Increase of Urinary Type IV Collagen in Normoalbuminuric Patients with Impaired Glucose Tolerance

Dear Sir,Microalbuminuria is the only early clinical sign of the subsequent diabetic nephropathy. However, it is also known that significant structural changes have already appeared even at the stage of microalbuminuria in non-insulin-dependent diabetes mellitus (NIDDM) patients. Thus, it is necessary to develop a more sensitive measurement for detecting the early stage of renal injury in patients with diabetic nephropathy. Since type IV collagen is the principal component of glomerular basement membrane and mesangial matrix, the levels of type IV collagen in sera and urinary samples may reflect the rate of its turnover, such as the balance of production by intrinsic renal cells and degradation by matrix proteinases in diseased kidneys.To investigate the alteration of renal turnover of type IV collagen in patients with impaired glucose tolerance (IGT), urinary type IV collagen (uIV) was measured by a highly sensitive one-step sandwich enzyme immunoassay (EIA) (Fuji Chemical Industries, Co. Ltd, Takaoka, Toyama, Japan) [1]. Diagnosis of NIDDM was made according to the criteria of the 75-gram oral glucose tolerance test (OGTT) of the Japanese Diabetic Research Council [2]. Levels of fasting plasma glucose in patients with NIDDM were significantly higher than those in IGT patients or healthy adults (p < 0.001, p < 0.0001, respectively). Urinary samples were obtained from 27 patients with IGT, 100 patients with NIDDM and 99 healthy adults. All these patients and healthy adults were age-matched and showed normoalbuminuria (<30 mg/g·creatinine (Cr) of urinary albumin). Six patients (22.2%) with IGT showed more than the normal range of uIV (mean + SD). Seventeen (17%) NIDDM patients showed more than the normal range of uIV (mean + SD). The levels of uIV in patients with IGT were significantly higher than those in healthy adults (4.43 ± 2.95 µg/g·Cr vs. 3.30 ± 1.42 µg/g·Cr, p < 0.01). The levels of uIV in NIDDM patients with normoalbuminuria (4.06 ± 2.83 mg/g·Cr) were also significantly higher than those in healthy adults (p < 0.025) (fig. 1). However, there were no significant changes in the levels of blood pressure and body weight among healthy adults, and IGT and NIDDM patients. Gel filtration analysis of urinary samples from both normal controls and NIDDM patients showed a similar pattern with a single peak at a molecular size of about 540 kD which is close to intact type IV collagen (preliminary study, data not shown). It is postulated that type IV collagen detected in the urine is due to release from renal tissues, but not from peripheral blood. It appears that the increase of uIV might reflect ongoing alteration of renal turnover of type IV collagen in IGT and early stage NIDDM patients with normoalbuminuria.