Renoprotection in Early Diabetic Nephropathy in Pima Indians

Condition(s) targeted: Diabetic Nephropathy

Intervention: Losartan (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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 ration less than 30 mg/g) or micoralbuminuria (albumin-to-creatinine ration = 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 less than 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 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 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. Within six months of the 96-month renal clearance study, ultrasound measurement of carotid intimal-medial thickness and electron beam computed tomographic scanning for detection of coronary calcium will be done to assess differences in cardiovascular risk factors in the treatment groups.

The major outcome measure will be 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 less than 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 the microalbuminuric 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. A secondary outcome measure will be group differences in the frequency of cardiovascular risk factors. Sequential analysis of accumulated follow-up data will be performed to identify treatment differences between the groups.

Official title: Renoprotection in Early Diabetic Nephropathy in Pima Indians

Study design: Treatment, Randomized, Double-Blind, Parallel Assignment, Safety/Efficacy Study

Primary outcome: 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.

Secondary outcome: Change in albumin excretion, change in serum creatinine concentration, and Glomerular morphology in all subjects.

Detailed description: 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 less than 30 mg/g) or micoralbuminuria (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 less than 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 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 will be 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 less than 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 the microalbuminuric 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. A secondary outcome measure will be group differences in the frequency of cardiovascular risk factors. Sequential analysis of accumulated follow-up data will be performed to identify treatment differences between the groups.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

Volunteers from the Gila River Indian Community who meet the eligibility criteria will be invited to participate.

To be eligible for participation in the study, subjects must meet the folloiwng criteria:

- Aged 18-65.

- Diagnosis of type 2 diabetes greater than or equal to 5 years.

- Serum creatinine concentration less than to 1. 4 mg/dl.

- Serum potassium concentration less than or equal to 5. 5 mEq/L.

- At least 2 of 3 weekly screening urinary albumin-to-creatinine ratios less than 300

mg/g. All screening tests are to be witin 3 months of enrollment.

- Willingness, after receiving a thorough explanation of the study, to participate.

EXCLUSION CRITERIA:

Subjects will be excluded for the following reasons:

- Clinically significant disorders of the liver, cardiovascular disease, cerebrovascular

disease, peripheral vascular disease, pulmonary diseases, renal-urinary disorders, gastrointestinal disorders, or hematocrit levels less than or equal to 30 percent in women or less than or equal to 35 percent in men.

- Renovascular or malignant hypertension; uncontrolled hypertension despite treatment

with three antihypertensive drugs; or hypertension that is being treated with antihypertensive medicines and the primary care physician or the patient refuses to adopt the blood pressure treatment regimen outlined in the study protocol.

- Hematuria of unknown etiology.

- Chronic debilitating disorders with or without treatment that would interfere with the

assessment of kidney function or that might reduce the chances of survival for a sufficient length of time to evaluate efficacy of treatment.

- Currently receiving a drug regimen that includes: steroids, immunosuppressants, or

investigational new drugs.

- Pregnancy. Women of childbearing potential must have a negative pregnancy test prior

to entry and every three months during the study.

- Evidence of inability to empty the bladder.

- Hypersensitivity to ACEi, ARBs, or iodine.

- Bleeding disorders, since kidney biopsies could not be performed safely in these

individuals.

- Massive obesity with body mass index greater than or equal to 45 kg/m(2).

- Non-diabetic renal disease.

- Conditions that are likely to interfere with informed consent or compliance with the

protocol.

Gila River Indian Reservation, Phoenix, Arizona, United States

Starting date: August 1995
Last updated: December 22, 2007