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Context:Chronic immunosuppression is associated with an increased risk of opportunistic infections. Although kidney transplant recipients with coronavirus disease 2019 (COVID-19) have higher mortality than the general population, data on their risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are unknown. Subject of Review:A recent single-center screening study from the UK (Transplantation. 2021 Jan 1;105(1):151–7) showed that 89 (10.4%) of 855 consecutive kidney transplant recipients tested positive for SARS-CoV-2 antibodies. Risk factors for infection included a nonwhite background, diabetes, and a history of allograft rejection. Risk factors for mortality in individuals who developed COVID-19 were older age and receiving steroids. Second Opinion:This study shows that the rate of SARS-CoV-2 infection in kidney transplant recipients is similar to the one observed in the general population in the same area (13%), indicating that transplant recipients are not at increased risk of COVID-19. However, the investigators raise the interesting point that since transplant individuals were advised to shelter earlier than the general population, they may be in fact more susceptible. This statement is hard to substantiate, but the identification of specific risk factors for infection and poor outcomes is crucial to tailor strategies to prevent spread of the infection. This is particularly important, considering that kidney transplant recipients may be at increased risk of prolonged viral spread and in-host viral mutations, making them not just a particularly fragile population for COVID-19 but also a potentially major source of further contagions.

Background:Biopsy-guided selection of older kidneys safely expands the organ pool, and pretransplant perfusion improves the preservation of these fragile organs. Herein, we studied morphofunctional variables associated with graft outcomes in perfused, histologically evaluated older kidneys. Methods:This single-center prospective cohort pilot study evaluated the relationships between preimplantation histologic scores and renal perfusion parameters during hypothermic, pulsatile, machine perfusion (MP) and assessed whether these morphofunctional parameters associated with GFR (iohexol plasma clearance) at 6 months after transplantation in 20 consecutive consenting recipients of a biopsy-guided single or dual kidney transplant from >60-year-old deceased donors. Results:The donor and recipient age was 70.4 ± 6.5 and 63.6 ± 7.9 years (p= 0.005), respectively. The kidney donor profile index (KDPI) was 93.3 ± 8.4% (>80% in 19 cases), histologic score 4.4 ± 1.4, and median (IQR) cold ischemia time 19.8 (17.8–22.8 h; >24 h in 5 cases). The 6-month GFR was 41.2 (34.9–55.7) mL/min. Vascular resistances positively correlated with global histologic score (p= 0.018) at MP start and then decreased from 0.88 ± 0.43 to 0.36 ± 0.13 mm Hg/mL/min (p< 0.001) in parallel with a three-fold renal flow increase from 24.0 ± 14.7 to 74.7 ± 31.8 mL/min (p< 0.001). Consistently, vascular resistance reductions positively correlated with global histologic score (p= 0.009, r= −0.429). Unlike KDPI or vascular resistances, histologic score was independently associated with 6-month GFR (beta standardized coefficient: −0.894, p= 0.005). Conclusions:MP safely improves graft perfusion, particularly in kidneys with severe histologic changes that would not be considered for transplantation because of high KDPI. The preimplantation histologic score associates with the functional recovery of older kidneys even in the context of a standardized program of pulsatile perfusion.

The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels.

Tacrolimus (Tac) is an effective anti‐rejection agent in kidney transplantation, but its off‐target effects make withdrawal desirable. Although studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs unsuccessful Tac removal are unknown. We performed microarray analyses of peripheral blood mononuclear cells (PBMC) RNA from subjects enrolled in the Clinical Trials in Organ Transplantation‐09 study in which we randomized stable kidney transplant recipients to Tac withdrawal or maintenance of standard immunosuppression beginning 6 months after transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a downregulatory and proapoptotic gene program enriched within T cells. Functional analyses suggested stronger donor‐reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data from a small, but unique, patient cohort support the conclusion that successful Tac withdrawal is not simply due to absence of donor‐reactive immunity but rather is associated with an active immunological process. Analysis of peripheral blood gene expression profiles in kidney transplant recipients who successfully withdrew from tacrolimus reveals induction of a Treg‐independent, active, pro‐apoptotic program enriched in T cells that is distinct from published B cell signatures observed in operationally tolerant transplant recipients.

Whether kidney transplant recipients are capable of mounting an effective anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) adaptive immune response despite chronic immunosuppression is unknown and has important implications for therapy. Herein, we analyzed peripheral blood cell surface and intracellular cytokine phenotyping by flow cytometry along with serum antibody testing in 18 kidney transplant recipients with active coronavirus disease 2019 (COVID‐19) infection and 36 matched, transplanted controls without COVID‐19. We observed significantly fewer total lymphocytes and fewer circulating memory CD4+and CD8+T cells in the COVID‐19 subjects. We also showed fewer anergic and senescent CD8+T cells in COVID‐19 individuals, but no differences in exhausted CD8+T cells, nor in any of these CD4+T cell subsets between groups. We also observed greater frequencies of activated B cells in the COVID‐19 patients. Sixteen of 18 COVID‐19 subjects tested for anti‐SARS‐CoV‐2 serum antibodies showed positive immunoglobulin M or immunoglobulin G titers. Additional analyses showed no significant correlation among immune phenotypes and degrees of COVID‐19 disease severity. Our findings indicate that immunosuppressed kidney transplant recipients admitted to the hospital with acute COVID‐19 infection can mount SARS‐CoV‐2‐reactive adaptive immune responses. The findings raise the possibility that empiric reductions in immunosuppressive therapy for all kidney transplant recipients with active COVID‐19 may not be required. Hospitalized kidney transplant recipients with COVID‐19 infection can mount anti‐SARS‐CoV‐2–adaptive immune responses, despite ongoing immunosuppression, raising the possibility that empiric reduction of immunosuppression may not be required.

Objective.Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis.Methods.Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls. Ex vivoNET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques.Results.Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3–C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant of DNASE1L3. Ex vivoNET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases.Conclusion.Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rare DNase1L3mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered at ClinicalTrials.gov, study number NCT02403115).

Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1−/−mice, myeloid cell–specific mice, and kidney tubule–specific C5ar1knockout mice. After aristolochic acid and folic acid injection, C5ar1−/−mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1−/−mice or myeloid cell–specific C5ar1deletion did not affect the outcomes of aristolochic acid–induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1−/−RTECs. Moreover, C5ar1−/−RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule–specific C5ar1knockout mice recapitulated exacerbated AKI observed in C5ar1−/−mice in AAN and folic acid nephropathy. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide, and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses. Therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease (TANGO) Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across three continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years post-transplant. Patients with a faster progression towards end-stage kidney disease (ESKD) were at higher risk of developing recurrent MN (hazard ratio (HR) of 0.55 per decade (95%CI; 0.35-0.88). Moreover, elevated pre-transplant levels of anti-PLA2R antibodies were strongly associated with recurrence (HR 18.58; 95%CI; 5.37- 64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving RAAS inhibition alone. In sum, MN recurs in one-third of patients post-transplant and serum PLA2R antibodies shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration–approved drugs.

Erythropoietin (EPO) is a glycoprotein produced mainly by the adult kidney in response to hypoxia and is the crucial regulator of red blood cell production. EPOreceptors (EPORs), however, are not confined to erythroid cells, but are expressed by many organs including the heart, brain, retina, pancreas, and kidney, where they mediate EPO‐induced, erythropoiesis‐independent, tissue‐protective effects. Some of these tissues also produce and locally release small amounts of EPOin response to organ injury as a mechanism of self‐repair. Growing evidence shows that EPOpossesses also important immune‐modulating effects. Monocytes can produce EPO, and autocrine EPO/EPORsignaling in these cells is crucial in maintaining immunologic self‐tolerance. New data in mice and humans also indicate that EPOhas a direct inhibitory effect on effector/memory T cells, while it promotes formation of regulatory T cells. This review examines the nonerythropoietic effects of EPO, with a special emphasis on its modulating activity on innate immune cells and T cells and on how it affects transplant outcomes. Cantarelli et al discuss current evidence on the nonerythropoietic effects of erythropoietin, with a special emphasis on murine and clinical studies in transplantation and autoimmunity.

Continuous antigen stimulation during chronic infection or malignancy can promote functional T cell silencing, a phenomenon called T cell exhaustion. The prevalence and impact of T cell exhaustion following organ transplantation, another immune stimulus with persistently high antigen load, are unknown. Here, we characterized serially collected peripheral blood mononuclear cells from 26 kidney transplant recipients using time-of-flight mass cytometry (CyTOF) to define distinct subsets of circulating exhausted T cells and their relationship to induction therapy and allograft function. We observed an increase in specific subsets of CD4+and CD8+exhausted T cells from pre-transplant to 6-months post-transplant, with greater increases in participants given anti-thymocyte globulin induction than in participants who received no induction or non-depleting induction. The percentages of exhausted T cells at 6 months correlated inversely with adenosine triphosphate (ATP) production (a surrogate of T cell function) and with allograft interstitial fibrosis. Guided by the CyTOF data, we delineated a PD-1+CD57−phenotype for CD4+and CD8+exhausted T cells, and confirmed that these cells have limited capacity for cytokine secretion and ATP production. In an independent cohort of 50 kidney transplant recipients, we confirmed the predicted increase of PD-1+CD57−exhausted T cells after lymphocyte-depleting induction therapy and its direct correlation with better allograft function. Our findings suggest that monitoring T cell exhaustion can be useful for post-transplant risk assessment and support the need to develop and test strategies aimed at augmenting T cell exhaustion following kidney transplantation.

Context:The increasing need for kidney grafts has led to a progressive expansion in the selection criteria for deceased and living donors (LDs). While concerns regarding the use of organs from suboptimal deceased donors relate to the quality of the graft, donation from “marginal” LDs may pose potential harm to the donor. Subject of Review:Living kidney donation is a safe procedure, but is associated with a small risk of end-stage kidney disease in the long- term. When elderly subjects and those with comorbidities are considered, long-term post-donation data are missing, making decisions regarding donation from these populations challenging. Further, vague guidelines have led to a wide heterogeneity in the criteria for living donation from marginal donors across centers and individuals. A recent survey by Lafranca et al. [PLoS One 2017;12:e0181846] collected information from 331 members (mainly physicians) of the European Society of Transplantation regarding several expanded LD criteria. Median refusal rate for potential expanded criteria (ECD) LDs is 15% and the authors found significant differences across regions in Europe in the acceptance of donors with ECD. Some transplant specialists did also deviate from their own transplant center policy, mainly to consider donors with high body mass index. Second Opinion:The survey by Lafranca et al. [PLoS One 2017;12:e0181846] documents extreme variability in the criteria for marginal LD selection. Many centers are deviating from the few agreed upon guideline criteria and are considering individuals with hypertension and minors for kidney donation. Intriguingly, one-fourth of the surgeons even deviate occasionally from center policy, especially when the issue is donor obesity. By and large, these data indicate that transplant community has a generally open approach toward extension of criteria for living donation, but long-term follow-up studies are needed to draw solid conclusions and guidelines.

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Context: Results of procurement biopsies often drive the decision to discard kidneys from deceased donors with advanced age or comorbidities. However, the criteria to perform, process, and score procurement graft biopsies are not standardized. Subject of Review: A recent retrospective, single-center study by Carpenter et al. [Clin J Am Soc Nephrol 2018; 13: 1876–1885] compared the scores obtained from 270 consecutive frozen kidney sections of biopsies at time of procurement with those of paraffin-embedded sections of biopsies at reperfusion and the correlation of both biopsy scores with graft survival. In 116 kidneys, procurement biopsies were repeated, allowing to test the reproducibility of this technique. Procurement biopsies were poorly reproducible, did not correlate with scores obtained with paraffin-embedded reperfusion biopsies, and were not significantly associated with transplant outcomes, while reperfusion biopsies provided an excellent prediction of graft survival. Based on these findings, the authors suggest “an urgent need to reexamine the role of procurement biopsies during allocation given their high resource requirements and association with discards.” Second Opinion: Carpenter’s paper is important because it emphasizes the crucial role of correct histological evaluation of kidney grafts to accurately predict their survival. In this study, procurement biopsies were frozen and read by on-call pathologists, often with no specific training in renal pathology, while reperfusion sections were paraffin embedded and scored by experienced renal pathologists at Columbia University, New York, NY, USA. This methodological difference per se represents an obvious explanation for the poor concordance between the 2 assessments. Use of wedge biopsies in procurement samples versus core-needle samples in reperfusion biopsies may further account for the discrepancies between scores even in seemingly objective measurements, such as the percentage of glomerulosclerosis. Therefore, these data should not mislead us regarding the importance of procurement biopsies to define organ suitability for transplantation. Rather, they should prompt more studies aimed at optimizing the strategies to score these samples properly for optimal organ allocation.

No field in health sciences has more interest than organ transplantation in fostering progress in regenerative medicine (RM) because the future of no other field more than the future of organ transplantation will be forged by progress occurring in RM. In fact, the most urgent needs of modern transplant medicine, namely, more organs to satisfy the skyrocketing demand and immunosuppression-free transplantation, cannot be met in full with current technologies and are at risk of remaining elusive goals. Instead, in the past few decades, groundbreaking progress in RM is suggesting a different approach to the problem. New, RM-inspired technologies among which decellularization, 3-dimensional printing and interspecies blastocyst complementation, promise organoids manufactured from the patients' own cells and bear potential to render the use of currently used allografts obsolete. Transplantation, a field that has traditionally been immunology-based, is therefore destined to become a RM-based discipline. However, the contours of RM remain unclear, mainly due to the lack of a universally accepted definition, the lack of clarity of its potential modalities of application and the unjustified and misleading hype that often follows the reports of clinical application of RM technologies. All this generates excessive and unmet expectations and an erroneous perception of what RM really is and can offer. In this article, we will (1) discuss these aspects of RM and transplant medicine, (2) propose a definition of RM, and (3) illustrate the state of the art of the most promising RM-based technologies of transplant interest.Regenerative medicine (RM) aims to replace, regenerate, or repair tissues or organs. RM has enormous clinical potential but also faces important obstacles like the ex vivo or in vivo regeneration of tissues and organs (with techniques such as decellularization, 3D printing, stem cells, organoids, and blastocyst complementation) but also ischemia reperfusion and immune and inflammatory -mediated reactions (regenerative immunology).