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Background: Chronic kidney disease (CKD) is an important independent risk factor for adverse cardiovascular events in patients waitlisted for kidney transplantation (KT). Although KT reduces cardiovascular risk, these patients still have a higher all-cause and cardiovascular mortality than the general population. This concerning situation is due to a high burden of traditional and nontraditional risk factors as well as uremia-related factors and transplant-specific factors, leading to 2 differentiated processes under the framework of CKD, atherosclerosis and arteriosclerosis. These can be initiated by insults to the vascular endothelial endothelium, leading to vascular calcification (VC) of the tunica media or the tunica intima, which may coexist. Several pathogenic mechanisms such as inflammation-related endothelial dysfunction, mineral metabolism disorders, activation of the renin-angiotensin system, reduction of nitric oxide, lipid disorders, and the fibroblast growth factor 23-klotho axis are involved in the pathogenesis of atherosclerosis and arteriosclerosis, including VC. Summary: This review focuses on the current understanding of atherosclerosis and arteriosclerosis, both in patients on the waiting list as well as in kidney transplant recipients, emphasizing the cardiovascular risk factors in both populations and the inflammation-related pathogenic mechanisms. Key Message: The importance of cardiovascular risk factors and the pathogenic mechanisms related to inflammation in patients waitlisted for KT and kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Background: The management and outcomes of nontuberculous mycobacterial (NTM) infections in solid organ transplant (SOT) recipients are poorly characterized. We aimed to describe the management and 1-y mortality of these patients., Methods: Retrospective, multinational, 1:2 matched case-control study included SOT recipients aged 12 y old or older diagnosed with NTM infection between January 1, 2008, and December 31, 2018. Controls were matched on transplanted organs, NTM treatment center, and posttransplant survival at least equal to the time to NTM diagnosis. The primary aim was 1-y mortality after NTM diagnosis. Differences between cases and controls were compared using the log-rank test, and Cox regression models were used to identify factors associated with mortality at 12 mo among cases., Results: In 85 patients and 169 controls, the median age at the time of SOT was 54 y (interquartile range, 40-62 y), 59% were men, and the lungs were the most common site of infection after SOT (57.6%). One-year mortality was significantly higher in cases than in controls (20% versus 3%; P < 0.001), and higher mortality was associated with lung transplantation (hazard ratio 3.27; 95% confidence interval [1.1-9.77]; P = 0.034). Median time (interquartile range) from diagnosis to treatment initiation (20 [4-42] versus 11 [3-21] d) or the reduction of net immunosuppression (36% versus 45%, hazard ratio 1.35 [95% CI, 0.41-4.43], P = 0.618) did not differ between survivors and those who died., Conclusions: NTM disease in SOT recipients is associated with a higher mortality risk, especially among lung transplant recipients. Time to NTM treatment and reduction in net immunosuppression were not associated with mortality., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors., Methods: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections., Results: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection., Conclusions: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors., Competing Interests: Potential conflicts of interest. C. M. C. reports the following grants or contracts unrelated to this work: Centers for Disease Control and Prevention (CDC) subaward from Johns Hopkins University to the Washington University in St. Louis (funding by the CDC grant number 1U54CK000617-01-00), vendor/individual agreement with Wayne State University for a case registry, and Associate Editor for Open Forum Infectious Diseases (1 May 2022 through 30 April 2023). D. F. P. reports payment or honoraria as a speaker for an antibiotic course for UMC Utrecht and as a teacher for Hospital Pharmacists in training for PAO; and participation on DSMB for the COBRA trial (Very short-course versus standard course antibiotic therapy in patients with acute Cholangitis after adequate endoscopic biliaRy drainage) in the Netherlands. M. J. M. reports consulting fees from Insmed and Biomerieux; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Microsoft Diagnostics (MSD), Insmed, and Teva; support for attending meetings and/or travel from MSD, Berlin Chemie; and participation on a Data Safety Monitoring Board or Advisory Board for Biomerieux, Insmed, MSD. J. T. S. reports payment or honoraria for manuscript writing for Gilead on subjects not related to this manuscript. M. B. reports support from Pfizer for attending a congress. N. K. reports royalties or licenses from Up To Date; consulting fees from Astellas, AstraZeneca, Biotest, ExeViR, Hansa, Merck Sharp and Dohme, Glasgow Smith Kline, Novartis Pharma, Takeda; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Astellas, Biotest, CSL Behring, Chiesi, Novartis Pharma, Sanofi, Sandoz, Takeda; and support for attending meetings and/or travel from Astellas, Novartis Pharma, Takeda. N. J. M. reports support for attending meetings and/or travel paid to author from Biotest; unpaid participation on a Data Safety Monitoring Board or Advisory Board for a CTX3 Study and paid participation on Advisory Boards for Takeda, MSD, and Pfizer. N. M. T. reports payment or honoraria for guest lecture for Boston Medical Center and Beth Israel Medical Center; payment for expert testimony for record review for Ficksman & Conley, LLP, in Boston, Massachusetts; participation on a Data Safety Monitoring Board or Advisory Board for United Network for Organ Sharing HIV Organ, Policy Equity (HOPE) Act Safety Review, and Workgroup (unpaid); role as Chair of the American Society of Transplantation and leadership or fiduciary role with Infectious Diseases Community of Practice (unpaid). O. M. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from MSD; and participation on a Data Safety Monitoring Board or Advisory Board for MSD. S. Be. reports grants or contracts unrelated to this work from Vancouver Costal Health Research Institute and Transplant Research Foundation of BC; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Merck; and participation on an Advisory Board for Evusheld (AstraZeneca). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: C3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare entity. Herein we analysed the clinical and histologic features of a cohort of C3G-MIg patients., Methods: We conducted a retrospective, multicentre, observational study. Patients diagnosed with C3G-MIg between 1995 and 2021 were enrolled. All had genetic studies of the alternative complement pathway. The degree of disease activity and chronicity were analysed using the C3G histologic index. Descriptive statistics and propensity score matching (PSM) analysis were used to evaluate the main outcome of the study [kidney failure (KF)]., Results: The study group included 23 patients with a median age 63 of years [interquartile range (IQR) 48-70], and 57% were males. Immunoglobulin G kappa was the most frequent MIg (65%). The diagnosis of C3G-MIg was made in transplanted kidneys in seven patients (30%). Five (22%) patients had C3 nephritic factor and five (22%) had anti-factor H antibodies. One patient carried a pathogenic variant in the CFH gene. During a follow-up of 40 months (IQR 14-69), nine patients (39%) reached KF and these patients had a significantly higher total chronicity score on kidney biopsy. Patients who received clone-targeted therapy had a significantly higher survival compared with other management. Those who achieved haematological response had a significantly higher kidney survival. Outcome was remarkably poor in kidney transplant recipients, with five of them (71%) reaching KF. By PSM (adjusting for age, kidney function, proteinuria and chronicity score), no significant differences were observed in kidney survival between C3G patients with/without MIg., Conclusions: The C3G histologic index can be used in patients with C3G-MIg to predict kidney prognosis, with higher chronicity scores being associated with worse outcomes. Clone-targeted therapies and the development of a haematological response are associated with better kidney prognosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Introduction: The association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure., Methods: This was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure., Results: The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13-41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56-0.97; P < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up., Conclusions: The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Peripheral vascular disease (PVD) is highly prevalent in patients on the waiting list for kidney transplantation (KT) and after transplantation and is associated with impaired transplant outcomes. Multiple traditional and nontraditional risk factors, as well as uremia- and transplant-related factors, affect 2 processes that can coexist, atherosclerosis and arteriosclerosis, leading to PVD. Some pathogenic mechanisms, such as inflammation-related endothelial dysfunction, mineral metabolism disorders, lipid alterations, or diabetic status, may contribute to the development and progression of PVD. Early detection of PVD before and after KT, better understanding of the mechanisms of vascular damage, and application of suitable therapeutic approaches could all minimize the impact of PVD on transplant outcomes. This review focuses on the following issues: (1) definition, epidemiological data, diagnosis, risk factors, and pathogenic mechanisms in KT candidates and recipients; (2) adverse clinical consequences and outcomes; and (3) classical and new therapeutic approaches., Competing Interests: The authors declare no conflicts of interests., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The impact of corticosteroid withdrawal on medium-term graft histological changes in kidney transplant (KT) recipients under standard immunosuppression is uncertain. As part of an open-label, multicenter, prospective, phase IV, 24-month clinical trial (ClinicalTrials.gov, NCT02284464) in low-immunological-risk KT recipients, 105 patients were randomized, after a protocol-biopsy at 3 months, to corticosteroid continuation (CSC, n = 52) or corticosteroid withdrawal (CSW, n = 53). Both groups received tacrolimus and MMF and had another protocol-biopsy at 24 months. The acute rejection rate, including subclinical inflammation (SCI), was comparable between groups (21.2 vs. 24.5%). No patients developed dnDSA. Inflammatory and chronicity scores increased from 3 to 24 months in patients with, at baseline, no inflammation (NI) or SCI, regardless of treatment. CSW patients with SCI at 3 months had a significantly increased chronicity score at 24 months. HbA1c levels were lower in CSW patients (6.4 ± 1.2 vs. 5.7 ± 0.6%; p = 0.013) at 24 months, as was systolic blood pressure (134.2 ± 14.9 vs. 125.7 ± 15.3 mmHg; p = 0.016). Allograft function was comparable between groups and no patients died or lost their graft. An increase in chronicity scores at 2-years post-transplantation was observed in low-immunological-risk KT recipients with initial NI or SCI, but CSW may accelerate chronicity changes, especially in patients with early SCI. This strategy did, however, improve the cardiovascular profiles of patients.

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches ( p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

Background and Objectives: C3 glomerulopathy is a complement-mediated disease arising from abnormalities in complement genes and/or antibodies against complement components. Previous studies showed that treatment with corticosteroids plus mycophenolate mofetil (MMF) was associated with improved outcomes, although the genetic profile of these patients was not systematically analyzed. This study aims to analyze the main determinants of disease progression and response to this therapeutic regimen., Design, Setting, Participants, & Measurements: We conducted a retrospective, multicenter, observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy ( n =81) or dense deposit disease ( n =16) between January 1995 and March 2018 were enrolled. Multivariable and propensity score matching analyses were used to evaluate the association of clinical and genetic factors with response to treatment with corticosteroids and MMF as measured by proportion of patients with disease remission and kidney survival (status free of kidney failure)., Results: The study group comprised 97 patients (84% C3 glomerulopathy, 16% dense deposit disease). Forty-two patients were treated with corticosteroids plus MMF, and this treatment was associated with a higher rate of remission and lower probability of kidney failure (79% and 14%, respectively) compared with patients treated with other immunosuppressives (24% and 59%, respectively), or ecluzimab (33% and 67%, respectively), or conservative management (18% and 65%, respectively). The therapeutic superiority of corticosteroids plus MMF was observed both in patients with complement abnormalities and with autoantibodies. However, patients with pathogenic variants in complement genes only achieved partial remission, whereas complete remissions were common among patients with autoantibody-mediated forms. The main determinant of no remission was baseline proteinuria. Relapses occurred after treatment discontinuation in 33% of the patients who had achieved remission with corticosteroids plus MMF, and a longer treatment length of MMF was associated with a lower risk of relapse., Conclusions: The beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study., (Copyright © 2020 by the American Society of Nephrology.)