Thomas F. Ferris

Oxygen free radicals in ischemic acute renal failure in the rat.

During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.

Effect of angiotensin and norepinephrine upon urate clearance in man

Abstract Angiotensin and norepinephrine given intravenously to normal men, in amounts sufficient to raise the diastolic pressure 20 mm. Hg, caused a marked reduction in the clearance of urate and the ratio of C urate to GFR. This reduction in urate clearance is not the result of a reduction in glomerular filtration rate (GFR) or osmolar clearance and appears to be related to a decrease in effective renal blood flow. The possible significance of these changes in urate clearance in contributing to the hyperuricemia observed in certain clinical situations is discussed.

Effect of Captopril on Uterine Blood Flow and Prostaglandin E Synthesis in the Pregnant Rabbit

Captopril, 5 mg/kg, administered to pregnant rabbits caused a reduction in mean arterial pressure (MAP) from 106+/-2 to 87+/-2 mmHg (P<0.01) without change in cardiac output or renal blood flow. Uterine blood flow fell from 31.9+/-2.5 to 21.3+/-3.4 ml/min (P<0.01) as uterine vein prostaglandin E series level (PGE) decreased from 127+/-23 ng/ml to 26+/-8 ng/ml (P<0.01). Saralasin also caused a reduction in MAP from 110+/-5 to 92+/-4.3 (P<0.01), a reduction in uterine blood flow from 28.8+/-1.6 to 21.8+/-1.7 ml/min (P<0.01) as uterine vein PGE decreased from 121.3+/-14.4 to 63.5+/-14.2 ng/ml (P<0.01). Plasma renin activity (PRA) was higher in the uterine vein, 11+/-3 ng/ml per h, than peripheral vein, 6+/-1.6 ng/ml per h, (P<0.05), before Captopril and rose in the uterine vein to 90+/-19 ng/ml per h (P<0.01) as peripheral vein PRA rose to 62+/-15 ng/ml per h (P<0.05) after Captopril. After saralasin uterine vein PRA rose from 4.6+/-1.5 to 14.8+/-6.3 ng/ml per h (P<0.05) and peripheral vein PRA rose from 3.7+/-1 to 6.5+/-2.1 (P<0.05). Reducing MAP with MgSO(4) from 98+/-4 to 70+/-2 (P<0.01) caused a significant fall in cardiac output from 695+/-33 to 588+/-49 (P<0.01) without change in renal or uterine blood flow. Uterine vein PGE concentration also did not change significantly following MgSO(4); 80+/-22 ng/ml before and 60+/-27 ng/ml (NS) during the administration of MgSO(4). Chronic administration of Captopril in doses of either 2.5 or 5.0 mg/kg per d from the 15th d of gestation caused an 86% fetal mortality at the lower and a 92% fetal mortality at the higher dose of the drug. These experiments point to the importance of uterine PGE synthesis in maintenance of uterine blood flow and fetal survival during pregnancy and suggest that uterine PGE synthesis is dependent upon angiotensin II. Synthesis of uterine renin and PGE may be necessary for maintenance of uterine blood flow and fetal survival during pregnancy.

Suppression of plasma renin activity by cyclosporine

Cyclosporine treatment is associated with hypertension and suppression of plasma renin activity, the causes of which are unclear. To determine whether suppressed plasma renin activity is due to extracellular fluid volume expansion, 10 cyclosporine-treated renal transplant recipients were compared with 10 azathioprine-treated renal transplant recipients and seven patients with renal insufficiency. Glomerular filtration rate and effective renal plasma flow were significantly lower in cyclosporine-treated patients than in azathioprine-treated patients. Upright plasma renin activity was suppressed in cyclosporine-treated patients (cyclosporine 2.9 +/- 0.9, azathioprine 4.7 +/- 0.9, renal insufficiency 5.2 +/- 1.9 ng/ml/hour) but could be stimulated by a four-day period of dietary sodium restriction and diuretic administration (cyclosporine 15.8 +/- 4.4 ng/ml/hour). Extracellular fluid volume tended to be higher in cyclosporine-treated patients (cyclosporine 30.7 +/- 2.3, azathioprine 26.7 +/- 2.5, renal insufficiency 25.5 +/- 1.4 percent lean body mass), although the difference between cyclosporine-treated and azathioprine-treated patients did not attain statistical significance. There were no differences in the urinary excretion of prostaglandin E2 or 6-keto prostaglandin F1 alpha between the two groups of renal transplant recipients. It is concluded that suppression of plasma renin activity by cyclosporine is physiologic and may reflect expansion of extracellular fluid volume, which can be reversed by sodium depletion.

Toxemia of pregnancy in sheep: a clinical, physiological, and pathological study

Toxemia was induced in 13 of 20 pregnant ewes by the stress of a change in environment and food deprivation late in pregnancy. Of the toxemic ewes, eight developed prominent neurological findings with convulsions, motor weakness, and blindness, whereas five ewes developed azotemia without neurological signs. Proteinuria and azotemia occurred in all but one of the toxemic animals. Seven animals did not develop clinical or laboratory evidence of toxemia. Hypertension did not occur with the onset of toxemia but all toxemic animals showed glomerular changes by light and electron microscopy. These abnormalities, which were similar to those seen in human preeclampsia, included endothelial cell swelling, focal reduplication of the basement membrane, and fusion of the epithelial cell foot processes. The toxemia could not be attributed to changes in hematocrit, plasma glucose, Na, Cl, CO(2), K, Ca, fibrinogen, arterial pH, lactate, or pyruvate concentrations. Cardiac output fell only in ewes with prominent neurological signs. Plasma renin rose strikingly in animals developing toxemia, without change in substrate concentration. In contrast to human and other species, sheep uterus and amniotic fluid contained no detectable quantities of renin. Thus in response to stress the pregnant ewe develops a toxemia which in the absence of hypertension has clinical and pathological similarities to human preeclampsia.

How Should Hypertension During Pregnancy Be Managed?: An Internist's Approach

Hypertension may occur during pregnancy under different clinical circumstances. One cause is toxemia, a systemic disease unique to pregnant women, in which hypertension is associated with proteinuria, CNS irritability, hepatic and renal functional abnormalities, and, in fulminant disease, a consumptive coagulopathy. Since it is clear in the non-pregnant population that the vascular complications of hypertension can be prevented with antihypertensive therapy and since toxemia is the most common cause of maternal mortality, there is no reason not to treat pregnant women with hypertension.

Effects of Nva2-cyclosporine on glomerular filtration rate and renal blood flow in the rat.

The effects of Nva2-cyclosporine on glomerular filtration and renal blood flow in rats were studied and compared with those of cyclosporine. An infusion of Nva2-cyclosporine (20 mg/kg) caused a 53% fall in glomerular filtration rate (1.0 +/- 0.08 to 0.47 +/- 0.09; P less than 0.001) and renal plasma flow (3.2 +/- 0.4 to 1.6 +/- 0.4; P less than 0.005). Nva2-cyclosporine when infused in a dose of 10 mg/kg caused a nearly identical fall in inulin clearance and renal plasma flow. By comparison an infusion of cyclosporine (20 mg/kg) caused a 50% decrease in inulin clearance and a fall in renal plasma flow from 2.6 +/- 0.3 to 0.9 +/- 0.3. Nva2-cyclosporine or cyclosporine was given chronically in a dose of 20 mg/kg intraperitoneally for seven days. Cyclosporine produced a 27% fall in creatinine clearance, whereas Nva2-cyclosporine produced a 19% decrease in creatinine clearance (NS). These studies suggest that Nva2-cyclosporine has adverse effects on renal blood flow and glomerular filtration rate similar to those seen with cyclosporine.

Diuretics in pregnancy

Publisher Summary At one time, diuretics were used routinely for edema occurring in pregnancy. Their use became controversial when it was reported that diuretics caused a reduction in the clearance of certain steroids metabolized by the placenta and that pregnant women with edema were noted to have heavier babies than women taking diuretics. However, there is no evidence in any study that diuretics are harmful to the fetus, and given their importance in the treatment of hypertension, this chapter examines their use in pregnancy complicated by hypertension. Edema is a frequent and normal finding in uncomplicated pregnancy, occurring in approximately 35% of pregnant women. A major stimulus for salt retention is the fall in peripheral vascular resistance that occurs with pregnancy. This results in increased vascular capacity, a recognized stimulus to renal sodium reabsorption. Although edema is common in pregnancy, edema associated with rapid weight gain and a rise in blood pressure, are the first signs of preeclampsia. The edema with preeclampsia shares some similarities with angioneurotic edema, with prominence in the hands and face, and occasionally, laryngeal stridor. Hypertension in pregnancy represents a risk factor to the mother and fetus even in the absence of preeclampsia. Women with essential hypertension should continue taking their usual antihypertensive medications, including diuretics, during pregnancy.

Chapter VA6 – Idiopathic Edema

Publisher Summary Idiopathic edema is a poorly understood disorder that affects primarily women and causes salt retention and edema in the absence of cardiac, renal, hepatic, or thyroid disease. Despite many studies of the various factors controlling the renal handling of sodium and water, the disease remains idiopathic. It may represent a heterogenous collection of edematous disorders, since a variety of abnormalities have been discovered in different subsets of patients. A uniform explanation for its pathophysiology has been lacking and the causes have been postulated to be hormonal, metabolic, or psychologic. The disorder provides a dramatic demonstration of the problem that occurs when fine control of extracellular volume is lost. The usual complaint is troublesome edema of the legs, hands, and periorbital region, with a sensation of swelling and distention in the abdomen. The edema may recur intermittently or can be persistent as discussed in this chapter. Although many women gain weight during the luteal phase of the menstrual cycle, premenstrual edema has not been a common complaint in patients with idiopathic edema. A high familial incidence of Type II diabetes has been reported in several series, and abnormal glucose tolerance has been noted in many patients; however, fewer than 50% of patients are overweight. There are some similarities between idiopathic edema and anorexia nervosa in that both are primarily noted in women and both can be associated with disturbances of body image. Due to the poorly understood nature of the disorder and its many postulated mechanisms, no single treatment for idiopathic edema exists.