Renin Angiotensin System Study (RASS/B-RASS)
Renin Angiotensin System Study (RASS/B-RASS)
To determine if renin angiotensin medications can prevent or delay the onset of diabetic
 kidney disease.
The primary objective of this research is to determine, in type 1 (insulin-dependent)
 diabetic patients without hypertension, diabetic nephropathy (DN), or levels of
 microalbuminuria (MA) predictive of underlying, already established serious lesion of
 diabetic nephropathy, if inhibition of renin-angiotensin system (RAS) activity can prevent or
 retard the rate of development of the histologic lesions associated with DN. This primary
 prevention study is designed to examine the effect of pharmacologic intervention on the
 earliest stages of diabetic kidney disease. At the stage of overt DN intervention studies
 have shown only a slowing, as opposed to arrest, in disease progression, and benefit a
 minority of treated patients. At the MA stage the renal lesions of DN are already usually
 firmly established; moreover, progression in MA patients may occur despite strict glycemic or
 anti-hypertensive control. Renal histologic change over time has been selected as the primary
 endpoint in order to study the early stages of this disease, since the time to functional
 endpoints from these earlier stages precludes practical study design.

 Specific Aim 1 To recruit 285 type 1 diabetic patients who do not have hypertension, diabetic
 nephropathy, or predictive levels of microalbuminuria into a 5-year study to determine the
 effect of inhibition of renin-angiotensin system activity with either losartan (angiotensin
 II blocker) or enalapril (converting enzyme inhibitor) on the development of diabetic renal
 disease. This aim has been accomplished and the study is entitled the Renin-Angiotension
 System Study (RASS).

 Specific Aim 2 To obtain two percutaneous renal biopsies from each patient, the first, at
 entry into the study, and the second after five years of drug therapy with either losartan or
 enalapril.

 Hypothesis Reduction of renin-angiotensin system activity will prevent or retard the
 development of histologic change in the kidney associated with diabetic nephropathy.

 A secondary objective of this study is to evaluate retinal lesions in the RASS cohort of
 patients in order to determine the relationship of these findings to the histologic changes
 of DN and to examine the effects of RAS inhibition and/or systemic blood pressure (BP) on the
 development and progression of diabetic retinopathy. This ancillary study has the following
 aims:

 Specific Aim To obtain baseline, 2.5 and 5 year retinal fundus photographs in the RASS
 patients.

 Hypothesis Cross-sectional and longitudinal relationships of retinal and renal structural
 abnormalities will emerge which will improve the predictive value of renal functional tests.
 Reduction of rennin-angiotensin system activity will prevent or retard the development of
 diabetic retinal lesions
Inclusion Criteria:

 -  type 1 diabetic (DM) for 2-20 yrs

 -  type 1 DM onset prior to 45; if onset was between ages 31-41, BMI <26; onset 41-45,
 positive GAD or ICA required

 -  normal or increased GFR

 -  normal BP

 -  normoalbuminuric (<20 ug/min on 2 of 3 time overnight urine collections)

 Exclusion Criteria:

 -  type 1 DM duration longer than 20 yrs

 -  hypertension (>85/135 mmHg)

 -  reduced GFR (<90 ml/min/1.73m2)

 -  microalbuminuria

 -  solitary kidney or evidence of unilateral renal disease

 -  evidence of other important kidney disease by history, ultrasound or biopsy

 -  other chronic diseases or conditions such as cystic fibrosis, serious mental illness,
 severe mental retardation, etc.

 -  pregnancy or females planning pregnancy within 2 years were excluded due to the drugs
 being used

 -  compliance (pt not taking at least 85% of two week placebo were excluded)