Short- and long-term glycaemic control and the state of the renin system in type 1 diabetes mellitus.

Renin system blockade in diabetes exerts a strong positive influence on complications, especially nephropathy. In hyperglycaemic diabetic subjects, however, blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors results in a marked rise in plasma renin. We investigated whether glycaemic fluctuations measured in hours, or those measured in weeks by Haemoglobin A(1C) (HbA(1C)) , influenced the plasma renin response to captopril. Fifty-four type 1 diabetic subjects were studied in high-salt balance. After an all night fast and in the supine position, baseline serum glucose level was drawn. Iv. glucose and insulin were then administered to keep serum glucose between 100 and 150 mg/dL (target). When target was reached, captopril 25 mg pre os was administered and plasma renin activity (PRA) and finger stick glucose were drawn, then serially every 45 minutes for 225 minutes. Baseline glucose and baseline PRA were drawn hours apart. Peak PRA corresponded to the renin level at peak captopril effect, 90' after administration. Renin response (RR) = peak PRA - baseline PRA. Correlation of baseline glucose with baseline PRA was weak (r=0.3, p=0.02), but strong with peak PRA (r=0.65; p=0.002). Drop in glucose had a weak, negative correlation with baseline PRA (r=-0.3, p=0.03) but a much stronger one with peak PRA (r=-0.7, p<0.0001). After adjustment for baseline PRA and baseline glucose, mean RR correlated strongly with mean drop in glucose (r=-0.72; p=0.008). Conversely, HbA1C correlated with none of the measures of renin system activation (r=0.05;p=0.7). In type 1 diabetic subjects, short-term hyperglycaemia, but not long-term glycaemic control, enhanced the RR to captopril.

Racial differences in renal vascular response to angiotensin blockade with captopril or candesartan.

OBJECTIVE: We compared the renal vascular response to captopril and candesartan among nondiabetic, normotensive black and white participants to explore angiotensin-converting enzyme-independent generation of angiotensin II. METHODS: Thirteen black individuals and 10 white individuals in low-salt balance were given captopril and candesartan on sequential study days, and the renal plasma flow responses to these agents were measured. RESULTS: Consistent with our prior observations, white individuals demonstrated a strong, significant correlation between responses to these drugs (r = 0.78, P = 0.008) and a significantly greater increase in the renal plasma flow in response to candesartan compared with captopril (104.2 +/- 26.8 versus 52.4 +/- 24.3 ml/min per 1.73 m; P = 0.03). In black participants, however, no correlation between responses to captopril and to candesartan was observed (r = 0.22, P = 0.47) and there was no difference in the renal plasma flow response between the two drugs (90.4 +/- 13.0 versus 80.4 +/- 15.3 ml/min per 1.73 m; P = 0.59). The difference in the response to the two drugs was significantly higher among white participants compared with black participants (P = 0.03). CONCLUSION: We confirmed the contribution of an angiotensin-converting enzyme-independent pathway for angiotensin II generation in the kidneys of nondiabetic, normotensive white, but not black, individuals.

Body mass index and angiotensin-dependent control of the renal circulation in healthy humans.

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 27+/-7 mL/min per 1.73 m2 (P<0.0001). 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 (r=0.55; P<0.0001; P=0.03 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.

Oral contraceptives, angiotensin-dependent renal vasoconstriction, and risk of diabetic nephropathy.

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 +/- 10 ml x min(-1) x 1.73 m(-2), P = 0.6). In comparison, nondiabetic OC users showed a significant increase (69 +/- 35 ml x min(-1) x 1.73 m(-2), P = 0.02) (P = 0.04 vs. nondiabetic OC nonusers). Diabetic OC nonusers demonstrated the anticipated vasodilator response (58 +/- 12 ml x min(-1) x 1.73 m(-2), P < 0.0001). Diabetic OC users showed the largest responses (84 +/- 12 ml x min(-1) x 1.73 m(-2), P = 0.002) (P = 0.04 vs. diabetic OC nonusers). Plasma renin activity did not vary with OC use (P = 0.3). The RPF responses to captopril and angiotensin receptor blocker were highly correlated (r = 0.72, P < 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 = 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 [95%CI 1.79-44.36], P = 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.

ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus.

BACKGROUND: The enormous contribution of renin-angiotensin system (RAS) interruption with ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers (ARB) in the treatment of diabetic nephropathy has led to interest in the factors involved in angiotensin II (Ang II) generation. In normal subjects, RAS interruption using an ARB produced a 50% greater renal plasma flow (RPF) rise than with an ACE inhibitor, suggesting a substantial contribution of non-ACE pathways. Moreover, immunohistochemistry studies in kidneys of overtly proteinuric diabetic subjects showed up-regulation of chymase, an alternative Ang II-generating enzyme. Our aim was to determine the degree to which the non-ACE pathways contribute to RAS activation in type 1 diabetes mellitus (DM). METHODS: Type 1 DM patients (N= 37, 14 M/23 F; age 31 +/- 2 years; DM duration 16 +/- 1.7 years; HbA1c 7.7.0 +/- 0.3%) were studied on a high-salt diet. They received captopril 25 mg po one day and candesartan 16 mg po the next day. RPF and glomerular filtration rate (GFR) were measured before and up to 4 hours after drug administration. RESULTS: Both captopril and candesartan induced a significant rise in RPF (baseline vs. peak <0.0001 for both), and the rise was concordant for the 2 drugs (r= 0.77, P < 0.001). However, the RPF responses were not significantly different between the 2 drugs (captopril 72 +/- 11 mL/min/1.73 m(2), candesartan 75 +/- 12, P= 0.841). CONCLUSION: In predominantly normoalbuminuric, normotensive type 1 DM, activation of the intrarenal RAS reflects a mechanism involving primarily the classic ACE pathway.

Renin release in response to Renin system blockade: activation of the Renin system in type 1 diabetes mellitus.

Activation of the renin-angiotensin system (RAS) in diabetes is thought to contribute to nephropathy. This is suggested by findings of an enhanced renovascular (RPF) response to RAS blockade with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs). An alternative approach to assess RAS activation is the evaluation of renin release following RAS blockade. Forty-four consecutively enrolled Type 1 diabetic patients (28.2+/-1.5 years) and 37 normal subjects (37+/-2.6 years) in high salt balance were given 25 mg of captopril and 16 mg of candesartan p.o. on consecutive days. All subjects were Caucasian. All, except one diabetic patient, had normal renal function. Plasma renin activity (PRA) and renal plasma flow (RPF) were measured for four hours after both drugs, and at eight, and 24 hours after candesartan. As anticipated, both drugs increased PRA. Peak responses (90' after captopril) were 5.6+/-1 ng/mL Ang I/hour in diabetic patients, and 1.7+/-0.9 ng/mL Ang I/hour in normal subjects (p<0.001). Responses to both drugs were correlated in diabetic patients for PRA (r=0.623; p=0.001) and for RPF (r=0.9; p<0.001). When the PRA response to captopril was below the median, the RPF response was limited (22.1+/-17.6 ml/minute/1.73 m2). When it was above the median, the RPF response was also larger (62.2+/-13.9 ml/minute/1.73 m2; p=0.006). Renin response to ACE-I and ARB confirms activation of the RAS in diabetic patients.

Plasma aldosterone concentration in the patient with diabetes mellitus.

BACKGROUND: Vascular injury at the microvascular and macrovascular levels plays a crucial role in the patient with diabetes mellitus. Evidence for renin-system activation in many patients with type 1 diabetes mellitus has raised the possibility that aldosterone-widely recognized as a contributor to vascular injury-could play a role. METHODS: We examined the state of the renin-angiotensin-aldosterone system (RAAS) in 58 subjects with type 1 diabetes mellitus and 64 age-matched normal control subjects. All studies were performed on a fixed sodium (200 mmol/day) and potassium (100 mmol/day intake), and samples were drawn at 8:00 a.m. to avoid the influence of circadian rhythms. RESULTS: The patient with diabetes mellitus showed an increase in plasma renin activity (PRA) (P < 0.01), plasma angiotensin II concentration (P < 0.01), and plasma aldosterone concentration (P < 0.001). A striking influence of the angiotensin receptor blocker, candesartan, on plasma aldosterone concentration in the patients with diabetes mellitus suggested strongly that renin-system activation is responsible for the elevated plasma aldosterone concentration. CONCLUSION: 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.

Renal perfusion in blacks: alterations caused by insuppressibility of intrarenal renin with salt.

We have reported that an increased intrarenal renin-angiotensin system activity may be responsible for the reduction in renal plasma flow (RPF) in apparently healthy blacks in comparison to healthy whites during high salt balance. To ascertain whether these differences only exist in the high salt state, we performed the following study, concentrating on the manipulation of the renin system during low salt intake. We measured in 19 healthy blacks and 22 healthy whites para-aminohippurate and inulin clearances as an indication of RPF and glomerular filtration rate, respectively, on both high (200 mmol/d) and low (10 mmol/d) salt balance in random order. A subset of 11 blacks and 12 whites additionally received an angiotensin II infusion while in low salt balance (3 ng/kg per minute for 45 minutes) and captopril to assess differences in RPF response to a converting enzyme inhibitor. The 19 whites had significantly higher RPF when compared with blacks (P=0.033) when studied on high salt. However, during low salt balance, the RPFs were comparable in the 2 groups. Plasma renin activity was similar in the 2 groups on both diets. In the subset that received angiotensin II and captopril while in low salt balance, the renal vascular response was not different in whites and blacks. These data provide additional support for the concept that the intrarenal tissue renin system is more active in blacks than whites on a typical (high salt) diet and that the difference reflects primarily incomplete tissue renin suppression with an increase in salt intake. The mechanism involved may contribute to the increased susceptibility to renal injury in blacks.