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Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin (MIg) produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end stage kidney disease (ESKD). The diagnosis is typically made by nephrologists through a kidney biopsy. Many distinct pathologies have been identified and they are classified based on the site or composition of the deposited Mig, or according to histological and ultrastructural findings. Therapy is directed towards the identified underlying clonal population and treatment decisions should be coordinated between hematologists and nephrologists in a multidisciplinary fashion, depend on the type of MGRS, the degree of kidney function impairment and the risk of progression to ESKD., Competing Interests: Disclosures The authors have no conflicts of interest to report., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: To externally validate the previously published Mayo clinic model for the prediction of early (<30 days) postoperative renal failure, which relies solely on preoperative estimated glomerular filtration rate (eGFR) and develop a novel model for the prediction of long-term (>30 days) renal function after partial nephrectomy (PN) and radical nephrectomy (RN), including patient factors and nephrometry scores., Patients and Methods: Retrospective, single-center cohort study on patients who underwent PN or RN for a unilateral renal tumor between 2003 and 2019 with a preoperative eGFR of at least 15 ml/min/1.73m 2 . Early postoperative renal failure was defined as eGFR <15 ml/min/1.73 m 2 or receipt of dialysis within 30 days. We determined the area under the receiver operating characteristics curve (AUC) to assess the Mayo clinic model's discriminative power. We used hierarchical linear mixed models with backward selection of candidate variables to develop a prediction model for long-term eGFR following PN and RN, separately. Their predictive ability was quantified using the marginal and conditional R 2 GLMM and an internal validation., Results: We included 421 patients (7,548 eGFR observations) who underwent PN and 271 patients (6,530 eGFR observations) who underwent RN. The Mayo clinic model for prediction of early postoperative renal failure following PN and RN showed an AUC of 0.816 (95% CI 0.718-0.920) and 0.825 (95% CI 0.688-0.962), respectively. In multivariable models, long-term eGFR following PN was associated with age, diabetes, the presence of a solitary kidney, tumor diameter and preoperative eGFR, while long-term eGFR following RN was associated with age, body mass index, RENAL nephrometry score and preoperative eGFR. Marginal and conditional R 2 GLMM were 0.591 and 0.855 for the PN model, and 0.363 and 0.849 for the RN model, respectively., Conclusions: The Mayo clinic model for short-term renal failure prediction showed good accuracy on external validation. Our long-term eGFR prediction models depend mostly on host factors as opposed to tumor complexity and can aid in decision-making when considering PN vs. RN., Competing Interests: Declaration of Competing Interest Eduard Roussel has received an unrestricted research grant from Ipsen and Pfizer. Benoit Beuselinck received an unrestricted research grant from Bristol-Myers-Squibb and honorarium from Merck, Pfizer, Bristol-Myers-Squibb, Ipsen, and Astra-Zeneca and is a senior clinical investigator of ‘Fonds voor wetenschappelijk onderzoek Vlaanderen’ (Belgium). Maarten Albersen received an unrestricted research grant from Ipsen and Pfizer and is a clinical investigator of ‘Stichting tegen kanker’ (Belgium). All other authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL., Competing Interests: VV reports consultancy fees from Beigene, BMS/Cellgene, Gilead/Kite, speaker fees from from Janssen, travel support from Amgen, Abbvie; all paid to her institution. CMD reports consultancy fees from Sirtex, PSI CRO, Terumo and Ipsen and speaker fees from Ipsen; all paid to his institution. WL reports consultancy fees from Boston-Scientific, Cook Medical, CLS Behring, Echosens, Evive Biotech, Genfit, Norgine, Abbvie, Gore and Intercept.; all paid to institution. TT reports consultancy and speaker fees from EUSApharma; all paid to his institution. TT holds a Mandate for Fundamental and Translational Research from the ‘Stichting tegen Kanker’ (2014-083 and 2019-091). DD reports grants/research support from Roche; personal fees/honoraria from Takeda, Novartis, Amgen, Atara Biotherapeutics, Incyte; all paid to his institution. DD holds a mandate for Clinical and Translational Research from “Kom op tegen Kanker” (2017/10908/2816). RV is a senior clinical research fellow of the Research Foundation Flanders (FWO). BS is a senior clinical investigator of the Research Foundation Flanders (1842919N) and received funding from the Foundation Against Cancer (Stichting tegen Kanker; C/2020/1380). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vergote, Deroose, Fieuws, Laleman, Sprangers, Uyttebroeck, Van Cleemput, Verhoef, Vos, Tousseyn and Dierickx.)

During development, nephron structures are derived from a SIX2+ stem cell population. After 36 weeks of gestation, these cells are exhausted, and no new nephrons are formed. We have previously described a non-invasive strategy to isolate and expand the native SIX2+ kidney stem cells from the urine of preterm neonates, named neonatal kidney stem/progenitor cells (nKSPC). Here, we investigated the safety and feasibility of administering nKSPC into human kidneys discarded for transplantation during normothermic machine perfusion (NMP) and evaluated the regenerative and immunomodulatory potential of nKSPC treatment. We found that nKSPC administration during NMP is safe and feasible. Interestingly, nKSPC induced the de novo expression of SIX2 in proximal tubular cells of the donor kidneys and upregulated regenerative markers such as SOX9 and VEGF. This is the first time that SIX2 re-expression is observed in adult human kidneys. Moreover, nKSPC administration significantly lowered levels of kidney injury biomarkers and reduced inflammatory cytokine levels via the tryptophan-IDO-kynurenine pathway. In conclusion, nKSPC is a novel cell type to be applied in kidney-targeted cell therapy, with the potential to induce an endogenous regenerative process and immunomodulation., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Rationale & Objective: The relationship between human leukocyte antigen (HLA) molecular mismatches and T-cell-mediated rejection (TCMR) is unknown. We investigated the associations between the different donor HLA-derived T-cell targets and the occurrence of TCMR and borderline histologic changes suggestive of TCMR after kidney transplantation., Study Design: Retrospective cohort study., Setting & Participants: All kidney transplant recipients at a single center between 2004 and 2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing (N = 893)., Exposure: Scores calculated by the HLA matching algorithm PIRCHE-II and HLA eplet mismatches., Outcome: TCMR, borderline changes suggestive of TCMR, and allograft failure., Analytical Approach: Multivariable cause-specific hazards models were fit to characterize the association between HLA epitopes targets and study outcomes., Results: We found 277 patients developed TCMR, and 134 developed only borderline changes suggestive of TCMR on at least 1 biopsy. In multivariable analyses, only the PIRCHE-II scores for HLA-DRB1 and HLA-DQB1 were independently associated with the occurrence of TCMR and with allograft failure; this was not the case for HLA class I molecules. If restricted to rejection episodes within the first 3 months after transplantation, only the T-cell epitope targets originating from the donor's HLA-DRB1 and HLA-DQB1, but not class I molecules, were associated with the early acute TCMR. Also, the median PIRCHE-II score for HLA class II was statistically different between the patients with TCMR compared to the patients without TCMR (129 [IQR, 60-240] vs 201 [IQR, 96-298], respectively; P < 0.0001). These differences were not observed for class I PIRCHE-II scores., Limitations: Observational clinical data and residual confounding., Conclusions: In the absence of HLA-DSA, HLA class II but not class I mismatches are associated with early episodes of acute TCMR and allograft failure. This suggests that current immunosuppressive therapies are largely able to abort the most deleterious HLA class I-directed alloimmune processes; however, alloresponses against HLA-DRB1 and HLA-DQB1 molecular mismatches remain insufficiently suppressed., Plain-Language Summary: Genetic differences in the human leukocyte antigen (HLA) complex between kidney transplant donors and recipients play a central role in T-cell-mediated rejection (TCMR), which can lead to failure of the transplanted kidney. Evaluating this genetic disparity (mismatch) in the HLA complex at the molecular (epitope) level could contribute to better prediction of the immune response to the donor organ posttransplantation. We investigated the associations of the different donor HLA-derived T-cell epitope targets and scores obtained from virtual crossmatch algorithms with the occurrence of TCMR, borderline TCMR, and graft failure after kidney transplantation after taking into account the influence of donor-specific anti-HLA antibodies. This study illustrates the greater importance of the molecular mismatches in class II molecules compared to class I HLA molecules., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Since their introduction into clinical practice a decade ago, immune checkpoint inhibitors (ICIs) have had an overwhelming impact on cancer treatment. Use of these agents in oncology continues to grow; however, the increased use of these agents has been associated with a parallel increase in ICI-associated immune-related adverse events, which can affect virtually any organ, including the kidneys. ICI-associated acute kidney injury (ICI-AKI) occurs in 2-5% of patients treated with ICIs. Its occurrence can have important consequences, including the temporary or permanent discontinuation of ICIs or other concomitant anticancer therapies and the need for prolonged treatment with corticosteroids. Various mechanisms have been proposed to underlie the development of ICI-AKI, including loss of tolerance to self-antigens, reactivation of drug-specific effector T cells, and the production of kidney-specific autoantibodies. ICI-AKI most commonly manifests as acute tubulo-interstitial nephritis on kidney biopsy and generally shows a favourable response to early initiation of corticosteroids, with complete or partial remission achieved in most patients. The evaluation of patients with suspected ICI-AKI requires careful diagnostic work-up and kidney biopsy for patients with moderate-to-severe ICI-AKI to ensure accurate diagnosis and inform appropriate treatment., (© 2022. Springer Nature Limited.)

The pathogenesis of systemic lupus erythematosus (SLE) remains elusive to this day; however, genetic, epigenetic, and environmental factors have been implicated to be involved in disease pathogenesis. Recently, it was demonstrated that in systemic lupus erythematosus (SLE) patients, interferon-regulated genes are hypomethylated in naïve CD4 + T cells, CD19 + B lymphocytes, and CD14 + monocytes. This suggests that interferon-regulated genes may have been epigenetically poised in SLE patients for rapid expression upon stimulation by different environmental factors. Additionally, environmental studies have identified DNA (hypo)methylation changes as a potential mechanism of environmentally induced health effects in utero, during childhood and in adults. Finally, epidemiologic studies have firmly established air pollution as a crucial SLE risk factor, as studies showed an association between fine particulate matter (PM 2.5 ) and traditional SLE biomarkers related to disease flare, hospital admissions, and an increased SLEDAI score. In this review, the relationship between aberrant epigenetic regulation, the environment, and the development of SLE will be discussed.

Many chemotherapeutic drugs used to treat malignancies undergo renal clearance. Thus, accurate knowledge of kidney function is critical to ensure proper dosing, maximize efficacy, and minimize toxicity of drugs that often have a narrow therapeutic index. Making this issue more salient is the fact that impaired kidney function, as assessed by glomerular filtration rate (GFR), is encountered commonly in patients with cancer. Recent data and expert guidelines recommend the use of the Chronic Kidney Disease-Epidemiology Collaboration equation to guide the assessment of kidney function, except when directly measured GFR is clinically necessary. Controversies regarding the measurement of kidney function include the use of race in this equation, indexing to body surface area, and dosing of medications based on stages of chronic kidney disease versus more discrete values of estimated GFR. The development of accurate, real-time GFR measures may hold great promise in allowing for more accurate dosing of these important drugs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity., Methods: The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k -means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval., Results: We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P <0.001), independent of the total activity scores (HR, 5.01; 95% CI, 2.83 to 7.00; P <0.001). These results were validated on an external cohort of 4031 biopsies from 2054 kidney transplant recipients., Conclusions: The evaluation of total chronicity provides information on kidney transplant pathology that complements the estimation of disease activity from acute lesion scores. Use of the data-driven algorithm used in this study, called RejectClass, may provide a holistic and quantitative assessment of kidney transplant injury phenotypes and severity., (Copyright © 2022 by the American Society of Nephrology.)

Background: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry provides complete population data on kidney disease epidemiology in the region of Flanders (Belgium), as it captures all native kidney biopsies performed in its population of 6.5 million inhabitants., Methods: From 2017 until 2019, 2054 adult kidney biopsies were included from 26 nephrology centers (one biopsy per patient). Data on nephrotic and nephritic syndrome were available in 1992 and 2026 biopsies, respectively. In a subgroup of 898 biopsies containing ≥10 glomeruli from 2018 to 2019, disease chronicity was graded using the Mayo Clinic Chronicity Score (MCCS). The association between clinical variables and MCCS was determined using simple and multiple linear regression models., Results: Nephrotic syndrome (present in 378 patients, 19.0%) was most frequently caused by minimal change disease in younger patients (18-44 years), membranous nephropathy in older patients (45-74 years) and amyloidosis in the elderly (>75 years). Nephritic syndrome (present in 421 patients, 20.8%) was most frequently caused by immunoglobulin A nephropathy (IgAN) in younger patients (18-64 years) and ANCA-associated vasculitis (AAV) in older patients (>64 years). AAV and IgAN were the most frequent underlying diagnoses in biopsies in which crescents were identified. In multivariable analysis, acute and chronic kidney disease and diagnoses of diabetic kidney disease, nephrosclerosis and hyperoxaluria/hypercalcemic nephropathy were associated with the highest MCCS increases., Conclusions: The FCGG registry validates data from previous Western European registries and provides a snapshot of disease chronicity in the whole biopsied Flemish population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration., Methods: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days)., Results: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively)., Conclusion: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed., Competing Interests: Competing interests: SG receives research funding from GE Healthcare and BTG International and is President and Founder of the American Society of Onconephrology. CGC has received travel and congress fees support from AstraZeneca, Esteve, NovoNordisk, Boehringer Ingelheim Lilly, Astellas, Otsuka, Novartis, Astellas, and Baxter and has given scientific lectures and participated in advisory boards organized by AstraZeneca, Boehringer Ingelheim Lilly, Mundipharma, and NovoNordisk. DSS participates in the speakers’ bureau at Genentech. FBC is a consultant for ChemoCentryx and Retrophin. AA is supported by the Division of Internal Medicine Immuno-Oncology Toxicity Award Program of the University of Texas MD Anderson Cancer Center. BS is a senior clinical investigator at the Research Foundation Flanders (F.W.O.) (1842919N) and is supported by Stichting tegen Kanker (grant C/2020/1380). AR is a consultant for Otsuka Pharmaceutical, and treasurer of the American Society of Onconephrology. SMH is supported by the Mayo Clinic K2R award. KB receives grant support from Olympia Morata Programme, Foundations Commission of University of Heidelberg, Rheumaliga Baden-Württemberg e.V., AbbVie, and Novartis. KB also serves as a consultant/receives speaker fee/travel reimbursements from AbbVie, BMS, Janssen, MSD, Viatris, Gilead/Galapagos, Lilly, Medac, Mundipharma, Novartis, Pfizer, Roche, and UCB. MES has served on a scientific advisory board for Mallinckrodt. LC serves as a consultant/receives honorarium/travel reimbursements from Pfizer, Bristol Myers Squibb, MSD. The remaining authors have no conflicts of interest or disclosures. MJS reports personal fees from NovoNordisk, Janssen, Mundipharma, AstraZeneca, Esteve, Fresenius, Ingelheim Lilly, Vifor, ICU, Pfizer, Bayer, Travere Therapeutics, GE Healthcare and Boehringer Ingelheim. MJS is a consultant for NovoNordisk, Travere Therapeutics, GE Healthcare, AstraZeneca, and Boehringer. MJS receives grant support form Boehringer Ingelheim, ISCIIII-FEDER and ISCIII-RETICS REDinREN, grant number PI17/00257, PI21/01292, RD16/0009/0030, RICORS RD21/0005/0016, Marató TV3 2020 421/C/2020, Marató TV3 2021 215/C/2021, and EIN2020-112338. MJS is elected Editor-in-Chief of Clinical Kidney Journal., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Urticarial vasculitis is a clinicopathologic entity defined by recurrent episodes of urticarial lesions that persist > 24 hours and demonstrate the histopathologic features of leukocytoclastic vasculitis. The most important prognostic feature is the presence of normo- or hypocomplementemia. In the latter, patients are much more likely to have systemic manifestations. Urticarial vasculitis is most often idiopathic, but it can arise in association with autoimmune connective diseases, cryoglobulinemia, infections, medications, and hematologic malignancies., Case Presentation: We present the case of a 61-year-old Caucasian woman with a skin eruption that consisted of erythematous plaques on the trunk and limbs that lasted > 24 hours but were asymptomatic. The skin eruption had an acute onset and persisted for 3 months upon initial presentation in our dermatology department. A punch biopsy showed signs of a leukocytoclastic vasculitis in the superficial dermis. On laboratory examination, signs of activation of the complement system were found with low complement C3, C4, and C1q, and with a high anti-C1q antibody titer. The clinical, histological, and lab results fit the diagnosis of hypocomplementemic urticarial vasculitis. There was also a positive antinuclear factor with elevated U1 small nuclear ribonucleoprotein and high double-stranded DNA determined by Farr method. On urinalysis, marked proteinuria and massive hematuria were found. Kidney biopsy showed focal crescentic and focal mesangial type of glomerular damage with a full-blown positivity of immunoglobulin A, immunoglobulin G, and C1q, leading to lupus nephritis class III-A (according to the International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis). The patient was treated with hydroxychloroquine, corticosteroids, and low-dose intravenous cyclophosphamide (Euro-Lupus regimen) as remission-inducing agent, followed by azathioprine as remission-maintaining agent. This treatment regimen gave good results, with total clearance of the skin lesions and remission of the lupus nephritis., Conclusion: Clinicopathologic recognition of urticarial vasculitis with correct screening for extracutaneous disease can lead to early diagnosis of serious organ involvement and thereby improve prognosis for the patient., (© 2022. The Author(s).)

Background and Objectives: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation., Design, Setting, Participants, & Measurements: To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA-derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy., Results: In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell-mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies., Conclusions: The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch., (Copyright © 2022 by the American Society of Nephrology.)

Kidney transplant injury processes are associated with molecular changes in kidney tissue, primarily related to immune cell activation and infiltration. How these processes are reflected in the circulating immune cells, whose activation is targeted by strong immunosuppressants, is poorly understood. To study this, we analyzed the molecular alterations in 384 peripheral blood samples from four European transplant centers, taken at the time of a kidney allograft biopsy, selected for their phenotype, using RNA-sequencing. In peripheral blood, differentially expressed genes in 136 rejection and 248 no rejection samples demonstrated upregulation of glucocorticoid receptor and nucleotide oligomerization domain-like receptor signaling pathways. Pathways enriched in antibody-mediated rejection (ABMR) were strongly immune-specific, whereas pathways enriched in T cell-mediated rejection were less immune related. In polyomavirus infection, upregulation of mitochondrial dysfunction and interferon signaling pathways was seen. Next, we integrated the blood results with transcriptomics of 224 kidney allograft biopsies which showed consistently upregulated genes per phenotype in both blood and biopsy. In single-cell RNASeq (scRNASeq) analysis of seven kidney allograft biopsies, the consistently overexpressed genes in ABMR were mostly expressed by infiltrating leukocytes in the allograft. Similarly, in peripheral blood scRNASeq analysis, these genes were overexpressed in ABMR in immune cell subtypes. Furthermore, overexpression of these genes in ABMR was confirmed in independent cohorts in blood and biopsy. Thus, our results highlight the immune activation pathways in peripheral blood leukocytes at the time of kidney allograft pathology, despite the use of current strong immunosuppressants, and provide a framework for future therapeutic interventions., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Chemotherapeutic agents used to treat cancer generally have narrow therapeutic indices along with potentially serious adverse toxicities. Many cancer drugs are at least partially excreted through the kidney and, thus, the availability of accurate data on safe and effective dosing of these drugs in patients with chronic kidney disease (CKD) is essential to guide treatment decisions. Typically, during drug development, initial clinical studies only include patients with normal or only mildly impaired kidney function. In subsequent preregistration studies, a limited number of patients with more severe kidney dysfunction are included. Data obtained from patients with either severe kidney dysfunction (here defined as an estimated glomerular filtration rate [eGFR] < 30 ml/min or stage 4G CKD) or end-stage kidney disease (ESKD) requiring kidney replacement treatment are particularly limited before drug registration and only a minority of new drug applications to the US Food and Drug Administration (FDA) include data from this population. Unfortunately, limited data and/or other safety concerns may result in a manufacturer statement that the drug is contraindicated in patients with advanced kidney disease, which hinders access to potentially beneficial drugs for these patients. This systemic exclusion of patients with CKD from cancer drug trials remains an unsolved problem, which prevents provision of optimal clinical care for these patients, raises questions of inclusion, diversity, and equity. In addition, with the aging of the population, there are increasing numbers of patients with CKD and cancer who face these issues. In this review, we evaluate the scientific basis to exclude patients with CKD from cancer trials and propose a comprehensive strategy to address this problem., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Commonly used immunosuppressive drugs are efficacious in the prevention of transplanted solid organ rejection but, are complicated by an increased rate of malignancies. Treatment of the latter with cancer immunotherapy is frequently associated with increased graft loss from rejection., Methods: B16 melanoma was inoculated subcutaneously (s.c.) in the ear of host B6 mice carrying a heterotopic allogenic murine heart. Intratumoral (i.t.) immunotherapy with anti-programmed death-1 (PD-1) and a toll-like receptor 9 (TLR9) agonist was conducted to treat cancer. Cyclosporine A (CsA) therapy or replaced by other immunosuppressive agents was conducted to preserve heart allograft tolerance, respectively., Results: Here we show that long-term allograft-bearing mice receiving CsA therapy and challenged with host-type melanoma resist cancer immunotherapy and reject their grafts after CsA withdrawal. However, when CsA therapy is replaced by intermittent administration of the PI4KIIIβ inhibitor UCB9608, effective antitumor immunity is induced while preserving graft tolerance. UCB9608 switch combined with i.t. immunotherapy resulted in donor-specific tolerance with preserved third-party responses. This operational tolerance may not be dependent on regulatory T cells (Tregs)., Conclusions: Immune effects induced by UCB9608 switch following CsA therapy allow for antitumor immunity, opening up new approaches to establish donor-specific operational tolerance in solid organ transplantation with cancer., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover., Study Design: Cross-sectional retrospective diagnostic test study., Setting & Participants: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies., Tests Compared: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b)., Outcome: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99)., Results: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis., Limitations: The single-center approach and heterogeneity of the study cohort are main limitations of this study., Conclusions: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease., (Copyright © 2021. Published by Elsevier Inc.)

Patients with malignancies have a high prevalence of kidney disease and are often treated with antineoplastic agents that undergo kidney metabolism or excretion or clearance via renal replacement therapies. Thus, the dosing of these agents, including classic chemotherapeutic drugs, targeted therapies, and immunotherapy, must take into account patients' kidney function. In this review, we will discuss the pitfalls of accurate measurement of kidney function and how kidney disease affects both pharmacodynamic and pharmacokinetic properties of drugs. Lastly, we will discuss specific agents and summarize current dosing strategies for use in patients with chronic kidney disease and end-stage kidney disease., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year., Methods: We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism., Results: Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P< 0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P <0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip., Conclusions: Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients., Clinical Trial Registry Name and Registration Number: Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950., (Copyright © 2022 by the American Society of Nephrology.)

Transplantation offers cure for some haematological cancers, end-stage organ failure, but at the cost of long-term complications. Renal transplantation is the best-known kidney replacement therapy and it can prolong end-stage renal disease patient lives for decades. However, patients after renal transplantation are at a higher risk of developing different complications connected not only with surgical procedure but also with immunosuppressive treatment, chronic kidney disease progression and rejection processes. Various blood disorders can develop in post-transplant patients ranging from relatively benign anaemia through cytopenias to therapy-related myelodysplasia and acute myeloid leukaemia (AML) and post-transplant lymphoproliferative disorders followed by a rare and fatal condition of thrombotic microangiopathy and haemophagocytic syndrome. So far literature mainly focused on the post-transplant lymphoproliferative disease. In this review, a variety of haematological problems after transplantation ranging from rare disorders such as myelodysplasia and AML to relatively common conditions such as anaemia and iron deficiency are presented with up-to-date diagnosis and management., (© The Author(s) 2020. Published by Oxford University Press on behalf of the ERA.)

Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Loon, Lamarthée, Barba, Claes, Coemans, de Loor, Emonds, Koshy, Kuypers, Proost, Senev, Sprangers, Tinel, Thaunat, Van Craenenbroeck, Schols and Naesens.)

Background: Many kidney allografts fail due to the occurrence of antibody-mediated rejection (ABMR), related to donor-specific anti-HLA antibodies (HLA-DSA). However, the histology of ABMR can also be observed in patients without HLA-DSA. While some non-HLA antibodies have been related to the histology of ABMR, it is not well known to what extent they contribute to kidney allograft injury. Here we aimed to investigate the role of 82 different non-HLA antibodies in the occurrence of histology of ABMR after kidney transplantation., Methods: We included all patients who underwent kidney transplantation between 2004-2013 in a single center and had biobanked serum. Pre- and post-transplant sera (n=2870) were retrospectively tested for the presence of 82 different non-HLA antibodies using a prototype bead assay on Luminex ( Immucor, Inc ). A ratio was calculated between the measured MFI value and the cut-off MFI defined by the vendor for each non-HLA target., Results: 874 patients had available pretransplant sera and were included in this analysis. Of them, 133 (15.2%) received a repeat kidney allograft, and 100 (11.4%) had pretransplant HLA-DSA. In total, 204 (23.3%) patients developed histology of ABMR after kidney transplantation. In 79 patients (38.7%) the histology of ABMR was explained by pretransplant or de novo HLA-DSA. The multivariable Cox analysis revealed that only the broadly non-HLA sensitized (number of positive non-HLA antibodies) patients and those with the highest total strength of the non-HLA antibodies (total ratios of the positive non-HLA antibodies) were independently associated with increased rates of histology of ABMR after transplantation. Additionally, independent associations were found for antibodies against TUBB (HR=2.40; 95% CI 1.37 - 4.21, p=0.002), Collagen III (HR=1.67; 95% CI 1.08 - 2.58, p=0.02), VCL (HR=2.04; 95% CI 1.12 - 3.71, p=0.02) and STAT6 (HR=1.47; 95% CI 1.01 - 2.15, p=0.04). The overall posttransplant non-HLA autoreactivity was not associated with increased rates of ABMRh., Conclusions: This study shows that patients highly and broadly sensitized against non-HLA targets are associated with an increased risk of ABMR histology after kidney transplantations in the absence of HLA-DSA. Also, some pretransplant non-HLA autoantibodies are individually associated with increased rates of ABMR histology. However, whether these associations are clinically relevant and represent causality, warrants further studies., Competing Interests: BR, JH, and CH are employees of Immucor Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Senev, Ray, Lerut, Hariharan, Heylen, Kuypers, Sprangers, Emonds and Naesens.)

Objectives: Renal fibrosis accompanies all chronic kidney disorders, ultimately leading to end-stage kidney disease and the need for dialysis or even renal replacement. As such, renal fibrosis poses a major threat to global health and the search for effective therapeutic strategies to prevent or treat fibrosis is highly needed. We evaluated the applicability of a highly positively charged human peptide derived from the COOH-terminal domain of the chemokine CXCL9, namely CXCL9(74-103), for therapeutic intervention. Because of its high density of net positive charges at physiological pH, CXCL9(74-103) competes with full-length chemokines for glycosaminoglycan (GAG) binding. Consequently, CXCL9(74-103) prevents recruitment of inflammatory leucocytes to sites of inflammation., Methods: CXCL9(74-103) was chemically synthesised and tested in vitro for anti-fibrotic properties on human fibroblasts and in vivo in the unilateral ureteral obstruction (UUO) mouse model., Results: CXCL9(74-103) significantly reduced the mRNA and/or protein expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and collagen III by transforming growth factor (TGF)-β1-stimulated human fibroblasts. In addition, administration of CXCL9(74-103) inhibited fibroblast migration towards platelet-derived growth factor (PDGF), without affecting cell viability. In the UUO model, CXCL9(74-103) treatment significantly decreased renal α-SMA, vimentin, and fibronectin mRNA and protein expression. Compared with vehicle, CXCL9(74-103) attenuated mRNA expression of TGF-β1 and the inflammatory markers/mediators MMP-9, F4/80, CCL2, IL-6 and TNF-α. Finally, CXCL9(74-103) treatment resulted in reduced influx of leucocytes in the UUO model and preserved tubular morphology. The anti-fibrotic and anti-inflammatory effects of CXCL9(74-103) were mediated by competition with chemokines and growth factors for GAG binding., Conclusions: Our findings provide a scientific rationale for targeting GAG-protein interactions in renal fibrotic disease., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is the first population-based native kidney biopsy registry in Flanders, Belgium. In this first analysis, we report on patient demographics, frequency distribution and incidence rate of biopsied kidney disease in adults in Flanders., Methods: From January 2017 to December 2019, a total of 2054 adult first native kidney biopsies were included. A 'double diagnostic coding' strategy was used, in which every biopsy sample received a histopathological and final clinical diagnosis. Frequency distribution and incidence rate of both diagnoses were reported and compared with other European registries., Results: The median age at biopsy was 61.1 years (interquartile range, 46.1-71.7); male patients were more prevalent (62.1%) and biopsy incidence rate was 129.3 per million persons per year. Immunoglobulin A nephropathy was the most frequently diagnosed kidney disease (355 biopsies, 17.3% of total) with a similar frequency as in previously published European registries. The frequency of tubulointerstitial nephritis (220 biopsies, 10.7%) and diabetic kidney disease (154 biopsies, 7.5%) was remarkably higher, which may be attributed to changes in disease incidence as well as biopsy practices. Discordances between histopathological and final clinical diagnoses were noted and indicate areas for improvement in diagnostic coding systems., Conclusions: The FCGG registry, with its 'double diagnostic coding' strategy, provides useful population-based epidemiological data on a large Western European population and allows subgroup selection for future research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Acute kidney injury (AKI), either of pre-renal, renal or post-renal origin, is an important complication in cancer patients, resulting in worse prognosis, withdrawal from effective oncological treatments, longer hospitalizations and increased costs. The aim of this article is to provide a literature review of general and cause-specific treatment strategies for AKI, providing a helpful guide for clinical practice. We propose to classify AKI as patient-related, cancer-related and treatment-related in order to optimize therapeutic interventions. In the setting of patient-related causes, proper assessment of hydration status and avoidance of concomitant nephrotoxic medications is key. Cancer-related causes mainly encompass urinary compression/obstruction, direct tumoural kidney involvement and cancer-induced hypercalcaemia. Rapid recognition and specific treatment can potentially restore renal function. Finally, a pre-treatment comprehensive evaluation of risks and benefits of each treatment should always be performed to identify patients at high risk of treatment-related renal damage and allow the implementation of preventive measures without losing the potentialities of the oncological treatment. Considering the complexity of this field, a multidisciplinary approach is necessary with the goal of reducing the incidence of AKI in cancer patients and improving patient outcomes. The overriding research goal in this area is to gather higher quality data from international collaborative studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Background: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation., Methods: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously., Results: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization., Conclusions: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

A bone biopsy with prior tetracycline labeling is the gold standard to diagnose renal osteodystrophy. In cases of missing tetracycline labels, it is still paramount to gain clinically relevant information from the extracted bone sample, by evaluating the static histomorphometry. This study investigates the diagnostic performance of static histomorphometry for the evaluation of high and low bone turnover. Transiliac bone biopsies taken pre- or post- kidney transplantation, of sufficient quality for a full histomorphometric analysis were included (n = 205). The cohort was randomly split to provide separate exploration and validation subsets. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover, and all were significant predictors of both high and low bone turnover (AUC 0.71-0.84). Diagnostic performance was very good for high turnover, as a combination of static parameters resulted in negative and positive predictive values (NPV and PPV) of 80% and 96%, respectively. For low turnover, the combined model resulted in PPV of 71% and NPV of 82%. We conclude that in the absence of tetracycline labels, static histomorphometry provide an acceptable alternative for a diagnosis of bone turnover in renal osteodystrophy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The interplay between donor-specific anti-HLA antibodies (HLA-DSA), histology of active antibody-mediated rejection (aABMR h ), transplant glomerulopathy (cg), and graft failure in kidney transplantation remains insufficiently understood. We performed a single-center cohort study (n = 1000) including 2761 protocol and 833 indication biopsies. Patients with pretransplant HLA-DSA were more prone to develop aABMRh (OR 22.7, 95% CI, 11.8-43.7, P < 0.001), cg (OR 5.76, 95% CI, 1.67-19.8, P = 0.006), and aABMRh/cg (OR 19.5, 95% CI, 10.6-35.9, P < 0.001). The negative impact of pre-transplant HLA-DSA on graft survival (HR 2.12, 95% CI, 1.41-3.20, P < 0.001) was partially mediated through aABMRh and cg occurrence. When adjusted for time-dependent HLA-DSA (HR 4.03, 95% CI, 2.21-7.15, P = 0.002), graft failure was only affected by aABMR h when cg was evident. In HLA-DSA negative patients, aABMR h was associated with impaired graft outcome only when evolving to cg (HR 1.32, 95% CI, 1.07-1.61, P = 0.008). We conclude that the kinetics of HLA-DSA are important to estimate the rate of graft failure, and that histological follow-up is necessary to discover, often subclinical, ABMR and cg. In the absence of HLA-DSA, patients experience similar histological lesions and the evolution to transplant glomerulopathy associates with impaired graft outcome., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer., Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI., Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI., Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I-mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage in vitro , and has been associated with HLA-DSA-negative MVI. However, missing self's clinical importance as a nonhumoral trigger of allograft rejection remains unclear., Methods: In a population-based study of 924 consecutive kidney transplantations between March 2004 and February 2013, we performed high-resolution donor and recipient HLA typing and recipient KIR genotyping. Missing self was defined as the absence of A3/A11, Bw4, C1, or C2 donor genotype, with the presence of the corresponding educated recipient inhibitory KIR gene., Results: We identified missing self in 399 of 924 transplantations. Co-occurrence of missing self types had an additive effect in increasing MVI risk, with a threshold at two concurrent types (hazard ratio [HR], 1.78; 95% confidence interval [95% CI], 1.26 to 2.53), independent of HLA-DSA (HR, 5.65; 95% CI, 4.01 to 7.96). Missing self and lesions of cellular rejection were not associated. No HLA-DSAs were detectable in 146 of 222 recipients with MVI; 28 of the 146 had at least two missing self types. Missing self associated with transplant glomerulopathy after MVI (HR, 2.51; 95% CI, 1.12 to 5.62), although allograft survival was better than with HLA-DSA-associated MVI., Conclusion: Missing self specifically and cumulatively increases MVI risk after kidney transplantation, independent of HLA-DSA. Systematic evaluation of missing self improves understanding of HLA-DSA-negative MVI and might be relevant for improved diagnostic classification and patient risk stratification., (Copyright © 2021 by the American Society of Nephrology.)

Posttransplant lymphoproliferative disorder (PTLD) is one of the most feared complications following kidney transplantation. Over a 10-year period, the risk of PTLD in kidney transplant recipients (KTRs) is 12-fold higher than in a matched nontransplanted population. Given the number of kidney transplants performed, KTRs who experience PTLD outnumber other organ transplant recipients who experience PTLD. Epstein-Barr virus infection is one of the most important risk factors for PTLD, even though 40% of PTLD cases in contemporary series are not Epstein-Barr virus-associated. The overall level of immunosuppression seems to be the most important driver of the increased occurrence of PTLD in solid organ transplant recipients. Reduction in immunosuppression is commonly accepted to prevent and treat PTLD. Although the cornerstone of PTLD treatment had been chemotherapy (typically cyclophosphamide-doxorubicin-vincristinr-prednisone), the availability of rituximab has changed the treatment landscape in the past 2 decades. The outcome of PTLD in KTRs has clearly improved as a result of the introduction of more uniform treatment protocols, improved supportive care, and increased awareness and use of positron emission tomography combined with computed tomography in staging and response monitoring. In this review, we will focus on the most recent data on epidemiology, presentation, risk factors, and management of PTLD in KTRs., (Copyright © 2021 National Kidney Foundation, Inc. All rights reserved.)

Single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) allow transcriptomic profiling of thousands of cells from a renal biopsy specimen at a single-cell resolution. Both methods are promising tools to unravel the underlying pathophysiology of glomerular diseases. This review provides an overview of the technical challenges that should be addressed when designing single-cell transcriptomics experiments that focus on glomerulopathies. The isolation of glomerular cells from core needle biopsy specimens for single-cell transcriptomics remains difficult and depends upon five major factors. First, core needle biopsies generate little tissue material, and several samples are required to identify glomerular cells. Second, both fresh and frozen tissue samples may yield glomerular cells, although every experimental pipeline has different (dis)advantages. Third, enrichment for glomerular cells in human tissue before single-cell analysis is challenging because no effective standardized pipelines are available. Fourth, the current warm cell-dissociation protocols may damage glomerular cells and induce transcriptional artifacts, which can be minimized by using cold dissociation techniques at the cost of less efficient cell dissociation. Finally, snRNA-seq methods may be superior to scRNA-seq in isolating glomerular cells; however, the efficacy of snRNA-seq on core needle biopsy specimens remains to be proven. The field of single-cell omics is rapidly evolving, and the integration of these techniques in multiomics assays will undoubtedly create new insights in the complex pathophysiology of glomerular diseases., (Copyright © 2021 by the American Society of Nephrology.)

Donor organs are exposed to sequential temperature changes during the transplantation process. The role of donor warm ischemia and cold ischemia times on post-transplant outcomes has been extensively studied. Much less attention has been paid to the transient ischemia occurring during donor organ removal and implantation. Recently, it has become clear that prolonged donor nephrectomy and implantation time are independently associated with delayed graft function after kidney transplantation. In addition, implantation time correlates with post-transplant kidney graft function, histology, and survival. Similar detrimental associations of donor hepatectomy and implantation time with early allograft dysfunction, ischemic cholangiopathy, and graft and patient survival after liver transplantation have been demonstrated. This review details kidney and liver temperature changes occurring during procurement and transplantation. It summarizes the effects of the ischemia the kidney and liver sustain during these phases on short- and long-term post-transplant outcomes, advocating the standardized reporting of donor hepatectomy, donor nephrectomy, and implantation times in (inter)national registries. The review also explores strategies to protect the graft from this ischemic injury., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Focal segmental glomerulosclerosis is a histopathological pattern of renal injury and comprises a heterogeneous group of clinical conditions with different pathophysiology, clinical course, prognosis, and treatment. Nevertheless, subtype differentiation in clinical practice often remains challenging, and we currently lack reliable diagnostic, prognostic, and therapeutic biomarkers. The advent of new transcriptomics techniques in kidney research poses great potential in the identification of gene expression biomarkers that can be applied in clinical practice., Summary: Transcriptomics techniques have been completely revolutionized in the last 2 decades, with the evolution from low-throughput reverse-transcription polymerase chain reaction and in situ hybridization techniques to microarrays and next-generation sequencing techniques, including RNA-sequencing and single-cell transcriptomics. The integration of human gene expression profiles with functional in vitro and in vivo experiments provides a deeper mechanistic insight into the candidate genes, which enable the development of novel-targeted therapies. The correlation of gene expression profiles with clinical outcomes of large patient cohorts allows for the development of clinically applicable biomarkers that can aid in diagnosis and predict prognosis and therapy response. Finally, the integration of transcriptomics with other "omics" modalities creates a holistic view on disease pathophysiology., Key Messages: New transcriptomics techniques allow high-throughput gene expression profiling of patients with focal segmental glomerulosclerosis (FSGS). The integration with clinical outcomes and fundamental mechanistic studies enables the discovery of new clinically useful biomarkers that will finally improve the clinical outcome of patients with FSGS., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by The Author(s). Published by S. Karger AG, Basel.)

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The Banff classification for antibody-mediated rejection (ABMR) has undergone important changes, mainly by inclusion of C4d-negative ABMR in Banff'13 and elimination of suspicious ABMR (sABMR) with the use of C4d as surrogate for HLA-DSA in Banff'17. We aimed to evaluate the numerical and prognostic repercussions of these changes in a single-center cohort study of 949 single kidney transplantations, comprising 3662 biopsies that were classified according to the different versions of the Banff classification. Overall, the number of ABMR and sABMR cases increased from Banff'01 to Banff'13. In Banff'17, 248 of 292 sABMR biopsies were reclassified to No ABMR, and 44 of 292 to ABMR. However, reclassified sABMR biopsies had worse and better outcome than No ABMR and ABMR, which was mainly driven by the presence of microvascular inflammation and absence of HLA-DSA, respectively. Consequently, the discriminative performance for allograft failure was lowest in Banff'17, and highest in Banff'13. Our data suggest that the clinical and histological heterogeneity of ABMR is inadequately represented in a binary classification system. This study provides a framework to evaluate the updates of the Banff classification and assess the impact of proposed changes on the number of cases and risk stratification. Two alternative classifications introducing an intermediate category are explored., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: It has been demonstrated that artemisinin (ART) possesses multiple immune modulatory effects. However, its role as immunosuppressant in allogeneic transplantation is undetermined. Here, we investigated the effect of ART on co-stimulatory signaling in OX40 + T cells and evaluated ART as a potential immunosuppressant in transplantation., Materials and Methods: Allogeneic skin transplantation was performed in C57BL/6 to BALB/c mice. Recipient mice were administrated with vehicle, ART or cyclosporine A daily from day 0 to day 19 post transplantation. Proportions of splenic CD4 + OX40 + and CD4 + CD44 hi CD62L hi cells, and serum IgG was measured by using flow cytometry. An in vitro lymphocyte stimulation with Con A or LPS under various concentrations of ART was performed, expression of CD4 + OX40 + and CD4 + CD44 hi CD62L hi cells was evaluated, and interleukin(IL)-6 production was measured by ELISA., Results: In in vivo allogeneic skin transplant model, ART significantly prolongs allogeneic skin survival. Furthermore, our in vitro studies demonstrate that the immune suppression of ART on T cells is associated with a reduction in OX40 + T cells and inhibition of IL-6 secretion., Conclusion: Our data indicate that the OX40-OX40L pathway and IL-6 are possibly involved in ART-induced immunosuppression, and ART is a potential novel immunosuppressant.

Immune checkpoint inhibitors (ICIs), immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis of patients with advanced malignancy. As the use of ICI therapy becomes increasingly widespread across different types of cancer, their use in patients receiving dialysis is likely to increase. In this review we summarize the current literature on the use of ICIs in end-stage kidney disease (ESKD) patients and provide aggregate data from reported cases and series. Based on available pharmacological information, ICIs require no dosing adjustment in ESKD patients. Analysis of the reported cases in the literature demonstrates a similar incidence of immune-related adverse events in patients with ESKD receiving dialysis as compared with the general population (49%). Severe reactions graded as 3 and 4 have been seen in 15 patients (16%). As such, it is important that these patients are monitored very closely for immune-related adverse events; however, the risk of these adverse events should not preclude patients on dialysis from receiving these therapies. Cancer remission (complete and partial) was seen in close to 30% of patients, stable disease was seen in 28% and progression of disease in ∼36%. One-third of the patients died. Urothelial and renal cell cancer represented approximately half of all treated cancers and accounted for ∼50% of all deaths reported. Additional data in the dialysis population with the use of ICIs and involvement in prospective studies are needed to better assess outcomes, particularly within specific cancer types., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure., Methods: The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance., Results: Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters., Conclusions: A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous., (Copyright © 2021 by the American Society of Nephrology.)

Introduction: Recurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis in the kidney graft is a rare event, described in limited reports. The aim of this study was to evaluate, in a large cohort of patients with long follow-up, the risk of recurrence of anti-GBM disease, the risk factors associated with clinical recurrence, and the long-term patient and graft survival., Methods: This was a multicenter retrospective study. Inclusion criteria were patients with anti-GBM glomerulonephritis who underwent transplantation of a kidney between 1977 and 2015. Exclusion criteria were systemic vasculitis, lupus erythematosus, and cryoglobulinemia. Recurrence was defined as reappearance of clinical signs of glomerulonephritis along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies., Results: A total of 53 patients were included. Recurrence of anti-GBM glomerulonephritis in a first kidney transplant occurred in only 1 patient 5 years after transplantation (a prevalence rate of 1.9%) in the context of cessation of immunosuppressive drugs, and resulted in graft loss due to recurrence. Linear IgG staining on kidney biopsy in the absence of histological signs of proliferative glomerulonephritis was observed in 4 patients, in the context of cellular rejection. Patient survival was 100%, 94%, and 89% at 5, 10, and 15 years, respectively. Death-censored first-graft survival rates were 88%, 83%, and 79% at 5, 10, and 15 years, respectively., Conclusion: The recurrence rate of anti-GBM glomerulonephritis after transplantation is very low but is associated with graft loss. The long-term patient and graft survival rates are excellent., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA using different activation models. CADA inhibited lymphocyte proliferation with low cellular toxicity in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads, phytohemagglutinin or anti-CD3 antibodies. The immunosuppressive effect of CADA involved both CD4 + and CD8 + T cells but was, surprisingly, most prominent in the CD8 + T cell subpopulation where it inhibited cell-mediated lympholysis. Immunosuppression by CADA was characterized by suppressed secretion of various cytokines, and reduced CD25, phosphoSTAT5 and CTPS-1 levels. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8 + T cells. More specifically, CADA blocked 4‑1BB protein biosynthesis by inhibition of its co-translational translocation into the ER in a signal peptide-dependent way. Taken together, this study demonstrates that CADA, as potent down-modulator of human CD4 and 4‑1BB receptor, has promising immunomodulatory characteristics. This would open up new avenues toward chemotherapeutics that act as selective protein down-modulators to treat various human immunological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Claeys, Pauwels, Humblet-Baron, Provinciael, Schols, Waer, Sprangers and Vermeire.)

Alloantibodies, in particular immunoglobulin G (allo-IgG), confer a rejection advantage to tumors sharing the same major histocompatibility complex (MHC) in mice. However, when administrated intratumorally, this effect can only be achieved in combination with dendritic cells (DCs) activation. Here, we developed high titer allo-IgG by multiple rounds of immunization with allogenic B16 melanoma cells, which allows for the strong binding with B16 cells. We demonstrate that B16 cells incubated with these allo-IgG (referred to as allo-IgG-B16) become highly immunogenic, which release tumor antigens that are efficiently presented by classic DCs in lymph nodes (LNs). Injection of allo-IgG-B16 turns the tumor into an immune hot one and even elicits a systemic antitumor response when used together with 5-fluorouracil (5-FU). This systemic response is tumor-specific and relies on the critical site - LNs. Our findings provide a rationale for the use of allo-IgG in cancer treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Artemisinin (ART) has been shown to suppress B cell activation and plasma cell formation. However, its effect on splenic marginal zone (MZ) B cells is unknown. Splenic MZ B cells play a critical role in rapidly induced Ab production against blood-borne foreign Ags. Dysfunction of MZ B cells, due to inhibition of its proliferation or displacement of its homing, results in an attenuated adaptive humoral response. Here, we investigate the effect of ART on splenic MZ B (CD19 + CD21 high CD23 low ) and B10 (CD19 + CD1d high CD5 + ) B cells to explore the mechanisms of ART-induced immunosuppression in T cell-deficient nude mice challenged with hamster xenoantigens. In this study, we demonstrate that ART decreases T cell-independent xenogeneic IgM Ab production and, this is associated with a strong suppression of MZ B cell proliferation and a relative increase of CD21 low CD23 + follicular and B10 B cells. In addition, this suppression impairs IL-10 production. Taken together, our data indicate that ART suppresses B cell immune responses through a distinctive effect on splenic MZ B and other B cells. This represents a new mechanism of ART-induced immunosuppression., (©2020 Society for Leukocyte Biology.)

Correct drug dosing of anticancer agents is essential to obtain optimal outcomes. Overdosing will result in increased toxicity, treatment interruption and possible cessation of anticancer treatment. Underdosing may result in suboptimal anti-cancer effects and may increase the risk of cancer-related mortality. As it is practical nor feasible to perform therapeutic drug monitoring for all anti-cancer drugs, kidney function is used to guide drug dosing for those drugs whose primary mode of excretion is through the kidney. However, it is not well-established what method should be utilized to measure or estimate kidney function and the choice of method does influence treatment decisions regarding eligibility for anti-cancer drugs and their dose. In this review, we will provide an overview regarding the importance of drug dosing, the preferred method to determine kidney function and a practical approach to drug dosing of anticancer drugs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Institut Georges Lopez-1 (IGL-1) solution is increasingly used for kidney preservation, although little information on outcomes is available. Outcomes of all deceased donor kidneys preserved by IGL-1, University of Wisconsin solution (UW), or histidine-tryptophan-ketoglutarate (HTK) and transplanted in our center (2000-2018) were analyzed. Multivariable analysis for delayed graft function (DGF), functional DGF, estimated glomerular filtration rate (eGFR, CKD-EPI equation), proteinuria, acute rejection, death-censored graft loss, and patient survival were performed. A double robust approach, consisting of propensity score weighting and correction for confounders, minimized the risk of bias. In total, 1943 transplants were included: 234 with IGL-1, 1046 with UW, and 663 with HTK. As IGL-1 was only introduced in 2014, a prespecified sensitivity analysis of 917 kidneys (2010-2018) was performed using the same statistical approach. After weighting, IGL-1 retained a higher proportion of kidneys donated after circulatory death (DCD). IGL-1 was not independently associated with any of the outcomes when compared to UW or HTK. Sensitivity analysis between 2010 and 2018 showed similar results. In this retrospective analysis, using robust methodology to reduce the risk of bias, IGL-1 preservation results in equal outcomes compared to UW or HTK, despite more DCD transplants in the IGL-1 group., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)