Faculty Bibliography

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: Controversy remains over the mortality benefit of single (SLT) versus double lung transplantation (DLT) in idiopathic pulmonary fibrosis (IPF). Independent of this controversy, hesitancy to perform SLT in this population exists on the basis of unclear one year functional status. We compared functional status at one year between IPF patients listed for both who ultimately received SLT or DLT. Method(s): All consecutive adult lung transplants for IPF provided by the Scientific Registry of Transplant Recipients were retrospectively reviewed (2007-2017). Isolated lobar transplants (n=4), patients listed only for SLT (n=1834) or DLT (n=2372), and patients with missing functional status data (n=715) were excluded. Group stratification was based on the ultimate procedure (SLT or DLT). Group propensity matching was performed based on 25 recipient/donor characteristics. We compared 'good functional status' defined as >70%, at one year. Result(s): During the study period, 45% (660/1464) and 55% (804/1464) of patients listed for both procedures ultimately received SLT and DLT, respectively. After propensity matching, 341 matched patients remained in each group. Donor and recipient characteristics were similar (Table). There was no statistically significant difference in 'good functional status' at one year between SLT (77%, 264/341) and DLT (81%, 275/341) (p=0.301). The same trend is present for patients younger than 50 who receive SLT (82%, 23/28) versus DLT (94%, 34/36) (p=0.225), and patients between 50 and 60 who receive SLT (78%, 86/110) versus DLT (84%, 97/115) (p=0.305). The opposite trend is noted in patients older than 70 who receive SLT (72%, 13/18) versus DLT (61%, 11/18) (p=0.725). Conclusion(s): In this cohort of lung transplant recipients listed for both SLT and DLT, functional status was statistically similar between groups, even in younger recipients. This data suggests that SLT should not be precluded in IPF patients on the basis of expected functional status at one year.

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.

Delayed graft function (DGF) complicates 20%-40% of deceased-donor kidney transplants and is associated with increased length of stay and subsequent allograft failure. Accurate prediction of DGF risk for a particular allograft could influence organ allocation, patient counseling, and postoperative planning. Mitochondrial dysfunction, a reported surrogate of tissue health in ischemia-perfusion injury, might also be a surrogate for tissue health after organ transplantation. To understand the potential of mitochondrial membrane potential (MMP) in clinical decision-making, we analyzed whether lower MMP, a measure of mitochondrial dysfunction, was associated with DGF. In a prospective, single-center proof-of-concept study, we measured pretransplant MMP in 28 deceased donor kidneys and analyzed the association between MMP and DGF. We used hybrid registry-augmented regression to adjust for donor and recipient characteristics, minimizing overfitting by leveraging Scientific Registry of Transplant Recipients data. The range of MMP levels was 964-28 333 units. Low-MMP kidneys (MMP<4000) were more likely from female donors (75% vs 10%, P = .002) and donation after cardiac death donors (75% vs 12%, P = .004). For every 10% decrease in MMP levels, there were 38% higher odds of DGF (adjusted odds ratio = _1.08 1.38_1.78 , P = .01). In summary, MMP might be a promising pretransplant surrogate for tissue health in kidney transplantation and, after further validation, could improve clinical decision-making through its independent association with DGF.

Background: Inheritance of two APOL1 risk variants accounts for the excess risk of non-diabetic ESRD in African Americans when compared to Caucasian, Hispanic and Asian Americans. African American living donors have a higher risk of ESRD than matched non-black donors. APOL1 genotyping in potential kidney donors of African descent may identify individuals at risk for progressive CKD following donation.
Method(s): We report the retrospective analysis of APOL1 genotyping in a cohort of African American potential kidney donors. In July 2016, we initiated targeted genotyping of all African American kidney donor candidates. African American candidates with two APOL1 risk variants were excluded from kidney donation.
Result(s): A total of 28 African American kidney donor candidates were evaluated between July 2016 and April 2018. 2 (7%) were found to have two APOL1 risk variants (high risk genotype). Low risk genotype was identified in 10 (36%) candidates who had one risk variant and 16 (57%) candidates who had none. To date, 15 candidates have completed their donor work-up. Of these, 7 (47%) have already undergone donor nephrectomy, and 4 (27%) were cleared for surgery and are awaiting operation. 4 (27%) of the candidates did not meet our center specific criteria for donation. 2 out these 4 candidates who were excluded from donation were ruled out expressly for having been found to have two APOL1 risk variants.
Conclusion(s): APOL1 genotyping led to the exclusion of two donors who might have previously been allowed to donate, possibly mitigating their risk of CKD/ESRD and suboptimal graft outcomes in recipients. (Table Presented)

Kidneys from donors with blood type A2 can be successfully transplanted into blood type B and O recipients without the need for desensitization if the recipient's starting anti-A hemagglutinin titer is within an acceptable range. National kidney allocation policy now offers priority for eligible B recipients to receive A2 or A2B deceased donor kidneys, and therefore, the frequency with which A2 or A2B to B transplants will occur is expected to increase. The precise mechanisms by which antibody-mediated rejection is averted in these cases despite the presence of both circulating anti-A antibody and expression of the A2 antigen on the graft endothelium are not known. Whether this process mirrors proposed mechanisms of accommodation, which can occur in recipients of ABO incompatible transplants, is also not known. Repeated exposure to mismatched antigens after retransplantation could elicit memory responses resulting in antibody rebound and accelerated antibody-mediated rejection. Whether this would occur in the setting of repeated A2 donor exposure was uncertain. Here we report the case of a patient with history of a prior A2 to B transplant which failed owing to nonimmunologic reasons; the patient successfully underwent a repeat A2 to B transplant. Neither rebound in anti-A2 antibody nor clinical evidence of antibody-mediated rejection were observed after the transplant. Current kidney allocation will likely enable more such transplants in the future, and this may provide a unique patient population in whom the molecular mechanisms of incompatible graft accommodation may be investigated.

OBJECTIVES/OBJECTIVE:The presence of a donor-specific positive crossmatch has been considered to be a contraindication to kidney transplantation because of the risk of hyperacute rejection. Desensitization is the process of removing hazardous preformed donor-specific antibody (DSA) in order to safely proceed with transplant. Traditionally, this involves plasmapheresis and intravenous immune globulin treatments that occur over days to weeks, and has been feasible when there is a living donor and the date of the transplant is known, allowing time for pre-emptive treatments. For sensitized patients without a living donor, transplantation has been historically difficult. SUMMARY OF BACKGROUND DATA/BACKGROUND:IdeS (imlifidase) is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG. METHODS:Here we present our single-center's experience with 7 highly sensitized (cPRA98-100%) kidney transplant candidates who had DSA resulting in positive crossmatches with their donors (5 deceased, 2 living) who received IdeS within 24 hours prior to transplant. RESULTS:All pre-IdeS crossmatches were positive and would have been prohibitive for transplantation. All crossmatches became negative post-IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and antibody-mediated rejection, which responded to standard of care therapies. Three patients had delayed graft function, which ultimately resolved. No serious adverse events were associated with IdeS. All patients have functioning renal allografts at a median follow-up of 235 days. CONCLUSION/CONCLUSIONS:IdeS may represent a groundbreaking new method of desensitization for patients who otherwise might have no hope for receiving a lifesaving transplant.

Retrospective studies of angiotensin II type 1 receptor antibodies (AT1R-Ab) and anti-endothelial cell antibodies (AECA) have linked these antibodies to allograft injury. Because rising healthcare costs dictate judicious use of laboratory testing, we sought to define characteristics of kidney transplant recipients who may benefit from screening for non-HLA antibodies. Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, were evaluated for AT1R-Ab and AECA. Pre-transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff' 2009-2013 criteria. AT1R-Ab and AECA were detected using ELISA and endothelial cell crossmatches, respectively. AT1R-Ab levels were higher in patients who were positive for AECAs. Re-transplanted patients (p < 0.0001), males (p = 0.008) and those with FSGS (p = 0.04) and younger (p = 0.04) at time of transplantation were more likely to be positive for AT1R-Ab prior to transplantation. Recipients who were positive for AT1R-Ab prior to transplantation had increases in serum creatinine within 3 months post-transplantation (p < 0.0001) and developed abnormal biopsies earlier than did AT1R-Ab negative patients (126 days versus 368 days respectively; p = 0.02). Defining a clinical protocol to identify and preemptively treat patients at risk for acute rejection with detectable non-HLA antibodies is an important objective for the transplant community.