Effect of Losartan on Prevention and Progression of Early Diabetic Nephropathy in American Indians With Type 2 Diabetes

Abstract

Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g; n = 91) or microalbuminuria (ACR 30–299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to ≤60 mL/min or to half the baseline value in subjects who entered with GFR <120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12–1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria.

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

“…To determine whether the transcriptional and metabolic changes found in the diabetic mice were recapitulated in humans with diabetes (26), we performed transcriptomic analysis of kidney biopsy samples obtained from 49 well-characterized Southwestern American Indians with type 2 diabetes (27,28). Similar to the mouse data, targeted pathway analysis identified significant enrichment of many pathways involved in fatty acid/lipid metabolism, along with several in glucose and amino acid metabolism (Supplemental Figure 5, A-D).…”

“…Kidneys were collected, and renal cortex was dissected. (28). GFR was measured by the urinary clearance of iothalamate as previously described (64).…”

Structural Predictors of Loss of Renal Function in American Indians with Type 2 Diabetes

“…One hundred sixty-nine adult Pima Indians from this longitudinal study who had type 2 diabetes participated in a 6-year clinical trial to evaluate the renoprotective efficacy of losartan (ClinicalTrials.gov no. NCT00340678) (20). The prespecified primary end point was a decline in GFR to #60 ml/min or one half the baseline value in participants who entered the study with GFR,120 ml/min.…”

“…who was masked to the clinical data. Parameters included mean glomerular volume, glomerular basement membrane (GBM) width, cortical interstitial fractional volume, mesangial fractional volume per glomerulus, glomerular filtration surface density, total filtration surface per glomerulus, number of nonpodocyte cells (endothelial cells and mesangial cells) per glomerulus, number of podocytes per glomerulus, podocyte foot process width, percentage of podocyte detachment, and percentage of normally fenestrated endothelium (12,19,20,25,26). An equation that accounts for the difference in probability of encountering a sclerotic or nonsclerotic glomerulus in a random cross-section was used to calculate the percentage of sclerotic glomeruli (27).…”

“…Unbiased random sampling of tissue sections provided digital images for study using quantitative morphometric methods to estimate renal structural parameters (20,24). Measurements were performed by an investigator (E.J.W.)…”