Cyclosporine nephrotoxicity and the role of cyclosporine in living-related donor transplantation.
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Cyclosporins↗
Biomedical subjects
M S Paller
Publications and source records attributed to M S Paller.
Dietary deficiency of antioxidants exacerbates ischemic injury in the rat kidney.
We examined the effects of dietary deficiency of vitamin E and selenium on the ischemia-reperfusion model of renal injury in the rat. Deficient diets imposed for six weeks on three-week-old weanling rats led to no significant differences in body weights, serum creatinine, GFR, RBF, TmPAH or urinary total protein excretory rates prior to ischemia. Twenty-four hours after one hour of ischemia, animals on the deficient diet demonstrated more markedly impaired GFR, RBF, TmPAH and urine to plasma creatinine concentrations and an increased renal failure index. Tubular damage was more severe injury in the deficient animals. Lipid peroxidation, 15 minutes after the release of the ischemic clamp, was increased in the deficient animals. We confirmed the effects of our dietary manipulation in impairing the oxidant scavenging system in the deficient animals since glutathione peroxidase activity was reduced to less than 5% in the basal state, and this striking reduction persisted following ischemia. Plasma vitamin E concentrations were also markedly depressed in the deficient diets. This dietary deficiency also worsened the course of acute renal injury and was accompanied by 50% mortality compared to 0% mortality in the control animals. Thus, dietary deficiency of vitamin E and selenium led to greater structural and functional renal impairment and increased lipid peroxidation following ischemia. These data provide support for the role of reactive oxygen species in mediating ischemia-reperfusion injury.
Animals↗
Cyclosporine augments renal but not systemic vascular reactivity.
Renal vasoconstriction and hypertension are major side effects of cyclosporine. We tested the acute effects of cyclosporine on renal and systemic vascular reactivity to norepinephrine, angiotensin II, and arginine vasopressin. Renal vascular reactivity was tested in anesthetized Sprague-Dawley rats with denervated kidneys. Renal blood flow was measured with an electromagnetic flow probe in response to graded intra-arterial infusions of vasoconstrictors before and after intravenous administration of cyclosporine. Cyclosporine augmented the decrease in renal blood flow and the increase in renal vascular resistance produced by intrarenal norepinephrine, angiotensin II, and arginine vasopressin. In these studies, systemic blood pressure did not change and cyclosporine caused no direct change in basal renal blood flow. In contrast, in conscious animals, cyclosporine did not increase the pressor response to intravenous norepinephrine or to angiotensin II. Rather, cyclosporine caused enhanced baroreflex slowing of heart rate and a decrease in the pressor response to both norepinephrine and angiotensin II. Even when the baroreceptor reflex was blocked by pentolinium, the pressor response to norepinephrine in cyclosporine-treated animals was diminished compared with vehicle-treated animals. Therefore, although cyclosporine augmented renal vasoconstriction in response to norepinephrine, angiotensin II, and arginine vasopressin, it did not acutely increase the systemic vascular response to these agents. Enhanced renal vascular responsiveness is an additional mechanism for cyclosporine-mediated renal vasoconstriction. Lack of enhanced peripheral vascular responsiveness suggests that hypertension is not likely to be due to direct effects on the systemic vasculature and is more likely to be a consequence of renal functional impairment.
Angiotensin II↗
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.
Blood Flow Velocity↗
Severe flank pain as the predominant symptom of IgA nephropathy.
Two patients with immunoglobulin (Ig)A nephropathy and severe flank pain as the presenting or predominant symptom are described. Recognition of the possible association between IgA nephropathy and severe pain may have altered the approach to these patients who underwent extensive evaluation for hematuria.
Adult↗
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.
Angiotensin II↗
Potassium depletion and regulation of angiotensin II receptors in vascular smooth muscle cells.
Mesenteric artery smooth muscle cells were grown in culture media containing high, normal, or low concentrations of potassium to study the effects on angiotensin II (Ang II) receptor regulation. Cell growth was similar among cells grown in the different culture media. Cells grown in high potassium media (K = 5.8 mEq/L) had an equilibrium dissociation constant, Kd, of 1.59 +/- 0.2 nM, whereas those grown in normal potassium media (K = 4.1 mEq/L) had a Kd of 1.79 +/- 0.2 nM and those grown in a low potassium media (K = 2.9 mEq/L) had a Kd of 1.19 +/- 0.12 nM (not significantly different, NS). Binding capacity of smooth muscle cells grown in high potassium media was 81 +/- 16.7 fmol/mg prot, 95.1 +/- 12.4 fmol/mg prot in those grown in normal potassium media and those grown in low potassium media 86.4 +/- 24.1 fmol/mg prot (NS). Binding of radiolabelled Ang II was reduced by approximately 70% in cells exposed to unlabelled Ang II for 30 or 60 minutes. However, this effect of exposure to Ang II to reduce subsequent binding of Ang II was identical in cells grown in high and low potassium medium. Therefore, we were unable to identify a direct effect of low potassium to induce changes in Ang II receptor binding affinity or binding capacity. Previously observed changes in these Ang II binding parameters in potassium-depleted rats was probably a consequence of other factors which were simultaneously altered by potassium deficiency.
Angiotensin II↗
Effect of neutrophil depletion on ischemic renal injury in the rat.
Oxygen free radicals have been implicated in postischemic renal injury. However, the source of these oxygen free radicals has not been well defined. One potential source is activated neutrophils. Neutrophil depletion was produced in rats by using two different techniques, and the effect on ischemic injury was examined. Rabbit anti-rat neutrophil serum was prepared by immunizing a rabbit with a Percoll gradient centrifugation-purified (approximately 90%) suspension of rat neutrophils. Rats received antineutrophil serum in one of four protocols and were subsequently subjected to 40 minutes of renal artery occlusion. Control animals received nonimmune rabbit serum. The serum creatinine levels 24 hours after ischemia were not different between control and immune serum-treated rats in any of the protocols despite significant reductions in absolute neutrophil count. In a separate study, nitrogen mustard was administered 40 hours before ischemia. Nitrogen mustard-treated rats developed moderate neutropenia and 24 hours after ischemia had lower serum creatinine levels and higher inulin clearance. However, nitrogen mustard-treated rats lost 31.5 +/- 5 gm body weight in the 2 days after nitrogen mustard administration, whereas control animals gained 5.9 +/- 5.9 gm during the same interval. Furthermore, among nitrogen mustard-treated rats there was no correlation between neutrophil count and postischemic renal function. It is thus possible that the beneficial effects of nitrogen mustard were caused by a mechanism other than neutrophil depletion. In summary, in four protocols that used antineutrophil serum, neutropenia did not protect against ischemic injury. Nitrogen mustard provided protection, but probably by a neutrophil-independent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role of iron in postischemic renal injury in the rat.
To determine whether iron participates in free radical-mediated postischemic renal injury and lipid peroxidation, we examined the effects of removal of endogenous iron or provision of exogenous iron following renal ischemia, as well as the effects of renal ischemia and reperfusion on renal venous and urinary "free" iron. Rats underwent 60 minutes of renal ischemia and were studied after either 24 hours (inulin clearance) or 15 minutes (renal malondialdehyde content) of reperfusion. Infusion of the iron chelator deferoxamine (200 mg/kg/hr) during the first 60 minutes of reperfusion resulted in a marked improvement in renal function (inulin clearance: 879 +/- 154 vs. 314 +/- 74 microliter/min; P less than 0.025) and a reduction in lipid peroxidation (renal malondialdehyde: 0.449 +/- 0.06 vs. 0.698 +/- 0.08 mmol/mg prot; P less than 0.05) compared to control animals. Infusion of 50 mg/kg/hr deferoxamine also protected renal function after ischemia (inulin clearance: 624 +/- 116 vs. 285 +/- 90 microliter/min; P less than 0.05) and resulted in less histologic injury. Iron-saturated deferoxamine had no protective effect. Conversely, infusion of the iron complex EDTA-FeCl3 during reperfusion exacerbated postischemic renal dysfunction and lipid peroxidation. Following renal ischemia there was no detectable increase in "free" iron in arterial or renal venous plasma. However, urinary "free" iron increased 10- to 20-fold following reperfusion. Iron chelators which underwent filtration and gained access to this free iron in the urine (free deferoxamine or inulin-conjugated deferoxamine) provided protection, whereas a chelator confined to the vascular space (dextran-conjugated deferoxamine) did not.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Renal work, glutathione and susceptibility to free radical-mediated postischemic injury.
Studies were performed to determine whether renal glutathione (GSH) is an important free-radical scavenger following ischemia and reperfusion, whether alterations in renal transport work affect renal GSH levels, and whether a decrease in renal work decreases susceptibility to postischemic renal injury via the first two effects. Following administration of either intravenous GSH to increase renal GSH or intraperitoneal diethylmaleate to decrease renal GSH, Sprague-Dawley rats underwent 60 minutes of renal ischemia. In animals with high renal GSH following GSH infusion, GFR 24 hours after ischemia was 0.43 +/- 0.08 ml/min compared to 0.15 +/- 0.02 ml/min in saline-infused control animals (P less than 0.01). When renal GSH was decreased by the administration of diethylmaleate postischemic renal dysfunction was accentuated. Twenty-four hours after ischemia GFR was 0.05 +/- 0.02 ml/min in diethylmaleate-treated animals and 0.28 +/- 0.06 ml/min in control animals (P less than 0.005). To test whether a decrease in renal transport work alters renal GSH the filtered load of sodium was reduced by producing unilateral renal artery stenosis. Alternatively, renal work was lessened when sodium reabsorption was interfered with by the infusion of a combination of natriuretic agents. Renal artery stenosis produced a 37% decrease in GFR. Renal GSH was 0.435 +/- 0.089 nmol/mg protein in intact kidneys and 0.804 +/- 0.239 nmol/mg protein in stenotic kidneys (P less than 0.05). The infusion of natriuretic agents produced no change in GFR or renal plasma flow but resulted in a striking elevation in renal GSH.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Kidney Injury↗
Effects of the prostaglandin E1 analog misoprostol on cyclosporine nephrotoxicity.
Acute infusion of cyclosporine in rats causes intense renal vasoconstriction and decreased glomerular filtration rate, effects that persist during short-term daily administration. We tested whether the orally active prostaglandin E1 analog misoprostol could reverse cyclosporine-induced renal vasoconstriction and restore the glomerular filtration rate. Male Sprague-Dawley rats were infused with cyclosporine (10 mg/kg) and then given an oral dose of misoprostol (100, 500, or 1000 micrograms/kg). Cyclosporine caused large decreases in glomerular filtration rate and renal blood flow and a large increase in renal vascular resistance. Misoprostol decreased renal vascular resistance and increased renal blood flow and glomerular filtration rate to near normal levels. The two highest doses of misoprostol caused severe hypotension only in cyclosporine-treated animals. However, when it was given in a dose of 100 micrograms/kg hypotension was not a serious problem. This dose of misoprostol resulted in an increase in glomerular filtration rate from 341 +/- 57 to 669 +/- 104 microliter/min (P less than 0.005) and renal blood flow from 2.23 +/- 0.36 to 4.25 +/- 0.65 ml/min (P less than 0.01), as well as a decrease in renal vascular resistance from 73.7 +/- 23.8 to 29.4 +/- 5.8 mmHg/ml/min (P less than 0.05) in cyclosporine-treated animals. When given to control animals, misoprostol had no effects on renal hemodynamics or renal function. In summary, acute cyclosporine-induced renal vasoconstriction and renal dysfunction in the rat were substantially reversed by oral administration of the prostaglandin E1 analog misoprostol.
Alprostadil↗
Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.
In ischemic acute renal failure oxygen free radicals may mediate injury. In addition, iron appears to play a critical role in hydroxyl radical formation and lipid peroxidation during reperfusion of ischemic kidneys. To determine whether iron may play a similar role in pigment (heme protein)-induced acute renal failure, we studied the effects of the iron chelator deferoxamine in two experimental models of pigment-induced acute renal failure, intramuscular glycerol injection and intravenous hemoglobin infusion without and with concurrent ischemia in the rat. Intramuscular injection of 50% glycerol (5 ml/kg) caused inulin clearance to fall to 0.13 +/- 0.03 (SE) ml/min (normal value, 1.0-1.2 ml/min). Continuous infusion of deferoxamine beginning at the time of glycerol injection significantly attenuated this renal dysfunction. Deferoxamine-treated animals had an inulin clearance of 0.37 +/- 0.06 ml/min (P less than 0.01). Glycerol injection was also associated with significant lipid peroxidation, measured as renal malondialdehyde content. Deferoxamine-treated glycerol-injected rats had renal malondialdehyde content not significantly different from control animals. In another model of heme pigment-induced renal injury, hemoglobin was infused to produce hemoglobinuria. Inulin clearance 1 h after hemoglobin infusion was significantly reduced to 0.84 +/- 0.5 ml/min (P less than 0.025). Infusion of deferoxamine after hemoglobin prevented the hemoglobin-induced decrease in inulin clearance. Thirty minutes of renal ischemia followed by infusion of hemoglobin resulted in more severe renal dysfunction with inulin clearance of 0.54 +/- 0.08 ml/min. Deferoxamine infused at the time of reperfusion attenuated the fall in glomerular filtration rate after ischemia and hemoglobin infusion:inulin clearance 1.04 +/- 0.07 (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Kidney Injury↗
The prostaglandin E1 analog misoprostol reverses acute cyclosporine nephrotoxicity.
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Alprostadil↗
Decreased pressor responsiveness in pregnancy: studies in experimental animals.
Pregnant animals of several species are resistant to the pressor effects of vasoconstrictor substances. Although a blunted pressor response to angiotensin II (AII) has been most thoroughly documented, resistance to the pressor effects of norepinephrine (NE), and arginine vasopressin (AVP) has also been found. In this review, possible mechanisms for decreased pressor responsiveness are discussed. Although antagonism of vasoconstriction by vasodilatory prostaglandins is the most likely cause for decreased pressor responsiveness in pregnancy, other possibilities have been proposed. Reduced pressor responsiveness to AII occurs in many conditions other than pregnancy, and the mechanisms involved include down-regulation of AII receptors, increased production of vasodilatory prostaglandins (as in pregnancy), and post-receptor defects in AII action. Several recent studies have also suggested a role of the sex hormones, particularly 17-beta-estradiol and prolactin, in stimulating prostaglandin production and causing the decreased pressor response to AII in pregnancy.
Angiotensin II↗
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.
Animals↗
Hypothyroidism protects against free radical damage in ischemic acute renal failure.
The effect of hypothyroidism on ischemic acute renal failure was studied in rats. Ten days after thyroidectomy with parathyroid reimplantation, rats underwent right uninephrectomy followed by occlusion of the left renal artery for 60 min. Plasma creatinine was lower in thyroidectomized than control rats 24 hr after ischemia; 1.3 +/- 0.5 vs. 3.2 +/- 0.6 mg%; P less than 0.05. Twenty-four hours after ischemia, inulin clearance was higher in thyroidectomized than control animals (0.40 +/- 0.06 vs. 0.17 +/- 0.03 mliter/min; P less than 0.01), despite an initially lower inulin clearance in thyroidectomized animals (0.81 vs. 1.1 +/- 0.07 mliter/min; P less than 0.05). Administration of the antithyroid drug prophylthiouracil for 14 days also resulted in lower plasma creatinine after ischemia. Kidneys from thyroidectomized animals showed less histologic damage 24 hr after ischemia. Renal cortical content of the lipid peroxidation product malondialdehyde was increased less in thyroidectomy than control kidneys after 60 min ischemia plus 15 min reflow (0.08 +/- 0.02 vs. 0.42 +/- 0.1 nmole/mg protein; P less than 0.005). Renal cortical glutathione content was higher in thyroidectomized animals by approximately 36%, 650 +/- 46 vs. 479 +/- 32 nmole/mg protein (P less than 0.02). In normal rats, glutathione infusion also increased renal cortical glutathione content and resulted in lower plasma creatinine 24 hr after renal artery ischemia. Therefore, hypothyroidism resulted in functional and histologic protection against injury after ischemia. Post-ischemic renal lipid peroxidation was reduced in thyroidectomized animals, perhaps the result of increased scavenging of reactive oxygen species (oxygen free radicals and H2O2) by glutathione.
Acute Kidney Injury↗
Pressor resistance to vasopressin in sodium depletion, potassium depletion, and cirrhosis.
Resistance to the pressor effects of angiotensin II, but not norepinephrine, has been observed in sodium depletion, potassium depletion, and cirrhosis. We tested the response to arginine vasopressin (AVP) in each of these conditions. Male Sprague-Dawley rats were made sodium depleted with furosemide and a low-sodium diet for 3 days, potassium depleted by feeding a low-potassium diet for 14-21 days, or cirrhotic by inhalation of carbon tetrachloride for 8 wk. In conscious rats, the pressor response to graded doses of AVP was reduced in sodium depletion by 27-43% compared with control rats. Sodium-depleted rats were also found to have enhanced baroreceptor reflexes, since the decrease in heart rate for a given increase in mean arterial pressure was greater than in control rats. When the ganglionic blocker pentolinium tartrate was given to sodium-depleted rats the pressor response to AVP was restored to control levels. In potassium-depleted rats the pressor response to AVP was 21-52% lower than that in controls, whereas cirrhotic rats also had a blunted response to AVP (14-41% lower than control). However, there was no evidence in either of these two states of enhanced baroreceptor activity, and pretreatment with pentolinium tartrate did not restore the pressor response to normal. Therefore, although resistance to the pressor effect of AVP was found in all three conditions, the mechanism of this effect was different in sodium depletion compared with potassium depletion and cirrhosis. We conclude that resistance to the pressor action of AVP in sodium depletion was secondary to resetting of the baroreceptors.
Animals↗
Dietary protein increases plasma renin and reduces pressor reactivity to angiotensin II.
The effect of dietary protein on the renin-angiotensin system was studied in rats. Rats were fed isocaloric, 50% (high protein, HP), or 6% (low protein, LP) protein diets with identical electrolyte content for 10 days. Food intake and electrolyte excretion were equivalent on the two diets. Plasma renin activity (PRA) was higher in HP (10.0 +/- 2.5 vs. 3.5 +/- 0.5 ng ANG I . ml-1 . h-1, P less than 0.02) as was plasma aldosterone. However, in conscious rats mean arterial pressure (MAP) was not different between groups. The pressor response to graded doses of angiotensin II (ANG II) was diminished by 30-60% with HP (all doses, P less than 0.05). ANG II binding by mesenteric artery smooth muscle particles did not differ between HP and LP. Chronic administration of captopril did not normalize the pressor response in HP. Urinary prostaglandin (PG) E and 6-keto-PGF1 alpha excretion was markedly increased by the HP diet. Acute inhibition of prostaglandin synthesis with meclofenamate restored the pressor response to ANG II in HP to that in LP. In summary, a HP diet increased PRA, plasma aldosterone, urinary PGE, and 6-keto-PGF1 alpha and decreased pressor responsiveness to ANG II. Resistance to ANG II was not reversed by chronic converting enzyme inhibition but was abolished by inhibition of prostaglandin synthesis.
Angiotensin II↗