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Background: Interstitial fibrosis and tubular atrophy (IFTA) is a critical factor in the prognosis of kidney health. Currently, IFTA quantitation in kidney biopsy samples is crucial for diagnosis and assessing disease severity, but the available non-invasive biomarkers are not satisfactory. Proteomic studies identified urinary vitronectin (VTN) as a potential biomarker for kidney fibrosis. As mass spectrometry techniques are not practical for use in clinical settings, we tested whether evaluation of urinary VTN levels through enzyme-linked immunosorbent assay (ELISA) can help monitor fibrotic changes in kidney transplant recipients and prove the clinical viability of the assay., Methods: A total of 58 kidney transplant (KTx) patients who underwent renal biopsy were included in the study. Patients were categorized into two groups referred as no fibrosis (0%) or with fibrosis (≥ 5%) based on their histological findings. In a subsequent/follow-up analysis, the time elapsed from transplantation was also considered. The urinary levels of VTN were measured using ELISA., Results: VTN (p = 0.0180) and VTN normalized by urinary creatinine levels (p = 0.0037), were significantly increased in patients with fibrotic grafts. When focusing on patients with long-term grafts (> 3 years from transplantation, n = 36), VTN exhibited superior potential in identifying fibrotic grafts compared to albuminuria (VTN p = 0.0040 vs. albuminuria p = 0.0132). Importantly, in this group, while albuminuria correctly identified 71% of fibrotic patients, the combination of VTN plus albuminuria correctly classified 89% of fibrotic grafts detected by renal biopsy., Conclusions: VTN has emerged as a valid indicator of renal fibrosis. Of interest, urinary levels of VTN in combination with conventional clinical parameters (such as albuminuria) significantly improved the non-invasive detection of renal fibrosis in kidney transplant patients., Competing Interests: Declarations Competing interests F.E.B. holds a related patent with the International Application Number PCT/EP2020/087290. The other authors declare no conflicts of interest., (© 2024. The Author(s).)

Renal transplantation is one of the primary approaches for curing end-stage kidney disease. With advancements in immunosuppressive agents, the short-term and long-term survival rates of transplanted kidneys have significantly improved. However, infections associated with potent immunosuppression have remained a persistent challenge. Among them, BK virus (BKV) reactivation following renal transplantation leading to BK virus-associated nephropathy (BKVAN) is a major cause of graft dysfunction. However, we still face significant challenges in understanding the pathogenesis, prevention, diagnosis, and treatment of BKVAN. These challenges include: 1. The mechanism of BKV reactivation under immunosuppressive conditions has not been well elucidated, leading to difficulties in breakthroughs in clinical research on prevention, diagnosis, and treatment. 2. Lack of proper identification of high-risk individuals, and effective personalized clinical management strategies. 3.Lack of early and sensitive diagnostic markers. 4. Lack of direct and effective treatment options due to the absence of specific antiviral drugs. The purpose of this review is to summarize the current status and cutting-edge advancements in BKV-related research, providing new methods and perspectives to address future research challenges., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Kidney transplant recipients (KTRs) show poor antibody response to the SARS-CoV-2 vaccine. There is limited data on immune response to non-mRNA vaccines in KTRs. We studied the antibody response to the SARS-CoV-2 non-mRNA vaccine in a cohort of kidney transplant recipients., Methods: We included KTRs following up in the tertiary care transplant outpatient clinic from February to April 2022. SARS-CoV-2 spike protein IgG antibody titers were measured using chemiluminescence immunoassay. Data on demographic, clinical, and laboratory characteristics were collected, and patients were characterized by the history of Coronavirus disease 2019 (COVID-19) infection in the past and the number of vaccine doses received. Predictors of antibody response were obtained using multivariate regression analysis., Results: S1/S2 IgG anti-SARS-CoV-2 antibodies were detected in 197 (87.94%) of 224 KTRs with a median [IQR] titers of 307.5 AU/ml [91 AU/ml - 400 AU/ml]. Neutralizing range antibody titers were found in 170/224 (75.9%) KTRs. Diabetes at the time of vaccination was associated with poorer antibody response (aOR 0.31, 95% confidence interval [CI] - 0.10, 0.90; p = 0.032) and vaccination with Covishield™ (ChAdOx1 nCoV- 19 Recombinant CoronaVirus Vaccine) showed higher antibody response as compared to Covaxin™ (BBV152) (aOR 5.04, 95% CI - 1.56, 16.22; p = 0.007). Graft dysfunction at baseline was associated with poorer antibody response., Conclusions: KTRs showed good antibody response after SARS-CoV-2 vaccination with non-mRNA vaccines. Diabetes and graft dysfunction were associated with poor seroconversion rates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Histoplasmosis is endemic in the central/northeast region of Argentina. It is estimated that the incidence of this mycosis is low in solid organ transplant recipients. This work aims to describe the epidemiology, clinical forms, and evolution of kidney transplant recipients diagnosed with histoplasmosis in Santa Fe city, Argentina. A retrospective study was carried out between 2015 and 2020 on kidney transplant patients with symptoms associated with histoplasmosis in Santa Fe. Histoplasmosis diagnosis was performed through histopathology, recovery of Histoplasma spp., by culture, and/or positive nested Polimerase Chain Reaction (PCR) specific for the Histoplasma Hc100 gene. During the study period, 360 kidney transplantations were performed. Of these patients, 12 were diagnosed with histoplasmosis (3.3%). The patients' median age was 51 years, and 75% were male. Eleven patients (92%) presented the disseminated form of the disease. Thirty-three percent were diagnosed with histoplasmosis in their first year post-transplantation (mostly 6-12 months), while 42% received their diagnosis 3 years after transplantation. Laboratory diagnosis was performed by histopathology, culture, and PCR in four cases (33%), by culture and PCR in three cases (25%), and by PCR alone in three cases (25%). Thus, all 12 patients showed positive nested PCR results. All patients received amphotericin B as initial treatment. A good response was observed in 83% of patients. We found a high incidence of histoplasmosis in kidney transplant recipients (up to 10 times higher than reports from other endemic areas). Diagnosis by histopathology/culture showed 75% sensitivity, while nested PCR showed better sensitivity and diagnostic speed., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: The effects of various risk and associated factors on post-kidney transplant anemia (PTA) have not been fully compared and estimated. This meta-analysis aims to elucidate factors contributing to PTA and determine the influence of erythropoietin-stimulating agents (ESAs) on renal outcomes, thus offering potential pathways for enhanced management strategies post-transplant., Methods: A systematic review was conducted in electronical database. Studies reporting on risk factors (with cause-effect relationships) and associated factors (without definite cause-effect relationships) of PTA, and the effects of ESAs on post-kidney transplant outcomes, were included. Pooled odds ratios (ORs) and weighted mean differences (WMDs) were analyzed using random-effects models., Results: This systematic review encompassed 38,233 patients from 85 studies. Factors increased PTA risk included African American, older donor age, human antigen leukocyte mismatches, and low pre-transplant hemoglobin levels. Poor allograft function, high interleukine-6, Cytomegalovirus, delayed graft function, allograft rejections, immunosuppressive medications, and renin-angiotensin system blockades were associated with PTA. Native autosomal dominant polycystic kidney disease was a protective factor against PTA. Administration of ESAs with the aim of normalizing hemoglobin levels in patients with chronic allograft dysfunction slowed the decline in eGFR and reduce the risk of death, with a pooled OR of 0.36 (95% CI: 0.14 to 0.89; p = 0.040)., Conclusions: The risks and associated factors for PTA have been elucidated, underscoring the need for individualized treatment approaches. Late ESA therapy, aimed at hemoglobin normalization, suggests a renal-protective effect and reduced mortality, which should be considered in the management of PTA., Systematic Review Registration: PROSPERO CRD42024545330., Competing Interests: Declarations Ethics approval and consent to participate The data in this systematic review and meta-analysis were derived from published literature, making it impossible to identify individual subjects. No data were directly obtained from human or animal subjects. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.

Metabolic syndrome is a significant risk factor for poor graft outcomes in kidney transplant (KT) patients. However, the effects of variability in metabolic parameters on graft outcomes in KT patients have not been completely elucidated. A total of 852 KT patients were included from the Korean Organ Transplantation Registry. The study exposure was variability in body mass index (BMI) or other metabolic parameters measured at 6 months, 1 year, and 2 years after KT. Patients were classified into tertiles according to the degree of variability. The primary outcome was a composite of adverse kidney outcomes, such as death-censored graft loss or ≥ 30% decline in estimated glomerular filtration rate. The adverse kidney outcomes occurred in 73 (8.6%) participants. The high-BMI variability group had a higher risk for adverse kidney outcomes compared to the low-variability group. High variabilities in triglyceride, fasting blood glucose, and systolic blood pressure were also associated with adverse kidney outcomes. Furthermore, high variability in metabolic syndrome-related composite indices, such as the triglyceride and glucose index and metabolic variability scores, showed a higher risk for adverse kidney outcomes. In conclusion, high variability in metabolic parameters could be associated with an increased risk of adverse kidney outcome in KT patients., (© 2024. The Author(s).)

Antibody-mediated rejection (AMR) is the leading cause of premature kidney transplant failure. The role of alloantibodies against Human Leukocyte Antigens (HLA) has been a primary focus in AMR. More recently autoantibodies and alloantibodies against the angiotensin II receptor type 1 (AT1R) and the endothelin A receptor (ETAR) have been linked to poor allograft outcomes in kidney transplantation. Nevertheless, evidence supporting routine testing remains insufficient. ELISA testing for anti-AT1R and anti-ETAR antibodies was performed in a pediatric renal transplant cohort. We selected 12 pediatric recipients who had undergone protocol biopsies and antibody measurements at 6 and 24 months post-transplant. Immunohistochemistry was performed on biopsies for AT1R and ETAR as well as the adhesion molecules ICAM-1 and VCAM-1. The analysis showed that ICAM-1 and VCAM-1 expression was significantly increased, along with the presence of circulating antibodies, in patients at 24 months post-transplant compared to patients without circulating antibodies. The presence of anti-AT1R and anti-ETAR antibodies does not seem to influence the expression of their receptors in the transplanted organ. Instead, the increase in adhesion molecules may precede the development of histological damage. Therefore, enlarging the cohort and extending long-term observation would help to understand the impact of anti-AT1R and anti-ETAR antibodies after transplantation.

Kidney transplant recipients (KTRs) are highly vulnerable to COVID-19. An intensified scheme of vaccination offers short-term protection to the 50%-75% of KTRs able to develop a germinal center reaction, required for the generation of neutralizing titers of antibodies (NAbs). However, the duration of this vaccinal protection is unknown. In-depth longitudinal analysis of the immune response to vaccination of 33 KTRs demonstrates that the low peak of IgGs, the progressive decline in antibody titers, and the emergence of a variant of concerns (VOC) of SARS-CoV2, synergize to let 2/3 of responders to vaccine without NAbs after only a few months. Yet, a retrospective study of an independent cohort of 274 KTRs, revealed that the risk of severe COVID-19 in the latter was low, similar to that of patients with serum neutralizing capacity against VOC. Our work links this late vaccine protection with the presence of memory B cells, which are generated during the initial vaccine-induced germinal center reaction, have a wide repertoire directed against conserved spike epitopes, and rapidly differentiate into IgG-producing plasma cells upon antigenic rechallenge. We conclude that in contrast with a serological layer that goes fading rapidly, the cellular layer of humoral memory provides an efficient long-term protection against VOC to KTRs. This illustration of the complementary roles of the two layers of the humoral memory has implications in immunopathology beyond the COVID-19 in KTRs., (© 2024 Wiley Periodicals LLC.)

Introduction. The existence of a mutual relationship between gut microbiota and immune homeostasis highlights its importance in the context of kidney transplantation. Gap statement. The translational utility of gut microbiota as a biomarker for allograft injury has not been assessed before. Aim. In this study, we aimed to characterize the gut microbial diversity in kidney transplant recipients and investigate the alterations in the gut microbial composition in association with allograft injury such as histopathological graft rejection and calcineurin inhibitor toxicity. In addition, we compared the gut microbial quantitation using 16S metagenomics and quantitative PCR (qPCR) to assess its translational utility. Methodology. In this prospective longitudinal cohort study, we enrolled 38 kidney transplant recipients and collected serial faecal specimens ( n =114), once before the induction therapy, and twice after transplant, during the first and third month. We characterized the gut microbial composition through 16S rRNA sequencing and qPCR from the DNA isolates of the samples. The recipients were clinically followed up for a median of 600 days post-transplant. Histopathological evidence of allograft rejection and calcineurin inhibitor toxicity were used for the correlational analysis with gut microbial diversity. Results. Significant differences in the gut microbial diversity were observed between the pre- and post-transplant samples. Pre-transplant gut microbiota revealed a higher relative abundance of phylum Bacteroidetes in the allograft rejection group, and a higher relative abundance of phylum Firmicutes was observed in the histopathological features of calcineurin inhibitor toxicity (hCNI toxicity) group. We found a high concordance between 16S metagenomics and qPCR outputs for assessing the gut microbial diversity. Furthermore, the receiver operating characteristic curve analysis has also proven that the pre-transplant levels of gut microbial dysbiosis, as a potential predictive biomarker for allograft injury. Conclusion. Our pilot study found a strong statistical association of gut microbial dysbiosis with kidney allograft injury, highlighting the potential of gut microbiota as a predictive biomarker and that qPCR serves as a more reliable and economic tool for assessing dysbiosis paving the way for its translational utility.

Background: Serial monitoring of dd-cfDNA and change from baseline can provide meaningful information beyond absolute thresholds. We describe dd-cfDNA trajectories from the baseline before and after acute rejection (AR) and de novo donor-specific antibodies (dnDSA) detection in kidney transplant recipients (KTRs)., Methods: We included KTR from 02/2019 to 03/2022 with serial dd-cfDNA. The primary analysis compared the time-varying change in dd-cfDNA from baseline in KTR first AR on biopsy [AR] to patients with no-AR on biopsy [no-AR]., Results: 151 KTR were analyzed (AR = 56 KTR, no-AR = 95 KTRs). In the AR group, dd-cfDNA rose ahead of diagnosis: median rise from baseline was 75% at -3 months, 32% at -2 months, and 325% at -1 month before biopsy. At the time of biopsy, the median rise in dd-cfDNA from baseline was 291% (IQR [interquartile range] 88%-1081%) in AR and 17% (IQR 0%- 194%) in no-AR (p < 0.0001). Following treatment, dd-cfDNA values fell in the AR group with a median change from baseline of 94.7% at +1 month, 10.5% at +2 months, and 0% at +3 months. These trajectories were not observed in the no-AR group. Similarly, there were no significant differences in eGFR (estimated glomerular filtration rate) trajectories between the two groups. The median change from baseline to dnDSA detection was 141% (IQR 112%-574%). In KTRs with persistent rejection, median dd-cfDNA was 0.95% (IQR 0.44-1.8) compared to 0.19% (IQR 0.12-0.31) in subjects with no rejection on follow-up (p < 0.001)., Conclusion: The significant changes from baseline observed before and after AR show how serial monitoring enhances dd-cfDNA utility and allows for earlier identification of evolving injury and monitoring treatment response., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Background: Kidney transplant (KT) candidates often experience hospitalizations, increasing their delirium risk. Hospitalizations and delirium are associated with worse post-KT outcomes, yet their relationship with pre-KT outcomes is less clear. Pre-KT delirium may worsen access to KT due to its negative impact on cognition and ability to maintain overall health., Methods: Using a prospective cohort of 2374 KT candidates evaluated at a single center (2009-2020), we abstracted hospitalizations and associated delirium records after listing via chart review. We evaluated associations between waitlist mortality and likelihood of KT with hospitalizations and hospitalized delirium using competing risk models and tested whether associations differed by gerontologic factors., Results: During a median of 1.8 years after listing, 735 (31.0%) candidates had ≥1 hospitalizations. Candidates with less education, frailty, depressive symptoms, and lower extremity function impairment were more likely to be hospitalized. Hospitalization was associated with higher waitlist mortality (aSHR = 3.65, 95% CI: 2.99-4.45) and a lower likelihood of KT (aSHR = 0.74, 95% CI: 0.66-0.84). Among candidates who were hospitalized, 80 (11%) had ≥1 delirium episodes. Candidates who were older, frail, and impaired in lower extremity function were more likely to have delirium, which was associated with higher waitlist mortality (aSHR = 4.87, 95% CI: 3.42-6.93) and a lower likelihood of KT (aSHR = 0.45, 95% CI: 0.27-0.74). The association between hospitalization and KT differed by candidate age (p interaction  < 0.001), with those aged ≥65 having a 61% lower likelihood of KT., Conclusion: Hospitalization and delirium are associated with worse pre-KT outcomes and have serious implications on candidates' access to KT. Providers should work to reduce preventable instances of delirium., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Torque Teno virus (TTV) load is linked with the functionality of its host's immune system and has been proposed as a potential monitoring tool for immune-modulating therapy. However, the immunological mechanisms of TTV control are incompletely understood. To assess the effect of the classical complement pathway on TTV, 64 healthy volunteers and 10 kidney transplant recipients treated with the anti-C1s antibody sutimlimab were analyzed for serum TTV copy numbers (c/mL) by qPCR. Overall, a correlation was observed between the decrease in complement activity caused by sutimlimab and the TTV load increase (ρ = -0.367, p < 0.001). Subgroup analysis indicated a trend toward TTV load increase in healthy volunteers following the highest sutimlimab dose compared to baseline (100 mg/kg body weight; median 3.5 log 10 c/mL, interquartile range [IQR] 2.8-4.4 vs. 2.9 log 10 c/mL, 0.8-3.5; p = 0.063). Administering multiple lower doses (30 mg/kg) also showed a trend toward TTV load increase in healthy volunteers (1.8 log 10 c/mL, 0-2.3 vs. 1.9, 1.3-2.8; p = 0.054) and a significant increase in transplant recipients (3.5 log 10 c/mL, 3.0-6.1 vs. 4.1, 3.5-6.4; p = 0.004). This report suggests a role for the classical complement pathway in controlling TTV load., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Post-transplant diabetes mellitus (PTDM) is a well-known complication of kidney transplantation that significantly impacts recipient morbidity and mortality. Over the recent years, the incidence of PTDM has increased considerably worldwide. Therefore, the primary purpose of this study was to evaluate the incidence and risk factors for PTDM in living donor kidney transplantation patients in Riyadh, Saudi Arabia., Methods: A retrospective cohort study was conducted at a tertiary transplant center in Riyadh, Saudi Arabia, and data were extracted between February 2016 and March 2022. Patients aged ≥ 18 years who underwent renal transplant with at least one year of post-transplant follow-up were included in the analysis, and their medical records were comprehensively reviewed. Patients < 18 years of age, history of diabetes mellitus, other organ transplants, or those who underwent transplantation outside the Kingdom of Saudi Arabia were excluded from the study., Results: The study included 247 living donor kidney transplant patients, with a mean age of 39.5 ± 14.6 years. 17.0% of the patients were diagnosed with PTDM. Patient age and fasting glucose levels at 6-months and 12-months after transplantation were found to be significant risk factors for the development of PTDM., Conclusion: An increased occurrence of PTDM emphasizes the importance of identifying high-risk patients prior to transplantation and implementing early interventions to prevent potential complications that could affect graft and patient survival., (© 2024. The Author(s).)

Introduction: Histopathological findings of chronic active T-cell-mediated rejection (CA-TCMR) have been reported to potentially improve with treatment. However, whether this improvement is associated with a better renal prognosis remains unclear. This study was performed to analyze the impact of the histological response to therapy on kidney allograft survival in patients with CA-TCMR., Methods: The data of patients diagnosed with CA-TCMR between January 2018 and May 2023 were retrospectively reviewed. A composite graft endpoint was defined as a two-fold increase in the serum creatinine level or the development of end-stage kidney disease., Results: Thirty-seven patients with CA-TCMR underwent 46 follow-up biopsies. Eleven patients who were diagnosed with CA-TCMR at the last biopsy were classified as the persistent group, while the remaining 26 patients were classified as the transient group. Both before and after treatment, there were no significant changes in serum creatinine, estimated glomerular filtration rate, or proteinuria in either group. However, the transient group showed a significant reduction in interstitial fibrosis and tubular atrophy without a specific etiology (IFTA). This improvement was attributed to better histopathological Banff scores after treatment. Patients with persistent CA-TCMR had significantly worse graft survival than those with transient CA-TCMR (p = 0.002), even after adjusting for significant clinical factors (hazard ratio: 11.4; 95% CI: 1.1-120.0; p = 0.043)., Conclusion: Our findings suggest that the persistence of histopathologic evidence of CA-TCMR after treatment is a significant risk factor for allograft loss compared with transient CA-TCMR., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We aimed to investigate the immune responses to homologous and heterologous COVID-19 booster vaccinations in renal transplant recipients (RTRs) and to identify factors affecting these responses. In this prospective multicenter observational study, we measured the antibody kinetics of 90 RTRs using the chemiluminescent microparticle immunoassay method. The mean age of participants was 45.2 ± 11.4 years, with 35.6% being female. On the 42nd day after the first vaccine dose, the median antibody level was 16.7 (IQR 2.5-249.5) AU/mL, and the seropositivity rate was 60% (n = 36). Mycophenolic acid (MFA) (OR: 0.087, 95% CI: 0.024-0.311) and ACE inhibitor use (OR: 0.203, 95% CI: 0.052-0.794) were identified as independent factors affecting seropositivity. Patients who received the Pfizer/BioNTech booster had significantly higher antibody levels compared to those who received the CoronaVac/Sinovac booster (p = 0.021). Additionally, a significantly higher rate of COVID-19 positivity was observed among patients who received the CoronaVac/Sinovac booster (p = 0.031). Heterologous COVID-19 booster vaccination is significantly more effective than homologous inactivated booster vaccination in enhancing immune responses and preventing new infections in RTRs. MFA and ACE inhibitor usage were independent factors affecting seropositivity. Additional COVID-19 vaccine doses are needed in this patient group., (Journal of Medical Virology© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Renal ischemia/reperfusion (I/R) injury is a common clinical challenge faced by clinicians in kidney transplantation. I/R is the leading cause of acute kidney injury, and it occurs when blood flow to the kidney is interrupted and subsequently restored. I/R impairs renal function in both short and long terms. Renal ischemic preconditioning refers to all maneuvers intended to prevent or attenuate ischemic damage. In this context, the present review focuses on the dual-specificity phosphatase 3 (DUSP3), also known as vaccinia H1-related phosphatase, an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 has different biological functions: (1) it acts as a tumor modulator and (2) it is involved in the regulation of immune response, thrombosis, hemostasis, angiogenesis, and genomic stability. These functions occur either through MAPK-dependent or MAPK-independent mechanisms. DUSP3 genetic deletion dampens kidney damage and inflammation caused by I/R in mice, suggesting DUSP3 as a potential target for preventing renal I/R injury. Here, we discuss the putative role of DUSP3 in ischemic preconditioning and the potential mechanisms of such an attenuated inflammatory response via improved kidney perfusion and adequate innate immune response., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination is severely impaired in patients on maintenance immunosuppression after kidney transplantation., Methods: We conducted a prospective cohort study of 194 kidney transplant recipients (KTR) who exhibited no response to SARS-CoV-2 vaccinations (i.e., SARS-CoV-2 spike protein antibodies ≤264 U/mL) and had no prior documented infection. Patients received 300 mg of cilgavimab/tixagevimab as SARS-CoV-2 pre-exposure prophylaxis (PrEP) between March 4, 2022, and May 3, 2022 and were contrasted to a matched cohort of 186 KTRs also without immunization again defined as SARS-CoV-2 spike protein antibodies ≤264 U/mL and no documented prior infection. The primary outcome was the serum kinetics of cilgavimab/tixagevimab, the secondary endpoints were time to SARS-CoV-2 breakthrough infection, severity of disease and variant specific live viral in vitro neutralization tests of patient sera., Findings: Longitudinal serum level monitoring showed a half-life of 91 days for both antibodies (95% CI 86-95 days for cilgavimab and 85-96 days for tixagevimab) in KTRs. In vitro neutralization tests showed effectiveness against the BA.2 omicron subvariant but not BA.5. The cumulative incidence of SARS-CoV-2 infections until May 15, 2022, (BA.2 dominance) was 15/194 vs 36/186 in the PrEP and control group respectively (OR = 0.35, 95% CI 0.18-0.66) but was not different thereafter (BA.4/5 dominance). The number of severe infections during the BA.2 period was lower in the prophylaxis than in the control group (OR = 0.37, 95% CI 0.17-0.79)., Interpretation: This study showed that SARS-CoV-2 PrEP with cilgavimab/tixagevimab demonstrated clinical effectiveness against variants that are neutralised (BA.2) but not against BA.4/5., Funding: This study was funded by the Medical University of Vienna and an unrestricted grant from AstraZeneca (ESR-21-21585)., Competing Interests: Declaration of interests “The authors declare no competing interests for this manuscript”, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Interest in kidney transplant studies in the elderly population is increasing as more research has been conducted on the immune system. With this review, we hope to encourage the need for research on kidney transplantation in the elderly.

Background: Skin cancer is a primary health concern in renal transplant recipients (RTRs). Existing research mainly stems from North America, Europe, and Australia, with limited data from Latin America., Methods: This 56-year (1967-2023) retrospective cohort study explores skin cancer incidence in Mexican RTRs. Our objective was to assess the long-term incidence of malignant cutaneous neoplasms in Mexican RTRs., Results: Over 56 years, 1642 RTRs (58% male) were studied. Median follow-up was 8.4 years; median age at transplantation was 32.6 years. Skin cancer incidence was 6.6% (95% CI: 5.5-7.9), with an incidence density rate of 6.5 (95% CI: 5.4-7.9) per 1000 person-years and a median latency of 9.8 years. Incidence increased with longer transplantation-related immunosuppression (TRI), with a relative risk for >30 years of TRI of 4.8 (95% CI: 2.6-9.1) for any skin cancer and 7.5 (95% CI: 3.8-14.6) for squamous cell carcinoma (SCC). SCC was the most common malignancy (76.1%), followed by basal cell carcinomas (BCC), with a 3.6:1 ratio. Metastatic SCC occurred in 6.5% of skin cancer patients, with a skin cancer-related mortality rate of 2.7%. Limitations of the study include its single-center and retrospective design and unassessed factors such as human papillomavirus infection and sun exposure., Conclusions: Our study provides unique insights into the epidemiology of skin cancer among Mexican RTRs. It constitutes the largest cohort of skin cancer cases among RTRs in Mexico and, to our knowledge, in Latin America. Despite the lack of recognition of a high skin cancer incidence in non-White RTRs, our 6.6% incidence underscores the need to enhance surveillance programs., (© 2024 the International Society of Dermatology.)

Background: Steroids are widely used in maintenance immunosuppression treatment in kidney transplant recipients. Older individuals undergo age-related immunosenescence that consequently decreases their ability to process and evoke a response to foreign antigens. Thus, steroids may not be necessary in preventing allograft rejection and may consequently increase older recipients' risk of long-term steroid-related adverse effects., Objective: The objective of this study was to analyze the adverse outcomes of long-term steroid immunosuppression in older kidney transplant recipients using real-world electronic medical record data., Methods: The TriNetX database "US Collaborative Network" was utilized to perform a propensity score-matched case-control study comparing 1-year, 3-year, and 5-year adverse effects of steroid immunosuppression in older adults (aged ≥ 65 years) kidney transplant recipients who underwent either an early-steroid withdrawal (ESW) maintenance regimen or a steroid continuous immunosuppression (SCI) regimen between 31 December, 2010 and 31 December, 2020. Early-steroid withdrawal was defined as tacrolimus plus mycophenolate mofetil maintenance with no prednisone after the seventh day post-transplant. Steroid continuous immunosuppression was defined as tacrolimus plus mycophenolate mofetil plus prednisone maintenance. Cohorts were matched on age, race/ethnicity, and risk factors for adverse steroid-related outcomes and rejection. Outcomes included post-transplant diabetes mellitus, dyslipidemia osteoporosis/fractures, myocardial infarction, glaucoma/cataract, stroke, pulmonary embolism, and malignancy. Secondary outcomes analyzed incidences of infection-related outcomes, graft-related outcomes, and recipient mortality., Results: After matching, there were 304 recipients in each group (ESW, SCI). Mean age at the time of transplant was 69.2 ± 3.7 years (ESW) and 69.2 ± 3.4 years (SCI, p = 0.96). The Kaplan-Meier analysis showed recipients who underwent SCI had increased incidences of post-transplant diabetes mellitus at 1 year (22.36% vs 30.37%, p = 0.01) and 3 years (34.89% vs 44.29%, p = 0.01), but this became non-significant at 5 years post-transplant (41.97% vs 42.6%, p = 0.34). Incidences of acute pancreatitis were higher for the SCI cohort at 3 years (p = 0.02) as well as incidences of acute myocardial infarction at 5 years post-kidney transplant (6.75% vs 14.39%, p < 0.01). No difference was found for other adverse outcomes. Early-steroid withdrawal recipients experienced significantly fewer infection-related outcomes, such as cytomegalovirus, BK virus, sepsis/bacteremia, and fungal infections, compared with SCI recipients. Last, recipients who underwent ESW experienced fewer incidences of rejection and death-censored graft failure at 5 years post-transplant., Conclusions: There is currently no standard maintenance immunosuppression protocol for older kidney transplant recipients. Death-censored graft survival, rejection, and patient survival were improved with ESW. Steroid minimization may be beneficial in this population given that it lowers the risk of drug-induced adverse effects., Competing Interests: Declarations Funding This research was supported by the UTMB Institute for Translational Sciences, supported in part by a Clinical and Translational Science Award (UL1 TR001439) from the National Center for Advancing Translational Sciences at the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflicts of interest/competing interests Michael L. Kueht owns shares in R and R Medical, LLC. John C. Johnson, Moosa Malik, Trine L. Engebretsen, Muhammad Mujtaba, A. Scott Lea, Heather L. Stevenson have no conflicts of interest that are directly relevant to the content of this article. Ethics approval TriNetX acts in accordance patient with the Health Insurance Portability and Accountability Act (“HIPPA”), EU Data Protection Law, the General Data Protection Regulation, and Regulation 2016/679 such that patient identifiers and associated protected health information is not disclosed to its users. Furthermore, to obtain access to the database at our institution, users are required to complete Collaborative Institutional Training Initiative (CITI Program) training and a Data Use Agreement to maintain research integrity. For these reasons, institutional review board approval was not required for this study. Consent to participate Not applicable. Consent for publication Not applicable. Availability of data and material The conditions under which the data were provided do not allow for the data to be made publicly available as the data are proprietary to TriNetX. Data underlying the findings described in this article may be obtained in agreement with the data licensing agreement for TriNetX. Researchers wishing to gain access to these data can request from TriNetX directly (join@trinetx.com). Code availability Not applicable. Authors’ contributions JCJ, TLE, and MLK were involved in the conceptualization and study design of this project. JCJ and MM conducted the data curation, statistical evaluation, and drafting of the manuscript. TLE MM, ASL, and HLS made pivotal revisions to the manuscript. All authors have reviewed and approved the final version of the manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alport syndrome (AS) is a hereditary disorder caused by pathogenic variants in COL4A3, COL4A4, or COL4A5 genes expressing α3, α4, and α5 chains of basement membrane type IV collagen (COL4). The triple-helical α3α4α5(IV) protomer is a major component of the mature glomerular basement membrane (GBM) whose defective formation in AS leads to structural GBM disruption and kidney dysfunction, often resulting in kidney replacement therapy. A genetically intact renal graft exposes the immune system to a non-tolerized α3α4α5(IV) component and an alloimmune response eventually ensues. So far, only IgG alloantibodies reacting against COL4 have been reported in AS alloimmune responses. Here, we report alloimmune glomerulonephritis mediated by IgA antibodies against the non-collagenous C-terminal domain 1 of the α5(IV) chain in a patient with autosomal recessive AS following a second kidney transplantation. The patient presented a not previously described biallelic variant in the COL4A4 gene. Immunological, diagnostic, and clinical implications are discussed., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are becoming more prevalent with advanced medical imaging and account for most of pancreatic cystic neoplasms (PCNs). Most incidental lesions should be surveyed, with resection reserved for specific, high-risk cases. Solid organ transplantation candidates may be high risk of resection before transplant and will require systemic immunosuppression after transplant, which has been theorized to alter the natural history of the IPMN. We aimed to describe the progression in surveilled cysts after solid organ transplantation., Methods: A prospectively maintained database of PCNs was queried for patients with IPMN. Patients who had received a previous solid organ transplantation and with ≥2 imaging studies >6 months apart after transplantation were included. Clinically relevant (CR) progression was defined as symptoms, worrisome/high-risk stigmata, or invasive carcinoma (IC). Growth ≥5 mm in 2 years is considered CR progression; size ≥3 cm alone is not., Results: Between 1997 and 2023, 252 patients received solid organ transplantation (liver, 86; kidney, 113; and lung, 54) and were diagnosed as having an IPMN. This cohort was compared with a set of 770 patients surveilled for IPMN who did not have previous transplantation. Median follow-up period was 3.7 years (IQR, 1.6-6.8). Moreover, 2 transplant patients (0.8%) developed IC, and 4 developed (1.6%) high-grade dysplasia (HGD). Both were less common in transplant patients than the nontransplant population (IC, 3.3%; HGD, 2.9%), although this was not significant on time-to-event analysis (IC, P = .152; HGD, P = .352). The rate of CR progression was high in the transplant cohort (n = 118; 47%). Features of CR progression included size growth (n = 79; 67%), other worrisome/high-risk stigmata (n = 25; 21%), and new main duct involvement (n = 14; 12%). Compared with the nontransplant (n = 128; 17%), transplant patients had a higher rate of CR progression (P < .001), which was mostly explained by a more frequent size growth (31% vs 9%; P < .001). However, no transplant patients with size growth CR progression developed IC. Moreover, 17 (6.7%) required pancreatic surgery for CR progression after transplant vs 58 (7.5%) in the nontransplant population. Furthermore, 6 resected cysts (35%) harbored high-risk pathology after transplant (IC, 2; HGD, 4) vs 40 (69%) in the general population (P < .001; IC, 29; HGD, 11)., Conclusion: Malignant transformation of BD-IPMNs is rare despite systemic immunosuppression in solid organ transplant patients. This supports transplantation in patients with IPMN without fear of worsening their risk of pancreatic cancer, although it was associated with a higher risk of disease progression. Patients with IPMNs should be surveilled with yearly scans after transplant, with pancreatic resection reserved for only high-risk features as we continue to define the optimal criteria for those with CR progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The frequency of natural disasters and man-made conflicts has risen significantly in the past two decades, coinciding with an increase in kidney transplant recipients globally. This review addresses the critical need for disaster preparedness to mitigate the severe impacts on this vulnerable patient cohort., Recent Findings: Kidney transplant recipients are highly dependent on robust healthcare infrastructures for ongoing care, including specialized medical staff, advanced diagnostics, and a consistent supply of immunosuppressive medications. Disasters disrupt these essential services, leading to increased risks of organ rejection, infections, and other medical complications. Strategies at various levels, from government to individual patients, can help maintain care continuity during such crises., Summary: Effective disaster preparedness plans involving strategic medication stockpiling, emergency communication systems, and patient education are crucial to support kidney transplant recipients. By implementing these measures, healthcare systems can better protect the health and well being of transplant patients during and after disasters., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Non-invasive biomarkers are promising tools for improving kidney allograft rejection monitoring, but their clinical adoption requires more evidence in specifically designed studies. To address this unmet need, we designed the EU-TRAIN study, a large prospective multicentric unselected cohort funded by the European Commission. Here, we included consecutive adult patients who received a kidney allograft in nine European transplant centers between November 2018 and June 2020. We prospectively assessed gene expression levels of 19 blood messenger RNAs, four antibodies targeting non-human leukocyte antigen (HLA) endothelial antigens, together with circulating anti-HLA donor-specific antibodies (DSA). The primary outcome was allograft rejection (antibody-mediated, T cell-mediated, or mixed) in the first year post-transplantation. Overall, 412 patients were included, with 812 biopsies paired with a blood sample. CD4 gene expression was significantly associated with rejection, while circulating anti-HLA DSA had a significant association with allograft rejection and a strong association with antibody-mediated rejection. All other tested biomarkers, including AKR1C3, CD3E, CD40, CD8A, CD9, CTLA4, ENTPD1, FOXP3, GZMB, ID3, IL7R, MS4A1, MZB1, POU2AF1, POU2F1, TCL1A, TLR4, and TRIB1, as well as antibodies against angiotensin II type 1 receptor, endothelin 1 type A receptor, C3a and C5a receptors, did not show significant associations with allograft rejection. The blood messenger RNAs and non-HLA antibodies did not show an additional value beyond standard of care monitoring parameters and circulating anti-HLA DSA to predict allograft rejection in the first year post-transplantation. Thus, our results open avenues for specifically designed studies to demonstrate the clinical relevance and implementation of other candidate non-invasive biomarkers in kidney transplantation practice., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain., Methods: We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m 2 (milliliter per minute per 1.73 m 2 , as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status., Results: Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m 2 ). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology Collaboration Cr/CysC equation., Conclusions: Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs., Competing Interests: A.A. received speaker fees from AstraZeneca and holds research grants from Otsuka, all outside of the submitted work. M.M.S. received speaker fees from AstraZeneca, Otsuka, Bayer, and GlaxoSmithKline, all outside of the submitted work. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial-to-mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single-cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1-mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin-6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin-mediated mitophagy., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Background: Pediatric patients with kidney failure often experience cognitive delays. However, academic delay (being more than one grade level below age-appropriate grade, or in special education) after pediatric kidney transplantation (KTx) has not been explored. We sought to identify patient characteristics associated with a higher risk of academic delay 1 year post-KTx., Methods: We used the United Network for Organ Sharing (UNOS) database to identify children aged 6-17 years who received a primary KTx between 2014 and 2021 and had a functioning graft 1 year after KTx. The primary outcome was the patient's academic progress at 1 year post-transplant. The secondary outcome was change in academic progress between transplant and 1-year follow-up: onset of new delay, resolution of pre-existing delay, persistence of delay, or no delay at either timepoint. Binomial and multinomial mixed effects logistic regression models were used to predict each outcome based on patient characteristics., Results: The study included 2197 patients, of whom 14% demonstrated academic delay at 1 year post-KTx, 4% demonstrated a new onset of academic delay, 5% demonstrated a resolution of academic delay, and 10% demonstrated persistent academic delay. Patients undergoing transplantation at a younger age, receiving a deceased donor kidney, experiencing longer waitlist times, and undergoing KTx for vascular or other disease indications for KTx were more likely to experience academic delays, including new-onset academic delays., Conclusions: Academic delays are frequently reported among pediatric KTx recipients. Additional academic support may help resolving or preventing academic delay for at-risk subgroups of children undergoing KTx., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Obesity is associated with increased complications, rejection, and graft loss after kidney transplantation in adult and pediatric recipients. Elevated body mass index (BMI) is a common contraindication to transplant at adult kidney transplant programs; however, there is no data on such limitations for pediatric patients., Methods: Between October and December 2022, we conducted a survey of Pediatric Nephrology Research Consortium centers assessing the use of BMI in pediatric kidney transplant evaluation. Centers reporting utilization of BMI cutoffs were invited to submit patient-level data on children declined for active transplant listing due to BMI., Results: Thirty-nine centers responded to the survey (42% response rate); 51% include BMI in their written listing criteria, with a median BMI "cutoff" of 39 kg/m 2 (range 30-50 kg/m 2 ). Between January 1, 2016, and December 31, 2021, 30 children at 15 transplant centers were declined for listing status due to BMI. Patient-level data was provided for 19 children (63%) who were denied active listing status; median BMI was 42 kg/m 2 (range 35.8-49.4 kg/m 2 ) and 84% were on dialysis. One year after evaluation, seven patients (37%) had proceeded to active wait list status. Eight (42%) remained in inactive status and four (21%) were unlisted; ten of these 12 patients (83%) were on dialysis., Conclusions: The use of BMI in pediatric kidney transplant evaluation and listing varies among centers, but BMI limits access to transplant for some children. More information is needed on the outcomes of obese pediatric kidney candidates who are and are not transplanted, to guide development of national and international consensus., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: The clinical importance of nutrition and inflammation in patients with end-stage renal disease is well established. In this study, we investigated the role of nutritional and inflammatory indicators in the patient outcomes of living donor kidney transplant recipients., Methods: We included 204 consecutive patients who underwent kidney transplantation at our institute between 2003 and 2022. We retrospectively reviewed medical charts to obtain clinical information. Six nutritional indicators and two inflammatory indicators were assessed. Patient outcomes were investigated, and predictive factors were explored., Results: The median patient age and follow-up period were 48 years and 99 months, respectively. The cohort included patients with preoperative malnutrition and microinflammation. No significant differences in graft survival were identified according to nutritional and inflammatory indicators, whereas the survival index, controlled nutritional status, and C-reactive protein levels were associated with patient survival. The survival index was an independent indicator of survival and death in patients with functioning grafts (P = 0.047 and P = 0.013, respectively). Furthermore, the C-reactive protein level could distinguish between low and high mortality risks in patients with good nutrition (P = 0.019)., Conclusions: Our findings suggest that nutrition and inflammation indicators play important roles in predicting outcomes in living donor kidney transplantation recipients. Further research is warranted to establish optimal management strategies., Competing Interests: Declarations Conflict of interest The authors have declared that no conflict of interest exists. Research involving human participants This study was approved by the research ethics committee of Nara Medical University (project identification code: 2014) and was conducted in compliance with the study protocol and the provisions of the Declaration of Helsinki (2013). Informed consent As the data for the study were obtained through retrospective chart review, a waiver of informed consent was approved by the institutional review board of Nara Medical University., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Objective: To evaluate outcomes of robotic-assisted transplant ureteral repair (RATUR) for the management of kidney transplant ureteral strictures (TUS)., Methods: We retrospectively analyzed 41 consecutive patients who underwent RATUR for TUS at multiple tertiary referral centers between January 2016 and December 2022. RATUR was performed utilizing a robotic-assisted transperitoneal approach. The primary outcome was stricture recurrence rate and secondary outcomes included postoperative complicate rate, determining factors impacting with allograft functional recovery, and rate of conversion to open surgery. Categorical and continuous variables are displayed as total number (Percentage) or median [Interquartile Range], respectively. Pearson correlation coefficient was utilized to assess categorical variable correlation with creatinine., Results: The median age was 56years [44,66]. The female-to-male ratio was 1.1:1. Approximately 66% of patients were dialysis-dependent prior to kidney transplantation. TUS was identified at a median time of 4months [2, 15.5] following kidney transplant. Median stricture length was 2 cm [1.22, 2.9 cm]. There were no TUS recurrences with a median follow-up of 36months [24,48]. There were 3 Clavien grade 2 and 1 Clavien grade 3 complications (9.5%). No baseline characteristics or preoperative diagnostics were correlated with a long-term decline in renal allograft function., Conclusion: RATUR has excellent and durable outcomes with low complication rates. These findings encourage the use of a minimally invasive definitive repair as a first-line treatment option for the management of TUS., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The TWO Study (Transplantation Without Overimmunosuppression) aimed to investigate a novel approach to regulatory T-cell (Treg) therapy in renal transplant patients, using a delayed infusion protocol at 6 mo posttransplant to promote a Treg-skewed lymphocyte repopulation after alemtuzumab induction. We hypothesized that this would allow safe weaning of immunosuppression to tacrolimus alone. The COVID-19 pandemic led to the suspension of alemtuzumab use, and therefore, we report the unique cohort of 7 patients who underwent the original randomized controlled trial protocol. This study presents a unique insight into Treg therapy combined with alemtuzumab and is therefore an important proof of concept for studies in other diseases that are considering lymphodepletion., Methods: Living donor kidney transplant recipients were randomized to receive autologous polyclonal Treg at week 26 posttransplantation, coupled with weaning doses of tacrolimus, (Treg therapy arm) or standard immunosuppression alone (tacrolimus and mycophenolate mofetil). Primary outcomes were patient survival and rejection-free survival., Results: Successful cell manufacturing and cryopreservation until the 6-mo infusion were achieved. Patient and transplant survival was 100%. Acute rejection-free survival was 100% in the Treg-treated group at 18 mo after transplantation. Although alemtuzumab caused a profound depletion of all lymphocytes, including Treg, after cell therapy infusion, there was a transient increase in peripheral Treg numbers., Conclusions: The study establishes that delayed autologous Treg therapy is both feasible and safe, even 12 mo after cell production. The findings present a new treatment protocol for Treg therapy, potentially expanding its applications to other indications., Competing Interests: G.L. is a founder of Quell Therapeutics Ltd. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Isolated v-lesion presents diagnostic stratification and clinical challenges. We characterized allograft outcomes for this entity based on posttransplant time (early: ≤1 month vs late: >1 month) and compared its molecular phenotype with other v+ rejection forms. Using the NanoString B-HOT panel, we analyzed 92 archival formalin-fixed paraffin-embedded tissue kidney biopsies from 3 centers: isolated v-lesion (n = 23), antibody-mediated rejection (ABMR) v+ (n = 26), T cell-mediated rejection (TCMR) v+ (n = 10), mixed rejection v+ (n = 23), and normal tissue (n = 10). Six gene sets (ABMR, DSAST, ENDAT, TCMR, early/acute injury, late injury) were assessed. Early isolated v-lesions had the poorest 1-year death-censored graft survival compared with late isolated v-lesions or other rejections (P = .034). Gene set analysis showed lower TCMR-related gene expression in isolated v+ groups than TCMR and mixed rejection (P < .001). Both early- and late isolated v-lesions had lower ABMR-related gene expression than ABMR, mixed rejection, and TCMR (P ≤ .022). Late isolated v-lesions showed reduced DSAST and ENDAT gene expression versus ABMR (P ≤ .046) and decreased early/acute injury gene expression than early isolated v+, ABMR, TCMR, and mixed rejection (P ≤ .026). In conclusion, isolated v-lesions exhibit distinct gene expression patterns versus other rejection v+ forms. Early isolated v+ is associated with poorer prognosis and increased early/acute injury gene expression than late isolated v+, suggesting distinct etiologies., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Patients with multiple myeloma (MM) frequently present with kidney involvement, of which a non-negligible proportion will progress to end-stage kidney disease. Kidney transplantation (KT) is the preferred kidney replacement therapy for selected patients; however, there are still many uncertainties regarding its application in MM patients. The risk of hematological relapse and subsequent graft loss or patient death often leads nephrologists to deem these patients unfit for KT. As such, data on KT in MM patients are heterogeneous and originate from individual case reports and small case series. Although MM is still an incurable disease, the addition of newer drugs and autologous hematopoietic stem cell transplant (HSCT) in the standard of care has been increasing patients' overall survival in recent decades. Risk stratification using cytogenetic studies and minimal residual disease detection are helpful in assessing the risk of relapse in patients who attain a complete response after HSCT. The greatest challenges remain the correct identification of patients who will most probably benefit from KT from a survival perspective and the determination of how long relapse-free survival should be before the transplant is performed.

Transplanting organs from cytomegalovirus-seropositive donors into cytomegalovirus-seronegative recipients is an accepted practice. However, outcomes following transplantation of organs from donors with active cytomegalovirus disease are unknown. We present a case involving a patient aged 61 years with end-stage renal disease, seropositive for cytomegalovirus, who underwent dual kidney transplant from a donor with high-grade cytomegalovirus viraemia. The donor was on immunosuppressive therapy for systemic lupus erythematosus and interstitial lung disease and had been admitted with respiratory failure. The donor had high-grade cytomegalovirus viraemia with probable cytomegalovirus pneumonitis (cytomegalovirus viral load >100 000 international units [IU]/mL in plasma and 319 000 IU/mL in bronchoalveolar lavage). Renal biopsy at organ procurement showed the absence of cytomegalovirus inclusions. Following transplantation, the recipient had delayed graft function, with renal recovery after 1 week. The patient received basiliximab induction and standard tacrolimus-based maintenance immunosuppression. He received ganciclovir and valganciclovir treatment for 1 month, followed by valganciclovir prophylaxis (or viral load monitoring, when prophylaxis had to be paused) for 2 additional months to prevent donor-derived cytomegalovirus infection. Transient cytomegalovirus viraemia (peaking at 4480 IU/mL) developed at 4 months and resolved with 1 month of valganciclovir treatment. The patient is doing well 1 year after transplantation, with adequate kidney function. This case highlights the successful and safe transplantation of kidneys from a donor with cytomegalovirus disease into a cytomegalovirus-seropositive recipient. Further research is needed to confirm our findings and define post-transplantation management., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely., Methods: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review., Results: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results., Conclusions: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Human leukocyte antigen (HLA) sensitization remains an impediment to successful solid organ transplantation, whether it be chances of receiving a transplant offer or subsequent transplant longevity. Current treatments targeting HLA antibodies lack long-term effectiveness; therefore, preventing HLA sensitization should remain a priority in all potential wait-list candidates and transplant recipients. Recent advances in the management of anemia in patients with chronic kidney disease may reduce the need for red cell transfusions. However, data from several anemia intervention studies of novel therapeutic agents have shown that a need for transfusion will remain. It has also been increasingly recognized that blood transfusions following kidney transplantation, especially in the peri-operative period, are common. Routine data on transfusion incidence, indications, and outcomes are not captured by most kidney and transplant registries across the globe. This restricts the evidence to inform both clinicians and patients on the clinical effects of transfusion, which have been considered both an allogeneic stimulus and to be immunomodulatory.This review aims to provide an update on what is currently known about transfusion-induced HLA sensitization in wait-list candidates and transplant recipients, summarizes where evidence is lacking, and demonstrates the distinct need for patient blood management guidelines in the field of kidney transplantation., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist with sedative and analgesic effects, has been suggested in recent studies to possess renoprotective properties. Dexmedetomidine may reduce the incidence of delayed graft function and contribute to effective pain control post-renal transplantation. The primary objective of this systematic review was to assess whether dexmedetomidine decreases the occurrence of delayed graft function in renal transplant patients., Methods: Databases including MEDLINE, EMBASE, and CENTRAL were comprehensively searched from their inception until March 2023. The inclusion criteria covered all Randomized Clinical Trials (RCTs) and observational studies comparing dexmedetomidine to control in adult patients undergoing renal transplant surgery. Exclusions comprised case series and case reports., Results: Ten RCTs involving a total of 1358 patients met the eligibility criteria for data synthesis. Compared to the control group, the dexmedetomidine group demonstrated a significantly lower incidence of delayed graft function (OR = 0.71, 95% CI 0.52-0.97, p = 0.03, GRADE: Very low, I 2 = 0%). Dexmedetomidine also significantly prolonged time to initiation of rescue analgesia (MD = 6.73, 95% CI 2.32-11.14, p = 0.003, GRADE: Very low, I 2 = 93%) and reduced overall morphine consumption after renal transplant (MD = -5.43, 95% CI -7.95 to -2.91, p < 0.0001, GRADE: Very low, I 2 = 0%). The dexmedetomidine group exhibited a significant decrease in heart rate (MD = -8.15, 95% CI -11.45 to -4.86, p < 0.00001, GRADE: Very low, I 2 = 84%) and mean arterial pressure compared to the control group (MD = -6.66, 95% CI -11.27 to -2.04, p = 0.005, GRADE: Very low, I 2 = 87%)., Conclusions: This meta-analysis suggests that dexmedetomidine may potentially reduce the incidence of delayed graft function and offers a superior analgesia profile as compared to control in adults undergoing renal transplants. However, the high degree of heterogeneity and inadequate sample size underscore the need for future adequately powered trials to confirm these findings., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)

Background: Optimizing long-term graft survival remains a major focus in transplant. Elderly kidney transplant recipients are vulnerable to acute kidney injury (AKI) and graft loss. This study assessed the safety and efficacy of ACEI/ARB in elderly kidney transplant recipients and impact on graft outcomes., Methods: Retrospective, longitudinal, cohort study of 500 patients age ≥60 years, who underwent kidney transplantation between 2005 and 2015. Demographic, transplant, and outcomes data were collected. Manual chart abstraction was conducted to determine medication use at discharge, one, three, and five years post-transplant. Univariate and multivariable Cox regression modeling were used to analyze outcomes., Results: Mean age of subjects was 66 years (range 60-81). 59% were males and 50% were African-American. 49% had chronic kidney disease (CKD) due to diabetes mellitus (DM). A total of 38, 134, 167, and 112 elderly kidney transplant recipients were on ACEI/ARB at discharge, one, three, and five years post-transplant respectively. ACEI/ARB initiated within one year of transplant was associated with lower risk of graft loss (HR=0.62, CI 0.38-0.99, p = 0.047). This was driven mainly by a lower risk of death (HR=0.41, CI 0.24-0.71, p = 0.002). ACEI/ARB use was associated with lower risk of AKI after 1 year (HR 0.70, CI 0.52-0.95, p = 0.02). ACEI/ARB was not associated with increased risk of acute rejection or hospitalization., Conclusion: Initiation of ACEI/ARB within one year of transplant is associated with lower risk of AKI and graft loss, driven by lower risk of death in elderly kidney transplant recipients. Clinicians should maximize ACEI/ARB therapy early on after kidney transplant., (Copyright © 2024 Southern Society for Clinical Investigation. All rights reserved.)

With the growth of the older adult population, the number of older adults waitlisted for and undergoing kidney and liver transplantation has increased. Transplantation is an important and definitive treatment for this population. We present a contemporary review of the unique preoperative, intraoperative, and postoperative issues that patients older than 65 y face when they undergo kidney or liver transplantation. We focus on geriatric syndromes that are common in older patients listed for kidney or liver transplantation including frailty, sarcopenia, and cognitive dysfunction; discuss important considerations for older transplant recipients, which may impact preoperative risk stratification; and describe unique challenges in intraoperative and postoperative management for older patients. Intraoperative challenges in the older adult include using evidence-based best anesthetic practices, maintaining adequate perfusion pressure, and using minimally invasive surgical techniques. Postoperative concerns include controlling acute postoperative pain; preventing cardiovascular complications and delirium; optimizing immunosuppression; preventing perioperative kidney injury; and avoiding nephrotoxicity and rehabilitation. Future studies are needed throughout the perioperative period to identify interventions that will improve patients' preoperative physiologic status, prevent postoperative medical complications, and improve medical and patient-centered outcomes in this vulnerable patient population., Competing Interests: M.A.M.-D. received speaking honoraria from Chiesi. M.E.N. is an elected member of the executive committee (or council) of the Society of Critical Care Medicine. The views presented are those of the author and do not represent the views of SCCM. The other authors declare no conflicts of interests., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: We report the partial regression of metastatic squamous cell carcinoma (SCC) after reduction of long-term azathioprine therapy while awaiting surgery. The patient was a 69-year-old man with a history of kidney transplantation. Moderately differentiated SCC arising in the anterior neck was initially diagnosed, followed later by poorly differentiated SCC metastases to cervical lymph nodes. Lymph node clearance was performed 28 days after a reduction in azathioprine dosage. The palpable lymph node lesion had noticeably decreased in size at the time of surgery, and subsequent histology only detected 7mm and 0.2mm deposits of poorly differentiated SCC in 2 of 5 level I nodes, and a further 10 reactive nodes from levels II and III. One positive level I and another benign level II/III node, demonstrated necrosis, histiocytic infiltration and fibrosis, interpreted as features of regression. Hence, we investigated the role of immune cells in the partial regression of metastatic SCC after reduction of long-term azathioprine therapy while awaiting surgery., Methods: Multispectral immunohistochemistry using custom markers was performed on regions of interest of excised cervical lymph nodes, encompassing the entire SCC deposit and the surrounding adjacent stroma to quantify to number and types of immune cells present., Results: Multispectral immunohistochemistry revealed the heavy infiltration of activated T cells in the tumour, as well as PD-L1+ antigen-presenting cells in the surrounding adjacent stroma, suggesting an immunologically mediated partial regression., Discussion: We hypothesize that this reaction was triggered by azathioprine dose reduction. Dose modification of long-term immunosuppressive medications in patients with a transplantation history who later develop SCCs warrants further investigation., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ormston, Da Gama Duarte, Quigley, Jackett, Whitlam, Behren and Gyorki.)

The QuantiFERON-Monitor assay (QTF-Monitor) is intended to assess innate and adaptive immune responses by quantifying interferon (IFN)-γ release upon whole blood stimulation with a TLR7/8 agonist and an anti-CD3 antibody. We performed the QTF-Monitor in 126 kidney transplant recipients (KTRs) at different points during the first 6 post-transplant months. The primary outcome was overall infection, whereas secondary outcomes included bacterial infection, opportunistic infection and de novo cancer. The association between IFN-γ production and outcomes was analyzed as "low" immune responses (<15 IU/mL) and as a continuous variable to explore alternative thresholds. There were no significant differences in the occurrence of overall infection according to the QTF-Monitor at any monitoring point. Regarding secondary outcomes, KTRs with a low response at week 2 experienced a higher incidence of bacterial infection (50.8% versus 24.4%; P -value = 0.006). Low response at month 1 was also associated with opportunistic infection (31.6% versus 14.3%; P -value = 0.033). The discriminative capacity of IFN-γ levels was poor (areas under the ROC curve: 0.677 and 0.659, respectively). No differences were observed for the remaining points or post-transplant cancer. In conclusion, the QTF-Monitor may have a role to predict bacterial and opportunistic infection in KTRs when performed early 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 © 2024 Fernández-Ruiz, Ruiz-Merlo, Rodríguez-Goncer, Caso, López-Medrano, Parra, San Juan, Polanco, González, Andrés, Aguado and Redondo.)

Background and Hypothesis: Advances in organ procurement, surgical techniques, immunosuppression regimens, and prophylactic antibiotic therapies have dramatically improved kidney transplant graft failure. It is unclear how these interventions have affected longer-term graft failure. It is hypothesized that graft failure has improved over the last 20 years., Methods: Data on all first kidney transplants from 1995 to 2014 were extracted from the Australia and New Zealand Dialysis and Transplant Registry with follow-up as of 31 December 2021. Primary exposure was transplant era, classified into 5-year intervals. Primary outcome was all-cause 5-year graft failure. Secondary outcomes included all-cause 10-year graft failure and cause-specific graft failure. Kaplan-Meier curves and multivariable Cox proportional hazards regression models were used to assess trends in all-cause graft failure. Fine-Gray subdistribution hazard models verified that changes in death rates were not biasing the Cox proportional hazards regression models. Cumulative incidence functions were used to assess temporal trends in cause-specific graft failure., Results: Across 10 871 kidney transplants, there was a shift towards transplanting more recipients aged >45 years old, with more comorbidities, longer dialysis vintage, body mass index >30 kg/m2, and greater human leukocyte antigen mismatches. Donor age has increased but no clear shift in donor source was observed. Compared to 1995-99 (reference), the adjusted hazard ratio for 5-year graft failure was 0.78 (95% CI 0.67-0.91), 0.70 (95% CI 0.59-0.83), and 0.60 (95% CI 0.50-0.73) for 2000-04, 2005-09, and 2010-14, respectively. Ten-year graft failure similarly reduced from 0.83 (95% CI 0.74-0.93) for 2000-04 to 0.78 (95% CI 0.68-0.89) for 2010-14, compared to 1995-99., Conclusion: Medium- and long-term all-cause graft failure has improved steadily since 1995-99. Significant reductions in graft failure due to rejection and vascular causes were observed at 5 years, and due to rejection, vascular causes, death, and glomerular disease at 10 years., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC., Methods: First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects., Results: There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites., Conclusions: The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI., Competing Interests: J.S.R. reports funding from GSK and Sanofi and fees from Travere Therapeutics and Astex. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products associated with this research to declare., (Copyright: © 2024 Nordström et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BACKGROUND The aim of this study was to investigate the clinical utility of ultrasound shear wave elastography (SWE) for assessment of renal fibrosis in post-renal transplant patients. MATERIAL AND METHODS We selected 183 patients who underwent renal transplantation. The complete dataset was randomly partitioned into a training cohort (128 cases) and a validation cohort (55 cases). All patients were subjected to SWE and renal allograft biopsy. The baseline data was compared using t-test, Z-test, or chi-square test. Through univariate and multivariate analyses, we identified independent risk factors influencing renal fibrosis after transplantation, a predictive model for post-transplant renal fibrosis was developed, and calibration curves, decision curve analyses, and ROC curves were generated. RESULTS Age, TST, Scr, GFR, and Emean showed significant differences (P<0.05). The C-index of the nomogram was 0.85, and the calibration curve and Hosmer-Lemeshow test demonstrated accurate diagnosis of fibrosis in both the training and validation sets (P>0.05). DCA showed that the prediction model effectively improved the diagnostic accuracy of fibrosis. The highest AUC of the nomogram for combined prediction of renal fibrosis in transplant patients was 0.902 in the training group and 0.871 in the validation group. These values were significantly higher compared to the AUCs of individual predictors (P<0.05). CONCLUSIONS Ultrasound SWE allows for early evaluation of renal fibrosis following transplantation. The prediction model, constructed by amalgamating other indicators, augments the accuracy and reliability of the prediction, providing more precise and accurate diagnostic and therapeutic recommendations for clinical practitioners.

Introduction: ABO-incompatible (ABOi) kidney transplantation (KT) has become an important option to overcome organ shortage. Plasmapheresis/rituximab-based desensitization therapy has successfully reduced anti-ABO antibody levels and suppressed antibody-mediated rejection (AMR) in ABOi KT. However, high titers of anti-ABO antibodies in some patients are refractory to standard desensitization, leading to loss of KT opportunities or AMR., Methods: Eculizumab treatment was used an adjunctive therapy to rescue high-titer ABOi KT patients refractory to plasmapheresis/rituximab-based desensitization. Molecular phenotypes of allograft biopsies and cellular phenotypes of peripheral blood mononuclear cells of eculizumab group were compared with those of control groups using the Banff Human Organ Transplant gene panel and flow-cytometric analysis, respectively., Results: The initial titers of anti-ABO antibodies in the two patients were 1:512 and >1:1024; the final pre-transplant titers after desensitization were 1:128 and 1:64. Both patients received eculizumab from KT day to two or four weeks post-KT and maintained stable renal function up to one-year post-transplantation without overt infection, despite early episodes of probable AMR or borderline T cell-mediated rejection. Molecular phenotype analysis revealed that gene expression patterns in the ABOi KT with eculizumab group overlapped with those in the ABOi KT with AMR group more than in the ABOi KT without AMR group, except for complement pathway-related gene expression. Anti-ABO antibody titers decreased to low levels 1-3 months post-transplant in the eculizumab group in parallel with decreasing anti-B-specific B cells., Conclusions: Short-term eculizumab therapy is promising for rescuing ABOi KT recipients with high anti-ABO antibody titers refractory to plasmapheresis-based desensitization therapy., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Heo, Jung, Piao, Kim, Kim, Lee, Huh, Kim and Yang.)

Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric kidney failure. Most cases of FSGS in children are idiopathic and have a high risk of post-transplantation recurrence and graft loss. Common treatments for recurrent FSGS (rFSGS) post-transplantation include plasmapheresis, immunoadsorption, and/or immunomodulatory therapy. This study retrospectively evaluated the efficacy and safety of early plasmapheresis followed by rituximab for inducing and maintaining remission in rFSGS. Between 2014 and 2023, 8 of 65 pediatric kidney transplant recipients at our center were diagnosed with idiopathic FSGS. rFSGS was diagnosed based on nephrotic range proteinuria with no other cause and managed with plasmapheresis. Rituximab therapy was used for those who did not achieve complete remission with prolonged plasmapheresis or remained plasmapheresis dependent. 6 of 8 (75%) transplant recipients with idiopathic FSGS experienced rFSGS. All patients achieved partial or complete remission with plasmapheresis, with response times ranging from 8 to 379 days (median 13 days). Rituximab therapy was introduced for 5 plasmapheresis-dependent patients, leading to sustained remission and cessation of plasmapheresis in 3 patients, while 2 showed improved proteinuria and reduced plasmapheresis frequency. Adverse effects included rituximab-induced serum sickness in one patient and one mild allergic reaction. One patient experienced graft loss due to humoral rejection, but no grafts were lost to rFSGS, and all other grafts remained functional over an average follow-up of 50 months. Early plasmapheresis followed by rituximab therapy effectively induces remission in most post-transplantation rFSGS cases, is well tolerated, and prevents graft loss. Larger studies are needed to confirm these findings., (© 2024. The Author(s).)

Introduction: The development of de novo anti-HLA donor specific antibodies (DSAs) is associated with poor outcomes in kidney transplant recipients. It is surmised that an interaction between DSAs and the graft endothelium cause tissue injury, however, the exact underlying pathomechanism and optimal management of patients with DSAs remain undetermined., Aims: We hypothesized that in kidney transplant recipients the presence of DSAs induce hemostasis alterations, including hypercoagulability, as assessed by the thrombin generation assay (TGA). Patients and methods. In this observational cohort study, 27 kidney transplant recipients with DSAs (DSA+ group) and 16 without DSAs (DSA- group) were enrolled. Venous blood samples were obtained, and besides routine laboratory tests, von Willebrand factor antigen (VWF), FVIII activity, soluble E selectin (sEsel), soluble P selectin (sPsel), TGA, clot lysis assay (CLA), complement levels (C3, C4) were measured. To correlate results with potential changes in DSA status over time, patients were followed and reassessed 6 ± 1.5 months later., Results: VWF and sPsel did not differ between groups, but both parameters were increased in the majority of patients. Endogenous thrombin potential (ETP) was significantly higher in the DSA+ group as compared to DSA- patients (median:1666; IQR:1438-2012 vs. 1230; IQR:1097-1659 nM*min, p=0.0019). Follow-up measurements indicated that the observed hemostasis alterations were not transient. CLA parameters, C3 and C4 did not differ between DSA+ and DSA- groups. The extent of anti-HLA II DSA positivity correlated positively with ETP, while tacrolimus levels negatively correlated with ETP and VWF/FVIII levels., Conclusions: In patients with anti-HLA class II DSAs, thrombin generation was significantly increased as compared to DSA- kidney transplant recipients, suggesting that the presence of antibodies is associated with hypercoagulability. Tacrolimus levels were negatively associated with TGA parameters. Hypercoagulability, associated with the presence of DSAs, may potentially contribute to the pathomechanism of antibody-mediated graft injury, warranting future prospective studies., 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 © 2024 Lóczi, P. Szabó, Orbán-Kálmándi, Hodossy-Takács, Szilvási, Szalai, Nagy, Antal-Szalmás, Nemes and Bagoly.)