Stakeholders' perspectives on transplant metrics: the 2022 Scientific Registry of Transplant Recipients' consensus conference.

In July 2022, the Scientific Registry of Transplant Recipients (SRTR) hosted an innovative, multistakeholder consensus conference to identify information and metrics desired by stakeholders in the transplantation system, including patients, living donors, caregivers, deceased donor family members, transplant professionals, organ procurement organization professionals, payers, and regulators. Crucially, patients, caregivers, living donors, and deceased donor family members were included in all aspects of this conference, including serving on the planning committee, participating in preconference focus groups and learning sessions, speaking at the conference, moderating conference sessions and breakout groups, and shaping the conclusions. Patients constituted 24% of the meeting participants. In this report, we document the proceedings and enumerate 160 recommendations, 10 of which have been highly prioritized. SRTR will use the recommendations to develop new presentations of information and metrics requested by stakeholders to support informed decision-making.

A Composite End Point of Graft Status and eGFR at 1 Year to Improve the Scientific Registry of Transplant Recipients' Five-Tier Rating System.

BACKGROUND: Performance of kidney transplant programs in the United States is monitored and publicly reported by the Scientific Registry of Transplant Recipients (SRTR). With relatively few allograft failure events per program and increasing homogeneity in program performance, quantifying meaningful differences in program competency based only on 1-year survival rates is challenging. METHODS: We explored whether the traditional end point of allograft failure at 1 year can be improved by incorporating a measure of allograft function (i.e., eGFR) into a composite end point. We divided SRTR data from 2008 through 2018 into a training and validation set and recreated SRTR tiers, using the traditional and composite end points. The conditional 5-year deceased donor allograft survival and 5-year eGFR were then assessed using each approach. RESULTS: Compared with the traditional end point, the composite end point of graft failure or eGFR <30 ml/min per 1.73 m2 at 1-year post-transplant performed better in stratifying transplant programs based on long-term deceased donor graft survival. For tiers 1 through 5 respectively, the 5-year conditional graft survival was 72.9%, 74.8%, 75.4%, 77.0%, and 79.7% using the traditional end point and 71.1%, 74.4%, 76.9%, 77.0%, and 78.4% with the composite end point. Additionally, with the five-tier system derived from the composite end point, programs in tier 3, tier 4, and tier 5 had significantly higher mean eGFRs at 5 years compared with programs in tier 1. There were no significant eGFR differences among tiers derived from the traditional end point alone. CONCLUSIONS: This proof-of-concept study suggests that a composite end point incorporating allograft function may improve the post-transplant component of the five-tier system by better differentiating between transplant programs with respect to long-term graft outcomes.

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection.

BACKGROUND: Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. METHODS: Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. RESULTS: An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. CONCLUSIONS: Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.

Developing simultaneous liver-kidney transplant medical eligibility criteria while providing a safety net: A 2-year review of the OPTN's allocation policy.

The OPTN's simultaneous liver-kidney (SLK) allocation policy, implemented August 10, 2017, established medical eligibility criteria for adult SLK candidates and created Safety Net kidney allocation priority for liver-alone recipients with new/continued renal impairment. OPTN SLK and kidney after liver (KAL) data were analyzed (registrations as of December 31, 2019, transplants pre-policy [March 20, 2015-August 9, 2017] vs. post-policy [August 10, 2017-December 31, 2019]). Ninety-four percent of SLK registrations met eligibility criteria (99% CKD: 50% dialysis, 50% eGFR). SLK transplant volume decreased from a record 740 (2017) to 676 (2018, -9%), with a subsequent increase to 728 (2019, 1.6% below 2017 volume). For KAL listings within 1 year of liver transplant, waitlist mortality rates declined post-policy versus pre-policy (27 [95% CI = 20.6-34.7] vs. 16 [11.7-20.5]) while transplant rates increased fourfold (46 [32.2-60.0] vs. 197 [171.6-224.7]). There were 234 KAL transplants post-policy (94% Safety Net priority eligible), and no significant difference in 1-year patient/graft survival vs. kidney-alone (patient: 95.9% KAL, 97.0% kidney-alone [p = .39]; graft: 94.2% KAL, 94.6% kidney-alone [p = .81]). From pre- to post-policy, the proportion of all deceased donor kidney and liver transplants that were SLK decreased (kidney: 5.1% to 4.3%; liver: 9.7% to 8.7%). SLK policy implementation interrupted the longstanding rise in SLK transplants, while Safety Net priority directed kidneys to liver recipients in need with thus far minimal impact to posttransplant outcomes.

Consensus conference on heart-kidney transplantation.

Simultaneous heart-kidney transplant (sHK) has enabled the successful transplantation of patients with end-stage heart disease and concomitant kidney disease, with non-inferior outcomes to heart transplant (HT) alone. The decision for sHK is challenged by difficulties in differentiating those patients with a significant component of reversible kidney injury due to cardiorenal syndrome who may recover kidney function after HT, from those with intrinsic advanced kidney disease who would benefit most from sHK. A consensus conference on sHK took place on June 1, 2019 in Boston, Massachusetts. The conference represented a collaborative effort by experts in cardiothoracic and kidney transplantation from centers across the United States to explore the development of guidelines for the interdisciplinary criteria for kidney transplantation in the sHK candidate, to evaluate the current allocation of kidneys to follow the heart for sHK, and to recommend standardized care for the management of sHK recipients. The conference served as a forum to unify criteria between the different specialties and to forge a pathway for patients who may need dual organ transplantation. Due to the continuing shortage of available donor organs, ethical problems related to multi-organ transplantation were also debated. The findings and consensus statements are presented.

Economic Evaluation of Extending Medicare Immunosuppressive Drug Coverage for Kidney Transplant Recipients in the Current Era.

BACKGROUND: Kidney transplant recipients must take immunosuppressant drugs to prevent rejection and maintain transplant function. Medicare coverage of immunosuppressant drugs for kidney transplant recipients ceases 36 months after transplantation, potentially increasing the risk of transplant failure. A contemporary economic analysis of extending Medicare coverage for the duration of transplant survival using current costs of immunosuppressant medications in the era of generic equivalents may inform immunosuppressant drug policy. METHODS: A Markov model was used to determine the incremental cost and effectiveness of extending Medicare coverage for immunosuppressive drugs over the duration of transplant survival, compared with the current policy of 36-month coverage, from the perspective of the Medicare payer. The expected improvement in transplant survival by extending immunosuppressive drug coverage was estimated from a cohort of privately insured transplant recipients who receive lifelong immunosuppressant drug coverage compared with a cohort of Medicare-insured transplant recipients, using multivariable survival analysis. RESULTS: Extension of immunosuppression Medicare coverage for kidney transplant recipients led to lower costs of -$3077 and 0.37 additional quality-adjusted life years (QALYs) per patient. When the improvement in transplant survival associated with extending immunosuppressant coverage was reduced to 50% of that observed in privately insured patients, the strategy of extending drug coverage had an incremental cost-utility ratio of $51,694 per QALY gained. In a threshold analysis, the extension of immunosuppression coverage was cost-effective at a willingness-to-pay threshold of $100,000, $50,000, and $0 per QALY if it results in a decrease in risk of transplant failure of 5.5%, 7.8%, and 13.3%, respectively. CONCLUSIONS: Extending immunosuppressive drug coverage under Medicare from the current 36 months to the duration of transplant survival will result in better patient outcomes and cost-savings, and remains cost-effective if only a fraction of anticipated benefit is realized.

A call to action: Feasible strategies to reduce the discard of transplantable kidneys in the United States.

Changes to the United States kidney allocation system targeted at reducing organ discard have failed to improve organ utilization. High Kidney Donor Profile Index kidneys continue to be discarded at high rates as a result of the regulatory and financial barriers to widespread utilization of these organs. However, there are potential changes to clinical practice that could improve organ utilization. Expediting the time from initial offer to final organ acceptance would reduce cold ischemic time and should improve utilization. Implementation of procurement biopsy standards to avoid biopsy of low risk organs may prevent organ discards due to inaccurate data or excessive cold ischemia time. Further, standardization of procurement biopsy pathological interpretation coupled with electronic accessibility would enable early acceptance of difficult to transplant organs. These changes to allocation practice patterns are vital given proposals to expand the geographic sharing of deceased donor kidneys. Implementation of new allocation policies must be evaluated to ensure they result in higher transplant rates and acceptable post-transplant outcomes.

Solid organ transplantation of viral hepatitis C positive donor organs into viral hepatitis C negative recipients.

PURPOSE OF REVIEW: Strategies are needed to reduce waitlist mortality and increase transplantation rates. Advances in hepatitis C therapy has allowed the transplant community to look toward utilization of grafts from hepatitis C viremic donors to expand the organ pool. Use of such grafts for hepatitis C-negative patients is being evaluated and debated, and early trial data are emerging. RECENT FINDINGS: Both hepatitis C antibody-positive/nucleic acid test-negative and viremic donors are currently underutilized. Outcomes for viral hepatitis C (HCV) viremic transplant recipients are improving in the setting of direct-acting antiviral therapy. Optimization of graft utilization from HCV 'positive' donors and expansion to use of viremic donors for HCV-negative recipients will likely reduce waitlist mortality and result in net overall reduction in healthcare expenditures. SUMMARY: Herein, we provide a review of recent advancements relating to hepatitis C in solid organ transplant and outline future directions. A primary future focus will be data collection of outcomes of transplantation of grafts from HCV 'viremic' donors to nonviremic recipients in formal clinical trial protocols.

Simultaneous liver kidney transplantation.

PURPOSE OF REVIEW: Simultaneous liver kidney transplantation (SLK) has taken center stage since the initiation of the new kidney allocation system (KAS). This review places SLK in the context of the changing landscape of organ allocation. RECENT FINDINGS: The introduction of the Mayo End-Stage Liver Disease score into liver allocation policy in 2002 resulted in a significant increase in the number of SLKs performed in the United States. Except for a brief respite in 2009, the rate of SLK has continued to increase with 2015 seeing 626 SLKs. KAS did not mandate sharing kidneys with regionally shared livers. It was anticipated this would reduce the number of SLKs. Additionally, the Kidney Donor Profile Index in KAS made possible a more granular assessment of the quality of the kidneys being allocated to SLK recipients. This revealed that nearly 50% of Kidney Donor Profile Index kidneys 0.35 or less, those to be allocated to children, were given to SLK recipients and that a significant proportion of them may not need a kidney. SUMMARY: Medical eligibility criteria, rules for the allocation of kidneys simultaneously with livers, and the establishment of a safety net, will provide nephrologists with the framework and authority to decide which liver disease patients truly need a kidney.

Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

New national allocation policy for deceased donor kidneys in the United States and possible effect on patient outcomes.

In 2013, the Organ Procurement and Transplantation Network in the United States approved a new national deceased donor kidney allocation policy that introduces the kidney donor profile index (KDPI), which gives scores of 0%-100% based on 10 donor factors. Kidneys with lower KDPI scores are associated with better post-transplant survival. Important features of the new policy include first allocating kidneys from donors with a KDPI≤20% to candidates in the top 20th percentile of estimated post-transplant survival, adding waiting time from dialysis initiation, conferring priority points for a calculated panel-reactive antibody (CPRA)>19%, broader sharing of kidneys for candidates with a CPRA≥99%, broader sharing of kidneys from donors with a KDPI>85%, eliminating the payback system, and allocating blood type A2 and A2B kidneys to blood type B candidates. We simulated the distribution of kidneys under the new policy compared with the current allocation policy. The simulation showed increases in projected median allograft years of life with the new policy (9.07 years) compared with the current policy (8.82 years). With the new policy, candidates with a CPRA>20%, with blood type B, and aged 18-49 years were more likely to undergo transplant, but transplants declined in candidates aged 50-64 years (4.1% decline) and ≥65 years (2.7% decline). These simulations demonstrate that the new deceased donor kidney allocation policy may improve overall post-transplant survival and access for highly sensitized candidates, with minimal effects on access to transplant by race/ethnicity and declines in kidney allocation for candidates aged ≥50 years.

Duration of prophylaxis against fungal infection in kidney transplant recipients.

OBJECTIVE: To compare the efficacy of 2 strategies that use nystatin to prevent thrush and Candida esophagitis in kidney transplant recipients. METHODS: A retrospective chart review was conducted of adult kidney transplant recipients at our center, where the protocol for prophylaxis against fungal infection was changed in March 2013. Before the protocol change, kidney transplant recipients received nystatin for 1 month (before group) and after the change they received nystatin for the duration of admission (after group). The primary outcome measure was the incidence of thrush and Candida esophagitis within 3 months after transplant. Analyses were conducted on all kidney transplant recipients (intention to treat) and on only those kidney transplant recipients who received at least 1 dose of nystatin (modified intention to treat). Additional data collected included the duration of nystatin and immunosuppression regimens. The Student t test and Fisher exact test were used to calculate P values for continuous and categorical data. RESULTS: A total of 84 kidney transplant recipients, 42 in each cohort, were included in the analysis. The groups did not differ significantly at baseline. Nystatin was administered for a mean of 29 days in the before group and 5.74 days in the after group. Overall, 3 kidney transplant recipients (4%), all from the after group, experienced an episode of thrush and no patients experienced Candida esophagitis. Two recipients who experienced thrush did not receive any nystatin. CONCLUSIONS: Limiting the administration of nystatin to the duration of admission after transplant may be sufficient for prophylaxis of fungal infections in kidney transplant recipients.