Robert W. Schrier

The Effect of Nisoldipine as Compared with Enalapril on Cardiovascular Outcomes in Patients with Non-Insulin-Dependent Diabetes and Hypertension

BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study. METHODS The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension. RESULTS Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8). CONCLUSIONS In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes

In eight patients exhibiting chemical diabetes mellitus with a poststimulative hypoglycemia, we observed that the pattern of the oral glucose tolerance test (OGTT) was improved when indigestible fiber was added to the oral glucose load. As compared with a standard OGTT, the peak blood glucose, expressed as per cent change from baseline, was particularly blunted by pectin or by cellulose phosphate but remained unchanged with cellulose supplementation. The time interval required to reach the blood glucose peak was significantly prolonged with pectin. The rate of blood glucose rise was reduced to a greater extent by pectin than by cellulose phosphate, which in turn was more efficient than cellulose. The blood glucose nadir expressed as per cent change from baseline was blunted by pectin, while the results were not significantly different after addition of either cellulose phosphate or cellulose. On the other hand, the plasma immunoreactive insulin did not show any significant change whether the glucose was given with or without one of the aforementioned types of fiber. From these results, it is concluded that an additional fiber intake may be of interest in the management of chemical diabetes. The use of pectin may diminish the poststimulative hypoglycemia.

Acute renal failure: definitions, diagnosis, pathogenesis, and therapy

Acute renal failure (ARF), characterized by sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes, and maintain fluid balance, is a frequent clinical problem, particularly in the intensive care unit, where it is associated with a mortality of between 50% and 80%. In this review, the epidemiology and pathophysiology of ARF are discussed, including the vascular, tubular, and inflammatory perturbations. The clinical evaluation of ARF and implications for potential future therapies to decrease the high mortality are described.

Hyponatremia: A Prospective Analysis of Its Epidemiology and the Pathogenetic Role of Vasopressin

We prospectively evaluated the frequency, cause, and outcome of hyponatremia (plasma sodium concentration, less than 130 meq/L), as well as the hormonal response to this condition, in hospitalized patients. Daily incidence and prevalence of hyponatremia averaged 0.97% and 2.48%, respectively. Two thirds of all hyponatremia was hospital acquired. Normovolemic states (so-called syndrome of inappropriate secretion of antidiuretic hormone) were the most commonly seen clinical setting of hyponatremia. The fatality rate for hyponatremic patients was 60-fold that for patients without documented hyponatremia. Nonosmotic secretion of vasopressin was present in 97% of hyponatremic patients in whom it was sought. In edematous and hypovolemic patients, plasma hormonal responses (increases in plasma renin activity and aldosterone and norepinephrine levels) were compatible with baroreceptor-mediated release of vasopressin. Hyponatremia is a common hospital-acquired electrolyte disturbance that is an indicator of poor prognosis. Nonosmotic secretion of arginine vasopressin is a major pathogenetic factor in this electrolyte disturbance.

Renal Failure in Cirrhosis

Renal failure, a challenging complication of cirrhosis, is one of the most important risk factors for liver transplantation. In recent years, substantial progress has been made toward understanding the pathogenesis and natural history of renal failure in cirrhosis. This review discusses recently identified information about renal failure in cirrhosis and clinical interventions that may assist in the prevention and management of this complication.

Pathogenesis of Sodium and Water Retention in High-Output and Low-Output Cardiac Failure, Nephrotic Syndrome, Cirrhosis, and Pregnancy

This article has analyzed the pathogenesis of sodium and water retention in several circumstances. The initiator of retention has been proposed to be either a fall in cardiac output (e.g., low-output cardiac failure and vasoconstrictor hypovolemic nephrotic syndrome) or peripheral arterial vasodilatation (e.g., high-output cardiac failure, cirrhosis, arteriovenous fistula, and pregnancy). In the only state discussed, in which the kidney is diseased and not merely responding to extrarenal reflexes--i.e., nephrotic syndrome--intrarenal mechanisms may predominate and lead to expansion of the arterial vascular tree and suppression of the renin-angiotensin-aldosterone system (i.e., hypervolemic nephrotic syndrome). Otherwise, when kidneys are healthy, either a fall in cardiac output or peripheral arterial vasodilatation may diminish arterial vascular filling and thereby initiate a series of hemodynamic and hormonal events that result in renal sodium and water retention (Fig. 7). Finally, the approach presented in this article should be considered to be a vantage point from which to evaluate states of sodium and water retention, but not to be an exclusive position.

Impaired IL-18 processing protects caspase-1–deficient mice from ischemic acute renal failure

We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1(-/-) mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1(-/-) ARF mice or sham-operated controls. We then injected wild-type mice with IL-18-neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1(-/-) mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1(-/-) or IL-18 antiserum-treated mice. Finally, we confirmed histologically that caspase-1(-/-) mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.

Radioimmunoassay of Plasma Arginine Vasopressin in Hyponatremic Patients with Congestive Heart Failure

HYPONATREMIA occurs frequently in patients with congestive heart failure who have moderate fluid intakes (1 to 3 liters per day).1 It is not clear whether persistent release of arginine vasopressin...

Potential Role of Increased Sympathetic Activity in Impaired Sodium and Water Excretion in Cirrhosis

In a study of 26 patients with cirrhosis, plasma norepinephrine concentrations were significantly higher in 19 patients who abnormally excreted an acute water load than in seven who excreted the load normally (8324 +/- 116 vs. 306 +/- 33 pg per milliliter; P less than 0.001). There was also a significant positive correlation between plasma levels of norepinephrine and arginine vasopressin after the water load, as well as a negative correlation between plasma norepinephrine and the percentage of the load excreted. A positive correlation between plasma norepinephrine and plasma renin activity, as well as between norepinephrine and aldosterone, was observed. In addition, there was a negative correlation between plasma norepinephrine and urinary sodium excretion. These findings indicate that increased sympathetic activity, as assessed by plasma levels of norepinephrine, correlates closely with sodium and water retention in cirrhotic patients and thus may be of pathogenetic importance.

Rapamycin Markedly Slows Disease Progression in a Rat Model of Polycystic Kidney Disease

Increased tubular epithelial cell proliferation is a prerequisite for cyst formation and expansion in polycystic kidney disease (PKD). Rapamycin is a potent antiproliferative agent. The aim of the present study was to determine the effect of rapamycin on tubular cell proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 wk of age and then treated with rapamycin 0.2 mg/kg per d intraperitoneally or vehicle (ethanol) for 5 wk. Vehicle-treated Cy/+ rats had a more than doubling of kidney size compared with +/+ rats. Rapamycin reduced the kidney enlargement by 65%. Rapamycin significantly reduced the cyst volume density in Cy/+ rats by >40%. Blood urea nitrogen was 59% increased in vehicle-treated Cy/+ rats compared with +/+ rats. Rapamycin reduced the blood urea nitrogen to normal in Cy/+ rats. The number of proliferating cell nuclear antigen (PCNA)-positive cells per noncystic tubule was eightfold increased in vehicle-treated Cy/+ compared with +/+ rats. Rapamycin significantly reduced the number of PCNA-positive cells in noncystic tubules of Cy/+ rats. In addition, the number of PCNA-positive cells per cyst in Cy/+ rats was significantly reduced by rapamycin. In summary, in a rat model of PKD, rapamycin treatment (1) decreases proliferation in cystic and noncystic tubules, (2) markedly inhibits renal enlargement and cystogenesis, and (3) prevents the loss of kidney function.