Background Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether early administration of drugs that block the renin-angiotensin system slows their progression. Methods The Renin Angiotensin System Study [RASS] was a multicenter controlled trial in 285 normoalbuminuric, normotensive type 1 diabetic patients who were randomized to losartan (100mg daily), enalapril (20mg daily) or placebo and followed for 5 years. The primary endpoint was change in glomerular mesangial fractional volume in kidney biopsies. The retinopathy endpoint was a 2-step or greater progression in retinopathy severity scale. Intention-to-treat data analyses used linear and logistic regression models. Results Ninety and 82% of patients had complete renal biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over 5 years in placebo (0.016 units) was not significantly different from enalapril (p=0.38) or losartan (p=0.26), nor were there significant changes in other biopsy assessed renal structural variables. Five-year cumulative microalbuminuria incidence was higher for losartan than placebo (14% vs. 4%; logrank p=0.015) but not for enalapril (6% vs. 4%; logrank p=0.96). Two-step or more retinopathy progression incidence was reduced by 65% in the enalapril (O.R. 0.35; 95% C.I., 0.14–0.85) and 70% in the losartan group (O.R. 0.30; 95% C.I., 0.12–0.73) independent of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 enalapril, 6 losartan and 4 placebo patients. Conclusions Early renin-angiotensin system blockade did not modify nephropathy progression in type 1 diabetic patients, but had important effects in slowing retinopathy.

Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially early in the disease processes. The aim of this study was to examine the association of severity of diabetic retinopathy with histological measures of diabetic nephropathy in normoalbuminuric patients with type 1 diabetes. The study included participants (n ‫؍‬ 285) in the Renin-Angiotensin System Study (RASS; a multicenter diabetic nephropathy primary prevention trial) who were aged >16 years and had 2-20 years of type 1 diabetes with normal baseline renal function measures. Albumin excretion rate (AER), blood pressure, serum creatinine, and glomerular filtration rate (GFR) were measured using standardized protocols. Diabetic retinopathy was determined by masked grading of 30°color stereoscopic fundus photographs of seven standard fields using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. Baseline renal structural parameters, e.g., fraction of the glomerulus occupied by the mesangium or mesangial fractional volume [Vv(Mes/glom)] and glomerular basement membrane width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies. No retinopathy was present in 36%, mild nonproliferative diabetic retinopathy in 53%, moderate to severe nonproliferative diabetic retinopathy in 9%, and proliferative diabetic retinopathy in 2% of the cohort. Retinopathy was not related to AER, blood pressure, serum creatinine, or GFR. All renal anatomical end points were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in type 1 diabetic patients. Diabetes 54: 527-533, 2005

Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.

Aims/hypothesis-To examine whether retinal vessel diameter in persons with type 1 diabetes mellitus (T1DM) is associated with changes in subclinical anatomic and functional diabetic nephropathy indicators.Methods-Persons with T1DM had both gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n=234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriolar (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural parameters (e.g., mesangial fractional volume and glomerular basement membrane width (GBMW) and the mesangial matrix fractional volume and GBMW composite glomerulopathy index) were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens.Results-While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5 year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume while change in CRVE was directly related to change in the volume fractions of cortex which was interstitium [Vv(Int/cortex)] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other renal anatomic or functional endpoints.Correspondence to: Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 460 WARF, Madison, WI 53705-2397, (608) FAX (608) 263-0279, kleinr@epi.ophth.wisc.edu. Duality of Interest:Dr. Zinman, lecture fees, consulting fees, and research grants from Merck; and Dr. Klein reports being an advisory board member for AstraZeneca (through the DIRECT study), Pfizer, Lilly, and Novartis. No other dualities of interest relevant to this article were reported. [7]. Moreover, additional indicators are needed because MA, although useful, is an imprecise predictor of progression to proteinuria (P). We have previously reported significant associations between diabetic retinopathy (DR) and preclinical morphologic changes of DN in baseline assessments of normoalbuminuric (NA), normotensive T1DM persons in the Renin-angiotensin System Study (RASS) [8]. There is suggestive evidence that an additional measurement, assessment of retinal vessel diameter, might also be a useful predictor of chronic kidney disease in persons with T1DM [9,10]. In this report we examine whether retinal vessel diameter ( Figure 2) in RASS patients is associated with changes in subclinical anatomic and functional signs of DN. No reprints NIH Public Access Research Design and Methods Description of CohortThe RASS was a parallel, double-blind, placebo controlled, multicenter, clinical trial of DN primary prevention and retinopathy development and progression conducted at three clinical centers in Minneapolis, Minnesota, United States and Montreal, Quebec and Toronto, Ontario, Canada. The study design and cohort description have been detailed ...

Elevated urinary MCP-1 concentration measured before clinical findings of DN in women with T1D was associated with changes in kidney interstitial volume, suggesting that inflammatory processes may be involved in the pathogenesis of early interstitial changes in DN.