• Decline in GFR less than or equal to 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of less than 120 ml/min. [ Time Frame: Unrestricted ] [ Designated as safety issue: Yes ]
  

• Change in albumin excretion, change in serum creatinine concentration, and Glomerular morphology in all subjects. [ Time Frame: Unrestricted ] [ Designated as safety issue: No ]
  

Drug: Losartan
Standard of care versus standard of care plus losartan.

This investigation is a continuation of a randomized, double-blinded, placebo-controlled clinical trial in adult diabetic Pima Indians with normal urinary albumin excretion (albumin-to-creatinine ratio < 30 mg/g) or microalbuminuria (albumin-to-creatinine ratio = 30-299 mg/g) to test the hypothesis that blockade of the renin-angiotensin system with the angiotensin receptor blocker (ARB) losartan can prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care, now including treatment with the angiotensin converting enzyme inhibitor (ACEi) lisinopril.

One hundred seventy subjects were recruited for the study, all of whom have type 2 diabetes for at least 5 years, serum creatinine concentrations < 1.4 mg/dl, and no evidence of non-diabetic renal diseases. Ninety-two of the subjects had normal urinary albumin excretion at baseline and the other 78 had microalbuminuria. All of the subjects, with the exception of normoalbuminuric women of childbearing potential who are not practicing birth control, will now be treated with the ACEi lisinopril. Subjects in each albumin excretion group were randomized to treatment with either the angiotensin II receptor antagonist, losartan, or placebo. Measurements of glomerular filtration rate (GFR), renal plasma flow (RPF) and fractional clearances of albumin and IgG will be made initially, at one month, and at 12-month intervals from baseline thereafter. A kidney biopsy will be performed after five-and-a-half years in all subjects. Morphometric analysis of renal biopsies will be used to determine differences in the prevalence of global sclerosis, the number of visceral epithelial cells per glomerulus, and the breadth of epithelial foot processes between treatment groups. Differences in a severity index computed from the joint distribution of these morphometric variables will be used to assess the renoprotective efficacy of losartan at the tissue level. Following the kidney biopsy and after the 72-month renal clearance study, treatment with all ACEi and ARBs will be stopped for six weeks. At the end of the six-week washout period a second clearance study will be performed. Randomized study treatment will end at that time, but quarterly follow-up visits and annual renal clearance studies will continue to the onset of kidney failure. Hence, there is no specific end date for this study.

The major outcome measure is a decline in GFR to less than or equal to 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of < 120 ml/min. Other measures of renoprotection will also be assessed, including group differences in 1) change in albumin excretion, 2) change in serum creatinine concentration, and 3) glomerular morphology in all subjects as outlined above. Amelioration in the rate of increase of urinary albumin excretion will not be considered sufficient evidence for renoprotection. On the other hand, significant differences in glomerular morphology will be considered sufficient evidence for renoprotection. Sequential analysis of accumulated follow-up data will be performed to identify treatment differences between the groups.