Mechanisms of Diabetic Kidney Disease in American Indians

The purpose of this protocol is to examine the long-term impact of treatment with the
angiotensin receptor blocker losartan on progression of diabetic kidney disease in American
Indians with type 2 diabetes. Data from this protocol will also be used to guide the search
for candidate biomarkers of diabetic end-organ damage in serum and urine and to identify
mechanisms of diabetic kidney disease that may be amenable to new treatment strategies. All
participants previously enrolled in a 6-year randomized clinical trial under Protocol
OH95-DK-N037 and their first-degree relatives who have type 2 diabetes will be invited to
participate. Participants in this protocol will undergo annual renal clearance studies to
measure glomerular filtration rate and renal plasma flow, unless they have developed kidney
failure. At each visit, we will also conduct tests of the peripheral and autonomic nervous
system to determine the frequency, severity, and rate of progression of diabetic neuropathy
in this cohort and identify linkages between diabetic kidney disease and diabetic neuropathy.
We will also perform a kidney biopsy at the initial visit. In those who had a previous
research kidney biopsy during the clinical trial, we will examine the extent of structural
changes that occurred since their last kidney biopsy done at the end of the clinical trial.
First-degree relatives and those who were enrolled in the clinical trial, but did not undergo
a research kidney biopsy as part of that trial, will be invited to undergo a second kidney
biopsy after 5-years of follow-up. Tissue from these biopsies will undergo morphometric
examination and compartment-specific gene expression and epigenetic profiling. A small punch
skin biopsy may be obtained at various times in some participants for assessment of
intraepidermal nerve fiber density or for fibroblast culture. The skin biopsy for fibroblast
culture will be done only once unless the culture fails, in which case the participant may be
invited to undergo another biopsy. We may invite participants to undergo skin biopsy on
several occasions for assessment of changes in nerve fiber density. We may also perform
magnetic resonance imaging of the kidneys or the brain in some participants. Imaging of the
kidneys will be done as near to the time of the kidney biopsy as possible. We many invite
participants to undergo the brain imaging on 2 occasions about 3-5 years apart. Participants
will be followed annually until death or development of end-stage renal disease.

- INCLUSION CRITERIA:

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

- Previous enrollment in protocol OH95-DK-N037 or a first-degree relative of an enrollee
who is aged greater than or equal to 18 years and has type 2 diabetes.

- 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 [cirrhosis, portal hypertension,
hepatitis, increased bilirubin (greater than or equal to 1.5 mg/dl), cardiovascular
disease (angina pectoris, history of myocardial infarction, left ventricular ejection
fraction <40%, congestive heart failure of New York Heart Association Class I to IV),
cerebrovascular disease, peripheral vascular disease, pulmonary diseases (asthma and
restrictive or obstructive lung disease requiring therapy), renal-urinary disorders
(calculi, urinary tract obstruction, glomerulonephritis, chronic infection),
gastrointestinal disorders (nausea, vomiting, diarrhea or anorexia sufficient to cause
weight loss or wasting), 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 (systolic blood
pressure greater than or equal to 160 or diastolic greater than or equal to 95 mm Hg)
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. Prior to entry into the study, any subject with
hematuria should be evaluated, the etiology established and documented, and treatment
rendered as appropriate.

- Chronic debilitating disorders with or without treatment (e.g., systemic lupus
erythematosus (SLE), cancer, amyloidosis, and chronic infection) that would interfere
with the assessment of kidney function. Participants who develop these disorders after
their original enrollment into one of our kidney studies will continue to be followed
in the protocol.

- Currently receiving a drug regimen that includes: steroids, immunosuppressants, or
investigational new drugs. Participants who receive these drugs following original
enrollment into one of our kidney studies will continue to be followed in the
protocol, unless they have known chronic significant effects on kidney morphology or a
high incidence of adverse effects on kidney function, in which case they will be
withdrawn from the study.

- Pregnancy. Women of childbearing potential must have a negative pregnancy test prior
to entry and prior to each renal clearance study. Women who are pregnant will be
offered the opportunity to participate following the conclusion of the pregnancy and
those who become pregnant during the study will be able to resume the study following
the conclusion of the pregnancy.

- Hypersensitivity to 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). Kidney
biopsies are more difficult and present greater hazards to persons with massive
obesity.

- Conditions likely to interfere with informed consent or compliance with the protocol.