The kidney is a particularly rich source for prostaglandins and prostaglandins modulate a broad range of renal functions including microvascular hemodynamics, renin release and tubular salt and water reabsorption. The normal adult mammalian kidney expresses COX2 and cyclooxygenase metabolites, and they have been implicated in functional and structural alterations in glomerular and tubulointerstitial inflammatory diseases. In experimental animal models of kidney disease, COX2 selective inhibitors decreased proteinuria and inhibited the development of glomerulosclerosis. In addition, the use of COX2 inhibitors decreased the expression of TGF-?1 in Type III and IV collagen. Clinical studies in humans have minimally examined the renal effects of the COX2 inhibitors. They have been demonstrated to decrease the urinary excretion of prostaglandins, reduce urinary sodium excretion and have conflicting results on acute changes in GFR. Nonsteroidal anti-inflammatory agents, which work less specifically than COX2 inhibitors in the kidney have been demonstrated to decrease proteinuria in subjects with refractory nephrotic syndrome. In this study, we propose to extend the animal and human data suggesting a potential beneficial effect of COX2 inhibitors in renal disease as manifested by its acute hemodynamic effects decreasing proteinuria and perhaps initially single nephron GFR. Recognizing there may be safety concerns in regards to hyperkalemia and acute renal failure in a subject population with preexisting diabetes and renal disease given COX2 inhibitors, we propose a short-term pilot study in humans with diabetes and modest chronic renal insufficiency and proteinuria. We will randomly assign 30 subjects with diabetic nephropathy already on ACE inhibitor therapy to a crossover design of either placebo (6 wks) - washout (3 wks) - COX2 inhibitor(6 wks) - washout (3 wks) or COX2 inhibitor (6 wks) - washout (3 wks) - placebo (6 wks) - washout (3 wks). This will allow us to both collect safety data in this population of subjects as well as examine the acute effects of COX2 inhibitors on proteinuria. We propose to use a decrease in proteinuria as a surrogate for renal function in this short-term pilot study. A decline in proteinuria in subjects randomized to COX2 inhibitors would support consideration of a larger, long-term trial to examine the efficacy of COX2 inhibitors in preserving renal function.
