients, adiponectinuria was associated with IMT (r = 0.479, P < 0.001) and proved to be a powerful independent predictor of IMT (β = 0.360, P < 0.001) in multivariable regression analyses. In a risk prediction model including variables of the UK Prospective Diabetes Study coronary heart disease risk engine urinary adiponectin, but not the albumin excretion rate, added significant value for the prediction of increased IMT (P = 0.007).

CONCLUSIONS

Quantification of urinary adiponectin excretion appears to be an independent indicator of vascular damage potentially identifying an increased risk for vascular events.Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes, and the identification of individual risk patterns is fundamental for the prevention and treatment of CVD. However, risk stratification in patients with diabetes is still vague (1,2), and, consequently, numbers needed to treat for prevention of a single cardiovascular event in clinical trials are ∼100–200 patients per year (3–5).Most of the recently described risk markers are metabolic or inflammatory molecules that do not directly indicate vascular damage. Therefore, these indirect markers show variations in risk prediction depending on the metabolic status of the study group (6,7). This becomes evident reviewing data on serum adiponectin; whereas low-circulating adiponectin was significantly associated with increased primary CVD risk in apparently healthy men (8), subsequent studies in high-risk populations, as well as patients with prevalent coronary heart disease (CHD), failed to confirm this association (9,10). A reason for this discrepancy between different groups of risk patients could be a reverse causality, where silent or apparent CVD might lead to compensatory rises in serum adiponectin. Consistently, it was shown in type 2 diabetic patients that adiponectin is lowest in the presence of impaired glucose regulation and early diabetes, whereas long diabetes duration is associated with a significant increase in circulating adiponectin (11).Adiponectin is a 30-kDa adipocyte-derived vasoactive peptide closely linked to components of the metabolic syndrome (rev. in 12). It has anti-inflammatory and antiatherosclerotic properties on endothelial cells by decreasing vascular inflammation, foam cell formation, and cell adhesion, which all are involved in the initiation and progression of vascular lesions (12). Recently, it was reported that adiponectin has a distinct role for glomerular homeostasis in an experimental model (13). Hence, adiponectin could be present on human renal endothelium and glomerular capillary stress in diabetes may promote shedding of adiponectin from endothelial surfaces by proteolytic cleavage, causing degradation of high-order complexes of adiponectin and subsequent appearance of the adiponectin monomer (∼28 kDa), dimer (∼56 kDa), and trimer (∼68 kDa) in urine.We hypothesized that adiponectin appears in urine consequently reflecting early glomerular vascular damage in type 2 diabetes rather than the metabolic changes associated with serum adiponectin. To characterize a possible diagnostic value of urinary adiponectin excretion, patients with type 2 diabetes and early diabetic nephropathy (i.e., a history of microalbuminuria) were studied, and the atherosclerotic burden of these patients was assessed by quantification of common carotid artery intima-media-thickness (IMT). Both urinary adiponectin and urinary albumin excretion rate (AER) as an established marker of micro- and macrovascular dysfunction in type 2 diabetes were evaluated for the prediction of increased IMT in comparative analyses.