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Interpretation of kidney graft biopsies using the Banff classification is still heterogeneous. In this study, extreme gradient boosting classifiers learned from two large training datasets (n = 631 and 304 cases) where the "reference diagnoses" were not strictly defined following the Banff rules but from central reading by expert pathologists and further interpreted consensually by experienced transplant nephrologists, in light of the clinical context. In three external validation datasets (n = 3744, 589, and 360), the classifiers yielded a mean ROC curve AUC (95%CI) of: 0.97 (0.92-1.00), 0.97 (0.96-0.97), and 0.95 (0.93-0.97) for antibody-mediated rejection (ABMR); 0.94 (0.91-0.96), 0.94 (0.92-0.95), and 0.91 (0.88-0.95) for T cell-mediated rejection; >0.96 (0.90-1.00) with all three for interstitial fibrosis-tubular atrophy. We also developed a classifier to discriminate active and chronic active ABMR with 95% accuracy. In conclusion, we built highly sensitive and specific artificial intelligence classifiers able to interpret kidney graft scoring together with a few clinical data and automatically diagnose rejection, with excellent concordance with the Banff rules and reference diagnoses made by a group of experts. Some discrepancies may point toward possible improvements that could be made to the Banff classification., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Exposure to non-inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo-antigens. In adult mice, the production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross-decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD-L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord blood. The average percentage of NIMA-XD among total DCs was 2.6% for myeloid and 4.5% for Plasmacytoid DC. These cells showed higher PD-L1 expression than their non-XD counterparts (mDC: p = .0016; pDC: p = .024). We detected CD9 + EVs bearing NIMA and PD-L1 in cord blood. To determine if this immune regulatory mechanism persists beyond the pregnancy, we analyzed NIMA-expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft-infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD-L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Intragraft events thought to be relevant to the development of tolerance are here subjected to a comprehensive mechanistic study during long-term spontaneous tolerance that occurs in C57BL/6 mice that receive life sustaining DBA/2 kidneys. These allografts rapidly develop periarterial Treg-rich organized lymphoid structures (TOLS) that form in response to class II but not to class I MHC disparity and form independently of lymphotoxin α and lymphotoxin β receptor pathways. TOLS form in situ in the absence of lymph nodes, spleen, and thymus. Distinctive transcript patterns are maintained over time in TOLS including transcripts associated with Treg differentiation, T cell checkpoint signaling, and Th2 differentiation. Pathway transcripts related to inflammation are expressed in early stages of accepted grafts but diminish with time, while B cell transcripts increase. Intragraft transcript patterns at one week posttransplant distinguish those from kidneys destined to be rejected, that is, C57BL/6 allografts into DBA/2 recipients, from those that will be accepted. In contrast to inflammatory tertiary lymphoid organs (iTLOs) that form in response to chronic viral infection and transgenic Lta expression, TOLS lack high endothelial venules and germinal centers. TOLS represent a novel, pathogenetically important type of TLO that are in situ markers of regulatory tolerance., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination may fail to sufficiently protect transplant recipients against coronavirus disease 2019 (COVID-19). We retrospectively evaluated COVID-19 in kidney transplant recipients (n = 226) after BNT162b2 mRNA vaccine administration. The control group consisted of unvaccinated patients (n = 194) during the previous pandemic wave. We measured anti-spike protein immunoglobulin G (IgG) levels and cellular responses, using enzyme-linked immunosorbent spot assay, in a prospective cohort after vaccination (n = 31) and recovery from COVID-19 (n = 19). COVID-19 was diagnosed in 37 (16%) vaccinated and 43 (22%) unvaccinated patients. COVID-19 severity was similar in both groups, with patients exhibiting a comparable need for hospitalization (41% vs. 40%, p = 1.000) and mortality (14% vs. 9%, p = .726). Short posttransplant periods were associated with COVID-19 after vaccination (p < .001). Only 5 (16%) patients achieved positive SARS-CoV-2 IgG after vaccination, and 17 (89%, p < .001) recovered from COVID-19 (median IgG levels, 0.6 vs. 52.5 AU/ml, p < .001). A cellular response following vaccination was present in the majority (n = 22, 71%), with an increase in interleukin 2 secreting T cells (p < .001). Despite detectable T cell immunity after mRNA vaccination, kidney transplant recipients remained at a high risk of severe COVID-19. Humoral responses induced by vaccination were significantly lower than that after COVID-19., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Despite decennia of research and numerous successful interventions in the preclinical setting, renal ischemia reperfusion (IR) injury remains a major problem in clinical practice, pointing toward a translational gap. Recently, two clinical studies on renal IR injury (manifested either as acute kidney injury or as delayed graft function) identified metabolic derailment as a key driver of renal IR injury. It was reasoned that these unambiguous metabolic findings enable direct alignment of clinical with preclinical data, thereby providing the opportunity to elaborate potential translational hurdles between preclinical research and the clinical context. A systematic review of studies that reported metabolic data in the context of renal IR was performed according to the PRISMA guidelines. The search (December 2020) identified 35 heterogeneous preclinical studies. The applied methodologies were compared, and metabolic outcomes were semi-quantified and aligned with the clinical data. This review identifies profound methodological challenges, such as the definition of IR injury, the follow-up time, and sampling techniques, as well as shortcomings in the reported metabolic information. In light of these findings, recommendations are provided in order to improve the translatability of preclinical models of renal IR injury., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

The question of whether transplant clinicians should mandate COVID-19 vaccination as a condition of transplant candidacy is complex. A vaccine mandate may be defensible on the grounds that transplant clinicians are obligated to ensure transplantation is conducted safely, and in a manner that entails the best use of a scarce public good. However, mandate proponents will inexorably predicate their arguments on contingent clinical judgments that meliorate rather than resolve core value disagreements. Vaccine mandates are conceivably defensible on narrow grounds, but may prove to be purchased at the expense of an attenuation of shared decision-making, proffering claims of risk reduction from a vaccine mandate beyond what the current evidence base supports, and unintentionally exacerbating durable inequities in access to transplantation., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidney transplant candidates (KTCs) who are HLA highly sensitized (calculated panel-reactive alloantibodies >95%) have poor access to deceased kidney transplantation. In this single-center prospective study, 13 highly sensitized desensitization-naïve KTCs received IV tocilizumab (8 mg/kg) every 4 weeks. We evaluated tolerability as well as immune responses, that is, T cell, B cell, T follicular helper (Tfh) subsets, blood cytokines (IL-6, soluble IL-6 receptor-sIL-6R-, IL-21), blood chemokines (CXCL10, CXCL13), and anti-HLA alloantibodies. Tocilizumab treatment was well-tolerated except in one patient who presented spondylodiscitis, raising a note of caution. Regarding immune parameters, there were no significant changes of percentages of lymphocyte subsets, that is, CD3 + , CD3 + /CD4 + , CD3 + /CD8 + T cells, and NK cells. This was also the case for Tfh cell subsets, B cells, mature B cells, plasma cells, pre-germinal center (GC) B cells, and post-GC B cells, whereas we observed a significant increase in naïve B cells (p = .02) and a significant decrease in plasmablasts (p = .046) over the tocilizumab treatment course. CXCL10, CXCL13, IL-21, total IgG, IgA, and IgM levels did not significantly change during tocilizumab therapy; conversely, there was a significant increase in IL-6 levels (p = .03) and a huge increase in sIL-6R (p = .00004). There was a marginal effect on anti-HLA alloantibodies (class I and class II). To conclude in highly sensitized KTCs, tocilizumab as a monotherapy limited B cell maturation; however, it had almost no effect on anti-HLA alloantibodies., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Nondirected kidney donors can initiate living donor chains that end to patients on the waitlist. We compared 749 National Kidney Registry (NKR) waitlist chain end transplants to other transplants from the NKR and the Scientific Registry of Transplant Recipients between February 2008 and September 2020. Compared to other NKR recipients, chain end recipients were more often older (53 vs. 52 years), black (32% vs. 15%), publicly insured (71% vs. 46%), and spent longer on dialysis (3.0 vs. 1.0 years). Similar differences were noted between chain end recipients and non-NKR living donor recipients. Black patients received chain end kidneys at a rate approaching that of deceased donor kidneys (32% vs. 34%). Chain end donors were older (52 vs. 44 years) with slightly lower glomerular filtration rates (93 vs. 98 ml/min/1.73 m 2 ) than other NKR donors. Chain end recipients had elevated risk of graft failure and mortality compared to control living donor recipients (both p < .01) but lower graft failure (p = .03) and mortality (p < .001) compared to deceased donor recipients. Sharing nondirected donors among a multicenter network may improve the diversity of waitlist patients who benefit from living donation., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Primary infection and/or reactivation of cytomegalovirus (CMV) in kidney transplant recipients (KTR) favor rejection and mortality. T follicular helper cells (TFH) could contribute to protection against CMV. Circulatory TFH (cTFH) were studied pretransplant and early posttransplant in 90 CMV seropositive KTR not receiving antithymocyte globulin or antiviral prophylaxis, followed-up for 1 year. Patients who presented CMV infection had significantly lower cTFH and activated cTFH pretransplant and early posttransplant. Pretransplant activated cTFH were also lower within patients who developed CMV disease. Pre- and 14 days posttransplant activated cTFH were an independent protective factor for CMV infection (HR 0.41, p = .01; and 0.52, p = .02, respectively). KTR with low cTFH 7 days posttransplant (<11.9%) had lower CMV infection-free survival than patients with high cTFH (28.2% vs. 67.6%, p = .002). cTFH were associated with CMV-specific neutralizing antibodies (Nabs). In addition, IL-21 increased interferon-γ secretion by CMV-specific CD8 + T cells in healthy controls. Thus, we show an association between cTFH and lower incidence of CMV infection, probably through their cooperation in CMV-specific Nab production and IL-21-mediated enhancement of CD8 + T cell activity. Moreover, monitoring cTFH pre- and early posttransplant could improve CMV risk stratification and help select KTR catalogued at low/intermediate risk who could benefit from prophylaxis., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

COVID-19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID-19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS-CoV-2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID-19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS-CoV-2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS-CoV-2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow-up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID-19, the most common being acute rejection with arteritis., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Healthcare systems worldwide were challenged during the COVID-19 pandemic. In Mexico, the public hospitals that perform most transplants were adapted to provide care for COVID-19 patients. Using a nationwide database, we describe the first report of the impact of COVID-19 and related transplantation healthcare policies in a middle-income country by comparing statistics before and during the pandemic (pre-COVID: March 2019-February 2020 vs. COVID era: March 2020-February 2021) and by type of institution (public vs. private). The global reduction in transplantation was higher in public institutions compared with private institutions, 89% versus 62%, respectively, p < .001. When analyzing by organ, kidney transplantation decreased by 89% at public versus 57% at private, p < .001; cornea by 88% at public versus 64% at private, p < .001; liver by 88% at public versus 35% at private, p < .001; and heart by 88% in public versus 67% at private institutions, p = .4. The COVID-19 pandemic along with the implemented health policies were associated with a decrease in donations, waiting list additions, and a decrease in transplantation, particularly at public institutions, which care for the most vulnerable., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Normothermic regional perfusion (NRP) allows the in situ perfusion of organs with oxygenated blood in donation after the circulatory determination of death (DCDD). We aimed at evaluating the impact of NRP on the short-term outcomes of kidney transplants in controlled DCDD (cDCDD). This is a multicenter, nationwide, retrospective study comparing cDCDD kidneys obtained with NRP versus the standard rapid recovery (RR) technique. During 2012-2018, 2302 cDCDD adult kidney transplants were performed in Spain using NRP (n = 865) or RR (n = 1437). The study groups differed in donor and recipient age, warm, and cold ischemic time and use of ex situ machine perfusion. Transplants in the NRP group were more frequently performed in high-volume centers (≥90 transplants/year). Through matching by propensity score, two cohorts with a total of 770 patients were obtained. After the matching, no statistically significant differences were observed between the groups in terms of primary nonfunction (p = .261) and mortality at 1 year (p =  .111). However, the RR of kidneys was associated with a significantly increased odds of delayed graft function (OR 1.97 [95% CI 1.43-2.72]; p < .001) and 1-year graft loss (OR 1.77 [95% CI 1.01-3.17]; p = .034). In conclusion, compared with RR, NRP appears to improve the short-term outcomes of cDCDD kidney transplants., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Neutropenia is common after kidney transplant. There are few data on febrile neutropenia episodes (FNE) after kidney transplant. We studied FNE in a single-center retrospective cohort of 1682 kidney transplant recipients. Neutropenia (absolute neutrophil count [ANC] <1000) occurred in 32% and FNE in 3%. There were 56 FNE. Median time to FNE was 143 days, and median time from onset of neutropenia to onset of FNE was 5.5 days. The most common sources of infection were urine, blood, and lungs, and in 20% of FNE no source was identified. No infectious organism was identified in 46% of FNE, and opportunistic infections were uncommon. Patient survival was similar among those with and without FNE, but FNE was associated with increased death-censored graft failure (DCGF). Following FNE, acute rejection occurred in 31% and DCGF in 15%, often in the setting of persistent reduced immunosuppression. In conclusion, FNE are common after kidney transplant and are associated with inferior long-term outcomes., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidneys from donation after circulatory death (DCD) donors are utilized variably worldwide, in part due to high rates of delayed graft function (DGF) and putative associations with adverse longer-term outcomes. We aimed to determine whether the presence of DGF and its duration were associated with poor longer-term outcomes after kidney transplantation from DCD donors. Using the UK transplant registry, we identified 4714 kidney-only transplants from controlled DCD donors to adult recipients between 2006 and 2016; 2832 recipients (60·1%) had immediate graft function and 1882 (39·9%) had DGF. Of the 1847 recipients with DGF duration recorded, 926 (50·1%) had DGF < 7 days, 576 (31·2%) had DGF 7-14 days, and 345 (18·7%) had DGF >14 days. After risk adjustment, the presence of DGF was not associated with inferior long-term graft or patient survivals. However, DGF duration of >14 days was associated with an increased risk of death-censored graft failure (hazard ratio 1·7, p = ·001) and recipient death (hazard ratio 1·8, p < ·001) compared to grafts with immediate function. This study suggests that shorter periods of DGF have no adverse influence on graft or patient survival after DCD donor kidney transplantation and that DGF >14 days is a novel early biomarker for significantly worse longer-term outcomes., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

This was an economic analysis of a 12-month, parallel arm, randomized controlled trial in adult kidney recipients 6 to 36 months posttransplant (NCT03247322). All participants received usual posttransplant care, while the intervention arm received supplemental clinical pharmacist-led medication therapy monitoring and management, via a smartphone-enabled mHealth app, integrated with risk-based televisits. Hospitalization charges were captured from the study institution accounts payable and non-study institution hospitalization charges were estimated using multiple imputation. Multivariable modeling was used to assess the impact of the intervention on charges. The intervention significantly reduced rates of hospitalization (1.08 per patient-year in the control arm vs 0.65 per patient-year in the intervention arm, p = .007). The control arm had estimated hospitalization costs of $870,468 vs $390,489 in the intervention arm. Modeling demonstrated a 49% lower hospitalization charge risk in the intervention arm (RR 0.51, 95% CI 0.28-0.91; p = .022). From a payer or societal perspective, the net estimated cost savings, after accounting for intervention delivery costs, was $368,839, with a return on investment (ROI) of $4.30 for every $1 spent. These results demonstrate that a mHealth-enabled, pharmacist-led intervention significantly reduced hospitalization costs for payers over a 12-month period and has a positive ROI., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss, respectively, in kidney transplant recipients (KTRs). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-center, phase II, parallel-group, randomized, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTRs were recruited between September 2017 and June 2018, and randomized 1:1 to vitamin K (menadiol diphosphate 5 mg; n = 45) or placebo (n = 45) thrice weekly. Baseline demographics, clinical history, and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect -0.23 [95% CI -0.75 to 0.29] × 10 -3  mmHg -1 ; p = .377), vascular calcification (treatment effect -141 [95% CI - 320 to 38] units; p = .124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The description of protective humoral and T cell immune responses specific against SARS-CoV-2 has been reported among immunocompetent (IC) individuals developing COVID-19 infection. However, its characterization and determinants of poorer outcomes among the at-risk solid organ transplant (SOT) patient population have not been thoroughly investigated. Cytokine-producing T cell responses, such as IFN-γ, IL-2, IFN-γ/IL-2, IL-6, IL-21, and IL-5, against main immunogenic SARS-CoV-2 antigens and IgM/IgG serological immunity were tracked in SOT (n = 28) during acute infection and at two consecutive time points over the following 40 days of convalescence and were compared to matched IC (n = 16) patients admitted with similar moderate/severe COVID-19. We describe the development of a robust serological and functional T cell immune responses against SARS-CoV-2 among SOT patients, similar to IC patients during early convalescence. However, at the infection onset, SOT displayed lower IgG seroconversion rates (77% vs. 100%; p = .044), despite no differences on IgG titers, and a trend toward decreased SARS-CoV-2-reactive T cell frequencies, especially against the membrane protein (7 [0-34] vs. 113 [15-245], p = .011, 2 [0-9] vs. 45 [5-74], p = .009, and 0 [0-2] vs. 13 [1-24], p = .020, IFN-γ, IL-2, and IFN-γ/IL-2 spots, respectively). In summary, our data suggest that despite a certain initial delay, SOT population achieve comparable functional immune responses than the general population after moderate/severe COVID-19., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

According to preliminary data, seroconversion after mRNA SARS-CoV-2 vaccination might be unsatisfactory in Kidney Transplant Recipients (KTRs). However, it is unknown if seronegative patients develop at least a cellular response that could offer a certain grade of protection against SARS-CoV-2. To answer this question, we prospectively studied 148 recipients of either kidney (133) or kidney-pancreas (15) grafts with assessment of IgM/IgG spike (S) antibodies and ELISpot against the nucleocapside (N) and the S protein at baseline and 2 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. At baseline, 31 patients (20.9%) had either IgM/IgG or ELISpot positivity and were considered to be SARS-CoV-2-pre-immunized, while 117 (79.1%) patients had no signs of either cellular or humoral response and were considered SARS-CoV-2-naïve. After vaccination, naïve patients who developed either humoral or cellular response were finally 65.0%, of which 29.9% developed either IgG or IgM and 35.0% S-ELISpot positivity. Factors associated with vaccine unresponsiveness were diabetes and treatment with antithymocytes globulins during the last year. Side effects were consistent with that of the pivotal trial and no DSAs developed after vaccination. In conclusion, mRNA-1273 SARS-CoV-2 vaccine elicits either cellular or humoral response in almost two thirds of KTRs., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Interleukin-6 (IL-6) is a proinflammatory cytokine and key regulator of Treg: T effector cell (Teff) balance. We hypothesized that IL-6 blockade with tocilizumab, a monoclonal antibody to IL-6R, would increase Tregs, dampen Teff function, and control graft inflammation. We conducted a randomized controlled clinical trial (2014-2018) of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first year posttransplant. Subjects received tocilizumab (8 mg/kg IV every 4 weeks; 6 doses; n = 16) or no treatment (controls; n = 14) on top of usual maintenance immunosuppression. Kidney biopsies pre- and post-treatment were analyzed using Banff criteria. Blood was analyzed for serum cytokines, Treg frequencies, and T cell effector molecule expression (IFN-γ, IL-17, granzyme B) post-stimulation ex vivo. Tocilizumab-treated subjects were more likely to show improved Banff ti-score (62.5% vs. 21.4%, p = .03), increased Treg frequency (7.1% ± 5.55% vs. 3.6% ± 1.7%, p = .0168), and a blunted Teff cytokine response compared to controls. Changes in Banff i- and t-scores were not significantly different. The treatment was relatively well tolerated with no patient deaths or graft loss. Blockade of IL-6 is a novel and promising treatment option to regulate the T cell alloimmune response in kidney transplant recipients. NCT02108600., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The incidence of simultaneous heart-kidney transplant (SHK) has increased markedly in the last 15 years. There are no universally agreed upon indications for SHK vs. heart alone (HA) transplant, and center evaluation processes vary widely. We utilized Scientific Registry of Transplant Recipients data from 2003 to 2017 to quantify changes in the practice of SHK, examine the survival of SHK vs. HA, and identify patients with marginal benefit from SHK. We used Kaplan-Meier curves and Cox proportional hazards to assess differences in survival. The incidence of SHK increased more than fourfold between 2003 and 2017 from 1.6% to 6.6% of total hearts transplanted, while the proportion of dialysis-dependent patients undergoing SHK has remained constant. SHK was associated with increased survival in dialysis-dependent patients (Median Survival SHK: 12.6 vs. HA: 7.1 years p < .0001) but not with nondialysis-dependent patients (Median Survival SHK: 12.5 vs. HA 12.3, p = .24). The marginal effect of SHK in decreasing the hazard of death diminished with increasing eGFR. Delayed graft function occurred in 26% of SHK recipients. Posttransplant chronic dialysis was similar for both operations (6.4% of HA and 6.0% of SHK). Further study is needed to define patients who benefit from SHK., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Transplantation is the optimal treatment for most patients with end-stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to recondition marginal organs; however, mechanisms by which NMP might benefit organs are not well understood. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global kidney transcriptome. We found that cold storage led to a global reduction in gene expression, including inflammatory pathway genes and those required for energy generation processes, such as oxidative phosphorylation (OXPHOS). In contrast, during NMP, there was marked upregulation OXPHOS genes, but also of a number of immune and inflammatory pathway genes. Using biopsies from kidneys undergoing NMP that were subsequently transplanted, we found that higher inflammatory gene expression occurred in organs with prolonged delayed graft function (DGF). Therefore, we used a hemoadsorber (HA) to remove pro-inflammatory cytokines. This attenuated inflammatory gene expression increased OXPHOS pathway genes and had potentially clinically important effects in reducing the expression of a DGF-associated gene signature. Together, our data suggest that adsorption of pro-inflammatory mediators from the perfusate represents a potential intervention which may improve organ viability., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Lack of donors hinders living donor kidney transplantation (LDKT) for African Americans. We studied the effectiveness of a transplant social worker intervention (TALK SWI) alone or paired with living donor financial assistance to activate African Americans' potential living kidney donors. African Americans (N = 300) on the transplant waiting list were randomly assigned to usual care; TALK SWI; or TALK SWI plus Living Donor Financial Assistance. We quantified differences in live kidney donor activation (composite rate of live donor inquiries, completed new live donor evaluations, or live kidney donation) after 12 months. Participants' mean age was 52 years, 56% were male, and 43% had annual household income less than $40,000. Most previously pursued LDKT. Participants were highly satisfied with TALK social workers, but they rarely utilized Financial Assistance. After 12 months, few (n = 39, 13%) participants had a new donor activation event (35 [12%] new donor inquiries; 17 [6%] new donor evaluations; 4 [1%] LDKT). There were no group differences in donor activation events (subdistribution hazard ratio [95% CI]: 1.09 [0.51-2.30] for TALK SWI and 0.92 [0.42-2.02] for TALK SWI plus Financial Assistance compared to Usual Care, p = 91). Alternative interventions to increase LDKT for African Americans on the waiting list may be needed. Trial registration: ClinicalTrials.gov (NCT02369354)., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We describe a proteomics analysis to determine the molecular differences between normothermically perfused (normothermic machine perfusion, NMP) human kidneys with urine recirculation (URC) and urine replacement (UR). Proteins were extracted from 16 kidney biopsies with URC (n = 8 donors after brain death [DBD], n = 8 donors after circulatory death [DCD]) and three with UR (n = 2 DBD, n = 1 DCD), followed by quantitative analysis by mass spectrometry. Damage-associated molecular patterns (DAMPs) were decreased in kidney tissue after 6 hours NMP with URC, suggesting reduced inflammation. Vasoconstriction was also attenuated in kidneys with URC as angiotensinogen levels were reduced. Strikingly, kidneys became metabolically active during NMP, which could be enhanced and prolonged by URC. For instance, mitochondrial succinate dehydrogenase enzyme levels as well as carbonic anhydrase were enhanced with URC, contributing to pH stabilization. Levels of cytosolic and the mitochondrial phosphoenolpyruvate carboxykinase were elevated after 24 hours of NMP, more prevalent in DCD than DBD tissue. Key enzymes involved in glucose metabolism were also increased after 12 and 24 hours of NMP with URC, including mitochondrial malate dehydrogenase and glutamic-oxaloacetic transaminase, predominantly in DCD tissue. We conclude that NMP with URC permits prolonged preservation and revitalizes metabolism to possibly better cope with ischemia reperfusion injury in discarded kidneys., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Graft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age of 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous 5-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in five of seven children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune postviral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pretransplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of postviral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We previously characterized the molecular changes in acute kidney injury (AKI) and chronic kidney disease (CKD) in kidney transplant biopsies, but parenchymal changes selective for specific types of injury could be missed by such analyses. The present study searched for injury changes beyond AKI and CKD related to specific scenarios, including correlations with donor age. We defined injury using previously defined gene sets and classifiers and used principal component analysis to discover new injury dimensions. As expected, Dimension 1 distinguished normal vs. injury, and Dimension 2 separated early AKI from late CKD, correlating with time posttransplant. However, Dimension 3 was novel, distinguishing a set of genes related to epithelial polarity (e.g., PARD3) that were increased in early AKI and decreased in T cell-mediated rejection (TCMR) but not in antibody-mediated rejection. Dimension 3 was increased in kidneys from older donors and was particularly important in survival of early kidneys. Thus high Dimension 3 scores emerge as a previously unknown element in the kidney response-to-injury that affects epithelial polarity genes and is increased in AKI but depressed in TCMR, indicating that in addition to general injury elements, certain injury elements are selective for specific pathologic mechanisms. (ClinicalTrials.gov NCT01299168)., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsies is part of the diagnostic criteria for chronic active TCMR (CA TCMR -- i-IFTA ≥ 2, ti ≥ 2, t ≥ 2). We evaluated i-IFTA and CA TCMR in the DeKAF indication biopsy cohorts: prospective (n = 585, mean time to biopsy = 1.7 years); cross-sectional (n = 458, mean time to biopsy = 7.8 years). Grouped by i-IFTA scores, the 3-year postbiopsy DC-GS is similar across cohorts. Although a previous acute rejection episode (AR) was more common in those with i-IFTA on biopsy, the majority of those with i-IFTA had not had previous AR. There was no association between type of previous AR (AMR, TCMR) and presence of i-IFTA. In both cohorts, i-IFTA was associated with markers of both cellular (increased Banff i, t, ti) and humoral (increased g, ptc, C4d, DSA) activity. Biopsies with i-IFTA = 1 and i-IFTA ≥ 2 with concurrent t ≥ 2 and ti ≥ 2 had similar DC-GS. These results suggest that (a) i-IFTA≥1 should be considered a threshold for diagnoses incorporating i-IFTA, ti, and t; (b) given that i-IFTA ≥ 2,t ≥ 2, ti ≥ 2 can occur in the absence of preceding TCMR and that the component histologic scores (i-IFTA,t,ti) each indicate an acute change (albeit i-IFTA on the nonspecific background of IFTA), the diagnostic category "CA TCMR" should be reconsidered., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Following solid organ transplantation, a substantial proportion of chronic allograft loss is attributed to the formation of donor-specific antibodies (DSAs) and antibody-mediated rejection (AbMR). The frequency and phenotype of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells is altered in the setting of kidney transplantation, particularly in patients who develop AbMR. However, the roles of Tfh and Tfr cells in AbMR after solid organ transplantation is unclear. We developed mouse models to inducibly and potently perturb Tfh and Tfr cells to assess the roles of these cells in the development of DSA and AbMR. We found that Tfh cells are required for both de novo DSA responses as well as augmentation of DSA following presensitization. Using orthotopic allogeneic kidney transplantation models, we found that deletion of Tfh cells at the time of transplantation resulted in less severe transplant rejection. Furthermore, using inducible Tfr cell deletion strategies we found that Tfr cells inhibit de novo DSA formation but only have a minor role in controlling kidney transplant rejection. These studies demonstrate that Tfh cells promote, whereas Tfr cells inhibit, DSA to control rejection after kidney transplantation. Therefore, targeting these cells represent a new therapeutic strategy to prevent and treat AbMR., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidney transplant recipients administered belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept-based maintenance regimens. Steroid-sparing, belatacept-based immunosuppression (following T cell-depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept-based regimen for minimizing early cellular AR occurrence., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Reduced renal function is associated with cardiovascular disease (CVD); however, how living donor nephrectomy affects the risk of CVD remains controversial. We conducted a nationwide cohort study including living kidney donors in Denmark from 1996 to 2018 to assess the risk of hypertension, atrial fibrillation/flutter (AF), major adverse cardiovascular events (MACE; composite of myocardial infarction, ischemic stroke, and death) and death after living kidney donation. As comparisons we identified: a cohort of healthy individuals from the general population and an external blood donor cohort. We followed kidney donors (1,103 when compared with the general population cohort; 1,007 when compared with blood donors) for a median of 8 years. Kidney donors had an increased risk of initiating treatment for hypertension when compared with blood donors (standardized incidence ratio [SIR], 1.40; 95% confidence interval [CI], 1.17-1.66) but they did not have increased risk of MACE neither when compared with the general population cohort (hazard ratio, 0.68; 95% CI, 0.52-0.89) nor with blood donors (SIR, 1.17; 95% CI, 0.88-1.55). Neither did they have increased risks of AF and death. Thus, living kidney donation may be associated with increased risk of hypertension; however, we did not identify increased risks of CVD or death., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = 0.77 1.40 2.56 ,P = .3) and moderately (wIRR = 0.88 1.35 2.06 ,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = 1.33 2.22 3.72 ,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = 2.62 3.57 4.88 , P < .001) and death-censored graft loss (wHR = 1.15 4.01 13.95 ,P = .03). Post-KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We studied the relative association of clinical, histologic, and molecular variables with risk of kidney transplant failure after an indication biopsy, both in all kidneys and in kidneys with pure antibody-mediated rejection (ABMR). From a prospective study of 1679 biopsies with histologic and molecular testing, we selected one random biopsy per patient (N = 1120), including 321 with pure molecular ABMR. Diagnoses were associated with actuarial survival differences but not good predictions. Therefore we concentrated on clinical (estimated GFR [eGFR], proteinuria, time posttransplant, donor-specific antibody [DSA]) and molecular and histologic features reflecting injury (acute kidney injury [AKI] and atrophy-fibrosis [chronic kidney disease (CKD)] and rejection. For all biopsies, univariate analysis found that failure was strongly associated with low eGFR, AKI, CKD, and glomerular deterioration, but not with rejection activity. In molecular ABMR, the findings were similar: Molecular and histologic activity and DSA were not important compared with injury. Survival in DSA-negative and DSA-positive molecular ABMR was similar. Multivariate survival analysis confirmed the dominance of molecular AKI, CKD, and eGFR. Thus, at indication biopsy, the dominant predictors of failure, both in all kidneys and in ABMR, were related to molecular AKI and CKD and to eGFR, not rejection activity, presumably because rejection confers risk via injury., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Patients with obesity have limited access to kidney transplantation, mainly due to an increased incidence of surgical complications, which could be reduced with selective use of robotic-assisted surgery. This prospective randomized controlled trial compares the safety and efficacy of combining robotic sleeve gastrectomy and robotic-assisted kidney transplant to robotic kidney transplant alone in candidates with class II or III obesity. Twenty candidates were recruited, 11 were randomized to the robotic sleeve gastrectomy and robotic-assisted kidney transplant group and 9 to the robotic kidney transplant group. At 12-month follow-up, change in body mass index was -8.76 ± 1.82 in the robotic sleeve gastrectomy and robotic-assisted kidney transplant group compared to 1.70 ± 2.30 in the robotic kidney transplant group (P = .0041). Estimated glomerular filtration rate, serum creatinine, readmission rates, and graft failure rates up to 12 months were not different between the two groups. Length of surgery was longer in the robotic sleeve gastrectomy and robotic-assisted kidney transplant group (405 minutes vs. 269 minutes, p = .00304) without increase in estimated blood loss (120 ml vs. 117 ml, p = .908) or incidence of surgical complications. Combined robotic-assisted kidney transplant and sleeve gastrectomy is safe and effective compared to robotic-assisted kidney transplant alone., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Patients with autosomal dominant polycystic disease (ADPKD) may require bilateral nephrectomy (BN) in addition to kidney transplantation (KT) for symptom control. This study aims to compare simultaneous BNKT to contemporaneous controls by reviewing our cohort of ADPKD patients who underwent KT from a living donor from January 2014 to October 2019. Symptomatic patients who underwent laparoscopic BNKT were compared to KT alone. Clinical differences related to undertaking bilateral nephrectomies showed increased total kidney volumes (P < .001). We assessed operative parameters, complications, and clinical outcomes. The complications were classified according to the Clavien-Dindo system. In 148 transplant recipients, 51 underwent BNKT, and 97 KT alone. There was no difference in baseline demographics. BNKT recipients had longer cold ischemia time, required more ICU care, increased blood transfusions and longer hospital stays. The kidney function was similar in the first year in both groups, with no difference in delayed graft function, readmissions or severe grade III and IV complications within 3 months after surgery. Laparoscopic BNKT is safe and feasible at the time of living donor KT. Although higher acuity care is needed with a longer initial hospital stay, there are comparable posttransplant patient and allograft outcomes., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Small reductions in calculated panel-reactive antibody (cPRA) are associated with increased kidney transplantation in 100% cPRA patients. However, the high level of antibody in these patients is such that desensitization may reduce antibody but not cPRA, thus the cPRA change on undiluted serum with desensitization is an insensitive measure of effectiveness. We evaluated cPRA reduction, calculated per antibody titer, as a desensitization trial endpoint. To accomplish this, two serum samples from 20 kidney transplant candidates with cPRA ≥99.9% (100%) were obtained and serially diluted in triplicate to determine the titer of individual human leukocyte antigen (HLA) antibody specificities. CPRA was computed per dilution to identify the titer at which cPRA drops below 98%. Inter- and intra-assay variability and changes overtime were determined. The dilution needed to reach a cPRA <98% was within 1 titer for replicates from the same sample, with 90% (36/40) concordance. This indicates that only changes >2 titers can be deemed clinically meaningful. The median (IQR) titer difference was 0 (0-1) from baseline to follow-up within 12 months. The cPRA per titer also risk-stratified candidates for trial inclusion. In conclusion, determining the cPRA per titer is a reliable approach to simplify complex antibody data and an ideal endpoint for desensitization trials., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3-73.1) in three French transplant centers. After a median follow-up of 13 days (7-30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2-14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidney transplantation prior to dialysis, known as "preemptive transplant," enables patients to live longer and avoid the substantial quality of life burdens due to chronic dialysis. Deceased donor kidneys are a public resource that ought to provide health benefits equitably. Unfortunately, White, better educated, and privately insured patients enjoy disproportionate access to preemptive transplantation using deceased donor kidneys. This problem has persisted for decades and is exacerbated by the first-come, first-served approach to kidney allocation for predialysis patients. In this Personal Viewpoint, we describe the diverse barriers to preemptive waitlisting and kidney transplant. The analysis focuses on healthcare system features that particularly disadvantage Black patients, such as the waitlisting eligibility criterion of a single glomerular filtration rate or creatinine clearance ≤20 ml/min, and neglect of wide variation in the rate of progression to end-stage kidney disease (ESKD) in allocating preemptive transplants. We propose initiatives to improve equity including: (1) standardization of waitlisting eligibility criteria related to kidney function; (2) aggressive education for clinicians about early transplant referral; (3) innovations in electronic medical record capabilities; and (4) rapid status 7 listing by centers. If those initiatives fail, the transplant field should consider eliminating preemptive waitlisting and transplantation with deceased donor kidneys., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)