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Variable oral absorption of cyclosporine : A biopharmaceutical risk factor for chronic renal allograft rejection

The inter- and intrapatient variability in cyclosporine (CsA) pharmacokinetics obfuscates the relationship between therapeutic outcome and administered dose, thereby impeding the development of secure algorithms for CsA therapy. In an attempt to understand these variabilities, we previously performed serial pharmacokinetic profiles on 160 renal transplant recipients during the first 3 posttransplant months. Drug exposure was estimated by the average CsA concentration (Cav), which was defined as a time-corrected (tau, hours) expression of the area under the concentration-time curve (AUC), i.e., Cav = (AUC/tau). Low Cav values correlated with an increased occurrence of acute rejection episodes and 1-year rate of renal transplant loss. The present study examines the results of serial pharmacokinetic profiling of a cohort of 204 patients treated for up to 5 years with CsA doses selected to achieve target Cav values. Multivariate analyses correlated demographic factors, laboratory values, clinical parameters, and CsA pharmacokinetic parameters with the occurrence of chronic rejection. The factors that predisposed to chronic rejection included a previous acute rejection episode, initial acute tubular necrosis, diastolic blood pressure above 85 mmHg, and African-American race. Once regression models were adjusted to account for the impact of these factors, we examined the association between the incidence of chronic rejection and individual pharmacokinetic parameters, including the mean values of the absolute and dose-corrected trough, peak, and Cav concentrations, as well as the percent coefficient of variation of each of these values. Receiver operating characteristic curves documented that 27% of the total risk for the occurrence of chronic rejection was attributable to a greater than 20% coefficient of variation of the dose-corrected Cav, namely, AUC/(tau.mg). This study suggests that variable oral bioavailability of CsA represents a biopharmaceutical risk factor for the occurrence of chronic rejection.

Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients.

Hyperlipidemia and hypertension, two major risk factors for accelerated atherosclerosis, undoubtedly contribute to the excessive cardiovascular morbidity and mortality experienced by renal transplant recipients. The present survey of posttransplant hyperlipidemia in 500 cyclosporine-treated patients documented a 37.6% incidence of hypercholesterolemia, which occurred within 6 months posttransplant in 82% of patients. An etiologic relation to corticosteroid therapy was suggested by the strong correlation between prednisone doses and cholesterol levels, by the reduced cholesterol levels in patients undergoing steroid withdrawal, and by the reduction in hypercholesterolemia to 13% by 3 years posttransplant when steroid doses were less than 10 mg daily. Hypertriglyceridemia, which was present in 14.7% of the patients, was more severe under CsA-prednisone compared with azathioprine-prednisone therapy. Hypertriglyceridemia, which occurred later in the posttransplant course than hypercholesterolemia, strongly correlated with an excessive percent relative weight and elevated serum creatinine but not with steroid or CsA doses. Increasing age, diabetes mellitus, β-blockers and nephrotic syndrome contribute to posttransplant hyperlipidemia in the CsA-Pred era as they did in the azathioprine era of immunosuppression.

Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay

In order to assess the impact of demographic factors on serum levels of cyclosporine (CsA) estimated by radioimmunoassay (RIA) in renal allograft recipients, 493 pharmacokinetic studies were performed in 212 patients. Neither the presence of diabetes mellitus nor the CsA dosing frequency affected the measured pharmacokinetic parameters. Age over 45 years led to slower CsA clearance with resultant increase in maximum serum concentration (Cmax) per administered milligram, and increased volume of distribution. Female patients showed more rapid drug clearance, but greater volume of distribution. Concomitant hepatic impairment reduced drug clearance, increasing the area under the curve (AUC) per administered milligram of drug, and the Cmax. Patients treated with a rapid steroid taper showed a shorter half-life and lower Cmax than those receiving a slow steroid taper. Nephrotoxicity was associated with increased AUC per administered mg, while patients with acute tubular necrosis requiring dialysis showed poorer drug absorption, lower Cmax, and longer time to peak. The only effect of cimetidine administration was a slightly shortened time to peak. Serial analyses posttransplant in 17 patients suggested a tendency toward improved drug absorption with no effect on other parameters. These studies demonstrating the significant impact of demographic factors thus afford a basis on which to predict the trend of anticipated CsA levels as measured by RIA in renal allograft recipients

The relationship among donor-recipient HLA mismatches, rejection, and death from coronary artery disease in cardiac transplant recipients

Review of 448 cyclosporine-treated heart transplant recipients was undertaken to examine the relationship of donor-recipient HLA compatibility to patient survival, rejection, and death from coronary artery disease (CAD). Pre-Tx crossmatching and panel-reactive antibody (PRA) were correlated to survival as well. Overall patient survivals were 78%, 70%, and 65% at 1, 3, and 5 years post-Tx, respectively. Matching of donor-recipient HLA did not improve outcome in that 1, 3, and 5 year survivals for well-matched (≤2 A, B, or 0–1DR mismatches [MMs]) vs. poorly matched (>2 A, B, or 2 DR MMs) recipients were comparable and not significantly different. Well-matched recipients, however, experienced significantly fewer rejections (1.06±1.2 vs. 1.96±1.0, P<0.01 for ≤2 A, B MMs vs. >2A, B MMs and 1.1±0.9 vs. 2.0±1.1 for 0–1 DR MMs vs. 2 DR MMs, P<0.01). Moreover, HLA-DR, but not HLA A, B, was a significant (P<0.01) predictor of early rejection (<30 days) in that 65% (165/254) of poorly matched vs. only 40% (95/194) of well-matched HLA-DR recipients experienced early rejections. Interestingly, an inverse relationship was found between HLA A and B MM, but not HLA-DR MM, and death from coronary artery disease in that 17% (19/111) of well-matched vs. 9% (32/327) of poorly matched patients died from CAD. Pre-Tx PRA did not impact patient survival or rejection. Donor-recipient crossmatching was performed utilizing the NIH and/or antiglobulin (AHG) procedures. No survival differences were observed at 1, 2, and 3 years post-Tx when comparing outcome for the 24 NIH cross-match (XM)-positive (+) with the 424 NIH-XM-nega-tive patients. Only 10 patients (10/125 AHG-tested recipients) displayed a positive AHG recipient antidonor reactivity. When these 10 AHG-XM (+) sera were treated with dithioerythritol (to inactivate IgM) all 10 converted to a negative reactivity, indicating that a positive crossmatch due to IgM reactivity should not be considered a contraindication to cardiac transplantation. These data also suggest that the reactivity of the 24 NLH-XM(+) sera were most likely due to IgM, and that poorly matched heart recipients may benefit from a more aggressive immunosuppressive regimen to prevent early rejections.

Quantitation of plasma azathioprine and 6-mercaptopurine levels in renal transplant patients.

The plasma of renal transplant patients was analyzed by high performance liquid chromatography (HPLC) for the presence of azathioprine and its primary metabolite, 6-mercaptopurine, after either oral or i.v. administration of azathioprine. Azathioprine was demonstrated in plasma at peak concentrations of 0.6 microgram/ml 15 min after i.v. injections of 100 to 200 mg. Within 90 min of injection, the azathioprine level fell to 10 ng/ml. Azathioprine was not detected in plasma at any time after an oral dose of 100 mg, indicating that the plasma concentration is less than 0.5 ng/ml, which is the sensitivity limit of this assay. 6-Mercaptopurine appeared in the plasma after either oral or i.v. azathioprine administration. Furthermore, decreased renal graft function has no effect on the rate of disappearance of azathioprine from plasma. These results demonstrate that high performance liquid chromatography can be used to determine azathioprine and 6-mercaptopurine levels in man, and that alteration in renal function does not influence early stages of azathioprine degradation.

Influence of HLA matching on rejections and short- and long-term primary cadaveric allograft survival

Distribution of cadaveric donor kidneys, based upon the donor-recipient HLA match grade, remains one of the major controversies in transplantation. To determine whether matching results in fewer rejection episodes and better graft survival, we retrospectively studied our single-center patient population of 683 cyclosporine-prednisone-treated primary cadaveric renal allograft recipients. For 237 recipients of well-matched HLA A, B kidneys (< or = 2 HLA A, B mismatches [MM]) the 1-, 3-, 5-, and 7-year graft survivals of 76%, 66%, 62%, and 61%, respectively, were not significantly different from those of 71%, 65%, 63%, and 63%, respectively, for the 446 poorly matched HLA A, B (> 2 HLA A, B MM) recipients. Similarly, the 1-, 3-, 5-, and 7-year graft survivals for the 307 recipients of well-matched HLA-DR kidneys (0 or 1 DR MM) of 74%, 65%, 63%, and 61%, respectively, were not significantly different from those of 72%, 65%, 63%, and 62%, respectively, for the 366 poorly matched (2 DR MM) recipients. Patient survivals were comparable at each time point for well- vs. poorly matched recipients. Similarly, donor-recipient HLA A, B, and DR matching was not beneficial in retransplant recipients who were transplanted following negative NIH and antiglobulin (AHG) crossmatches when testing both historical (high-PRA) and pretransplant sera. Since rejection episodes may be a more sensitive indicator of immune response than graft loss, we also analyzed the relationship between donor-recipient HLA match grade and posttransplant rejections. A total of 60% (n = 413) of recipients experienced no rejections and had 1-, 3-, 5-, and 7-year graft survivals of 82%, 78%, 74%, and 73%, respectively; 32% (n = 215) of patients who experienced 1 rejection had 1-, 3-, 5-, and 7-year graft survivals of 58%, 48%, 44%, and 43%, respectively (P < 0.001 for graft survival of 0 vs. 1 rejection). The remaining 8% (n = 55) of recipients experienced more than 1 (> 1) rejection and had 1-, 3-, 5-, and 7-year graft survivals of 62%, 38%, 36%, and 36%, respectively (P < 0.001 for graft survival of 0 vs. > 1 rejection and P < 0.01 for graft survival of 1 vs. > 1 rejection). The mean numbers of rejections/patient experienced by well-matched vs. poorly matched recipients were comparable and not significantly different.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of cyclosporine in living-related renal transplantation. Donor-specific hyporesponsiveness and steroid withdrawal.

Fourteen HLA- identical (HLA-ID) and 62 haploiden- tical (HP-ID) living-related donor (LRD) renal allograft recipients were transplanted using cyclosporine (CsA) and prednisone immunosuppression. No patients were preconditioned with pretransplant blood transfusions (third-party or donor-specific)—and, therefore, none were sensitized to their donor. Patient 93% (13/14) and graft 93% (13/14) survival for the HLA-ID patients is not significantly different (P>.1) compared with patient 98% (61/62) and graft 91% (56/62) survival in the HP-ID patients, with a mean follow-up of 16.3 (8–30) and 14.7 (2–35) months, respectively. A significant difference was noted in the incidence of treated rejection episodes (0% vs. 31%, P<.01) and the mean serum (mg/ dl) creatinine (1.37 vs. 1.71, P<.05) at 18 months between the HLA-ID and the HP-ID recipients, respectively. Ten of 22 HP-ID recipients demonstrated donorspecific mixed lymphocyte culture hyporesponsiveness one year posttransplant that may have been due to the emergence of monocytoid suppressor cells. Nine of these HP-ID and seven HLA-ID recipients were subjected to a protocol of steroid withdrawal. Eleven of these patients are currently on CsA monodrug therapy and two are on alternate-day steroids from 9–18 months after discontinuation of prednisone. These findings suggest that CsA is an effective steroid-sparing agent in LRD renal transplantation that diminishes the frequency of treated rejection episodes and may permit monodrug therapy in selected individuals.

Improved allograft survival of strong immune responder-high risk recipients with adjuvant antithymocyte globulin therapy.

The pretransplant cellular immune responsiveness of 90 renal failure patients was correlated with subsequent allograft survival. Patients were subdivided on two bases: whether the pretransplant immune parameter values were above (strong responder) or below (weak responder) the group median, and whether they were responsive or anergic to recall skin test antigens. In a group of 72 cadaveric renal allograft recipients, treated with only Imuran and prednisone, the overall 1-year graft survival was 48%. Pretransplant immunocompetence correlated with graft survival: factors predicting longer allograft survival (P < 0.01) included: percentage of active T rosette-forming cells (A-T RFCs) < 36.5%, anergy to microbial skin test (ST) antigens, in vitro spontaneous blastogenesis (SB) < 14,600 cpm, and response to a panel of five donors in mixed lymphocyte culture (PMLC) < 28,000 cpm. In the two groups, weak and strong responders, the 1-year graft survival rates differed: 63% versus 32% when segregated by the A-T RFC parameter, 63% versus 33% for ST, 57% versus 36% for SB, and 63% versus 35% for PMLC. There were no significant differences in the number of HLA mismatches between the two groups. An additional group of 18 patients was treated with adjuvant immunosuppressive therapy by prophylactic administration of antithymocyte globulin (ATG; Upjohn Co.). Strong, but not weak, responders treated with ATG displayed a significantly improved (P < 0.01) 1-year graft survival over that of the untreated group. Thus, pretransplant immunological assessment may guide the selection of adjuvant immunosuppressive therapy to improve renal allograft survival in strong immune responders at high risk of rejection.