Renal blood flow, glomerular filtration rate, and renal morphology in cyclosporine-induced acute renal failure in Munich-Wistar rats

The mechanism of clinical cyclosporine nephrotoxicity has remained unclear. We have established an animal model of cyclosporine-induced acute renal failure in the male Munich-Wistar rat by giving four daily doses of parenteral cyclosporine 60 mg/kg intraperitoneally (IP). In this model, 20 minutes of bilateral renal ischemia preceding the first cyclosporine dose did not significantly increase the renal failure, but did increase mortality (65% v 17%), which was due in part to the CNS effect of cyclosporine. Pair-fed and pair-watered vehicle and saline controls were used. The renal morphologic changes induced by the castor oil vehicle of the commercial parenteral cyclosporine solution were quantitatively similar to those induced by cyclosporine, although the severity of the changes by light microscopy was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum were also seen in other groups. Renal blood flow determined by electromagnetic flow probe showed a significant decline during 2 hours after a single IP injection of cyclosporine (6.6 +/- 0.4 to 5.0 +/- 0.6 mL/min). A similar decline was seen following injection of the castor oil vehicle of the commercial cyclosporine parenteral preparation (6.6 +/- 0.5 to 5.1 +/- 0.5 mL/min), but not after an injection of a similar volume of mineral oil (6.7 +/- 0.3 to 6.3 +/- 0.2 mL/min). These studies suggest that brief renal ischemia does not increase cyclosporine nephrotoxicity significantly in this rat model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of verapamil with conventional immunosuppression after porcine renal transplantation

It has recently been suggested that the use of calcium channel-blocking agents may improve the results of renal transplantation either by enhancing the immunosuppressive effects of ciclosporin, or by improving posttransplant acute renal failure. In the present study, unlike others, verapamil was administered to the animals for 10 days posttransplant, alone or in conjunction with ciclosporin and/or solumedrol. In the group in which all three agents were given together, there were minimal changes in plasma urea or creatinine for the 10 days after transplantation. However, survival and the histological appearances of the kidneys at autopsy showed no improvement as compared with those in animals treated with cicloporin and steroids. There is thus no evidence from this study to suggest that verapamil could advantageously be added to a clinical immunosuppressive regime.     

Prevention of cyclosporine-induced nephrotoxicity with pentoxifylline

Although cyclosporine (CSA) is established in the prevention of allograft rejection, its use has been associated with dose-limiting toxicities, most notably to the kidney and liver. To date, the pathogenesis of the acute form of nephrotoxicity is unclear but may be related to inhibition of vasodilatory prostaglandins resulting in vasoconstriction and ischemia. The present study investigated the coadministration of CSA with a unique hemorheologic agent, pentoxifylline (PTX), in the murine model. A total of 48 rats were orally dosed with CSA 25 mg/kg for 10 days with either PTX 45 mg/kg i.p. or saline every 12 hr. Posttreatment renal function, assessed by creatinine (CCR) and inulin (CIN) clearances and renal electrolyte handling, was compared with baseline data and between groups. In an attempt to assess prostaglandin-mediated changes in enteral absorption, oral CSA pharmacokinetics with and without PTX were compared to the pharmacokinetics of similar groups (N = 8) administered i.v. CSA. Mean CIN of rats coadministered CSA and PTX (942 +/- 214 microliters/min/g KW) was similar to control rats 884 +/- 185 microliters/min/g KW); both were significantly greater than CSA alone (537 +/- 211 microliters/min/g KW; p less than .01). Likewise, percent of baseline CCR was significantly reduced in rats treated CSA (61 +/- 24%) compared to controls 113 +/- 41%) and rats coadministered PTX (117 +/- 75%; p less than .05). No differences in percent change from baseline electrolyte handling were observed among groups. Further, no differences in CSA pharmacokinetics with or without PTX were found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pretreatment of renal allograft recipients with immunosuppression and donor-specific blood

The induction of immunologic unresponsiveness to improve renal allograft survival was attempted in 64 patients by the pretransplant administration of donor-specific whole blood or buffy coat in conjunction with continuous azathioprine immunosuppression. All donor/recipient combinations were at least one-haplotype-disparate. Presensitization, defined as a positive Amos or antiglobulin crossmatch or a high-titer (greater than 1:8) B-cell-positive crossmatch, was present in 6 patients and not present in 58 patients. Attempts at desensitization of the already sensitized group were uniformly unsuccessful. Treatment of the 58 nonpresensitized patients resulted in transient sensitization in 2 patients, permanent sensitization in 1 patient, and no evidence of sensitization in 55 patients. Fifty-three patients underwent renal transplantation from the specific blood donor, and only two have experienced renal allograft rejection loss during a mean follow-up period of 22 months (5-45 months); 57% have never experienced a rejection episode. The two-year renal allograft survival rate was 85%. This is significantly (P less than 0.01) better than our historical experience of 64% with one-haplotype living-related transplants. The low rate of sensitization (5%) has permitted almost all patients to undergo eventual renal transplantation from the specific blood donor. This and the low rate of rejection (4%) argues for a modification of the immunologic response, rather than a selecting-out process as the mechanism for improved allograft survival.     

Angiotensin converting enzyme inhibition and chronic cyclosporine-induced renal dysfunction in type 1 diabetes

AIM.: This study was designed to evaluate whether the angiotensinconverting enzyme inhibitor enalapril could prevent cyclosporine-inducedrenal dysfunction in diabetic patients treated with CsA in monotherapy. DESIGN.: Twenty-four recent onset insulin-dependent diabetic patientswithout prior renal involvement were randomized to receive a3 month course of either cyclosporine (CsA) alone (7.5 mg/kg.b.i.d. in olive oil) or CsA$enalapril (20 mg p.o. oad.). END POINTS.: were mean arterial pressure, plasma creatinine, GFR, renal plasmaflow, renal vascular resistance, sodium and lithium clearancesmeasured before and after 3 months of treatment. RESULTS.: Baseline values were identical in both groups except for meanarterial pressure which was slightly higher in the subjectssubsequently receiving CsA$enalapril. Three month treatmentwith CsA increased significantly mean arterial pressure andrenal vascular resistance by 9 and 24% respectively, while decreasingsignificantly glomerular filtration rate and renal plasma flowby 17 and 14% respectively. Enalapril was able to prevent thedecline in GFR and the increase in blood pressure induced byCsA. This effect was demonstrated despite a similar increasein renal vascular resistance suggesting a dissociation betweenchanges in glomerular filtration rate and renal vascular resistanceduring angiotensin converting-enzyme inhibition. CONCLUSION.: Chronic angiotensin converting-enzyme inhibition could affordsome degree of protection against CsA-induced renal dysfunction.Whether these results can be extrapolated to transplant recipientsin whom CsA is usually associated to treatment by glucocorticosteroids,deserves further evaluation.     

Renal blood flow in experimental septic acute renal failure

Reduced renal blood flow (RBF) is considered central to the pathogenesis of septic acute renal failure (ARF). However, no controlled experimental studies have continuously assessed RBF during the development of severe septic ARF. We conducted a sequential animal study in seven female Merino sheep. Flow probes were implanted around the pulmonary and left renal arteries. Two weeks later, systemic hemodynamics and RBF were monitored continuously during a 48-h control period and, after a week, during a 48-h period of hyperdynamic sepsis induced by continuous Escherichia coli infusion. Infusion of E. coli induced hyperdynamic sepsis with significantly increased cardiac output (3.8+/-0.4 vs 9.8+/-1.1 l/min; P<0.05), decreased mean arterial pressure (89.2+/-3.2 vs 64.3+/-5.3 mm Hg; P<0.05), and increased total peripheral conductance (42.8+/-3.5 in controls vs 153.7+/-24.7 ml/min/mm Hg in septic animals; P<0.05). Hyperdynamic sepsis was associated with marked renal vasodilatation (renal conductance: 3.0+/-0.7 vs 11.4+/-3.4 ml/min/mm Hg; P<0.05) and a marked increase in RBF (262.3+/-47.7 vs 757.4+/-250.1 ml/min; P<0.05). Serum creatinine increased over 48 h (73+/-18 vs 305+/- micromol/l; P<0.05) whereas creatinine clearance decreased (95.5+/-25.9 vs 20.1+/-19.3 ml/min; P<0.05). After 24 h, urine output decreased from 1.4 to 0.3 ml/kg/h (P<0.05). Infusion of E. coli induced hyperdynamic sepsis and ARF. Septic ARF in this setting was associated with a marked increase in RBF and with renal vasodilatation.     

Effect of thromboxane inhibition on renal blood flow in dogs with complete unilateral ureteral obstruction

The effect of the thromboxane synthetase inhibitor OKY-046 on renal blood flow and ureteral pressure in awake dogs during 18 hours of complete unilateral ureteral obstruction was studied. OKY-046 was infused continuously throughout the period of obstruction and post-release. Renal blood flow and ureteral pressure were constantly monitored during the study. Urinary thromboxane B2 and prostaglandin E2 excretion served as markers for inhibition of renal thromboxane A2 synthesis. The triphasic relationship between ipsilateral renal blood flow and ureteral pressure previously found following unilateral ureteral obstruction was observed despite OKY-046 infusion. Inhibition of ipsilateral urinary thromboxane B2 excretion was greater than 90% compared to control while ipsilateral urinary prostaglandin E2 excretion was not consistently decreased showing specific thromboxane inhibition. These results suggest that urinary thromboxane B2 may serve as a useful marker for determining the effects of inhibition on renal thromboxane A2 production. At the level of inhibition of thromboxane synthesis achieved we did not observe any change in the late decrease in renal blood flow which is typically seen with chronic unilateral ureteral obstruction.     

Acute effect of a selective endothelin-A receptor antagonist, S-0139, against cyclosporine-induced reduction in renal cortical blood flow

Background Cyclosporine is a potent immunosuppressant with nephrotoxic effects. The decreased effective renal blood flow caused by vasoconstriction of afferent arterioles is now considered the main mechanism of cyclosporine-induced nephrotoxicity. It has been suggested that endothelin (ET) receptor antagonists might have beneficial effects against cyclosporine-induced vasoconstriction. We studied the acute effect of a nonpeptide selective ET-A receptor antagonist, S-0139, against cyclosporine-induced reduction of renal cortical blood flow (RCBF). Methods Male Wistar rats were divided into 3 groups (10 rats each). Both cyclosporine and S-0139 were dissolved in normal saline solution and infused into the femoral vein. Group 1 received cyclosporine at a dose of 0.1 mg/kg per minute. Group 2 received cyclosporine at the same dose and S-0139 at 0.2 mg/kg per minute. Group 3 received the medium as a control. RCBF was measured every 30 minutes for 4 hours by the hydrogen gas clearance method under urethane anesthesia. Serum creatinine, serum potassium, plasma endothelin 1 (ET1) concentrations and plasma renin activity were then measured. Results Group 1 showed a significant decrease in RCBF, while groups 2 and 3 showed no change. Serum creatinine and serum potassium were significantly higher in group 1 than in groups 2 and 3. Plasma ET1 levels were both significantly higher in groups 1 and 2 than in group 3. There were no significant differences among the 3 groups in plasma renin activity. Conclusion We conclude that S-0139 has an acute preventive effect against cyclosporine-induced RCBF reduction.     

Dissociation of glomerular filtration and renal blood flow in HgCl2-induced acute renal failure

This study evaluates the role of early renal vasoconstriction in the pathogenesis of mercuric chloride (HgCl2)-induced acute renal failure (ARF) in the dog. Within 3 hr after mercury, glomerular filtration rate (GFR), from 45 +/- 4 25 +/- 2 ml/min, and renal blood flow (RBF), from 268 +/- 22 to 161 +/- 19 ml/min, decreased simultaneously. A rise in diuresis and urinary solute excretion occurred. Morphological and functional studies excluded a major role for tubular leakage or obstruction. An attempt was made to prevent the early renal vasoconstriction, by the administration of Haemaccel, a plasma volume expander, alone or in combination with phentolamine. In both settings the fall in RBF after mercury was prevented. Haemaccel volume expansion alone provoked a significant rise in GFR before HgCl2, but the GFR fell by 29% 3 hr after HgCl2. The Haemaccel/phentolamine combination had no influence on pre-mercury GFR values. In this group, a decrease of GFR by 44% was noted 3 hr after mercury. In conclusion, changes in GFR and renal hemodynamics can be dissociated in the early phase of nephrotoxic ARF. The fall in GFR can be attributed either to a decrease in glomerular ultrafiltration capacity and/or changes in glomerular afferent and efferent resistances, leading to a decrease in glomerular hydrostatic pressure.     

Prevention of post-traumatic immunosuppression with dimexide

Experimental studies in mice have shown that Dimexid injected after trauma can protect the immune system from inhibiting effects of trauma factors. Dimexid when used in the complex treatment of a severe mechanical trauma can reduce the risk of posttraumatic infectious complications.     

Beneficial effect of intrarenal verapamil in human acute renal failure

Cellular Ca2+ influx during the reperfusion period after an ischemic insult has been proposed to be a crucial pathogenetic factor in the development of experimental acute renal failure (ARF). The present study, therefore, examined the potential beneficial effect of intrarenal verapamil, a calcium entry blocking agent, on ARF in patients. Twelve patients were enrolled in the study. Six ARF patients (experimental group)--ARF caused by malaria (4 patients) and leptospirosis (2 patients)--had a catheter placed in their renal artery; verapamil was infused at 100 micrograms/min for 3 h and intravenous furosemide, 0.8 mg/kg/h x 24 h was also administered. Another six ARF patients (control group)--ARF caused by malaria (5 patients) and leptospirosis (1 patient)--were treated with intravenous furosemide alone. Baseline renal function was comparable in both groups; GFR (3.16 +/- 3.24 vs 0.7 +/- 1.5 mL/min, NS), serum creatinine (Scr), (9.1 +/- 2.1 vs 11.3 +/- 2.2 mg/dL, NS), and urine volume (V) (41.79 +/- 4.77 vs 34.54 +/- 13.52 mL/h, NS), were comparable in the experimental and control groups. Twenty-four hours posttreatment, the increment of GFR (9.66 +/- 4.25 vs 1.32 +/- 0.50 mL/min, P less than .02) and V (181.8 +/- 61.7 vs 79 +/- 18 mL/h, P less than .04), were significantly greater in the experimental group as compared to the control group. The course of ARF was also shorter in the experimental group (6.5 +/- 2.1 vs 13 +/- 1.1 days, P less than .05), who also required less dialysis. Thus, combination of a renal arterial infusion of verapamil and intravenous furosemide significantly improves the renal function in tropical ARF as compared to intravenous furosemide alone.     

Host-derived angiogenesis maintains bone blood flow after withdrawal of immunosuppression

A novel method of living bone allotransplantation combining microvascular repair of the nutrient circulation, implantation of host-derived arteriovenous (AV) bundles, and short-term immunosuppression is described. We hypothesized that neoangiogenesis from the implanted vessels would maintain graft viability and circulation after withdrawal of FK506 (Tacrolimus) immunosuppression. Vascularized femoral transplantation was performed between DA and PVG rats. In addition to microsurgical pedicle anastomoses, a saphenous AV bundle from the recipient animal was implanted in the medullary space. Ninety-seven rats were randomly allocated to groups differing in immunosuppression and AV bundle patency. Implanted vessels significantly improved capillary density and bone blood flow in nonimmunosuppressed and immmunosuppressed groups, respectively. A lower incidence of spontaneous AV bundle thrombosis was found with Tacrolimus treatment. More viable osteocytes were seen at 4 weeks when the AV bundle was patent. Further investigations may confirm host-derived neoangiogenesis as an alternative to tolerance induction or immunosuppression in bone allotransplantation.