The objective of this project is to submit an application to the FDA for approval of a new in vitro diagnostic for quantitative measurement of urinary type IV collagen to assess risk for progressive decline in renal function in patients with diabetes. Currently, the measurement of urinary albumin is the only in vitro diagnostic approved by the FDA for assessment of early diabetic renal disease. Although microalbuminuria has become the established predictive marker for the development of diabetic nephropathy, not all patients with microalbuminuria progress to overt nephropathy with rising serum creatinine, and some patients progress without antecedent microalbuminuria. Recent studies in the diabetic db/db mouse indicate that urinary collagen IV becomes elevated as renal involvement progresses, coinciding with morphometric evidence of glomerular mesangial matrix expansion and reflecting the transition from leaky (albuminuric) to occluded glomeruli in which filtration surface area is reduced. In a survey of samples from human diabetic patients and using a sensitive and specific enzyme linked immunoassay constructed for this purpose, we have found that an elevated urinary collagen IV significantly correlates with declining filtration function, assessed by the reciprocal of the serum creatinine, but does not correlate with albumin excretion.
The Specific Aims of Phase I, which will constitute milestones, are to: 1) Conduct a cross-sectional survey of 100 patients with type 1 diabetes, 100 patients with type 2 diabetes, and 50 patients with glomerular disease due to causes other than diabetes with respect to urinary collagen IV, amount of albumin excretion, and renal function assessed by the reciprocal of the serum creatinine (RSC); and 2) Begin refinement of the collagen IV immunoassay to ensure sensitivity, specificity, and ease of performance in a routine laboratory setting. The major goals in Phase II of this project are to: a) complete optimization of the immunoassay; b) define its performance characteristics; c) determine in prospective studies whether changes in filtration function over a two year period correlate with baseline and/or interim collagen IV excretion levels and compare the predictive values of urinary collagen IV versus albumin in this regard; and d) to assemble the data and prepare an application to the FDA.
