Yasir Qazi

Strategies for the management of adverse events associated with mTOR inhibitors

Mammalian target of rapamycin (mTOR) inhibitors are used as potent immunosuppressive agents in solid-organ transplant recipients (everolimus and sirolimus) and as antineoplastic therapies for various cancers (eg, advanced renal cell carcinoma; everolimus, temsirolimus, ridaforolimus). Relevant literature, obtained from specific PubMed searches, was reviewed to evaluate the incidence and mechanistic features of specific adverse events (AEs) associated with mTOR inhibitor treatment, and to present strategies to effectively manage these events. The AEs examined in this review include stomatitis and other cutaneous AEs, wound-healing complications (eg, lymphocele, incisional hernia), diabetes/hyperglycemia, dyslipidemia, proteinuria, nephrotoxicity, delayed graft function, pneumonitis, anemia, hypertension, gonadal dysfunction, and ovarian toxicity. Strategies for selecting appropriate patients for mTOR inhibitor therapy and minimizing the risks of AEs are discussed, along with best practices for identifying and managing side effects. mTOR inhibitors are promising therapeutic options in immunosuppression and oncology; most AEs can be effectively detected and managed or reversed with careful monitoring and appropriate interventions.

Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database.

Background De novo posttransplant malignancy (PTM) is a serious complication of transplantation. Incidences may vary among solid organ transplantations (SOTs) and may take to particular screening recommendations and posttransplantation care. Methods Adult recipients, from the U.S. Organ Procurement Transplant Network/United Network for Organ Sharing database (data as of September 3, 2010), of a primary kidney transplantation (KT), liver transplantation (LT), heart transplantation (HT) or lung transplantation (LuT) performed in the United States between 1999 and 2008 were selected. Multiple-organ recipients and those whose grafts failed within 2 weeks after transplantation were excluded. The incidence of PTM (in 1000 person-years) was estimated using the Kaplan-Meier product-limit method and compared with SOT and the general population. Results The cohort included 193,905 recipients (123,380 KT; 43,106 LT; 16511 HT; and 10,908 LuT). PTM incidence was 8.03, 11.0, 14.3, and 19.8 in KT, LT, HT, and LuT, respectively. In general, PTM recipients were 3 to 5 years older, mostly whites, and are males in all SOTs. In KT, the type of cancer with the highest incidence was posttransplant lymphoproliferative disorder (PTLD, 1.58%), followed by lung (1.12%), prostate (0.82%), and kidney (0.79%) cancers; in LT, PTLD (2.44%), lung and bronchial (2.18%), primary hepatic (0.91%), and prostate (0.88%) cancers; in HT, lung and bronchial (3.24%) and prostate (3.07%) cancers, and PTLD (2.24%); and in LuT, lung and bronchial cancers (5.94%), PTLD (5.72%), and colorectal cancer (1.38%). PTLD, Kaposi sarcoma, and lung and bronchial cancers were increased in all SOTs, when compared with an older (55- to 59-year-old) population. Conclusions Cancer incidence is different among solid organ transplantations, and ratios may be higher than those in the 55- to 59-year-old population.

The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function.

Abstract:  The introduction of cyclosporine (CYA) to the immunosuppressive armamentarium has had a significant effect on graft survival. An improvement in the formulation from the oil‐based to a microemulsion‐based form has resulted in better absorption and more predictable CYA bioavailability. Since the introduction of the first microemulsion form (Neoral), several bioequivalent formulations are now available and are switched in a 1:1 fashion at pharmacies to curtail costs. The purpose of our study was to study the effect of a 1:1 switch from Neoral to Gengraf on CYA trough levels and serum creatinine (SRC) in renal transplant recipients with stable graft function. Eighty‐two renal transplant recipients with stable graft function were enrolled in the study, and of these, 73 were switched to Gengraf, whereas nine remained on Neoral. The 13 patients switched to Gengraf required a dosage change after the mean CYA trough levels changed from 234±96 ng/mL at baseline to 289±102 ng/mL (p<0.05) at 2 wk. With the adjustments in dosage, the levels approached the baseline trough concentrations (239±151 ng/dL). The nine patients who remained on Neoral had no change in the CYA levels or SCR. Nearly 20% of patients who switched to a bioequivalent CYA preparation required a dose adjustment to return to pre‐conversion CYA trough levels. Our study raises serious concerns regarding the switchability of generic CYA for Neoral without careful follow‐up therapeutic drug monitoring.

A rapid and efficient method BK polyomavirus genotyping by high-resolution melting analysis.

A small percentage of renal patients become infected with the BK polyomavirus (BKV), a pathogenic virus that causes BKV‐associated nephropathy (BKVN), after kidney transplantation. This study presents a simple, rapid, high‐throughput method for BKV genotyping using high‐resolution melt analysis (HRMA). Using this novel method, BKV genotypes were analyzed in 49 samples taken from BKV‐positive renal transplantation patients for classification into 1 of 3 genotypes: GI‐1 (subgroups Ia, Ib1, and Ic), GI‐2 (subgroup Ib2), and GII‐IV (subtypes II, III, and IV). HRMA was performed to compare each sample sequence to a reference sequence that contained a combination of 2 of the 3 genotype groups, and the findings validated by conventional DNA sequencing. Of the 49 samples, 20 samples were classified as GI‐1, 18 as GI‐2, and 11 as GII‐IV, suggesting that the predominant BKV strain (77.6%) in these patients was subtype I (GI‐1 and GI‐2). The HRMA method presented here is a time‐saving, reliable, and low‐cost procedure that can be developed as a diagnostic tool in the detection of the specific BKV genotypes associated with BKVN. J. Med. Virol. 83:2128–2134, 2011.

Development of a real-time quantitative PCR assay for detection of a stable genomic region of BK virus

BackgroundBK virus infections can have clinically significant consequences in immunocompromised individuals. Detection and monitoring of active BK virus infections in certain situations is recommended and therefore PCR assays for detection of BK virus have been developed. The performance of current BK PCR detection assays is limited by the existence of viral polymorphisms, unknown at the time of assay development, resulting in inconsistent detection of BK virus. The objective of this study was to identify a stable region of the BK viral genome for detection by PCR that would be minimally affected by polymorphisms as more sequence data for BK virus becomes available.ResultsEmploying a combination of techniques, including amino acid and DNA sequence alignment and interspecies analysis, a conserved, stable PCR target region of the BK viral genomic region was identified within the VP2 gene. A real-time quantitative PCR assay was then developed that is specific for BK virus, has an analytical sensitivity of 15 copies/reaction (450 copies/ml) and is highly reproducible (CV ≤ 5.0%).ConclusionIdentifying stable PCR target regions when limited DNA sequence data is available may be possible by combining multiple analysis techniques to elucidate potential functional constraints on genomic regions. Applying this approach to the development of a real-time quantitative PCR assay for BK virus resulted in an accurate method with potential clinical applications and advantages over existing BK assays.

Costimulation targeting therapies in organ transplantation.

Purpose of reviewLong-term side effects of posttransplant immunosuppressive agents contribute to graft loss and death. This article reviews recent publications on the potential role of costimulation targeting therapies, especially belatacept, in solid organ transplantation. Recent findingsBelatacept, currently undergoing phase III clinical trials in renal transplantation, has shown promise as a safe and effective alternative immunosuppression regimen to calcineurin inhibitor and steroid-based therapies. Phase II trials demonstrated similar efficacy to cyclosporine, with greatly improved renal function. Although its side effects are not yet well characterized, belatacept has shown a decrease of the renal, cardiovascular, and metabolic side effects associated with calcineurin inhibitors. SummaryBelatacept appears to be a safe and effective alternative to calcineurin inhibitor and steroid-based immunosuppressive strategies. Using belatacept in combination with another agent that blocks a different costimulatory pathway has proved especially effective. The results of ongoing and future phase III trials will be needed to validate current findings and determine the most effective belatacept-based regimen for patient populations.

Bortezomib in kidney transplantation.

Purpose of reviewThe purpose of this review is to evaluate the effectiveness of bortezomib in the recent literature for the prevention and treatment of kidney transplant rejection. Recent findingsSeveral studies have analyzed bortezomib alone and in comparison to more traditional immunosuppressive agents during the last 2 years. If administered prior to transplant or soon thereafter, bortezomib appears to lower donor-specific antibody levels and improves graft survival. Its role as a treatment option for antibody-mediated rejection after transplant remains unclear, with limited evidence supporting its long-term success. SummaryBortezomib appears to be a promising early desensitizing agent in the world of kidney transplantation and high short-term success rates have been observed. However, additional randomized trials would be useful to more conclusively demonstrate its effectiveness and optimal administration time in relation to transplant surgery.

Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

The pharmacokinetics of enteric-coated mycophenolate sodium and its gastrointestinal side effects in de novo renal transplant recipients of Hispanic ethnicity.

Objective: The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity. Materials and Methods: The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured. Results: The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032). Discussion and Conclusion: The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

Incentivizing living organ donation.

Purpose of reviewThe number of organs available for the patients on the transplant waitlist remains at a disproportionate low. All possible methods to curtail this shortage, including providing donors with incentives, have been proposed. This article reviews recent publications addressing the benefits and risks involved in incentivizing living donation. Recent findingsThe debate about the ethics, feasibility, and possible models for compensating organ donors has been prominent in recent literature. As certain countries take lead on this initiative, others are cautiously weighing in on the impact implementations of such policies may have on the society, especially on the underprivileged. SummaryThe shortage of organs has resulted in proposal of strategies that encroach on certain moral and ethical principles. Providing incentives to donors is one such strategy that is likely to receive a lot of attention in the next few years.