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Hsu FM, Pickering H, Rubbi L, Thompson M, Reed EF, Pellegrini M, Schaenman JM. DNA methylation predicts infection risk in kidney transplant recipients. Life Sci Alliance 2025; 8:e202403124. [PMID: 40324822 PMCID: PMC12053434 DOI: 10.26508/lsa.202403124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 05/07/2025] Open
Abstract
Kidney transplantation (KTx) is the method of choice for treating kidney failure. Identifying biomarkers predictive of transplant (Tx) outcomes is critical to optimize KTx; however, the immunosuppressive therapies required after KTx must also be considered. We applied targeted bisulfite sequencing (TBS-seq) to PBMCs isolated from 90 patients, with samples collected pre- and post-Tx (day 90), to measure DNA methylation changes. Our findings indicate that the PBMC DNA methylome is significantly affected by induction immunosuppression with anti-thymocyte globulin (ATG). We discovered that the risk of infection can be predicted using DNA methylation profiles, but not gene expression profiles. Specifically, 515 CpG loci associated with 275 genes were significantly impacted by ATG induction, even after accounting for age, sex, and cell-type composition. Notably, ATG-associated hyper-methylation down-regulates genes critical for immune response. In conclusion, this clinical omics study reveals that the immunosuppressant ATG profoundly impacts the DNA methylome of KTx recipients and identifies biomarkers that could be used in pre-Tx screening of patients vulnerable to infection, thereby informing immunosuppression strategies post-Tx.
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Affiliation(s)
- Fei-Man Hsu
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
- Institute for Quantitative and Computational Biosciences - The Collaboratory, University of California Los Angeles, Los Angeles, CA, USA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Liudmilla Rubbi
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Michael Thompson
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
- Institute for Quantitative and Computational Biosciences - The Collaboratory, University of California Los Angeles, Los Angeles, CA, USA
| | - Joanna M Schaenman
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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Stanicki B, Puntiel DA, Peticca B, Egan N, Prudencio TM, Robinson SG, Karhadkar SS. Investigating the controversial link between pediatric obesity and graft survival in kidney transplantation. World J Nephrol 2025; 14:101961. [DOI: 10.5527/wjn.v14.i2.101961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/02/2025] [Accepted: 02/08/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Childhood obesity is a significant public health concern, particularly amongst children with chronic kidney disease requiring kidney transplant (KT). Obesity, defined as a body mass index (BMI) of 30 kg/m² or greater, is prevalent in this population and is associated with disease progression. While BMI influences adult KT eligibility, its impact on pediatric transplant outcomes remains unclear. This study investigates the effect of BMI on graft survival and patient outcomes, addressing gaps in the literature and examining disparities across BMI classifications.
AIM To assess the impact of BMI classifications on graft and patient survival following KT.
METHODS A retrospective cohort study analyzed 23081 pediatric transplant recipients from the Standard Transplant Analysis and Research database (1987-2022). Patients were grouped into six BMI categories: Underweight, healthy weight, overweight, and Class 1, 2, and 3 obesity. Data were analyzed using one-way way analysis of variance, Kruskal-Wallis tests, Chi-squared tests, Kaplan-Meier survival analysis with log-rank tests, and Cox proportional hazard regressions. Statistical significance was set at P < 0.05.
RESULTS Class 3 obese recipients had lower 1-year graft survival (88.7%) compared to healthy-weight recipients (93.1%, P = 0.012). Underweight recipients had lower 10-year patient survival (81.3%, P < 0.05) than healthy-weight recipients. Class 2 and 3 obese recipients had the lowest 5-year graft survival (67.8% and 68.3%, P = 0.013) and Class 2 obesity had the lowest 10-year graft survival (40.7%). Cox regression identified increases in BMI category as an independent predictor of graft failure [hazard ratio (HR) = 1.091, P < 0.001] and mortality (HR = 1.079, P = 0.008). Obese patients experienced longer cold ischemia times (11.6 and 13.1 hours vs 10.2 hours, P < 0.001). Class 3 obesity had the highest proportion of Black recipients (26.2% vs 17.9%, P < 0.001).
CONCLUSION Severe obesity and underweight status are associated with poorer long-term outcomes in pediatric KT recipients, emphasizing the need for nuanced transplant eligibility criteria addressing obesity-related risks and socioeconomic disparities.
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Affiliation(s)
- Brooke Stanicki
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
| | - Dante A Puntiel
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
| | - Benjamin Peticca
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
| | - Nicolas Egan
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
| | - Tomas M Prudencio
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
| | - Samuel G Robinson
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
| | - Sunil S Karhadkar
- Department of Surgery, Temple University Hospital, Philadelphia, PA 19140, United States
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Sunder T, Ramesh P, Kumar M. Atrial arrhythmias following lung transplantation: A state of the art review. World J Transplant 2025; 15:101005. [DOI: 10.5500/wjt.v15.i2.101005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/25/2024] [Accepted: 11/19/2024] [Indexed: 02/21/2025] Open
Abstract
Lung transplantation (LT) is now an accepted therapy for end stage lung disease in appropriate patients. Atrial arrhythmias (AA) can occur after LT. Early AA after LT are most often atrial fibrillation, whereas late arrhythmias which occur many months or years after LT are often atrial tachycardia. The causes of AA are multifactorial. The review begins with a brief history of LT and AA. This review further describes the pathophysiology of the AA. The risk factors, incidence, recipient characteristics including intra-operative factors are elaborated on. Since there are no clear and specific guidelines on the management of atrial arrhythmia following LT, the recommended guidelines on the management of AA in general are often extrapolated and used in the setting of post LT arrhythmia. The strategy of rate control vs rhythm control is discussed. The pros and cons of various drug regimen, need for direct current cardioversion and catheter ablation therapies are considered. Possible methods to prevent or reduce the incidence of AA after LT are considered. The impact of AA on the short-term and long-term outcomes following LT is discussed.
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Affiliation(s)
- Thirugnanasambandan Sunder
- Department of Heart Lung Transplantation and Mechanical Circulatory Support, Apollo Hospitals, Chennai 600086, Tamil Nadu, India
| | - Paul Ramesh
- Department of Heart Lung Transplantation and Mechanical Circulatory Support, Apollo Hospitals, Chennai 600086, Tamil Nadu, India
| | - Madhan Kumar
- Department of Heart Lung Transplantation and Mechanical Circulatory Support, Apollo Hospitals, Chennai 600086, Tamil Nadu, India
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Hu J, Liu D, Liao G, Guo Y, Li M, Liao J, Chen H, Zhou S, Yang S, Li S, Liu Y, Zhao M. Fecal microbiota transplantation alleviates immunosuppressant-associated diarrhea and recurrent urinary tract infection in kidney transplant recipients: a retrospective analysis. Gut Pathog 2025; 17:28. [PMID: 40369623 PMCID: PMC12079832 DOI: 10.1186/s13099-025-00705-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 04/25/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Immunosuppressant administration subsequent to organ transplantation exerts a substantial influence on gut microbiota composition, thereby affecting patients' prognosis and quality of life. METHODS AND RESULTS We conducted a retrospective analysis involving 18 patients who experienced severe diarrhea or recurrent urinary tract infection (rUTI) due to prolonged immunosuppressant usage after kidney transplantation. Following episodes of severe diarrhea or rUTI, these individuals underwent fecal microbiota transplantation (FMT), resulting in notable alleviation of clinical symptoms. No unexpected adverse or serious adverse events were reported. In comparison to the pre-FMT period, the α-diversity of the intestinal microbiota in patients did not exhibit a significant difference following FMT; however, there was a notable distinction in the β-diversity and analysis of similarity (ANOSIM). In addition, our findings indicated a significant decline in the relative abundance of the bacterial genera Veillonella, Enterococcus, and Oribacterium, whereas a marked elevation was observed in the relative abundance of Faecalibacterium, Roseburia, Sutterella, Parasutterella, and Ruminiclostridium 5 after FMT in patients. Furthermore, there was a notable alteration in the metabolic pathway of gut microbiota in patients following FMT, with a significant enrichment observed in pathways such as Flavone and flavonol biosynthesis, Cytoskeleton proteins, Chromosome-related processes, NOD-like receptor signaling pathway, Progesterone-mediated oocyte maturation, and Antigen processing and presentation. CONCLUSION FMT exhibited an effective approach for managing rUTI and diarrhea arising from postoperative immunosuppressant exposure in kidney transplant recipients.
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Affiliation(s)
- Jianmin Hu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Ding Liu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Guorong Liao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Ying Guo
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Min Li
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Jun Liao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Hua Chen
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Song Zhou
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Siqiang Yang
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Shichao Li
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China
| | - Yongguang Liu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China.
| | - Ming Zhao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, No.253 Industrial Avenue, Haizhu District, Guangzhou, 510282, China.
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Chen YA, Lai TS, Tsao HM, Chen YT. Comparison of outcomes between kidney transplant-naïve and post-transplant graft failure peritoneal dialysis patients. J Formos Med Assoc 2025:S0929-6646(25)00210-4. [PMID: 40328595 DOI: 10.1016/j.jfma.2025.04.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/23/2025] [Accepted: 04/30/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND This study was conducted to compare clinical outcomes between transplant-naïve peritoneal dialysis (PD) patients and those returning to PD after a failed allograft. METHODS In this retrospective cohort study during 2006 and 2016, we included a total of 786 patients on chronic PD. Of them 679 were transplant-naïve, 75 patients underwent a successful transplantation, and 32 patients returned to PD after a failed kidney allograft. Baseline demographics and clinical characteristics were analyzed in relation to the outcomes of all-cause mortality and peritonitis rate. We employed the Kaplan-Meier method and Cox proportional hazards model to evaluate survival, while Poisson regression was utilized to estimate rate ratios for peritonitis. RESULTS During a median follow-up of 6.37 years, 56.68 % death and 146.62 episodes of peritonitis/patient-year were observed. Compared with patients who received a kidney graft, transplant-naïve patients were older, more with diabetes and having higher mortality (58.6 ± 15.8, 40.5 % and 57.73 %, p < 0.0001). After accounting for age, gender, and comorbidities, the adjusted hazards ratios were 0.26 (95 % CI 0.13-0.53) in patients with a functioning graft and 1.12 (95 % CI 0.61-2.06) in patients returning to PD after graft failure, compared respectively with concurrent PD patients without kidney transplant. The adjusted rate ratio of peritonitis in patients resuming PD after graft failure was 0.55 (95 % CI: 0.22-1.14) compared to those without kidney transplant. CONCLUSIONS Patients restarting PD after graft failure exhibited clinical outcomes comparable to transplant-naïve PD patients. These findings support the feasibility of reinitiating PD after kidney transplant fails.
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Affiliation(s)
- Yung-An Chen
- Department of Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan
| | - Tai-Shuan Lai
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsiao-Mei Tsao
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ting Chen
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Division of Blood Purification, Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
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Ruberto F, Lai Q, Piazzolla M, Poli L, Zullino V, Diamantini G, Brisciani M, Giovanardi F, Melandro F, Quaresima S, Rossi M, Garofalo M, Pugliese F. Short (2-Hour) Non-Oxygenated End-Ischemic Hypothermic Perfusion Versus Cold Storage in the Setting of Renal Transplantation. Artif Organs 2025; 49:831-841. [PMID: 39861988 PMCID: PMC12019098 DOI: 10.1111/aor.14953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/22/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Kidney transplantation (KT) is the most effective treatment for end-stage renal disease. End-ischemic hypothermic machine perfusion (EI-HMP) has emerged as a promising method for preserving grafts before transplantation. This study aimed to compare graft function recovery in KT recipients of deceased brain-death (DBD) grafts preserved with EI-HMP versus static cold storage (SCS). The primary outcome was the rate of delayed graft function (DGF). Secondary outcomes included urine output, intensive care unit (ICU) stay, hospital stay duration, and survival rates. METHODS A retrospective, single-center observational study was conducted at Sapienza University of Rome, analyzing 313 KT patients between January 2014 and September 2021. Patients were stratified into two groups based on graft preservation methods (EI-HMP, n = 95; SCS, n = 218). A stabilized inverse probability treatment weighting (IPTW) method was employed to adjust for potential confounders. RESULTS There were no significant differences in DGF rates between the two groups (17.9% vs. 15.6% in SCS and EI-HMP cases, respectively; p = 0.75). EI-HMP group demonstrated a higher urine output on day 2 (p = 0.046), a shorter ICU stay (p < 0.0001), and a trend toward a shorter overall hospital stay (p = 0.07). No statistically significant differences were found between EI-HMP and SCS cases in 1- and 3-year overall survival rates (3.2% and 6.7% vs. 5.6% and 6.6%, respectively; log-rank p = 0.53) or in death-censored graft loss rates (5.4% and 8.9% vs. 5.7% and 7.3%, respectively; log-rank p = 0.88). In a sub-analysis of expanded criteria donors (ECD), EI-HMP demonstrated a protective effect by reducing the risk of DGF (OR = 0.31, 95% CI = 0.09-0.95; p = 0.047). CONCLUSION EI-HMP was associated with certain short-term benefits, including increased urine output and reduced ICU stays, but showed no significant impact on long-term survival outcomes. A reduction in DGF rates was observed only in the ECD subgroup. Randomized controlled trials are necessary to further investigate the long-term clinical benefits of EI-HMP.
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Affiliation(s)
- Franco Ruberto
- Department of Anesthesiology, Critical Care Medicine and Pain TherapySapienza University of RomeRomeItaly
| | - Quirino Lai
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Mario Piazzolla
- Department of Anesthesiology, Critical Care Medicine and Pain TherapySapienza University of RomeRomeItaly
| | - Luca Poli
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Veronica Zullino
- Department of Anesthesiology, Critical Care Medicine and Pain TherapySapienza University of RomeRomeItaly
| | - Giulia Diamantini
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Matteo Brisciani
- Department of Anesthesiology, Critical Care Medicine and Pain TherapySapienza University of RomeRomeItaly
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Fabio Melandro
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Silvia Quaresima
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Massimo Rossi
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Manuela Garofalo
- General Surgery and Organ Transplantation UnitSapienza University of RomeRomeItaly
| | - Francesco Pugliese
- Department of Anesthesiology, Critical Care Medicine and Pain TherapySapienza University of RomeRomeItaly
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7
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Bourgonje AR, Knobbe TJ, Kremer D, Bulthuis MLC, Bemelman FJ, Berger SP, Navis GJ, Bakker SJL, Corpeleijn E, van Goor H. Effect of lifestyle intervention on systemic oxidative stress in kidney transplant recipients: A post-hoc analysis of the Active Care after Transplantation (ACT) randomized controlled trial. Free Radic Biol Med 2025; 232:412-420. [PMID: 40043960 DOI: 10.1016/j.freeradbiomed.2025.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Oxidative stress is associated with adverse outcomes in kidney transplant recipients (KTR), including graft failure, morbidity, and mortality. Since both exercise training and dietary modifications have the potential to improve redox status, we aimed to investigate the potential mitigating effects of exercise or exercise plus diet intervention on circulating levels of free thiols (R-SH) as marker of systemic redox status in KTR. METHODS We conducted a post-hoc analysis of the Active Care after Transplantation (ACT) study, a randomized controlled lifestyle intervention trial which proved to enhance physical functioning of KTR. Systemic R-SH levels were quantified at baseline, 3-months, and 15-months (end of study) using a colorimetric detection method. Estimated marginal means (EMM) were reported using general linear mixed models. RESULTS KTR were randomized to usual care (n = 40), exercise intervention (n = 54), or exercise plus diet intervention (n = 55). At 3 months post-baseline, systemic R-SH concentrations decreased significantly in the control group, while the intervention groups showed a less pronounced decrease, although the difference compared to control nearly reached statistical significance in either the exercise intervention group (EMM +20.2 μM (95%CI -1.4, +41.9), P = 0.067) or the exercise plus diet intervention group (EMM +18.9 μM (95%CI -2.7, +40.4), P = 0.086). At 15 months post-baseline, R-SH concentrations further decreased in the exercise intervention group, resulting in a difference compared to control of +9.0 μM (95%CI -14.4, +32.3; P = 0.45), whereas R-SH concentrations increased to above baseline in the exercise plus diet intervention group, with a statistically significant difference compared to control of +32.8 μM (95%CI +9.4, +56.2; P = 0.006). CONCLUSIONS Lifestyle changes involving exercise and diet positively impacted systemic R-SH, suggesting that reducing oxidative stress through lifestyle interventions could potentially contribute to clinical benefits in KTR.
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Affiliation(s)
- Arno R Bourgonje
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, the Netherlands; The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tim J Knobbe
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, the Netherlands
| | - Daan Kremer
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, the Netherlands
| | - Marian L C Bulthuis
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
| | - Frederike J Bemelman
- Department of Internal Medicine, Division of Nephrology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Stefan P Berger
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, the Netherlands
| | - Gerjan J Navis
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, the Netherlands
| | - Stephan J L Bakker
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, the Netherlands
| | - Eva Corpeleijn
- University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands
| | - Harry van Goor
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands.
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Levan ML, Kaplow K, Downey MC, Sidoti CN, Reed RD, Richards K, Liebman SE, Gordon EJ, Rudow DL, Segev DL, Kayler LK, Lindower C, Kimberly LL. Early Steps of the Kidney Transplant Process: What Are the Experiences of Dialysis Social Workers? Clin Transplant 2025; 39:e70182. [PMID: 40391920 DOI: 10.1111/ctr.70182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 04/22/2025] [Accepted: 04/29/2025] [Indexed: 05/22/2025]
Abstract
INTRODUCTION Dialysis social workers (DSWs) educate and advocate for end-stage kidney disease (ESKD) patients during the kidney transplantation (KT) process. However, little is known about the barriers DSWs face as they help patients get waitlisted and how to best support their efforts. We interviewed DSWs across New York (NY) State to examine their experiences, supports, and challenges in helping dialysis patients progress through KT education, referral, and evaluation. METHODS We conducted semi-structured interviews with DSWs in NY State who had participated or expressed interest in a program designed to educate DSWs about KT and used rapid qualitative analysis to identify themes. FINDINGS We interviewed 17 DSWs. Seven themes emerged: (1) DSWs report involvement in KT interest assessment, education, referral, and evaluation support, (2) DSWs report varying nephrologist support in helping patients progress to KT, (3) DSWs perceive social support and adherence as key factors in KT centers' eligibility determinations, (4) DSWs have knowledge gaps around living donation and appreciate learning about KT from transplant centers and non-profit organizations, (5) Patients express KT concerns and DSWs counsel them about these concerns, (6) DSWs report solutions to help patients complete KT evaluation appointments, and (7) DSWs report communication deficiencies between dialysis centers and transplant centers, and patients. CONCLUSIONS Education for DSWs, support from nephrologists, and resources to help patients complete KT evaluation steps facilitated DSW engagement throughout the pre-transplant process, underscoring the need for multi-level, cross-disciplinary programs to support these efforts.
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Affiliation(s)
- Macey L Levan
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA
- Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA
| | - Katya Kaplow
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA
| | - Max C Downey
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA
| | - Carolyn N Sidoti
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA
| | - Rhiannon D Reed
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA
| | - Kristy Richards
- New York Center for Kidney Transplantation, Lake Grove, New York, USA
| | | | - Elisa J Gordon
- Department of Surgery, Center for Biomedical Ethics & Society, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Dianne LaPointe Rudow
- Recanati Miller Transplantation Institute, Mount Sinai Medical Hospital, New York, New York, USA
| | - Dorry L Segev
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA
- Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA
| | - Liise K Kayler
- Department of Surgery, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Carrie Lindower
- New York Center for Kidney Transplantation, Lake Grove, New York, USA
| | - Laura L Kimberly
- Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA
- Hansjörg Wyss Department of Plastic Surgery, NYU Grossman School of Medicine, New York, New York, USA
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9
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Vabres B, Pleyer U, Hjortdal J, Murphy CC, Armitage WJ, Imrie L, Cadoux M, Danger R, Bylesjo M, Mac Gabhann P, Tole D, Walkinshaw MD, Griffin MD, Brouard S, Degauque N. Corneal Graft Rejection: Is It Reflected in Peripheral Immune Cells? Results of a Prospective Multicenter Study (VISICORT). Transplantation 2025; 109:794-805. [PMID: 39663555 DOI: 10.1097/tp.0000000000005280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
BACKGROUND Allogeneic graft rejection is the leading cause of graft failure in corneal transplantation (CT) despite the immune privilege of the anterior chamber and corneal bed. The ability to identify patients at higher risk of acute rejection before or after CT could have a major impact on the clinical management of these patients. METHODS To address this important issue, a multicenter European cohort of low-risk (n = 142) and high-risk (n = 102) CT recipients was established, and the immune system was evaluated in detail in peripheral blood mononuclear cells and plasma before and 6 and 12 mo posttransplantation. Eleven patients in the low-risk group and 11 in the high-risk group experienced acute rejection. RESULTS Mass spectrometry analysis of plasma showed a high similarity in composition between patients with and without acute rejection, regardless of their preexisting clinical risk. Pretransplant and longitudinal immune cell analysis of peripheral blood mononuclear cells using deconvolution of transcriptomic profiling and high-dimensional flow cytometry revealed a lack of immune-related biomarkers associated with acute rejection. CONCLUSIONS Our results indicate that the immune response leading to acute rejection of CT is unlikely to be detected in the peripheral blood and suggest that analysis of compartments in close proximity to the cornea is more likely to yield clinically applicable predictive biomarkers.
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Affiliation(s)
- Bertrand Vabres
- Nantes Université, CHU Nantes, Service Ophtalmologie, Nantes, France
| | - Uwe Pleyer
- Department of Ophthalmology, Charité University Hospital, Berlin, Germany
| | - Jesper Hjortdal
- Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Conor C Murphy
- Royal Victoria Eye and Ear Hospital, Dublin, Ireland
- Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - W John Armitage
- Translational Health Sciences, University of Bristol, Bristol, United Kingdom
- Tissue and Eye Services, NHS Blood and Transplant, Bristol, United Kingdom
| | - Lisa Imrie
- Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Marion Cadoux
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- CHU Nantes, Institut De Transplantation Urologie Néphrologie (ITUN), Nantes, France
| | - Richard Danger
- Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Translational Health Sciences, University of Bristol, Bristol, United Kingdom
| | - Max Bylesjo
- Fios Genomics Ltd, Nine Edinburgh Bioquarter, Edinburgh, United Kingdom
| | | | - Derek Tole
- University Hospitals Bristol NHS Foundations Trust, Bristol Eye Hospital, Bristol, United Kingdom
| | - Malcolm D Walkinshaw
- Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
| | - Sophie Brouard
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- CHU Nantes, Institut De Transplantation Urologie Néphrologie (ITUN), Nantes, France
| | - Nicolas Degauque
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- CHU Nantes, Institut De Transplantation Urologie Néphrologie (ITUN), Nantes, France
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10
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Diebold M, Vietzen H, Schatzl M, Mayer KA, Haindl S, Heinzel A, Hittmeyer P, Herz CT, Hopfer H, Menter T, Kühner LM, Berger SM, Puchhammer-Stöckl E, Doberer K, Steiger J, Schaub S, Böhmig GA. Functional Natural Killer-cell Genetics and Microvascular Inflammation After Kidney Transplantation: An Observational Cohort Study. Transplantation 2025; 109:860-870. [PMID: 39402708 PMCID: PMC12011434 DOI: 10.1097/tp.0000000000005228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/26/2024] [Indexed: 04/23/2025]
Abstract
BACKGROUND Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection. METHODS We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes ( FCGR3AV/F158 [rs396991], KLRC2wt/del , KLRK1HNK/LNK [rs1049174], and rs9916629-C/T). RESULTS MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P = 0.052). CONCLUSIONS Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Martina Schatzl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Susanne Haindl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Philip Hittmeyer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Carsten T. Herz
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Hopfer
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Thomas Menter
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Laura M. Kühner
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Sarah M. Berger
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | | | - Konstantin Doberer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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11
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Knobbe TJ, Kremer D, Bültmann U, Annema C, Navis G, Berger SP, Bakker SJ, Meuleman Y. Insights Into Health-Related Quality of Life of Kidney Transplant Recipients: A Narrative Review of Associated Factors. Kidney Med 2025; 7:100986. [PMID: 40182980 PMCID: PMC11964492 DOI: 10.1016/j.xkme.2025.100986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025] Open
Abstract
Life expectancy and graft survival continue to improve after transplantation. However, improved posttransplant clinical outcomes do not necessarily translate into improved health-related quality of life (HRQoL). Therefore, there is an increased focus on HRQoL in kidney transplant recipients (KTRs). The HRQoL of KTRs is worse than that of the general population, but interventions that improve HRQoL in KTRs are scarce, and health care professionals in nephrology care do not routinely address HRQoL. To improve HRQoL, it is essential to understand which factors play a role in HRQoL and to pinpoint areas for intervention. This narrative review maps the concept of HRQoL within the KTR population and provides a comprehensive overview of factors associated with posttransplant HRQoL. The results are structured using an easy-to-understand conceptual model of HRQoL, which is instrumental for understanding how HRQoL is constituted of many clinical and nonclinical factors. We conclude that symptom burden among KTRs is high, which is likely a key driver of the limited HRQoL in this population. Moreover, myriad other clinical and nonclinical factors are associated with HRQoL, but the majority of the evidence is observational.
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Affiliation(s)
- Tim J. Knobbe
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Daan Kremer
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ute Bültmann
- Community and Occupational Medicine, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Coby Annema
- Section of Nursing Science, Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerjan Navis
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Stefan P. Berger
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Stephan J.L. Bakker
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Yvette Meuleman
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
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12
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Madhvapathy SR, Cho S, Gessaroli E, Forte E, Xiong Y, Gallon L, Rogers JA. Implantable bioelectronics and wearable sensors for kidney health and disease. Nat Rev Nephrol 2025:10.1038/s41581-025-00961-2. [PMID: 40301646 DOI: 10.1038/s41581-025-00961-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2025] [Indexed: 05/01/2025]
Abstract
Established clinical practices for monitoring kidney health and disease - including biopsy and serum biomarker analysis - suffer from practical limitations in monitoring frequency and lack adequate sensitivity for early disease detection. Engineering advances in biosensors have led to the development of wearable and implantable systems for monitoring of kidney health. Non-invasive microfluidic systems have demonstrated utility in the detection of kidney-relevant biomarkers, such as creatinine, urea and electrolytes in peripheral body fluids such as sweat, interstitial fluid, tears and saliva. Implantable systems may aid the identification of early transplant rejection through analysis of organ temperature and perfusion, and enable real-time assessment of inflammation through the use of thermal sensors. These technologies enable continuous, real-time monitoring of kidney health, offering complementary information to standard clinical procedures to alert physicians of changes in kidney health for early intervention. In this Review, we explore devices for monitoring renal biomarkers in peripheral biofluids and discuss developments in implantable sensors for the direct measurement of the local, biophysical properties of kidney tissue. We also describe potential clinical applications, including monitoring of chronic kidney disease, acute kidney injury and allograft health.
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Affiliation(s)
- Surabhi R Madhvapathy
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA
| | - Soongwon Cho
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA
| | - Elisa Gessaroli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
- Department of Medicine, Division of Nephrology, University of Illinois College of Medicine, Chicago, IL, USA
| | - Eleonora Forte
- Department of Medicine, Division of Nephrology, University of Illinois College of Medicine, Chicago, IL, USA
| | - Yirui Xiong
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA
| | - Lorenzo Gallon
- Department of Medicine, Division of Nephrology, University of Illinois College of Medicine, Chicago, IL, USA.
| | - John A Rogers
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA.
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA.
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
- Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.
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13
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Ruiz-Merlo T, Rodríguez-Goncer I, López-Medrano F, Polanco N, González E, Trujillo H, Fayos M, Redondo N, San Juan R, Andrés A, Aguado JM, Fernández-Ruiz M. Knowledge and Adherence to Lifestyle Habits to Prevent Complications Associated With Immunosuppression in Kidney Transplant Recipients: A Single-Center Survey. Transpl Infect Dis 2025:e70038. [PMID: 40285521 DOI: 10.1111/tid.70038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/07/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Chronic immunosuppression associated with certain lifestyle habits render kidney transplant (KT) recipients more susceptible to infection and cancer. We assessed the level of knowledge and adherence to safe living strategies to minimize the occurrence of posttransplant complications. METHODS Consecutive KT recipients were offered a self-administered questionnaire covering the following areas: demographics and socioeconomic factors; generic hygiene habits; sun exposure; smoking and alcohol consumption; vaccination status; animal contact and gardening; international travelling; and food safety and habits. RESULTS Between May 2019 and May 2021, 130 KT recipients responded the survey at a median of 61.5 posttransplant days (completion rate of 94.9%). Only 19.7% of participants visited the dentist at least every 3-6 months. Although the majority (88.5%) were aware of the need of sunscreen, only 23.3% used it throughout the year. Self-reported influenza vaccine uptake in the last session was 69.1%. Pet ownership was reported by 41.7% of participants, of which more than one-third had considered to give up the care of their animals. Gardening and international travel were uncommon. A notable proportion of participants acknowledged to consume the following products either "usually" or "often": raw or undercooked meat (12.4%), undercooked fish (24.8%), raw seafood (8.8%), homemade sausages or cured ham (51.5%), pâté or meat spreads (35.2%), and "ready-to-eat" salads (31.8%). Adherence was poorer among non-native-speaking patients and those with lower education and household incomes. CONCLUSION There is room for improvement in health education and promotion practices among KT recipients, particularly those with potential cultural and socioeconomic barriers.
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Affiliation(s)
- Tamara Ruiz-Merlo
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Rodríguez-Goncer
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Francisco López-Medrano
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Natalia Polanco
- Department of Nephrology, Hospital Universitario '12 de Octubre', Instituto de Investigación Sanitaria Hospital '12 de Octubre' (imas12), Madrid, Spain
| | - Esther González
- Department of Nephrology, Hospital Universitario '12 de Octubre', Instituto de Investigación Sanitaria Hospital '12 de Octubre' (imas12), Madrid, Spain
| | - Hernando Trujillo
- Department of Nephrology, Hospital Universitario '12 de Octubre', Instituto de Investigación Sanitaria Hospital '12 de Octubre' (imas12), Madrid, Spain
| | - Marina Fayos
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Natalia Redondo
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Rafael San Juan
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Amado Andrés
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
- Department of Nephrology, Hospital Universitario '12 de Octubre', Instituto de Investigación Sanitaria Hospital '12 de Octubre' (imas12), Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
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14
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Wang W, Gao T, Wang Y, Wang R, He M, Wang L, Zhou W, Ding M, Song Y, Ji X, Li X, Song Y, Zhu Y, Zhang Y, Xie Y, Chen Y, Jin Q, Xie M, Zhang L. Macrophage-Tased Dual-Phase T Cell Immunomodulation to Combat Transplant Rejection. Adv Healthc Mater 2025:e2403591. [PMID: 40264278 DOI: 10.1002/adhm.202403591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 03/31/2025] [Indexed: 04/24/2025]
Abstract
Transplant rejection remains a major challenge, driven primarily by the activation of alloreactive T cells. While enhancement of PD-L1 checkpoint molecules has exhibited potential in inhibiting T cell activity, its efficacy is often hindered by limited specificity and inadequate efficiency. Herein, a novel dual-phase immune modulation strategy is developed in which CTLA4-Ig and PD-L1 provide distinct, non-redundant inhibitory signals during the initial activation phase and the post-activation phase of T cells. PD-L1 is stably expressed on macrophages (sPD-L1 M) through lentiviral transduction, allowing them to leverage their chemotactic and antigen-presenting functions to target and deliver PD-L1 to transplant rejection sites. Notably, sPD-L1 M exhibited adaptive targeting capabilities, increasing their migration to grafts in response to heightened rejection. In an allograft skin model, the combined intravenous administration of sPD-L1 M and subcutaneous administration of CTLA4-Ig demonstrated synergistic efficacy, significantly suppressing alloreactive T cell activation, enhancing the recruitment of regulatory T cells (Tregs), downregulating pro-inflammatory cytokines, and prolonging allograft survival compared to either treatment alone. This study presents a promising strategy to effectively suppress T cell activity and prevent allogeneic immune responses without systemic immunosuppression.
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Affiliation(s)
- Wenyuan Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Tang Gao
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yihui Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Rui Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mengrong He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Lufang Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wuqi Zhou
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mengdan Ding
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yuan Song
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xiang Ji
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Xueke Li
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yishu Song
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Ye Zhu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yiwei Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yuji Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yan Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Qiaofeng Jin
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Clinical Research Center for Medical Imaging, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
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15
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Chandar J, Sigurjonsdottir V, Defreitas M, Gavcovich T, Zhou M, Glehn-Ponsirenas R, Burke G. Donor-derived cell-free DNA testing in pediatric kidney transplant recipients: indications and clinical utility. Pediatr Nephrol 2025:10.1007/s00467-025-06770-w. [PMID: 40229569 DOI: 10.1007/s00467-025-06770-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND We describe our single-center experience in performing donor-derived cell-free DNA (dd-cfDNA) testing for a clinical indication in pediatric kidney transplant recipients. METHODS Dd-cfDNA was done for increase in creatinine, appearance of de novo anti-HLA antibodies (dnHLAab) and for a clinical indication. We compared clinical characteristics of patients with dd-cfDNA > 1 with those with dd-cfDNA ≤ 1 and also compared dd-cfDNA in patients with no biopsy proven rejection (BPAR) or dnHLAab with those with BPAR, and those with dnHLAab and no BPAR. RESULTS Chart review was performed in 106 patients with a mean age of 11.0 ± 5.5 years. When compared with 62 patients with dd-cfDNA ≤ 1, 59.0% (26/44) of patients with dd-cfDNA > 1 had BPAR (OR 13.5: 95%CI 4.6,38; p < 0.0001), and 88.1% (37/44) had dnHLAab (OR 60.3 95%CI 17.2,192.2; p < 0.0001). Patients with DQ and DR dnHLAab (OR 115.2: 95%CI 24.8, 509.5; p < 0.0001) and those with donor-specific antibodies (DSAs) (OR 50.8: 95%CI 13.0, 168.7; p < 0.0001) were likely to have dd-cfDNA > 1. A repeated measures linear mixed effect model revealed a significant difference in dd-cfDNA between those with no antibodies or BPAR (p < 0.0001) and patients with BPAR and dnHLAab, with or without DSA. At the end of the follow-up period, eGFR was 72 mL/min/1.73 m2 in those without BPAR or dnHLAab and was significantly different from those with BPAR (eGFR 51 mL/min/1.73 m2 (p < 0.0001). CONCLUSIONS Elevated dd-cfDNA is strongly associated with BPAR, class II dnHLAab and DSAs. Conversely, low values are observed in immunoquiescent states. Dd-cfDNA can be a useful tool for non-invasive clinical decision-making.
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Affiliation(s)
- Jayanthi Chandar
- Department, of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA.
- Miami Transplant Institute, Jackson Health System, Miami, FL, USA.
| | - Vaka Sigurjonsdottir
- Department, of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA
- Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - Marissa Defreitas
- Department, of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA
- Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - Tara Gavcovich
- Department, of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Mingming Zhou
- Biostatistics and Data Sciences Department, CareDx, Inc, Brisbane, CA, USA
| | | | - George Burke
- Miami Transplant Institute, Jackson Health System, Miami, FL, USA
- Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine, Miami, FL, USA
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16
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Stewart DE, Gragert L, Mankowski MA. Optimizing kidney allocation: challenges and solutions. Curr Opin Organ Transplant 2025; 30:61-73. [PMID: 40040564 DOI: 10.1097/mot.0000000000001195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
PURPOSE OF REVIEW With the kidney nonuse rate approaching 30%, one-fifth of kidneys placed out of sequence, and unsatisfactory long-term recipient outcomes, U.S. kidney allocation is at a crossroads. This review highlights recent studies and efforts geared toward improving the system. RECENT FINDINGS The Organ Procurement & Transplantation Network's kidney transplantation committee is tasked with migrating kidney allocation policy, currently based on 250 nautical mile circles, to a fully continuous, points-based system. Challenges in designing a system assured to improve, not worsen, placement efficiency have hampered progress. OPO and transplant center practice patterns have adapted to a rapidly changing donation landscape. Advances in transplant immunology, particularly involving molecular HLA typing methods, are opening doors for more precise donor-recipient matching that appear to hold promise for improved long-term outcomes. SUMMARY The largely one-size-fits-all kidney allocation system is in desperate need of an overhaul. The continuous distribution paradigm is flexible enough to accommodate bold, new ideas for addressing major pain points in an equitable way. The OPTN should use policy variances to conduct time-limited, controlled experiments with various continuous distribution policies and build upon what works. Advances in transplant immunology, such as eplet matching, should increasingly be incorporated into kidney offer decision-making and, eventually, the allocation algorithm.
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Affiliation(s)
| | - Loren Gragert
- Deming Department of Medicine, Section of Biomedical Informatics and Genomics, Tulane University School of Medicine, New Orleans, Los Angeles, USA
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17
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Mohan S, Yu M, Husain SA. Equity and the operational considerations of the kidney transplant allocation system. Curr Opin Organ Transplant 2025; 30:146-151. [PMID: 39760137 PMCID: PMC11962740 DOI: 10.1097/mot.0000000000001201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
Abstract
PURPOSE OF REVIEW Demonstrate the impact of allocation system design on access to the waitlist and transplantation for patients with end-stage kidney disease (ESKD). RECENT FINDINGS Minoritized groups are more likely to be declined from transplant listing owing to psychosocial criteria. Lack of consistent definitions, screening tools with differential subgroup validity, and insufficient evidence-base contribute to concerns about reliance on psychosocial factors in transplant listing decisions. SUMMARY Although kidney transplantation is the preferred treatment choice, a shrinking proportion of prevalent patients are waitlisted for this option in the United States, even among our youngest ESKD patients. Recent HRSA proposals to expand data collection to encompass the prewaitlisting process suggest a timely need to capture additional data on transplant referrals to improve access to transplantation. In 2021, KAS250 was implemented in response to concerns of geographic inequities in transplant rates. However, updates to this system have also resulted in a dramatic rise in organ offers, the number of offers needed to successfully place an organ and lowered utilization rates. Since KAS250, the use of alternative pathways to improve organ utilization rates, such as out-of-sequence placements has increased dramatically across the organ quality spectrum and risk exacerbating disparities in access to transplant. Additionally, the current absence of meaningful oversight risks undermining the perception of the transplant system as an objective process. SUMMARY There is a need for a more robust evaluation of recent iterative changes in waitlist and organ allocation practices to ensure equity in access for our most vulnerable patients.
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Affiliation(s)
- Sumit Mohan
- Division of Nephrology, Department of Medicine, Vagelos
College of Physicians & Surgeons, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public
Health, Columbia University, New York, NY
- Columbia University Renal Epidemiology Group, New York,
NY
| | - Miko Yu
- Division of Nephrology, Department of Medicine, Vagelos
College of Physicians & Surgeons, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public
Health, Columbia University, New York, NY
| | - S Ali Husain
- Division of Nephrology, Department of Medicine, Vagelos
College of Physicians & Surgeons, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public
Health, Columbia University, New York, NY
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18
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Basile G, Fallara G, Bandini M, Cazzaniga W, Negri F, Dieguez L, Montorsi F, Salonia A, Breda A, Fankhauser C, Territo A. Testis and penile cancers in kidney transplant recipients: A systematic review of epidemiology, treatment options and oncological outcomes by the EAU-YAU Penile and Testis Cancer Working Group. Actas Urol Esp 2025; 49:501683. [PMID: 39952563 DOI: 10.1016/j.acuroe.2025.501683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 10/03/2024] [Indexed: 02/17/2025]
Abstract
INTRODUCTION Kidney transplant (KT) recipients are at an elevated risk of developing de novo cancers. However, penile (PeCa) and testis cancers have received limited attention in this setting. OBJECTIVE To summarize the epidemiology, treatment options, and oncological outcomes of penile and testis cancer in KT recipients. EVIDENCE ACQUISITION We conducted a systematic review of prospective, retrospective and national transplant registries studies published up to December 2023. Data on the incidence of penile and testis cancers among KT recipients, diagnostic protocols, screening recommendations, and therapeutic strategies tailored for KT recipients were collected. The risk of bias (RoB) of included studies was determined using the Newcastle and Ottawa scale. EVIDENCE SYNTHESIS Overall, 21 studies involving 67924 KT male recipients were included. PeCa was diagnosed in 33 patients, yielding an incidence ranging from 0.04% to 0.3%. Additionally, 67 cases of testicular cancer were recorded, with an incidence ranging from 0.03% to 0.55%. Most tumors were localized, and histology variants were uncommon. While the surgical treatment of the primary tumor remains consistent with that of the general population, the use of radiotherapy and cytotoxic treatments are less frequently reported in this setting. These therapies should be considered on an individualized basis to minimize the risk of graft injury. CONCLUSIONS Penile and testis cancers are relatively uncommon among KT recipients. General screening protocols and deviation from current treatment guidelines are not recommended in localized diseases. Given the risk of graft damage, any non-cytotoxic option should be preferred in locally advanced cases.
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Affiliation(s)
- G Basile
- Departamento de Urología, Instituto de Investigación Urológica, Instituto Científico San Raffaele, Milán, Italy.
| | - G Fallara
- División de Urología, Instituto Europeo de Oncología IRCCS, Milán, Italy
| | - M Bandini
- Departamento de Urología, Instituto de Investigación Urológica, Instituto Científico San Raffaele, Milán, Italy
| | - W Cazzaniga
- The Royal Marsden NHS Foundation Trust, Londres, United Kingdom
| | - F Negri
- Departamento de Urología, Instituto de Investigación Urológica, Instituto Científico San Raffaele, Milán, Italy
| | - L Dieguez
- Servicio de Urología, Fundación Puigvert, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - F Montorsi
- Departamento de Urología, Instituto de Investigación Urológica, Instituto Científico San Raffaele, Milán, Italy
| | - A Salonia
- Departamento de Urología, Instituto de Investigación Urológica, Instituto Científico San Raffaele, Milán, Italy
| | - A Breda
- Servicio de Urología, Fundación Puigvert, Universidad Autónoma de Barcelona, Barcelona, Spain
| | | | - A Territo
- Servicio de Urología, Fundación Puigvert, Universidad Autónoma de Barcelona, Barcelona, Spain
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19
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Byrne MM, Ganay-Vasquez J, Jacobs ML, Wirth K, Hendzlik P, Martens J, Dokus MK, Melaragno JI, Tariq H, Taylor J, DeWolfe D, Nair A, Kashyap R, Hernandez-Alejandro R, Cupertino P, Wilson NA, Pineda-Solis K. Association of Socioeconomic Disadvantage and Deceased Donor Kidney Transplant Graft Function. J Surg Res 2025; 308:243-249. [PMID: 40121751 DOI: 10.1016/j.jss.2025.02.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/13/2025] [Accepted: 02/20/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION The study of social determinants of health in kidney transplantation has historically focused on equitable access, with limited evidence on the short- and long-term outcomes beyond graft loss and mortality. Our purpose is to identify and assess factors to ensure equitable outcomes after kidney transplant by identifying targets for health-care interventions in the posttransplant phase of care. METHODS This is a single institution, cohort study of adults who received deceased donor kidney transplantation at a high-volume transplant center. Transplant recipients were stratified by social deprivation index (SDI) at the population mean of 60. The primary outcome is change in estimated glomerular filtration rate (eGFR). RESULTS A total of 236 recipients were included, 48% (n = 113) were from higher deprivation neighborhoods (SDI >60). These recipients were younger, more likely to be black, and had lower estimated posttransplant survival scores. Both groups received grafts with similar kidney donor profile index scores. Despite similar discharge eGFR, recipients from high SDI neighborhoods had significantly lower eGFRs at all follow-up points, confirmed with mixed-effect analysis. CONCLUSIONS Recipients from neighborhoods with higher deprivation index have worse short- and long-term graft function, despite being younger, having lower estimated posttransplant survival scores, and similar graft kidney donor profile index at transplantation. This unexplained compromise in graft function is an opportunity for community-based interventions after recipients receive deceased donor kidney transplantation.
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Affiliation(s)
- Matthew M Byrne
- Department of Surgery, University of Rochester Medical Center, Rochester, New York.
| | - Jenny Ganay-Vasquez
- University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Marie L Jacobs
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Korry Wirth
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Peter Hendzlik
- University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - John Martens
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | - M Katherine Dokus
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | - Jennifer I Melaragno
- Department of Pharmacy, University of Rochester Medical Center, Rochester, New York
| | - Hafsa Tariq
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | - Jeremy Taylor
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | - David DeWolfe
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | - Amit Nair
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | - Randeep Kashyap
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
| | | | - Paula Cupertino
- Department of Public Health Sciences, University of Rochester Medical Center, Rochester, New York
| | - Nicole A Wilson
- Division of Pediatric Surgery, Department of Surgery, University of Rochester Medical Center, Golisano Children's Hospital, Rochester, New York
| | - Karen Pineda-Solis
- University of Rochester Medical Center, Transplant Institute, Rochester, New York
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20
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Gedaly R, Orozco G, Lewis LJ, Valvi D, Chapelin F, Khurana A, Hidalgo GE, Shmookler A, Tripathi A, Zhang C, Zwischenberger JB, Marti F. Effect of mitochondrial oxidative stress on regulatory T cell manufacturing for clinical application in transplantation: Results from a pilot study. Am J Transplant 2025; 25:720-733. [PMID: 39515758 PMCID: PMC11973835 DOI: 10.1016/j.ajt.2024.10.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 09/25/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
The manufacturing process of regulatory T (Treg) cells for clinical application begins with the positive selection of CD25+ cells using superparamagnetic iron oxide nanoparticle (SPION)-conjugated anti-CD25 antibodies (spCD25) and immunomagnetic cell separation technology. Our findings revealed that the interaction of spCD25 with its cell target induced the internalization of the complex spCD25-interleukin-2 receptor. Accumulation of intracellular spCD25 triggered oxidative stress, causing delayed Treg expansion and temporary reduction in suppressor activity. This activation delay hindered the efficient generation of clinically competent cells. During this early phase, Treg cells exhibited elevated mitochondrial superoxide and lipid peroxidation levels, with a concomitant decrease in mitochondrial respiration rates. The results uncovered the increased mitochondrial unfolded protein response. This protective, redox-sensitive activity is inherent in Tregs when contrasted with homologous, spCD25-treated, conventional T cells. Although the temporary effects of spCD25 on clinically competent cells did not impede their use in a safety/feasibility pilot study with kidney transplant recipients, it is reasonable to anticipate a potential reduction in their therapeutic efficacy. The mechanistic understanding of the adverse effects triggered by spCD25 is crucial for improving the manufacturing process of clinically competent Treg cells, a pivotal step in the successful implementation of immune cell therapy in transplantation.
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Affiliation(s)
- Roberto Gedaly
- Department of Surgery - Transplant Division, College of Medicine, University of Kentucky, Lexington, Kentucky, USA; Lucille Parker Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA; Division of Transplantation, Quality and Biostatistics Section, University of Kentucky, College of Medicine, Lexington, Kentucky, USA; Alliance Research Initiative (TILT Alliance), University of Kentucky College of Medicine, Lexington, Kentucky, USA.
| | - Gabriel Orozco
- Department of Surgery - Transplant Division, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
| | - Lillie J Lewis
- Department of Surgery - Transplant Division, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
| | - Deepa Valvi
- Department of Surgery - Transplant Division, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
| | - Fanny Chapelin
- Lucille Parker Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA; Alliance Research Initiative (TILT Alliance), University of Kentucky College of Medicine, Lexington, Kentucky, USA; Department of Biomedical Engineering, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
| | - Aman Khurana
- Lucille Parker Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA; Alliance Research Initiative (TILT Alliance), University of Kentucky College of Medicine, Lexington, Kentucky, USA; Department of Radiology, University of Kentucky, College of Medicine, Lexington, Kentucky, USA
| | - Giovanna E Hidalgo
- Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
| | - Aaron Shmookler
- Pathology and Laboratory Medicine, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
| | - Aashutosh Tripathi
- Department of Microbiology, Immunology, and Molecular Genetics. University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
| | - Cuiping Zhang
- Flow Cytometry & Immune Monitoring Core Facility, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
| | - Joseph B Zwischenberger
- Department of Surgery - Transplant Division, College of Medicine, University of Kentucky, Lexington, Kentucky, USA; Lucille Parker Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
| | - Francesc Marti
- Department of Surgery - Transplant Division, College of Medicine, University of Kentucky, Lexington, Kentucky, USA; Lucille Parker Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA; Alliance Research Initiative (TILT Alliance), University of Kentucky College of Medicine, Lexington, Kentucky, USA.
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21
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He J, Liu P, Cao L, Su F, Li Y, Liu T, Fan W. A machine learning-based nomogram for predicting graft survival in allograft kidney transplant recipients: a 20-year follow-up study. Front Med (Lausanne) 2025; 12:1556374. [PMID: 40236452 PMCID: PMC11996767 DOI: 10.3389/fmed.2025.1556374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/21/2025] [Indexed: 04/17/2025] Open
Abstract
Background Kidney transplantation is the optimal form of renal replacement therapy, but the long-term survival rate of kidney graft has not improved significantly. Currently, no well-validated model exists for predicting long-term kidney graft survival over an extended observation period. Methods Recipients undergoing allograft kidney transplantation at the Organ Transplantation Center of the First Affiliated Hospital of Kunming Medical University from 1 August 2003 to 31 July 2023 were selected as study subjects. A nomogram model was constructed based on least absolute selection and shrinkage operator (LASSO) regression, random survival forest, and Cox regression analysis. Model performance was assessed by the C-index, area under the curve of the time-dependent receiver operating characteristic curve, and calibration curve. Decision curve analysis (DCA) was utilized to estimate the net clinical benefit. Results The machine learning-based nomogram included cardiovascular disease in recipients, delayed graft function in recipients, serum phosphorus in recipients, age of donors, serum creatinine in donors, and donation after cardiac death for kidney donation. It demonstrated excellent discrimination with a consistency index of 0.827. The calibration curves demonstrated that the model calibrated well. The DCA indicated a good clinical applicability of the model. Conclusion This study constructed a nomogram for predicting the 20-year survival rate of kidney graft after allograft kidney transplantation using six factors, which may help clinicians assess kidney transplant recipients individually and intervene.
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Affiliation(s)
- Jiamin He
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Pinlin Liu
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lingyan Cao
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Feng Su
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yifei Li
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tao Liu
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wenxing Fan
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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22
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El Rifai R, Bhunia K, Fontana L, Swanson KJ, Jackson S, Smith BH, Riad SM. Long-term outcomes of induction immunosuppression for kidney transplant recipients with HIV who have average immunologic risk: An inverse probability treatment weighting analysis. Am J Transplant 2025; 25:756-766. [PMID: 39515757 DOI: 10.1016/j.ajt.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
We analyzed the Scientific Registry of Transplant Recipients (2004-2022) for primary kidney transplant recipients with HIV who had average immunologic risk and were discharged on tacrolimus/mycophenolate mofetil (with or without corticosteroids). Recipients were grouped by induction type: rabbit antithymocyte globulin (r-ATG, n = 688) and human interleukin-2 receptor antagonist (IL2Ra, n = 467). Kaplan-Meier curves were generated to examine recipient and graft survival by induction type. We used mixed Cox proportional hazard models to determine associations between induction type and outcomes of interest, with adjustments for recipient and donor factors and transplant center as a random effect. Regression with propensity score weighting reduced selection bias from nonrandom induction allocation. The unadjusted 10-year survival rate was 57% for those receiving r-ATG and 64% for those receiving IL2Ra (P < .001). Adjusted risk of death was significantly lower for IL2Ra induction than r-ATG induction with Cox multivariable (hazard ratio, 0.65; 95% CI, 0.47-0.91; P = .01) and inverse probability treatment weighting (hazard ratio, 0.38; 95% CI, 0.29-0.50; P < .01) models. Death-censored kidney graft survival did not differ by induction type in either model. The 1-year rejection rate was 10.1% and 11.6% for r-ATG and IL2Ra recipients, respectively (P = .52). Overall, IL2Ra conferred better long-term survival than r-ATG without increased risk of graft loss.
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Affiliation(s)
- Rasha El Rifai
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kaushik Bhunia
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA; Division of Nephrology, Minneapolis VA Medical Center, Minneapolis, Minnesota, USA
| | - Lauren Fontana
- Division of Infectious Diseases, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kurtis J Swanson
- Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Scott Jackson
- Complex Care Analytics, M Health Fairview, Minneapolis, Minnesota, USA
| | - Byron H Smith
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
| | - Samy M Riad
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
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23
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Gade N, Seifert P, Gerckens M, Mümmler C, Kauke T, Dick A, Veit T, Roden D, Hoffmann S, Scherzer M, Höpler J, Binzenhöfer L, Lanz H, Michel S, Schneider C, Irlbeck M, Tomasi R, Hatz R, Hagl C, Massberg S, Milger K, Behr J, Lüsebrink E, Kneidinger N. Association of HLA Mismatch With Adverse Cardiovascular Events Following Lung Transplantation: A Single-Center Study. Clin Transplant 2025; 39:e70157. [PMID: 40245267 DOI: 10.1111/ctr.70157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/12/2025] [Accepted: 04/02/2025] [Indexed: 04/19/2025]
Abstract
AIMS Coronary artery disease (CAD) is a frequent comorbidity in lung transplant (LuTx) candidates. The impact of allogenic organ transplantation and the corresponding alterations in immune response on the progression of CAD remains poorly understood. In this study, we sought to analyze the effect of donor-recipient overall human leukocyte antigen (HLA) and HLA-DQ mismatch on cardiovascular outcomes following LuTx. METHODS AND RESULTS This retrospective analysis of adult patients receiving lung transplantation at the LMU University Hospital between 2012 and 2018 included 310 patients, the majority of whom (67.4%) had undergone double lung transplantation. There were no significant differences in the incidence of the primary composite endpoint between patients with high/low HLA mismatches (22 [7.9%] vs. 4 [12.9%]; p = 0.311). Numerically higher rates of the primary endpoint, myocardial infarction, and cardiovascular death in the low HLA mismatch group can partially be explained by differences in baseline rates of CAD and coronary sclerosis. Notably, neither HLA-DQ mismatch nor the occurrence of rejection episodes or cytomegalovirus (CMV) infection was associated with the occurrence of cardiovascular events following transplantation. CONCLUSION In this study cohort, high HLA mismatch and HLA-DQ mismatch were not associated with increased adverse cardiovascular events. Furthermore, neither transplant rejection nor CMV infection increased the risk for cardiovascular events. The high cardiovascular event rates following LuTx necessitate meticulous cardiovascular follow-up, irrespective of immunological matching.
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Affiliation(s)
- Nils Gade
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Paula Seifert
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Michael Gerckens
- Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center of Lung Research (DZL), Munich, Germany
- Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Carlo Mümmler
- Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center of Lung Research (DZL), Munich, Germany
- Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Teresa Kauke
- Klinik für Thoraxchirurgie, Klinikum der Universität München, Munich, Germany
| | - Andrea Dick
- Laboratory for Immunogenetics, Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, Germany
| | - Tobias Veit
- Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Daniel Roden
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Sabine Hoffmann
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Marie Scherzer
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Julia Höpler
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Leonhard Binzenhöfer
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Hugo Lanz
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Sebastian Michel
- Herzchirurgische Klinik und Poliklinik, Klinikum der Universität München, Munich, Germany
| | - Christian Schneider
- Klinik für Thoraxchirurgie, Klinikum der Universität München, Munich, Germany
| | - Michael Irlbeck
- Klinik für Anästhesiologie, Klinikum der Universität München, Munich, Germany
| | - Roland Tomasi
- Klinik für Anästhesiologie, Klinikum der Universität München, Munich, Germany
| | - Rudolf Hatz
- Klinik für Thoraxchirurgie, Klinikum der Universität München, Munich, Germany
| | - Christian Hagl
- Herzchirurgische Klinik und Poliklinik, Klinikum der Universität München, Munich, Germany
| | - Steffen Massberg
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Katrin Milger
- Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Jürgen Behr
- Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Enzo Lüsebrink
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany
| | - Nikolaus Kneidinger
- Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center of Lung Research (DZL), Munich, Germany
- Department of Internal Medicine, Division of Respiratory Medicine, Lung Research Cluster, Medical University of Graz, Graz, Austria
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24
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Yoo J. Effect of Physical Function on Access to Repeat Kidney Transplantation. Biol Res Nurs 2025; 27:193-204. [PMID: 39451028 DOI: 10.1177/10998004241271380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
Background: The long-term success rate of kidney transplantation is disappointing, with repeat transplantation necessary for more than half of recipients. When a repeat kidney transplantation is needed, patients are often elderly and suffer from underlying advanced kidney disease, comorbidities, and adverse effects of immunosuppressants, leading to physical function limitations. Limited physical function is known to hinder access to an initial kidney transplantation, but there is no information about its impact on repeat transplantations. Objective: This study aimed to determine the effect of physical function on access to wait-listing for repeat transplantation. Methods: Data from the national registry was utilized to analyze 28,884 kidney transplant recipients. Physical function was assessed with Karnofsky scores, and patients were categorized into three strata: total assistance, some assistance, and no assistance. Logistic regression and multivariate Cox proportional hazard models were used to assess the impact of physical function on waiting list access and duration until wait-listing, respectively. Results: Patients with greater physical independence were more likely to be wait-listed for repeat kidney transplantation. Highly sensitized patients, those with diabetes, Black patients, and elderly individuals had a lower likelihood of access to wait-listing after kidney failure. Interestingly, those with limited physical function, provided they remained in the work-up process, experienced a relatively shorter duration to wait-listing after graft failure.Conclusions: These findings highlight the need to promote and support physical function throughout the kidney transplant journey to improve access to repeat transplantation and subsequent patient outcomes.
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Affiliation(s)
- Jongwon Yoo
- College of Nursing, Rush University, Chicago, IL, USA
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25
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Smith S, Kelly M, Ryu WHA, Kark J, Orina J, Philipp T, Yoo J. Complication, Readmission, Intensive Care Unit Admission, and Revision Incidence Following Anterior Cervical Discectomy and Fusion Surgery in End-stage Renal Disease and Renal Transplant Patients. Clin Spine Surg 2025:01933606-990000000-00470. [PMID: 40163629 DOI: 10.1097/bsd.0000000000001785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/11/2025] [Indexed: 04/02/2025]
Abstract
STUDY DESIGN Retrospective cross-sectional study aimed to investigate the postoperative outcomes following anterior cervical discectomy and fusion (ACDF) surgery in patients with end-stage renal disease (ESRD) and renal transplant recipients, using data from a large national database. Three patient groups were analyzed: control group, ESRD group, and renal transplant group. OBJECTIVE To investigate the postoperative outcomes following ACDF surgery in patients with ESRD and renal transplant recipients, utilizing data from a large national database. BACKGROUND Patients with ESRD and renal transplant recipients face unique health challenges, and there is a paucity of comprehensive research examining their postoperative surgical experiences, especially in the context of spine surgery. MATERIALS AND METHODS Data from 158,101 ACDF procedures performed between 2016 and 2019 were analyzed. Patients were stratified into 3 groups: control, end-stage renal failure, and renal transplant. The primary outcomes included 30-day medical complications, 30-day intensive care unit admissions, 90-day readmissions, and 1-year revision surgery. Multivariable logistic regression was employed for analysis. RESULTS Patients with ESRD had significantly higher rates of 30-day medical complications (56%) and 90-day readmissions (38%) compared with the control patients (3% and 3%, respectively). Renal transplant patients also showed elevated rates of medical complications and readmissions, 12% and 10%, respectively, but lower than patients with ESRD. Patients with ESRD had significantly higher odds of intensive care unit admission. There were no significant differences in revision rates among the groups. CONCLUSIONS Patients with ESRD and renal transplant recipients undergoing ACDF surgery face increased risks of medical complications and readmissions, with patients with ESRD showing surprisingly high rates. Tailored care strategies and close monitoring are crucial for these patient cohorts, emphasizing the need for specialized postoperative care. The study's findings highlight the multifaceted nature of surgical outcomes in medically complex populations and the importance of holistic assessment.
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Affiliation(s)
| | | | - Won Hyung A Ryu
- Department of Neurological Surgery, Oregon Health and Science University, Portland, OR
| | | | - Josiah Orina
- Department of Neurological Surgery, Oregon Health and Science University, Portland, OR
| | | | - Jung Yoo
- Department of Orthopedics and Rehabilitation
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26
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Ahmed S, Pfeiffer RM, Volesky-Avellaneda K, Blosser CD, Snyder JJ, Israni AK, Lynch CF, Qiao B, Rees JR, Zwald F, Yu KJ, Engels EA. Real-world evidence regarding cancer, mortality, and graft failure risk with de novo belatacept use among kidney transplant recipients in the United States. Am J Transplant 2025:S1600-6135(25)00107-8. [PMID: 40064297 DOI: 10.1016/j.ajt.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 03/04/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
Belatacept is a selective T cell costimulation blocker used in maintenance immunosuppression for kidney transplant recipients (KTRs), but evidence on cancer risk and other outcomes is limited. This retrospective cohort study used linked US transplant and cancer registry data on KTRs treated with belatacept (N = 1514) or tacrolimus (N = 7570) as initial maintenance therapy. We used multivariable Cox regression models to compare the incidence of invasive cancer, cutaneous squamous cell carcinoma, posttransplant lymphoproliferative disorder (PTLD), death, and graft failure/retransplantation (GF/RT) between belatacept and tacrolimus users. Overall, cancer incidence was 10.1 and 12.6 per 1000 person-years in belatacept and tacrolimus users, respectively. We did not find increased risk with belatacept for cancer overall (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.53-1.30), individual cancer types, or cutaneous squamous cell carcinoma. Belatacept was associated with increased risk of death (adjusted HR, 1.22; 95% CI, 1.04-1.43) but lower risk of GF/RT >4 years after transplantation (adjusted HR, 0.54; 95% CI, 0.35-0.83). PTLD risk was increased among Epstein-Barr virus-seropositive KTRs (adjusted HR, 1.96; 95% CI, 1.03-3.73). This study provides reassurance that belatacept does not increase cancer risk among KTRs, and there was a long-term protective association for GF/RT. However, we found evidence suggesting a potentially increased risk of PTLD and death with belatacept use.
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Affiliation(s)
- Shyfuddin Ahmed
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | | | - Christopher D Blosser
- Department of Medicine, University of Washington and Fred Hutch Cancer Center, Seattle, Washington
| | - Jon J Snyder
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota
| | - Ajay K Israni
- University of Texas Medical Branch, Galveston, Texas
| | - Charles F Lynch
- Department of Epidemiology, The University of Iowa, Iowa City, Iowa
| | - Baozhen Qiao
- New York State Department of Health, Bureau of Cancer Epidemiology, Albany, New York
| | - Judy R Rees
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire
| | - Fiona Zwald
- Department of Dermatology, The University of Colorado Denver, Aurora, Colorado
| | - Kelly J Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
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27
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Sahi SS, Garcia Valencia O, Na J, Lemke A, Duffy D, Smith B, Navratil P, Budhiraja P, Diwan TS, Issa N, Stegall MD, Denic A, Abdelrheem AA, Wadei HM, Park WD, Shah P, Kudva YC, Kukla A. Benefits of Glucagon-like Peptide-1 Receptor Agonists After Kidney Transplantation. Endocr Pract 2025:S1530-891X(25)00068-0. [PMID: 40054529 DOI: 10.1016/j.eprac.2025.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 04/02/2025]
Abstract
OBJECTIVE Benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in kidney transplant (KT) recipients have not been adequately studied. METHODS We retrospectively examined the effects of GLP-1 RA on mortality, kidney outcomes and metabolic parameters in KT recipients with type 2 diabetes mellitus (T2DM) treated versus not treated with GLP-1 RA. A reference group of KT recipients not treated with GLP-1 RA was used for comparison. Data were analyzed using analysis of variance, χ2 tests, and generalized estimating equation models. GLP-1 RA was used as a time-dependent model in Cox regression modeling. For survival analysis, the final model fitting was stratified by race-ethnicity. RESULTS Seventy-seven KT recipients with T2DM were treated with GLP-1 RA for at least 12 months. Reference group included 2094 patients not on GLP-1 RA. The mean (SD) age at transplant was 57.9 (9.5) and 60.8 (9.5) years for the treatment and reference groups, respectively. Median follow-up time from the index date for mortality was 1.5 (IQR 0.99, 2.4) in the treatment and 5.8 (IQR 3.4, 9.1) years in the reference group. GLP-1 RA use was associated with improved survival (P = .049), decreased urine albumin to creatinine ratio (net reduction of 10.62 mg/g per year, P = .003), slower estimated glomerular filtration rate decline (1.04 vs 1.56 mL/min/1.73 m2 per year, P = .04), and lower troponin levels. CONCLUSIONS GLP-1 RA in KT recipients with T2DM was associated with reduced mortality, and improved kidney function compared to the reference group. Larger, prospective studies are needed to fully evaluate the risks and benefits of GLP-1 RA therapy in KT recipients.
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Affiliation(s)
- Sukhdeep S Sahi
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Oscar Garcia Valencia
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Jie Na
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota
| | - Adley Lemke
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Dustin Duffy
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota
| | - Byron Smith
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota
| | - Pavel Navratil
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; Department of Urology, University Hospital Hradec Kralove, Czechia; Charles University, Faculty of Medicine in Hradec Kralove, Czechia
| | - Pooja Budhiraja
- Department of Internal Medicine Division of Nephrology and Transplant, Mayo Clinic, Phoenix, Arizona
| | - Tayyab S Diwan
- Department of Surgery and Immunology, Mayo Clinic, Rochester, Minnesota; Von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota
| | - Naim Issa
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Mark D Stegall
- Department of Surgery and Immunology, Mayo Clinic, Rochester, Minnesota; Von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota
| | - Aleksandar Denic
- Department of Nephrology and Hypertension Research, Mayo Clinic, Rochester, Minnesota
| | | | - Hani M Wadei
- Department of Transplant, Mayo Clinic, Jacksonville, Florida
| | - Walter D Park
- Department of Cardiovascular Surgery Research, Mayo Clinic, Rochester, Minnesota
| | - Pankaj Shah
- Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic Rochester, Minnesota
| | - Yogish C Kudva
- Von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota; Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic Rochester, Minnesota
| | - Aleksandra Kukla
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; Von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota.
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28
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Collins KE, Gilbert E, Mauduit V, Benson KA, Elhassan EAE, O’Seaghdha C, Hill C, McKnight AJ, Maxwell AP, van der Most PJ, de Borst MH, Guan W, Jacobson PA, Israni AK, Keating BJ, Lord GM, Markkinen S, Helanterä I, Hyvärinen K, Partanen J, Madden SF, Lanktree MB, Limou S, Cavalleri GL, Conlon PJ. Donor and Recipient Polygenic Risk Scores Influence Kidney Transplant Function. Transpl Int 2025; 38:14171. [PMID: 40104404 PMCID: PMC11913612 DOI: 10.3389/ti.2025.14171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 02/21/2025] [Indexed: 03/20/2025]
Abstract
Kidney transplant outcomes are influenced by donor and recipient age, sex, HLA mismatch, donor type, anti-rejection medication adherence and disease recurrence, but variability in transplant outcomes remains unexplained. We hypothesise that donor and recipient polygenic burden for traits related to kidney function may also influence graft function. We assembled a cohort of 6,060 living and deceased kidney donor-recipient pairs. We calculated polygenic risk scores (PRSs) for kidney function-related traits in both donors and recipients. We investigated the association between these PRSs and recipient eGFR at 1- and 5-year post-transplant as well as graft failure. Donor: hypertension PRS (P < 0.001), eGFR PRS (P < 0.001), and intracranial aneurysm PRS (P = 0.01), along with recipient eGFR PRS (P = 0.001) were associated with eGFR at 1-year post-transplantation. Clinical factors explained 25% of the variation in eGFR at 1-year and 13% at 5-year, with PRSs cumulatively adding 1% in both cases. PRSs were not associated with long-term graft survival. We demonstrate a small, but statistically significant association between donor and recipient PRSs and recipient graft function at 1- and 5-year post-transplant. This effect is, at present, unlikely to have clinical application and further research is required to improve PRS performance.
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Affiliation(s)
- Kane E. Collins
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
- SFI Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland
| | - Edmund Gilbert
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
| | - Vincent Mauduit
- Ecole Centrale Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR1064, Nantes University, Nantes, France
| | - Katherine A. Benson
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
| | - Elhussein A. E. Elhassan
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Conall O’Seaghdha
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Claire Hill
- Centre for Public Health, Queen’s University Belfast, Belfast, United Kingdom
| | - Amy Jayne McKnight
- Centre for Public Health, Queen’s University Belfast, Belfast, United Kingdom
| | | | - Peter J. van der Most
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Martin H. de Borst
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Weihua Guan
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, United States
| | - Pamala A. Jacobson
- College of Pharmacy, University of Minnesota, Minneapolis, MN, United States
| | - Ajay K. Israni
- Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Brendan J. Keating
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Graham M. Lord
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Salla Markkinen
- Finnish Red Cross Blood Service, Research and Development, Biomedicum 1, Helsinki, Finland
| | - Ilkka Helanterä
- Helsinki University Hospital, Transplantation and Liver Surgery, Helsinki, Finland
| | - Kati Hyvärinen
- Finnish Red Cross Blood Service, Research and Development, Biomedicum 1, Helsinki, Finland
| | - Jukka Partanen
- Finnish Red Cross Blood Service, Research and Development, Biomedicum 1, Helsinki, Finland
| | - Stephen F. Madden
- Data Science Centre, Beaux Lane House, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Matthew B. Lanktree
- Division of Nephrology, Departments of Medicine and Health Research Methodology, Evidence and Impact, St. Joseph’s Healthcare Hamilton, McMaster University and Population Health Research Institute, Hamilton, ON, Canada
| | - Sophie Limou
- Ecole Centrale Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR1064, Nantes University, Nantes, France
| | - Gianpiero L. Cavalleri
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
- SFI Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland
| | - Peter J. Conlon
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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29
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van de Laar SC, de Weerd AE, Bemelman FJ, Idu MM, de Vries AP, Alwayn IP, Berger SP, Pol RA, van Zuilen AD, Toorop RJ, Hilbrands LB, Poyck PP, Christiaans MH, van Laanen JH, van de Wetering J, Kimenai HJ, Reinders ME, Porte RJ, Dor FJ, Minnee RC. Favorable Living Donor Kidney Transplantation Outcomes within a National Kidney Exchange Program: A Propensity Score-Matching Analysis. Clin J Am Soc Nephrol 2025; 20:440-450. [PMID: 39879095 PMCID: PMC11906000 DOI: 10.2215/cjn.0000000611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 01/10/2025] [Indexed: 01/31/2025]
Abstract
Key Points KEP recipients have comparable long-term graft survival to direct living donor kidney transplantation recipients, which underscores the need to prioritize KEP over other's therapies. Our outcomes can be achieved regardless of whether the donor travels or the graft is transported, offering flexibility in program implementation. Background KEPs (kidney exchange programs) facilitate living donor kidney transplantations (LDKTs) for patients with incompatible donors, who are typically at higher risk than non-KEP patients because of higher sensitization and longer dialysis vintage. We conducted a comparative analysis of graft outcomes and risk factors for both KEP and non-KEP living donor kidney transplants. Methods All LDKTs performed in The Netherlands between 2004 and 2021 were included. The primary outcome measures were 1-, 5-, and 10-year death-censored graft survival. The secondary outcome measures were delayed graft function, graft function, rejection rates, and patient survival. We used a propensity score–matching model to account for differences at baseline. Results Of 7536 LDKTs, 694 (9%) were transplanted through the KEP. Ten-year graft survival was similar for KEP (0.916; 95% confidence interval, 0.894 to 0.939) and non-KEP (0.919; 0.912 to 0.926, P = 0.82). We found significant differences in 5-year rejection (12% versus 7%) and 5-year patient survival (KEP: 84%, non-KEP: 90%), which was nonsignificant after propensity score matching. Significant risk factors of lower graft survival included high donor age, retransplantations, extended dialysis vintage, higher panel reactive antibodies, and nephrotic syndrome as the cause of ESKD. Conclusions Transplantation through KEP offers a viable alternative for patients lacking compatible donors, avoiding specific and invasive pre- and post-transplant treatments. KEP's similar survival rate to non-KEPs suggests prioritizing KEP LDKTs over deceased donor kidney transplantation, desensitization, and dialysis. However, clinicians should consider the identified risk factors when planning and managing pre- and post-transplant care to enhance patient outcomes. Thus, we advocate for the broad adoption of KEP and establishment in regions lacking such programs, alongside initiation and expansion of international collaborations.
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Affiliation(s)
- Stijn C. van de Laar
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Annelies E. de Weerd
- Department of Internal Medicine, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Frederike J. Bemelman
- Department of Internal Medicine, Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mirza M. Idu
- Department of Surgery, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Aiko P.J. de Vries
- Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Ian P.J. Alwayn
- Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefan P. Berger
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert A. Pol
- Division of Transplant Surgery, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Arjan D. van Zuilen
- Department of Nephrology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Raechel J. Toorop
- Department of Surgery, Utrecht University Medical Centre, Utrecht, The Netherlands
| | - Luuk B. Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Paul P.C. Poyck
- Department of Vascular and Transplant Surgery, Radboudumc, Nijmegen, The Netherlands
| | - Maarten H.L. Christiaans
- Division of Nephrology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Jorinde H.H. van Laanen
- Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jacqueline van de Wetering
- Department of Internal Medicine, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Hendrikus J.A.N. Kimenai
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marlies E.J. Reinders
- Department of Internal Medicine, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert J. Porte
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Frank J.M.F. Dor
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Robert C. Minnee
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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30
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Cravedi P, Maggiore U, Molinari P, Levitsky J, Zorn E. Where Are All the Clinical Trials for Chronic Rejection? Transplantation 2025; 109:411-417. [PMID: 39748180 DOI: 10.1097/tp.0000000000005081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Chronic rejection is arguably the main obstacle to long-term graft survival. Yet, clinical trials focusing on this condition are disappointingly scarce. Significant advances in treating chronic rejection cannot happen if there is no conduit for testing novel therapies. Here, we identified the main hurdles holding back clinical trials for chronic rejection and outlined a series of actions to address these roadblocks. We suggest that a new strategic plan combining expertise in basic and clinical research and leveraging complementary resources be launched to specifically target chronic rejection and achieve long-awaited progress. We only need the will.
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Affiliation(s)
- Paolo Cravedi
- Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - Paolo Molinari
- Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Emmanuel Zorn
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY
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31
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Thongprayoon C, Garcia Valencia OA, Miao J, Craici IM, Mao SA, Mao MA, Tangpanithandee S, Pham JH, Leeaphorn N, Cheungpasitporn W. Impact of Multiple Kidney Retransplants on Post-Transplant Outcomes in the United States. Transplant Proc 2025; 57:214-222. [PMID: 39826993 DOI: 10.1016/j.transproceed.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 12/15/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Kidney retransplantation offers a valuable treatment option for patients who experience graft failure after their initial transplant. There is an increasing number of patients undergoing multiple retransplants. However, the impact of multiple kidney retransplants on post-transplant outcomes remains unclear. This study aimed to assess the association between the number of kidney retransplants and post-transplant outcomes in kidney retransplant recipients. METHODS We used the Organ Procurement and Transplantation Network and United Network for Organ Sharing (OPTN/UNOS) database to identify kidney-only retransplant recipients in United States from 2010 through 2019. We categorized kidney retransplant recipients based on their number of kidney retransplant into one and two plus kidney retransplant groups. The association of one vs two plus kidney retransplants with death-censored graft failure and patient death was assessed using Cox proportional hazard analysis, and acute rejection using logistic regression analysis. RESULTS Of 17,433 kidney retransplant recipients included in this study, 15,821 (91%) and 1612 (9%) had one and two plus kidney retransplants, respectively. Patients with two plus kidney retransplants were younger, predominantly White, had higher panel reactive antibody (PRA), public insurance, and education, but had less history of diabetes mellitus and total HLA mismatch compared with patients with one kidney retransplant. After adjusting for potential confounders, having two plus kidney retransplants was significantly associated with increased risk of death-censored graft failure (hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 1.02-1.42) and allograft rejection (odds ratio [OR] = 1.30, 95% CI = 1.09-1.54), but it was not significantly associated with patient death. CONCLUSIONS Patients undergoing multiple kidney retransplants face a higher risk of graft failure and rejection compared with those with a single retransplant. These findings underscore the need for tailored management and monitoring strategies to improve outcomes for patients receiving multiple kidney retransplants.
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Affiliation(s)
- Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
| | - Oscar A Garcia Valencia
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Jing Miao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Iasmina M Craici
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Shennen A Mao
- Division of Transplant Surgery, Mayo Clinic, Jacksonville, Florida
| | - Michael A Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, Florida
| | - Supawit Tangpanithandee
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Justin H Pham
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Napat Leeaphorn
- Division of Transplant Surgery, Mayo Clinic, Jacksonville, Florida
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
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Harriman D, Ng A, Bronowski M, Kazakov H, Nguan C, Dang T, Sherwood K, Miller A, Lange D. Characterizing the urobiome and associated metabolic profiles during acute rejection in renal transplant patients: A pilot study. Transpl Immunol 2025; 89:102170. [PMID: 39778631 DOI: 10.1016/j.trim.2024.102170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/19/2024] [Accepted: 12/25/2024] [Indexed: 01/11/2025]
Abstract
Characteristic alterations in the urinary microbiome, or urobiome, are associated with renal transplant pathology. To date, there has been no direct study of the urobiome during acute allograft rejection. The goal of this study was to determine if unique urobiome alterations are present during acute rejection in renal transplant recipients. We performed shotgun metagenomic sequencing of 32 mid-stream urine samples obtained from 15 transplant recipients pre-transplant, 1- and 3-months post-transplant, and at time of rejection discovered with for-cause biopsy. Within individuals, there was a 40-60 % difference in urobiome composition from pre-to-post-transplant in both rejectors and non-rejectors. The taxa Ureaplasma was enriched in rejectors compared to non-rejectors. However, a greater number of microbial genes were enriched in non-rejectors compared to rejectors, except for genes associated with tetracycline resistance, the lysophosphatidic acid synthesis pathway, and tryptophanyl-tRNA synthetase. Together, our findings suggest that the urobiome is significantly altered post-transplant with certain taxa and/or microbial genes potentially associated with acute allograft rejection/inflammation.
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Affiliation(s)
- David Harriman
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
| | - Alex Ng
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Monica Bronowski
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Herman Kazakov
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Christopher Nguan
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Thien Dang
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America
| | - Karen Sherwood
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Aaron Miller
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America
| | - Dirk Lange
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
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Fallois JD, Günzel A, Daniel C, Stumpf J, Busch M, Pein U, Paliege A, Amann K, Wiech T, Hantmann E, Wolf G, Pfeifer F, Girndt M, Lindner TH, Weimann A, Seehofer D, Bachmann A, Budde K, Biemann R, Isermann B, Engel C, Dittrich K, Hugo C, Halbritter J. Deceased donor urinary Dickkopf-3 associates with future allograft function following kidney transplantation. Am J Transplant 2025; 25:516-530. [PMID: 39303796 DOI: 10.1016/j.ajt.2024.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/09/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024]
Abstract
Predicting future kidney allograft function is challenging. Novel biomarkers, such as urinary Dickkopf-3 (uDKK3), may help guide donor selection and improve allograft outcomes. In this prospective multicenter pilot trial, we investigated whether donor uDKK3 reflects organ quality and is associated with future allograft function. We measured uDKK3/crea ratios (uDKK3/crea) from 95 deceased and 46 living kidney donors. Prenephrectomy uDKK3/crea levels were 100× higher in deceased than in living donors (9888 pg/mg vs 113 pg/mg; P < .001). Among deceased donor transplantations, recipients were stratified by their corresponding uDKK3/crea donor levels ranging below (group A, n = 68) or above (group B, n = 65) median. The primary end point of best estimated glomerular filtration rate (eGFR) within the first 3 months after kidney transplantation was superior in group A (56.3 mL/min/1.73 m2) than that in group B (44.2 mL/min/1.73 m2; P = .0139). Second, the composite clinical end point consisting of death, allograft failure or eGFR decline >50% occurred less frequent in group A. By mixed linear regression modeling, donor uDKK3/crea remained an independent predictor of eGFR after transplantation, with a slope of -4.282 mL/min/1.73 m2 per logarithmic increase in donor uDKK3/crea. In summary, uDKK3 may serve as a noninvasive, donor-dependent biomarker for assessing organ quality and future allograft function.
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Affiliation(s)
- Jonathan de Fallois
- Division of Nephrology, Department of Internal Medicine, University Medical Center Leipzig, Leipzig, Germany.
| | - Anna Günzel
- Division of Nephrology, Department of Internal Medicine, University Medical Center Leipzig, Leipzig, Germany
| | - Christoph Daniel
- Department of Nephropathology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Julian Stumpf
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Martin Busch
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany
| | - Ulrich Pein
- Department of Internal Medicine II, University Hospital Halle (Saale), Halle (Saale), Germany
| | - Alexander Paliege
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Kerstin Amann
- Department of Nephropathology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Thorsten Wiech
- Nephropathology Section, Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elena Hantmann
- Division of Nephrology, Department of Internal Medicine, University Medical Center Leipzig, Leipzig, Germany; Department of Nephrology and Medical Intensive Care, Charité Berlin, Berlin, Germany
| | - Gunter Wolf
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany
| | - Felix Pfeifer
- German Organ Procurement Organization (DSO), Region East, Leipzig, Germany
| | - Matthias Girndt
- Department of Internal Medicine II, University Hospital Halle (Saale), Halle (Saale), Germany
| | - Tom H Lindner
- Division of Nephrology, Department of Internal Medicine, University Medical Center Leipzig, Leipzig, Germany
| | - Antje Weimann
- Division of Visceral Surgery and Transplantation Medicine, University Medical Center Leipzig, Leipzig, Germany
| | - Daniel Seehofer
- Division of Visceral Surgery and Transplantation Medicine, University Medical Center Leipzig, Leipzig, Germany
| | - Anette Bachmann
- Division of Nephrology, Department of Internal Medicine, University Medical Center Leipzig, Leipzig, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Berlin, Berlin, Germany
| | - Ronald Biemann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Christoph Engel
- Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
| | - Katalin Dittrich
- German Organ Procurement Organization (DSO), Region East, Leipzig, Germany; Division of Pediatric Nephrology and Transplantation, Department of Pediatrics, University Medical Center Leipzig, Leipzig, Germany
| | - Christian Hugo
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Jan Halbritter
- Division of Nephrology, Department of Internal Medicine, University Medical Center Leipzig, Leipzig, Germany; Department of Nephrology and Medical Intensive Care, Charité Berlin, Berlin, Germany.
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Mankani MH, Mahmud O, Hafeez MS, Javed MA, Arain MA, Ul-Haq M, Rana AA. Factors Associated With Long-term Kidney Allograft Survival: A Contemporary Analysis of the UNOS Database. Transplant Proc 2025; 57:194-207. [PMID: 39893091 DOI: 10.1016/j.transproceed.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 01/18/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Various clinicopathologic markers, such as 1-year serum creatinine (Cr), have been used to prognosticate kidney allografts after transplantation. However, a contemporary analysis of their relationship with long-term graft survival is lacking. This study aimed to analyze recent data on the association of prognostic factors with kidney allograft survival in patients who underwent transplantation in the modern era. METHODS Adult kidney-transplant recipients in the UNOS database (2008-2020) were identified. Living and deceased donor allografts were analyzed separately and stratified by 1-year serum Cr level: ≤1.0, 1.0 to 1.5, 1.5 to 2.0, and >2.0 mg/dL. Time-to-event analysis was performed with long-term death-censored graft survival as the primary outcome. In addition, factors associated with raised 1-year serum Cr and with long-term allograft failure were identified. RESULTS 174,547 patients were included. Ten-year survival decreased with increasing 1-year creatinine, and these trends persisted on adjusted analysis for both living donor (Cr ≤ 1.0 mg/dL: reference; Cr 1.0-1.5 mg/dL aHR = 1.77 [1.59-1.96]; Cr 1.5-2.0 mg/dL aHR = 3.24 [2.89-3.64] and; Cr > 2.0 mg/dL aHR = 9.78, [8.64-11.07], P < .01) as well as deceased donor allografts (Cr ≤ 1.0 mg/dL: reference; Cr 1.0-1.5 mg/dL aHR = 1.74 [1.63-1.86]; Cr 1.5-2.0 mg/dL aHR = 3.06 [2.84-3.30] and; Cr > 2.0 mg/dL aHR = 8.51, [7.89-9.18], P < .01). CONCLUSION These results characterize the association between 1-year serum creatinine levels and other clinicopathologic factors with long-term kidney allograft survival. We demonstrate the ability of prognostic factors to stratify patients by risk of graft failure in a contemporary patient cohort that is representative of current practice and outcomes.
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Affiliation(s)
| | - Omar Mahmud
- Medical College, Aga Khan University Hospital, Karachi, Pakistan
| | | | | | | | - Muneeb Ul-Haq
- Medical College, Aga Khan University Hospital, Karachi, Pakistan
| | - Abbas A Rana
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Baylor College of Medicine, Houston, Texas
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Zaky ZS, Clifford SA, Fleming JN. Diagnostic Performance of Gene Expression and dd-cfDNA in Multiorgan Transplant Recipients. Transplant Direct 2025; 11:e1772. [PMID: 39995959 PMCID: PMC11850034 DOI: 10.1097/txd.0000000000001772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/27/2024] [Accepted: 01/19/2025] [Indexed: 02/26/2025] Open
Abstract
Background The aim of this analysis was to evaluate early signals of the utility of gene expression profile (GEP) and donor-derived cell-free DNA (dd-cfDNA) for ruling out subclinical rejection in multiorgan transplant recipients. Methods This was a prospective, single-center, observational pilot study that began enrolling patients in September 2022. Participants were enrolled after providing informed consent and had biomarker samples drawn before surveillance or for-cause biopsy. GEP result of TX was considered negative and a dd-cfDNA of ≤0.69% was considered negative, regardless of a nonrenal organ. Results There were 49 participants with 55 surveillance and/or for-cause biopsies. After exclusion of biopsies not paired with biomarkers, 51 biopsies were evaluated with at least 1 biomarker. Fifty-one biopsies had paired GEP results, whereas 47 biopsies had paired dd-cfDNA results. Overall, there were 12 biopsy-proven acute rejections (24%), 5 of which were T cell-mediated rejections (4-1A and 1-1B), 2 were antibody-mediated rejections, and 5 were borderline for T cell-mediated rejections. GEP by itself in 51 biopsies demonstrated a sensitivity of 17%, specificity of 74%, positive predictive value of 17%, negative predictive value of 74%, and balanced accuracy of 61%. Among 47 paired biopsies, dd-cfDNA demonstrated a sensitivity of 67% and specificity of 37%. Median dd-cfDNA was above the positivity threshold for both participants with rejection on biopsy and without (1.86% versus 1.35%, respectively). When evaluating GEP, specifically in surveillance biopsies and patients with liver transplants, diagnostic performance was maintained. Conclusions In this pilot analysis, GEP maintained a high negative predictive value in a multiorgan cohort, regardless of the nonrenal organ. dd-cfDNA did not have good performance when using the kidney threshold cutoff, which was expected and driven by the liver component of multiorgan recipients. Further technological advances with dd-cfDNA to differentiate organs and multiple donors could be impactful. The results support the use of GEP for ruling out kidney rejection in a multiorgan population, including those with a liver transplant. Further evaluation is necessary to confirm the results.
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Affiliation(s)
- Ziad S Zaky
- Department of Kidney Medicine, Cleveland Clinic, Cleveland, OH
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Leung J, Qu L, Ye Q, Zhong Z. The immune duality of osteopontin and its therapeutic implications for kidney transplantation. Front Immunol 2025; 16:1520777. [PMID: 40093009 PMCID: PMC11906708 DOI: 10.3389/fimmu.2025.1520777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Osteopontin (OPN) is a multifunctional glycoprotein with various structural domains that enable it to perform diverse functions in both physiological and pathological states. This review comprehensively examines OPN from multiple perspectives, including its protein structure, interactions with receptors, interactions with immune cells, and roles in kidney diseases and transplantation. This review explores the immunological duality of OPN and its significance and value as a biomarker and therapeutic target in kidney transplantation. In cancer, OPN typically promotes tumor evasion by suppressing the immune system. Conversely, in immune-related kidney diseases, particularly kidney transplantation, OPN activates the immune system by enhancing the migration and activation of immune cells, thereby exacerbating kidney damage. This immunological duality may stem from different OPN splice variants and the exposure, after cleavage, of different structural domains, which play distinct biological roles in cellular interactions. Additionally, OPN has a significant biological impact posttransplantation and on chronic kidney disease and, highlighting its importance as a biomarker and potential therapeutic target. Future research should further explore the specific mechanisms of OPN in kidney transplantation to improve treatment strategies and enhance patient quality of life.
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Affiliation(s)
- Junto Leung
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
| | - Lei Qu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
- The 3rd Xiangya Hospital of Central South University, NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, China
| | - Zibiao Zhong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
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37
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Hamidinia M, Gu Y, Ser Z, Brzostek J, Tay NQ, Yap J, Chua YL, Lim YT, Wood KJ, Vathsala A, Sobota RM, MacAry PA, Gascoigne NRJ. Occlusion of TCR binding to HLA-A*11:01 by a non-pathogenic human alloantibody. Cell Mol Life Sci 2025; 82:94. [PMID: 40009199 PMCID: PMC11865395 DOI: 10.1007/s00018-025-05614-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025]
Abstract
Over the last decades, organ transplantation has made rapid progress as a curative therapy for organ failure. However, the adaptive immune system-alloreactive T cells and antibodies targeting human leukocyte antigens (HLA)-is the leading cause of graft rejection. The presence of anti-donor HLA antibodies is considered a risk factor that disqualifies a particular donor-recipient pair. However, alloantibodies are found in some long-term graft survivors, suggesting a protective blocking function of some alloantibodies. Therefore, whether alloantibodies can have a positive as well as a negative effect in transplantation remains unclear. Here, HLA-A*11:01-specific monoclonal antibodies were generated from a human non-immune antibody library, and the effect of these antibodies was investigated on activation of A*11:01- specific T cells. We identified an A*11:01-specific monoclonal antibody with the capacity to block TCR recognition, TCR recruitment to the immune synapse, and T cell activation. The antibody reduced translocation of the transcription factor NFAT1 and phosphorylation of the MAP kinase ERK, which are both required for T cell effector function and TCR signal transduction. Cross-linking mass spectrometry was used to identify the epitope, demonstrating that this alloantibody can inhibit TCR from binding to the HLA molecule. These findings indicate that some HLA-specific alloantibodies can reduce T cell responses to the allograft. This has significant implications for interpretation of the existence of donor-specific antibodies, since some of them can protect the graft. Moreover, such antibodies may have therapeutic potential as specific treatments targeting mismatched donor HLA molecules.
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Affiliation(s)
- Maryam Hamidinia
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yue Gu
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - Zheng Ser
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Joanna Brzostek
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Neil Q Tay
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - Jiawei Yap
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yen Leong Chua
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - Yan Ting Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Kathryn J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Anantharaman Vathsala
- National University Centre for Organ Transplantation (NUCOT), National University Hospital, Singapore, Singapore
- Division of Nephrology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Radoslaw M Sobota
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Paul A MacAry
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - Nicholas R J Gascoigne
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Immunology Center of Georgia, Augusta University, Augusta, GA, USA.
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Sablik M, Sannier A, Raynaud M, Goutaudier V, Divard G, Astor BC, Weng P, Smith J, Garro R, Warady BA, Zahr RS, Twombley K, Dharnidharka VR, Dandamudi RS, Fila M, Huang E, Sellier-Leclerc AL, Tönshoff B, Rabant M, Verine J, Del Bello A, Berney T, Boyer O, Catar RA, Danger R, Giral M, Yoo D, Girardin FR, Alsadi A, Gourraud PA, Morelon E, Le Quintrec M, Try M, Villard J, Zhong W, Bestard O, Budde K, Chauveau B, Couzi L, Brouard S, Hogan J, Legendre C, Anglicheau D, Aubert O, Kamar N, Lefaucheur C, Loupy A. Microvascular Inflammation of Kidney Allografts and Clinical Outcomes. N Engl J Med 2025; 392:763-776. [PMID: 39450752 DOI: 10.1056/nejmoa2408835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
BACKGROUND The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. METHODS We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression. RESULTS A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation. CONCLUSIONS Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.).
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Affiliation(s)
- Marta Sablik
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
| | - Aurélie Sannier
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Department of Pathology, Bichat Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris
| | - Marc Raynaud
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
| | - Valentin Goutaudier
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
| | - Gillian Divard
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Kidney Transplant Department, Saint-Louis Hospital, AP-HP, Paris
| | - Brad C Astor
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
| | - Patricia Weng
- Pediatric Nephrology, David Geffen School of Medicine at UCLA, UCLA Mattel Children's Hospital, Los Angeles
| | - Jodi Smith
- Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle
| | - Rouba Garro
- Division of Pediatric Nephrology, Emory University School of Medicine, Children's Pediatric Institute, Atlanta
| | - Bradley A Warady
- Division of Pediatric Nephrology, University of Kansas City, Children's Mercy Hospital, Kansas City, MO
| | - Rima S Zahr
- Division of Pediatric Nephrology and Hypertension, University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis
| | - Katherine Twombley
- Acute Dialysis Units, Pediatric Kidney Transplant, Medical University of South Carolina, Charleston
| | - Vikas R Dharnidharka
- Division of Pediatric Nephrology, Hypertension, and Apheresis, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis
- Department of Pediatrics, Robert Wood Johnson Medical School at Rutgers University, New Brunswick, NJ
| | - Raja S Dandamudi
- Division of Pediatric Nephrology, Hypertension, and Apheresis, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis
| | - Marc Fila
- Department of Pediatric Nephrology, Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier, France
| | - Edmund Huang
- Cedars-Sinai Comprehensive Transplant Center, Los Angeles
| | - Anne-Laure Sellier-Leclerc
- Pediatric Nephrology Department, Hôpital Universitaire Mère-Enfant, Hospices Civils de Lyon (HCL), Lyon, France
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children Hospital Heidelberg, Heidelberg, Germany
| | - Marion Rabant
- Department of Pathology, Necker Hospital, AP-HP, Paris
| | - Jérôme Verine
- Department of Pathology, Saint-Louis Hospital, AP-HP, Paris
| | - Arnaud Del Bello
- Department of Nephrology-Dialysis-Transplantation, CHU de Toulouse, Toulouse, France
| | - Thierry Berney
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva
| | - Olivia Boyer
- Division of Pediatric Nephrology, Necker Hospital, AP-HP, Université Paris Cité, Paris
| | - Rusan Ali Catar
- Department of Nephrology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Berlin Institute of Health, Berlin
| | - Richard Danger
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology-Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
| | - Magali Giral
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology-Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
| | - Daniel Yoo
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
| | - François R Girardin
- Division of Clinical Pharmacology, Department of Medicine and Department of Laboratory Medicine and Pathology, Lausanne University Hospital, Faculty of Medicine, University of Lausanne, Lausanne, Switzerland
| | - Alaa Alsadi
- Department of Pathology, University of Wisconsin, Madison
| | - Pierre-Antoine Gourraud
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology-Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
| | - Emmanuel Morelon
- Department of Transplantation, Edouard Herriot University Hospital, HCL, University of Lyon I, Lyon, France
| | | | - Mélanie Try
- Department of Kidney Transplantation, Necker Hospital, AP-HP, Paris
| | - Jean Villard
- Division of Transplantation Immunology, University Hospital of Geneva, Geneva
| | - Weixiong Zhong
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology-Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
| | - Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d'Hebrón University Hospital, Barcelona
| | - Klemens Budde
- Department of Nephrology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Berlin Institute of Health, Berlin
| | | | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France
| | - Sophie Brouard
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology-Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
| | - Julien Hogan
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Division of Pediatric Nephrology, Robert Debré Hospital, AP-HP, Paris
| | - Christophe Legendre
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Department of Kidney Transplantation, Necker Hospital, AP-HP, Paris
| | - Dany Anglicheau
- Department of Kidney Transplantation, Necker Hospital, AP-HP, Paris
| | - Olivier Aubert
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Department of Kidney Transplantation, Necker Hospital, AP-HP, Paris
| | - Nassim Kamar
- Department of Nephrology-Dialysis-Transplantation, CHU de Toulouse, Toulouse, France
| | - Carmen Lefaucheur
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Kidney Transplant Department, Saint-Louis Hospital, AP-HP, Paris
| | - Alexandre Loupy
- Université Paris Cité, INSERM Unité 970, Paris Institute for Transplantation and Organ Regeneration, Paris
- Department of Kidney Transplantation, Necker Hospital, AP-HP, Paris
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Holle J, Reitmeir R, Behrens F, Singh D, Schindler D, Potapenko O, McParland V, Anandakumar H, Kanzelmeyer N, Sommerer C, Hartleif S, Andrassy J, Heemann U, Neuenhahn M, Forslund-Startceva SK, Gerhard M, Oh J, Wilck N, Löber U, Bartolomaeus H. Gut microbiome alterations precede graft rejection in kidney transplantation patients. Am J Transplant 2025:S1600-6135(25)00093-0. [PMID: 39978595 DOI: 10.1016/j.ajt.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/22/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease, with graft survival critically affected by the recipient's immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might associate with allograft rejection by analyzing the gut microbiome using 16S rRNA gene amplicon sequencing of a multicenter prospective study involving 562 samples from 245 individuals of which 217 received KT. Overall, gut microbiome composition showed gradual recovery post-KT, mirroring CKD-to-health transition as indicated by an increase of Shannon diversity. Prior to graft rejection, we observed a decrease in microbial diversity and SCFA-producing taxa. Functional analysis highlighted a decreased potential for SCFA production in patients preceding the rejection event, validated by quantitative PCR for the production potential of propionate and butyrate. Post-rejection analysis revealed normalization of these microbiome features. Comparison to published microbiome signatures from CKD patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Our findings suggest that alterations in gut microbiome composition and function may precede and influence KT rejection, suggesting potential implications as biomarkers or for early therapeutic microbiome-targeting interventions.
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Affiliation(s)
- Johannes Holle
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of General Pediatrics and Hematology/Oncology, University Children's Hospital, University Hospital Tübingen, Tübingen, Germany.
| | - Rosa Reitmeir
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Felix Behrens
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Dharmesh Singh
- Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany; German Center for Infection Research (DZIF), Partner Site München, Germany
| | - Daniela Schindler
- German Center for Infection Research (DZIF), Partner Site Braunschweig, Germany
| | - Olena Potapenko
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Victoria McParland
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Harithaa Anandakumar
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Nele Kanzelmeyer
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Children's Hospital, Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover, Germany
| | - Claudia Sommerer
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF), Partner Site Heidelberg, Germany
| | - Steffen Hartleif
- Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany; German Center for Infection Research (DZIF), Partner Site Tübingen, Germany
| | - Joachim Andrassy
- German Center for Infection Research (DZIF), Partner Site München, Germany; Klinik für Allgemeine, Viszeral, und Transplantationschirurgie, Klinikum der Universität München, Munich, Germany
| | - Uwe Heemann
- German Center for Infection Research (DZIF), Partner Site München, Germany; Department of Nephrology, Technical University of Munich, Munich, Germany
| | - Michael Neuenhahn
- Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany; German Center for Infection Research (DZIF), Partner Site München, Germany
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Markus Gerhard
- Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany; German Center for Infection Research (DZIF), Partner Site München, Germany
| | - Jun Oh
- Department of Pediatric Nephrology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Wilck
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Ulrike Löber
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Hendrik Bartolomaeus
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Institute of Experimental Biomedicine, University Hospital Würzburg, Germany
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Zhanzak Z, Johnson AC, Foster P, Cardenas MA, Morris AB, Zhang J, Karadkhele G, Badell IR, Morris AA, Au-Yeung BB, Roversi FM, Silva JAF, Breeden C, Hadley A, Zhang W, Larsen CP, Kissick HT. Identification of indirect CD4 + T cell epitopes associated with transplant rejection provides a target for donor-specific tolerance induction. Immunity 2025; 58:448-464.e6. [PMID: 39889703 DOI: 10.1016/j.immuni.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 09/24/2024] [Accepted: 01/10/2025] [Indexed: 02/03/2025]
Abstract
Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4+ T cell epitopes-donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II-in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4+ T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287-301) derived from the donor H2-Kd. Tetramer-binding Kd287+ CD4+ T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287+ CD4+ T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.
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Affiliation(s)
- Zhuldyz Zhanzak
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Aileen C Johnson
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Petra Foster
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Maria A Cardenas
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Anna B Morris
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Joan Zhang
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Geeta Karadkhele
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - I Raul Badell
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Alanna A Morris
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Byron B Au-Yeung
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Division of Immunology, Department of Medicine, Lowance Center for Human Immunology, Emory University School of Medicine Atlanta, GA, USA
| | - Fernanda M Roversi
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Juliete A F Silva
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Cynthia Breeden
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Annette Hadley
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Weiwen Zhang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Christian P Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute of Emory University, Atlanta, GA, USA.
| | - Haydn T Kissick
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute of Emory University, Atlanta, GA, USA; Emory Vaccine Center, Emory University, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
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41
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Voroneanu L, Covic A, Tesar V, Kanbay M, Covic A. Advances in Multitarget Therapeutic Approaches for Immune-Mediated Glomerular Diseases. Life (Basel) 2025; 15:243. [PMID: 40003652 PMCID: PMC11857484 DOI: 10.3390/life15020243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 02/27/2025] Open
Abstract
Glomerulonephritis (GN) encompasses a diverse group of immune-mediated diseases that damage the glomerular component of the nephron. While kidney biopsy remains the gold standard for diagnosis, it often fails to provide adequate insight into the underlying etiology of GN. Current classification systems have limited our understanding of the disease's pathophysiology and hinder the development of targeted therapies. Immunosuppressive treatments, such as glucocorticoids, calcineurin inhibitors, cyclophosphamide, and rituximab, remain the mainstay of therapy, though many patients fail to achieve remission or experience significant adverse effects. Moreover, the complex and multifactorial nature of GN pathogenesis calls for more refined therapeutic approaches. In recent years, multitarget therapies-combining different immunosuppressive agents targeting distinct immune pathways-have emerged as promising alternatives. Evidence suggests that multitarget therapy may offer superior outcomes compared to standard treatments. Despite early success, further studies are needed to optimize these regimens, reduce toxicity, and extend benefits to a broader range of GN patients. The development of personalized, biomarker-driven treatments, potentially leveraging innovative drug delivery systems and targeted biologics, holds promise for transforming GN care in the future.
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Affiliation(s)
- Luminita Voroneanu
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T Popa”, 700115 Iasi, Romania; (A.C.); (A.C.)
- Nephrology Clinic, Dialysis, and Renal Transplant Center, “C.I. Parhon” University Hospital, 700503 Iasi, Romania
| | - Andreea Covic
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T Popa”, 700115 Iasi, Romania; (A.C.); (A.C.)
- Nephrology Clinic, Dialysis, and Renal Transplant Center, “C.I. Parhon” University Hospital, 700503 Iasi, Romania
| | - Vladimir Tesar
- General University Hospital, Charles University, 700820 Prague, Czech Republic;
| | - Mehmet Kanbay
- Division of Nephrology, Department of Internal Medicine, Koc University School of Medicine, 34010 Istanbul, Turkey;
| | - Adrian Covic
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T Popa”, 700115 Iasi, Romania; (A.C.); (A.C.)
- Nephrology Clinic, Dialysis, and Renal Transplant Center, “C.I. Parhon” University Hospital, 700503 Iasi, Romania
- Academy of Romanian Scientists (AOSR), 3 Ilfov Street, Sector 5, 50044 Bucharest, Romania
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42
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van de Laar SC, Wiltschut BW, Oudmaijer CAJ, Muller K, Massey EK, Porte RJ, Dor FJMF, Minnee RC. Health-related quality of life in living kidney donors participating in kidney exchange programmes. Clin Kidney J 2025; 18:sfae374. [PMID: 39917536 PMCID: PMC11799774 DOI: 10.1093/ckj/sfae374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Indexed: 02/09/2025] Open
Abstract
Background Kidney exchange programmes (KEPs) have revolutionized living donor kidney transplantation (LDKT) by enabling transplants for patients with HLA- or ABO-incompatible donors. However, the implications for donors participating in KEPs, particularly regarding postoperative health-related quality of life (HRQoL), are not well elucidated. This study compares the HRQoL of donors participating in KEPs with donors donating directly (non-KEPs). Methods The study included 724 donors, with 121 in the KEP group and 603 in the non-KEP group. Outcomes were assessed using the mental component summary (MCS), physical component summary (PCS), EQ-5D-3L, MVI-20 score, and self-rated pain level. We used a mixed-effects regression model to assess differences between KEP and non-KEP over time, accounting for repeated measures within subjects. Results There was a significant temporary decline in both the MCS and PCS post-donation; however, these outcomes returned to pre-donation levels after an interval of 2 months. Donors participating in the KEP had higher PCS and MCS 1-year post-donation. Comparable results were observed in the self-assessed HRQoL using the EQ-5D-3L instrument, as well as in the fatigue scores measured by the MVI-20. Conclusions We found that participation in KEPs does not adversely affect donors' short- or long-term mental and physical HRQoL outcomes and that LDKT donors have HRQoL of pre-donation levels soon after donation. These insights are reassuring, indicating that donors participating in KEPs can expect HRQoL comparable to those who do not. This reinforces the viability of KEPs as a safe option for expanding LDKT and findings can inform patient and donor education.
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Affiliation(s)
- Stijn C van de Laar
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Berwout W Wiltschut
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Chris A J Oudmaijer
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Kelly Muller
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Emma K Massey
- Erasmus MC Transplant Institute, Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Robert J Porte
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Frank J M F Dor
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Robert C Minnee
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
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Artan AS, Mirioglu S, Ünal E, Suleymanova V, Akin Oto O, Ozturk S, Yazici H, Saraç Sivrikoz T, Turkmen A. Maternal and neonatal outcomes in kidney transplant recipients: a single-center observational study. Wien Klin Wochenschr 2025; 137:89-97. [PMID: 39231814 DOI: 10.1007/s00508-024-02425-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024]
Abstract
OBJECTIVE Pregnancy poses a high risk for adverse maternal and neonatal outcomes in kidney transplant recipients (KTRs), and data on long-term allograft functions compared to the healthy population are still limited. Therefore, we aimed to conduct a comparative analysis of maternal and neonatal outcomes in KTRs. SUBJECT AND METHODS In this retrospective single-center study, KTRs who experienced pregnancy after transplantation were evaluated in comparison with an age-matched non-transplanted control group. Maternal outcomes included obstetric complications (preeclampsia, peripartum hemorrhage, duration of maternal hospitalization) and a composite kidney outcome for KTRs defined as progression to graft failure necessitating dialysis or retransplantation or doubling of serum creatinine at the end of follow-up. Neonatal outcomes were gestational age, preterm birth, newborn mortality, admittance to the neonatal intensive care unit (NICU), Apgar scores, and birth weight. RESULTS In 53 KTRs, 68 pregnancies occurred. Preeclampsia (p < 0.001) and preterm birth (p = 0.003) were significantly higher in KTRs. The KTR pregnancies had lower mean birth weights (p = 0.001) and longer durations of maternal hospitalization (p = 0.001). Neonatal mortality, NICU admissions, peripartum hemorrhage rates, and Apgar scores were similar between groups. Follow-up for a median of 105 months after the index birth showed higher serum creatinine levels at postpartum visits (p < 0.001) and at the last follow-up (p = 0.001) compared to baseline. Of the KTRs 6 (11.3%) experienced composite kidney outcomes, including 5 patients with graft failure and 1 with a doubling of serum creatinine. CONCLUSION The KTRs exhibit comparable neonatal mortality and NICU admission rates but have higher rates of preeclampsia and preterm birth. Importantly, graft functions worsen significantly during postpartum follow-up.
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Affiliation(s)
- Ayse Serra Artan
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey.
| | - Safak Mirioglu
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Elif Ünal
- Department of Obstetrics and Gynecology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Vafa Suleymanova
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ozgur Akin Oto
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Savas Ozturk
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Halil Yazici
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Tuğba Saraç Sivrikoz
- Department of Obstetrics and Gynecology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Aydin Turkmen
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Coemans M, Tran TH, Döhler B, Massie AB, Verbeke G, Segev DL, Gentry SE, Naesens M. A competing risks model to estimate the risk of graft failure and patient death after kidney transplantation using continuous donor-recipient age combinations. Am J Transplant 2025; 25:355-367. [PMID: 39111667 DOI: 10.1016/j.ajt.2024.07.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 09/08/2024]
Abstract
Graft failure and recipient death with functioning graft are important competing outcomes after kidney transplantation. Risk prediction models typically censor for the competing outcome thereby overestimating the cumulative incidence. The magnitude of this overestimation is not well described in real-world transplant data. This retrospective cohort study analyzed data from the European Collaborative Transplant Study (n = 125 250) and from the American Scientific Registry of Transplant Recipients (n = 190 258). Separate cause-specific hazard models using donor and recipient age as continuous predictors were developed for graft failure and recipient death. The hazard of graft failure increased quadratically with increasing donor age and decreased decaying with increasing recipient age. The hazard of recipient death increased linearly with increasing donor and recipient age. The cumulative incidence overestimation due to competing risk-censoring was largest in high-risk populations for both outcomes (old donors/recipients), sometimes amounting to 8.4 and 18.8 percentage points for graft failure and recipient death, respectively. In our illustrative model for posttransplant risk prediction, the absolute risk of graft failure and death is overestimated when censoring for the competing event, mainly in older donors and recipients. Prediction models for absolute risks should treat graft failure and death as competing events.
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Affiliation(s)
- Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Public Health & Primary Care, Leuven Biostatistics and Statistical Bioinformatics Centre (L-Biostat), KU Leuven, Leuven, Belgium
| | - Thuong Hien Tran
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany
| | - Bernd Döhler
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany
| | - Allan B Massie
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA; Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA
| | - Geert Verbeke
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-Biostat), Universiteit Hasselt and KU Leuven, Hasselt and Leuven, Belgium
| | - Dorry L Segev
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA; Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA
| | - Sommer E Gentry
- Department of Surgery, NYU Grossman School of Medicine, New York, New York, USA; Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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45
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Massey EK, Rule AD, Matas AJ. Living Kidney Donation: A Narrative Review of Mid- and Long-term Psychosocial Outcomes. Transplantation 2025; 109:259-272. [PMID: 38886889 PMCID: PMC11652709 DOI: 10.1097/tp.0000000000005094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 06/20/2024]
Abstract
Living kidney donors make a significant contribution to alleviating the organ shortage. The aim of this article is to provide an overview of mid- and long-term (≥12 mo) living donor psychosocial outcomes and highlight areas that have been understudied and should be immediately addressed in both research and clinical practice. We conducted a narrative review by searching 3 databases. A total of 206 articles were included. Living donors can be divided into those who donate to an emotionally or genetically related person, the so-called directed donors, or to an emotionally or genetically unrelated recipient, the so-called nondirected donors. The most commonly investigated (bio)psychosocial outcome after living donation was health-related quality of life. Other generic (bio)psychological outcomes include specific aspects of mental health such as depression, and fatigue and pain. Social outcomes include financial and employment burdens and problems with insurance. Donation-specific psychosocial outcomes include regret, satisfaction, feelings of abandonment and unmet needs, and benefits of living kidney donation. The experience of living donation is complex and multifaceted, reflected in the co-occurrence of both benefits and burden after donation. Noticeably, no interventions have been developed to improve mid- or long-term psychosocial outcomes among living donors. We highlight areas for methodological improvement and identified 3 areas requiring immediate attention from the transplant community in both research and clinical care: (1) recognizing and providing care for the minority of donors who have poorer long-term psychosocial outcomes after donation, (2) minimizing donation-related financial burden, and (3) studying interventions to minimize long-term psychosocial problems.
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Affiliation(s)
- Emma K. Massey
- Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Department of Internal Medicine, Rotterdam, Zuid Holland, the Netherlands
| | - Andrew D. Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Arthur J. Matas
- Department of Surgery, Transplantation Division, University of Minnesota, Minneapolis, MN
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46
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Peticca B, Khalil IY, Robinson SG, Prudencio TM, Inlaw C, Majeethia H, Di Carlo A, Karhadkar SS. Underappreciated Effects of Delayed Graft Function in Pediatric Kidney Transplantation. Pediatr Transplant 2025; 29:e14901. [PMID: 39688245 DOI: 10.1111/petr.14901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 12/18/2024]
Abstract
PURPOSE In kidney transplantation (KT), delayed graft function (DGF) is associated with worse outcomes. However, it is unclear what effect DGF plays in long-term survival compared to the impact of the various transplant, donor, and recipient risk factors associated with DGF. This study aims to determine the effect of DGF alone on long-term survival in pediatric deceased donor kidney transplant recipients (DDKTRs). METHODS Using a national database, 1728 pediatric patients who received a kidney transplant between 1994 and 2009 (n = 978) and 2010 and 2022 (n = 750) were identified. Cases and controls were matched by DGF status for transplant date, cold ischemia time, distance from the transplant center, HLA mismatch level, PRA, KDPI, recipient and donor age, BMI, sex assigned at birth, and ethnicity. Kaplan-Meier curves were analyzed with a log-rank test. Pearson's chi-squared tests were used to compare survival proportions between groups at time benchmarks. RESULTS Pediatric DDKTRs with DGF had worse graft (p < 0.001) and patient (p < 0.001) survival compared to non-DGF patients in both eras. Between 1994 and 2009, graft survival rates were lower in the DGF cohort at 1 (p < 0.001), 3 (p < 0.001), 5 (p < 0.001), and 10 years (p = 0.010). Patient survival rates were lower in the DGF cohort at 1 (p = 0.017) and 5 years (p = 0.019) post-DDKT. There was no difference in 3 (p = 0.071) and 10-year patient survival rates (p = 0.141). Between 2010 and 2022, graft and patient survival rates were lower in the DGF cohort at 1, 3, 5, and 10 years (all p < 0.001). There was no difference in rates of retransplantation (p = 0.307 and p = 0.771) between groups for either era. CONCLUSIONS DGF alone is associated with worse outcomes in pediatric DDKTRs. DGF should be taken seriously, especially in cases where pediatric DDKTRs do not possess known, attributable risk factors for DGF.
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Affiliation(s)
- Benjamin Peticca
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Ibrahim Y Khalil
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Samuel G Robinson
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Tomas M Prudencio
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Christopher Inlaw
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Heli Majeethia
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Antonio Di Carlo
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
- Department of Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA
| | - Sunil S Karhadkar
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
- Department of Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA
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47
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Peruzzo MB, Oliveira Calegari L, Demarchi Foresto R, Tedesco-Silva H, Medina Pestana J, Requião-Moura L. Persistent Mortality Risk From Device-related Healthcare-associated Infection in Kidney Transplant Recipients Despite Multifaceted Interventions Action Calls for a Zero-tolerance Policy. Transplant Direct 2025; 11:e1754. [PMID: 39802200 PMCID: PMC11723676 DOI: 10.1097/txd.0000000000001754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 01/16/2025] Open
Abstract
Background Although multifaceted control intervention actions (bundles) are highly effective in reducing the risk of device-related healthcare-associated infections (d-HAIs), no studies have explored their impact on the outcomes of kidney transplant recipients (KTRs) or the extent of risk reduction achievable through the bundle implementation. Methods Seven hundred ninety-eight prevalent KTRs admitted to the intensive care unit (ICU) requiring invasive devices were included: 449 patients from the bundle preimplementation period and 349 from the postimplementation period. The primary outcome was mortality within 90 d of ICU admission. Using Poisson regression models, the magnitude of risk reduction for d-HAIs after the bundle implementation and the impact of d-HAIs on the risk of death was estimated. Results The 90-d survival rate was significantly lower in patients with d-HAIs (37.7% versus 71.7%; P < 0.001). The bundle implementation reduced the risk of d-HAIs by 58% (relative risk, 0.42; P = 0.005). Despite the significant reduction in d-HAIs after the bundle implementation, d-HAIs were associated with a 2.6-fold higher risk of death (hazard ratio [HR], 2.63; P < 0.001) regardless of the study period. Additional variables associated with increased risk of death included age (HR, 1.03; P < 0.001), baseline immunosuppression (HR based on mycophenolate versus others 0.74; P = 0.02), time since transplantation (HR, 1.003; P < 0.001), platelet count at ICU admission (HR, 0.998; P < 0.001), and sepsis as the reason for ICU admission (HR, 1.67; P < 0.001). Conclusions The persistent risk associated with d-HAIs, despite the implementation of multifaceted control intervention actions in an ICU specialized in KTR care, underscores the need for a zero-tolerance policy toward d-HAIs.
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Affiliation(s)
- Maria Bethânia Peruzzo
- Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, Brazil
- Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Luana Oliveira Calegari
- Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, Brazil
- Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Renato Demarchi Foresto
- Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, Brazil
- Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Helio Tedesco-Silva
- Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, Brazil
- Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil
| | - José Medina Pestana
- Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, Brazil
- Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Lúcio Requião-Moura
- Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, Brazil
- Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil
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48
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Avalos-de Leon CG, Thomson AW. Regulatory Immune Cell-derived Exosomes: Modes of Action and Therapeutic Potential in Transplantation. Transplantation 2025:00007890-990000000-00994. [PMID: 39865513 DOI: 10.1097/tp.0000000000005309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Reduced dependence on antirejection agents, improved long-term allograft survival, and induction of operational tolerance remain major unmet needs in organ transplantation due to the limitations of current immunosuppressive therapies. To address this challenge, investigators are exploring the therapeutic potential of adoptively transferred host- or donor-derived regulatory immune cells. Extracellular vesicles of endosomal origin (exosomes) secreted by these cells seem to be important contributors to their immunoregulatory properties. Twenty years ago, it was first reported that donor-derived exosomes could extend the survival of transplanted organs in rodents. Recent studies have revealed that regulatory immune cells, such as regulatory myeloid cells (dendritic cells, macrophages, or myeloid-derived suppressor cells), regulatory T cells, or mesenchymal stem/stromal cells can suppress graft rejection via exosomes that express a cargo of immunosuppressive molecules. These include cell surface molecules that interact with adaptive immune cell receptors, immunoregulatory enzymes, and micro- and long noncoding RNAs that can regulate inflammatory gene expression via posttranscriptional changes and promote tolerance through promotion of regulatory T cells. This overview analyzes the diverse molecules and mechanisms that enable regulatory immune cell-derived exosomes to modulate alloimmunity and promote experimental transplant tolerance. We also discuss the potential benefits and limitations of their application as therapeutic entities in organ transplantation.
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Affiliation(s)
- Cindy G Avalos-de Leon
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh PA
| | - Angus W Thomson
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh PA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh PA
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49
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Hu L, Zhang X, Zhang W, Jin S, Zhao J, Zheng J, Song W, Shen Z. Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation. Front Immunol 2025; 16:1539645. [PMID: 39911401 PMCID: PMC11794815 DOI: 10.3389/fimmu.2025.1539645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/06/2025] [Indexed: 02/07/2025] Open
Abstract
Objective T cell-mediated rejection (TCMR) remains a significant challenge in organ transplantation. This study aimed to define a TCMR-associated cytokine gene set and identify drugs to prevent TCMR through drug repurposing. Methods Gene expression profiles from kidney, heart, and lung transplant biopsies were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between TCMR and non-TCMR groups were identified, and their intersection with cytokine-related genes yielded an 11-gene TCMR-associated cytokine gene set (TCMR-Cs). To evaluate the effectiveness of this gene set, a diagnostic predictive model was constructed using Lasso regression and multivariate logistic regression, with validation in independent datasets. Connectivity Map (CMap) analysis was employed to screen drugs targeting TCMR-Cs. Experimental validation of the identified drug was performed in vitro using T cell activation and Th1 differentiation assays, and in vivo in a mouse skin transplant model with survival analysis. Results The TCMR-Cs exhibited outstanding predictive performance for TCMR, achieving an AUC of 0.99 in the training cohorts and maintaining strong performance in the test cohorts. CMap analysis identified peroxisome proliferator-activated receptor gamma (PPARγ) agonists as potential therapeutic candidates. Experimental validation showed that the PPARγ agonist rosiglitazone significantly suppressed T cell activation and reduced Th1 differentiation in vitro without cytotoxic effects. The combination of rosiglitazone and rapamycin significantly prolonged graft survival. Conclusions This study defined a novel TCMR-associated cytokine gene set that effectively predicts TCMR and identified PPARγ agonists, which prevent TCMR and improve graft survival when combined with rapamycin.
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Affiliation(s)
- Lu Hu
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
- Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China
| | - Xiaohan Zhang
- Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China
- School of Medicine, Nankai University, Tianjin, China
| | - Weiqi Zhang
- Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China
- School of Medicine, Nankai University, Tianjin, China
| | - Shuai Jin
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
- Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China
| | - Jie Zhao
- Department of Renal Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Jianming Zheng
- Department of Renal Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Wenli Song
- Department of Renal Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Zhongyang Shen
- Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China
- NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
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50
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Prosser AC, Klenerman P, Lucas M. Understanding Liver Transplantation Outcomes Through the Lens of Its Tissue-resident Immunobiome. Transplantation 2025:00007890-990000000-00973. [PMID: 39780303 DOI: 10.1097/tp.0000000000005303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Tissue-resident lymphocytes (TRLs) provide a front-line immunological defense mechanism uniquely placed to detect perturbations in tissue homeostasis. The heterogeneous TRL population spans the innate to adaptive immune continuum, with roles during normal physiology in homeostatic maintenance, tissue repair, pathogen detection, and rapid mounting of immune responses. TRLs are especially enriched in the liver, with every TRL subset represented, including liver-resident natural killer cells; tissue-resident memory B cells; conventional tissue-resident memory CD8, CD4, and regulatory T cells; and unconventional gamma-delta, natural killer, and mucosal-associated invariant T cells. The importance of donor- and recipient-derived TRLs after transplantation is becoming increasingly recognized, although it has not been examined in detail after liver transplantation. This review summarizes the evidence for the roles of TRLs in liver transplant immunology, focusing on their features, functions, and potential for their harnessing to improve transplant outcomes.
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Affiliation(s)
- Amy C Prosser
- Medical School, University of Western Australia, Perth, WA, Australia
| | - Paul Klenerman
- Translational Gastroenterology and Liver Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom
| | - Michaela Lucas
- Medical School, University of Western Australia, Perth, WA, Australia
- Department of Immunology, PathWest Laboratory Medicine, Perth, WA, Australia
- Department of Immunology, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Department of Immunology, Perth Children's Hospital, Perth, WA, Australia
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