Faculty Bibliography

AIMS/OBJECTIVE:The risk of HeartMate II (HMII) left ventricular assist device (LVAD) thrombosis has been reported, and serum lactate dehydrogenase (LDH), a biomarker of haemolysis, increases secondary to LVAD thrombosis. This study evaluated longitudinal measurements of LDH post-LVAD implantation, hypothesizing that LDH trends could timely predict future LVAD thrombosis. METHODS AND RESULTS/RESULTS:From October 2004 to October 2014, 350 HMIIs were implanted in 323 patients at Cleveland Clinic. Of these, patients on 339 HMIIs had at least one post-implant LDH value (7996 total measurements). A two-step joint model combining longitudinal biomarker data and pump thrombosis events was generated to assess the effect of changing LDH on thrombosis risk. Device-specific LDH trends were first smoothed using multivariate boosted trees, and then used as a time-varying covariate function in a multiphase hazard model to analyse time to thrombosis. Pre-implant variables associated with time-varying LDH values post-implant using boostmtree were also investigated. Standardized variable importance for each variable was estimated as the difference between model-based prediction error of LDH when the variable was randomly permuted and prediction error without permuting the values. The larger this difference, the more important a variable is for predicting the trajectory of post-implant LDH. Thirty-five HMIIs (10%) had either confirmed (18) or suspected (17) thrombosis, with 15 (43%) occurring within 3 months of implant. LDH was associated with thrombosis occurring both early and late after implant (P < 0.0001 for both hazard phases). The model demonstrated increased probability of HMII thrombosis as LDH trended upward, with steep changes in LDH trajectory paralleling trajectories in probability of pump thrombosis. The most important baseline variables predictive of the longitudinal pattern of LDH were higher bilirubin, higher pre-implant LDH, and older age. The effect of some pre-implant variables such as sodium on the post-implant LDH longitudinal pattern differed across time. CONCLUSIONS:Longitudinal trends in surveillance LDH for patients on HMII support are useful for dynamic prediction of pump thrombosis, both early after implant and late. Incorporating upward and downward trends in LDH that dynamically update a model of LVAD thrombosis risk provides a useful tool for clinical management and decisions.

BACKGROUND:The national opioid epidemic may have expanded the donor pool for lung transplantation, but concerns remain regarding infectious risks and allograft function. This study compared donor/recipient characteristics, outcomes, and reasons for organ discard between overdose death donors (ODD) and all other mechanism-of-death donors. METHODS:Data on adult lung transplants from 2000-2017 were provided by the Scientific Registry of Transplant Recipients. Pulmonary allografts used in multiple organ transplantations were excluded. Donor/recipient demographics, outcomes, and organ discard were analyzed with regards to ODD since 2010. Discard analysis was limited to donors who had at least one organ transplanted but their pulmonary allografts discarded. RESULTS:From 2010-2017, 7.3% (962/13,196) of lung transplantations were from ODD, over a 3-fold increase from the 2.1% (164/7,969) in 2000-2007. ODD were younger but more likely to have a history of smoking, hepatitis C, or an abnormal bronchoscopy finding. Overall survival was similar between ODD and non-ODD groups. ODD of discarded pulmonary allografts were younger and more likely to be hepatitis C positive, but were less likely to have a history of smoking than their non-ODD counterparts. CONCLUSIONS:Rates of ODD utilization in lung transplantation have increased in accordance with the opioid epidemic, but there remains a significant pool of ODD pulmonary allografts with favorable characteristics that are discarded. With no significant difference in survival between ODD and non-ODD recipients, further expansion of this donor pool may be appropriate and pulmonary allografts should not be discarded based solely on ODD status.

BACKGROUND:The national opioid epidemic has expanded the donor pool for heart transplantation, but concerns remain regarding infectious risk and allograft function. This study compared donor and recipient characteristics, outcomes, and reasons for organ discard between overdose-death donors (ODDs) and donors with all other mechanism of death. METHODS:Data on adult cardiac transplants from 2010 to 2017 were provided by the Scientific Registry of Transplant Recipients. Cardiac allografts used in multiple organ transplantations were excluded. Recipient and donor characteristics and organ discard were analyzed with regard to ODDs. Kaplan-Meier curves and log-rank tests described mortality survival. RESULTS:A total of 1,710 of 15,904 (10.8%) cardiac transplantations were from ODDs, approximately a 10-fold increase from 2000 (1.2%). ODDs were more frequently older than 40 years of age (87.2% vs 70.1%; p < 0.001), had higher rates of substance abuse, were more likely hepatitis C positive (1.3% vs 0.2%; p < 0.001), and less frequently required inotropic support at the time of procurement (38.4% vs 44.8%; p < 0.001). Overall survival was not different between the groups (p = 0.066). Discarded ODD allografts were more likely to be hepatitis C positive (30.8% vs 5.3%; p < 0.001) and to be identified as conveying increased risk by the Public Health Services (63.3% vs 13.2%; p < 0.001), but they were less likely to be discarded because of a diseased organ state (28.2% vs 36.1%; p < 0.001). CONCLUSIONS:Rates of ODDs have increased corresponding with the worsening opioid epidemic. Even though ODDs have higher rates of hepatitis C, cardiac allograft quality indices are favorable, and recipient outcomes are similar when compared with non-ODDs, a finding indicating that greater use of this donor pool may be appropriate.

Purpose: Heart transplantation (HTx) from hepatitis C virus (HCV) positive donors to HCV negative recipients may reduce waitlist time and increase access to viable organs. Direct acting antivirals (DAAs) are highly successful at curing HCV infection, but the effect of DAAs on the pharmacokinetics of calcineurin inhibitors is largely unknown. We describe the effect on tacrolimus dosage requirements in recipients of HCV viremic donors. Method(s): We retrospectively reviewed HCV negative HTx patients who received a HCV positive organ. All patients received an 8 week course of glecaprevir-pibrentasvir (GP) for HCV treatment and were on standard triple immunosuppression therapy. Patients receiving concomitant medications that affect tacrolimus metabolism were excluded. All tacrolimus dosages and trough levels were collected from the time of initiation post-HTx until 1 month after completion of GP treatment. Tacrolimus dose normalized concentrations using the concentration:dose ration (ng/mL:mg/kg) were compared before, during, and after GP treatment. Result(s): Seven HTx recipients were included in the analysis. Tacrolimus dose normalized concentrations were 124.8, 163.4, and 196.7 (ng/mL)/(mg/kg/d) before, during and after GP treatment, respectively (Figure 1). Tacrolimus dosage requirements did not differ during GP treatment as compared to before or after GP treatment. The percentage of tacrolimus trough levels within goal range and the incidence of supratherapeutic tacrolimus levels, was 51% vs. 41% and 4% vs. 0% during GP treatment as compared to after GP treatment. Conclusion(s): We did not find a difference in tacrolimus dosage requirements while receiving GP treatment as compared to before or after GP treatment; however, this study was limited by a small sample size. No empiric dosage adjustments can be recommended when initiating or discontinuing GP treatment at this time. Further data will be needed to strengthen these findings.

Purpose: The opioid epidemic has expanded the cardiac donor pool, but the concern for primary graft dysfunction (PGD) remains a barrier to wider utilization of these hearts. We analyzed donor characteristics in transplanted and discarded cardiac allografts from overdosed donors (ODD) to determine if viable ODD hearts are being unnecessarily discarded due to inappropriate bias. Method(s): Data on adult cardiac transplantation from 2010-2017 were provided by the SRTR. Eight donor characteristics associated with PGD were analyzed: age, gender, hypertension, high creatinine, cocaine abuse, inotropic support, LVEF, and cardiac arrest. Donor characteristics of transplanted and discarded hearts were compared between ODD and non-ODD. Result(s): ODD comprised 11% (1710/15904) of transplanted hearts and 7% (2600/32678) of discarded hearts. Among transplanted hearts, ODD more frequently were younger than 50 (98% vs 90%), did not have hypertension (86% vs 83%), and did not require inotropic support (62% vs 55%) compared to non-ODD; ODD less frequently were male (63% vs 70%), had no history of cocaine abuse (57% vs 84%), or had creatinine <=1.5 (62% vs 81%). Among discarded hearts, ODD more frequently were younger than 50 (87% vs 46%), had no history of hypertension (78% vs 49%), and did not require inotropic support (51% vs 41%); ODD less often had no history of cocaine abuse (50% vs 86%) or creatinine <=1.5 (61% vs 69%) (Table). Donors known to have at least 6 of 8 favorable qualities comprised 36% (942/2600) of discarded ODD hearts, compared to 28% (9152/32678) of discarded non-ODD hearts (p<0.001). The most common reasons given for discard of ODD hearts with favorable qualities were poor organ function (18%), refusal by all programs (16%), and lack of recipient (11%). Conclusion(s): ODD hearts with favorable qualities are being discarded at disproportionally higher rates than non-ODD hearts. Further studies and better documentation are needed to understand current discard practices and if further expansion into this donor pool is appropriate.