Roberto Bigazzi

Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension

Background Some patients with essential hypertension manifest greater than normal urinary excretion of albumin (UAE). Authors of a few retrospective studies have suggested that there is an association between microalbuminuria and cardiovascular risk. Objective To evaluate whether microalbuminuria is associated with a greater than normal risk of cardiovascular and renal events. Methods We performed a retrospective cohort analysis of 141 hypertensive individuals followed up for approximately 7 years. Hypertensive patients were defined as having microalbuminuria if the baseline average UAE of three urine collections was in the range 30–300 mg/24 h. Results Fifty-four patients had microalbuminuria and 87 had normal UAE. At baseline, the two groups were similar for age, weight, blood pressure, and rate of clearance of creatinine. Serum levels of cholesterol, triglycerides, and uric acid in patients with microalbuminuria were higher than levels in those with normal UAE, whereas levels of high-density lipoprotein cholesterol in patients with microalbuminuria were lower than levels in patient with normal UAE. During follow-up, 12 cardiovascular events occurred among the 54 (21.3%) patients with microalbuminuria and only two such events among the 87 patients with normal UAE (P < 0.0002). Stepwise logistic regression analysis showed that UAE (P = 0.003), cholesterol level (P = 0.047) and diastolic blood pressure (P = 0.03) were independent predictors of the cardiovascular outcome. Rate of clearance of creatinine from patients with microalbuminuria decreased more than did that from those with normal UAE (decrease of 12.1 ± 2.77 versus 7.1 ± 0.88 ml/min, P < 0.03). Conclusions This study suggests that hypertensive individuals with microalbuminuria manifest a greater incidence of cardiovascular events and a greater decline in renal function than do patients with normal UAE.

Effect of Insulin on Renal Sodium and Uric Acid Handling in Essential Hypertension

In normal subjects, insulin decreases the urinary excretion of sodium, potassium, and uric acid. We tested whether these renal effects of insulin are altered in insulin resistant hypertension. In 37 patients with essential hypertension, we measured the changes in urinary excretion of sodium, potassium, and uric acid in response to physiological euglycemic hyperinsulinemia (by using the insulin clamp technique at an insulin infusion rate of 6 pmol/min/kg). Glucose disposal rate averaged 26.6 +/- 1.5 mumol/min/kg, i.e., 20% lower than in normotensive controls (33.1 +/- 2.1 mumol/min/kg, P = .015) In the basal state, fasting plasma uric acid concentrations were higher in men than women (P < .001), were positively related to body mass index (r = 0.38, P = .02), waist/hip ratio (r = 0.35, P < .05), and serum triglyceride levels (r = 0.59, P = .0001), and negatively related to HDL cholesterol concentrations (r = -0.59, P = .0001) and glucose disposal rate (r = 0.42, P < .01). Uric acid clearance, on the other hand, was inversely related to body mass index (r = 0.41, P = .01), plasma uric acid (r = 0.65, P < .0001) and triglyceride concentrations (r = 0.39, P < .02), and directly related to HDL cholesterol levels (r = 0.52, P < .001). During insulin infusion, blood pressure, plasma uric acid and sodium concentration, and creatinine clearance did not change. In contrast, hyperinsulinemia caused a significant decrease in the urinary excretion of uric acid (2.67 +/- 0.12 to 1.86 +/- .14 mumol/min/1.73 m2, P = .0001), sodium (184 +/- 12 to 137 +/- 14 mumol/min/1.73 m2, P = .0001), and potassium (81 +/- 7 to 48 +/- 4 mumol/ min/1.73 m2, P = .0001). Both in absolute terms (clearance and fractional excretion rates) and percentagewise, these changes were similar to those found in normotensive subjects. Insulin-induced changes in urate excretion were coupled (r = 0.55, P < .0001) to the respective changes in sodium excretion. In hypertensive patients, higher uric acid levels and lower renal urate clearance rates cluster with insulin resistance and dyslipidemia. Despite insulin resistance of glucose metabolism, acute physiological hyperinsulinemia causes normal antinatriuresis, antikaliuresis, and antiuricosuria in these patients.

Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors.

We previously showed that a high salt diet increases glomerular capillary pressure in salt-sensitive hypertensive patients and suggested that this may underlie the greater propensity of these patients to develop renal failure. Because microalbuminuria is considered an initial sign of renal damage, we have tested whether salt-sensitive patients display greater urinary albumin excretion than salt-resistant hypertensive patients. Twenty-two patients were placed on a low sodium intake (20 mEq/d) for 7 days followed by a high sodium diet (250 mEq/d) for 7 more days. Twelve patients were classified as salt sensitive and 10 as salt resistant. Urinary albumin excretion was greater in salt-sensitive than salt-resistant patients (54 +/- 11 versus 22 +/- 5 mg/24 h, P < .01). During the low sodium diet, glomerular filtration rate, renal plasma flow, and filtration fraction were similar between the two groups. During the high sodium intake, glomerular filtration, renal plasma flow, filtration fraction, and calculated intraglomerular pressure did not change in salt-resistant patients; in salt-sensitive patients, however, renal plasma flow decreased, and filtration fraction and intraglomerular pressure increased, whereas glomerular filtration rate did not change. Urinary albumin excretion was significantly correlated with glomerular capillary pressure. Salt-sensitive patients displayed higher serum levels of low-density lipoprotein cholesterol and lipoprotein(a) and lower levels of high-density lipoprotein cholesterol than salt-resistant patients. These studies have shown greater urinary albumin excretion and serum concentrations of atherogenic lipoproteins in salt-sensitive than in salt-resistant hypertensive patients, suggesting that salt sensitivity may be a marker for greater risk of renal and cardiovascular complications.

Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications.

Some patients with essential hypertension manifest greater than normal urinary albumin excretion (UAE). The significance of this association, which is the object of this review, is not well established. Hypertensive patients with microalbuminuria manifest greater levels of blood pressure, particularly at night, and higher serum levels of cholesterol, triglycerides, and uric acid than patients with normal UAE. Levels of high-density lipoprotein cholesterol, on the other hand, were lower in patients with microalbuminuria than in those with normal UAE. Patients with microalbuminuria manifested greater incidence of insulin resistance and thicker carotid arteries than patients with normal UAE. After a follow-up of 7 years, we observed that 12 cardiovascular events occurred among 54 (21.3%) patients with microalbuminuria and only two such events among 87 patients with normal UAE (P < 0.0002). Stepwise logistic regression analysis showed that UAE, cholesterol level, and diastolic blood pressure were independent predictors of the cardiovascular outcome. Rate of creatinine clearance from patients with microalbuminuria decreased more than that from those with normal UAE. In conclusion, these studies suggest that hypertensive individuals with microalbuminuria manifest a variety of biochemical and hormonal derangements with pathogenic potential, which results in hypertensive patients having a greater incidence of cardiovascular events and a greater decline in renal function than patients with normal UAE.

Abnormal renal hemodynamics in black salt-sensitive patients with hypertension.

African-Americans with essential hypertension are more prone to the development of renal failure and are frequently salt-sensitive as well. Because alterations of intrarenal hemodynamics are important in the progression of renal disease and because salt-sensitive animal models with hypertension manifest a greater propensity to develop glomerulosclerosis in association with a rise in glomerular capillary pressure, we tested whether the renal hemodynamic adaptation to high dietary Na+ intake differs in salt-sensitive and salt-resistant hypertensive patients. We studied 17 black and nine white patients with essential hypertension who were placed on a low Na+ diet (20 meq/day) for 9 days, followed by a high Na+ diet (200 meq/day) for 14 days. During the last 4 days of each diet regimen, they received 30 mg/day of slow-release nifedipine. Eleven blacks were salt-sensitive, and all whites were salt-resistant. During the low Na+ diet period, salt-sensitive and salt-resistant patients had similar mean arterial pressure, glomerular filtration rate, effective renal plasma flow, and filtration fraction. During the high Na+ intake period, glomerular filtration rate did not change in either group; effective renal blood flow increased in salt-resistant patients (from 455±25 to 524±27.7 ml/min, p<0.01), but it decreased in salt-sensitive patients (from 538±20 to 426±15.8 ml/min, p<0.01); filtration fraction decreased (from 21±1.8 to 19±1.5%) in salt-resistant patients, but it increased (from 19±0.9 to 23±1.5%, p<0.01) in salt-sensitive patients; glomerular pressure decreased (from 58±2.0 to 52±1.5 mm Hg, p<0.01) in salt-resistant patients, but it increased (from 48±1.6 to 58±1.5 mm Hg, p<0.01) in salt-sensitive patients. During the period of high Na+ intake, nifedipine decreased arterial pressure, renal vascular resistance, and filtration fraction and increased renal blood flow in salt-sensitive but not in salt-resistant patients. These studies show that an abnormal renal hemodynamic adaptation occurs in salt-sensitive patients during high Na+ intake. The rise in filtration fraction and in intraglomerular pressure during high Na+ suggests that these renal hemodynamic derangements might be partially responsible for the greater propensity to renal failure in hypertensive African-Americans.

Prevalence of Microalbuminuria in a Large Population of Patients with Mild to Moderate Essential Hypertension

To determine the prevalence of increased urinary albumin excretion (UAE) in essential hypertension and to establish whether this abnormality is associated with deranged renal function, we have measured UAE in a group of 123 patients with essential hypertension and in 110 normal subjects. Mean arterial pressure (MAP) was 96 +/- 0.6 mm Hg in normal subjects and 121 +/- 0.3 mm Hg in patients with essential hypertension (p less than 0.01). Mean UAE was 8.6 +/- 0.5 in normal subjects and 32.9 +/- 3.3 mg/24 h in patients with essential hypertension (p less than 0.01). Forty percent of patients with essential hypertension manifested a UAE exceeding 30 mg/24 h and had an average UAE of 72.0 +/- 4.7 mg/24 h. MAP in patients with increased UAE was similar to that in subjects with normal UAE (121 +/- 0.5 vs. 121 +/- 0.4 mm Hg). Creatinine clearance was also not different between these two groups (91 +/- 1.8 vs. 94 +/- 1.5 ml/min). No correlation was found between UAE and MAP or creatinine clearance. Long-term prospective studies are needed to extablish whether an increase in UAE may predict future nephrosclerosis in essential hypertension.

Salt Intake and Plasma Atrial Natriuretic Peptide and Nitric Oxide in Hypertension

In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO2+NO3 in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (P < .01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO2+NO3 levels were higher (P < .05) in salt-sensitive (189 +/- 7.9 mumol/L) and salt-resistant (195 +/- 13.5 mumol/L) black patients than in control subjects (108 +/- 9.7 mumol/L). During high salt intake, plasma NO2+NO3 decreased significantly (P < .01) in both salt-sensitive (150 +/- 7.0 mumol/L) and salt-resistant (142 +/- 9.0 mumol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.

Clustering of Cardiovascular Risk Factors in Salt-Sensitive Patients with Essential Hypertension: Role of Insulin

Hyperinsulinemia, insulin resistance, or both have been described in a proportion of patients with essential hypertension, and also are considered a risk for atherosclerotic cardiovascular disease. In this study, we have examined whether salt sensitivity and hyperinsulinemia are associated in patients with essential hypertension. We have measured blood insulin and glucose response to an acute oral glucose load in a group of hypertensive patients, classified according to their salt sensitivity. To determine salt sensitivity, patients received a diet containing a low (20 mEq/day) Na+ intake for 1 week followed by a high (250 mEq/day) Na+ intake for 1 week more. Twenty-nine patients were classified as salt sensitive, and 23 as salt resistant. Baseline plasma glucose and insulin were not different between salt-sensitive and salt-resistant patients. Following an oral glucose load, the area-under-the curve of glucose was greater (P < .05) in salt-sensitive than in salt-resistant hypertensive patients (900 +/- 26.4 and 810 +/- 29.1 mmol/L x 2 h, respectively). The area-under-the curve of insulin was greater (P < .01) in salt-sensitive (52,664 +/- 3,666 pmol/L x 2 h) than in salt-resistant patients (37,977 +/- 3,300 pmol/L x 2 h). A direct correlation was present between insulin area-under-the curve and salt sensitivity (r = 0.26), but did not reach statistical significance (P < .06). Salt-sensitive patients manifested increased serum levels of total cholesterol, LDL-cholesterol and increased urinary albumin excretion when compared with salt-resistant patients. In conclusion, these studies have demonstrated that in response to an oral glucose load, salt-sensitive patients with essential hypertension manifest increased insulin secretion. The studies have confirmed the presence of increased urinary albumin excretion and serum levels of atherogenic lipoproteins in salt-sensitive compared with salt-resistant patients. In salt-sensitive hypertensive patients, hyperinsulinemia, hyperlipidemia and microalbuminuria form a cluster with possible atherogenic potential. Salt sensitivity can be a marker for increased cardiovascular risk in patients with essential hypertension.

Elevated Serum Insulin Levels in Patients With Essential Hypertension and Microalbuminuria

Hyperinsulinemia, insulin resistance, or both have been described in patients with essential hypertension. Previous work from our laboratory has shown that in hypertensive patients with microalbuminuria, dyslipidemia and abnormal patterns in the diurnal variations of blood pressure are frequently associated. Whether hyperinsulinemia and microalbuminuria are directly related has not been determined. To test this possibility, we measured the plasma insulin response to an oral glucose load in 25 patients with or without microalbuminuria and 20 normotensive control subjects. Serum lipid profile and 24-hour ambulatory blood pressure were obtained. In the hypertensive patients as a group, the plasma insulin response to glucose (evaluated as the insulin area under the curve) was significantly enhanced compared with a group of 20 normotensive healthy control subjects (46,311 +/- 3745 and 27,557 +/- 2563 pmol/L x 2 hours, P < .01). When the hypertensive patients were subdivided according to their albumin excretion rate, the microalbuminuric patients had significantly higher plasma glucose (969 +/- 45.2 versus 762 +/- 28.7 mmol/L x 2 hours, P < .01) and insulin (59,172 +/- 5964 versus 37,737 +/- 3422 pmol/L x 2 hours, P < .01) area under the curve values. In addition, a significant direct correlation was found to exist between insulin area under the curve and the urinary albumin excretion rate (r = .63, P < .001). Serum levels of lipoprotein(a) were significantly greater (P < .01) in patients with than in those without microalbuminuria and in control subjects. Furthermore, daytime diastolic blood pressure and nighttime systolic and diastolic blood pressure values were greater in patients with than in those without microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Resistance in Microalbuminuric Hypertension: Sites and Mechanisms

Microalbuminuria in patients with essential hypertension is a marker of incipient glomerular dysfunction and clusters with lipid and hemodynamic abnormalities. Recent evidence has shown that hypertensive patients with microalbuminuria have a hyperinsulinemic response to oral glucose, suggesting the presence of insulin resistance. To directly test this possibility we studied insulin action in two accurately matched groups (n = 10 each) of hypertensive patients with or without microalbuminuria (14 +/- 2 versus 52 +/- 7 mg/24 h-1, mean of three 24-hour collections). In response to glucose ingestion microalbuminuric patients showed slight hyperglycemia (area under the curve, 928 +/- 43 versus 784 +/-19 nmol/L-1/2h-1, P < .02) and a marked hyperinsulinemia (26.8 +/- 3.3 versus 49.8 +/- 3.7 nmol/L-1/2h-1, P < 0.01). Basal arterial blood pressure, heart rate, and forearm blood flow were similar in the two groups and did not change significantly during a 2-hour euglycemic insulin clamp. Insulin-stimulated wholebody glucose uptake was 25% lower in microalbuminuric patients (33.5 +/- 2.5 versus 25.2 +/- 2.1 mumol/min-1/kg-1, P < .02). This difference was entirely due to a 40% reduction in glycogen synthesis (12.9 +/- 1.8 versus 21.3 +/- 3.2 mumol/min-1/kg-1, P < .05) as glucose oxidation was similarly stimulated in the two groups. In contrast there was no difference in the ability of insulin to suppress hepatic glucose production (by approximately 100% at the end of the clamp), to decrease fractional sodium and potassium excretions (by 35%), to lower circulating free fatty acids (by 80%), and to reduce plasma potassium concentrations (by 10%).(ABSTRACT TRUNCATED AT 250 WORDS)