Correlation of cystatin-C with glomerular filtration rate by inulin clearance in pregnancy.

OBJECTIVE: To test utility of cystatin-C as a marker of glomerular filtration rate during pregnancy, we performed serial correlations with inulin clearance during pregnancy and postpartum. METHODS: Twelve subjects received inulin infusions and serum cystatin-C at three time points. Pearson's correlation coefficient was calculated. RESULTS: Cystatin-C levels ranged 0.66-1.48 mg/L during pregnancy, and 0.72-1.26 mg/L postpartum. Inulin clearance ranged 130-188 mL/min during pregnancy, and 110-167 mL/min postpartum. Cystatin-C did not correlate with inulin clearance at any time point. CONCLUSION: Serum cystatin-C did not correlate with inulin clearance during pregnancy or postpartum.

Oral contraceptive progestins and angiotensin-dependent control of the renal circulation in humans.

Oral contraceptive (OC) use is associated with increased intrarenal renin-angiotensin-aldosterone system (RAA System) activity and risk of nephropathy, though the contribution of progestins contained in the OC in the regulation of angiotensin-dependent control of the renal circulation has not been elucidated. A total of 18 OC users (8 non-diabetic, 10 Type 1 diabetic) were studied in high salt balance, a state of maximal RAA System suppression. Progestational and androgenic activity of the progestin in each OC was standardized to that of the reference progestin norethindrone. Renal plasma flow (RPF) was measured by para-aminohippurate clearance at baseline and in response to angiotensin-converting enzyme (ACE) inhibition. There was a positive correlation between OC progestational activity and the RPF response to ACE inhibition (r=0.52, P=0.03). Similar results were noted with OC androgenic activity (r=0.54, P=0.02). On subgroup analysis, only non-diabetic subjects showed an association between progestational activity and angiotensin-dependent control of the renal circulation (r=0.71, P=0.05 non-diabetic; r=0.14, P=0.7 diabetic; P=0.07 between groups). Similar results were noted with respect to androgenic activity (r=0.88, P=0.005 non-diabetic; r=-0.33, P=0.3 diabetic; P=0.002 between groups). Our results suggest that the OC progestin component is a significant influence on the degree of angiotensin-dependent control of the renal circulation, though these findings may not apply to women with diabetes.

Obesity and the kidney: why is the kidney at risk?

Two recent studies may help to account for the increase in risk of renal injury associated with obesity. One study pointed to a role for renin-system activation. In the other study, the pattern of renal hemodynamics was compatible with a renin mechanism.

Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan.

AIM: Our recent studies revealed a striking but variable enhancement of renal vasodilator responses to blockers of the renin-angiotensin system in subjects with diabetes mellitus, possibly reflecting the level of intrarenal activation of the renin-angiotensin system, and thus a risk of nephropathy. As obesity is a common finding in diabetic individuals, and obesity has been linked to an increase in plasma angiotensinogen levels, we enrolled diabetic subjects with a wide range of body mass index (BMI) for this study. METHODS: Twelve Type 2 diabetic subjects in balance on a low sodium diet participated after baseline renal plasma flow and glomerular filtration measurements were made. Each subject then received 150 mg irbesartan, and renal function was measured every 45 min for 4 h. RESULTS: The average vasodilator response to irbesartan was 174 +/- 33 ml/min. No correlation was found between renal plasma flow response to irbesartan and duration of diabetes, baseline glucose, or HbA1c level. BMI, our measure of obesity, was highly correlated to the renal response to irbesartan (r = 0.7; P = 0.01). CONCLUSIONS: Our findings suggest an important role for obesity in activating the intrarenal renin system, perhaps via production of angiotensinogen. BMI may be an indicator of risk of nephropathy.

AT(1)-receptor blockade and the kidney: importance of non-ACE pathways in health and disease.

Large-scale trials with angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT(1))-receptor blockers have clearly shown that blockade of the renin-angiotensin system reduces the deterioration in renal function associated with diabetes. AT(1)-receptor blockers represent a more rational approach to blockade of this system than ACE inhibitors, due to the presence of non-ACE pathways of angiotensin II formation. Studies in healthy volunteers maintained on a low-salt diet indicate that such pathways account for approximately 30-40% of total angiotensin II formation, and this figure increases to 60-70% in individuals maintained on a high-salt diet (resembling the situation in most human populations). Activation of the renin-angiotensin system is increased in diabetic patients, and comparison of the renal vascular responses to captopril and candesartan shows a strong correlation between the effects of ACE inhibition and AT(1)-receptor blockade, indicating that the deleterious effects of renin-angiotensin system activation in diabetes are mediated largely through angiotensin II. The presence of multiple risk factors, such as genetic predisposition, hyperglycaemia, obesity and tissue damage, places diabetic patients at high risk of disease related to activation of the renin-angiotensin system. Effective and early blockade of this system is therefore an important aspect of management.

Potential of the angiotensin II receptor 1 blocker eprosartan in the management of patients with hypertension or heart failure.

When angiotensin-converting enzyme (ACE) inhibition first became available to block the renin system, few could have predicted the evolution that would occur in this field. The advent of angiotensin II receptor 1 (AT(1)) blockers has created new opportunities. These agents, including eprosartan, are extraordinarily well tolerated, not only when compared with antihypertensive agents but also in comparison with the ACE inhibitors, which are rather well tolerated. The AT(1) blocker class is growing rapidly, at least in part because many believe that these drugs will share with the ACE inhibitors the special ability to reduce morbidity and mortality. Does eprosartan have a special role within this class? Eprosartan differs structurally from the other AT(1) blockers in that it is not a biphenyl tetrazole. It differs functionally in vitro in being a pure competitive antagonist, as opposed to the nonequilibrium, insurmountable characteristics of the other blockers. This feature may prove to be useful for titration in the fragile patient. The reduction in catecholamine release induced by eprosartan that has been observed in animal models may account for some special examples of increased efficacy. One such example pertains to the difference in the dose-response relationship for the action of eprosartan on the renal blood supply in comparison with other AT(1) blockers. Eprosartan doses well below those required for control of blood pressure have a pronounced effect on the kidney. If research already under way supports these early suggestions, then eprosartan will be an important addition to our therapeutic armamentarium.

Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism.

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na(+) intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (P=0.0001). Blacks, on the other hand, showed no gender difference (P=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.

Renal implications of angiotensin receptor blockers.

The role of the renin-angiotensin system (RAS) in the regulation of blood pressure and the pathogenesis of both hypertension and renal complications involves an intricate interplay of genetic and environmental factors. In the case of diabetic nephropathy, the genes governing the RAS are an obvious choice in the search for contributing factors. These genetic components can reflect polygenetic mechanisms or a major gene effect. During recent years, polymorphisms of the genes governing both angiotensin converting enzyme (ACE) and angiotensinogen have been studied, with varying outcomes. Investigation of the interaction between ACE inhibition and the glycemic state yields equally interesting results. In healthy subjects on a high salt diet, the hyperglycemic state produced significant increases in renal plasma flow (RPF) in response to administration of the ACE inhibitor captopril. A similar study using the angiotensin receptor blocker (ARB) eprosartan demonstrated again that the agent had little effect on RPF in subjects in a normal glycemic state; however, when administered during a hyperglycemic state, a marked increase in RPF occurred. Implications for the prevention of nephropathy and endstage renal disease (ESRD) in diabetics with hypertension are significant. Until recently, pharmacologic intervention in the RAS has focused on the ACE step, with documented success being reported in the prevention of diabetic nephropathy and ESRD using ACE inhibitors. Despite this success, data suggest that greater therapeutic benefit might be accomplished by blocking the deleterious effects of angiotensin II at the receptor site. From a renoprotective perspective, the ARB appear to have tremendous potential in the management of hypertension.

Familial factors in the antihypertensive response to lisinopril.

BACKGROUND: Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS: This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS: Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION: Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.

Renal vascular responses to captopril and to candesartan in patients with type 1 diabetes mellitus.

BACKGROUND: Enhanced renal vasodilator responses to angiotensin-converting enzyme (ACE) inhibition in diabetes mellitus despite a normal or low plasma renin activity level have suggested intrarenal activation of the renin-angiotensin system in this disease. There is, however, a continuing debate as to the mediators of the renal hemodynamic response to ACE inhibition-reduced angiotensin II formation or pathways involving kinins, prostaglandins, and nitric oxide. METHODS: Twelve patients with type 1 diabetes mellitus of 18 +/- 3.2 (SEM) years of duration (7 females and 5 males, ages 17 to 50, 32 +/- 4.0 years) who were free of sustained microalbuminuria and on a high-salt diet were given the ACE inhibitor captopril (25 mg orally) on one day and the AT1 receptor blocker candesartan (16 mg orally) on another day. Renal plasma flow (RPF) and glomerular filtration rate were measured before and for four hours after administration. RESULTS: Both drugs caused a significant increase in RPF (captopril 574 +/- 26 to 625 +/- 37 mL/min/1.73 m2, P = 0.008; candesartan 577 +/- 26 to 643 +/- 37, P = 0.004). There was a highly significant correlation between the responses to captopril and to candesartan (r = 0.86, P < 0.001). Seven subjects had an RPF response to captopril that was accentuated (90 +/- 13 mL/min/1.73 m2), while five had a response that was normal (-4 +/- 9). There was no significant change in glomerular filtration rate on either drug. CONCLUSION: The remarkable rise in RPF in response to captopril and candesartan despite high-salt balance suggests the intrarenal activation of the renin-angiotensin system in diabetes that is not reflected in plasma renin levels. The high correlation between the renal hemodynamic response to captopril and to candesartan indicates that reduced angiotensin II formation is the main mechanism of action of the ACE inhibitor.

Renal perfusion and function in healthy African Americans.

BACKGROUND: Despite their increased risk of nephropathy, remarkably little is known about renal perfusion and function in healthy African Americans. METHODS: We enrolled 32 healthy African Americans and compared renal perfusion and function in 82 age-matched healthy Caucasians. Studies were performed on a diet containing 200 mmol of sodium and 100 mmol of potassium per day. In a separate study of 28 subjects, 10 African American and 18 Caucasians, the contribution of the renin-angiotensin system was assessed by measuring renal hemodynamic responses to angiotension II (Ang II) and captopril. RESULTS: Although glomerular filtration rate (GFR) was similar, renal plasma flow (RPF) was significantly less in age-matched African Americans (568 +/- 18) than Caucasians (620 +/- 13 mL/min/1.73 m(2), P = 0.0063). After captopril, African Americans had a sevenfold greater vasodilator response and a rise in RPF (35.3 +/- 4.9 vs. 4.9 +/- 12.4 mL/min/1.73 m(2) in African Americans and Caucasians, respectively, P < 0.028). Ang II administration caused a significantly smaller vasoconstrictor response in African Americans (Ang II-induced fall in RPF, -97 +/- 18 vs. -150 +/- 9 mL/min/1.73 m(2), P = 0.05), and angiotensin-converting enzyme (ACE) inhibition enhanced the response to Ang II in African Americans significantly. CONCLUSIONS: A reduction in RPF, blunting of the renal vascular response to Ang II, and an accentuated renal vasodilator response to captopril, which in turn corrects the blunting of responsiveness to Ang II, all suggest activation of the renin system in apparently healthy African Americans. As PRA was identical in Caucasians and African Americans, the findings suggest that it is the intrarenal-renin system that is activated in African Americans. This difference in normal control mechanisms could predispose to nephropathy.

Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake.

OBJECTIVE: Homeostasis Model Assessment (HOMA index) is predictive of insulin sensitivity in normal and diabetic patients. This study was designed to see if insulin resistance in hypertensives, measured using the HOMA index, differs, based on salt sensitivity, renin status and sodium intake. METHODS: Fasting insulin and glucose were determined in subsets of 426 essential hypertensives, and normotensives. HOMA was calculated as fasting glucose (mmol) x fasting insulin (muU/ml)/22.5. RESULTS: Four hundred and twenty-six essential hypertensives and normotensives from four HERMES centers form the basis of this report. There was no difference in the HOMA index between hypertensives and normotensives (P= 0.291) or between hypertensives grouped according to blood pressure salt sensitivity (P = 0.153). However, when essential hypertensives were subgrouped by renin status, the low-renin group had significantly lower (P< 0.01) HOMA index than the normal/high-renin group. When normal/high-renin group was divided into modulators and non-modulators, the nonmodulators had significantly higher HOMA index (P< 0.001) than other hypertensive subsets. The effect of sodium intake on the HOMA index was significant only for non-modulators (P< 0.002), with salt restriction increasing insulin resistance. CONCLUSION: Insulin sensitivity differs among subsets of essential hypertension, non-modulators being most insulin resistant and the low-renin subset insulin sensitive. Salt restriction might have an adverse effect on insulin sensitivity in non-modulators. The reduction in cardiovascular risk seen in low-renin hypertensives may be related to their increased insulin sensitivity; in contrast, the clustering of cardiovascular risk factors seen in nonmodulators may be due to increased insulin resistance.

Is there a future for renin inhibitors?

Pharmacological interruption of the renin-angiotensin system is possible at three major sites, the angiotensin-converting enzyme (ACE), the AT1 receptor and at the interaction of renin with its substrate, angiotensinogen. Skeggs and his associates in 1957 argued logically but without prognostic accuracy that 'since renin is the initial and rate-limiting substance in the renin-angiotensin system, it would seem that the renin inhibition approach would be the most likely to succeed'. In fact, the development of agents that act at all three levels has enjoyed substantial success, yet renin inhibition, which showed early progress in studies in humans, has languished. Our task in this essay is to review the reasons for the slow evolution of renin inhibition and to discuss the potential of such agents in modern pharmacotherapy. All of the structure-action relationships have involved variation on the original peptide structure. The possibility that alternative approaches based on x-ray crystallography and reconstruction of the structure of the active site would lead to novel agents, appears not to have been explored systematically. This opportunity is all the more attractive because renin is one of the few targets that is actually soluble and amenable to x-ray crystallographic studies. At the moment, it appears that all renin inhibitor development programs have been closed, although hints periodically reappear to indicate that one company or another is pursuing a novel agent. The decision to close programs seems to have reflected not the therapeutic potential of renin inhibitors, but rather the cost of their synthesis, continuing problems with bioavailability and the remarkable success of the competitor class--the AngII antagonists. We believe that the potential of renin inhibition in human therapy has been under estimated and still shows substantial promise.

Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man.

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30-40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165+/-14 mL/min/1.73 m2) significantly exceeded the response to captopril (118+/-12 mL/min/1.73 m2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97+/-20 mL/min/1.73 m2) also significantly exceeded the response to captopril on the same diet(30+/-15 mL/min/1.73 m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet,when compared with the response to captopril,suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60-70% range.

Angiotensin receptor blockers in diabetic nephropathy.

Where shall we place angiotensin receptor blockers in the scheme of the prevention of diabetic nephropathy? Only the results of a large, randomized double-blind trial with a comparable and appropriate alternative would prove therapeutic efficacy. The results of several trials with angiotensin-converting enzyme (ACE) inhibitors have proven them to be the standard of care for diabetics and their kidneys. As reviewed in this article, the results of three large such clinical trials have recently been completed with angiotensin receptor blockers in patients with type 2 diabetes mellitus. Initial results appear favorable. However, whether angiotensin blockers have more to offer than ACE inhibitors is still speculative. The renin-angiotensin system plays an important role in the pathogenesis of diabetic nephropathy. Since alternative pathways to ACE have been uncovered in the formation of angiotensin II, inhibition at the final end point would provide favored blockade. Because angiotensin receptor blockers do provide this specific blockade, they offer far more promise than ACE inhibitors.

Renal hemodynamic and hormonal responses to the angiotensin II antagonist candesartan.

The development of very specific blockers for the angiotensin II type 1 (AT(1)) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT(1) receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33+/-2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142+/-13 mL. min(-1). 1.73 m(-2)) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3+/-1.6 ng. L(-1). s(-1); 55.0+/-5.6 ng angiotensin I. mL(-1). h(-1)) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non-ACE-dependent angiotensin II generation in the kidney.