Effect of Angiotensin Converting Enzyme Inhibitor, Lisinopril, on Renal Blood Flow and Its Correlation With Proteinuria Reduction in Subjects With Type 2 Diabetes and Kidney Disease

Blockers of renin angiotensin aldosterone system (RAAS) are considered the standard of care
in treatment of diabetic nephropathy. Their effects are thought to be through multiple
mechanisms, including reducing intraglomerular pressure. However, due to the lack of a
sensitive, practical and noninvasive method of monitoring renal hemodynamics, the magnitude
of hemodynamic effects of these agents and its contribution to proteinuria reduction has not
been studied in humans. At the same time, it is not clear if treatment with blockers of the
RAAS have similar renal hemodynamic effects in individuals with and without diabetes and
kidney disease.

Up to 36 subjects with type 2 diabetes and more than 150 mg of proteinuria who are on stable
doses of ACE inhibitors or angiotensin receptor blockers (ARBs) and up to 18 healthy
volunteers will be enrolled in this study. Subjects with type 2 diabetes will be asked to
stop their ACE inhibitor or ARB medications for 10 days. Between 7 to 10 days after stopping
these medications renal blood flow (RBF) will be measured using contrast enhanced ultrasound
(CEU) and urine protein will be measured as well for comparison to baseline. Subjects' ACE
inhibitors or ARB will be restarted and RBF measurement using CEU and measurement of urine
protein excretion will be repeated after 7 days. For comparison, RBF will be measured by CEU
in up to 18 healthy volunteers. They will then be started on Lisinopril 10 mg orally once a
day for 7 days. On day 7 RBF measurement will be repeated to assess the effect of ACE
inhibitors on RBF in healthy individuals as compared to those with diabetic nephropathy.

Inclusion For subjects with diabetic nephropathy,

1. Adults (ages 40 - 75 years)

2. Diagnosis of type 2 diabetes for more than 5 years

3. Evidence of diabetic nephropathy as evidenced by

a. More than 150 mg of proteinuria per day in a 24-hour urine collection, or a spot
morning urine protein to creatinine of greater than 0.15, or a spot morning urine
albumin to creatinine ratio greater than 100 confirmed on two separate occasions
within 12 months

4. Treatment with a blocker of the renin -angiotensin-aldosterone system (either ACE
inhibitor or ARB)

For healthy controls,

1. Adults (ages 40 - 75 years)

2. Good general health

Exclusion For subjects with diabetic nephropathy,

1. Type 1 diabetes

2. Glomerular filtration rate less than 40 ml/min/1.73 m2 by MDRD formula

3. Hemoglobin A1C greater than 10%

4. Blood pressure greater than 150/90 mm Hg or less than 100/55 mm Hg

5. History of kidney transplantation

6. Oxygen saturation is less than 80%

7. History of unstable cardiopulmonary conditions, known intracardiac shunts, or
pulmonary hypertension

8. History of active cancer within the last 3 years

For healthy controls,

1. History or clinical evidence of any chronic disease

2. Chronic and regular use of any medications except for oral contraceptives and
vitamins

3. Clinically significant abnormal screening laboratory values

4. Pregnancy or lactation for women

5. Blood pressure at screening visit less than 110/60

6. History of unstable cardiopulmonary conditions, known intracardiac shunts, or
pulmonary hypertension

7. History of active cancer within the last 3 years