Kamran Mahalati

Neoral Monitoring By Simplified Sparse Sampling Area Under The Concentration-time Curve: Its Relationship to Acute Rejection and Cyclosporine Nephrotoxicity Early After Kidney Transplantation

BACKGROUND Cyclosporine (CsA) dosing is traditionally based on trough blood levels (C0) rather than area under the concentration-time curve (AUC), although AUC correlates better with posttransplantation clinical events. For Neoral, AUC based on limited sampling correlates closely with full 12-hr AUC. The purpose of our study was to correlate C0 with AUC based on CsA levels at 0, 1, 2, 3, and 4 hr after dose (PK0-4) and to compare this AUC with C0 in predicting acute rejection (AR) and acute cyclosporine nephrotoxicity (CsANT) in de novo first kidney transplant patients. METHODS PK0-4 was done 2-4 days after starting Neoral for 156 patients. All received CsA-based triple-drug immunosuppression without antibody induction. AUC was calculated as projected 12-hr (AUC0-12) and actual 4-hr (AUC0-4) from the PK0-4 using the parallel trapezoid rule. Neoral dosing was based on C0 not AUC. AUC was retrospectively compared with C0 as a predictor of AR and CsANT during the first 90 days. RESULTS C0 correlated poorly with AUC0-12 and AUC0-4 (r=0.61 and r=0.42). C0 (mean+/-SEM) levels were not significantly different in 34 patients with and 109 without AR (293+/-21 vs. 294+/-11 microg/L, P=0.95). AUC0-12 and AUC0-4 were significantly lower in patients with than without AR (AUC0-12 9090+/-598 vs. 10608+/-336 microg x h/L, P=0.01; AUC0-4 3934+/-306 vs. 4802+/-166 microg.h/L, P=0.006). In stepwise regression analysis only AUC0-12 or AUC0-4 (P=0.03/P=0.02) and delayed graft function (P=0.007) predicted AR. AUC0-12, AUC0-4, and C0 were all significantly higher in patients with CsANT than without CsANT (AUC0-12 11746+/-650 vs. 10023+/-301 microg x h/L, P=0.01; AUC0-4 5270+/-358 vs. 4474+/-150 microg x h/L, P=0.01; C0 343+/-18 vs. 287+/-10 microg/L, P=0.01), but in stepwise regression analysis C0 was not an independent predictor of CsANT. Patients with AUC0-12 in the range of 9500 to 11500 microg x h/L or AUC0-4 between 4400 and 5500 microg x h/L had the lowest incidence of AR (13% and 7%, respectively) without significantly higher risk for CsANT. CONCLUSION C0 correlates poorly with AUC based on PK0-4. Early AUC based on PK0-4 is more closely associated with AR and CsANT than is C0. Our data suggest that a target AUC0-12 of 9500-11500 or AUC0-4 of 4400-5500 microg x h/L may provide optimal Neoral immunosuppression.

Is routine ureteric stenting needed in kidney transplantation? A randomized trial.

Background. Whether routine ureteric stenting in low-urological-risk patients reduces the risk of urological complications in kidney transplantation is not established. Methods. Eligible patients were recipients of single-organ renal transplants with normal lower urinary tracts. Patients were randomized intraoperatively to receive either routine stenting or stenting only in the event of technical difficulties with the anastomosis. All patients underwent Lich-Gregoire ureteroneocystostomy. Results. Between June 1994 and December 1997, 331 kidney transplants were performed at a single center, 305 patients were eligible, and 280 patients were enrolled and randomized. Donor and recipient age, sex, donor source, whether first or subsequent grafts, ureteric length, native renal disease, and immunosuppression were similar in each group. In the no-routine-stenting group 6 of 137 patients (4.4%) received stents after randomization for intraoperative events that in the surgeon’s opinion required use of a stent. In an intention-to-treat analysis there was no difference between groups in the primary outcome cluster of obstruction or leak [routine stenting 5 of 143 (3.5%) vs. no routine stenting 9 of 137 (6.6%);P =0.23], or in either of these complications analyzed separately. All urological complications were successfully managed without major morbidity. Living donor organs and shorter ureteric length (after trimming) were univariate risk factors for leaks, although increasing donor age was associated with obstruction. Conclusions. Routine ureteric stenting is unnecessary in kidney transplantation in patients at low risk for urological complications. Careful surgical technique with selective stenting of problematic anastomoses yields similar results.

Conversion to rapamycin immunosuppression in renal transplant recipients : Report of an initial experience

Background. The aim of thisstudy is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity. Methods. Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months. Results. In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233±34 to 210±56 &mgr;mol/liter (P <0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients. Conclusions. RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

Adequate Early Cyclosporin Exposure is Critical to Prevent Renal Allograft Rejection: Patients Monitored by Absorption Profiling

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration‐time curve during the first 4 h after cyclosporin‐microemulsion dosing (AUC0−4) and cyclosporin (CyA) levels immediately before and at 2 and 3 h after dosing (C0, C2 and C3) to predict the risk of biopsy‐proven acute rejection (AR) at 6 months. Ninety‐eight kidney transplant recipients treated with CyA‐microemulsion‐based triple therapy immunosuppression were studied on post‐transplant days 3, 5, and 7, and at increasing intervals thereafter.

A Clinical Pharmacokinetic Study of Tacrolimus and Sirolimus Combination Immunosuppression Comparing Simultaneous to Separated Administration

The pharmacokinetic (PK) interaction between tacrolimus (TAC) and sirolimus (SRL), similarly structured immunosuppressive compounds that share binding proteins, is unknown. The combination of SRL with cyclosporin (CsA) has been studied, and a 4-hour interval between dosing of the two drugs is recommended even though it is inconvenient for patients and may affect compliance. Twenty-five liver and kidney–pancreas transplant recipients treated with a combination of SRL and low-dose TAC completed full PK studies while being treated with 4-hour interval dosing (ID) and then with simultaneous dosing. Whole blood was sampled for immunoassay measurement of TAC and SRL levels. Blood concentration/dose ratios of SRL and TAC varied between patients by a factor of 8 and 5, respectively, but correlation between trough concentration levels (C0) and drug exposure area under the concentration–time curve (AUC) was excellent (TAC: r2 = 0.82; SRL: r2 = 0.83). Neither PK profiles of SRL nor those of TAC were altered by simultaneous administration. Dose-corrected AUC and C0 of TAC correlated with SRL (r2 = 0.8 and 0.8, respectively). Bone marrow suppression and nephrotoxicity were not enhanced nor were any new toxicities observed when TAC and SRL were used in combination. These data confirm that simultaneous dosing of TAC and SRL after transplantation is safe and that trough level monitoring is adequate to control therapy.

IS 3-HOUR CYCLOSPORINE BLOOD LEVEL SUPERIOR TO TROUGH LEVEL IN EARLY POST-RENAL TRANSPLANTATION PERIOD?

PURPOSE Cyclosporine dose is traditionally based on trough blood levels. Cyclosporine trough blood level correlates poorly with acute rejection and cyclosporine nephrotoxicity after renal transplantation. We determined whether cyclosporine blood level at any other time point is superior to cyclosporine trough blood level as a predictor of acute rejection and cyclosporine nephrotoxicity. MATERIALS AND METHODS Cyclosporine blood level was measured before (trough), and 1, 2, 3 and 4 hours after the dose in 156 initial renal transplant cases 2 to 4 days after the initiation of cyclosporine micro-emulsion formula administration. The cylosporine micro-emulsion dose was based on cyclosporine trough blood level targeting 250 to 400 microg./l. RESULTS Regression analysis revealed that only delayed graft function (p = 0.007) and cyclosporine blood level after 3 hours (p = 0.008) predicted acute rejection. Mean cyclosporine trough blood level plus or minus standard error was not significantly different in patients with and without acute rejection (293+/-21 versus 294+/-11 microg./l.). Mean cyclosporine blood level after 3 hours was significantly lower in patients with acute rejection (1,156+/-90 versus 1,421+/-50, p = 0.008). Cases were divided into tertiles at levels after 3 hours (1,100 and 1,500 microg./l.). The group in which the level after 3 hours was less than 1,100 microg./l. had the highest acute rejection rate (22 of 50 patients, 44%) and a cyclosporine nephrotoxicity rate of 13% (7 of 52 patients). The group in which the level after 3 hours was 1,100 to 1,500 microg./l. had the lowest acute rejection rate (5 of 46 patients, 11%) without increased cyclosporine nephrotoxicity (7 of 52 patients, 13%). A level after 3 hours of greater than 1,500 microg./l. was associated with a rejection rate of 15% (7 of 47 patients) but significantly higher cyclosporine nephrotoxicity (16 of 52 patients, 30%). CONCLUSIONS Cyclosporine blood level after 3 hours in the early post-transplantation period is associated with acute rejection and cyclosporine nephrotoxicity. A cyclosporine blood level range after 3 hours of 1,100 to 1,500 microg./l. is associated with an optimal outcome. Our data suggest that cyclosporine blood level after 3 hours may represent a better method of monitoring cyclosporine micro-emulsion dose than cyclosporine trough blood level. This hypothesis must be further studied in randomized trials.