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Antibody-mediated rejection (AMR) is the major cause of graft loss in kidney transplant recipients. The Banff classification defines two classes of AMR, active and chronic active but over time this classification has become increasingly complex. To simplify the approach to AMR, we developed activity and chronicity indices based on kidney transplant biopsy findings and examined their association with graft survival in 147 patients with active or chronic active AMR, all of whom had donor-specific antibodies and were treated for AMR. The activity index was determined as the sum of Banff glomerulitis (g), peritubular capillaritis (ptc), arteritis (v) and C4d scores, with a maximum score of 12. The chronicity index was the sum of interstitial fibrosis (ci), tubular atrophy (ct), chronic vasculopathy (cv), and chronic glomerulopathy (cg) scores, the latter doubled, with a maximum score of 15. While the activity index was generally not associated with graft loss, the chronicity index was significantly associated with graft loss with an optimal threshold value of 4 or greater for predicting graft loss. The association of the chronicity index of 4 or greater with graft loss was independent of other parameters associated with graft loss, including the estimated glomerular filtration rate at the time of biopsy, chronic active (versus active) AMR, AMR with de novo (versus persistent/rebound) donor-specific antibodies, Banff (g+ptc) scores, concurrent T cell-mediated rejection and donor-specific antibody reduction post-biopsy. The association of the chronicity index of 4 or greater with graft loss was confirmed in an independent cohort of 61 patients from Necker Hospital, Paris. Thus, our findings suggest that the chronicity index may be valuable as a simplified approach to decision-making in patients with AMR.

With recent advances and commercial implementation of minimally invasive biomarkers in kidney transplantation, new strategies for the surveillance of allograft health are emerging. Blood and urine-based biomarkers can be used to detect the presence of rejection, but their applicability as diagnostic tests has not been studied. A Banff working group was recently formed to consider the potential of minimally invasive biomarkers for integration into the Banff classification for kidney allograft pathology. We review the existing data on donor-derived cell-free DNA, blood and urine transcriptomics, urinary protein chemokines, and next-generation diagnostics and conclude that the available data do not support their use as stand-alone diagnostic tests at this point. Future studies assessing their ability to distinguish complex phenotypes, differentiate T cell-mediated rejection from antibody-mediated rejection, and function as an adjunct to histology are needed to elevate these minimally invasive biomarkers from surveillance tests to diagnostic tests.

Interleukin-6 (IL-6) is a cytokine critical for innate and adaptive immune responses. However, persistent expression of high levels of IL-6 are associated with a number of pathologic conditions including autoimmune diseases and capillary leak syndrome. Importantly, in kidney transplant patients, IL-6 may play a role in mediation of cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). This is likely due to the importance of IL-6 in stimulating B cell responses with pathogenic donor-specific antibody (DSA) generation and stimulation of T effector cell responses while inhibiting T regulatory cells. Data from preliminary clinical trials and clinical observations show that tocilizumab (anti-IL-6R) and clazakizumab (anti-IL-6) may have promise in treatment of CMR, AMR and chronic (cAMR). This has led to a phase 3 placebo, randomized clinical trial of clazakizumab for treatment of cAMR, a condition for which there is currently no treatment. The identification of IL-6 production in vascular endothelia cells after alloimmune activation reveals another potential pathway for vasculitis as endothelia cell IL-6 may stimulate immune cell responses that are potentially inhibitable with anti-IL-6/IL-6R treatment. Importantly, anti-IL-6/IL-6R treatments have shown the ability to induce Treg and Breg cells in vivo which may have potential importance for prevention and treatment of DSA development and allograft rejection.

Interleukin-6 (IL-6) is an important mediator of inflammation and activation of T cells, B cells, and plasma cells. Excessive IL-6 production is linked to human diseases characterized by unregulated antibody production, including alloimmunity, where persistence of donor-specific antibodies (DSAs), chronic active antibody-mediated rejection (cAMR), and graft loss are noted. Here, we report our experience investigating clazakizumab, a novel IL-6 inhibitor, in treating human leukocyte antigen (HLA)-sensitized patients with cAMR.Between February 2018 and January 2019, 10 adults with biopsy-proven cAMR were enrolled in a phase 2, single-center, open-label study. Patients received clazakizumab 25 mg subcutaneously (s.c.) monthly for 12 months, with a 6-month protocol biopsy. Primary end points included patient survival, graft survival, estimated glomerular filtration rate (eGFR), and safety. Secondary end points assessed immune markers (DSAs, IgG, T-regulatory [Treg] cells). At 12 months, stable patients entered a long-term extension (LTE).LTE patients received clazakizumab for2.5 years. Mean eGFRs showed significant declines from -24 months to study initiation (0 months) (52.8 ± 14.6 to 38.11 ± 12.23 ml/min per 1.73 mIn this small cohort of patients with cAMR, clazakizumab treatment showed a trend toward stabilization of eGFR and reductions in DSA and graft inflammation. No significant safety issues were observed. A randomized, placebo-controlled clinical trial (IMAGINE) of clazakizumab in cAMR treatment is underway (NCT03744910).

The IgG-degrading enzyme derived from Streptococcus pyogenes (Imlifidase, Hansa Biopharma) is a novel agent that cleaves all four human subclasses of IgG and has therapeutic potential for HLA desensitization in kidney transplantation and antibody-mediated rejection. Data from clinical trials in kidney transplantation demonstrated rapid degradation of anti-HLA donor-specific antibodies facilitating HLA-incompatible transplantation, which led to conditional approval of imlifidase by the European Medicines Agency for desensitization in kidney transplant recipients of a deceased donor with a positive cross match. Important considerations arising from the early experiences with imilfidase on kinetics of donor-specific antibodies after administration, timing of complementary therapeutic monoclonal or polyclonal IgG antibodies, and interference with cross match assays should be recognized as imlifidase emerges as a therapeutic agent for clinical transplantation.

Donor-derived cell-free DNA (dd-cfDNA) is a biomarker validated to detect rejection when measured to assess kidney allograft dysfunction. However, it remains unclear whether routine surveillance with dd-cfDNA provides additional information over standard monitoring of kidney allografts with creatinine and donor-specific antibodies (DSAs), particularly among those with little suspicion of rejection or injury. We investigated the value of measuring dd-cfDNA in patients with preserved allograft function and describe its association with future events.Three-hundred seventeen kidney transplant recipients with a creatinine ≤1.5 mg/dL, no current DSA, and no prior rejection were assessed with dd-cfDNA and categorized into low (dd-cfDNA0.5%; n = 239), moderate (dd-cfDNA 0.5% to1.0%; n = 43), and high (dd-cfDNA ≥1.0%; n = 35) groups. The occurrence of rejection, DSA, graft loss, and change in estimated glomerular filtration rate over time after dd-cfDNA assessment was compared.Over follow-up, rejections were more commonly found among patients with high vs low dd-cfDNA (17% versus 5%; P = 0.01); a similar nonsignificant trend was observed among patients with moderate compared to low dd-cfDNA (12% versus 5%; P = 0.13). DSA development was uncommon and not different between groups (low: 4%; moderate: 3%; high: 0%; P = 0.52). There was only 1 graft loss in a patient with low dd-cfDNA, and dd-cfDNA was not associated with graft dysfunction over time.Most patients with elevated dd-cfDNA in conjunction with preserved allograft function remained stable over follow-up without deterioration in function or graft loss. Studies are needed to differentiate patients with elevated dd-cfDNA who will develop adverse outcomes from those who will remain clinically stable.

Because highly sensitized kidney transplant candidates must draw from a large donor pool to find a biologically compatible donor, living donor transplantation is uncommon among HLA-sensitized patients in need of kidney transplantations. We review current data on treatment options for highly sensitized kidney transplant candidates and provide recommendations based on the evidence and our clinical experience. As kidney paired donation becomes more common in the USA, recent studies have published outcomes from large, multi-center national exchange programs. Recent national studies have also provided data on experience with HLA-incompatible kidney transplantation options for the highly sensitized candidate including paired kidney exchange, desensitization with HLA-incompatible transplantation, or waiting for a deceased donor transplant. This review summarizes the pros and cons of these options and provides recommendations for the highly sensitized patient with an incompatible living donor. Considerations include the likelihood of finding a biologically compatible donor, the degree of HLA-incompatibility and their associated outcomes in comparison to compatible transplantation, the downside of remaining on dialysis while waiting for a more suitable donor, and patient preference. Given the challenges in finding biologically compatible donors, HLA-incompatible transplantation is an appropriate option for many highly sensitized kidney transplant candidates.

Objective: Elevated levels of pro-inflammatory cytokines are observed in severe COVID-19 infections, and cytokine storm is associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, is used to treat chimeric antigen receptor T cell-induced cytokine release syndrome and may attenuate the dysregulated immune response in COVID-19. We compared outcomes among tocilizumab-treated and non-tocilizumab-treated critically ill COVID-19 patients. Design, setting, and participants: This was a retrospective observational study conducted at a tertiary referral center investigating all patients admitted to the intensive care unit for COVID-19 who had a disposition from the hospital because of death or hospital discharge between March 1 and May 18, 2020 (n = 96). The percentages of death and secondary infections were compared between patients treated with tocilizumab (n = 55) and those who were not (n = 41). Measurements and main results: More tocilizumab-treated patients required mechanical ventilation (44/55, 80%) compared to non-treated patients (15/41, 37%; P < 0.001). Of 55 patients treated with tocilizumab, 32 (58%) were on mechanical ventilation at the time of administration, and 12 (22%) progressed to mechanical ventilation after treatment. Of patients treated with tocilizumab requiring mechanical ventilation, 30/44 (68%) were intubated within 1 day of administration. Fewer deaths were observed among tocilizumab-treated patients, both in the overall population (15% vs 37%; P = 0.02) and among the subgroup of patients requiring mechanical ventilation (14% vs 60%; P = 0.001). Secondary infections were not different between the 2 groups (tocilizumab: 31%, non-tocilizumab: 17%; P = 0.16) and were predominantly related to invasive devices, such as urinary and central venous catheters. Conclusions: Tocilizumab treatment was associated with fewer deaths compared to non-treatment despite predominantly being used in patients with more advanced respiratory disease.

Antibody-mediated rejection (ABMR) is implicated as the leading cause of late kidney allograft failure. Current therapies inadequately control the antibody response and persistent donor-specific antibodies lead to chronic ABMR and allograft failure. Imlifidase is an IgG endopeptidase derived from Streptococcus pyogenes that cleaves human IgG into F(ab’)2 and Fc fragments, thereby protecting against complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Favorable outcomes with its use for desensitization in HLA-incompatible kidney transplantation have engendered interest in its use for ABMR. The experiences with imlifidase for a variety of antibody-mediated diseases, including anti-glomerular basement membrane disease, thrombotic thrombocytopenic purpura, and desensitization in HLA-incompatible kidney transplantation, are reviewed to provide a rationale for using imlifidase to treat ABMR in kidney transplantation. Imlifidase is currently being evaluated in comparison to plasmapheresis in a clinical trial and is a potential therapy for ABMR in kidney transplantation.

BackgroundHomozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization.MethodsWe measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls.ResultsWe found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization.ConclusionsThis study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.

Assessing the composition of immune responses to SARS-CoV-2 vaccines is critical for our understanding of protective immunity, especially for immune compromised patients. The Pfizer (BNT162b2) vaccination showed90% efficacy in protecting individuals from infection. However, these studies did not examine responses in immunocompromised kidney transplant patients (KT). Subsequent reports in KT have shown severe deficiencies in Spike-specific immunoglobin G (IgG) responses prompting booster vaccinations, but a broader understanding of T-cell immunity to vaccinating is lacking.We examined SARS-CoV-2 Spike IgG and CD4+/CD8+ Spike-specific T-cell responses in 61 KT patients maintained on different immunosuppressive protocols (ISP) (Tac + mycophenolate mofetil + prednisone) versus (belatacept + MMF + prednisone) and compared to 41 healthy controls. We also examined cytomegalovirus-cytotoxic T-cell responses (CMV-Tc) in both groups to assess T-cell memory.Our data confirmed poor Spike IgG responses in vaccinated KT patients with both ISP (21% demonstrating Spike IgG 1M post-second dose of BNT162b2 vs. 93% in controls). However, 35% of Spike IgG (-) patients demonstrated CD4+ and/or CD8+ T-cell responses. All but one CMV-IgG+ patient demonstrated good CMV-Tc responses. No differences in T-cell immunity by ISP were seen.Immunocompromised KT recipients showed severe defects in humoral and T-cell immune response after vaccination. No differences in immune responses to SARS-CoV-2 Spike peptides were observed in KT patients by ISP post-vaccination. The detection of Spike-specific T-cell immunity in the absence of Spike IgG suggests that vaccination in immunocompromised KT patients may provide partial immunity, although not preventing infection, T-cell immunity may limit its severity.

Background Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. Methods We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations Results Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. Conclusions Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

Background and objectives Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial. Design, setting, participants, & measurements This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model. Results Three deaths occurred among C1 esterase inhibitor–treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor–treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor–treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but was stable in C1 esterase inhibitor–treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2). Conclusions Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

Alloantibodies are a significant barrier to successful transplantation. While desensitization has emerged, efficacy is limited. Interleukin-6 (IL-6) is an important mediator of inflammation and immune cell activation. Persistent IL-6 production increases the risk for alloantibody production. Here we report our experience with clazakizumab (anti-IL-6) for desensitization of highly HLA-sensitized patients (HS). From March 2018 to September 2020, 20 HS patients were enrolled in an open label pilot study to assess safety and limited efficacy of clazakizumab desensitization. Patients received PLEX, IVIg, and clazakizumab 25 mg monthly X6. If transplanted, graft function, pathology, HLA antibodies and regulatory immune cells were monitored. Transplanted patients received standard immunosuppression and clazakizumab 25 mg monthly posttransplant. Clazakizumab was well tolerated and associated with significant reductions in class I and class II antibodies allowing 18 of 20 patients to receive transplants with no DSA rebound in most. Significant increases in T

Bu et al. report that elevated donor-derived cell-free DNA detected on serial measurements performed for both surveillance and assessment of kidney allograft dysfunction was associated with rejection, future de novo donor-specific antibodies, and decline in estimated glomerular filtration rate. Their data suggest that donor-derived cell-free DNA may be a useful indicator of kidney allograft health. In this commentary, we discuss the expanding role of donor-derived cell-free DNA for allograft surveillance and highlight potential limitations.

Introduction Persistent EBV DNAemia (PEBV) is associated with late-onset PTLD. The efficacy of rituximab in PEBV is not conclusive. We monitored PEBV and DSA in pediatric kidney transplant patients with or without rituximab. Methods 13 PEBV patients received standard treatment with immunosuppression reduction and valganciclovir, with or without IVIG; 5/13 were further treated with rituximab. Results All Rituximab-treated and 6/7 No-Rituximab patients were EBV seronegative at transplant and seroconverted post-transplant. Peak EBV PCR levels were lower in No-Rituximab than Rituximab patients and all No-Rituximab patients cleared PEBV after standard treatment. Additional 1-2 doses of rituximab reduced EBV PCR levels in all 5 Rituximab patients, 3 cleared PEBV. One No-Rituximab patient developed localized PLTD. None of Rituximab patients developed de novo DSA, while 4/8 No-Rituximab patients did: 2/4 had ABMR. 1/5 Rituximab and 5/8 No-Rituximab patients had acute rejection. There was no change in eGFR between pre-EBV DNAemia and follow-up in Rituximab patients, while reduction in No-Rituximab patients was found. There was no difference in graft and patient survival. Conclusions While early intervention with rituximab in pediatric patients with PEBV may reduce viral load and PTLD, we observed a slower development of de novo DSA, and rejection and maintenance of eGFR.

Background Viral infections are controlled primarily by viral-specific T cells, raising concern for adequate T-cell response to clear CMV infection in transplant recipients receiving lymphocyte-depleting agents (LDA). We examined the rates of CMV viremia and clearance, seroconversion, and CMV-specific CD8+ T cell (CMV-Tc) activity with class of induction agent received. Methods Retrospective review of 45 pediatric renal transplant recipients who received induction with LDA (n = 31) or non-LDA (NLDA; n = 14) received valganciclovir prophylaxis for 6 months post-transplant and CMV-PCR monitoring. CMV-Tc was measured by intracellular IFNγ flow cytometry, when possible, at baseline, 1 month after CMV viremia (>5 copies/PCR) and serially until CMV-Tc was positive (≥0.2%). Results Viremia rates at 1, 2, and 4 years post-transplant were higher in LDA vs. NLDA (46.3% vs. 7.2%, 64.2% vs. 7.2%, and 64.2% vs. 7.2%, respectively; p = .002). Viremia rates at these time points in seronegative LDA (50.3%, 71.6%, 71.6%) were significantly or near significantly higher than seronegative NLDA (9.1%, 9.1%, 9.1%; p = .004), seropositive-LDA (22.3%, 22.3%, 22.3%; p = .07), or seropositive NLDA (0%, 0%, 0%; p = .07). Eleven of 17 (64.7%) viremic subjects required valganciclovir dose reduction during the prophylaxis period for leukopenia. All viremic LDA patients developed CMV-Tc. One viremic NLDA patient did not develop CMV-Tc. No patients developed CMV disease. Conclusion CMV seronegative pediatric renal transplant patients receiving LDA are more likely to have valganciclovir prophylaxis dose reduction and develop subclinical CMV viremia; however, all developed CMV-Tc. Larger prospective studies are needed to further understand the effects of induction agents on CMV-Tc and CMV-Tc's role post-transplant.

Donor-derived cell-free DNA (dd-cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd-cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor-specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd-cfDNA was higher among patients with antibody-mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%-1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%-1.10%; P < .001) and cell-mediated rejection (CMR; median: 0.27%, IQR: 0.19%-1.30%; P = .01). The dd-cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17-0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71-0.93) and a dd-cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd-cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.

In kidney-alone recipients, dual-kidney transplantation using "higher-risk" donor organs has shown outcomes comparable to those of single-kidney transplantation using extended criteria donor (ECD) organs. To investigate the feasibility of a similar approach with combined kidney-liver transplantation, we identified 22 dual-kidney liver transplantations (DKLTs) and 3044 single-kidney liver transplantations (SKLTs) performed in the United States between 2002 and 2012 using United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data. We compared donor/recipient characteristics as well as graft/recipient survival between DKLT recipients and SKLT recipients of "higher-risk" kidneys (ECD and high kidney donor profile index [KDPI; >85%] donors). Despite having overall similar donor and recipient characteristics compared with both "higher-risk" donor groups, recipient survival in the DKLT group at 36 months was markedly inferior at 40.9% (compared with 67.5% for ECD SKLT recipients and 64.5% for high-KDPI SKLT recipients); nondeath-censored graft survival did not differ. Death was the most common cause of graft loss in all groups. Contrary to dual-kidney transplantation data in kidney-alone recipients, DKLT recipients in our study had inferior survival when compared with SKLT recipients of "higher-risk" donor kidneys. These findings would suggest that dual kidney-liver transplantation has an uncertain role as a strategy to expand the existing kidney donor pool in combined transplantation.

Background Tocilizumab is an interleukin-6 receptor antagonist recently described as a promising treatment for antibody-mediated rejection. We compared infectious complications among tocilizumab-treated kidney transplant patients with those receiving intravenous immunoglobulin (IVIG)/rituximab. Methods Infections occurring among 148 kidney recipients treated with tocilizumab 8 mg/kg IV monthly (n = 83) or IVIG/rituximab (n = 65) for donor-specific antibodies and antibody-mediated rejection through 1 year after treatment cessation were reviewed. Incidence rates of infections were compared using Poisson regression. Results There were 106 infections observed over 190.1 person-years, yielding an incidence rate of 558 infections/1000 patient-years. A lower incidence rate of infections was observed among tocilizumab-treated compared with IVIG/rituximab-treated patients (463 infections/1000 patient-years versus 730 infections/1000 patient-years; P = 0.02). Twenty-five of 49 infections (51%) in the IVIG/rituximab group required hospitalization compared with 31 of 57 (54%; P = 0.85) in the tocilizumab group. There were no infection-related deaths in either group. Urinary tract infections and pneumonia were the most common types of infections, whereas gastrointestinal, blood, skin/soft tissue, viral, and fungal infections were less common. On multivariable Poisson regression, there was a lower incidence rate of infections associated with tocilizumab compared with IVIG/rituximab (incidence rate ratio, 0.63; 95% confidence interval, 0.43-0.93). Conclusions Among kidney transplant patients treated with tocilizumab, there was no excess risk of infections compared with standard therapy with IVIG/rituximab.

Chronic active T cell–mediated rejection (CA TCMR) is a newly described variant of kidney allograft rejection associated with long-term graft loss. Whether this form of rejection is related to under immunosuppression is debated and the benefit of immunosuppressive therapy in CA TCMR is unknown. Here we investigate the amenability of CA TCMR to treatment and examine the impact of clinical, histologic, and molecular parameters on outcomes. In a retrospective single institution review, we identified 48 cases of isolated CA TCMR, of which 44 were treated with pulse steroids or anti-thymocyte globulin, or both. Defining treatment response as an at least 50% estimated glomerular filtration rate recovery, a response was achieved in 20% of cases at four weeks post initiation of immunosuppressive therapy. Treatment responsiveness did not reflect the presence of concomitant acute T cell–mediated rejection, and was not significantly different between cases with mild, moderate, and severe parenchymal scarring. Although not statistically significant, there was a trend toward greater treatment responsiveness in cases with moderate as opposed to severe tubulitis. By targeted transcriptional profiling, increased allograft mast cells and alterations in lipid metabolism were identified as possible features of treatment resistant CA TCMR. Thus, our study shows that although its prognosis is generally poor, CA TCMR is not a homogenous entity and in a subset of cases, improvement in kidney function can be achieved with immunosuppressive therapy.

International audience; Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.

Background Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown. Methods This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival. Results In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years. Conclusions In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed.

Background The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. Methods We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. Results We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P=0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P=0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. Conclusions Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.)

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COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients’, families’, and society’s mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University’s library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer’s disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

Background Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. Methods and Results A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed LVEF 58% (with EF 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously x1 dose. Within 24 hours, he noted significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers. There was a transient leukopenia which improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. Conclusion Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide., Highlights • Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. • A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein, interleukin-6 (IL-6), and other inflammatory markers. Echocardiogram showed normal LV function. • The patient received clazakizumab (anti-IL-6 monoclonal antibody) 25 mg as a single dose, with significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers within 24 hours, and discharge to home on day 11. He had a negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, developed a positive serum COVID-19 IgG antibody, and was continuing to do well clinically on day 60. • Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19.

Supplemental Digital Content is available in the text., Background. Higher Banff inflammation and chronicity scores on kidney transplant biopsies are associated with poorer graft survival, although histology alone has limitations in predicting outcomes. We investigated if integrating donor-derived cell-free DNA (dd-cfDNA, Allosure; CareDx, Inc.) with Banff biopsy scores into a predictive model for estimated glomerular filtration rate over time can improve prognostic assessment versus histology alone. Methods. We identified 180 kidney transplant patients with dd-cfDNA assessed within 1 mo of biopsy. Using linear mixed–effects models, a prediction model of Banff histology scores and dd-cfDNA on estimated glomerular filtration rate over time was derived. Nested models were compared using the likelihood-ratio test, Akaike Information Criterion, and Bayesian Information Criterion to assess if inclusion of dd-cfDNA into a model consisting of Banff biopsy scores would improve model fit. Results. Univariate models identified significant covariate-by-time interactions for cg = 3 versus

Interleukin 6 (IL-6) is a cytokine with critical innate and adaptive immunity functions. It's diverse immunologic and physiologic actions include direction of immune cell differentiation, initial response to invading pathogens and ischemic injury, sustained plasma cell growth, and immunoglobulin production. IL-6 transcriptional dysregulation is commonly seen in patients with autoimmune or inflammatory disorders. Emerging information suggests IL-6 transcription is upregulated in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft, leading to allograft rejection and vasculopathy. IL-6 directed therapeutics include monoclonal antibodies directed at IL-6, the IL-6 receptor (IL-6R) and Janus Kinase (JAK) inhibitors. IL-6 mediated signaling to cell targets is unique, involving classic signaling (IL-6->IL-6R) cell membrane receptors, trans signaling (IL-6->soluble IL-6R->gp130) which activates any cell, and the recently discovered IL-6/IL-6R transpresentation where antigen presenting cells (APC) synthesize and express IL-6/IL-6R complexes which are transported through the cell membrane subsequently interacting with gp130 to costimulate T-cells. Currently, there are new trials in autoimmunity and heart and kidney transplantation to determine effectiveness of inhibiting IL-6/IL-6R to ameliorate chronic allograft rejection and coronary allograft vasculopathy. Therapeutic trials aimed at prevention of ischemia/reperfusion injury (IRI) to allografts based on animal data should be considered.

Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell-directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody-mediated rejection (AMR) treatment by targeting CD20 found on B-lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

JC virus-associated nephropathy is rare in kidney transplant recipients, and even rarer in recipients of other solid organ transplants. We present a case of JC virus-associated nephropathy in a heart-kidney transplant recipient, which to our knowledge is the first case reported in the literature. We discuss the findings on renal biopsy for JC virus nephropathy and our management approach to this rare complication.

Background The efficacy and safety of belatacept when converted from calcineurin inhibitors (CNI) in HLA-sensitized (HS) kidney transplant recipients has not been established. Methods The study included 108 kidney transplant recipients converted from CNI to belatacept between July 1, 2012, and September 30, 2017. Rejection-free, patient, and graft survival over 5 years follow-up were compared between HS and non-HLA-sensitized (non-HS) recipients using the Kaplan-Meier product-limit method. The estimated glomerular filtration rate slope postconversion was compared using linear mixed effects models. Results There were 29 HS and 79 non-HS recipients included. Rejections after conversion were mostly cell-mediated. There was no difference in rejection-free survival (log-rank P = 0.30; at 5 y, HS: 82%; non-HS: 84.6%); however, rejection-free survival was lower among HS recipients converted within the first-year posttransplant compared to non-HS recipients (log-rank P = 0.03; at 5 y, HS: 55.6%; non-HS: 75.0%). There was no difference in patient survival (log-rank P = 0.75; at 5 y, HS: 85.7%, non-HS: 83.7%) or graft survival (log-rank P = 0.17; at 5 y, HS: 78.5%, non-HS: 89.8%) in the 2 groups. On average, estimated glomerular filtration rate slope improved postconversion in non-HS (0.28 mL/min/1.73 m/y [0.03 to 0.53]) but declined in HS recipients (-0.44 mL/min/1.73 m/y [-0.85 to -0.03]). Conclusions There was no difference in rejection-free, patient, or graft survival after conversion to belatacept over 5 years among HS and non-HS recipients. However, rejection-free survival was lower in HS recipients converted to belatacept within the first-year posttransplant. Conversion from CNI to belatacept should be done cautiously in high immunologic risk patients.

BackgroundBK virus infection remains an important cause of loss of allograft function after kidney transplantation. We sought to determine whether polyfunctional T cells secreting multiple cytokines simultaneously, which have been shown to be associated with viral control, could be detected early after start of BK viremia, which would provide insight into the mechanism of successful antiviral control.MethodsPeripheral blood mononuclear cells collected during episodes of BK viral replication were evaluated by multiparameter flow cytometry after stimulation by overlapping peptide pools of BK virus antigen to determine frequency of CD8+ and CD4+ T cells expressing 1 or more cytokines simultaneously, as well as markers of T-cell activation, exhaustion, and maturation.ResultsBK virus controllers, defined as those with episodes of BK viremia of 3 months or less, had an 11-fold increase in frequency of CD8+ polyfunctional T cells expressing multiple cytokines, as compared with patients with prolonged episodes of BK viremia. Patients with only low level BK viremia expressed low frequencies of polyfunctional T cells. Polyfunctional T cells were predominantly of the effector memory maturation subtype and expressed the cytotoxicity marker CD107a.ConclusionsNoninvasive techniques for immune assessment of peripheral blood can provide insight into the mechanism of control of BK virus replication and may allow for future patient risk stratification and customization of immune suppression at the onset of BK viremia.

Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.

© 2017 by the American Society of Nephrology. Background and objectives Waitlist inactivity is a barrier to transplantation, because inactive candidates cannot receive deceased donor organ offers. We hypothesized that temporarily inactive kidney transplant candidates living in linguistically isolated communities would be less likely to achieve active waitlist status. Design, setting, participants, & measurements We merged Organ Procurement and Transplantation Network/ United Network for Organ Sharing data with five-digit zip code socioeconomic data from the 2000 US Census. The cumulative incidence of conversion to active waitlist status, death, and delisting before conversion among 84,783 temporarily inactive adult kidney candidates from 2004 to 2012 was determined using competing risks methods. Competing risks regression was performed to characterize the association between linguistic isolation, incomplete transplantation evaluation, and conversion to active status. A household was determined to be linguistically isolated if all members ≥14 years old speak a non-English language and also, speak English less than very well. ResultsA total of 59,147 candidates (70% of the studypopulation) achieved active status over the studyperiod of 9.8 years. Median follow-up was 110 days (interquartile range, 42–276 days) for activated patients and 815 days (interquartile range, 361–1244 days) for candidates not activated. The cumulative incidence of activation over the studyperiod was 74%, the cumulative incidence of death before conversion was 10%, and the cumulative incidence of delisting was 13%. After adjusting for other relevant covariates, living in a zip code with higher percentages of linguistically isolated households was associated with progressively lower subhazards of activation both in the overall population (reference