Jason R. Wellen

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.

Quantifying the Risk of Incompatible Kidney Transplantation: A Multicenter Study

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti‐HLA donor‐specific antibody (DSA). Program‐specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15–2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71–6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28–3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98–7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKTs effect on the risk of being flagged. Compared to equal‐quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19‐, 1.33‐ and 1.73‐fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22‐, 4.09‐ and 10.72‐fold higher odds. Failure to account for ILDKTs increased risk places centers providing this life‐saving treatment in jeopardy of regulatory intervention.

Advanced Donor Age Alone Does Not Affect Patient or Graft Survival after Liver Transplantation

BACKGROUND Individuals greater than 60 years old donate an important portion of the organs available for orthotopic liver transplantation (OLT), but use of donors in this age group remains controversial. We hypothesized that proper selection of donors older than age 60 would not disadvantage recipients in terms of patient and graft survival. STUDY DESIGN All OLTs performed at our center between January 1, 1990, and July 31, 2007, were divided into groups based on donor age: donors 60 years old or more and donors less than 60 years old. Recipients in each group were compared based on graft and patient survival at 1, 3, and 5 years, Model for End-Stage Liver Disease (MELD) scores, cold ischemic times, and era of transplant (before or after 2001). RESULTS There were 741 recipients who met inclusion criteria. Ninety-one patients received livers from donors 60 years old or older, and 650 patients had donors younger than 60 years old. Overall patient survival rates in the group using donors 60 or older were 86.8%, 72.6%, and 67.6% at 1, 3, and 5 years, respectively, and did not differ significantly from survival in the group receiving transplants from donors less than 60 (87.1%, 81.8%, and 75.5%; p=0.39). The 1-, 3-, and 5-year graft survivals in patients receiving transplants from donors 60 or older were 82.4%, 65%, and 62.5%, respectively, and were not significantly different from those in the group using donors younger than 60 (84%, 78.6%, and 72.3%, respectively; p=0.39). Neither patient survival nor graft survival in recipients of organs from donors 60 or older was affected by Model of End-Stage Liver Disease score. Recipients of older-donor livers had improved outcomes after 2001, which correlated with significant improvements in cold ischemic times. CONCLUSIONS Our data suggest that age alone does not adversely affect recipient outcomes. When properly selected, donors older than 60 represent an important and safe increase in the liver donor pool.

Focus on mTOR inhibitors and tacrolimus in renal transplantation: Pharmacokinetics, exposure-response relationships, and clinical outcomes☆

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.

Interplay between Immune responses to HLA and Non-HLA self-antigens in allograft rejection

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis

OBJECTIVE The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival. METHODS A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m(2) , 18.0-24.9 kg/m(2) , 25.0-29.9 kg/m(2) , 30.0-35.0 kg/m(2) , 35.1-40.0 kg/m(2) and >40 kg/m(2) , respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis. RESULTS A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m(2) was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m(2) showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival. CONCLUSIONS Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients.

Short- and long-term outcomes after steatotic liver transplantation.

OBJECTIVE To determine if the use of steatotic grafts adversely affects outcomes in liver transplantation. DESIGN A retrospective review of a prospectively maintained database. SETTING A single center. PATIENTS Four hundred ninety adults who underwent liver transplantation from January 1, 2002, to December 31, 2008, at a single center. Graft biopsies were available in 310 (63.3%) cases. Grafts were classified based on amount of macrovesicular steatosis: 5% or less (n = 222), more than 5% to less than 35% (n = 66), and 35% or more (n = 22). MAIN OUTCOME MEASURES Recipient demographics, Model for End-Stage Liver Disease (MELD) score, patient/graft survival, complications, transfusion rates, and liver function test results. RESULTS One-, 3-, and 5-year patient and graft survivals, respectively, were similar (90.38%, 84.7%, and 74.4%, respectively, P = .3; and 88.7%, 82.5%, and 73.3%, respectively, P = .15). Median follow-up was 25 months. Recipient age, sex, body mass index, laboratory MELD score, and ischemia times were similar among all groups. Packed red blood cell (3 vs 8 U, P < .001), fresh frozen plasma (2 vs 4 U, P = .007), and cryoprecipitate transfusion rates were significantly increased in grafts with 35% or more steatosis. Intensive care unit (5 vs 11 days, P = .02) and hospital (11 vs 21 days, P < .001) stay was also increased in those with grafts with 35% or more steatosis compared with those with 5% or less steatosis. The grafts with 35% or more steatosis had higher transaminase peaks and longer times for bilirubin to normalize (P < .001). CONCLUSIONS Use of carefully selected steatotic grafts was not associated with higher rates of primary nonfunction or poorer outcomes. However, the use of steatotic grafts is associated with increased resource use in the perioperative period.

Outcomes Using Grafts from Donors after Cardiac Death

BACKGROUND Previous reports suggest that donation after cardiac death (DCD) liver grafts have increased primary nonfunction (PNF) and cholangiopathy thought to be due to the graft warm ischemia before cold flushing. STUDY DESIGN In this single-center, retrospective study, 866 adult liver transplantations were performed at our institution from January 2005 to August 2014. Forty-nine (5.7%) patients received DCD donor grafts. The 49 DCD graft recipients were compared with all recipients of donation after brain death donor (DBD) grafts and to a donor and recipient age- and size-matched cohort. RESULTS The DCD donors were younger (age 28, range 8 to 60 years) than non-DCD (age 44.3, range 9 to 80 years) (p < 0.0001), with similar recipient age. The mean laboratory Model for End-Stage Liver Disease (MELD) was lower in DCD recipients (18.7 vs 22.2, p = 0.03). Mean cold and warm ischemia times were similar. Median ICU and hospital stay were 2 days and 7.5 days in both groups (p = 0.37). Median follow-ups were 4.0 and 3.4 years, respectively. Long-term outcomes were similar between groups, with similar 1-, 3- and 5-year patient and graft survivals (p = 0.59). Four (8.5%) recipients developed ischemic cholangiopathy (IC) at 2, 3, 6, and 8 months. Primary nonfunction and hepatic artery thrombosis did not occur in any patient in the DCD group. Acute kidney injury was more common with DCD grafts (16.3% of DCD recipients required dialysis vs 4.1% of DBD recipients, p = 0.01). An increased donor age (>40 years) was shown to increase the risk of IC (p = 0.006). CONCLUSIONS Careful selection of DCD donors can provide suitable donors, with results of liver transplantation comparable to those with standard brain dead donors.

Liver Transplantation for Hepatocellular Carcinoma: Long-Term Results Suggest Excellent Outcomes

BACKGROUND Selected 5-year survival results after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be 70%. Our hypothesis was that liver transplantation is effective for long-term cancer control for HCC. STUDY DESIGN A 20-year retrospective review of a prospectively collected database was carried out. Demographic data and patient survival were calculated. RESULTS There were 1,422 liver transplantations performed between January 1990 and April 2011. Of these, 264 had HCC and 157 (59%) were pretreated with transarterial chemoembolization. Recipient age was 55.9 (± 7.9) years and 208 (79%) of patients were male. The underlying disease was hepatitis C virus in 155 (58.7%), hepatitis B virus in 16 (6%), alcohol in 21 (8%), and miscellaneous in the remaining 72 cases. The mean number of tumors was 1.8 (± 1.7) and the mean largest tumor diameter was 2.3 (± 1.3) cm in the explanted liver. One, 5, and 10-year patient survival was 88.5%, 69.1%, and 40.5%, respectively; disease-specific survival was 99.1%, 94.4% and 87.9%; and disease-free survival was 86.0%, 64.6%, and 40.1%. One, 5, and 10-year graft survival was 87.3%, 68.0%, and 41.8%. Nine (3.4%) patients required retransplantation; 75 patients (28.4%) have died, but only 10 of 75 (13.3%) died of recurrent HCC (3.7% of all HCC patients receiving a transplant) and 6 (8%) died of recurrent viral hepatitis. An additional 9 recipients developed recurrence (total HCC recurrence, n = 19 [7%]), 4 of whom died of causes other than HCC. The remaining 5 are disease-free post-treatment (mean 5.5 years after orthotopic liver transplantation). CONCLUSIONS Orthotopic liver transplantation offers an effective treatment strategy for HCC in the setting of cirrhosis, even in the setting of hepatitis C virus. Hepatocellular carcinoma recurrence is uncommon in properly selected patients and disease-specific long-term survival approaches 90%.

A Novel Organ Donor Facility: A Decade of Experience With Liver Donors

Transplant surgeons have historically traveled to donor hospitals, performing complex, time‐sensitive procedures with unfamiliar personnel. This often involves air travel, significant delays, and frequently occurs overnight. In 2001, we established the nations first organ recovery center. The goal was to increase efficiency, reduce costs and reduce surgeon travel. Liver donors and recipients, donor costs, surgeon hours and travel time, from April 1, 2001 through December 31, 2011 were analyzed. Nine hundred and fifteen liver transplants performed at our center were analyzed based on procurement location (living donors and donation after cardiac death donors were excluded). In year 1, 36% (9/25) of donor procurements occurred at the organ procurement organization (OPO) facility, rising to 93% (56/60) in the last year of analysis. Travel time was reduced from 8 to 2.7 h (p < 0.0001), with a reduction of surgeon fly outs by 93% (14/15) in 2011. Liver organ donor charges generated by the donor were reduced by 37% overall for donors recovered at the OPO facility versus acute care hospital. Organs recovered in this novel facility resulted in significantly reduced surgeon hours, air travel and cost. This practice has major implications for cost containment and OPO national policy and could become the standard of care.