[Show abstract][Hide abstract] ABSTRACT: Mammalian target of rapamycin (mTOR)-inhibitor–containing immunosuppressive regimens have been developed as part of calcineurin inhibitor (CNI) minimization/withdrawal strategies for renal transplant recipients, with the goal of avoiding CNI-associated nephrotoxicity. This review focuses on the pharmacokinetic interactions and exposure-response relationships of mTOR inhibitors and tacrolimus (TAC), the most widely used CNI. We also discuss key randomized clinical studies that have evaluated use of this combination in renal transplantation. Pharmacokinetic studies have shown that mTOR inhibitors, everolimus (EVR) and sirolimus (SRL), have a large intra- and inter-patient variability in drug exposure, and narrow therapeutic windows (trough levels [C0] 3–8 ng/mL and 5–15 ng/mL, respectively). Consequently, routine therapeutic drug monitoring of EVR and SRL is recommended to optimize efficacy and minimize toxicity in individual patients. As there is a good correlation between C0 and area under the curve (AUC), C0 can be used as a convenient and reliable measure of mTOR drug exposure. Clinical data on the use of EVR or SRL in TAC minimization strategies in renal transplantation are limited. Available evidence suggests that treatment with EVR allows early and substantial TAC minimization when used with basiliximab induction and corticosteroids, to achieve good renal function without compromising efficacy or safety. However, data comparing this combination with other regimens are lacking. Results with SRL are more mixed. SRL in combination with reduced TAC has been shown to provide less nephrotoxicity than the SRL/standard TAC combination, with comparable efficacy and safety. However, this approach has been shown to be inferior to other regimens in terms of patient/graft survival and biopsy-proven acute rejection (vs MMF/TAC) as well as renal function (vs MMF/TAC and SRL/MMF). Further studies are needed to define the therapeutic window for TAC when used in combination with mTOR inhibitors, evaluate EVR/reduced TAC versus other regimens, assess long-term outcomes, and determine efficacy and safety in high-risk patients.
[Show abstract][Hide abstract] ABSTRACT: The use of prophylactic antifungal therapy is suggested after kidney transplantation. However, efficacy of low-dose (50 mg) oral fluconazole and its effect on tacrolimus trough levels in patients maintained on tacrolimus and mycophenolic acid, with or without corticosteroids, is unknown.
A retrospective analysis to evaluate efficacy was performed in 305 kidney transplant recipients. An additional analysis to evaluate the fluconazole-tacrolimus drug interaction was performed in 103 patients. Complete tacrolimus area under the curve measurements were also performed in seven patients to further evaluate this drug interaction.
The incidence of fungal infections was very low (0.6%, n = 2). The average tacrolimus trough level at the time of discontinuation and one wk after stopping fluconazole was unchanged (11.69 ± 3.18 and 11.15 ± 3.69 ng/mL, p = 0.145, n = 103). Tacrolimus trough levels on and off of fluconazole in a subgroup of patients continued on corticosteroids, was not significantly different (p = 0.952) but was significantly lower after fluconazole discontinuation if corticosteroids were withdrawn (p = 0.037). However, data from complete tacrolimus pharmacokinetics in the corticosteroid withdrawal group demonstrated no clinically significant differences.
Low-dose, once daily oral fluconazole is effective antifungal prophylaxis after kidney transplantation without significant effects on tacrolimus trough levels or overall exposure.
[Show abstract][Hide abstract] ABSTRACT: Nonadherence in kidney transplant recipients was evaluated in this report using a questionnaire with five binary questions and one question on a continuous scale. Study participants at the University of Utah Transplant Program (n = 199) were 43.0 ± 14.2 years old; 67% were males, and 81% were White. Two questions that produced heterogeneous outcome were analyzed: 'Do you ever forget to take your medication?' (79% no, 21% yes) and 'Have you ever taken your medications late?' (67% no, 33% yes). Responses to these questions correlated (χ² 65.2, p < 0.001; correlation coefficient 0.57, p < 0.001). We performed a logistic regression analysis to identify factors associated with the combined outcome of forgetting/not taking medications altogether or taking medications off schedule. Higher comorbidity index [odds ratio (OR) 2.19, p < 0.001], living (compared to deceased) donor (OR 2.81, p = 0.005) and full-time employment were associated with forgetting medications or taking them late (OR 3.12, p = 0.01). Recipient age tended to be associated with lower risk of nonadherence, but did not reach statistical significance (OR 0.98 per year of age, p = 0.13). Education level, smoking status, recipient race, dialysis modality, number of medications and the time since first kidney transplantation were not associated with the outcome. In conclusion, renal transplant recipients with greater comorbidity, receiving kidney from a living donor and with full-time employment reported lower levels of medication adherence.
Nephron Clinical Practice 01/2011; 117(1):c33-9. DOI:10.1159/000319645 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The genetic determinants of acute kidney transplant rejection (AR) are not well studied, and familial aggregation has never been demonstrated. The goal of this retrospective case-control study was to exploit the unique nature of the Utah Population Database (UPDB) to evaluate if AR or rejection-free survival aggregates in families.
We identified 891 recipients with genealogy data in the UPDB with at least one year of follow-up, of which 145 (16.1%) had AR and 77 recipients had biopsy-proven rejection graded >or=1A. We compared the genealogical index of familiality (GIF) in cases and controls (i.e. recipients with random assignment of rejection status).
We did not find evidence for familial clustering of AR in the entire patient population or in the subgroup with early rejection (n = 52). When the subgroup of recipients with rejection grade >or=1A (n = 77) was analysed separately, we observed increased familial clustering (GIF = 3.02) compared to controls (GIF = 1.96), although the p-value did not reach the level of statistical significance (p = 0.17). Furthermore, we observed an increase in familial clustering in recipients who had a rejection-free course (GIF = 2.45) as compared to controls (GIF = 2.08, p = 0.04). When all recipients were compared to non-transplant controls, they demonstrated a much greater degree of familiality (GIF = 2.03 versus GIF 0.63, p < 0.001).
There is a familial component to rejection-free transplant course and trend to familial aggregation in recipients with AR grade 1A or higher. If a genetic association study is performed, there are families in Utah identified in the current study that can be targeted to increase the power of the test.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine the effect of early corticosteroid cessation on the occurrence of de novo human leukocyte antigen (HLA) antibody posttransplant. Renal transplant recipients (n=37) were randomized to early corticosteroid withdrawal at day 7 posttransplant (n=21 patients), or to chronic steroids (n=16), all in combination with thymoglobulin as induction agent, tacrolimus and mycophenolic acid as maintenance therapy. To establish the time course of HLA antibody appearance, sera collected pretransplant and for up to 5 years posttransplant were screened for the appearance of HLA antibodies. In this 5-year longitudinal study, only one patient in the control group developed a de novo donor-specific HLA antibody. We conclude that renal transplant recipients on steroid withdrawal by the end of week 1 are not at higher risk for developing HLA antibodies compared with a standard steroid regimen up to 5 years posttransplant.
[Show abstract][Hide abstract] ABSTRACT: Data of long-term immunosuppressive protocol comparison are lacking. The goal of this study was to compare kidney transplant outcome using three common immunosuppressive protocols. A retrospective study was performed of the graft and recipient survival using US Renal Data System data (n = 31,012) between January 1, 1995, and December 31, 1999, with the follow-up through December 31, 2000, on prednisone + cyclosporine + mycophenolate mofetil (PCM; n = 17,108), prednisone + tacrolimus + mycophenolate mofetil (PTM; n = 7225), or prednisone + cyclosporine + azathioprine (PCA; n = 6679). Compared with PCM, there is an increased risk for allograft failure associated with PTM (hazard ratio [HR] 1.09; P < 0.05) and PCA (HR 1.15; P < 0.001). Similar associations were demonstrated in the following subgroups: Early (before 1997) and late (in or after 1997) transplant periods, in living-donor transplants, and in adult and kidney-only recipients. This association also was found between PCA regimen and graft survival in the entire patient population (HR 1.15; P < 0.001) and in the studied subgroups. PCA (HR 1.15; P < 0.005), but not PTM (HR 1.01; P = 0.816), regimen was associated with increased recipient mortality in the entire patient population and in patient subgroups. Secondary outcomes (serum creatinine values at given time points, acute rejection rate, and posttransplantation malignancies) are also discussed. These data suggest that a PCM regimen is associated with lower risk for graft failure compared with a PTM regimen and with lower risk for graft failure and recipient death compared with a PCA regimen.
Clinical Journal of the American Society of Nephrology 05/2006; 1(3):563-74. DOI:10.2215/CJN.00640805 · 4.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the effect of basiliximab (BAS) induction therapy on acute rejection rates and overall costs in adult living related donor (LRD) renal transplant recipients. Design. Retrospective chart review and cost-effectiveness analysis of the first 12 months after transplantation.
University hospital and outpatient renal transplant clinic.
Sixty consecutive adult LRD renal transplant recipients.
The treatment group received BAS 20 mg intravenously on postoperative days 0 and 4. The control group received no induction agents. Both groups received cyclosporine microemulsion, azathioprine, and corticosteroids for maintenance immunosuppression.
Six patients (three in each group) were excluded; three had received muromonab-CD3 as an induction agent and three were lost to follow-up. At 12-months, the frequency of acute rejection episodes was 15% (4/27) in the control group and 22% (6/27) in the BAS group (NS). Renal function, as measured by average serum creatinine level, was similar at months 1, 2, 3, 6, and 12 for both groups. The frequency of infectious complications was similar in both groups. No adverse effects were associated with BAS. Mean initial hospitalization charges were dollar 51,970.01 and dollar 68,093.90 in the control and BAS groups, respectively (p < 0.05). The control group had more readmissions (18 vs 14 in the BAS group), but the average charge/readmission was lower (dollar 10,148.50 vs dollar 21,952.58 in the BAS group; NS). All costs were adjusted to 2000 dollars (US).
Basiliximab induction therapy did not provide clear clinical efficacy benefit or prove to be cost-effective compared with no induction in LRD recipients.