Cyclosporine-treated Renal Allograft Recipients Research Articles

Inhibition of Plasminogen Activator Inhibitor-1 by Angiotensin II Receptor Blockers on Cyclosporine-Treated Renal Allograft Recipients

Introduction We previously showed that proteinuria from a renal graft was significantly decreased by administration of losartan potassium, an angiotensin II receptor blockers (ARB). To further evaluate the mechanism, we performed another clinical study focusing on the change in plasma plasminogen activator inhibitor-1 (PAI-1) levels among cyclosporine (CyA)-treated renal allograft recipients. Methods Among 12 hypertensive CyA-treated kidney transplant patients, four received 25 to 50 mg/day of losartan; four, 4 to 8 mg/day of candesartan cilexetil; and another four, 20 to 40 mg/day of nifedipine. Four CyA-treated kidney-transplanted patients without hypertension were selected as a control group. Informed consent was obtained from all participants. PAI-1 and serum creatinine (S-Cr) levels were monitored every 3 months for 1 year. Results Considering the pretreatment of PAI-1 as 100%, the mean percent of PAI-1 at 1 year after the onset of study for losartan, candesartan, nifedipine, and control groups were 78.6 ± 6.7%, 81.4 ± 8.0%, 96.7 ± 7.6%, and 110.4 ± 9.2%, respectively. The ARB groups demonstrated significant differences from the control group ( P < .01), while the nifedipide group did not. S-Cr levels among ARB-administered groups were increased slightly but temporarily. As for S-Cr levels, no significant differences were seen among the four groups. Conclusions Control of hypertension itself is important for all renal graft recipients; however, PAI-1 reduction by ARBs was thought to be a key for renal preservation. We expect that ARBs will contribute to prolonged renal allograft survival.

Flow-mediated vasodilation and distensibility of the brachial artery in renal allograft recipients

Alterations of large artery function and structure are frequently observed in renal allograft recipients. However, endothelial function has not yet been assessed in this population. Flow-mediated vasodilation is a useful index of endothelial function. We measured the diameter and distensibility of the brachial artery at rest using high-resolution ultrasound and Doppler frequency analysis of vessel wall movements in the M mode. Thereafter, changes in brachial artery diameter were measured during reactive hyperemia (after 4 min of forearm occlusion) in 16 cyclosporine-treated renal allograft recipients and 16 normal controls of similar age and sex ratio. Nitroglycerin-mediated vasodilation was measured to assess endothelium-independent vasodilation. Brachial artery blood pressure was measured using an automatic sphygmomanometer, and brachial artery flow was estimated using pulsed Doppler. Distensibility was reduced in renal allograft recipients (5.31 +/- 0. 74 vs. 9.10 +/- 0.94 x 10-3/kPa, P = 0.003, mean +/- sem), while the brachial artery diameter at rest was higher (4.13 +/- 0.14 vs. 3.25 +/- 0.14 mm, P < 0.001). Flow-mediated vasodilation was significantly reduced in renal allograft recipients (0.13 +/- 0.08 vs. 0.60 +/- 0.08 mm or 3 +/- 2 vs. 19 +/- 3%, both P < 0.001). However, nitroglycerin-mediated vasodilation was similar in renal allograft recipients and controls (0.76 +/- 0.10 vs. 0.77 +/- 0.09 mm, NS, or 19 +/- 3 vs. 22 +/- 2%, NS). There were no significant differences in brachial artery flow at rest and during reactive hyperemia between both groups. The impairments of flow-mediated vasodilation and distensibility in renal allograft recipients remained significant after correction for serum cholesterol, creatinine, parathyroid hormone concentrations, end-diastolic diameter, as well as blood pressure levels, and were also present in eight renal allograft recipients not treated with cyclosporine. Flow-mediated vasodilation was not related to distensibility in either group. The results show impaired endothelial function and reduced brachial artery distensibility in renal allograft recipients. The impairments of flow-mediated vasodilation and distensibility are not attributable to a diminished brachial artery vasodilator capacity, because endothelium-independent vasodilation was preserved in renal allograft recipients.

Divergent effects of calcium channel and angiotensin converting enzyme blockade on glomerulotubular function in cyclosporine-treated renal allograft recipients

The effects of amlodipine and perindopril on renal hemodynamics and tubular function in cyclosporine-treated hypertensive renal allograft recipients were evaluated in a randomized, double-blind crossover fashion. Ten patients were studied after a 2-week placebo run-in and, after 8 weeks of active treatment, allowing a 2-week placebo washout between treatments. At the end of each period, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured as 51Cr-EDTA and 123I-hippuran clearance, respectively, and tubular function evaluated by the lithium clearance technique was determined. Both drugs maintained GFR and ERPF and lowered mean arterial pressure (MAP, mm Hg) to a similar extent (time × treatment, P = 0.466): amlodipine from 126.9 ± 2.5 to 115.9 ± 2.2; perindopril from 126.9 ± 2.5 to 117.9 ± 3.9 (time effect of all treatments together, P = 0.003). Accordingly, renal vascular resistance (RVR, mm Hg/mL/min/1.73 m 2) was equally reduced (time × treatment, P = 0.955): amlodipine from 0.36 ± 0.03 to 0.30 ± 0.02; perindopril from 0.36 ± 0.03 to 0.32 ± 0.01 (time effect all treatments together, P = 0.043). Sodium clearance and fractional excretion of sodium were not affected by either drug. Output of fluid from the proximal tubules measured as clearance of lithium (C Li, mL/min) and uric acid (C Ur, mL/min) was higher after amlodipine than after perindopril (C Li 19.1 ± 2.1 v 16.5 ± 1.7, P = 0.036 and C Ur 7.0 ± 0.6 v 5.9 ± 0.4, P = 0.007). As a consequence, after amlodipine, distal absolute reabsorption of sodium was higher (DAR Na 2.57 ± 0.28 v 2.19 ± 0.22 mEq/min, P = 0.027) and serum uric acid was lower (5.9 ± 0.3 v 6.7 ± 0.4 mg/dL, P = 0.001) in comparision with perindopril. In cyclosporine-treated renal allograft hypertensives, amlodipine and perindopril lower blood pressure equally and reduce RVR to the same extent. Overall sodium excretion is not affected by either agent. Urate clearance is higher and serum uric acid lower on amlodipine as compared with perindopril.

Long-term renal function in cyclosporine-treated renal allograft recipients

Objectives The purpose of this study was to analyze the factors affecting long-term renal function in cyclosporine-treated kidney transplants. Methods The study population comprised 167 patients with more than 5 years of graft function on cyclosporine therapy. Patients were subdivided into those with a serum creatinine level 2.0 mg/dL or less (group I, n = 123) versus those with a level more than 2.0 mg/dL (group II, n = 44) at 5 years post-transplant. Patient survival, graft survival, rejection episodes, renal function, cyclosporine dose and trough level, and proteinuria were compared in these two groups. Results There was no significant difference between groups I and II in terms of race, sex, donor source, donor age, primary renal disease, retransplants, transfusions, presensitization, histocompatibility locus antigen match, or initial nonfunction. At 6 months post-transplantation, the mean serum creatinine level in group II was significantly higher than group I ( P = 0.00001), and this difference increased at subsequent follow-up intervals. The incidence of proteinuria was significantly higher in group II compared with group I ( P < 0.001). Renal allograft survival beyond 5 years post-transplant was significantly better in group I compared with group II ( P = 0.005). There was no significant difference in the mean cyclosporine dose or the mean cyclosporine trough level between groups I and II at any time following transplantation. The most important difference between groups I and II was the finding of significantly more early ( P < 0.001) and late ( P < 0.001) rejection episodes in group II. Conclusions These data suggest that long-term renal function in cyclosporine-treated kidney transplant patients is primarily influenced by the occurrence of early and late rejection episodes rather than by the dosage or duration of cyclosporine therapy.

Blood levels of cyclosporine, acute rejections and the prognosis of the allografts in pediatric renal allograft recipients

Results of a total of 46 pediatric (mean age; 9.0 years), living-related, cyclosporine-treated renal allograft recipients were analyzed retrospectively to study 1), the effects of an acute rejection on the long-term allograft function and 2), the relationship between the cyclosporine blood levels and the frequency of acute rejections. In addition, sequential allograft biopsies (100 days, one, two and three years post-transplant) were performed in all cases to see if clinical symptoms correlated with histological changes. After a mean follow up of 3.3 (range 1-6) years, 15 of 22 (68%) recipients who had no signs of acute rejection, 6 of 12 (50%) who had acute rejections but responded completely to therapy, and none of the remaining 12 cases who failed to recover completely from acute rejections showed good allograft functions and normal histology on biopsy. Thirty-four of 46 cases had no clinical signs of rejection at 100-day allograft biopsy. Yet, histological changes compatible with acute rejection were noted in 11 of 34. Treatments of the rejection were promptly started on these patients and the prognosis was excellent in six cases. The mean blood trough levels of cyclosporine were significantly lower in patients who developed an acute rejection during the first week following transplantation as compared to those without rejection episodes during the same period, 165.5 ng/ml and 204.1 ng/ml, respectively. Furthermore, the mean blood cyclosporine trough levels in patients who experienced rejections during two, three and five weeks after transplantation were definitely lower than those who did not experience such episodes; 124.5 ng/ml, 101 ng/ml and 149.3 ng/ml versus 241.7 ng/ml, 217.7 ng/ml and 201.1 ng/ml respectively, although the number of the cases was too small to reach statistical significance. The results indicate that the long-term allograft function would depend on whether there were episodes of acute rejections, and/or how the allograft responded to the treatments. Since the introduction of cyclosporine has made it difficult to detect acute rejections by clinical findings alone such as blood chemistry or urinalysis, the role of routine allograft biopsies is very important in renal transplantation. It seems likely that low blood levels and/or acute decline of cyclosporine during early postransplant period could increase the possibility of episodes of acute rejection. Since it is well documented that cyclosporine induces less renal parenchymal damages in children, the blood through levels of the drug should be kept at between 200 and 300 ng/ml within 5 weeks of transplantation in order to reduce the risk of acute rejections and to improve the chance of long-term allograft survival.

The Effect of Routine Magnesium Supplementation on Blood Pressure and Blood Lipids in Cyclosporine-Treated Renal Allograft Recipients

Objective: To determine whether routine magnesium supplementation has beneficial effects on blood lipids and blood pressure in cyclosporine-treated stable renal allograft recipients. Design: Randomized, double-blind, cross-over trial. Setting: University-affiliated medical center. Patients: Twenty-six cyclosporine-treated renal transplant patients with a serum creatinine level less than 220 μmol/L (2.5 mg/dL). Intervention: Oral magnesium hydroxide (approximately 20 to 30 mmol/d [40 to 60 mEq/d]) or placebo. Main outcome measure: Blood pressure and serum lipids. Results: Magnesium supplementation resulted in an increase in serum magnesium (0.74 ± 0.02 mmol/L [1.5 ± 0.1 mEq/L] to 0.81 ± 0.02 mmol/L [1.6 ± 0.1 mEq/L]; P P P P Conclusion: Routine, short-term magnesium supplementation in stable, well-functioning renal transplant recipients has favorable effects on blood lipids.

Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients

To characterize morphologic changes in the early post-transplant period in cyclosporine-treated renal allograft recipients, we examined biopsies from three groups of cyclosporine-treated patients: normal function (N = 9), ischemic acute renal failure or "acute tubular necrosis" (N = 12), and cyclosporine toxicity (N = 7). Groups were compared with each other and with previously studied groups of azathioprine-treated patients and native kidney patients. The interstitial infiltrate commonly observed in normally functioning azathioprine-treated grafts was not observed in normally functioning cyclosporine-treated grafts, but two of nine such grafts had a significant venulitis, a change also seen in three of the patients with cyclosporine nephrotoxicity. "Acute tubular necrosis" (ATN) in cyclosporine-treated graft recipients was characterized by focal necrosis of complete tubular cross sections, a finding normally rare in other types of ATN, and by shedding into the tubular lumen of tubular cells with non-pyknotic nuclei, a finding supporting our previous observation of detachment of viable tubular cells in ATN but not in the normal kidney. Hyaline arteriolar thickening was the only morphologic finding on biopsy which distinguished patients with cyclosporine nephrotoxicity from other groups. In summary, the morphologic changes observed in cyclosporine-treated renal allograft recipients with ATN or normal function are quite different from those observed in azathioprine-treated patients. Cyclosporine appears to enhance the tubular injury observed in ATN. Hyaline arteriolar thickening is the main distinguishing feature of cyclosporine nephrotoxicity.

Effects of thromboxane synthase inhibition with CGS 13080 in human cyclosporine nephrotoxicity.

Cyclosporine is a potent immunosuppressive agent, however, its use is limited by nephrotoxicity. Increased production of the potent vasoconstrictor thromboxane A2 contributes to cyclosporine nephrotoxicity in animal models, but the role of thromboxane in human cyclosporine nephrotoxicity has not been established. We therefore studied cyclosporine-treated renal allograft recipients who had evidence of toxicity manifested by decreased renal function. We measured GFR and PAH clearance (CPAH) before, during, and one week after a 48-hour intravenous infusion of the thromboxane synthase inhibitor CGS 13080. At baseline, the urinary excretion of TXB2 and 2,3-dinor-TXB2 was elevated in the study patients compared to healthy subjects. CGS 13080 infusion caused selective and nearly complete inhibition of thromboxane metabolite excretion in all patients. Mean CPAH improved 33% from 223 +/- 45 to 298 +/- 59 ml/min/m2 (P = 0.055) during infusion, while mean GFR improved 9% from 50.1 +/- 3.9 at baseline to 54.6 +/- 4.5 ml/min/1.73 m2 (P = 0.111). The effect on GFR occurred primarily in those patients taking calcium channel blockers. The mean increase in GFR in these 5 patients was 10.0 +/- 2.8 versus -1.0 +/- 2.8 ml/min/m2 in the remainder. We conclude that thromboxane synthase inhibitors may be useful in attenuating the nephrotoxic effects of cyclosporine following renal transplantation.

Retrospective analysis of posttransplantation diabetes mellitus in black renal allograft recipients.

To study the incidence, outcome, and possible etiopathogenic factors involved in posttransplantation diabetes mellitus in cyclosporine-treated black renal allograft recipients. One hundred thirty-eight nondiabetic black renal transplant recipients whose grafts survived greater than 1 yr were studied retrospectively. Twenty-eight (20.3%) patients developed posttransplantation diabetes mellitus, 46 and 75% were diagnosed by 6- and 12-mo posttransplantation, respectively, and 46% were insulin dependent. Diabetes was more frequently encountered in older recipients and recipients of cadaveric kidneys but was independent of sex, number of transplants, incidence of acute rejection, percentage of body weight gain, steroid or cyclosporine dose, and use of beta-blockers and/or diuretics. Renal function was similar in the diabetic group compared with the control group. Actuarial 5-yr graft survival was 82% in the diabetic cohort compared with 78% in the control group, with chronic rejection accounting for all graft losses within the diabetic group. Twenty percent of black cyclosporine-treated renal allograft recipients developed diabetes mellitus in the posttransplantation period. However, its presence did not appear to influence intermediate-term graft or patient survival.

Does H2-receptor antagonist alter the renal function of cyclosporine-treated kidney grafts?

Histamine-type 2 antagonists (H2-blockers) as represented by cimetidine have been shown to adversely affect renal allograft function, particularly when coadministered with cyclosporine, currently a major immunosuppressant. To determine whether or not a newer and more powerful H2-blocker, famotidine, would produce similar adverse effects, we assessed seven cyclosporine-treated renal allograft recipients with regard to changes in their renal function on or off the H2-blocker over a one-week period. Neither the administration nor withdrawal of famotidine (20-40 mg/day) resulted in any significant changes in serum creatine, BUN, urine output or cyclosporine trough levels, suggesting that famotidine can be safely administered as an H2-blocker to cyclosporine-treated renal allograft recipients.

GLOMERULOTUBULAR FUNCTION IN LONG-TERM RENAL ALLOGRAFT RECIPIENTS

Glomerular and tubular function were assessed, using a lithium clearance technique, in two groups of renal allograft recipients at least one year after transplantation. Group 1 comprised 14 patients receiving low-dose prednisolone and cyclosporine, and group 2, 14 patients receiving low-dose prednisolone and azathioprine. There were no significant differences in creatinine clearances between the two groups, although the clearances of lithium (which is absorbed almost exclusively from the proximal tubule) and sodium were significantly lower in the cyclosporine-treated group. Fractional lithium excretion was also significantly lower in group 1 than in group 2, but there was no significant difference in fractional sodium excretion. The absolute proximal reabsorption of sodium and water did not differ between the groups, although the fractional proximal reabsorption of sodium and water was significantly higher in group 1. In contrast, the distal reabsorption of sodium and of water was significantly lower in the cyclosporine-treated patients than in the azathioprine-treated patients; there were, however, no significant differences in the distal fractional reabsorptions of sodium and water between the two groups. In addition there was no correlation in group 1 between whole-blood cyclosporine levels or time since transplantation and any of the assessed parameters of renal function. These results indicate that tubular concentrating abnormalities in cyclosporine-treated renal allograft recipients are similar to those observed in rodent models of cyclosporine nephrotoxicity. They suggest that the pathogenesis of cyclosporine nephrotoxicity may be similar in renal allograft recipients to that in experimental models.

Onset of Dialysis Encephalopathy in Cyclosporine-Treated Renal Allograft Recipients

Three patients who developed typical features of dialysis encephalopathy following renal transplantation are presented. No patient had evidence of overt neurological dysfunction pretransplantation. All patients were taking cyclosporine at the time of onset of neurological disease. Two patients died as a result of their neurological condition. The third patient made a satisfactory recovery. Factors responsible for the onset of dialysis encephalopathy in the renal posttransplantation period are discussed. We propose that cyclosporine may have been an important precipitating factor of the neurological syndrome of these patients.

Cyclosporine-induced renal dysfunction in human renal allograft recipients.

Cyclosporine-treated renal allograft recipients frequently suffer CsA-related nephrotoxicity and hypertension. This study demonstrates that glomerular filtration rate is reduced acutely by 13% (P less than 0.02) and renal vascular resistance increased by 30% (P less than 0.05), immediately after patients take their CsA dose. The reduction in GFR is directly related to their trough CsA level (r = 0.82; P less than 0.01). The lower the trough CsA level the greater the fall in GFR after the CsA dose. Plasma renin activity does not increase after the CsA dose (pre-CsA 0.6 +/- 0.2 ng/L/sec vs. post-CsA 0.4 +/- 0.1 ng/L/sec; P = NS), and therefore cannot be responsible for the reduction in renal function. Short-term nifedipine treatment is effective in preventing the acute reduction in GFR (P less than 0.05). This occurred despite no apparent effect of nifedipine in altering trough or post-dose CsA levels. Furthermore nifedipine was effective in lowering both the mean arterial blood pressure (109 mmHg to 94 mmHg; P less than 0.01) and the elevated renal vascular resistance (25% reduction; P less than 0.02) observed in these patients. These results suggest that nifedipine may be a suitable agent for limiting acute CsA nephrotoxicity and for treating CsA-associated hypertension in renal allograft recipients.

Hyperuricemia after renal transplantation

Hyperuricemia is common in cyclosporine-treated renal allograft recipients. An increased incidence of gout in patients receiving both diuretics and cyclosporine has been reported, but the effect of hyperuricemia on renal allograft function has not been studied. In a prospective, randomized trial of cyclosporine and prednisone versus azathioprine, prednisone, and antilymphocyte globulin for immunosuppression in renal allograft recipients, 105 of 131 cyclosporine and prednisone-treated patients (80 percent) experienced hyperuricemia (serum uric acid level above 8 mg/dl) and 13 of 131 (10 percent) were severely hyperuricemic (serum uric acid level above 14 mg/dl). In contrast, hyperuricemia developed in 63 of 115 patients (55 percent) treated with azathioprine, prednisone, and antilymphocyte globulin (p less than 0.002). Despite the frequent occurrence of hyperuricemia, gout was rare. Clinical gout developed in six patients in the cyclosporine and prednisone group and in 0 patients in the azathioprine, prednisone, and antilymphocyte globulin group between 1 and 43 months (median 22.5 months) after transplantation. Neither severe hyperuricemia nor diuretic therapy were associated with a significantly increased incidence of gout. The mean serum creatinine concentration of severely hyperuricemic patients (all on cyclosporine and prednisone) was similar to that of normouricemic cyclosporine and prednisone patients (1.8 mg/dl versus 1.6 mg/dl, p greater than 0.2), and the severely hyperuricemic patients had a 4-year graft survival rate of 90 percent. Asymptomatic hyperuricemia after renal transplantation does not adversely affect allograft function, requires no specific therapy, and is not a contraindication to use of diuretics.

Failure of cyclosporine-treated renal allograft recipients to increase glomerular filtration rate following an amino acid infusion.

Renal allograft recipients treated with cyclosporine (CsA) have increased renal vascular resistance that falls when CsA is stopped. With the aim of identifying whether CsA-treated patients with excellent renal function also have an alteration in renal vascular tone and to investigate which vessels are affected, we have studied the response of GFR and effective renal plasma flow (ERPF) to an infusion of an amino acid solution in a group of 9 CsA-treated renal transplant recipients with a normal plasma creatinine concentration (104 +/- 3.8 mumol/L [mean +/- SEM]). A similar group of 9 azathioprine-treated patients with good renal function (91 +/- 3.6 mumol/L) were used as controls. The azathioprine group had significant increases in both GFR (22%, P less than 0.05) and ERPF (19%, P less than 0.05) following a protein load, whereas there was no increase in either function in the CsA group. Amino acid infusions increase GFR and ERPF in normal kidneys--at least in part by producing afferent glomerular arteriolar dilatation. The difference we found between the two groups indicates a direct effect of cyclosporine on intrarenal vascular tone, even when renal function is considered to be normal.

Natural killer-cell activity in cyclosporine-treated renal allograft recipients.

We prospectively studied natural killer (NK)-cell activity in 16 cyclosporine-treated renal transplant recipients. NK function remained intact in the group as a whole in the initial 6 months following transplantation. The percentage of CD16-positive cells within the peripheral blood mononuclear-cell population was highly correlated with NK activity both prior to and following transplantation in the absence of rejection. During rejection, the correlation was poor. A marked increase in NK activity occurred during 9 of 12 rejection episodes; similar increases in NK activity were rarely observed in the absence of rejection. Significant infiltrates of NK cells, as determined by expression of CD16, were not demonstrated in stained biopsy specimens obtained from rejecting allografts. Pretransplant NK activity did not predict clinical outcome of the allograft. Our results indicate that NK cells are activated during allograft rejection in cyclosporine-treated patients, but their exact role in the rejection process is unknown.

Increase in natural killer activity in cyclosporine-treated renal allograft recipients during rejection

Natural killer (NK) activity was assessed in a prospective fashion in 15 renal transplant recipients receiving single HLA-haplotype matched allografts and maintained on cyclosporine (CYA) immunosuppression. There was marked variability in NK activity pretransplantation in this population; however, a strong correlation ( r = 0.92, p < 0.01) was found between determinations in an individual patient upon repeated testing. No significant depression of NK activity occurred within the first 12 weeks following transplantation. Whole blood CYA levels did not correlate with NK activity. Although NK activity prior to transplantation did not predict clinical outcome of the allograft, a marked rise in NK activity was observed in patients undergoing rejection compared with those not rejecting ( p < 0.01). A large increment in activity was seen in eight of 11 rejection episodes; a similar increase was rarely seen in the absence of rejection. These results indicate that NK activity is stimulated during allograft rejection in CYA treated renal transplant recipients. It remains to be determined whether this rise in NK function represents a manifestation of alloreactivity accompanying the rejection process or whether NK cells directly contribute to allograft destruction.

Immunopharmacodynamic evaluation of cyclosporine-treated renal allograft recipients.

Since the mode of action of cyclosporine (CsA) in man is incompletely understood, there are no monitoring tools to assess immunosuppressive effect in vivo. In vitro CsA inhibits lymphoproliferation in response to allogeneic and mitogenic stimuli, presumably due to reversible suppression of T helper cell generation of interleukin-2. Therefore the present studies examined the immunosuppressive effect of patient sera on a third-party mixed lymphocyte reaction (MLR) as a pharmacodynamic approach to quantify patient responses to CsA administration. Four kinetic patterns of in vitro immunosuppressive activity were discerned: 24/28 (86%) patients showing two cycles of MLR inhibition--namely, a first peak corresponding to absorption of CsA and an independent second peak of immunosuppression (type I), were free of rejection; while 17/23 (74%) patients demonstrating one cycle corresponding to the peak of CsA absorption (type II) suffered rejection episodes (P less than 0.001). In addition, 20 patients generating continuously high levels of in vitro serum activity (type III) were almost all free of rejection, but manifested nephrotoxicity; while two patients showing continuously low levels (type IV) suffered graft loss due to irreversible rejection (P less than 0.01). Thus failure to display either a second peak or continuously high levels of MLR inhibition was associated with a markedly increased incidence of rejection (76% versus 16%). The in vitro functional characteristics of peak-2 were similar to those of CsA, as assessed by the kinetics of inhibition of MLR lymphoproliferation or cell-mediated lympholysis (CML), and by gross chemical properties of partitioning into organic solvents and heat stability. These findings suggest that pharmacodynamic analysis by MLR inhibition not only affords a useful parameter of immunosuppression, but also may provide an in vitro model to dissect the generation and biotransformation of active CsA metabolites.

Effect of HLA Typing and Transfusions on Cyclosporine-Treated Renal-Allograft Recipients

Effect of HLA Typing and Transfusions on Cyclosporine-Treated Renal-Allograft Recipients