Long-term effects of cyclosporine on renal function in organ transplant recipients.

To evaluate whether cyclosporine nephrotoxicity is progressive, glomerular filtration rate and renal plasma flow were determined by isotopic techniques in 24 cyclosporine-treated organ transplant recipients (12 heart, 1 pancreas, and 11 kidney recipients). The cyclosporine group demonstrated reductions in glomerular filtration rate and renal plasma flow, with higher renal vascular resistance and mean arterial pressure as compared with an azathioprine-treated control group. However, longitudinal studies over a mean time period of 23 months in eight cyclosporine-treated renal transplant recipients showed renal function to remain stable. In the entire group of 24 cyclosporine-treated patients, longer duration of cyclosporine treatment was associated with decreased but stable glomerular filtration rate, increased renal plasma flow, decreased renal vascular resistance, and lower daily doses of cyclosporine. Evaluation of intrarenal resistances demonstrated a greater decrease in efferent than afferent arteriolar resistance, consistent with the fall in plasma renin activity that occurred with time. Short-term treatment of 12 patients with prazosin produced no beneficial effect on renal function, whereas treatment of nine patients with captopril produced a 20% increase in renal plasma flow, with a significant reduction in renal vascular resistance. We conclude that although cyclosporine treatment produces decreased renal function, the loss in renal function is not necessarily progressive. Treatment with captopril may improve the abnormal renal hemodynamics of cyclosporine-treated patients.

Pressor responsiveness in pseudopregnant and pregnant rats: role of maternal factors.

During pregnancy the pressor response to vasoconstrictor substances such as angiotensin II (ANG II) is diminished, and renal, uterine, and vascular prostaglandin (PG) production may increase. However, little is known about the factors that alter vascular reactivity or stimulate PG synthesis during pregnancy. To ascertain whether these factors are of maternal or fetal-placental origin, we studied vascular reactivity and urinary PGE excretion in pseudopregnant rats. Pseudopregnant rats had plasma progesterone and weight gain similar to that observed in pregnant rats. Urinary PG excretion in nonpregnant rats was approximately 70 ng/24 h and remained constant during a 12-day observation. In contrast, urinary PG excretion in both pregnant and in pseudopregnant rats rose to levels approximately twice control within 4-6 days. The pressor response to ANG II was diminished in pseudopregnant rats compared with nonpregnant rats. When the PG synthesis inhibitor meclofenamate was given there was no change in the pressor response to ANG II in nonpregnant animals, but in pseudopregnant animals meclofenamate produced a significant increase in the pressor response to ANG II. The pressor response to norepinephrine and arginine vasopressin (AVP) was not diminished in pseudopregnant animals, and meclofenamate did not increase the pressor response to these agents. Therefore, a developing fetus and placenta is not necessary for the decrease in pressor response to ANG II nor for the early increase in urinary PGE excretion. Like in pregnancy, the pressor response to ANG II was increased after meclofenamate in pseudopregnancy. Increased PG production may, therefore, be partly responsible for the decrease in pressor responsiveness to ANG II. However, pseudopregnancy, unlike pregnancy, did not affect pressor responsiveness to norepinephrine or AVP. Both maternal and fetal-placental factors seem required for the reduction in responsiveness to norepinephrine and AVP in 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.

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.

Effect of cyclosporine administration on renal hemodynamics in conscious rats.

The effect of acute and chronic administration of cyclosporine on systemic and renal hemodynamics was studied in conscious rats. Infusion of cyclosporine in a dose of 20 mg/kg (Cy 20) resulted in a significant fall in renal blood flow (RBF) (3.4 vs. 6.5 ml/min/g, P less than 0.05) and a rise in renal vascular resistance (RVR) (36.9 vs. 20.6 mm Hg/ml/min/g, P less than 0.05). Infusion of cyclosporine at a dose of 10 mg/kg (Cy 10) did not result in a significant change in RBF or RVR. Both doses of cyclosporine resulted in stimulation of plasma renin activity (PRA) from control values of 5.6 +/- 0.8 ng/ml/hr to 11.6 +/- 2.0 with 10 mg/kg and 26.7 +/- 5.6 with 20 mg/kg. Urinary 6-keto-PGF1 alpha excretion increased from control values of 14.0 +/- 2.0 ng/6 hr to 22.7 +/- 2.2 with 10 mg/kg and 25.0 +/- 2.0 with 20 mg/kg. Similar effects on RBF, RVR, PRA, and 6-keto-PGF1 alpha excretion were seen after chronic administration of cyclosporine (20 mg/kg i.p. for 7 days). Pretreatment of animals with captopril did not prevent the fall in RBF after cyclosporine, suggesting that the vasoconstriction was not mediated by angiotensin II. Animals treated with meclofenamate demonstrated reduction in RBF with 10 mg/kg cyclosporine (4.3 vs. 7.0 ml/min/g, P less than 0.05), suggesting that prostaglandins protect against the vasoconstrictor effect of cyclosporine. Administration of phenoxybenzamine after cyclosporine improved RBF (5.0 vs. 3.4 ml/min/g) and restored RVR to normal. Similarly, renal denervation dramatically reduced the fall in RBF after cyclosporine (innervated right kidney 3.6 vs. denervated left kidney 6.0 ml/min/g, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients.

To evaluate the mechanism of cyclosporine-induced hyperkalemia, the renin-angiotensin-aldosterone system and renal potassium clearance were compared in ten renal transplant recipients treated with cyclosporine and treated with azathioprine. After stimulation by a low-sodium diet and furosemide, cyclosporine-treated patients demonstrated lower plasma renin activity when supine (1.9 +/- 0.3 v 7.8 +/- 1.4 ng/mL/hr) and after standing (3.0 +/- 0.7 v 12.2 +/- 1.5 ng/mL/hr). Supine plasma aldosterone levels tended to be lower in cyclosporine-treated patients, (4.8 +/- v 10.5 +/- 2.6 ng/dL), although standing plasma aldosterone levels were not different (10.8 +/- 3.0 v 12.3 +/- 2.0 ng/dL). After administration of 0.75 mEq of potassium chloride per kilogram of body weight, cyclosporine-treated patients excreted 52% +/- 7.1% of the potassium load in six hours compared with excretion of 67% +/- 7.0% by the azathioprine-treated patients, although there was no difference in plasma aldosterone levels in response to the potassium load in the two groups. These data suggest that cyclosporine causes suppression of plasma renin activity and a tubular insensitivity to aldosterone, both of which may impair potassium excretion.

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.

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.

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.

Studies of the effects of essential fatty acid deficiency in the rat.

We report a model of prostaglandin depletion induced in rats by fasting for 11 days, followed by institution of an essential fatty acid-deficient diet. Urinary prostaglandin E, 2 weeks after this diet had been implemented, was 22 +/- 2 ng/24 hours compared to 113 +/- 8.5 ng/24 hours in controls (P less than 0.01). There was no difference in 24-hour urine volume or solute excretion in controls and essential fatty acid-deficient rats. Five hours after administration of NaCl, 10 mM/kg, essential fatty acid-deficient diet rats excreted 1.85 +/- 0.78 ml urine compared to 6.42 +/- 2.26 ml in control (p less than 0.01) with Na+ excretion 447 +/- 273 muEq in essential fatty acid-deficient rats vs 1483 +/- 366 muEq in control (P less than 0.01). Intravenous isotonic NaCl, 1.5% body weight, resulted in increased urine flow rate in control rats from 8.3 +/- 2 microliter/min to 28.7 +/- 8.8 microliter/min with sodium excretion increasing from 0.19 +/- 0.2 to 3.3 +/- 0.9 muEq/min. In the essential fatty acid-deficient diet animals, there was no significant change in flow rate, 6.07 +/- 2.43 to 9.85 +/- 4.29 microliter/min, or sodium excretion, 0.09 +/- 0.03 to 0.40 +/- 0.24 muEq, after saline infusion. There was no difference in the glomerular filtration rate of plasma aldosterone in the two groups after the salt load. When given a water load, 3 ml/100 g body weight, essential fatty acid-deficient diet rats excreted 2.5 +/- 0.7 ml in 5 hours compared to 6.3 +/- 1.4 ml in controls (P less than 0.01). The defect in water excretion was not due to increased sensitivity to antidiuretic hormone, since similar sensitivity to this hormone was demonstrated in the essential fatty acid-deficient diet and control rats during a water diuresis. When isotonic saline was substituted for drinking water, there was an increase in systolic blood pressure in essential fatty acid-deficient diet rats from 124 +/- 2 to 142 +/- 3 mm Hg over 9 days (P less than 0.01) compared to 122 +/- 2 before and 122 +/- 2 mm Hg after saline drinking in controls. The administration of linoleic acid for 4 days increased urinary prostaglandin E excretion to 114 +/- 15 ng/24 hours from 23 +/- 4 (P less than 0.01), and the alterations in the ability to excrete a sodium and water load were reversed. In essential fatty acid-deficient diet animals made hypertensive by 9 days of saline drinking, the institution of linoleic acid to the diet normalized the blood pressure despite the continued administration of saline. These studies demonstrate that essential fatty acid-deficient diet animals develop salt-sensitive hypertension with a combined defect in both sodium and water excretion which is reversed following correction of the essential fatty acid deficiency.