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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

International audience; Background and objectives The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day. Design, setting, participants, & measurements We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon ( ante meridiem [ am ] clamping group; 65%) or clamped between noon and midnight ( post meridiem [ pm ] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%). Results Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P =0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P =0.37). No significant association of declamping time with delayed graft function or graft survival was observed. Conclusions Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes.

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., The authors perform a proteomics analysis to identify molecular differences between normothermically machine perfused and discarded human kidneys with urine recirculation and urine replacement using lactated Ringers.

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., Kirk et al. discuss available data on alternative de novo belatacept‐based immunosuppression regimens in place of the approved belatacept regimen to reduce acute rejection rates in kidney transplant recipients.

International audience; 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.

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, Among living donor kidney transplant recipients, infections are most common in patients who receive high‐intensity desensitization, and patients with more than 4 infections in the first year posttransplant are at increased risk of adverse outcomes.

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.

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., This meta‐analysis defines a noninferiority margin to use in the design of a phase II/III delayed calcineurin inhibitor substitution trial in kidney transplantation.

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P, Alloimmune risk categorization using HLA‐DR/DQ molecular mismatch risk correlates with the severity, frequency, and persistence of T cell–mediated rejection and with graft survival, independent of de novo DSA.

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.

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.

International audience; There are no studies which have compared the risk of severe Covid-19 and related mortality between transplant recipients and non-transplant patients. We enrolled two groups of patients hospitalized for Covid-19, i.e., kidney transplant recipients from the French Registry of Solid Organ Transplant (n=306) and a single-center cohort of non-transplant 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 non-transplant 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 non-transplant patients; however, 30-day Covid-19-related mortality was significantly higher in KTR (17.9% versus 11.4%, respectively, p=0.038). 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. Kidney transplant recipients had a higher Covid-19-related mortality compared to non-transplant hospitalized patients.

Funder: NIHR Cambridge Biomedical research Centre, 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.

Immunosuppressed organ‐transplanted patients are considered at risk for severe forms of COVID‐19. Moreover, exaggerated innate and adaptive immune responses might be involved in severe progression of the disease. However, no data on the immune response to SARS‐CoV‐2 in transplanted patients are currently available. Here, we report the first assessment of antibody and T cell responses to SARS‐CoV‐2 in 11 kidney‐transplanted patients recovered from RT‐PCR–confirmed (n = 5) or initially suspected (n = 6) COVID‐19. After reduction of immunosuppressive therapy, RT‐PCR–confirmed COVID‐19 transplant patients were able to mount vigorous antiviral T cell and antibody responses, as efficiently as two nontherapeutically immunosuppressed COVID‐19 patients on hemodialysis. By contrast, six RT‐PCR–negative patients displayed no antibody response. Among them, three showed very low numbers of SARS‐CoV‐2–reactive T cells, whereas no T cell response was detected in the other three, potentially ruling out COVID‐19 diagnosis. Low levels of T cell reactivity to SARS‐CoV‐2 were also detected in seronegative healthy controls without known exposure to the virus. These results suggest that during COVID‐19, monitoring both T cell and serological immunity might be helpful for the differential diagnosis of COVID‐19 but are also needed to evaluate a potential role of antiviral T cells in the development of severe forms of the disease.

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 1996-2018 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.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)‐DR/DQ molecular mismatch to predict de novo donor‐specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA‐DR and ‐DQ eplet mismatches were determined between 444 donor‐recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low‐ (N = 119), intermediate‐ (N = 153), and high‐ (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA‐DR and HLA‐DQ eplet mismatches, respectively. Compared to low‐risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01‐118.09, p = .009) and high‐risk (HR 23.81, 95% CI 3.17‐178.66, p = 0.002) categories. Intermediate‐ and high‐risk patients with a mean tacrolimus 8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05‐5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management., DR/DQ molecular mismatch predicts the development of de novo donor‐specific antibodies after kidney transplantation, with a graded increase in risk for intermediate and high molecular mismatch patients that is modulated by differences in tacrolimus exposure. Jackson and Pinelli's editorial is on page 9.

Results of the study by Grupper et al (1) should not be surprising, since, as mentioned by the authors, most previous vaccines immunogenicity studies showed less response in transplant recipients (references 25 to 29 in that publication.) Cellular immune response to the COVID-19 vaccine may be more important that the humoral immune response as recently described in a preprint publication by Chen et al (2). Cellular immune response to the COVID-19 vaccine was not assessed in the study by Grupper et al.

International audience; Antibody‐mediated rejection (AMR) that resists to standard of care (SOC) therapy remains a major challenge after kidney transplantation and leads to graft failure in a majority of cases. The use of anti‐IL6 receptor antibodies was suggested to treat chronic antibody‐mediated rejection (cAMR) after failure of classical treatments. We treated nine patients with AMR resistant to apheresis, rituximab, and intravenous immunoglobulins, with a monthly infusion of tocilizumab and compared them with a historical cohort of 37 patients with similar clinical, immunological, and histological characteristics. The 1‐year graft survival and the decline in renal function did not differ between patients who received tocilizumab and those who did not. Histological follow‐up showed that despite a decrease in inflammation and tubulitis scores after tocilizumab, the course of antibody‐mediated lesions and chronic glomerulopathy were similar in both groups. In our study, the addition of monthly infusions of tocilizumab did not alter the course of AMR that resist to SOC therapy. Large randomized studies are urgently needed to assess the effect of tocilizumab in this context.

Kidney transplanted patients still have significantly higher mortality compared with the general population. The innate immune system may play an important role during periods, with suppression of the adaptive immune system. In the present study, two soluble pattern recognition molecules of the innate immune system were investigated, collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1). Potential associations of their pretransplant levels and long-term graft and recipient survival were examined. The levels of CL-L1 and CL-K1 were measured at the time of transplantation in 382 patients (≥17 years) transplanted in 2000-2001. The cohort was subsequently followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Both high CL-L1 (≥376 ng/mL) and high CL-K1 (≥304 ng/mL) levels were significantly associated with overall mortality in multivariate Cox analyses with hazard ration (HR) 1.50, 95% confidence interval (CI) 1.09-2.07, p = 0.013 and HR 1.43, 95% CI 1.02-1.99, p = 0.038, respectively. Moreover, high CL-K1 levels were significantly associated with cardiovascular mortality. No association between measured biomarkers and death-censored graft loss was found. Finally, there was a significant correlation between these two collectins, r = 0.83 (95% CI 0.80-0.86). In conclusion, CL-L1 and CL-K1 were significantly associated with mortality in kidney transplant recipients.

International audience; There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new‐generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon‐free sofosbuvir‐based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty‐five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated‐interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti‐HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New‐generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.