Renoprotection in Early Diabetic Nephropathy in Pima Indians

National Institutes of Health (NIH)

Status and phase: Completed; Phase 3

Conditions: Diabetic Nephropathy

Treatments: Drug: Losartan; Drug: Placebo

Study type: Interventional

Funder types: NIH

Identifiers

NCT00340678

999995037

OH95-DK-N037 (Other Identifier)

Details and patient eligibility

About

This investigation is 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 microalbuminuria (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.

One hundred seventy subjects were recruited for the study, all of whom had 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. 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 was performed after six years in 111 subjects. Morphometric analysis of renal biopsies was used to determine differences in glomerular structure between treatment groups.

Full description

This investigation is 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.

One hundred seventy subjects were recruited for the study, all of whom had 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. 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 immunoglobulin G (IgG) were made initially, at one month, and at 12-month intervals from baseline thereafter. A kidney biopsy was be performed after six years in 111 subjects. Morphometric analysis of renal biopsies was used to determine differences in glomerular structure between treatment groups.

The major outcome measure was 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 were 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.

Enrollment: 170 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 following 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 milliequivalents (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 within 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 angiotensin-converting enzyme inhibitors (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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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170 participants in 4 patient groups, including a placebo group

Normoalbuminuria Losartan

Experimental group

Description:

Subjects with normal urinary albumin excretion were treated with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.

Treatment:

Drug: Losartan

Normoalbuminuria Placebo

Placebo Comparator group

Description:

Subjects with normal urinary albumin excretion were treated with placebo corresponding to each dose of losartan.

Treatment:

Drug: Placebo

Microalbuminuria Losartan

Experimental group

Description:

Subjects with microalbuminuria were treated with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.

Treatment:

Drug: Losartan

Microalbuminuria Placebo

Placebo Comparator group

Description:

Subjects with Microalbuminuria were treated with placebo corresponding to each dose of losartan.

Treatment:

Drug: Placebo