Combined use of sirolimus and voriconazole in renal transplantation: a report of two cases.

Voriconazole is currently contraindicated for use with sirolimus. We report our experience with voriconazole/sirolimus in two renal transplant recipients. To our knowledge, this is the first experience with voriconazole/sirolimus. An interaction requiring a 75% to 87.5% sirolimus dose reduction was noted, but goal trough levels and clinical tolerability were achieved.

Interaction of chloramphenicol and the calcineurin inhibitors in renal transplant recipients.

Several case reports have described a pharmacokinetic interaction between chloramphenicol and the calcineurin inhibitors (CNIs). Based on these reports, we set out to characterize the effects of chloramphenicol on cyclosporine and tacrolimus trough concentrations in renal transplant recipients. We retrospectively evaluated daily trough CNI concentrations and compared them with baseline CNI concentrations prior to chloramphenicol. Six adult renal or pancreas/kidney transplant recipients received 11 courses of chloramphenicol. Of these, three received cyclosporine (6 episodes) and three received tacrolimus (5 episodes). The mean dose and duration of chloramphenicol was not significantly different between groups. Chloramphenicol coadministration increased mean cyclosporine troughs maximally by 41.3% on day 4, though overall differences were not significant using analysis of variance (anova). Tacrolimus trough levels increased to 99% above baseline on day 2, 151% on day 3, 161% on day 4, 191% on day 5, and to 207% on day 6 and reached statistical significance by anova (P = 0.001). These results confirm case reports and suggest that careful trough monitoring should be implemented if chloramphenicol is to be used with the CNIs.

Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis.

INTRODUCTION: Although multiple studies of demographic variables have been associated with allograft thrombosis, these results are not routinely reproducible. Are ESRD patients with hypercoagulable states (HCS) (antithrombin III deficiency, protein S or C deficiency, activated protein C resistance, and anticardiolipin antibodies) at predictably greater risk for allograft thrombosis? METHODS: Between 1996 and 1999, all renal transplant candidates were screened for hypercoagulability risk factors [HRF] (multiple arteriovenous access thromboses, prior deep vein thrombosis, prior allograft thrombosis, collagen vascular disease, multiple miscarriages, diabetes, autoimmune disease, and Fabry's disease). HRF(+) candidates were then tested for HCS status. We administered preemptive posttransplant i.v. Heparin in HCS(+) patients and observed the impact of this intervention upon the incidence of allograft thrombosis. We compared demographic data and incidence of allograft thrombosis in an historic control (346 patients transplanted between June 31, 1992, and March 5, 1996) not tested for HCS and a study cohort (502 patients transplanted between March 6, 1996, and June 31, 1999) prospectively screened for HRF. HRF(+) patients who were HCS(+) in the study cohort received i.v. heparin immediately after transplant and p.o. warfarin as outpatients. RESULTS: Demographic characteristics previously implicated in allograft thrombosis were equivalently distributed in both cohorts with the exceptions that more living-donor transplants (33.1% vs. 15.3%) were performed in study cohort, CIT>24 hr occurred in more control patients (37.3% vs. 22.1%) and more study patients (16.7% vs. 0%) received tacrolimus. Hypercoagulable states were found upon reevaluating five of seven controls (71.4%), who lost prior allografts to thrombosis. Hypercoagulable states were prospectively detected in 10 study patients with hypercoagulability risk factors. Most (9 of 10) study patients receiving anticoagulation have achieved long-term allograft function. Study group allograft thrombosis incidence was reduced (1.59% vs. 4.05%). Hypercoagulable states were demonstrated in most episodes of allograft thrombosis. Control patients who lost prior allografts to thrombosis were anticoagulated after retransplantation and 100% achieved long-term allograft function. CONCLUSIONS: Long-term allograft function has been achieved in 90% of study patients when prophylactically anticoagulating study patients with hypercoagulable states. A 2.6-fold reduction in the expected incidence of allograft thrombosis was observed in anticoagulated patients with hypercoagulable states.

Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors.

BACKGROUND: Calcineurin inhibitors (CNI) and azole antifungal agents have been reported to interact in a disparate manner. The azole dose and route and the level of involvement of the liver and intestines have been implicated, although data are limited. A significant interaction may result in CNI toxicity, and withdrawal of the azole may result in subtherapeutic CNI concentrations. Fluconazole, available in both intravenous and oral formulations, is commonly used in transplant recipients and is ideal for determining the presence of a disparate effect on CNI concentrations. We retrospectively investigated the interaction of CNIs with fluconazole, evaluating CNI blood troughs corrected for daily CNI dose, the factors influencing the interaction, and the effect on clinical outcomes in renal and simultaneous pancreas kidney transplant recipients. METHODS: Twenty-eight patients received a CNI and fluconazole during the calendar year 1999, but only 19 patients had documented CNI blood troughs and outpatient follow-up. There were 25 episodes of use in the 19 included patients. CNI blood troughs were evaluated for changes induced by fluconazole, given by both routes, and clinical outcomes were tracked. RESULTS: Data demonstrated both intravenous and oral fluconazole alter CNI blood concentrations. Two metabolic patterns were observed, and we termed these convergent and divergent. Divergent metabolizers did not have significant interaction (n=5), and convergent metabolizers did have a significant interaction (n=15). One patient had a divergent episode after a previous convergent episode. The main contributors to the lack of interaction appeared to be female sex and African American ethnicity. Additionally, tacrolimus levels were significantly more affected than cyclosporine, during and after fluconazole administration. No patient experienced nephrotoxicity or cellular rejection related to antifungal therapy. CONCLUSIONS: Oral and intravenous fluconazole appear to increase oral CNI trough concentrations to a similar extent even after adjusting for daily calcineurin dose. These interactions appear to be chiefly influenced by sex and ethnicity. Further prospective study is necessary to clarify this issue.

Coadministration of digoxin with itraconazole in renal transplant recipients.

Digoxin toxicity is a major public health issue in the United States. Often this is due to drug interactions, and renal transplant recipients are at particularly high risk for drug-drug interactions. We present cases of 2 renal transplant recipients who received itraconazole and digoxin concomitantly and experienced digoxin toxicity. We have also reviewed the relevant literature to elicit the mechanisms, signs, and symptoms of digoxin toxicity in the presence of itraconazole. When clinicians know the potential drug-drug interactions that may lead to digoxin toxicity, the mechanisms of interaction, the signs and symptoms of digoxin toxicity, and appropriate monitoring, digoxin toxicity is largely preventable.

The effect of Daclizumab in a high-risk renal transplant population.

INTRODUCTION: African-American (AA) renal transplant recipients have a higher incidence of acute rejection when compared to Caucasian renal transplant recipients. This higher rejection rate holds true even with the addition of several of the newer immunosuppressive agents (e.g. mycophenolate mofetil (MMF) and Rapamycin). Acute rejection rates among Hispanic (H) renal transplant recipients are higher in some settings, while lower or the same as in Caucasians in other settings. IL-2 receptor antibodies have been shown to decrease rejection rates when added to a regimen of cyclosporine (CsA), azathioprine and prednisone. Limited data are available on these agents in conjunction with triple CsA, MMF and prednisone therapy, particularly in higher risk group patients. We studied the effect of the addition of the IL-2 receptor antibody Daclizumab to a CsA, MMF, prednisone regimen in a group of African American and high-risk Hispanic renal transplant recipients. METHODS: This was a non-randomized, prospective study. A total of 49 renal transplant recipients (29 African American and 20 Hispanic) were studied and followed. A simultaneous cohort of 56 (31 African-American and 25 Hispanic) renal transplant recipients receiving CsA, MMF and prednisone with no standard induction agent served as the control group. The study cohort received the same regimen with the addition of Daclizumab at 1 mg/kg for five doses over 10 wk. Multivariate analysis was performed to isolate independent factors influencing the study's results. RESULTS: A total of 56 patients in the control group and 49 patients in the Daclizumab group received an average follow-up of 17.1 +/- 6.9 and 12.7 +/- 5.1 months, respectively. Acute rejection rates were lower in the Daclizumab group as compared to the control group 26.4% versus 49.3% per patient years, respectively. A total of eight recurrent rejections in 6 patients occurred in the control group and none in the Daclizumab arm. Graft loss at this follow-up was no different between the groups. CONCLUSION: The addition of Daclizumab to a regimen of CsA, MMF and prednisone decreases acute rejection episodes in a high-risk group of African American and Hispanic renal transplant recipients.

Efficacy of Daclizumab in an African-American and Hispanic renal transplant population.

Current immunosuppressive regimens have decreased acute rejection rates during the 1st year after renal transplantation. However, this decrease has not been as marked in high-risk groups, such as African-American and Hispanic renal transplant recipients. We compared two simultaneous cohorts of altogether 36 African-American and Hispanic renal transplant recipients. Cohort one received a regimen of mycophenolate mofetil, prednisone, and a calcineurin inhibitor. The second cohort received the same protocol with the addition of Daclizumab (1 mg/kg for five doses given every 2 weeks). The median follow-up was 15.2 months (range 11.8-19.9 months). One patient in the Daclizumab-treated group and seven patients in the control group experienced an acute rejection episode. The rejection-free survival was significantly higher in the Daclizumab-treated group (94.4 %) as compared to the control group (66.7 %, Log-rank < 0.05) at 17 months after transplantation. A Cox Proportional Hazard model revealed lack of Daclizumab therapy as the only significant risk factor for acute rejection. (hazard ratio 7.0, 95 % CI = 1.1-48). The addition of the IL-2 receptor blocker Daclizumab to a triple therapy regimen may decrease early acute rejection in the high-risk groups of African-American and Hispanic patients.

Allograft loss in renal transplant recipients with Fabry's disease and activated protein C resistance.

INTRODUCTION: Fabry's disease is associated with an increased incidence of thrombotic events and rejection. Spontaneous thrombosis of a functioning cadaveric renal allograft in a recipient with Fabry's disease prompted prospective evaluation of all transplant candidates with Fabry's disease for hypercoagulability. MATERIALS AND METHODS: Transplant candidates with Fabry's disease were tested for hypercoagulability, analyzed for HLA-type and ABO group, and comorbid conditions suggestive of hypercoagulability. RESULTS: A unique association of Fabry's disease with activated protein C Resistance was documented in a cohort of Caucasian male renal transplant recipients with Fabry's disease. Four of five patients were blood group A and had no significant comorbid conditions suggestive of hypercoagulability. The resistance to activation of protein C (APCR)(+) patients shared HLA loci-B8 and Dr3, although the APCR(-) patients shared HLA loci-B27 and -B38. CONCLUSIONS: Due to the observed increase in the incidence of APCR in our Fabry's cohort, we suggest screening all patients with Fabry's disease for APCR. Because factor V and factor Va receptors are found on vascular endothelium and peripheral blood monocytes, APCR in the presence of Fabry's disease may be a nonimmunological stimulus for rejection. Analysis of HLA typing in patients with Fabry's disease may further elucidate HLA-based association of Fabry's disease and resistance to activated protein C with the risk of thrombosis and rejection.

Evaluation of voiding cystourethrography prior to renal transplantation.

In many centers, voiding cystourethrography is a routine part of pretransplantation assessment of the lower urinary tract. To assess the value of this investigation, a retrospective review of transplant candidates evaluated in our center over 2 years was undertaken. A total of 517 patients were fully evaluable. Only 13 voiding cystourethrograms (VCUGs) (2.5%) of 517 were found to be abnormal. Three patients with reflux alone did not require intervention before transplantation. Four patients with decreased bladder capacity underwent hydrodistention. Two patients increased their capacity to over 150 ml and two patients failed distention, one requiring an ileal conduit and the other requiring an augmentation cystoplasty. Three patients had increased postvoid residual (PVR). Two patients started clean intermittent catheterization. One required prostate resection for benign prostatic hypertrophy. One patient with reflux and decreased bladder capacity refused treatment. One patient with reflux combined with increased PVR started clean intermittent catheterization and was cleared for transplant surgery. One patient with decreased bladder capacity and increased PVR had a stroke and was excluded from transplantation. All 13 patients with abnormal VCUGs had a prior urologic history. In total, only 56 of 517 patients evaluated had a prior urological history. Each VCUG costs approximately $500. Limiting VCUG studies to those patients with a prior urological history would have resulted in a significant cost savings. Hence, we recommend that only patients with a prior urological history should undergo this costly and often distressing examination.

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.

Acute interstitial nephritis due to methicillin.

Fourteen patients are described with a syndrome of methicillin-induced interstitial nephritis. In all patients severe renal dysfunction developed with an average peak serum creatinine of 8 mg/100 ml. An increased total peripheral eosinophil count was found in all patients. All patients had sterile pyuria and each of nine patients studied by Wright's stain of urine sediment had marked eosinophiluria. These findings are suggestive of methicillin-induced interstitial nephritis, although proteinura was a variable finding in our patients. Eight of 14 patients in our study received prednisone therapy for their interstitial nephritis, and the time lapse between maximal and final base line serum creatinine levels was statistically less in the prednisone-treated compared to the nontreated groups. Clinical manifestations of this syndrome are discussed, and the light and electron microscopic and immunofluorescent findings on renal biospy are described.