Abstract-Obesity is increasingly recognized as a risk factor for renal disease, but the mechanism is unclear. Renal plasma flow response to captopril, as an index of renin-angiotensin system activity, was measured by para-aminohippurate clearance technique in 100 healthy, normotensive subjects in balance on a high-salt diet. Of the 100 subjects, body mass index exceeded 25 in 56 and exceeded 30 in 22. The average vasodilator response to captopril was 27Ϯ7 mL/min per 1.73 m 2 (PϽ0.0001). After adjustment for other predictors of the renal plasma flow response to captopril using a multivariate linear regression model, there was a highly significant relationship between age-and plasma renin activity-adjusted body mass index and the renal plasma flow response to captopril; however, a quadratic model provided a substantially better fit (rϭ0.55; PϽ0.0001; Pϭ0.03 versus linear correlation). The strong association between increasing body mass index and angiotensin-dependent control of the renal circulation suggests that this may be a mechanism by which obesity contributes to renal disease. Weight loss should be considered in the overweight or obese patient for renal protection. Ն30) 1 and each year, an estimated 300 000 US adults die prematurely of obesity-related causes. 2 Obesity is an independent risk factor for the development of kidney disease. [3][4][5][6] There is little doubt that excess weight gain is a major cause of hypertension and type 2 diabetes, which, together, account for Ͼ70% of end-stage renal disease in the United States. 7 Moreover, evidence also suggests that even in nondiabetic obese patients, there is some degree of renal dysfunction that can lead to more serious injury to the kidneys because metabolic and hemodynamic disturbances worsen with prolonged obesity. 4,6,8,9 The mechanism by which obesity predisposes to kidney damage is unclear, but animal studies suggest an important role for the renin-angiotensin system (RAS). 9 -11 Because animal studies typically involve rapid weight gain from overfeeding, and obesity in humans represents a much more gradual weight gain over years, it has not been clear to what extent these observations in animal models apply to humans. Two observations from our laboratory brought this potential relationship to our attention. Hopkins et al observed that obesity was associated with a blunted renovascular response to angiotensin II (Ang II) infusion, a finding consistent with increased intrarenal Ang II production. 12 Price et al later reported that BMI accounted for Ϸ50% of the renal plasma flow (RPF) response to irbesartan in type 2 diabetic subjects. 13 Because activation of the RAS is associated with progression of kidney disease, 14 these observations raised the question of whether obesity is associated with activation of the intrarenal RAS. We hypothesized that a positive relationship existed between BMI and activation of the intrarenal RAS. We thus examined renal hemodynamic function at baseline and in response to the angiotensin-converting enzyme (ACE) inhibit...

Pharmacologic interruption of the effects of aldosterone at the tissue level could be especially useful in patients with diabetes mellitus. The dose of agents that block the renin-angiotensin system (RAS) should be adjusted to maximize the fall in plasma aldosterone concentration.

OBJECTIVE -Diabetes, the leading cause of end-stage renal disease in the U.S., is believed to involve activation of the renin angiotensin system (RAS) as a risk factor for nephropathy. RAS activation occurs in healthy women using oral contraceptives (OCs), but the effects of OC use on the diabetic kidney are unclear.RESEARCH DESIGN AND METHODS -Renal plasma flow (RPF) response to captopril, as an index of RAS activity, was investigated in 92 women (41 nondiabetic OC nonusers, 10 nondiabetic OC users, 29 diabetic OC nonusers, and 12 diabetic OC users). Based on the hemodynamic findings, we examined the impact of OC use on the development of nephropathy as a post hoc analysis in an inception cohort of 114 female patients with newly diagnosed type 1 diabetes followed for a median of 20.7 years (range 1-24).RESULTS -Nondiabetic OC nonusers showed minimal RPF vasodilator response to captopril (9 Ϯ 10 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 , P ϭ 0.6). In comparison, nondiabetic OC users showed a significant increase (69 Ϯ 35 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 , P ϭ 0.02) (P ϭ 0.04 vs. nondiabetic OC nonusers). Diabetic OC nonusers demonstrated the anticipated vasodilator response (58 Ϯ 12 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 , P Ͻ 0.0001). Diabetic OC users showed the largest responses (84 Ϯ 12 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 , P ϭ 0.002) (P ϭ 0.04 vs. diabetic OC nonusers). Plasma renin activity did not vary with OC use (P ϭ 0.3). The RPF responses to captopril and angiotensin receptor blocker were highly correlated (r ϭ 0.72, P Ͻ 0.001), suggesting clear involvement of the RAS. In the observational study, 18% (6/33 [95% CI 4.3-32.1]) of OC users developed macroalbuminuria compared with 2% (2/81 [0 -5.9]) of OC nonusers (P ϭ 0.003, univariate analysis). After adjustment for known risk factors with a Cox regression model, OC use remained a predictor for the development of macroalbuminuria (relative risk 8.90 , P ϭ 0.008).CONCLUSIONS -The strong association of OC use with angiotensin-dependent control of the renal circulation and the development of macroalbuminuria suggest that OC use may be a risk factor for diabetic nephropathy. Large prospective studies are required to further investigate this relationship. 28:1988 -1994, 2005 D iabetes is the leading cause of endstage renal disease in the U.S. Moreover, the number of patients diagnosed each year with end-stage renal disease secondary to diabetes is expected to grow from 41,000 in the year 2000 to 300,000 in the year 2030 (1). Activation of the renin angiotensin system (RAS) is associated with progression of both diabetic and nondiabetic kidney disease (2). Numerous studies have demonstrated that RAS blockade lowers the rate of urinary albumin excretion (UAE) and retards decline of renal function in diabetes (3-7). This protective effect probably reflects both the hemodynamic and nonhemodynamic effects of ACE inhibitors and angiotensin II (Ang II) receptor blockers. Diabetes CareFemale sex is a protective factor in the development of renal disease (8), but the mechanism remains elusive. Estrogen plays a role ...