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1
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Spector BL, Koseva BS, Sante D, Cheung WA, Alisch RS, Kats A, Bergmann P, Grundberg E, Wyckoff GJ, Willig LK. Total plasma cfDNA methylation in pediatric kidney transplant recipients provides insight into acute allograft rejection pathophysiology. Clin Immunol 2025; 275:110475. [PMID: 40107586 DOI: 10.1016/j.clim.2025.110475] [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: 12/23/2024] [Revised: 03/11/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
Cell-free DNA (cfDNA) is a marker of organ injury and immune response. DNA methylation is an epigenetic regulator of gene expression. Here, we elucidate total plasma cfDNA methylation from kidney transplant recipients in presence versus absence of rejection. In doing so, we exploit cfDNA as a real-time biomarker to define molecular pathways of rejection. Twenty plasma cfDNA samples from pediatric kidney transplant recipients were collected at allograft biopsy. Differentially methylated cytosine residues (>20 % methylation difference, q-value <0.05) were identified in presence (N = 7) versus absence (N = 9) of acute rejection. Separate analyses were performed comparing borderline rejection (N = 4) to rejection and non-rejection. In rejection versus non-rejection, there were 1269 differentially methylated genes corresponding to 533 pathways. These numbers were 4-13× greater than comparisons against borderline samples. Enriched pathways between rejection and non-rejection samples were related to immune cell/inflammatory response, lipid metabolism, and tryptophan-kynurenine metabolism, suggesting differential methylation of these pathways contributes to rejection.
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Affiliation(s)
- Benjamin L Spector
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, United States.
| | - Boryana S Koseva
- Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, United States
| | - Drinnan Sante
- Division of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City School of Pharmacy, Kansas City, MO, United States
| | - Warren A Cheung
- Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, United States
| | - Reid S Alisch
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Alexander Kats
- Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, United States
| | - Phillip Bergmann
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Elin Grundberg
- Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, United States
| | - Gerald J Wyckoff
- Division of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City School of Pharmacy, Kansas City, MO, United States
| | - Laurel K Willig
- Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, United States
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Corradetti V, Gessaroli E, Bari F, Bini C, Grandinetti V, Napoletano A, Cuna V, Pizzuti V, Demetri M, Ravaioli M, Provenzano M, La Manna G, Comai G. Risk Factors of Acute Rejection: Impact on Graft Outcomes in a Cohort of Kidney Transplant Recipients. J Clin Med 2025; 14:3373. [PMID: 40429368 PMCID: PMC12112150 DOI: 10.3390/jcm14103373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Revised: 04/29/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Acute rejection (AR) in kidney transplant (KT) recipients remains a significant challenge for short- and long-term graft survival even in the most recent years characterized by extended criteria donors and older and more comorbid recipients. Methods: We analyzed risk factors and outcomes of AR in 339 KT recipients treated at St. Orsola-Malpighi Hospital, Bologna (Italy), between 1 January 2019 and 31 December 2021. Demographic, immunological, and transplant data (type, cold ischemia time, complications) were recorded with a follow-up period of up to 24 months. Key outcomes included estimated glomerular filtration rate (eGFR), 24 h proteinuria, delayed graft function (DGF), biopsy-proven AR, and graft loss. Results: During the first year after transplant, 57 AR episodes occurred: 19 antibody-mediated rejections (AMR), 18 borderline T cell-mediated rejections (TCMR), 18 TCMR, 2 mixed AMR/TCMR, and 11 graft losses. AR was linked to older donor age (59.9 ± 12.8 vs. 55.5 ± 15.1, p = 0.040), longer cold ischemia time (690 vs. 570 min, p = 0.044), higher DGF rates (61.40% vs. 39.57%, p = 0.002), and lower eGFR (39 vs. 52 mL/min, p = 0.003). AR was consistently prevalent in patients who underwent an AB0-incompatible (AB0-i) transplant (8.8% vs. 2.5%, p = 0.020). HLA matching was strongly associated with a reduced risk of AMR (HLA-DR: OR 0.35, HLA-A: OR 0.33, HLA-C: OR 0.35), while DGF was linked to a higher risk (OR 4.04). TCMR risk was associated with donor age (OR 1.05). The development of post-transplant donor-specific antibodies (DSAs) at 24 months showed no significant association with AR (AMR: p = 0.769; TCMR: p = 0.938). The decline in eGFR over time (24 months) did not differ between patients with and without AR (difference, -0.69 mL/min/year; Standard Error, 0.92; p = 0.452). Similarly, 24 h proteinuria change over time did not differ between patients with and without AR (difference, -0.12 g/24 h; Standard Error, 0.28; p = 0.657). Conclusions: Understanding the risk factors of AR is crucial to identifying KTs at more risk of rejection and to guiding targeted therapeutic decisions. In the most recent era of extended criteria donors and more vulnerable recipients, early diagnosis and prompt and tailored treatment of AR play a critical role in stabilizing renal function over time.
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Affiliation(s)
- Valeria Corradetti
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
| | - Elisa Gessaroli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
| | - Federico Bari
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
| | - Claudia Bini
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
| | - Valeria Grandinetti
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
| | - Angelodaniele Napoletano
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
| | - Vania Cuna
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
| | - Valeria Pizzuti
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
| | - Marcello Demetri
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
| | - Matteo Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
- Hepato-Biliary Surgery and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy
| | - Michele Provenzano
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
- Nephrology, Dialysis and Renal Transplant Unit, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende—Hospital ‘SS. Annunziata’, 87100 Cosenza, Italy
| | - Gaetano La Manna
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
| | - Giorgia Comai
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (V.C.); (C.B.); (V.G.); (A.N.); (V.C.); (V.P.); (G.L.M.); (G.C.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; (E.G.); (F.B.); (M.D.); (M.R.)
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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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Vinson AJ, Matas A. Late Allograft Loss and Contemporary Cardiorenal Metabolic Therapies. J Am Soc Nephrol 2025:00001751-990000000-00615. [PMID: 40193211 DOI: 10.1681/asn.0000000726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025] Open
Abstract
Late kidney allograft loss occurs through one of two mechanisms: ( 1 ) deterioration of kidney function leading to retransplantation or dialysis (death-censored graft loss) and ( 2 ) premature death with a normally functioning transplant (death with graft function)-each accounting for approximately 50% of late kidney graft losses. Late death-censored graft loss typically results from a combination of immune and nonimmune events leading to common nonspecific end points ( e.g ., tubular atrophy, interstitial fibrosis, and glomerulosclerosis). Conversely, leading causes of death with graft function typically include cardiovascular events, malignancy, and infection. With an improved understanding of the multiple mechanism by which late graft dysfunction develops, there is an opportunity to identify patients at greatest risk and institute novel strategies to quell the process. Newer cardiometabolic agents with proven benefit in the general population have not been well-studied in kidney transplant recipients. However, in addition to their potential benefits in reducing cardiovascular, infectious, and malignancy end points (thus minimizing death with graft function risk), many novel agents may have additional anti-inflammatory and/or antifibrotic benefit (minimizing death-censored graft loss risk) in the kidney transplant population. In this review, we summarize existing literature regarding major causes of death-censored graft loss and death with graft function and discuss the potential roles of new cardiorenal metabolic agents including sodium-glucose cotransport 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, glucagon-like peptide 1 receptor agonists, and dual endothelin and angiotensin receptor antagonists in the kidney transplant population, including potential mechanisms to improve death with graft function and death-censored graft loss outcomes.
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Affiliation(s)
- Amanda J Vinson
- Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
- Kidney Research Institute of Nova Scotia
| | - Arthur Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota
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5
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Canizares S, Montalvan A, Eckhoff D, Sureshkumar KK, Chopra B. Long Term Outcomes of Transplant Recipients Comparing Belatacept vs. Tacrolimus: A UNOS Database Analysis. Clin Transplant 2025; 39:e70075. [PMID: 39869107 DOI: 10.1111/ctr.70075] [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: 09/03/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/28/2025]
Abstract
Calcineurin inhibitors have been the choice for maintenance immunosuppression (IS) in kidney transplant recipients (KTR), but they are associated with nephrotoxicity and metabolic side effects. We aim to compare the long-term outcomes of KTR on belatacept (bela) versus tacrolimus (tac) IS, in all KTRs and various subgroups. Using the UNOS-STAR files, we identified adult first-KTR from 2010 to 2022. Patients were categorized based on maintenance-IS at index transplant admission by creating a propensity score matched cohort at 1:5 rate using several clinical characteristics. Primary outcomes included patient death, graft failure (GF), and death-censored graft failure (DCGF). Secondary outcomes included delayed graft function (DGF), acute-rejections (AR) within a year, and serum creatinine (Cr) at 1-year. The propensity-matched cohort included KTRs on bela (N = 2612) and tac (N = 12760). There was no significant difference in the hazard ratio of death (1.03 [0.92, 1.14]), GF (1.07 [0.97, 1.17]), or DCGF (1.11 [0.98, 1.25]). A sensitivity analysis comparing a propensity-matched cohort of bela + tac (n = 2033) versus tac (n = 9004); demonstrated significantly reduced risks of death (0.87 [0.76-1.00], p = 0.043) and GF (0.73 [0.64-0.83] p < 0.001) compared to those on Tac alone. In conclusion, bela + tac seems to be a nephron-sparing and rejection-lowering IS regimen with overall improved graft and patient outcomes when compared to the current standard of tacrolimus. Larger Randomized Controlled studies are needed.
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Affiliation(s)
- Stalin Canizares
- Department of Transplant Surgery, Transplant Surgery Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Adriana Montalvan
- Department of Transplant Surgery, Transplant Surgery Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Devin Eckhoff
- Department of Transplant Surgery, Transplant Surgery Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Kalathil K Sureshkumar
- Department of Transplant Nephrology, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
| | - Bhavna Chopra
- Department of Transplant Nephrology, Transplant Surgery Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Campbell PM, Cantarovich M, Gangji A, Houde I, Jevnikar AM, Monroy-Cuadros FM, Nickerson PW, Pâquet MR, Prasad GVR, Senécal L, Wolff JL, Schwartz JJ, Rush DN. A Five-Year Prospective, Randomized, Open-Label Study of Standard-Dose Versus Low-Dose Prolonged-Release Tacrolimus With or Without Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Post Kidney Transplantation. Clin Transplant 2025; 39:e70067. [PMID: 39739990 DOI: 10.1111/ctr.70067] [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: 06/21/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 01/02/2025]
Abstract
INTRODUCTION Novel approaches to improve long-term outcomes in kidney transplant recipients are required. Here, we present the 5-year data from a multicenter, prospective, Phase 3b trial evaluating treatment outcomes with standard (STD) or low (LOW) dose prolonged-release tacrolimus (TAC) combined with ACEi/ARB or other antihypertensive therapy (OAHT) in Canadian kidney transplant recipients. METHODS Adult de novo kidney transplant recipients were randomized 2 × 2 to STD or LOW dose TAC and ACEi/ARB or OAHT. Patients had received a first or second transplant from a living or deceased donor and had ≥ 1 human leukocyte antigen mismatch with their donor. RESULTS There were 281 patients from 13 sites across Canada. Overall patient survival was 95.7% and was comparable between groups. Graft survival at study end was 89.7% in the LOW+OAHT group and 94.4%-97.1% in the other groups and BPAR, and Class II de novo donor-specific antibodies (dnDSA) were higher in the LOW+OAHT group than in the other groups. However, these differences were not statistically significant. Graft function, blood pressure (BP), and proteinuria were similar between the groups; however, between 2 and 5 years there was a 2-fold or greater increase in the use of ACEi/ARB in patients randomized initially to OAHT, mostly because of hypertension and proteinuria. There were no unexpected safety findings. CONCLUSION Patients randomized to LOW TAC with renin-angiotensin system (RAS) blockade had similar outcomes at 5 years as patients treated with STD TAC with or without RAS blockade, whereas those randomized to LOW TAC without RAS blockade showed a non-significant trend towards more rejections and dnDSA TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00933231.
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Affiliation(s)
- Patricia M Campbell
- Department of Laboratory Medicine and Pathology, University of Alberta Hospitals, Edmonton, Alberta, Canada
| | - Marcelo Cantarovich
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada
| | - Azim Gangji
- Department of Medicine, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
| | - Isabelle Houde
- Department of Medicine, L'Hôtel-Dieu de Québec, Québec City, Québec, Canada
| | - Anthony M Jevnikar
- Department of Internal Medicine, London Health Sciences Centre, London, Ontario, Canada
| | | | - Peter W Nickerson
- Department of Internal Medicine and Immunology, Health Sciences Centre, Winnipeg, Manitoba, Canada
| | - Michel R Pâquet
- Division of Nephrology, Hôpital Notre-Dame du CHUM, Montréal, Québec, Canada
| | - G V Ramesh Prasad
- Division of Nephrology, St Michael's Hospital, Toronto, Ontario, Canada
| | - Lynne Senécal
- Department of Medicine, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada
| | - Jean-Luc Wolff
- Department of Medicine, Centre Hospitalier Universitaire, Sherbrooke, Québec, Canada
| | - Jason J Schwartz
- Medical Affairs, Astellas Pharma Global Development, Northbrook, Illinois, USA
| | - David N Rush
- Department of Internal Medicine and Immunology, Health Sciences Centre, Winnipeg, Manitoba, Canada
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Torres Sánchez MJ, Ruiz Fuentes MC, Clavero García E, Rísquez Chica N, Espinoza Muñoz K, Espigares Huete MJ, Caba Molina M, Osuna A, Wangensteen R. Hydroxyproline in Urine Microvesicles as a Biomarker of Fibrosis in the Renal Transplant Patient. Biomedicines 2024; 12:2836. [PMID: 39767742 PMCID: PMC11673537 DOI: 10.3390/biomedicines12122836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Interstitial fibrosis/tubular atrophy in kidney transplantation is an unspecific lesion induced by immune and non-immune factors, which determines the progression of chronic kidney disease. Hydroxyproline is an imino acid that is part of the molecule of collagen. The aim of this study was to assess hydroxyproline in urine microvesicles as a marker of fibrosis in the renal transplant patient. Patients and Methods: An observational cross-sectional study was conducted on 46 renal transplant patients who had undergone renal biopsy with diagnostic intention, as well as 19 healthy controls. Clinical, histological, and laboratory variables were collected at the time of marker determination and renal function was analyzed 2 years later. Hydroxyproline was measured in urine microvesicles. Results: Renal transplant patients showed a higher microvesicular concentration of hydroxyproline compared to the control group, with the following medians (interquartile range (IQR)): 28.024 (5.53) ng/mL vs. 2.51 (1.16) ng/mL, p < 0.001. In the transplanted patients, patients in whom biopsy showed some score of total cortical parenchymal inflammation (ti) displayed a significantly higher concentration of hydroxyproline in urine microvesicles than those patients who did not score for cortical parenchymal inflammation (29.91 ± 2.797 ng/mL vs. 22.72 ± 8.697 ng/mL, p = 0.034). No significant correlation was observed between urinary markers and serum creatinine, calcium, and parathyroid hormone (PTH). Conclusions: The concentration of hydroxyproline in urinary microvesicles increased in renal transplant patients relative to healthy controls. Hydroxyproline in urinary microvesicles is a marker of chronic renal inflammation in transplanted patients, and further studies are required to confirm this finding in other pathologies, as well as the association with fibrosis and the evolution of renal function.
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Affiliation(s)
- María José Torres Sánchez
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - María Carmen Ruiz Fuentes
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
- Department of Medicine, University of Granada, 18071 Granada, Spain;
| | - Elena Clavero García
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - Noelia Rísquez Chica
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - Karla Espinoza Muñoz
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - María José Espigares Huete
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - Mercedes Caba Molina
- Department of Pathological Anatomy, Provincial Unit of Pathological Anatomy of Granada (UPIGAP), Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain;
| | - Antonio Osuna
- Department of Medicine, University of Granada, 18071 Granada, Spain;
| | - Rosemary Wangensteen
- Area of Physiology, Department of Health Sciencies, University of Jaen, 23071 Jaen, Spain;
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8
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Zhong Z, Ye Y, Xia L, Na N. Identification of RNA-binding protein genes associated with renal rejection and graft survival. Ren Fail 2024; 46:2360173. [PMID: 38874084 PMCID: PMC11182075 DOI: 10.1080/0886022x.2024.2360173] [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: 12/07/2023] [Accepted: 05/21/2024] [Indexed: 06/15/2024] Open
Abstract
Rejection is one of the major factors affecting the long-term prognosis of kidney transplantation, and timely recognition and aggressive treatment of rejection is essential to prevent disease progression. RBPs are proteins that bind to RNA to form ribonucleoprotein complexes, thereby affecting RNA stability, processing, splicing, localization, transport, and translation, which play a key role in post-transcriptional gene regulation. However, their role in renal transplant rejection and long-term graft survival is unclear. The aim of this study was to comprehensively analyze the expression of RPBs in renal rejection and use it to construct a robust prediction strategy for long-term graft survival. The microarray expression profiles used in this study were obtained from GEO database. In this study, a total of eight hub RBPs were identified, all of which were upregulated in renal rejection samples. Based on these RBPs, the renal rejection samples could be categorized into two different clusters (cluster A and cluster B). Inflammatory activation in cluster B and functional enrichment analysis showed a strong association with rejection-related pathways. The diagnostic prediction model had a high diagnostic accuracy for T cell mediated rejection (TCMR) in renal grafts (area under the curve = 0.86). The prognostic prediction model effectively predicts the prognosis and survival of renal grafts (p < .001) and applies to both rejection and non-rejection situations. Finally, we validated the expression of hub genes, and patient prognosis in clinical samples, respectively, and the results were consistent with the above analysis.
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Affiliation(s)
- Zhaozhong Zhong
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yongrong Ye
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liubing Xia
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ning Na
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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9
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Charmetant X, Pettigrew GJ, Thaunat O. Allorecognition Unveiled: Integrating Recent Breakthroughs Into the Current Paradigm. Transpl Int 2024; 37:13523. [PMID: 39588197 PMCID: PMC11586167 DOI: 10.3389/ti.2024.13523] [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: 07/12/2024] [Accepted: 10/29/2024] [Indexed: 11/27/2024]
Abstract
In transplantation, genetic differences between donor and recipient trigger immune responses that cause graft rejection. Allorecognition, the process by which the immune system discriminates allogeneic grafts, targets major histocompatibility complex (MHC) and minor histocompatibility antigens. Historically, it was believed that allorecognition was solely mediated by the recipient's adaptive immune system recognizing donor-specific alloantigens. However, recent research has shown significant roles for innate immune components, such as lymphoid and myeloid cells, which are sometimes triggered by the mere absence of a self-protein in the graft. This review integrates recent breakthroughs into the current allorecognition paradigm based on the well-established direct and indirect pathways, emphasizing the semi-direct pathway where recipient antigen-presenting cells (APCs) acquire donor MHC molecules, and the inverted direct pathway where donor CD4+ T cells within the graft activate recipient B cells to produce donor-specific antibodies (DSAs). The review also explores the role of natural killer (NK) cells in both promoting and inhibiting graft rejection, highlighting their dual role in innate allorecognition. Additionally, it discusses the emerging understanding of myeloid cell-mediated allorecognition and its implications for initiating adaptive immune responses. These insights aim to provide a more comprehensive understanding of allorecognition, potentially leading to improved transplant outcomes.
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Affiliation(s)
- Xavier Charmetant
- Centre International de Recherche en Infectiologie, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Lyon-Est Faculty of Medicine, Claude Bernard University (Lyon 1), Villeurbanne, France
| | - Gavin J. Pettigrew
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Olivier Thaunat
- Centre International de Recherche en Infectiologie, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Lyon-Est Faculty of Medicine, Claude Bernard University (Lyon 1), Villeurbanne, France
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10
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Littera R, Mocci S, Argiolas D, Littarru L, Lai S, Melis M, Sanna C, Mereu C, Lorrai M, Mascia A, Angioi A, Mascia G, Matta V, Lepori N, Floris M, Manieli C, Bianco P, Onnis D, Rassu S, Deidda S, Carta MG, Giuressi E, Perra A, Chessa L, Giglio S, Pani A. MICA and NKG2D gene polymorphisms influence graft survival, and response to therapy in kidney transplantation. Front Immunol 2024; 15:1440887. [PMID: 39575256 PMCID: PMC11578996 DOI: 10.3389/fimmu.2024.1440887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/18/2024] [Indexed: 11/24/2024] Open
Abstract
Background Antibody-mediated rejection is a significant cause of kidney transplant failure. Recent studies have shown that the MHC class I MICA gene influences the transplantation outcome. However, the role of the primary MICA receptor, NKG2D, has yet to be explored. Aim We aimed to investigate the correlation between recipient/donor MICA allele matching and NKG2D genotype with the risk of antibody-mediated rejection and their potential clinical effects and implications for organ maintenance therapy. Methods Of the 524 patients who underwent transplantation, 387 were eligible for the study. Complete MICA allele and two functional polymorphisms of NKG2D (rs1049174C>G and rs2255336G>A) were analyzed in 148 transplanted patients and 146 controls. Results Increased recipient/donor MICA allele mismatches correlate with an elevated risk of antibody-mediated rejection (X2 = 6.95; Log-rank=0.031). Notably, the rs1049174[GG] genotype contributes to a significantly increased risk of antibody-mediated rejection (X2 = 13.44; Log-rank=0.001 and X 2 = 0.34; Log-rank=0.84). The combined effect of two MICA allele mismatches and rs1049174[GG] genotype shows the highest risk (X2 = 23.21; Log-rank<0.001). Most importantly, patients with rs1049174[GG] and rs2255336[AA] genotypes may respond less to mTOR inhibitor immunosuppressive therapy than Calcineurin inhibitors (rs1049174[GG]; P=0.035; and rs2255336[AA]; P=0.002). Conclusion Recipient/donor MICA allele mismatches and specific NKG2D variants, as well as their combinations, influence kidney transplant outcomes, providing insights for personalized treatment and enhancing graft survival.
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Affiliation(s)
- Roberto Littera
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
| | - Stefano Mocci
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- Center for Research University Services (CeSAR), (Centro Servizi di Ateneo per la Ricerca), University of Cagliari, Monserrato, Italy
| | - Davide Argiolas
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Letizia Littarru
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Sara Lai
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
| | - Maurizio Melis
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
| | - Celeste Sanna
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Caterina Mereu
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Michela Lorrai
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Alessia Mascia
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andrea Angioi
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Giacomo Mascia
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Valeria Matta
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Nicola Lepori
- Department of Medical Science and Public Health, University of Cagliari, Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Matteo Floris
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Cristina Manieli
- U.O. Anatomia Patologica, P.O. San Michele, ARNAS “G Brotzu”, Cagliari, Italy
| | - Paola Bianco
- U.O. Anatomia Patologica, P.O. San Michele, ARNAS “G Brotzu”, Cagliari, Italy
| | - Daniela Onnis
- U.O. Anatomia Patologica, P.O. San Michele, ARNAS “G Brotzu”, Cagliari, Italy
| | | | - Silvia Deidda
- Pneumology Unit, R. Binaghi Hospital, ASSL Cagliari, Cagliari, Italy
| | - Mauro Giovanni Carta
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | | | - Andrea Perra
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Luchino Chessa
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Liver Unit, Department of Internal Medicine, University Hospital of Cagliari, Cagliari, Italy
| | - Sabrina Giglio
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Center for Research University Services (CeSAR), (Centro Servizi di Ateneo per la Ricerca), University of Cagliari, Monserrato, Italy
| | - Antonello Pani
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
- Department of Medical Science and Public Health, University of Cagliari, Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu” Cagliari, Consiglio Nazionale delle Ricerche, Cagliari, Italy
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11
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Zeng Z, Zhang Y. Improvement in Central Serous Chorioretinopathy in Renal Transplant Recipients Following Hemodialysis: Case Report. Transplant Proc 2024; 56:2058-2062. [PMID: 39462703 DOI: 10.1016/j.transproceed.2024.10.012] [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: 07/18/2024] [Accepted: 10/04/2024] [Indexed: 10/29/2024]
Abstract
INTRODUCTION This case report describes an elderly man experienced recurrent central serous chorioretinopathy (CSCR) for several years following a kidney transplant. Despite various treatments, his subretinal fluid was unexpectedly absorbed following hemodialysis after the loss of graft kidney function. Optical coherence tomography (OCT) imaging and best-corrected visual acuity (BCVA) measures were taken. The patient has been followed for approximately 10 years. CONCLUSION Hemodialysis should be considered early if there is persistent and refractory serous retinal detachment despite reducing or discontinuing glucocorticoid therapy and in the presence of decreased glomerular filtration rate.
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Affiliation(s)
- Zhuoran Zeng
- Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, China
| | - Yonghong Zhang
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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12
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Chambon M, Koenig A. NK Cells: Not Just Followers But Also Initiators of Chronic Vascular Rejection. Transpl Int 2024; 37:13318. [PMID: 39479216 PMCID: PMC11521863 DOI: 10.3389/ti.2024.13318] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 09/23/2024] [Indexed: 11/02/2024]
Abstract
Chronic graft rejection represents a significant threat to long-term graft survival. Early diagnosis, understanding of the immunological mechanisms and appropriate therapeutic management are essential to improve graft survival and quality of life for transplant patients. Knowing which immune cells are responsible for chronic vascular rejection would allow us to provide effective and appropriate treatment for these patients. It is now widely accepted that natural killer (NK) cells play an important role in chronic vascular rejection. They can either initiate chronic vascular rejection by recognizing missing self on the graft or be recruited by donor-specific antibodies to destroy the graft during antibody-mediated rejection. Whatever the mechanisms of activation of NK cells, they need to be primed to become fully activated and damaging to the graft. A better understanding of the signaling pathways involved in NK cell priming and activation would pave the way for the development of new therapeutic strategies to cure chronic vascular rejection. This review examines the critical role of NK cells in the complex context of chronic vascular rejection.
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Affiliation(s)
- Mathilde Chambon
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France
| | - Alice Koenig
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
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13
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Berishvili E, Piemonti L, de Koning EJP, Lindstedt S, Scholz H, Scott WE, Auxenfans C, Johnson P, Martin DE, Gunther P, Mey D, Potena L, Thaunat O. ESOT Roadmap for Advanced Therapy Medicinal Products in Transplantation: Navigating Regulatory Challenges to Enhance Access and Care. Transpl Int 2024; 37:13485. [PMID: 39469665 PMCID: PMC11513584 DOI: 10.3389/ti.2024.13485] [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: 07/03/2024] [Accepted: 09/19/2024] [Indexed: 10/30/2024]
Abstract
The field of organ transplantation is experiencing a transformative shift with the rise of Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products. These therapies offer new, potentially curative treatments for longstanding medical challenges, impacting numerous patients. However, their adoption is hindered by complex regulatory frameworks, high production costs, and inconsistent access across Europe. The ESOT ATMP Task Force's position paper analyzes these challenges from research to clinical application, advocating for a coordinated strategy to position Europe as a leader in ATMP development. It proposes specific actions such as streamlining regulatory pathways to accelerate approvals, boosting funding for ATMP research, and creating specialized facilities for development and implementation. The paper also highlights the critical roles of patient engagement and real-world evidence in optimizing clinical and regulatory practices.
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Affiliation(s)
- Ekaterine Berishvili
- Cell Isolation and Transplantation Centre, Department of Surgery, Geneva University Hospitals, Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Lorenzo Piemonti
- Diabetes Research Institute, IVita-Salute San Raffaele University, Milan, Italy
| | - Eelco J. P. de Koning
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Sandra Lindstedt
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
| | - Hanne Scholz
- Hybrid Technology Hub Centre of Excellence, Institute of Basic Medical Science, University of Oslo, Oslo, Norway
| | - William E. Scott
- Regenerative Medicine, Stem Cells, and Transplantation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Celine Auxenfans
- Banque de Tissus et de Cellules des Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Paul Johnson
- Oxford Consortium for Islet Transplantation, Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, United Kingdom
| | - Dominique E. Martin
- School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, VIC, Australia
| | | | - Devi Mey
- The European Society for Organ Transplantation, Amsterdam, Netherlands
| | - Luciano Potena
- Istituto di Ricovero e Cura a Carattere Scientifico (Scientific Institute for Research, Hospitalization, and Healthcare) (IRCCS) University Hospital of Bologna Sant Orsola Polyclinic, Bologna, Italy
| | - Olivier Thaunat
- Centre International de Recherche en Infectiologie (CIRI), Université de Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
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14
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Hendriks SH, Heidt S, Reinders ME, Koning F, van Kooten C. Allogenic MSC infusion in kidney transplantation recipients promotes within 4 hours distinct B cell and T cell phenotypes. Front Immunol 2024; 15:1455300. [PMID: 39450174 PMCID: PMC11500071 DOI: 10.3389/fimmu.2024.1455300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Background Infusion of mesenchymal stromal cells (MSCs) has been proposed as immune-modulatory therapy in solid organ transplantation. The use of allogenic MSCs could improve standardization and allow for direct availability of the product. Method The nonrandomized phase Ib Neptune clinical trial provided safety and feasibility data on the use of allogenic bone-marrow-derived MSCs, infused in 10 patients at week 25 and 26 post kidney transplantation. Here, we performed detailed analysis on the peripheral blood immune cell composition of these patients up to 52 weeks post transplantation. We used a 40 marker antibody panel with mass cytometry to assess potential effects of MSC therapy on the immune system. Results We showed minor changes in major immune lineages at week 27, 34 and 52 post kidney transplantation after MSC infusion at week 25 and week 26, confirming previous data with regular flow cytometry. However, in a direct comparison between pre- and post MSC infusion, as soon as 4 hours after MSC infusion, we observed a significant increase in cell numbers of B cell and T cell subsets that shared a unique expression of CD11b, CD11c, CD38, CD39, and Ki-67. Conclusion Exploring these CD11b+CD11c+CD38+CD39+Ki-67+ B cells and T cells in the context of MSC infusion after kidney transplantation may be a promising avenue to better understand the immunological effects of MSC therapy.
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Affiliation(s)
- Sanne H. Hendriks
- Department of Immunology, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden University, Leiden, Netherlands
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Marlies E.J. Reinders
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, Netherlands
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Frits Koning
- Department of Immunology, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Cees van Kooten
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
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15
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Gavzy SJ, Kensiski A, Saxena V, Lakhan R, Hittle L, Wu L, Iyyathurai J, Dhakal H, Lee ZL, Li L, Lee YS, Zhang T, Lwin HW, Shirkey MW, Paluskievicz CM, Piao W, Mongodin EF, Ma B, Bromberg JS. Early Immunomodulatory Program Triggered by Protolerogenic Bifidobacterium pseudolongum Drives Cardiac Transplant Outcomes. Transplantation 2024; 108:e91-e105. [PMID: 38587506 PMCID: PMC11188630 DOI: 10.1097/tp.0000000000004939] [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: 07/14/2023] [Revised: 10/24/2023] [Accepted: 11/20/2023] [Indexed: 04/09/2024]
Abstract
BACKGROUND Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. METHODS In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. RESULTS In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment. CONCLUSIONS These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.
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Affiliation(s)
- Samuel J. Gavzy
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Allison Kensiski
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Vikas Saxena
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Ram Lakhan
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Lauren Hittle
- University of Maryland School of Medicine, Institute for Genome Sciences, Baltimore, MD
| | - Long Wu
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Jegan Iyyathurai
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Hima Dhakal
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Zachariah L. Lee
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Lushen Li
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Young S. Lee
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Tianshu Zhang
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Hnin Wai Lwin
- University of Maryland School of Medicine, Institute for Genome Sciences, Baltimore, MD
| | - Marina W. Shirkey
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Christina M. Paluskievicz
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Wenji Piao
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
| | - Emmanuel F. Mongodin
- University of Maryland School of Medicine, Institute for Genome Sciences, Baltimore, MD
| | - Bing Ma
- University of Maryland School of Medicine, Institute for Genome Sciences, Baltimore, MD
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | - Jonathan S. Bromberg
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
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16
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Friedmann J, Schuster A, Reichelt-Wurm S, Banas B, Bergler T, Steines L. Serum IL-6 predicts risk of kidney transplant failure independently of immunological risk. Transpl Immunol 2024; 84:102043. [PMID: 38548029 DOI: 10.1016/j.trim.2024.102043] [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: 11/23/2023] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/07/2024]
Abstract
Interleukin-6 (IL-6) is an important immune mediator and a target for novel antibody therapies. In this study, we aimed to determine whether serum IL-6 levels are associated with immunological risk, allograft rejection and outcomes in kidney transplant (Ktx) patients. We retrospectively analyzed the data of 104 patients who underwent Ktx at our center between 2011 and 2015. The patients were divided into high- and low-risk groups (n = 52 per group) based on panel reactive antibody (PRA) percentage ≥ 35%, the existence of pre-Ktx donor-specific antibodies (DSA), or a previous transplant. IL-6 concentrations were measured before and at 3 months, 12 months, and 3 years after Ktx. Serum IL-6 levels tended to be higher in high-risk patients than in low-risk patients prior to Ktx and at 12 months after Ktx; however, the difference did not reach statistical significance (pre-Ktx, high-risk: 1.995 ± 2.79 pg/ml vs. low-risk: 1.43 ± 1.76 pg/ml, p = 0.051; 12 mo. high-risk: 1.16 ± 1.87 pg/ml vs. low-risk: 0.78 ± 1.13 pg/ml, p = 0.067). IL-6 levels were correlated with the types (no rejection, T cell mediated rejection (TCMR), antibody-mediated rejection (ABMR), or both) and time (<1 year vs. >1 year after Ktx) of rejection, as well as patient and graft survival. Patients with both TCMR and ABMR had significantly higher IL-6 levels at 3 months (14.1 ± 25.2 pg/ml) than patients with ABMR (3.4 ± 4.8 pg/ml, p = 0.017), with TCMR (1.7 ± 1.3 pg/ml, p < 0.001), and without rejection (1.7 ± 1.4 pg/ml, p < 0.001). Three years after Ktx, patients with AMBR had significantly higher IL-6 levels (5.30 ± 7.66 pg/ml) than patients with TCMR (1.81 ± 1.61 pg/ml, p = 0.009) and patients without rejection (1.19 ± 0.95 pg/ml; p = 0.001). Moreover, three years after Ktx IL-6 levels were significantly higher in patients with late rejections (3.5 ± 5.4 pg/ml) than those without rejections (1.2 ± 1.0 pg/ml) (p = 0.006). The risk of death-censored graft failure was significantly increased in patients with elevated IL-6 levels at 12 months (IL-6 level > 1.396 pg/ml, HR 4.61, p = 0.007) and 3 years (IL-6 level > 1.976 pg/ml, HR 6.75, p = 0.003), but elevated IL-6 levels were not associated with a higher risk of death. Overall, our study highlights IL-6 as a risk factor for allograft failure and confirms that IL-6 levels are higher in patients developing ABMR compared to TCMR alone or no rejection.
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Affiliation(s)
- Julius Friedmann
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Antonia Schuster
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | | | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Tobias Bergler
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany; Department of Nephrology, Hospital Ingolstadt, Ingolstadt, Germany
| | - Louisa Steines
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
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17
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Udomkarnjananun S, Schagen MR, Hesselink DA. A review of landmark studies on maintenance immunosuppressive regimens in kidney transplantation. ASIAN BIOMED 2024; 18:92-108. [PMID: 39175954 PMCID: PMC11338012 DOI: 10.2478/abm-2024-0015] [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] [Indexed: 08/24/2024]
Abstract
Immunosuppressive medications play a pivotal role in kidney transplantation, and the calcineurin inhibitors (CNIs), including cyclosporine A (CsA) and tacrolimus (TAC), are considered as the backbone of maintenance immunosuppressive regimens. Since the introduction of CNIs in kidney transplantation, the incidence of acute rejection has decreased, and allograft survival has improved significantly. However, CNI nephrotoxicity has been a major concern, believed to heavily impact long-term allograft survival and function. To address this concern, several CNI-sparing regimens were developed and studied in randomized, controlled, clinical trials, aiming to reduce CNI exposure and preserve long-term allograft function. However, more recent information has revealed that CNI nephrotoxicity is not the primary cause of late allograft failure, and its histopathology is neither specific nor pathognomonic. In this review, we discuss the historical development of maintenance immunosuppressive regimens in kidney transplantation, covering the early era of transplantation, the CNI-sparing era, and the current era where the alloimmune response, rather than CNI nephrotoxicity, appears to be the major contributor to late allograft failure. Our goal is to provide a chronological overview of the development of maintenance immunosuppressive regimens and summarize the most recent information for clinicians caring for kidney transplant recipients (KTRs).
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Affiliation(s)
- Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok10330, Thailand
- Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok10330, Thailand
- Renal Immunology and Transplantation Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok10330, Thailand
| | - Maaike R. Schagen
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam3000, The Netherlands
| | - Dennis A. Hesselink
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam3000, The Netherlands
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Sridharan K, Shah S, Hammad MA, Mohammed FA, Veeramuthu S, Taher MA, Hammad MM, Jawad L, Farid E. Correlations between serum kidney injury molecule-1, cystatin C and immunosuppressants: A cross-sectional study of renal transplant patients in Bahrain. J Biomed Res 2024; 38:269-277. [PMID: 38528676 PMCID: PMC11144937 DOI: 10.7555/jbr.37.20220211] [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: 09/25/2022] [Revised: 10/24/2022] [Accepted: 11/06/2022] [Indexed: 03/27/2024] Open
Abstract
Renal transplant patients receive several immunosuppressive drug regimens that are potentially nephrotoxic for treatment. Serum creatinine is the standard for monitoring kidney function; however, cystatin C (Cys C) and kidney injury molecule-1 (KIM-1) have been found to indicate kidney injury earlier than serum creatinine and provide a better reflection of kidney function. Here, we assessed Cys C and KIM-1 serum levels in renal transplant patients receiving mycophenolate mofetil, tacrolimus, sirolimus, everolimus, or cyclosporine to evaluate kidney function. We used both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation, which is based on creatinine and combined creatinine with Cys C, and the CKD-EPI 2012 equation, which is based on Cys C alone, to estimate glomerular filtration rate (GFR). Then, we assessed the association between serum KIM-1 and GFR < 90 mL per minute per 1.73 m 2. We observed significantly higher serum Cys C levels in patients with the elevated serum creatinine, compared with those with normal serum creatinine. The estimated GFRs based on creatinine were significantly higher than those based on the other equations, while a significant positive correlation was observed among all equations. Serum KIM-1 levels were negatively correlated with the estimated GFRs by the CKD-EPI Cys C and the combined creatinine with Cys C equations. A serum KIM-1 level above 0.71 ng/mL is likely to indicate GFR < 90 mL per minute per 1.73 m 2. We observed a significant correlation between serum creatinine and Cys C in our renal transplant patients. Therefore, serum KIM-1 may be used to monitor renal function when using potentially nephrotoxic drugs in renal transplants.
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Affiliation(s)
- Kannan Sridharan
- Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Shamik Shah
- Department of Nephrology, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
- Department of Internal Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | | | - Fatima Ali Mohammed
- Department of Nephrology, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
| | - Sindhan Veeramuthu
- Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Mona Abdulla Taher
- Department of Nephrology, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
| | | | - Lamees Jawad
- Department of Laboratory Medicine, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
| | - Eman Farid
- Department of Laboratory Medicine, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
- Department of Microbiology, Immunology, and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
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19
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Kanbay M, Copur S, Yilmaz ZY, Baydar DE, Bilge I, Susal C, Kocak B, Ortiz A. The role of anticomplement therapy in the management of the kidney allograft. Clin Transplant 2024; 38:e15277. [PMID: 38485664 DOI: 10.1111/ctr.15277] [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: 10/30/2023] [Revised: 02/04/2024] [Accepted: 02/16/2024] [Indexed: 03/19/2024]
Abstract
As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Zeynep Y Yilmaz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Dilek Ertoy Baydar
- Department of Pathology, Koc University School of Medicine, Istanbul, Turkey
| | - Ilmay Bilge
- Department of Pediatrics, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
| | - Caner Susal
- Transplant Immunology Research Center of Excellence, Koc University Hospital, Istanbul, Turkey
| | - Burak Kocak
- Department of Urology, Koc University School of Medicine, Istanbul, Turkey
| | - Alberto Ortiz
- Department of Medicine, Universidad Autonoma de Madrid and IIS-Fundacion Jimenez Diaz, Madrid, Spain
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Efe O, Gassen RB, Morena L, Ganchiku Y, Al Jurdi A, Lape IT, Ventura-Aguiar P, LeGuern C, Madsen JC, Shriver Z, Babcock GJ, Borges TJ, Riella LV. A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models. J Clin Invest 2024; 134:e173107. [PMID: 38426492 PMCID: PMC10904054 DOI: 10.1172/jci173107] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 01/05/2024] [Indexed: 03/02/2024] Open
Abstract
Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.
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Affiliation(s)
- Orhan Efe
- Center for Transplantation Sciences, Department of Surgery
- Division of Nephrology, Department of Medicine, and
| | | | - Leela Morena
- Center for Transplantation Sciences, Department of Surgery
| | | | - Ayman Al Jurdi
- Center for Transplantation Sciences, Department of Surgery
- Division of Nephrology, Department of Medicine, and
| | | | | | | | - Joren C. Madsen
- Center for Transplantation Sciences, Department of Surgery
- Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | | - Leonardo V. Riella
- Center for Transplantation Sciences, Department of Surgery
- Division of Nephrology, Department of Medicine, and
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Pérez Valdivia MÁ, Calvillo Arbizu J, Portero Barreña D, Castro de la Nuez P, López Jiménez V, Rodríguez Benot A, Mazuecos Blanca A, de Gracia Guindo MC, Bernal Blanco G, Gentil Govantes MÁ, Bedoya Pérez R, Rocha Castilla JL. Predicting Kidney Transplantation Outcomes from Donor and Recipient Characteristics at Time Zero: Development of a Mobile Application for Nephrologists. J Clin Med 2024; 13:1270. [PMID: 38592072 PMCID: PMC10932177 DOI: 10.3390/jcm13051270] [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: 01/10/2024] [Revised: 02/14/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024] Open
Abstract
(1) Background: We report on the development of a predictive tool that can estimate kidney transplant survival at time zero. (2) Methods: This was an observational, retrospective study including 5078 transplants. Death-censored graft and patient survivals were calculated. (3) Results: Graft loss was associated with donor age (hazard ratio [HR], 1.021, 95% confidence interval [CI] 1.018-1.024, p < 0.001), uncontrolled donation after circulatory death (DCD) (HR 1.576, 95% CI 1.241-2.047, p < 0.001) and controlled DCD (HR 1.567, 95% CI 1.372-1.812, p < 0.001), panel reactive antibody percentage (HR 1.009, 95% CI 1.007-1.011, p < 0.001), and previous transplants (HR 1.494, 95% CI 1.367-1.634, p < 0.001). Patient survival was associated with recipient age (> 60 years, HR 5.507, 95% CI 4.524-6.704, p < 0.001 vs. < 40 years), donor age (HR 1.019, 95% CI 1.016-1.023, p < 0.001), dialysis vintage (HR 1.0000263, 95% CI 1.000225-1.000301, p < 0.01), and male sex (HR 1.229, 95% CI 1.135-1.332, p < 0.001). The C-statistics for graft and patient survival were 0.666 (95% CI: 0.646, 0.686) and 0.726 (95% CI: 0.710-0.742), respectively. (4) Conclusions: We developed a mobile app to estimate survival at time zero, which can guide decisions for organ allocation.
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Affiliation(s)
| | - Jorge Calvillo Arbizu
- Biomedical Engineering Group, University of Sevilla, 41092 Sevilla, Spain;
- Department of Telematics Engineering, University of Sevilla, 41092 Sevilla, Spain;
| | | | | | | | | | | | | | - Gabriel Bernal Blanco
- Nephrology Service, Hospital Virgen del Rocío, 41013 Sevilla, Spain; (G.B.B.); (M.Á.G.G.); (J.L.R.C.)
| | | | - Rafael Bedoya Pérez
- Pediatric Nephrology Service, Hospital Virgen del Rocío, 41013 Sevilla, Spain;
| | - José Luis Rocha Castilla
- Nephrology Service, Hospital Virgen del Rocío, 41013 Sevilla, Spain; (G.B.B.); (M.Á.G.G.); (J.L.R.C.)
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22
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Jørgensen IF, Muse VP, Aguayo-Orozco A, Brunak S, Sørensen SS. Stratification of Kidney Transplant Recipients Into Five Subgroups Based on Temporal Disease Trajectories. Transplant Direct 2024; 10:e1576. [PMID: 38274475 PMCID: PMC10810574 DOI: 10.1097/txd.0000000000001576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 11/02/2023] [Accepted: 11/28/2023] [Indexed: 01/27/2024] Open
Abstract
Background Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Considerable clinical research has focused on improving graft survival and an increasing number of kidney recipients die with a functioning graft. There is a need to improve patient survival and to better understand the individualized risk of comorbidities and complications. Here, we developed a method to stratify recipients into similar subgroups based on previous comorbidities and subsequently identify complications and for a subpopulation, laboratory test values associated with survival. Methods First, we identified significant disease patterns based on all hospital diagnoses from the Danish National Patient Registry for 5752 kidney transplant recipients from 1977 to 2018. Using hierarchical clustering, these longitudinal patterns of diseases segregate into 3 main clusters of glomerulonephritis, hypertension, and diabetes. As some recipients are diagnosed with diseases from >1 cluster, recipients are further stratified into 5 more fine-grained trajectory subgroups for which survival, stratified complication patterns as well as laboratory test values are analyzed. Results The study replicated known associations indicating that diabetes and low levels of albumin are associated with worse survival when investigating all recipients. However, stratification of recipients by trajectory subgroup showed additional associations. For recipients with glomerulonephritis, higher levels of basophils are significantly associated with poor survival, and these patients are more often diagnosed with bacterial infections. Additional associations were also found. Conclusions This study demonstrates that disease trajectories can confirm known comorbidities and furthermore stratify kidney transplant recipients into clinical subgroups in which we can characterize stratified risk factors. We hope to motivate future studies to stratify recipients into more fine-grained, homogenous subgroups to better discover associations relevant for the individual patient and thereby enable more personalized disease-management and improve long-term outcomes and survival.
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Affiliation(s)
- Isabella F. Jørgensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Victorine P. Muse
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Alejandro Aguayo-Orozco
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Søren S. Sørensen
- Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark
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Okumura K, Ohira S, Kai M, Misawa R, Wolfe K, Sogawa H, Veillette G, Nishida S, Spielvogel D, Lansman S, Dhand A. High Rate of Kidney Graft Failure after Simultaneous Heart-Kidney Transplantation. KIDNEY360 2024; 5:252-261. [PMID: 38268085 PMCID: PMC10914208 DOI: 10.34067/kid.0000000000000365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 01/11/2024] [Indexed: 01/26/2024]
Abstract
Key Points Simultaneous heart–kidney transplant is associated with high rates of kidney graft failure which are worse when compared with kidney transplant alone. The major causes of kidney graft failure in simultaneous heart–kidney transplant recipients were patient death and primary nonfunction of kidney graft. Background The indications and outcomes of simultaneous heart–kidney transplantation (SHKT) remain suboptimally defined. Risk factors for renal graft failure after SHKT also remain poorly defined. Methods We analyzed the renal graft outcomes among SHKT recipients using United Network for Organ Sharing database from 2015 to 2020. To evaluate for factors associated with poor renal outcomes, we compared SHKT and kidney transplantation alone recipients using propensity score matching. Results Among SHKT recipients, the rate of primary nonfunction (PNF) of kidney graft was 3%, the 30-day kidney graft failure rate was 7.0%, and the 30-day post-transplant mortality rate was 4.1%. The incidence of kidney delayed graft function was 27.5%. Kidney graft failure was seen early post-SHKT with most common causes of patient death (43.9%) and PNF of kidney graft (41.5%). One- and 2-year patient survival was 89.2% and 86.5%, and 1- and 2-year freedom from kidney graft failure was 85.4% and 82.7%, respectively. In subgroup analysis of SHKT recipients, use of pretransplant mechanical cardiac support (adjusted odds ratio [aOR], 2.57; P = 0.017), higher calculated panel reactive antibody (aOR, 1.76; P = 0.016), and older donor age per 10 years (aOR, 1.94; P = 0.001) were associated with PNF. Pretransplant extracorporeal membrane oxygenation support was associated with the increased risk of 30-day recipient mortality (aOR, 5.55; P = 0.002). Increased 30-day graft failure was seen in SHKT recipients with pretransplant mechanical cardiac support (aOR, 1.77; P = 0.038) and dialysis at the time of transplant (aOR, 1.72; P = 0.044). Multivariable Cox hazard analysis demonstrated that SHKT, when compared with kidney transplantation alone, is associated with increased kidney graft failure (hazard ratio, 2.56; P < 0.001) and recipient mortality (hazard ratio, 2.65; P < 0.001). Conclusions SHKT is associated with high rates of kidney graft failure. Identification of risk factors of renal graft failure can help optimize recipient selection for SHKT versus kidney after heart transplantation, especially after introduction of the new safety-net policy.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - Suguru Ohira
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
- Division of Cardiothoracic Surgery, Department of Surgery, Westchester Medical Center, Valhalla, New York
| | - Masashi Kai
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
- Division of Cardiothoracic Surgery, Department of Surgery, Westchester Medical Center, Valhalla, New York
| | - Ryosuke Misawa
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - Kevin Wolfe
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - Gregory Veillette
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - Seigo Nishida
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
| | - David Spielvogel
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
- Division of Cardiothoracic Surgery, Department of Surgery, Westchester Medical Center, Valhalla, New York
| | - Steven Lansman
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
- Division of Cardiothoracic Surgery, Department of Surgery, Westchester Medical Center, Valhalla, New York
| | - Abhay Dhand
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, New York
- Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, New York
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24
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Jung HY, Ryu JH, Kim MG, Huh KH, Lee KW, Jung HY, Kang KP, Ro H, Han S, Yang J. Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT. Am J Nephrol 2024; 55:245-254. [PMID: 38198780 DOI: 10.1159/000536198] [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: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/12/2024]
Abstract
INTRODUCTION Serum activin A has been reported to contribute to vascular calcification and kidney fibrosis in chronic kidney disease. We aimed to investigate whether higher serum activin levels were associated with poor allograft outcomes in patients with kidney transplantation (KT). METHODS A total of 860 KT patients from KNOW-KT (Korean Cohort Study for Outcome in Patients with Kidney Transplantation) were analyzed. We measured serum activin levels pre-KT and 1 year after KT. The primary outcome was the composite of a ≥50% decline in estimated glomerular filtration rate and graft failure. Multivariable cause-specific hazard model was used to analyze association of 1-year activin levels with the primary outcome. The secondary outcome was coronary artery calcification score (CACS) at 5 years after KT. RESULTS During the median follow-up of 6.7 years, the primary outcome occurred in 109 (12.7%) patients. The serum activin levels at 1 year were significantly lower than those at pre-KT (488.2 ± 247.3 vs. 704.0 ± 349.6). When patients were grouped based on the median activin level at 1 year, the high-activin group had a 1.91-fold higher risk (95% CI, 1.25-2.91) for the primary outcome compared to the low-activin group. A one-standard deviation increase in activin levels as a continuous variable was associated with a 1.36-fold higher risk (95% CI, 1.16-1.60) for the primary outcome. Moreover, high activin levels were significantly associated with 1.56-fold higher CACS (95% CI, 1.12-2.18). CONCLUSION Post-transplant activin levels were independently associated with allograft functions as well as coronary artery calcification in KT patients.
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Affiliation(s)
- Hui-Yun Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Jung-Hwa Ryu
- Department of Internal Medicine, Ewha Womans University Medical Center, Seoul, Republic of Korea
| | - Myung-Gyu Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyu Ha Huh
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Kyo Won Lee
- Department of Surgery, Sungkyunkwan University, Seoul Samsung Medical Center, Seoul, Republic of Korea
| | - Hee-Yeon Jung
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Kyung Pyo Kang
- Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Han Ro
- Department of Internal Medicine, Gachon University, Gil Hospital, Incheon, Republic of Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University, Dongsan Medical Center, Daegu, Republic of Korea
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
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Karatas M, Tatar E, Okut G, Yildirim AM, Kocabas E, Tasli Alkan F, Simsek C, Dogan SM, Uslu A. Efficacy of mTOR Inhibitors and Intravenous Immunoglobulin for Treatment of Polyoma BK Nephropathy in Kidney Transplant Recipients: A Biopsy-Proven Study. EXP CLIN TRANSPLANT 2024; 22:118-127. [PMID: 38385385 DOI: 10.6002/ect.mesot2023.o29] [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: 02/23/2024]
Abstract
OBJECTIVES We investigated the efficacy of a predetermined protocol that consisted of immunosuppressive drug reduction/withdrawal and intravenous immunoglobulin administration for the treatment of polyoma BK virus nephropathy. MATERIALS AND METHODS Patients with biopsy-proven polyoma BK virus nephropathy received a treatment regimen based on discontinuation of both calcineurin inhibitors and antiproliferative agents and switching to mTOR inhibitors accompanied by intravenous immunoglobulin administration. RESULTS Our study included 508 patients, with polyoma BK viremia detected in 80 patients. The mean age was 45.3 ± 9.5 years (range, 18-71 y), 64% were male, and mean follow-up was 37 ± 21 months (6-94 mo). All 16 patients who developed polyoma BK virus nephropathy and 9 patients who had highgrade polyoma BK viremia without nephropathy received intravenous immunoglobulin treatment. Compared with patients with viremia, patients with polyoma BK virus nephropathy had significantly higher rates of graft loss due to rejection (18.8% vs 1.6%; P = .024) and all-cause graft loss (31.2% vs 6.3%; P = .014). Histopathologically, viral inclusion bodies disappeared and SV40 became negative after treatment in all 13 patients who underwent protocol biopsies. Unfortunately, histopathologically complete recovery without chronic tubular and interstitial tissue damage was achieved in only 4 patients after treatment. In addition, 3 patients lost their grafts due to acute antibody-mediated or mixed-type rejection (18.8%). CONCLUSIONS In patients with polyoma BK virus nephropathy, clearance of viremia and SV40 should not be the sole outcomes to obtain. Aggressive reductions in maintenance immunosuppression and switching to double-drug therapy combined with high-dose intravenous immunoglobulin leads to high rates of graft loss/rejection and sequalae of chronic histological changes.
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Affiliation(s)
- Murat Karatas
- From the Department of General Surgery and Transplantation, University of Health Sciences, Izmir Bozyaka Education and Research Hospital, Izmir, Turkey
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Kitchens WH, Larsen CP, Badell IR. Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future. Kidney Int Rep 2023; 8:2529-2545. [PMID: 38106575 PMCID: PMC10719580 DOI: 10.1016/j.ekir.2023.08.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/01/2023] [Accepted: 08/28/2023] [Indexed: 12/19/2023] Open
Abstract
Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.
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Affiliation(s)
- William H. Kitchens
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Christian P. Larsen
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - I. Raul Badell
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
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Kumar N, Tandon A, Rana R, Rana DS, Bhalla AK, Gupta A, Sachdeva MP, Huirem RS, Chauhan K, Yashavarddhan MH, Basnal A, Gupta R, Mallick PK, Ganguly NK. Donor-Derived Cell-Free DNA as a Non-Invasive Biomarker for Graft Rejection in Kidney Transplant Recipients: A Prospective Study among the Indian Population. Diagnostics (Basel) 2023; 13:3540. [PMID: 38066781 PMCID: PMC10706139 DOI: 10.3390/diagnostics13233540] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 12/23/2024] Open
Abstract
Monitoring graft health and detecting graft rejection is crucial for the success of post-transplantation outcomes. In Western countries, the use of donor-derived cell-free DNA (dd-cfDNA) has gained widespread recognition as a diagnostic tool for kidney transplant recipients. However, the role of dd-cfDNA among the Indian population remains unexplored. The recipients were categorized into two groups: the post-transplant recipient (PTR) group (n = 16) and the random recipient (RR) group (n = 87). Blood samples were collected daily from the PTR group over a 7-day period, whereas the RR group's samples were obtained at varying intervals. In this study, we used a targeted approach to identify dd-cfDNA, which eliminated the need for genotyping, and is based on the minor allele frequency of SNP assays. In the PTR group, elevated dd-cfDNA% levels were observed immediately after transplantation, but returned to normal levels within five days. Within the RR group, heightened serum creatinine levels were directly proportional to increased dd-cfDNA%. Sixteen recipients were advised to undergo biopsy due to elevated serum creatinine and other pathological markers. Among these sixteen recipients, six experienced antibody-mediated rejection (ABMR), two exhibited graft dysfunctions, two had active graft injury, and six (37.5%) recipients showed no rejection (NR). In cases of biopsy-proven ABMR and NR, recipients displayed a mean ± SD dd-cfDNA% of 2.80 ± 1.77 and 0.30 ± 0.35, respectively. This study found that the selected SNP assays exhibit a high proficiency in identifying donor DNA. This study also supports the use of dd-cfDNA as a routine diagnostic test for kidney transplant recipients, along with biopsies and serum creatinine, to attain better graft monitoring.
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Affiliation(s)
- Naveen Kumar
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India; (N.K.); (R.S.H.); (K.C.); (M.H.Y.)
- Department of Nephrology, Sir Ganga Ram Hospital, New Delhi 110060, India (A.K.B.)
- Department of Anthropology, University of Delhi, New Delhi 110007, India; (A.T.); (M.P.S.)
| | - Archita Tandon
- Department of Anthropology, University of Delhi, New Delhi 110007, India; (A.T.); (M.P.S.)
| | - Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India; (N.K.); (R.S.H.); (K.C.); (M.H.Y.)
| | - Devinder Singh Rana
- Department of Nephrology, Sir Ganga Ram Hospital, New Delhi 110060, India (A.K.B.)
| | - Anil Kumar Bhalla
- Department of Nephrology, Sir Ganga Ram Hospital, New Delhi 110060, India (A.K.B.)
| | - Anurag Gupta
- Department of Nephrology, Sir Ganga Ram Hospital, New Delhi 110060, India (A.K.B.)
| | - Mohinder Pal Sachdeva
- Department of Anthropology, University of Delhi, New Delhi 110007, India; (A.T.); (M.P.S.)
| | - Rohit Singh Huirem
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India; (N.K.); (R.S.H.); (K.C.); (M.H.Y.)
| | - Kirti Chauhan
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India; (N.K.); (R.S.H.); (K.C.); (M.H.Y.)
| | - M. H. Yashavarddhan
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India; (N.K.); (R.S.H.); (K.C.); (M.H.Y.)
| | - Atul Basnal
- Laboratory Oncology, Dr BRAIRCH, All India Institute of Medical Sciences, New Delhi 110029, India; (A.B.)
| | - Ritu Gupta
- Laboratory Oncology, Dr BRAIRCH, All India Institute of Medical Sciences, New Delhi 110029, India; (A.B.)
| | | | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India; (N.K.); (R.S.H.); (K.C.); (M.H.Y.)
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Benning L, Morath C, Fink A, Rudek M, Speer C, Kälble F, Nusshag C, Beimler J, Schwab C, Waldherr R, Zeier M, Süsal C, Tran TH. Donor-Derived Cell-Free DNA (dd-cfDNA) in Kidney Transplant Recipients With Indication Biopsy-Results of a Prospective Single-Center Trial. Transpl Int 2023; 36:11899. [PMID: 38020751 PMCID: PMC10654198 DOI: 10.3389/ti.2023.11899] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023]
Abstract
Donor-derived cell-free DNA (dd-cfDNA) identifies allograft injury and discriminates active rejection from no rejection. In this prospective study, 106 kidney transplant recipients with 108 clinically indicated biopsies were enrolled at Heidelberg University Hospital between November 2020 and December 2022 to validate the clinical value of dd-cfDNA in a cohort of German patients. dd-cfDNA was quantified at biopsy and correlated to histopathology. Additionally, dd-cfDNA was determined on days 7, 30, and 90 post-biopsy and analyzed for potential use to monitor response to anti-rejection treatment. dd-cfDNA levels were with a median (IQR) % of 2.00 (0.48-3.20) highest in patients with ABMR, followed by 0.92 (0.19-11.25) in patients with TCMR, 0.44 (0.20-1.10) in patients with borderline changes and 0.20 (0.11-0.53) in patients with no signs of rejection. The AUC for dd-cfDNA to discriminate any type of rejection including borderline changes from no rejection was at 0.72 (95% CI 0.62-0.83). In patients receiving anti-rejection treatment, dd-cfDNA levels significantly decreased during the 7, 30, and 90 days follow-up compared to levels at the time of biopsy (p = 0.006, p = 0.002, and p < 0.001, respectively). In conclusion, dd-cfDNA significantly discriminates active rejection from no rejection. Decreasing dd-cfDNA following anti-rejection treatment may indicate response to therapy. Clinical Trial Registration: https://drks.de/search/de/trial/DRKS00023604, identifier DRKS00023604.
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Affiliation(s)
- Louise Benning
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Morath
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Annette Fink
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Markus Rudek
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Claudius Speer
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian Kälble
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Nusshag
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jörg Beimler
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Constantin Schwab
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Rüdiger Waldherr
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Caner Süsal
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
- Transplant Immunology Research Center of Excellence, Koç University Hospital, Istanbul, Türkiye
| | - Thuong Hien Tran
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
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29
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Kindem IA, Åsberg A, Midtvedt K, Bjerre A. Optimizing medication adherence with home-monitoring - A feasibility study using capillary microsampling and mHealth in solid organ-transplanted adolescents. Pediatr Transplant 2023; 27:e14590. [PMID: 37543722 DOI: 10.1111/petr.14590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 06/08/2023] [Accepted: 07/25/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND Reliable methods to detect and reduce medication nonadherence in solid organ-transplanted (SOT) adolescents are warranted. We aimed to evaluate the feasibility of combining a medication-manager application (TusenTac®-app) with home-sampling of tacrolimus (Tac) in young SOT recipients. METHODS Kidney and combined SOT recipients between 14 and 25 years were included. During an 8-week intervention period, the participants were instructed to use the transplant-specific, age-adapted TusenTac®-app daily and to perform weekly at-home Tac trough finger-prick microsampling. Microsample Tac concentrations were controlled against timed venous samples twice. Medication implementation and persistence adherence were measured with BAASIS© questionnaires, TusenTac®-registrations, Tac trough concentration coefficient of variation (CV%) and self-reporting by interview. For comparison, venous Tac trough CV% were obtained from the year before and after the short-term intervention. RESULTS Twenty-two recipients were included, two withdrawals, leaving 20; median age 17.9 (14.5-24.8) years, 12 females (60%). The participants registered their dosage intake 88% (1502/1703) of the expected times, and 90% (106/118) of the microsamples were obtained correctly. At inclusion, 11 recipients (55%) were nonadherent assessed with BAASIS© questionnaire, four of these (36%) turned adherent during the intervention period. At the end, 70% reported improved timing-adherence at the interview. There was no significant change in TacCV% from the year before to the year after the short-term intervention. Home-sampling was reliable and measured Tac concentrations accurately. CONCLUSIONS Home-monitoring, combining Tac finger-prick microsampling and a medication-manager app, is feasible in adolescent SOT recipients with 70% perceived improvement in medication timing-adherence. There were no significant long-term changes in TacCV% confirming the need for continuous use and individualized interventions.
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Affiliation(s)
- Ingvild Andrea Kindem
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Karsten Midtvedt
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Anna Bjerre
- Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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30
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Hreško S, Maďarová M, Dobošová M, Palušeková N, Niznerová P, Žiaran S, Varga I. The Diagnostic Significance of C3d Antigen in Kidney and Skin Histopathology - The Current State-Of-The-Art and Practical Examples. Physiol Res 2023; 72:S225-S232. [PMID: 37888966 PMCID: PMC10669952 DOI: 10.33549/physiolres.935175] [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: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 12/01/2023] Open
Abstract
The aim of this narrative review is to summarize recent knowledge about the diagnostic significance of immunobiological detection of C3d with a focus on renal and skin tissue biopsies. We completed the present narrative review with our own experiences with preparation and practical use of monoclonal C3d antibodies at a small national level.
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Affiliation(s)
- S Hreško
- DB Biotech, a.s., Košice, Slovak Republic.
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31
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González-López E, Ocejo-Vinyals JG, Renuncio-García M, Roa-Bautista A, San Segundo Arribas D, Escagedo C, García-Saiz MDM, Valero R, García-Berbel P, Ruíz San Millán JC, Rodrigo E. Donor-Derived Cell-Free DNA at 1 Month after Kidney Transplantation Relates to HLA Class II Eplet Mismatch Load. Biomedicines 2023; 11:2741. [PMID: 37893114 PMCID: PMC10604614 DOI: 10.3390/biomedicines11102741] [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: 08/16/2023] [Revised: 10/03/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage.
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Affiliation(s)
- Elena González-López
- Immunology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (E.G.-L.); (M.R.-G.); (A.R.-B.); (D.S.S.A.)
| | - Javier Gonzalo Ocejo-Vinyals
- Immunology Department, Infectious Diseases and Clinical Microbiology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain;
| | - Mónica Renuncio-García
- Immunology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (E.G.-L.); (M.R.-G.); (A.R.-B.); (D.S.S.A.)
| | - Adriel Roa-Bautista
- Immunology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (E.G.-L.); (M.R.-G.); (A.R.-B.); (D.S.S.A.)
| | - David San Segundo Arribas
- Immunology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (E.G.-L.); (M.R.-G.); (A.R.-B.); (D.S.S.A.)
| | - Clara Escagedo
- Nephrology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (C.E.); (R.V.); (J.C.R.S.M.)
| | - María del Mar García-Saiz
- Clinical Pharmacology Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain;
| | - Rosalía Valero
- Nephrology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (C.E.); (R.V.); (J.C.R.S.M.)
| | - Pilar García-Berbel
- Pathological Anatomy Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain;
| | - Juan Carlos Ruíz San Millán
- Nephrology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (C.E.); (R.V.); (J.C.R.S.M.)
| | - Emilio Rodrigo
- Nephrology Department, Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39008 Santander, Spain; (C.E.); (R.V.); (J.C.R.S.M.)
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Hinrichs GR, Nielsen JR, Birn H, Bistrup C, Jensen BL. Amiloride evokes significant natriuresis and weight loss in kidney transplant recipients with and without albuminuria. Am J Physiol Renal Physiol 2023; 325:F426-F435. [PMID: 37560772 DOI: 10.1152/ajprenal.00108.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/14/2023] [Accepted: 08/03/2023] [Indexed: 08/11/2023] Open
Abstract
Albuminuria in kidney transplant recipients (KTRs) is associated with hypertension and aberrant glomerular filtration of serine proteases that may proteolytically activate the epithelial Na+ channel (ENaC). The present nonrandomized, pharmacodynamic intervention study aimed to investigate if inhibition of ENaC increases Na+ excretion and reduces extracellular volume in KTRs dependent on the presence of albuminuria. KTRs with and without albuminuria (albumin-to-creatinine ratio > 300 mg/g, n = 7, and <30 mg/g, n = 7, respectively) were included and ingested a diet with fixed Na+ content (150 mmol/day) for 5 days. On the last day, amiloride at 10 mg was administered twice. Body weight, 24-h urine electrolyte excretion, body water content, and ambulatory blood pressure as well as plasma renin, angiotensin II, and aldosterone concentrations were determined before and after amiloride. Amiloride led to a significant decrease in body weight, increase in 24-h urinary Na+ excretion, and decrease in 24-h urinary K+ excretion in both groups. Urine output increased in the nonalbuminuric group only. There was no change in plasma renin, aldosterone, and angiotensin II concentrations after amiloride, whereas a significant decrease in nocturnal systolic blood pressure and increase in 24-h urine aldosterone excretion was observed in albuminuric KTRs only. There was a significant correlation between 24-h urinary albumin excretion and amiloride-induced 24-h urinary Na+ excretion. In conclusion, ENaC activity contributes to Na+ and water retention in KTRs with and without albuminuria. ENaC is a relevant pharmacological target in KTRs; however, larger and long-term studies are needed to evaluate whether the magnitude of this effect depends on the presence of albuminuria.NEW & NOTEWORTHY Amiloride has a significant natriuretic effect in kidney transplant recipients (KTRs) that relates to urinary albumin excretion. The epithelial Na+ channel may be a relevant direct pharmacological target to counter Na+ retention and hypertension in KTRs. Epithelial Na+ channel blockers should be further investigated as a mean to mitigate Na+ and water retention and to potentially obtain optimal blood pressure control in KTRs.
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Affiliation(s)
- Gitte Rye Hinrichs
- Department of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Department of Nephrology, University Hospital of Southern Denmark, Esbjerg, Denmark
| | | | - Henrik Birn
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Claus Bistrup
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Boye Lagerbon Jensen
- Department of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
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Thorsen IS, Bleskestad IH, Åsberg A, Jonsson G, Skadberg Ø, Heldal K, Gøransson LG. Klotho and Fibroblast Growth Factor 23 Are Independent of Vitamin D, and Unlike Vitamin D, Are Not Associated With Graft- and Patient Survival After Kidney Transplantation. Transplant Direct 2023; 9:e1522. [PMID: 37575950 PMCID: PMC10414697 DOI: 10.1097/txd.0000000000001522] [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: 03/30/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 08/15/2023] Open
Abstract
Short-term survival after kidney transplantation is excellent but long-term survival remains suboptimal. The aim of the study was to explore the relationship between soluble α-Klotho (sKlotho) and intact fibroblast growth factor 23 (iFGF23) measured 8 wk and 1 y posttransplant with long-term graft- and patient survival in a cohort of kidney transplant recipients with deficient and nondeficient vitamin D (25[OH]D) levels. Methods Vitamin D, sKlotho, and iFGF23 were measured 8 wk and 1 y posttransplant in 132 recipients transplanted between November 2012 and October 2013. Results Of the 132 kidney transplant recipients, 49 had deficient vitamin D levels (<30 nmol/L) and 83 had nondeficient vitamin D levels (≥30 nmol/L) at 8 wk posttransplant. The mean age was 51 y and the median follow-up was 7.4 y. At 1 y posttransplant, vitamin D increased significantly. There were no significant differences in sKlotho or iFGF23 levels between the 2 vitamin D groups neither at 8 wk nor 1 y. sKlotho increased significantly and iFGF23 decreased significantly in the whole cohort. During the follow-up, there were 36 graft losses (27%) and 27 deaths (20%). Ninety-four percent of the transplant recipients with nondeficient vitamin D levels were alive with a well-functioning graft after 5 y using Kaplan-Meier survival estimates, compared with 84% of the patients with deficient vitamin D levels (P = 0.014). Klotho and FGF23 levels did not influence graft- and patient survival. Conclusions In this nationwide cohort of kidney transplant recipients, long-term graft- and patient survival were significantly better in patients with vitamin D ≥30 nmol/L 8 wk posttransplant compared with those with vitamin D <30 nmol/L. sKlotho levels increased and iFGF23 levels decreased from 8 wk to 1 y posttransplant. Klotho and FGF23 levels were not associated with graft- and patient survival.
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Affiliation(s)
- Inga Strand Thorsen
- Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
- Norwegian Renal Registry, Oslo, Norway
| | - Grete Jonsson
- Department of Medical Biochemistry, Stavanger University Hospital, Stavanger, Norway
| | - Øyvind Skadberg
- Department of Medical Biochemistry, Stavanger University Hospital, Stavanger, Norway
| | - Kristian Heldal
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Lasse Gunnar Gøransson
- Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Guinn MT, Szuter ES, Yokose T, Ge J, Rosales IA, Chetal K, Sadreyev RI, Cuenca AG, Kreisel D, Sage PT, Russell PS, Madsen JC, Colvin RB, Alessandrini A. Intragraft B cell differentiation during the development of tolerance to kidney allografts is associated with a regulatory B cell signature revealed by single cell transcriptomics. Am J Transplant 2023; 23:1319-1330. [PMID: 37295719 PMCID: PMC11232115 DOI: 10.1016/j.ajt.2023.05.036] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/23/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023]
Abstract
Mouse kidney allografts are spontaneously accepted in select, fully mismatched donor-recipient strain combinations, like DBA/2J to C57BL/6 (B6), by natural tolerance. We previously showed accepted renal grafts form aggregates containing various immune cells within 2 weeks posttransplant, referred to as regulatory T cell-rich organized lymphoid structures, which are a novel regulatory tertiary lymphoid organ. To characterize the cells within T cell-rich organized lymphoid structures, we performed single-cell RNA sequencing on CD45+ sorted cells from accepted and rejected renal grafts from 1-week to 6-months posttransplant. Analysis of single-cell RNA sequencing data revealed a shifting from a T cell-dominant to a B cell-rich population by 6 months with an increased regulatory B cell signature. Furthermore, B cells were a greater proportion of the early infiltrating cells in accepted vs rejecting grafts. Flow cytometry of B cells at 20 weeks posttransplant revealed T cell, immunoglobulin domain and mucin domain-1+ B cells, potentially implicating a regulatory role in the maintenance of allograft tolerance. Lastly, B cell trajectory analysis revealed intragraft differentiation from precursor B cells to memory B cells in accepted allografts. In summary, we show a shifting T cell- to B cell-rich environment and a differential cellular pattern among accepted vs rejecting kidney allografts, possibly implicating B cells in the maintenance of kidney allograft acceptance.
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Affiliation(s)
- Michael Tyler Guinn
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Edward S Szuter
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Takahiro Yokose
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jifu Ge
- Boston's Children Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ivy A Rosales
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kashish Chetal
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ruslan I Sadreyev
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alex G Cuenca
- Boston's Children Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel Kreisel
- Departments of Surgery, Pathology, and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Peter T Sage
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paul S Russell
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Joren C Madsen
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Division of Cardiac Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Robert B Colvin
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alessandro Alessandrini
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
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Chancharoenthana W, Traitanon O, Leelahavanichkul A, Tasanarong A. Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review. Front Immunol 2023; 14:1206929. [PMID: 37675106 PMCID: PMC10477600 DOI: 10.3389/fimmu.2023.1206929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 07/31/2023] [Indexed: 09/08/2023] Open
Abstract
Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.
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Affiliation(s)
- Wiwat Chancharoenthana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Tropical Immunology and Translational Research Unit (TITRU), Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Opas Traitanon
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Adis Tasanarong
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
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Mayrdorfer M, Liefeldt L, Osmanodja B, Naik MG, Schmidt D, Duettmann W, Hammett C, Schrezenmeier E, Friedersdorff F, Wu K, Halleck F, Budde K. A single centre in-depth analysis of death with a functioning kidney graft and reasons for overall graft failure. Nephrol Dial Transplant 2023; 38:1857-1866. [PMID: 36477607 PMCID: PMC10387383 DOI: 10.1093/ndt/gfac327] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Indexed: 08/01/2023] Open
Abstract
BACKGROUND High numbers of unknown classifications and inconsistent methodologies in previous studies make the interpretation of causes leading to graft loss difficult. In addition, data on a holistic view looking at both death with a functioning graft (DWFG) and death-censored graft failure (DCGF) are sparse. METHODS In this single-centre study we included 1477 adult kidney transplants performed between 1997 and 2017, of which all 286 DWFGs until the end of observation were analysed and causes for death assigned. Additionally, the results were compared with the causes of 303 DCGFs of the same cohort to evaluate the impact of causes for overall graft loss. RESULTS The most frequent causes for DWFG were cardiovascular disease (CVD) in 30.8%, malignancy in 28.3% and infections in 21%. Only 9.4% of reasons for DWFG were unknown. Sudden death occurred in 40% (35/88) of patients classified as DWFG due to CVD. Overall graft loss was related to the effect of immunosuppression in 36.2% [infection 20.9% (123/589), malignancy 15.3% (90/589)] and CVD in 22.4% (132/589). In 27.4% (161/589), graft failure was associated with underimmunosuppression (rejection). For infections (60 DWFG, 63 DCGF) and CVD (88 DWFG, 44 DCGF), a considerable overlap was observed between DWFG and DCGF. For patients >70 years of age at transplantation, medical events accounted for 78% of overall graft losses and only 6.5% were associated with rejection. CONCLUSIONS DWFG and DCGF share more causes for graft loss than previously reported and sudden death plays an underestimated role in death with a functioning graft.
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Affiliation(s)
- Manuel Mayrdorfer
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria
| | - Lutz Liefeldt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Bilgin Osmanodja
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Marcel G Naik
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Danilo Schmidt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Wiebke Duettmann
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Charlotte Hammett
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Frank Friedersdorff
- Department of Urology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Kaiyin Wu
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Abuazzam F, Dubrawka C, Abdulhadi T, Amurao G, Alrata L, Yaseen Alsabbagh D, Alomar O, Alhamad T. Emerging Therapies for Antibody-Mediated Rejection in Kidney Transplantation. J Clin Med 2023; 12:4916. [PMID: 37568318 PMCID: PMC10419906 DOI: 10.3390/jcm12154916] [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: 06/30/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Despite the advances in immunosuppressive medications, antibody-mediated rejection (AMR) continues to be a major cause of kidney allograft failure and remains a barrier to improving long-term allograft survival. Recently, there have been significant advances in the understanding of the pathophysiological process of AMR, along with the development of new therapeutic options. Additionally, surveillance protocols with donor-derived cell-free DNA and gene profile testing have been established, leading to the early detection of AMR. A multitude of clinical trials are ongoing, opening numerous opportunities for improving outcome in kidney transplant recipients. In this brief review, we discuss the emerging therapies for managing both active and chronic active AMR and highlight the ongoing clinical trials.
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Affiliation(s)
- Farah Abuazzam
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
| | - Casey Dubrawka
- Department of Pharmacy, Barnes Jewish Hospital, St. Louis, MO 63110, USA;
| | - Tarek Abdulhadi
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
| | - Gwendolyn Amurao
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
| | - Louai Alrata
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
| | - Dema Yaseen Alsabbagh
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
| | - Omar Alomar
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
| | - Tarek Alhamad
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (F.A.); (T.A.); (G.A.); (L.A.); (D.Y.A.); (O.A.)
- Transplant Epidemiology Research Collaboration (TERC), Institute of Public Health, Washington University School of Medicine, St. Louis, MO 63110, USA
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38
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Sadozai H, Rojas-Luengas V, Farrokhi K, Moshkelgosha S, Guo Q, He W, Li A, Zhang J, Chua C, Ferri D, Mian M, Adeyi O, Seidman M, Gorczynski RM, Juvet S, Atkins H, Levy GA, Chruscinski A. Congenic hematopoietic stem cell transplantation promotes survival of heart allografts in murine models of acute and chronic rejection. Clin Exp Immunol 2023; 213:138-154. [PMID: 37004176 PMCID: PMC10324556 DOI: 10.1093/cei/uxad038] [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: 08/11/2022] [Revised: 02/19/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
The ability to induce tolerance would be a major advance in the field of solid organ transplantation. Here, we investigated whether autologous (congenic) hematopoietic stem cell transplantation (HSCT) could promote tolerance to heart allografts in mice. In an acute rejection model, fully MHC-mismatched BALB/c hearts were heterotopically transplanted into C57BL/6 (CD45.2) mice. One week later, recipient mice were lethally irradiated and reconstituted with congenic B6 CD45.1 Lin-Sca1+ckit+ cells. Recipient mice received a 14-day course of rapamycin both to prevent rejection and to expand regulatory T cells (Tregs). Heart allografts in both untreated and rapamycin-treated recipients that did not undergo HSCT were rejected within 33 days (median survival time = 8 days for untreated recipients, median survival time = 32 days for rapamycin-treated recipients), whereas allografts in HSCT-treated recipients had a median survival time of 55 days (P < 0.001 vs. both untreated and rapamycin-treated recipients). Enhanced allograft survival following HSCT was associated with increased intragraft Foxp3+ Tregs, reduced intragraft B cells, and reduced serum donor-specific antibodies. In a chronic rejection model, Bm12 hearts were transplanted into C57BL/6 (CD45.2) mice, and congenic HSCT was performed two weeks following heart transplantation. HSCT led to enhanced survival of allografts (median survival time = 70 days vs. median survival time = 28 days in untreated recipients, P < 0.01). Increased allograft survival post-HSCT was associated with prevention of autoantibody development and absence of vasculopathy. These data support the concept that autologous HSCT can promote immune tolerance in the setting of allotransplantation. Further studies to optimize HSCT protocols should be performed before this procedure is adopted clinically.
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Affiliation(s)
- Hassan Sadozai
- Center for Sport, Exercise and Life Sciences, Coventry University, Coventry, UK
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Vanessa Rojas-Luengas
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Kaveh Farrokhi
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Sajad Moshkelgosha
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Qinli Guo
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Wei He
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Angela Li
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Jianhua Zhang
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Conan Chua
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Dario Ferri
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Muhtashim Mian
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Oyedele Adeyi
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Michael Seidman
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
| | - Reginald M Gorczynski
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Stephen Juvet
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Harold Atkins
- Division of Hematology, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Gary A Levy
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Andrzej Chruscinski
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Alhamad T, Murad H, Dadhania DM, Pavlakis M, Parajuli S, Concepcion BP, Singh N, Murakami N, Casey MJ, Ji M, Lubetzky M, Tantisattamo E, Alomar O, Faravardeh A, Blosser CD, Basu A, Gupta G, Adler JT, Adey D, Woodside KJ, Ong SC, Parsons RF, Lentine KL. The Perspectives of General Nephrologists Toward Transitions of Care and Management of Failing Kidney Transplants. Transpl Int 2023; 36:11172. [PMID: 37456682 PMCID: PMC10348051 DOI: 10.3389/ti.2023.11172] [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: 01/05/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023]
Abstract
The management of failing kidney allograft and transition of care to general nephrologists (GN) remain a complex process. The Kidney Pancreas Community of Practice (KPCOP) Failing Allograft Workgroup designed and distributed a survey to GN between May and September 2021. Participants were invited via mail and email invitations. There were 103 respondents with primarily adult nephrology practices, of whom 41% had an academic affiliation. More than 60% reported listing for a second kidney as the most important concern in caring for patients with a failing allograft, followed by immunosuppression management (46%) and risk of mortality (38%), while resistant anemia was considered less of a concern. For the initial approach to immunosuppression reduction, 60% stop antimetabolites first, and 26% defer to the transplant nephrologist. Communicating with transplant centers about immunosuppression cessation was reported to occur always by 60%, and sometimes by 29%, while 12% reported making the decision independently. Nephrologists with academic appointments communicate with transplant providers more than private nephrologists (74% vs. 49%, p = 0.015). There are heterogeneous approaches to the care of patients with a failing allograft. Efforts to strengthen transitions of care and to develop practical practice guidelines are needed to improve the outcomes of this vulnerable population.
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Affiliation(s)
- Tarek Alhamad
- John T. Milliken Department of Medicine, Washington University in St. Louis, Saint Louis, MO, United States
| | - Haris Murad
- John T. Milliken Department of Medicine, Washington University in St. Louis, Saint Louis, MO, United States
| | - Darshana M. Dadhania
- Department of Transplantation Medicine, Weill Cornel Medicine - New York Presbyterian Hospital, New York, NY, United States
| | - Martha Pavlakis
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard University, Boston, MA, United States
| | - Sandesh Parajuli
- Department of Medicine, University of Wisconsin - Madison, Madison, WI, United States
| | | | - Neeraj Singh
- John C. McDonald Regional Transplant Center, Willis Knighton Health System, Shreveport, LA, United States
| | - Naoka Murakami
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Michael J. Casey
- Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Mengmeng Ji
- John T. Milliken Department of Medicine, Washington University in St. Louis, Saint Louis, MO, United States
| | - Michelle Lubetzky
- Division of Abdominal Transplantation, Department of Surgery and Perioperative Care, Dell Medical School, University of Texas at Austin, Austin, TX, United States
| | - Ekamol Tantisattamo
- Department of Medicine, University of California, Irvine, Orange, CA, United States
| | - Omar Alomar
- John T. Milliken Department of Medicine, Washington University in St. Louis, Saint Louis, MO, United States
| | - Arman Faravardeh
- SHARP Kidney and Pancreas Transplant Center, San Diego, CA, United States
| | - Christopher D. Blosser
- Department of Medicine, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
| | - Arpita Basu
- Department of Medicine, Emory University, Atlanta, GA, United States
| | - Gaurav Gupta
- Department of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Joel T. Adler
- Division of Abdominal Transplantation, Department of Surgery and Perioperative Care, Dell Medical School, University of Texas at Austin, Austin, TX, United States
| | - Deborah Adey
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | | | - Song C. Ong
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ronald F. Parsons
- Department of Medicine, Emory University, Atlanta, GA, United States
| | - Krista L. Lentine
- Center for Abdominal Transplantation, Saint Louis University, Saint Louis, MO, United States
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40
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Hendriks SH, Heidt S, Schulz AR, de Fijter JW, Reinders MEJ, Koning F, van Kooten C. Peripheral Blood Immune Cell Composition After Autologous MSC Infusion in Kidney Transplantation Recipients. Transpl Int 2023; 36:11329. [PMID: 37426430 PMCID: PMC10326287 DOI: 10.3389/ti.2023.11329] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/09/2023] [Indexed: 07/11/2023]
Abstract
Tacrolimus is the backbone of immunosuppressive agents to prevent transplant rejection. Paradoxically, tacrolimus is nephrotoxic, causing irreversible tubulointerstitial damage. Therefore, infusion of mesenchymal stromal cells (MSC) 6 and 7 weeks post-transplantation was assessed to facilitate withdrawal of tacrolimus in the randomized phase II TRITON trial. Here, we performed detailed analysis of the peripheral blood immune composition using mass cytometry to assess potential effects of MSC therapy on the immune system. We developed two metal-conjugated antibody panels containing 40 antibodies each. PBMC samples from 21 MSC-treated patients and 13 controls, obtained pre-transplant and at 24 and 52 weeks post-transplantation, were analyzed. In the MSC group at 24 weeks, 17 CD4+ T cell clusters were increased of which 14 Th2-like clusters and three Th1/Th2-like clusters, as well as CD4+FoxP3+ Tregs. Additionally, five B cell clusters were increased, representing either class switched memory B cells or proliferating B cells. At 52 weeks, CCR7+CD38+ mature B cells were decreased. Finally, eight Tc1 (effector) memory cytotoxic T cell clusters were increased. Our work provides a comprehensive account of the peripheral blood immune cell composition in kidney transplant recipients after MSC therapy and tacrolimus withdrawal. These results may help improving therapeutic strategies using MSCs with the aim to reduce the use of calcineurin inhibitors. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02057965.
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Affiliation(s)
- Sanne H. Hendriks
- Department of Immunology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Axel R. Schulz
- German Rheumatism Research Center (DRFZ), Berlin, Germany
| | - Johan W. de Fijter
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
| | - Marlies E. J. Reinders
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC Transplant Institute, Erasmus University Medical Center, Leiden, Netherlands
| | - Frits Koning
- Department of Immunology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Cees van Kooten
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, Leiden, Netherlands
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Reyes NS, Laham G, Boccia N, García G, Jara R, Hermida E, Ricarte C, Diaz C, Soler Pujol G, Poletta FA, Echavarria M. Prospective cohort study of Torque Teno Virus (TTV) viral load kinetics and the association with graft rejection in renal transplant patients. J Clin Virol 2023; 165:105501. [PMID: 37379781 DOI: 10.1016/j.jcv.2023.105501] [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: 01/30/2023] [Revised: 04/13/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023]
Abstract
INTRODUCTION Graft survival is mainly determined by rejections and infectious complications in transplant recipients. Torque Teno Virus (TTV), a nonpathogenic and ubiquitous single-stranded DNA virus, has been proposed as a biomarker of the immune status in transplant patients. This study aimed to determine the correlation between a Home-Brew TTV PCR and R-GENE®PCR; the TTV viral load kinetics in renal transplant recipients and the association with graft rejection. MATERIALS AND METHODS Prospective cohort study on 107 adult renal transplant recipients. TTV viral load was determined in 746 plasma samples collected before and after renal transplantation by a Home-Brew PCR and a commercial PCR (R-GENE®PCR). Associations of TTV viral load with graft rejections were analyzed. RESULTS Agreement of both PCR assays was 93.2% and Pearson correlation coefficient was r: 0.902 (95%CI: 0.8881-0.9149, p < 0.0001). TTV viral load kinetics showed an initial gradual increase reaching a peak at 3 months. This highest value was followed by a slight decrease, reaching a plateau significantly higher than the initial baseline at 6 months (p < 0.0001). Between (181-270) days post-transplantation, TTV median viral load in patients with graft rejection was significantly lower, 3.59 Log10 copies/mL (by Home-Brew PCR) and 3.10 Log10 copies/mL (by R-GENE®PCR) compared to patients without graft rejection (6.14 and 5.96 Log10 copies/mL, respectively). CONCLUSIONS Significantly lower TTV viral load was observed in patients with renal rejection occurring at a median of 243 days post-transplantation. Given the dynamic behavior of TTV viral load post-transplantation, cut-off values for risk stratification to predict rejection might be determined in relation to the post-transplant period.
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Affiliation(s)
- N S Reyes
- Virology Unit (CEMIC-CONICET), Centro de Educación Médica e Investigaciones Clínicas University Hospital (CEMIC), Argentina.
| | - G Laham
- Nephrology section, CEMIC University Hospital, Argentina
| | - N Boccia
- Nephrology section, CEMIC University Hospital, Argentina
| | - G García
- Nephrology section, CEMIC University Hospital, Argentina
| | - R Jara
- Virology Unit (CEMIC-CONICET), Centro de Educación Médica e Investigaciones Clínicas University Hospital (CEMIC), Argentina
| | - E Hermida
- Virology Unit (CEMIC-CONICET), Centro de Educación Médica e Investigaciones Clínicas University Hospital (CEMIC), Argentina
| | - C Ricarte
- Virology Unit (CEMIC-CONICET), Centro de Educación Médica e Investigaciones Clínicas University Hospital (CEMIC), Argentina
| | - C Diaz
- Nephrology section, CEMIC University Hospital, Argentina
| | - G Soler Pujol
- Nephrology section, CEMIC University Hospital, Argentina
| | - F A Poletta
- Genetic Epidemiology Laboratory (CEMIC-CONICET), Argentina
| | - M Echavarria
- Virology Unit (CEMIC-CONICET), Centro de Educación Médica e Investigaciones Clínicas University Hospital (CEMIC), Argentina; Virology Laboratory, CEMIC, Argentina
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42
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Gibson B, Connelly C, Moldakhmetova S, Sheerin NS. Complement activation and kidney transplantation; a complex relationship. Immunobiology 2023; 228:152396. [PMID: 37276614 DOI: 10.1016/j.imbio.2023.152396] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/07/2023]
Abstract
Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement's role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.
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Affiliation(s)
- B Gibson
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - C Connelly
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - S Moldakhmetova
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - N S Sheerin
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK.
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Edinoff AN, Wu NW, Parker K, Dudossat E, Linquest L, Flanagan CJ, Dharani A, Patel H, Willett O, Cornett EM, Kaye AM, Kaye AD. Proton Pump Inhibitors, Kidney Damage, and Mortality: An Updated Narrative Review. Adv Ther 2023; 40:2693-2709. [PMID: 37140707 PMCID: PMC10157135 DOI: 10.1007/s12325-023-02476-3] [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: 12/22/2022] [Accepted: 02/20/2023] [Indexed: 05/05/2023]
Abstract
Since their approval by the Food and Drug Administration (FDA) in 1989, proton pump inhibitors (PPIs) have become one of the most highly utilized drugs in the United States, assuming a position as one of the top 10 most prescribed medications in the country. The purpose of PPIs is to limit the amount of gastric acid secreted by the parietal cells via irreversible inhibition of the H+/K+-ATPase pump, therefore maintaining an elevated gastric acid pH of greater than 4 for 15-21 h. Even though PPIs have many clinical uses, they are not without their adverse effects, mimicking achlorhydria. Besides electrolyte abnormalities and vitamin deficiencies, long-term use of PPIs has been linked to acute interstitial nephritis, bone fractures, poor COVID-19 infection outcomes, pneumonia, and possibly an increase in all-cause mortality. The causality between PPI use and increased mortality and disease risk can be questioned since most studies are observational. Confounding variables can greatly affect an observational study and explain the wide-ranging associations with the use of PPIs. Patients on PPIs are generally older, obese, sicker with a higher number of baseline morbidities, and on more medications than the compared PPI non-users. These findings suggest that PPI users are at a higher risk of mortality and complications based on pre-existing conditions. This narrative review aims to update readers on the concerning effects that proton pump inhibitor use can have on patients and give providers a resource to create informed decisions on appropriate PPI use.
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Affiliation(s)
- Amber N. Edinoff
- Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 USA
| | - Natalie W. Wu
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103 USA
| | - Katelyn Parker
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103 USA
| | - Edwin Dudossat
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103 USA
| | - Lauren Linquest
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103 USA
| | - Chelsi J. Flanagan
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, USA
| | - Anam Dharani
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, USA
| | - Hirni Patel
- Louisiana State University Health Sciences Center at Shreveport, LSU New Orleans, Louisiana State University Health Sciences Center at Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932, 71103 USA
| | - Olga Willett
- Louisiana State University Health Sciences Center at Shreveport, LSU New Orleans, Louisiana State University Health Sciences Center at Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932, 71103 USA
| | - Elyse M. Cornett
- Louisiana State University Health Sciences Center at Shreveport, LSU New Orleans, Louisiana State University Health Sciences Center at Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932, 71103 USA
| | - Adam M. Kaye
- Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211 USA
| | - Alan D. Kaye
- Louisiana State University Health Sciences Center at Shreveport, LSU New Orleans, Louisiana State University Health Sciences Center at Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932, 71103 USA
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Lovasik BP, Kim SC, Higginbotham L, Wakwe W, Mathews DV, Breeden C, Farris AB, Larsen CP, Ford ML, Nadler S, Adams AB. CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.03.539333. [PMID: 37205571 PMCID: PMC10187313 DOI: 10.1101/2023.05.03.539333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST ∼270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.
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Redondo-Pachón D, Calatayud E, Buxeda A, Pérez-Sáez MJ, Arias-Cabrales C, Gimeno J, Burballa C, Mir M, Llinàs-Mallol L, Outon S, Pascual J, Crespo M. Evolution of kidney allograft loss causes over 40 years (1979-2019). Nefrologia 2023; 43:316-327. [PMID: 37507293 DOI: 10.1016/j.nefroe.2023.07.003] [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: 07/23/2021] [Accepted: 12/01/2021] [Indexed: 07/30/2023] Open
Abstract
INTRODUCTION The improvement of kidney allograft recipient and graft survival showed a decrease over the last 40 years. Long-term graft loss rate remained stable during a 25-year time span. Knowing the changing causes and the risk factors associated with graft loss requires special attention. The present study aimed to assess the causes of graft loss and kidney allograft recipient death. Also, we aimed to compare two different periods (1979-1999 and 2000-2019) to identify changes in the characteristics of the failed allografts and recipient and donors profile. METHODS AND PATIENTS We performed a single-center cohort study. We included all the kidney transplant recipients at the Hospital del Mar (Barcelona) between May 1979 and December 2019. Graft loss was defined as recipient death with functioning graft and as loss of graft function (return to dialysis or retransplantation). We assessed the causes of graft loss using clinical and histological information. We also analyzed the results of the two different transplant periods (1979-1999 and 2000-2019). RESULTS Between 1979 and 2019, 1522 transplants were performed. The median follow-up time was 56 (IQR 8-123) months. During follow-up, 722 (47.5%) grafts were lost: 483 (66.9%) due to graft failure and 239 (33.1%) due to death with functioning graft. The main causes of death were cardiovascular (25.1%), neoplasms (25.1%), and infectious diseases (21.8%). These causes were stable between the two periods of time. Only the unknown cause of death has decreased in the last period. The main cause of graft failure (loss of graft function) was the allograft chronic dysfunction (75%). When histologic information was available, antibody-mediated rejection (ABMR) and interstitial fibrosis/tubular atrophy (IF/TA) were the most frequent specific causes (15.9% and 12.6%). Of the graft failures, 213 (29.5%) were early (<1 year of transplantation). Vascular thrombosis was the main cause of early graft failure in the second period (2000-2019) (46.7%) and T-cell-mediated rejection (TCMR) was the main cause (31.3%) in the first period (1979-1999). The causes of late graft loss were similar between the two periods. CONCLUSIONS The causes of kidney allograft recipient death are still due to cardiovascular and malignant diseases. Vascular thrombosis has emerged as a frequent cause of early graft loss in the most recent years. The evaluation of the causes of graft loss is necessary to improve kidney transplantation outcomes.
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Affiliation(s)
| | - Emma Calatayud
- Servicio de Nefrología, Hospital Universitario Doctor Peset, Valencia, Spain
| | - Anna Buxeda
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | | | | | - Javier Gimeno
- Servicio de Anatomía Patológica, Hospital del Mar, Barcelona, Spain
| | - Carla Burballa
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | - Marisa Mir
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | | | - Sara Outon
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | - Marta Crespo
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
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Herr F, Dekeyser M, Le Pavec J, Desterke C, Chiron AS, Bargiel K, Mercier O, Vernochet A, Fadel E, Durrbach A. mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4 +CD57 + T Cells In Vivo and In Vitro. Pharmaceutics 2023; 15:pharmaceutics15041299. [PMID: 37111784 PMCID: PMC10142381 DOI: 10.3390/pharmaceutics15041299] [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: 02/20/2023] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Calcineurin inhibitors have improved graft survival in solid-organ transplantation but their use is limited by toxicity, requiring a switch to another immunosuppressor in some cases. Belatacept is one option that has been shown to improve graft and patient survival despite being associated with a higher risk of acute cellular rejection. This risk of acute cellular rejection is correlated with the presence of belatacept-resistant T cells. We performed a transcriptomic analysis of in vitro-activated cells to identify pathways affected by belatacept in belatacept-sensitive cells (CD4+CD57-) but not in belatacept-resistant CD4+CD57+ T cells. mTOR was significantly downregulated in belatacept-sensitive but not belatacept-resistant T cells. The inhibition of mTOR strongly decreases the activation and cytotoxicity of CD4+CD57+ cells. In humans, the use of a combination of mTOR inhibitor and belatacept prevents graft rejection and decreases the expression of activation markers on CD4 and CD8 T cells. mTOR inhibition decreases the functioning of belatacept-resistant CD4+CD57+ T cells in vitro and in vivo. It could potentially be used in association with belatacept to prevent acute cellular rejection in cases of calcineurin intolerance.
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Affiliation(s)
- Florence Herr
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
| | - Manon Dekeyser
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
- Hôpital Henri Mondor, Service de Néphrologie, Assistance Publique-Hôpitaux de Paris, 94010 Creteil, France
| | - Jerome Le Pavec
- Inserm, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Université Paris-Saclay, 92350 Le Plessis Robinson, France
- Centre Hospitalier Marie Lannelongue, 92350 Le Plessis Robinson, France
| | - Christophe Desterke
- Inserm, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France
| | - Andrada-Silvana Chiron
- Unité des Technologies Chimiques et Biologiques pour la Santé, CNRS, INSERM, UTCBS, Université de Paris, 75006 Paris, France
- Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicetre, France
| | - Karen Bargiel
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
| | - Olaf Mercier
- Inserm, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Université Paris-Saclay, 92350 Le Plessis Robinson, France
- Centre Hospitalier Marie Lannelongue, 92350 Le Plessis Robinson, France
| | - Amelia Vernochet
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
| | - Elie Fadel
- Inserm, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Université Paris-Saclay, 92350 Le Plessis Robinson, France
- Centre Hospitalier Marie Lannelongue, 92350 Le Plessis Robinson, France
| | - Antoine Durrbach
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
- Hôpital Henri Mondor, Service de Néphrologie, Assistance Publique-Hôpitaux de Paris, 94010 Creteil, France
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Silva BDPC, Lasmar MF, Nascimento E, Fabreti-Oliveira RA. Impact of early blood transfusion after kidney transplantation on the clinical outcomes and allograft survival. Transpl Immunol 2023; 77:101807. [PMID: 36842568 DOI: 10.1016/j.trim.2023.101807] [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: 10/04/2022] [Revised: 02/21/2023] [Accepted: 02/21/2023] [Indexed: 02/26/2023]
Abstract
INTRODUCTION Anemia in chronic kidney disease is of great concern regarding blood transfusions and the possibility of allosensitization for future kidney transplants and the occurrence of rejection and allograft loss in the post-transplant period. The aim of this study was to evaluate the effect of early blood transfusion on the occurrence of rejections, allograft function and survival in the first year after transplantation. MATERIAL AND METHODS This retrospective study was carried out with 445 patients submitted to kidney transplant allocated to two groups. The first group received early blood transfusions after transplant (n = 125, 28.09%), and the second group did not receive blood transfusions (n = 320, 71.91%). The patient outcomes were evaluated during a 1-year follow-up. RESULTS 14 patients given blood transfusion (11.2%) lost their allograft in the first year in comparison with 8 (2.5%) without transfusion (p < 0.001). There were 9 deaths in each group, which corresponded to 7.2% of the patients who received blood transfusions and 2.81% of those who did not (p < 0.035). Patient hospitalization lasted 15 days in transfusion group and 8.5 days in non-transfusion group (p < 0.001). Creatinine levels were higher in the patients who received blood transfusion than in those without transfusion in the first and third months after transplantation (p = 0.012 and 0.038, respectively). During the first year, the patients who received blood products experienced more antibody-mediated rejection (ABMR) (13.60%) than patients who did not (4.38%) (p < 0.001). Those who received blood transfusions also developed de novo DSA in higher proportion than those without transfusion against both class I and class II HLA (p < 0.001). CONCLUSION This study showed that blood transfusions in the first month after transplantation had a negative impact on kidney function, graft survival, and contributed to the development of de novo DSA, an increased risk of ABMR and infections.
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Affiliation(s)
- Bernardo D P C Silva
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil; University Hospital of the Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil.
| | - Marcus Faria Lasmar
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil; University Hospital of the Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil
| | - Evaldo Nascimento
- IMUNOLAB - Laboratory of Histocompatibility, Belo Horizonte, Minas Gerais, Brazil; Institute of Research and Education of the Hospital Santa Casa, Belo Horizonte, Minas Gerais, Brazil..
| | - Raquel A Fabreti-Oliveira
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais, Brazil; IMUNOLAB - Laboratory of Histocompatibility, Belo Horizonte, Minas Gerais, Brazil.
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Yuan Z, Chao S, Xu Y, Niu Y. Chemoprophylaxis for the prevention of tuberculosis in kidney transplant recipients: A systematic review and meta-analysis. Front Pharmacol 2023; 14:1022579. [PMID: 37007009 PMCID: PMC10060851 DOI: 10.3389/fphar.2023.1022579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 02/23/2023] [Indexed: 03/18/2023] Open
Abstract
Background: A systematic review and meta-analysis was performed to investigate the efficacy and safety of isoniazid (INH) prophylaxis to prevent tuberculosis (TB) infection in kidney transplant recipients (KTRs). Methods: Web of Science, SCOPUS, and PubMed were searched to identify relevant studies that compared the effects among patients who received INH prophylaxis after transplantation. Results: A total of 13 studies (involving 6,547 KTRs) were included in our analysis. We found that the risk of active TB infection (RR: 0.35, 95%CI 0.27-0.45, p < 0.01) for KTRs was lower in the INH treatment group than in those without prophylaxis. However, there was no significant difference between the two groups in mortality (RR: 0.93, 95%CI 0.67-1.28, p = 0.64), acute rejection (RR: 0.82, 95%CI 0.44-1.51, p = 0.52), and hepatotoxicity (RR: 1.25, 95%CI 0.94-1.65, p = 0.12). Conclusion: Isoniazid prophylaxis is a safe and effective for KTRs on reactivation of latent TB infection.
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Affiliation(s)
| | | | | | - Yulin Niu
- Department of Transplantation Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
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Comparative transcriptome profile of mouse macrophages treated with the RhoA/Rock pathway inhibitors Y27632, Fingolimod (Gilenya), and Rezurock (Belumosudil, SLx-2119). Int Immunopharmacol 2023; 118:110017. [PMID: 36931169 DOI: 10.1016/j.intimp.2023.110017] [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: 12/02/2022] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
Macrophages play a crucial role in, the currently uncurable, chronic rejection of transplants. In rodent transplantation models, inhibition of the RhoA/Rock pathway disrupts actin-related functions of macrophages, preventing them from entering the graft, and reducing vessel occlusion, fibrosis, and chronic rejection. Among RhoA/Rock inhibitors that inhibit chronic rejection in mouse transplantation are Y27632, Fingolimod, and Rezurock. In a mouse model, Rezurok is more effective in preventing fibrosis and less effective in preventing vessel occlusion than Y27632 or Fingolimod. Fingolimod is FDA-approved for treating multiple sclerosis (MS) and Rezurock for chronic graft versus host disease (GVHD). Still, none had been tested for chronic rejection in humans. To explain the differences in the anti-chronic rejection properties of Y27632, Fingolimod, and Rezurock, we compared the transcriptome profile of mouse macrophages treated with these compounds separately. Treatment with Y27632 or Fingolimod downregulated GTPase and actin pathways involved in cell migration. Rezurock downregulated genes related to fibrosis, such as PTX3, CCR2, CCL2, cell cycle, DNA replication, adaptive immune response, and organelle assembly, while Fingolimod also specifically downregulated NOTCH1 at mRNA . The result of this study not only uncovers which pathways are shared or specific for these drugs but will help in the development of macrophage pathway-targeted therapies in human transplantation, MS, and GVHD. Because macrophages are the major players in immune response, tissue regeneration, renewal, and homeostasis, and development of many diseases, including cancer, the data compiled here will help in designing novel or improved therapies in many clinical applications.
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50
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Nascimento E, Filho AS, Lucas-Junior FDM, Jobim LFJ, Lasmar MF, Tavares-Filho HA, Fabreti-Oliveira RA. Remarkable 107-year-old kidney with a 49-year of long-term allograph survival through continuous azathioprine monotherapy. Transpl Immunol 2023; 78:101821. [PMID: 36921732 DOI: 10.1016/j.trim.2023.101821] [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: 09/19/2022] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/14/2023]
Abstract
BACKGROUND The main goal of kidney allograft transplantation is to improve survival in patients with end-stage kidney failure. Herein, we report a 49-year long-term allograft survival with non-identical human leukocyte antigens (HLA). The purpose of this study was to report the successful clinical outcome of 49 years of transplant survival in a 79-year-old patient with a 107-year-old kidney undergoing continued immunosuppressive monotherapy. MATERIAL AND METHODS The patient was evaluated clinically and immunologically with HLA typing and anti-HLA antibodies before transplantation. Post-transplant, the patient's clinical and immunological survival were monitored for 49 years. The state of the chimerism was assessed using the polymerase chain reaction to amplify 24 short tandem repeats using a DNA thermocycler and DNA analyzer. RESULTS The patient and donor were haploidentical and the patient was treated with azathioprine monotherapy. Donor-specific antibodies were detected only for the HLA-DPB1* 03:01 mismatch. This patient developed multiple skin tumors 26 years after transplant, which were successfully treated with topical therapy or surgical removal. The patient developed an intestinal adenocarcinoma 43 years after kidney transplantation, which was surgically removal; six years later, adenocarcinoma was diagnosed in a finger, followed by axillar and hepatic metastases. After 49 years of graft survival of a kidney of 107 years old in a patient with 79 years of age, the patient's health worsened with severe dehydration, anemia, and bacterial infection. The patient was hospitalized with a serum creatinine level of 3.45 mg/dL, urea level of 188 mg/dL, and estimated glomerular filtration rate of 22 mL/1.72 m2; septicemia developed and was treated with antibiotics. The patient had poor clinical progress, was intubated, and later died due to septic shock. CONCLUSIONS To the best of our knowledge, this is the first case of a 107-year-old kidney, transplanted into a recipient who was treated with azathioprine monotherapy for 49 years.
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Affiliation(s)
- Evaldo Nascimento
- Clinical Hospital, Kidney Transplant Unit, Belo Horizonte, MG, Brazil; Faculty of the Hospital Santa Casa, Belo Horizonte, MG, Brazil; IMUNOLAB - Laboratory of Transplant Immunology, Belo Horizonte, MG, Brazil.
| | | | | | - Luiz F J Jobim
- Clinical Hospital of Porto Alegre, Rio Grande do Sul, Brazil.
| | | | | | - Raquel A Fabreti-Oliveira
- IMUNOLAB - Laboratory of Transplant Immunology, Belo Horizonte, MG, Brazil; Faculty of Medical Sciences of Minas Gerais, Belo Horizonte, MG, Brazil.
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