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OBJECTIVE To improve prognosis, it is important to predict the incidence of renal failure and cardiovascular disease in type 2 diabetic patients before the progression to advanced nephropathy. We investigated the predictive effects of urinary liver-type fatty acid–binding protein (L-FABP), which is associated with renal tubulointerstitial damage, in renal and cardiovascular prognosis. RESEARCH DESIGN AND METHODS Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and without overt proteinuria were enrolled between 1996 and 2000 and followed up until 2011. Baseline urinary L-FABP was measured with an enzyme-linked immunosorbent assay. The primary end points were renal and cardiovascular composites (hemodialysis, myocardial infarction, angina pectoris, stroke, cerebral hemorrhage, and peripheral vascular disease). The secondary renal outcomes were the incidence of a 50% decline in estimated glomerular filtration rate (eGFR), progression to an eGFR RESULTS During a 12-year median follow-up, 103 primary end points occurred. The incidence rate of the primary end point increased in a stepwise manner with increases in urinary L-FABP. In Cox proportional hazards analysis, the adjusted hazard ratio in patients with the highest tertile of urinary L-FBAP was 1.93 (95% CI 1.13–3.29). This relationship was observed even when analyzed separately in normoalbuminuria and microalbuminuria. Patients with the highest tertile of urinary L-FABP also demonstrated a higher incidence of the secondary renal outcomes. CONCLUSIONS Our results indicate that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type 2 diabetic patients without advanced nephropathy.

OBJECTIVE Cross-sectional studies have reported increased levels of urinary type IV collagen in diabetic patients with progression of diabetic nephropathy. The aim of this study was to determine the role of urinary type IV collagen in predicting development and progression of early diabetic nephropathy and deterioration of renal function in a longitudinal study. RESEARCH DESIGN AND METHODS Japanese patients with type 2 diabetes (n = 254, 185 with normoalbuminuria and 69 with microalbuminuria) were enrolled in an observational follow-up study. The associations of urinary type IV collagen with progression of nephropathy and annual decline in estimated glomerular filtration rate (eGFR) were evaluated. RESULTS At baseline, urinary type IV collagen levels were higher in patients with microalbuminuria than in those with normoalbuminuria and correlated with urinary β2-microglobulin (β = 0.57, P < 0.001), diastolic blood pressure (β = 0.15, P < 0.01), eGFR (β = 0.15, P < 0.01), and urinary albumin excretion rate (β = 0.13, P = 0.01) as determined by multivariate regression analysis. In the follow-up study (median duration 8 years), urinary type IV collagen level at baseline was not associated with progression to a higher stage of diabetic nephropathy. However, the level of urinary type IV collagen inversely correlated with the annual decline in eGFR (γ = −0.34, P < 0.001). Multivariate regression analysis identified urinary type IV collagen, eGFR at baseline, and hypertension as factors associated with the annual decline in eGFR. CONCLUSIONS Our results indicate that high urinary excretion of type IV collagen is associated with deterioration of renal function in type 2 diabetic patients without overt proteinuria.

OBJECTIVE Albuminuria in type 2 diabetic patients is a risk factor for cardiovascular disease. We investigated the correlation between albuminuria and spontaneous microaggregation of platelets (SMAP) formed under shear stress. RESEARCH DESIGN AND METHODS The study subjects were 401 type 2 diabetic individuals (252 with normoalbuminuria and 149 with albuminuria) who were examined for SMAP under conditions of shear stress only (no agonist stimulation) and the reversibility of platelet microaggregation after stimulation with 1 μmol/l ADP, measured by a laser light-cattering method. Active glycoprotein IIb/IIIa (GPIIb/IIIa) and P-selectin expression levels on platelets as an index of platelet activation were measured by whole-blood flow cytometry. RESULTS SMAP formation was noted in 53% of diabetic patients. All patients with SMAP showed an irreversible pattern of platelet microaggregates by a low dose of ADP. SMAP was observed in 75% of diabetic subjects with albuminuria and in 39% of those with normoalbuminuria. Multivariate logistic regression analysis identified urinary albumin excretion rate and brachial-ankle pulse-wave velocity as independent factors associated with SMAP. The degree of SMAP correlated with active GPIIb/IIIa (γ = 0.59, P < 0.001) and P-selectin (γ = 0.55, P < 0.001) expression levels. These early-activated platelet profiles were significantly inhibited in albuminuric patients with aspirin intake, although the effect was incomplete. CONCLUSIONS Our study demonstrated an independent association between albuminuria and early changes in activated platelet profiles of type 2 diabetic patients. Further follow-up and intervention studies are needed to establish whether the inhibition of SMAP affects the course of cardiovascular disease in type 2 diabetic patients.

Reduction of microalbuminuria in patients with type 2 diabetes mellitus: the Shiga Microalbuminuria Reduction Trial (SMART) Received for publication 8 December 2006 and accepted in revised form 2 March 2007. Takashi Uzu, Makoto Sawaguchi, Hiroshi Maegawa, Atsunori Kashiwagi, for the Shiga Microalbuminuria Reduction Trial (SMART) group*

Prevention of cardiovascular disease is an important therapeutic goal in patients with type 2 diabetes mellitus (1). Although a low dose of aspirin is recommended for this purpose, some patients were resistant to aspirin (2). We previously reported that spontaneous microaggregation of platelets (SMAPs) formed under no stimulation with exogenous agonists were frequently observed in type 2 diabetic patients (3,4) and a considerable number of patients receiving aspirin still showed SMAP formation (4). The aim of the current study was to investigate whether a switch from aspirin to another antiplatelet drug could improve an insufficient platelet response to aspirin in diabetic patients. This was an open-label, single-arm, uncontrolled trial of antiplatelet treatment with 200 mg cilostazol daily (a phosphodiesterase III inhibitor) as an alternative to aspirin in 24 Japanese type 2 diabetic patients who persistently showed the inadequate SMAP formation despite treatment with …