Diabetic Nephropathy
Conditions
Keywords
Angiotensin II Receptor Antagonist, Therapeutic Trial, Glomerular Filtration Rate, Kidney Biopsy, Non-Insulin Dependent Diabetes Mellitus
Brief summary
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.
Detailed 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.
Interventions
DRUGLosartan
Treatment with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.
DRUGPlacebo
Treatment with placebo corresponding to each dose of losartan.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Decline in GFR | Up to 6 years | Participants were monitored for up to 6 years. This is the number of participants who had 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 during the time of observation. |
Secondary
| Measure | Time frame |
|---|---|
| Glomerular Volume | 6 years after first treatment |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled between 1996 and 2001, the last biopsy was performed in 2007, and morphometric evaluation was completed in 2012.
Pre-assignment details
Of 313 patients with type 2 diabetes who were screened, 79 were ineligible, 50 declined to participate, and 14 had other reasons that prevented participation despite meeting eligibility requirements.
Participants by arm
| Arm | Count |
|---|---|
| Normoalbuminuria Losartan 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. | 46 |
| Normoalbuminuria Placebo Subjects with normal urinary albumin excretion were treated with placebo corresponding to each dose of losartan. | 46 |
| Microalbuminuria Losartan 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. | 39 |
| Microalbuminuria Placebo Subjects with Microalbuminuria were treated with placebo corresponding to each dose of losartan. | 39 |
| Total | 170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Normoalbuminuria Losartan | Normoalbuminuria Placebo | Microalbuminuria Losartan | Microalbuminuria Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.5 years STANDARD_DEVIATION 10.6 | 41.9 years STANDARD_DEVIATION 11.7 | 41.8 years STANDARD_DEVIATION 8.9 | 42.3 years STANDARD_DEVIATION 10.9 | 41.3 years STANDARD_DEVIATION 10.6 |
| Blood pressure, diastolic | 75 mmHg STANDARD_DEVIATION 7 | 75 mmHg STANDARD_DEVIATION 7 | 77 mmHg STANDARD_DEVIATION 9 | 77 mmHg STANDARD_DEVIATION 7 | 76 mmHg STANDARD_DEVIATION 7 |
| Blood pressure, mean | 88 mmHg STANDARD_DEVIATION 7 | 89 mmHg STANDARD_DEVIATION 9 | 90 mmHg STANDARD_DEVIATION 10 | 92 mmHg STANDARD_DEVIATION 8 | 90 mmHg STANDARD_DEVIATION 9 |
| Blood pressure, systolic | 115 mmHg STANDARD_DEVIATION 11 | 118 mmHg STANDARD_DEVIATION 14 | 118 mmHg STANDARD_DEVIATION 15 | 123 mmHg STANDARD_DEVIATION 13 | 118 mmHg STANDARD_DEVIATION 13 |
| BMI | 37.4 kg/(m^2) STANDARD_DEVIATION 8.8 | 36.6 kg/(m^2) STANDARD_DEVIATION 8 | 34.6 kg/(m^2) STANDARD_DEVIATION 9.1 | 33.8 kg/(m^2) STANDARD_DEVIATION 7.2 | 35.7 kg/(m^2) STANDARD_DEVIATION 8.3 |
| Diabetes duration | 8.8 years STANDARD_DEVIATION 4.7 | 10.4 years STANDARD_DEVIATION 6 | 10.3 years STANDARD_DEVIATION 5.2 | 14.1 years STANDARD_DEVIATION 8.4 | 10.8 years STANDARD_DEVIATION 6.2 |
| Glomerular filtration rate (GFR) | 171 mL/min STANDARD_DEVIATION 38 | 152 mL/min STANDARD_DEVIATION 40 | 166 mL/min STANDARD_DEVIATION 43 | 168 mL/min STANDARD_DEVIATION 43 | 164 mL/min STANDARD_DEVIATION 41 |
| HbA1c | 9.2 % STANDARD_DEVIATION 2 | 8.1 % STANDARD_DEVIATION 2.2 | 9.5 % STANDARD_DEVIATION 2.3 | 10.3 % STANDARD_DEVIATION 2.1 | 9.2 % STANDARD_DEVIATION 2.1 |
| Region of Enrollment United States | 46 participants | 46 participants | 39 participants | 39 participants | 170 participants |
| Sex: Female, Male Female | 36 Participants | 33 Participants | 28 Participants | 27 Participants | 124 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 11 Participants | 12 Participants | 46 Participants |
| Urinary albumin to creatinine ratio | 15 mg/g | 14 mg/g | 66 mg/g | 80 mg/g | 47 mg/g |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 84 | 0 / 85 |
| serious Total, serious adverse events | 3 / 84 | 6 / 85 |
Outcome results
Primary
Number of Participants With Decline in GFR
Participants were monitored for up to 6 years. This is the number of participants who had 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 during the time of observation.
Time frame: Up to 6 years
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normoalbuminuria Losartan | Number of Participants With Decline in GFR | 2 participants |
| Normoalbuminuria Placebo | Number of Participants With Decline in GFR | 2 participants |
| Microalbuminuria Losartan | Number of Participants With Decline in GFR | 1 participants |
| Microalbuminuria Placebo | Number of Participants With Decline in GFR | 4 participants |
Secondary
Glomerular Volume
Time frame: 6 years after first treatment
Population: Intention-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normoalbuminuria Losartan | Glomerular Volume | 5.4 *10^6 cubic microns | Standard Deviation 1.8 |
| Normoalbuminuria Placebo | Glomerular Volume | 5.6 *10^6 cubic microns | Standard Deviation 1.1 |
| Microalbuminuria Losartan | Glomerular Volume | 6.4 *10^6 cubic microns | Standard Deviation 2.3 |
| Microalbuminuria Placebo | Glomerular Volume | 7.0 *10^6 cubic microns | Standard Deviation 3 |