Dual-Organ Transplantation: Indications, Evaluation, and Outcomes for Heart-Kidney and Heart-Liver Transplantation: A Scientific Statement From the American Heart Association.

Although heart transplantation is the preferred therapy for appropriate patients with advanced heart failure, the presence of concomitant renal or hepatic dysfunction can pose a barrier to isolated heart transplantation. Because donor organ supply limits the availability of organ transplantation, appropriate allocation of this scarce resource is essential; thus, clear guidance for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation is urgently required. The purposes of this scientific statement are (1) to describe the impact of pretransplantation renal and hepatic dysfunction on posttransplantation outcomes; (2) to discuss the assessment of pretransplantation renal and hepatic dysfunction; (3) to provide an approach to patient selection for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation and posttransplantation management; and (4) to explore the ethics of multiorgan transplantation.

Cytomegalovirus Treatment in Solid Organ Transplantation: An Update on Current Approaches.

OBJECTIVE: The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. DATA SOURCES: A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation. STUDY SELECTION AND DATA EXTRACTION: Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded. DATA SYNTHESIS: After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV. CONCLUSIONS: Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration.

A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation.

BACKGROUND: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial.

BACKGROUND: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes. METHODS: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR. RESULTS: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06). CONCLUSIONS: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077).

Spatiotemporal profile of atrophy in the first year following moderate-severe traumatic brain injury.

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate-severe TBI who had primarily high-velocity and high-impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post-injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post-injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post-injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post-injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study.

Consensus Definitions of BK Polyomavirus Nephropathy in Renal Transplant Recipients for Clinical Trials.

BACKGROUND: BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients. RESULTS AND DISCUSSION: Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective. METHODS: To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives. CONCLUSIONS: These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients.

Critically important outcomes for infection in trials in kidney transplantation: An international survey of patients, caregivers, and health professionals.

BACKGROUND: Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. METHODS: In an international online survey, participants rated the absolute importance of 16 infections and eight severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. RESULTS: 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, eight who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5, respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1), and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top three most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top three severity dimensions. Relative importance (best-worst) scores were consistent. CONCLUSIONS: Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections, and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes.

Donor Derived Cell Free DNA in Kidney Transplantation: The Circa 2020-2021 Update.

The routine surveillance of kidney transplant allografts has relied on imperfect non-invasive biomarkers such as creatinine and urinary indices, while the gold standard allograft biopsy is associated with risk of bleeding, organ injury and sampling errors. Donor derived cell free DNA (dd-cfDNA) is being employed as a biomarker that addresses limitations of these surveillance methods, albeit has inherent drawbacks. This review provides an update on the enhanced understanding of dd-cfDNA and its expanded use beyond the conventional indication of detecting allograft rejection.

Morphometrical Brain Markers of Sex Difference.

Many major neuropsychiatric pathologies, some of which appear in adolescence, show differentiated prevalence, onset, and symptomatology across the biological sexes. Therefore, mapping differences in brain structure between males and females during this critical developmental period may provide information about the neural mechanisms underlying the dimorphism of these pathologies. Utilizing a large dataset collected through the Adolescent Brain Cognitive Development study, we investigated the differences of adolescent (9-10 years old) male and female brains (n = 8325) by using a linear Support-Vector Machine Classifier to predict sex based on morphometry and image intensity values of structural brain imaging data. The classifier correctly classified the sex of 86% individuals with the insula, the precentral and postcentral gyri, and the pericallosal sulcus as the most discernable features. These results demonstrate the existence of complex, yet robustly measurable morphometrical brain markers of sex difference.

Securing the future of kidney transplantation by addressing the challenges of transplant nephrology.

Kidney transplant is a life-changing procedure, and transplant nephrologists, as part of a larger transplant team, play an important role in the field by managing the complex medical needs of transplant patients. The subspecialty of transplant nephrology, however, faces structural challenges related to its workforce, reporting structures, compensation, research and innovation, and health care information technology. The position of transplant nephrology at the academic and operational intersection of medicine and surgery may limit its access to critical resources, hinder academic promotion, and contribute to physician burnout. The authors provide an overview of the subspecialty transplant nephrology and propose solutions. Collaborative efforts that fortify the subspecialty of transplant nephrology will ultimately improve the lives of patients suffering from kidney disease.

Long-term kidney transplant graft survival-Making progress when most needed.

Current short-term kidney post-transplant survival rates are excellent, but longer-term outcomes have historically been unchanged. This study used data from the national Scientific Registry of Transplant Recipients (SRTR) and evaluated 1-year and 5-year graft survival and half-lives for kidney transplant recipients in the US. All adult (≥18 years) solitary kidney transplants (n = 331,216) from 1995 to 2017 were included in the analysis. Mean age was 49.4 years (SD +/-13.7), 60% male, and 25% Black. The overall (deceased and living donor) adjusted hazard of graft failure steadily decreased from 0.89 (95%CI: 0.88, 0.91) in era 2000-2004 to 0.46 (95%CI: 0.45, 0.47) for era 2014-2017 (1995-1999 as reference). Improvements in adjusted hazards of graft failure were more favorable for Blacks, diabetics and older recipients. Median survival for deceased donor transplants increased from 8.2 years in era 1995-1999 to an estimated 11.7 years in the most recent era. Living kidney donor transplant median survival increased from 12.1 years in 1995-1999 to an estimated 19.2 years for transplants in 2014-2017. In conclusion, these data show continuous improvement in long-term outcomes with more notable improvement among higher-risk subgroups, suggesting a narrowing in the gap for those disadvantaged after transplantation.

Inpatient COVID-19 outcomes in solid organ transplant recipients compared to non-solid organ transplant patients: A retrospective cohort.

Immunosuppression and comorbidities might place solid organ transplant (SOT) recipients at higher risk from COVID-19, as suggested by recent case series. We compared 45 SOT vs. 2427 non-SOT patients who were admitted with COVID-19 to our health-care system (March 1, 2020 - August 21, 2020), evaluating hospital length-of-stay and inpatient mortality using competing-risks regression. We compared trajectories of WHO COVID-19 severity scale using mixed-effects ordinal logistic regression, adjusting for severity score at admission. SOT and non-SOT patients had comparable age, sex, and race, but SOT recipients were more likely to have diabetes (60% vs. 34%, p < .001), hypertension (69% vs. 44%, p = .001), HIV (7% vs. 1.4%, p = .024), and peripheral vascular disorders (19% vs. 8%, p = .018). There were no statistically significant differences between SOT and non-SOT in maximum illness severity score (p = .13), length-of-stay (sHR: 0.9 1.11.4 , p = .5), or mortality (sHR: 0.1 0.41.6 , p = .19), although the severity score on admission was slightly lower for SOT (median [IQR] 3 [3, 4]) than for non-SOT (median [IQR] 4 [3-4]) (p = .042) Despite a higher risk profile, SOT recipients had a faster decline in disease severity over time (OR = 0.76 0.810.86 , p < .001) compared with non-SOT patients. These findings have implications for transplant decision-making during the COVID-19 pandemic, and insights about the impact of SARS-CoV-2 on immunosuppressed patients.

Association between dd-cfDNA levels, de novo donor specific antibodies, and eGFR decline: An analysis of the DART cohort.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is a marker of allograft injury in transplant recipients; however, the relationship between dd-cfDNA and other clinical parameters associated with adverse allograft outcomes is not well-characterized. METHODS: We performed a retrospective analysis of kidney transplant recipients from the DART cohort (ClinicalTrials.gov Identifier: NCT02424227) to evaluate the associations between eGFR decline, de novo donor-specific antibodies (dnDSA), and dd-cfDNA. RESULTS: Both elevated dd-cfDNA (≥1%) and dd-cfDNA variability (≥.34%) in the first post-transplant year were associated with decline in eGFR ≥25% in the second year (21.4% vs. 4.1%, P = .005; 25% vs. 3.6%, P = .002, respectively). Compared to samples from DSA negative patients, samples from patients with concurrent de novo HLA DSAs had higher dd-cfDNA levels (P < .0001). DISCUSSION: Abnormalities in dd-cfDNA levels are associated with clinical parameters commonly used as surrogate endpoints for adverse allograft outcomes, raising the possibility that molecular injury as characterized by dd-cfDNA could help identify patients at risk of these outcomes.

Cognitive impairment burden in older and younger adults across the kidney transplant care continuum.

BACKGROUND: Younger kidney transplant (KT) candidates and recipients may have cognitive impairment due to chronic diseases and reliance on dialysis. METHODS: To quantify cognitive impairment burden by age across the KT care continuum, we leveraged a two-center cohort study of 3854 KT candidates at evaluation, 1114 recipients at admission, and 405 recipients at 1-year post-KT with measured global cognitive performance (3MS) or executive function (Trail Making Test). We also estimated burden of severe cognitive impairment that affects functional dependence (activities of daily living [ADL] < 6 or instrumental activities of daily living [IADL] < 8). RESULTS: Among KT candidates, global cognitive impairment (18-34 years: 11.1%; 35-49 years: 14.0%; 50-64 years: 19.5%; ≥65 years: 22.0%) and severe cognitive impairment burden (18-34 years: 1.1%; 35-49 years: 3.0%; 50-64 years: 6.2%; ≥65 years: 7.7%) increased linearly with age. Among KT recipients at admission, global cognitive impairment (18-34 years: 9.1%; 35-49 years: 6.1%; 50-64 years: 9.3%; ≥65 years: 15.7%) and severe cognitive impairment burden (18-34 years: 1.4%; 35-49 years: 1.4%; 50-64 years: 2.2%; ≥65 years: 4.6%) was lower. Despite lowest burden of cognitive impairment among KT recipients at 1-year post-KT across all ages (18-34 years: 1.7%; 35-49 years: 3.4%; 50-64 years: 4.3%; ≥65 years: 6.5%), many still exhibited severe cognitive impairment (18-34 years: .0%; 35-49 years: 1.9%; 50-64 years: 2.4%; ≥65 years: 3.5%). CONCLUSION: Findings were consistent for executive function impairment. While cognitive impairment increases with age, younger KT candidates have a high burden comparable to community-dwelling older adults, with some potentially suffering from severe forms. Transplant centers should consider routinely screening patients during clinical care encounters regardless of age.

Long-term kidney function and survival in recipients of allografts from living kidney donors with hypertension: a national cohort study.

Allografts from living kidney donors with hypertension may carry subclinical kidney disease from the donor to the recipient and, thus, lead to adverse recipient outcomes. We examined eGFR trajectories and all-cause allograft failure in recipients from donors with versus without hypertension, using mixed-linear and Cox regression models stratified by donor age. We studied a US cohort from 1/1/2005 to 6/30/2017; 49 990 recipients of allografts from younger (<50 years old) donors including 597 with donor hypertension and 21 130 recipients of allografts from older (≥50 years old) donors including 1441 with donor hypertension. Donor hypertension was defined as documented predonation use of antihypertensive therapy. Among recipients from younger donors with versus without hypertension, the annual eGFR decline was -1.03 versus -0.53 ml/min/m2 (P = 0.002); 13-year allograft survival was 49.7% vs. 59.0% (adjusted allograft failure hazard ratio [aHR] 1.23; 95% CI 1.05-1.43; P = 0.009). Among recipients from older donors with versus without hypertension, the annual eGFR decline was -0.67 versus -0.66 ml/min/m2 (P = 0.9); 13-year allograft survival was 48.6% versus 52.6% (aHR 1.05; 95% CI 0.94-1.17; P = 0.4). In secondary analyses, our inferences remained similar for risk of death-censored allograft failure and mortality. Hypertension in younger, but not older, living kidney donors is associated with worse recipient outcomes.

Contemporary incidence and risk factors of post transplant Erythrocytosis in deceased donor kidney transplantation.

BACKGROUND: Post-Transplant erythrocytosis (PTE) has not been studied in large recent cohorts. In this study, we evaluated the incidence, risk factors, and outcome of PTE with current transplant practices using the present World Health Organization criteria to define erythrocytosis. We also tested the hypothesis that the risk of PTE is greater with higher-quality kidneys. METHODS: We utilized the Deceased Donor Study which is an ongoing, multicenter, observational study of deceased donors and their kidney recipients that were transplanted between 2010 and 2013 across 13 centers. Eryrthocytosis is defined by hemoglobin> 16.5 g/dL in men and> 16 g/dL in women. Kidney quality is measured by Kidney Donor Profile Index (KDPI). RESULTS: Of the 1123 recipients qualified to be in this study, PTE was observed at a median of 18 months in 75 (6.6%) recipients. Compared to recipients without PTE, those with PTE were younger [mean 48±11 vs 54±13 years, p < 0.001], more likely to have polycystic kidney disease [17% vs 6%, p < 0.001], have received kidneys from younger donors [36 ±13 vs 41±15 years], and be on RAAS inhibitors [35% vs 22%, p < 0.001]. Recipients with PTE were less likely to have received kidneys from donors with hypertension [16% vs 32%, p = 0.004], diabetes [1% vs 11%, p = 0.008], and cerebrovascular event (24% vs 36%, p = 0.036). Higher KDPI was associated with decreased PTE risk [HR 0.98 (95% CI: 0.97-0.99)]. Over 60 months of follow-up, only 17 (36%) recipients had sustained PTE. There was no association between PTE and graft failure or mortality, CONCLUSIONS: The incidence of PTE was low in our study and PTE resolved in majority of patients. Lower KDPI increases risk of PTE. The underutilization of RAAS inhibitors in PTE patients raises the possibility of under-recognition of this phenomenon and should be explored in future studies.

Early Steroid Withdrawal in Deceased-Donor Kidney Transplant Recipients with Delayed Graft Function.

BACKGROUND: Early steroid withdrawal (ESW) is associated with acceptable outcomes in kidney transplant (KT) recipients. Recipients with delayed graft function (DGF), however, often have a suboptimal allograft milieu, which may alter the risk/benefit equation for ESW. This may contribute to varying practices across transplant centers. METHODS: Using the Scientific Registry of Transplant Recipients, we studied 110,019 adult deceased-donor KT recipients between 2005 and 2017. We characterized the association of DGF with the use of ESW versus continued steroid maintenance across KT centers, and quantified the association of ESW with acute rejection, graft failure, and mortality using multivariable logistic and Cox regression with DGF-ESW interaction terms. RESULTS: Overall 29.2% of KT recipients underwent ESW. Recipients with DGF had lower odds of ESW (aOR=0.600.670.75). The strength of this association varied across 261 KT centers, with center-specific aOR of <0.5 at 31 (11.9%) and >1.0 at 22 (8.4%) centers. ESW was associated with benefits and harms among recipients with immediate graft function (IGF), but only with harms among recipients with DGF. ESW was associated with increased acute rejection (aOR=1.091.161.23), slightly increased graft failure (aHR=1.011.061.12), but decreased mortality (aHR=0.860.890.93) among recipients with IGF. Among recipients with DGF, ESW was associated with a similar increase in rejection (aOR=1.12; 95% CI, 1.02 to 1.23), a more pronounced increase in graft failure (aHR=1.16; 95% CI, 1.08 to 1.26), and no improvement in mortality (aHR=1.00; 95% CI, 0.94 to 1.07). DGF-ESW interaction was statistically significant for graft failure (P=0.04) and mortality (P=0.003), but not for rejection (P=0.6). CONCLUSIONS: KT centers in the United States use ESW inconsistently in recipients with DGF. Our findings suggest ESW may lead to worse KT outcomes in recipients with DGF.

Donor-Derived Cell-Free DNA in Kidney Transplantation: Origins, Present and a Look to the Future.

Since its first detection in 1948, donor-derived cell-free DNA (dd-cfDNA) has been employed for a myriad of indications in various medical specialties. It has had a far-reaching impact in solid organ transplantation, with the most widespread utilization in kidney transplantation for the surveillance and detection of allograft rejection. The purpose of this review is to track the arc of this revolutionary test-from origins to current use-along with examining challenges and future prospects though the lens of transplant nephrology.

Kidney retransplantation after anti-programmed cell death-1 (PD-1)-related allograft rejection.

In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete antitumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living-unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of antitumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple antitumor and anti-allograft immunity.

Identifying scenarios of benefit or harm from kidney transplantation during the COVID-19 pandemic: A stochastic simulation and machine learning study.

Clinical decision-making in kidney transplant (KT) during the coronavirus disease 2019 (COVID-19) pandemic is understandably a conundrum: both candidates and recipients may face increased acquisition risks and case fatality rates (CFRs). Given our poor understanding of these risks, many centers have paused or reduced KT activity, yet data to inform such decisions are lacking. To quantify the benefit/harm of KT in this context, we conducted a simulation study of immediate-KT vs delay-until-after-pandemic for different patient phenotypes under a variety of potential COVID-19 scenarios. A calculator was implemented (http://www.transplantmodels.com/covid_sim), and machine learning approaches were used to evaluate the important aspects of our modeling. Characteristics of the pandemic (acquisition risk, CFR) and length of delay (length of pandemic, waitlist priority when modeling deceased donor KT) had greatest influence on benefit/harm. In most scenarios of COVID-19 dynamics and patient characteristics, immediate KT provided survival benefit; KT only began showing evidence of harm in scenarios where CFRs were substantially higher for KT recipients (eg, ≥50% fatality) than for waitlist registrants. Our simulations suggest that KT could be beneficial in many centers if local resources allow, and our calculator can help identify patients who would benefit most. Furthermore, as the pandemic evolves, our calculator can update these predictions.