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Li J, Lin Q, Ren C, Li X, Li X, Li H, Li S. The perspective of modern transplant science - transplant arteriosclerosis: inspiration derived from mitochondria associated endoplasmic reticulum membrane dysfunction in arterial diseases. Int J Surg 2025; 111:3430-3440. [PMID: 40146783 DOI: 10.1097/js9.0000000000002362] [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] [Accepted: 03/16/2025] [Indexed: 03/29/2025]
Abstract
The mitochondria-associated endoplasmic reticulum membrane (MAM) is a crucial structure connecting mitochondria and the endoplasmic reticulum (ER), regulating intracellular calcium homeostasis, lipid metabolism, and various signaling pathways essential for arterial health. Recent studies highlight MAM's significant role in modulating vascular endothelial cells (EC) and vascular smooth muscle cells (VSMC), establishing it as a key regulator of arterial health and a contributor to vascular disease pathogenesis. Organ transplantation is the preferred treatment for end-stage organ failure, but transplant arteriosclerosis (TA) can lead to chronic transplant dysfunction, significantly impacting patient survival. TA, like other vascular diseases, features endothelial dysfunction and abnormal proliferation and migration of VSMC. Previous research on TA has focused on immune factors; the pathological and physiological changes in grafts following immune system attacks have garnered insufficient attention. For example, the potential roles of MAM in TA have not been thoroughly investigated. Investigating the relationship between MAM and TA, as well as the mechanisms behind TA progression, is essential. This review aims to outline the fundamental structure and the primary functions of MAM, summarize its key molecular regulators of vascular health, and explore future prospects for MAM in the context of TA research, providing insights for both basic research and clinical management of TA.
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Affiliation(s)
- Jingyi Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Qian Lin
- Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Chao Ren
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Xiaodong Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Xiaowei Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Haofeng Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Shadan Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
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2
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Garg S, Astor BC, Lim SS, Raval AN, Zhong W, Panzer SE, Khosroshahi A, Rovin B, Bartels CM. Renal arteriosclerosis in kidney biopsies associated with higher 10-year atherosclerotic cardiovascular disease in lupus nephritis. Rheumatology (Oxford) 2025; 64:2665-2675. [PMID: 39700421 PMCID: PMC12048066 DOI: 10.1093/rheumatology/keae699] [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: 08/14/2024] [Revised: 11/07/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024] Open
Abstract
OBJECTIVE Patients with lupus nephritis (LN), including those below age 50, face significantly higher risk of atherosclerotic cardiovascular disease (ASCVD) vs peers. This highlights the need for identifying specific ASCVD risk factors in LN. Renal arteriosclerosis in kidney biopsies (subclinical arteriosclerosis) may be able to predict future clinical ASCVD events. However, renal arteriosclerosis is under-reported in LN biopsies and is not taken into consideration when ASCVD risk is calculated. Therefore, we aimed to systematically grade renal arteriosclerosis in kidney biopsies at LN diagnosis and examined associations with 10-year and 20-year ASCVD occurrence. METHODS Adults with biopsy-proven LN were included. Clinical ASCVD, including fatal and non-fatal events, were adjudicated. Utilizing standard Banff grading criteria, all biopsies at LN diagnosis were re-read to grade renal arteriosclerosis. Covariables (e.g. socio-demographics, comorbidities, med exposure) were abstracted. Using Cox models, factors (including renal arteriosclerosis) associated with 10-year and 20-year clinical ASCVD were examined. RESULTS Among 209 patients, 36 and 49 clinical ASCVD occurred within 10 and 20 years. Renal arteriosclerosis (>25%) was associated with 3× higher 10-year ASCVD. High area deprivation index (>80) and longer angiotensin converting enzyme inhibitor (ACEi) exposure were associated with 4× higher and 0.65× lower ASCVD occurrence. Adding renal arteriosclerosis >25% improved model performance for 10-year ASCVD risk estimation from 65% to 80%. Similar associations were seen with 20-year ASCVD. CONCLUSION Renal arteriosclerosis >25%, area deprivation and ACEi exposure could inform ASCVD risk stratification in LN. Prospective studies should validate findings and inform clinical use.
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Affiliation(s)
- Shivani Garg
- Division of Rheumatology, Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Brad C Astor
- Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI, USA
- Department of Population Health Sciences, University of Wisconsin, Madison, WI, USA
| | - S Sam Lim
- Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA, USA
| | - Amish N Raval
- Division of Cardiology, Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Weixiong Zhong
- Department of Pathology, University of Wisconsin, Madison, WI, USA
| | - Sarah E Panzer
- Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Arezou Khosroshahi
- Division of Nephrology, Department of Medicine, Ohio State University, Columbus, OH, USA
| | - Brad Rovin
- Division of Nephrology, Department of Medicine, Ohio State University, Columbus, OH, USA
| | - Christie M Bartels
- Division of Rheumatology, Department of Medicine, University of Wisconsin, Madison, WI, USA
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Beaudrey T, Bedo D, Weschler C, Caillard S, Florens N. From Risk Assessment to Management: Cardiovascular Complications in Pre- and Post-Kidney Transplant Recipients: A Narrative Review. Diagnostics (Basel) 2025; 15:802. [PMID: 40218153 PMCID: PMC11988545 DOI: 10.3390/diagnostics15070802] [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: 02/14/2025] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 04/14/2025] Open
Abstract
Kidney transplantation remains the best treatment for chronic kidney failure, offering better outcomes and quality of life compared with dialysis. Cardiovascular disease (CVD) is a major cause of morbidity and mortality in kidney transplant recipients and is associated with decreased patient survival and worse graft outcomes. Post-transplant CVD results from a complex interaction between traditional cardiovascular risk factors, such as hypertension and diabetes, and risk factors specific to kidney transplant recipients including chronic kidney disease, immunosuppressive drugs, or vascular access. An accurate assessment of cardiovascular risk is now needed to optimize the management of cardiovascular comorbidities through the detection of risk factors and the screening of hidden pretransplant coronary artery disease. Promising new strategies are emerging, such as GLP-1 receptor agonists and SGLT2 inhibitors, with a high potential to mitigate cardiovascular complications, although further research is needed to determine their role in kidney transplant recipients. Despite this progress, a significant gap remains in understanding the optimal management of post-transplant CVD, especially coronary artery disease, stroke, and peripheral artery disease. Addressing these challenges is essential to improve the short- and long-term outcomes in kidney transplant recipients. This narrative review aims to provide a comprehensive overview of cardiovascular risk assessment and post-transplant CVD management.
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Affiliation(s)
- Thomas Beaudrey
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
| | - Dimitri Bedo
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
| | - Célia Weschler
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
| | - Sophie Caillard
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
| | - Nans Florens
- Nephrology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; (T.B.); (D.B.); (C.W.); (S.C.)
- Inserm UMR_S 1109 Immuno-Rhumatology Laboratory, Translational Medicine Federation of Strasbourg (FMTS), FHU Target, Faculté de Médecine, Université de Strasbourg, 67000 Strasbourg, France
- INI-CRCT (Cardiovascular and Renal Trialists), F-CRIN Network, 67000 Strasbourg, France
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Prabhahar A, Batta A, Hatwal J, Kumar V, Ramachandran R, Batta A. Endothelial dysfunction in the kidney transplant population: Current evidence and management strategies. World J Transplant 2025; 15:97458. [PMID: 40104196 PMCID: PMC11612885 DOI: 10.5500/wjt.v15.i1.97458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/04/2024] [Accepted: 11/04/2024] [Indexed: 11/26/2024] Open
Abstract
The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators. Endothelial dysfunction (ED), characterized by impaired vasodilation, inflammation, and thrombosis, triggers future cardiovascular (CV) diseases. Chronic kidney disease, a state of chronic inflammation caused by oxidative stress, metabolic abnormalities, infection, and uremic toxins damages the endothelium. ED is also associated with a decline in estimated glomerular filtration rate. After kidney transplantation, endothelial functions undergo immediate but partial restoration, promising graft longevity and enhanced CV health. However, the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED, culminating in poor CV health and graft survival. ED in kidney transplant recipients is an under-recognized and poorly studied entity. CV diseases are the leading cause of death among kidney transplant candidates with functioning grafts. ED contributes to the pathogenesis of many of the CV diseases. Various biomarkers and vasoreactivity tests are available to study endothelial functions. With an increasing number of transplants happening every year, and improved graft rejection rates due to the availability of effective immunosuppressants, the focus has now shifted to endothelial protection for the prevention, early recognition, and treatment of CV diseases.
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Affiliation(s)
- Arun Prabhahar
- Department of Telemedicine (Internal Medicine and Nephrology), Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Akshey Batta
- Department of Urology and Renal Transplant, Neelam Hospital, Rajpura 140401, Punjab, India
| | - Juniali Hatwal
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Vivek Kumar
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Raja Ramachandran
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Akash Batta
- Department of Cardiology, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
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Naimimohasses S, Keshavjee S, Wang B, Brudno M, Sidhu A, Bhat M. Proceedings of the 2024 Transplant AI Symposium. FRONTIERS IN TRANSPLANTATION 2024; 3:1399324. [PMID: 39319335 PMCID: PMC11421390 DOI: 10.3389/frtra.2024.1399324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024]
Abstract
With recent advancements in deep learning (DL) techniques, the use of artificial intelligence (AI) has become increasingly prevalent in all fields. Currently valued at 9.01 billion USD, it is a rapidly growing market, projected to increase by 40% per annum. There has been great interest in how AI could transform the practice of medicine, with the potential to improve all healthcare spheres from workflow management, accessibility, and cost efficiency to enhanced diagnostics with improved prognostic accuracy, allowing the practice of precision medicine. The applicability of AI is particularly promising for transplant medicine, in which it can help navigate the complex interplay of a myriad of variables and improve patient care. However, caution must be exercised when developing DL models, ensuring they are trained with large, reliable, and diverse datasets to minimize bias and increase generalizability. There must be transparency in the methodology and extensive validation of the model, including randomized controlled trials to demonstrate performance and cultivate trust among physicians and patients. Furthermore, there is a need to regulate this rapidly evolving field, with updated policies for the governance of AI-based technologies. Taking this in consideration, we summarize the latest transplant AI developments from the Ajmera Transplant Center's inaugural symposium.
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Affiliation(s)
- Sara Naimimohasses
- Division of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Shaf Keshavjee
- Department of Innovation, University Health Network, Toronto, ON, Canada
| | - Bo Wang
- Department of Laboratory Medicine and Pathobiology, The Temerty Centre for AI Research and Education in Medicine, Toronto, ON, Canada
| | - Mike Brudno
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
| | - Aman Sidhu
- Division of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Mamatha Bhat
- Division of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
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Falahat P, Scheidt U, Pörner D, Schwab S. Recent Insights in Noninvasive Diagnostic for the Assessment of Kidney and Cardiovascular Outcome in Kidney Transplant Recipients. J Clin Med 2024; 13:3778. [PMID: 38999343 PMCID: PMC11242869 DOI: 10.3390/jcm13133778] [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: 06/17/2024] [Revised: 06/25/2024] [Accepted: 06/25/2024] [Indexed: 07/14/2024] Open
Abstract
Kidney transplantation improves quality of life and prolongs survival of patients with end-stage kidney disease. However, kidney transplant recipients present a higher risk for cardiovascular events compared to the general population. Risk assessment for graft failure as well as cardiovascular events is still based on invasive procedures. Biomarkers in blood and urine, but also new diagnostic approaches like genetic or molecular testing, can be useful tools to monitor graft function and to identify patients of high cardiovascular risk. Many biomarkers have been introduced, whereas most of these biomarkers have not been implemented in clinical routine. Here, we discuss recent developments in biomarkers and diagnostic models in kidney transplant recipients. Because many factors impact graft function and cardiovascular risk, it is most likely that no biomarker will meet the highest demands and standards. We advocate to shift focus to the identification of patients benefitting from molecular and genetic testing as well as from analysis of more specific biomarkers instead of finding one biomarker fitting to all patients.
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Affiliation(s)
- Peyman Falahat
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
| | - Uta Scheidt
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
| | - Daniel Pörner
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
| | - Sebastian Schwab
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
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Tsuda T, Patel G. Coronary microvascular dysfunction in childhood: An emerging pathological entity and its clinical implications. AMERICAN HEART JOURNAL PLUS : CARDIOLOGY RESEARCH AND PRACTICE 2024; 42:100392. [PMID: 38680649 PMCID: PMC11046079 DOI: 10.1016/j.ahjo.2024.100392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/07/2024] [Indexed: 05/01/2024]
Abstract
Coronary microvascular dysfunction (CMD) encompasses a spectrum of structural and functional alterations in coronary microvasculature resulting in impaired coronary blood flow and consequent myocardial ischemia without obstruction in epicardial coronary artery. The pathogenesis of CMD is complex involving both functional and structural alteration in the coronary microcirculation. In adults, CMD is predominantly discussed in context with anginal chest pain or existing ischemic heart disease and its risk factors. The presence of CMD suggests increased risk of adverse cardiovascular events independent of coronary atherosclerosis. Coronary microvascular dysfunction is also known in children but is rarely recognized due to paucity of concommitent coronary artery disease. Thus, its clinical presentation, underlying mechanism of impaired microcirculation, and prognostic significance are poorly understood. In this review article, we will overview variable CMD reported in children and delineate its emerging clinical significance.
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Affiliation(s)
- Takeshi Tsuda
- Nemours Cardiac Center, Nemours Children's Health, Wilmington, DE 19803, USA
- Department of Pediatrics, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Gina Patel
- Nemours Cardiac Center, Nemours Children's Health, Wilmington, DE 19803, USA
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Mickiewicz L, Zahreddine R, Cormier K, Peries S, Del Bello A, Laffargue M, Smirnova NF. A minor tweak in transplant surgery protocols alters the cellular landscape of the arterial wall during transplant vasculopathy. FRONTIERS IN TRANSPLANTATION 2024; 3:1260125. [PMID: 38993774 PMCID: PMC11235260 DOI: 10.3389/frtra.2024.1260125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 04/02/2024] [Indexed: 07/13/2024]
Abstract
Introduction Transplant vasculopathy (TV) is a major complication after solid organ transplantation, distinguished by an arterial intimal thickening that obstructs the vascular lumen and leads to organ rejection. To date, TV remains largely untreatable, mainly because the processes involved in its development remain unclear. Aortic transplantation in mice, used to mimic TV, relies on highly variable experimental protocols, particularly regarding the type of anastomosis used to connect the donor aorta to the recipient. While the amount of trauma undergone by a vessel can dramatically affect the resulting pathology, the impact of the type of anastomosis on TV in mice has not been investigated in detail. Methods In this study, we compare the cellular composition of aortic grafts from BALB/C donor mice transplanted into C57BL/6J recipient mice using two different anastomosis strategies: sleeve and cuff. Results While both models recapitulated some aspects of human TV, there were striking differences in the cellular composition of the grafts. Indeed, aortic grafts from the cuff group displayed a larger coverage of the neointimal area by vascular smooth muscle cells compared to the sleeve group. Aortic grafts from the sleeve group contained higher amounts of T cells, while the cuff group displayed larger B-cell infiltrates. Discussion Together, these data indicate that a seemingly minor technical difference in transplant surgery protocols can largely impact the cellular composition of the graft, and thus the mechanisms underlying TV after aortic transplantation in mice.
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Affiliation(s)
- Laura Mickiewicz
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, University of Toulouse 3, Toulouse, France
| | - Rana Zahreddine
- CREFRE-Anexplo, Services Phénotypage et Microchirurgie, UMS006, INSERM, Université de Toulouse, UT3, ENVT, Toulouse, France
| | - Kévin Cormier
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, University of Toulouse 3, Toulouse, France
| | - Sophie Peries
- Center for Biological Ressources (Centres de Ressources Biologiques, CRB), IUCT Oncopole, Toulouse University Hospital (CHU de Toulouse), Toulouse, France
| | - Arnaud Del Bello
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, University of Toulouse 3, Toulouse, France
- Department of Nephrology and Organ Transplantation, Toulouse University Hospital (CHU de Toulouse), Toulouse, France
| | - Muriel Laffargue
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, University of Toulouse 3, Toulouse, France
| | - Natalia F Smirnova
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, University of Toulouse 3, Toulouse, France
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9
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Rajnochova Bloudickova S, Janek B, Machackova K, Hruba P. Standardized risk-stratified cardiac assessment and early posttransplant cardiovascular complications in kidney transplant recipients. Front Cardiovasc Med 2024; 11:1322176. [PMID: 38327495 PMCID: PMC10847279 DOI: 10.3389/fcvm.2024.1322176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 01/11/2024] [Indexed: 02/09/2024] Open
Abstract
Introduction Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in kidney transplant recipient (KTR). There is a dearth of standardized guidelines on optimal cardiovascular evaluation of transplant candidates. Methods This single-center cohort study aims to determine the effectiveness of our standardized risk-stratified pretransplant cardiovascular screening protocol, which includes coronary angiography (CAG), in identifying advanced CVD, the proper pretransplant management of which could lead to a reduction in the incidence of major cardiac events (MACE) in the early posttransplant period. Results Out of the total 776 KTR transplanted between 2017 and 2019, CAG was performed on 541 patients (69.7%), of whom 22.4% were found to have obstructive coronary artery disease (CAD). Asymptomatic obstructive CAD was observed in 70.2% of cases. In 73.6% of cases, CAG findings resulted in myocardial revascularization. MACE occurred in 5.6% (N = 44) of the 23 KTR with pretransplant CVD and 21 without pretransplant CVD. KTR with posttransplant MACE occurrence had significantly worse kidney graft function at the first year posttransplant (p = 0.00048) and worse patient survival rates (p = 0.0063) during the 3-year follow-up period compared with KTR without MACE. After adjustment, the independent significant factors for MACE were arrhythmia (HR 2.511, p = 0.02, 95% CI 1.158-5.444), pretransplant history of acute myocardial infarction (HR 0.201, p = 0.046, 95% CI 0.042-0.970), and pretransplant myocardial revascularization (HR 0.225, p = 0.045, 95% CI 0.052-0.939). Conclusion Asymptomatic CVD is largely prevalent in KTR. Posttransplant MACE has a negative effect on grafts and patient outcomes. Further research is needed to assess the benefits of pretransplant myocardial revascularization in asymptomatic kidney transplant candidates.
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Affiliation(s)
| | - Bronislav Janek
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Karolina Machackova
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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10
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Yoo D, Divard G, Raynaud M, Cohen A, Mone TD, Rosenthal JT, Bentall AJ, Stegall MD, Naesens M, Zhang H, Wang C, Gueguen J, Kamar N, Bouquegneau A, Batal I, Coley SM, Gill JS, Oppenheimer F, De Sousa-Amorim E, Kuypers DRJ, Durrbach A, Seron D, Rabant M, Van Huyen JPD, Campbell P, Shojai S, Mengel M, Bestard O, Basic-Jukic N, Jurić I, Boor P, Cornell LD, Alexander MP, Toby Coates P, Legendre C, Reese PP, Lefaucheur C, Aubert O, Loupy A. A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients. Nat Commun 2024; 15:554. [PMID: 38228634 PMCID: PMC10791605 DOI: 10.1038/s41467-023-44595-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 12/21/2023] [Indexed: 01/18/2024] Open
Abstract
In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.
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Affiliation(s)
- Daniel Yoo
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
| | - Gillian Divard
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Marc Raynaud
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
| | | | | | | | - Andrew J Bentall
- Division of Nephrology and Hypertension, Mayo Clinic Transplant Center, Rochester, MN, USA
| | | | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Huanxi Zhang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Changxi Wang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Juliette Gueguen
- Néphrologie-Immunologie Clinique, Hôpital Bretonneau, CHU Tours, Tours, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Paul Sabatier University, INSERM, Toulouse, France
| | - Antoine Bouquegneau
- Department of Nephrology-Dialysis-Transplantation, Centre hospitalier universitaire de Liège, Liège, Belgium
| | - Ibrahim Batal
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Shana M Coley
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - John S Gill
- Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Federico Oppenheimer
- Kidney Transplant Department, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain
| | - Erika De Sousa-Amorim
- Kidney Transplant Department, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain
| | - Dirk R J Kuypers
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Antoine Durrbach
- Department of Nephrology, AP-HP Hôpital Henri Mondor, Créteil, Île de France, France
| | - Daniel Seron
- Nephrology Department, Hospital Vall d'Hebrón, Autonomous University of Barcelona, Barcelona, Spain
| | - Marion Rabant
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Jean-Paul Duong Van Huyen
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Patricia Campbell
- Faculty of Medicine & Dentistry - Laboratory Medicine & Pathology Dept, University of Alberta, Edmonton, AB, Canada
| | - Soroush Shojai
- Faculty of Medicine & Dentistry - Laboratory Medicine & Pathology Dept, University of Alberta, Edmonton, AB, Canada
| | - Michael Mengel
- Faculty of Medicine & Dentistry - Laboratory Medicine & Pathology Dept, University of Alberta, Edmonton, AB, Canada
| | - Oriol Bestard
- Nephrology Department, Hospital Vall d'Hebrón, Autonomous University of Barcelona, Barcelona, Spain
| | - Nikolina Basic-Jukic
- Department of nephrology, arterial hypertension, dialysis and transplantation, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Ivana Jurić
- Department of nephrology, arterial hypertension, dialysis and transplantation, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Lynn D Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Mariam P Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - P Toby Coates
- Department of Renal and Transplantation, University of Adelaide, Royal Adelaide Hospital Campus, Adelaide, SA, Australia
| | - Christophe Legendre
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
- Department of Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Peter P Reese
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadephia, PA, USA
| | - Carmen Lefaucheur
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Olivier Aubert
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France
- Department of Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015, Paris, France.
- Department of Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
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11
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Kobashigawa J, Hall S, Shah P, Fine B, Halloran P, Jackson AM, Khush KK, Margulies KB, Sani MM, Patel JK, Patel N, Peyster E. The evolving use of biomarkers in heart transplantation: Consensus of an expert panel. Am J Transplant 2023; 23:727-735. [PMID: 36870390 PMCID: PMC10387364 DOI: 10.1016/j.ajt.2023.02.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
In heart transplantation, the use of biomarkers to detect the risk of rejection has been evolving. In this setting, it is becoming less clear as to what is the most reliable test or combination of tests to detect rejection and assess the state of the alloimmune response. Therefore, a virtual expert panel was organized in heart and kidney transplantation to evaluate emerging diagnostics and how they may be best utilized to monitor and manage transplant patients. This manuscript covers the heart content of the conference and is a work product of the American Society of Transplantation's Thoracic and Critical Care Community of Practice. This paper reviews currently available and emerging diagnostic assays and defines the unmet needs for biomarkers in heart transplantation. Highlights of the in-depth discussions among conference participants that led to development of consensus statements are included. This conference should serve as a platform to further build consensus within the heart transplant community regarding the optimal framework to implement biomarkers into management protocols and to improve biomarker development, validation and clinical utility. Ultimately, these biomarkers and novel diagnostics should improve outcomes and optimize quality of life for our transplant patients.
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Affiliation(s)
- Jon Kobashigawa
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA.
| | - Shelley Hall
- Department of Cardiology, Baylor University Medical Center, Dallas, Texas, USA
| | - Palak Shah
- Department of Cardiology, Inova Heart and Vascular Institute, Falls Church, Virginia, USA
| | - Barry Fine
- Department of Cardiology, Columbia University Irving Medical Center, New York, USA
| | - Phil Halloran
- Department of Medicine Division of Nephrology, University of Alberta, Edmonton, Canada
| | - Annette M Jackson
- Department of Surgery, Duke University, Durham, North Carolina, USA; Department of Immunology, Duke University, Durham, North Carolina, USA
| | - Kiran K Khush
- Department of Medicine, Stanford University, Stanford, California, USA
| | - Kenneth B Margulies
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maryam Mojarrad Sani
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA
| | - Jignesh K Patel
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA
| | - Nikhil Patel
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA
| | - Eliot Peyster
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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12
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Shimizu T, Omoto K, Inui M, Nozaki T, Takagi T, Ishida H. Clinicopathological Analyses of Chronic Renal Allograft Arteriopathy after Kidney Transplantation. Nephron Clin Pract 2023; 147 Suppl 1:22-27. [PMID: 37231866 DOI: 10.1159/000531177] [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: 12/05/2022] [Accepted: 05/15/2023] [Indexed: 05/27/2023] Open
Abstract
INTRODUCTION Herein, we discuss clinicopathological analyses of cases of chronic renal allograft arteriopathy (CRA) after renal transplantation and clarify the mechanisms underlying the development and prognostic significance of CRA. METHODS CRA was diagnosed in 34 renal allograft biopsy specimens (BSs) obtained from 27 renal transplant patients who were followed up at the Department of Urology and Transplant Surgery, Toda Chuo General Hospital, between January 2010 and December 2020. RESULTS CRA was diagnosed at a median of 33.4 months post-transplantation. Of the 27 patients, 16 had a history of rejection. Among the 34 BSs showing evidence of CRA, CRA was mild (cv1 in Banff's classification) in 22, moderate (cv2) in 7, and severe (cv3) in 5 patients. We then classified the 34 BSs showing evidence of CRA based on their overall histopathological features as follows: cv alone seen in 11 (32%) BSs, cv + antibody-mediated rejection (AMR) in 12 (35%), and cv + T-cell-mediated rejection (TCMR) in 8 (24%). Loss of the renal allograft occurred during the observation period in 3 patients (11%). Of the remaining patients with functioning grafts, deterioration of renal allograft function after biopsies occurred in 7 cases (26%). CONCLUSIONS Our study results suggest that AMR contributes to CRA in 30-40% of cases, TCMR in 20-30% of cases, isolated v lesions in 15% of cases, and cv lesions alone in 30%. The intimal arteritis was a prognostic factor in CRA.
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Affiliation(s)
- Tomokazu Shimizu
- Department of Transplant Surgery, Toda Chuo General Hospital, Saitama, Japan
- Department of Urology, Toda Chuo General Hospital, Saitama, Japan
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuya Omoto
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masashi Inui
- Department of Urology, Tokyo Women's Medical University, Yachiyo Medical Center, Chiba, Japan
| | - Taiji Nozaki
- Department of Urology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
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13
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Lund KP, Eriksson F, Pedersen BK, Sørensen SS, Bruunsgaard H. Pretransplant serum levels of endothelial cell activation markers are associated with graft loss and mortality after kidney transplantation. Scand J Immunol 2023; 97:e13225. [PMID: 36598149 PMCID: PMC10078193 DOI: 10.1111/sji.13225] [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: 05/27/2022] [Revised: 10/11/2022] [Accepted: 10/16/2022] [Indexed: 01/06/2023]
Abstract
Long-term allograft survival remains a challenge in kidney transplantation. In this study, we aimed to identify biomarkers for potentially modifiable pathways involved in the outcome of kidney transplantation. We tested the hypothesis that a pre-existing systemic environment with endothelial cell activation in the recipient is associated with the outcome after kidney transplantation. In a retrospective study cohort of 611 kidney transplanted patients, we investigated associations between serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) before transplantation and delayed graft function, acute rejection, graft loss and mortality after transplantation. We adjusted associations for age, sex, preformed donor-specific antibodies (DSA), pretransplant diabetes, cardiovascular disease and dialysis. Additionally, we investigated if associations between endothelial cell activation markers and outcomes differed in recipients with and without preformed DSA. Serum levels of endothelial cell activation markers were associated with delayed graft function and mortality but not with rejection. Additionally, high levels of sICAM-1 were associated with graft loss. Associations were most pronounced in recipients without DSA, adjusted for potential confounders. Data suggest that endothelial cell activation at the time of transplantation is associated with graft loss and mortality after kidney transplantation, especially in transplant candidates without preformed DSA.
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Affiliation(s)
- Kit Peiter Lund
- Department of Clinical Immunology 7631, University Hospital of Copenhagen - Rigshospitalet, Copenhagen, Denmark
| | - Frank Eriksson
- Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Bente Klarlund Pedersen
- Center of Inflammation and Metabolism and Centre for Physical Activity Research, University Hospital of Copenhagen - Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Søren Schwartz Sørensen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Department of Nephrology P, University Hospital of Copenhagen - Rigshospitalet, Copenhagen, Denmark
| | - Helle Bruunsgaard
- Department of Clinical Immunology 7631, University Hospital of Copenhagen - Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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14
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Symptomatic atherosclerotic vascular disease and graft survival in primary kidney transplant recipients – Observational analysis of the united network of organ sharing database. Transpl Immunol 2022; 75:101734. [DOI: 10.1016/j.trim.2022.101734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
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15
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Liu D, Ghani D, Wain J, Szeto WY, Laudanski K. Concomitant elevated serum levels of tenascin, MMP-9 and YKL-40, suggest ongoing remodeling of the heart up to 3 months after cardiac surgery after normalization of the revascularization markers. Eur J Med Res 2022; 27:208. [PMID: 36271425 PMCID: PMC9585873 DOI: 10.1186/s40001-022-00831-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/24/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The recovery from cardiac surgery involves resolving inflammation and remodeling with significant connective tissue turnover. Dynamics of smoldering inflammation and injury (white blood cells, platelets, CRP, IL-8, IL-6), vascular inflammation (IL-15, VEGF, RANTES), connective tissue remodeling (tenascin, MMP-9), cardiac injury and remodeling (YKL-40), and vascular remodeling (epiregulin, MCP-1, VEGF) were assessed up to 3 months after cardiac surgery. We hypothesize that at 3 months, studied markers will return to pre-surgical levels. METHODS Patients (n = 139) scheduled for non-emergent heart surgery were included, except for patients with pre-existing immunological aberrancies. Blood was collected before surgery(tbaseline), 24 h later(t24h) after the first sample, 7 days(t7d), and 3 months(t3m) after tbaseline. Serum markers were measured via multiplex or ELISA. Electronic medical records (EMR) were used to extract demographical, pre-existing conditions and clinical data. Disposition (discharge home, discharge to facility, death, re-admission) was determined at 28 days and 3 months from admission. RESULTS Not all inflammatory markers returned to baseline (CRP↑↑, leukocytosis, thrombocytosis, IL-8↓, IL-6↓). Tenascin and YKL-40 levels remained elevated even at t3m. YKL-40 serum levels were significantly elevated at t24h and t7d while normalized at t3m. VEGF returned to the baseline, yet MCP-1 remained elevated at 3 months. CCL28 increased at 3 months, while RANTES and IL-15 declined at the same time. Disposition at discharge was determined by serum MMP-9, while YKL-40 correlated with duration of surgery and APACHE II24h. CONCLUSIONS The data demonstrated an ongoing extracellular matrix turnover at 3 months, while acute inflammation and vascular remodeling resolved only partially.
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Affiliation(s)
- Da Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Danyal Ghani
- College of Art and Sciences, Drexel University, Philadelphia, PA, USA
| | - Justin Wain
- Campbell University School of Osteopathic Medicine, Buies Creek, NC, USA
| | - Wilson Y Szeto
- Department of Cardiac Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Krzysztof Laudanski
- Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, USA. .,Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. .,Leonard Davis Institute for Health Economics, University of Pennsylvania, JMB 127, 3620 Hamilton Walk, Philadelphia, PA, 19146, USA.
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16
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Garg S, Raval AN, Hansen KE, Zhong W, Huang Y, Smith M, Panzer SE, Bartels CM. Association of Renal Arteriosclerosis With Atherosclerotic Cardiovascular Disease Risk in Lupus Nephritis. Arthritis Care Res (Hoboken) 2022; 74:1105-1112. [PMID: 33421305 PMCID: PMC10637686 DOI: 10.1002/acr.24552] [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: 08/13/2020] [Revised: 12/16/2020] [Accepted: 01/05/2021] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Lupus nephritis (LN) predicts a 9-fold higher atherosclerosis cardiovascular disease (ASCVD) risk, highlighting the urgent need to target ASCVD prevention. Studies in IgA nephropathy reported that severe renal arteriosclerosis (r-ASCL) in diagnostic biopsies strongly predicted ASCVD risk. We recently found that 50% of LN pathology reports overlooked r-ASCL reporting, which could explain prior negative LN ASCVD risk studies. The present study was undertaken to examine associations between a composite of reported and overread r-ASCL and ASCVD events in LN. METHODS Data were abstracted from all LN patients who underwent diagnostic biopsy between 1994 and 2017, including demographic information, ASCVD risk factors, and pathology reports at the time of LN diagnosis. We manually validated all incident ASCVD events. We overread 25% of the biopsies to grade r-ASCL using the Banff criteria. We supplemented the overread r-ASCL grade, when available, to determine the composite of reported and overread r-ASCL grade. RESULTS Among 189 incident LN patients, 78% were female, 73% White, and the median age was 25 years. Overall, 31% had any reported r-ASCL, and 7% had moderate-to-severe r-ASCL. After incorporating systematically re-examined r-ASCL grade, the prevalence of any and moderate-to-severe r-ASCL increased to 39% and 12%, respectively. We found 22 incident ASCVD events over 11 years of follow-up. Using a composite of reported and overread r-ASCL grade, we found that severe r-ASCL in diagnostic LN biopsies was associated with 9-fold higher odds of ASCVD. CONCLUSION Severe r-ASCL can predict ASCVD in LN; therefore, larger studies are required to systematically report r-ASCL and examine ASCVD associations.
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Affiliation(s)
| | | | | | | | - Yabing Huang
- RenMin Hospital of Wuhan University, Hubei, China
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17
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Gowrishankar S. Banff classification from 1991 to 2019. A significant contribution to our understanding and reporting of allograft renal biopsies. Indian J Nephrol 2022; 32:1-7. [PMID: 35283563 PMCID: PMC8916159 DOI: 10.4103/ijn.ijn_270_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/04/2020] [Accepted: 10/09/2020] [Indexed: 11/05/2022] Open
Abstract
The Banff schema of classification of renal allograft biopsies, first proposed at the meeting in Banff, Canada in 1991 has evolved through subsequent meetings held once in two years and is the internationally accepted scheme of classification which is consensual, current, validated and in clinical use. This review traces the evolution of the classification and our understanding of renal transplant pathology, with emphasis on alloimmune reactions. The proceedings of the meetings and the important studies which have shaped the classification are covered.
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18
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Loupy A, Mengel M, Haas M. 30 years of the International Banff Classification for Allograft Pathology: The Past, Present and Future of Kidney Transplant Diagnostics. Kidney Int 2021; 101:678-691. [DOI: 10.1016/j.kint.2021.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/06/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
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19
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Chronic Rejection and Atherosclerosis in Post-Transplant Cardiovascular Mortality: Two Sides of the Same Coin. Heart Lung Circ 2021; 31:162-166. [PMID: 34848149 DOI: 10.1016/j.hlc.2021.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/05/2021] [Accepted: 09/09/2021] [Indexed: 11/22/2022]
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20
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Ponticelli C, Campise MR. The inflammatory state is a risk factor for cardiovascular disease and graft fibrosis in kidney transplantation. Kidney Int 2021; 100:536-545. [PMID: 33932457 DOI: 10.1016/j.kint.2021.04.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/07/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023]
Abstract
Several factors, such as donor brain death, ischemia-reperfusion injury, rejection, infection, and chronic allograft dysfunction, may induce an inflammatory state in kidney transplantation. Furthermore, inflammatory cells, cytokines, growth factors, complement and coagulation cascade create an unbalanced interaction with innate and adaptive immunity, which are both heavily involved in atherogenesis. The crosstalk between inflammation and thrombosis may lead to a prothrombotic state and impaired fibrinolysis in kidney transplant recipients increasing the risk of cardiovascular disease. Inflammation is also associated with elevated levels of fibroblast growth factor 23 and low levels of Klotho, which contribute to major adverse cardiovascular events. Hyperuricemia, glucose intolerance, arterial hypertension, dyslipidemia, and physical inactivity may create a condition called metaflammation that concurs in atherogenesis. Another major consequence of the inflammatory state is the development of chronic hypoxia that through the mediation of interleukins 1 and 6, angiotensin II, and transforming growth factor beta can result in excessive accumulation of extracellular matrix, which can disrupt and replace functional parenchyma, leading to interstitial fibrosis and chronic allograft dysfunction. Lifestyle and regular physical activity may reduce inflammation. Several drugs have been proposed to control the graft inflammatory state, including low-dose aspirin, statins, renin-angiotensin inhibitors, xanthine-oxidase inhibitors, vitamin D supplements, and interleukin-6 blockade. However, no prospective controlled trial with these measures has been conducted in kidney transplantation.
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Affiliation(s)
- Claudio Ponticelli
- Division of Nephrology, Ospedale Maggiore Policlinico, Milano, Italy (retired).
| | - Maria Rosaria Campise
- Division of Nephrology and Dialysis, Ca' Granda Foundation, Scientific Institute Ospedale Maggiore Policlinico di Milano, Milano, Italy
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21
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Garg S, Bartels CM, Hansen KE, Zhong W, Huang Y, Semanik MG, Smith M, Panzer SE. High Burden of Premature Arteriosclerosis on Renal Biopsy Results in Incident Lupus Nephritis. Arthritis Care Res (Hoboken) 2021; 73:394-401. [PMID: 31909878 DOI: 10.1002/acr.24138] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 12/31/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Cardiovascular disease (CVD) is accelerated in patients with systemic lupus erythematosus and lupus nephritis (LN). Despite the literature suggesting that renal arteriosclerosis predicts CVD in other glomerulonephritis diseases, arteriosclerosis grading and reporting might be particularly overlooked in LN biopsies. Our objective was to examine the burden of renal arteriosclerosis in LN and to assess whether arteriosclerosis is underreported in LN biopsies. METHODS We identified all patients with LN undergoing kidney biopsy between 1994 and 2017 at an academic center. We interpreted LN biopsy reports to classify the Banff categories of absent, mild, moderate, or severe renal arteriosclerosis. The prevalence of renal arteriosclerosis was compared with the prevalence published for age-matched healthy peers, and predictors of arteriosclerosis were examined. We overread biopsies for Banff renal arteriosclerosis grading and compared to pathology reports. RESULTS Among 189 incident patients with LN, renal arteriosclerosis prevalence was 2 decades earlier compared to their healthy peers, affecting 40% of patients ages 31-39 years with LN compared to 44% of healthy peers ages 50-59 years. A multivariable analysis showed a 3-fold higher odds of renal arteriosclerosis in patients ages ≥30 years with LN. LN chronicity on biopsy results predicted a 4-fold higher odds of renal arteriosclerosis. The overreads determined that 50% of standard LN biopsy reports missed reporting the presence or absence of renal arteriosclerosis. CONCLUSION Renal arteriosclerosis is accelerated by 2 decades in patients with LN compared to their healthy peers and is overlooked by pathologists in half of the routine biopsy reports. We propose incorporating Banff renal arteriosclerosis grading in all LN biopsy reports.
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Affiliation(s)
| | | | | | | | - Yabing Huang
- RenMin Hospital of Wuhan University, Wuhan, China
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22
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De Vusser K, Martens D, Lerut E, Kuypers D, Nawrot TS, Naesens M. Replicative senescence and arteriosclerosis after kidney transplantation. Nephrol Dial Transplant 2021; 35:1984-1995. [PMID: 33067610 DOI: 10.1093/ndt/gfaa151] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 04/24/2020] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Replicative senescence is associated with telomere shortening. In native kidneys, obtained prior to transplantation, we recently described and validated a significant association between shorter intrarenal telomere length and renal arteriosclerosis. After renal transplantation, animal experiments suggested that ischaemia-reperfusion injury, acute rejection episodes and cytomegalovirus disease associate with accelerated renal allograft senescence. The association between post-transplant events and replicative senescence has not yet been evaluated in a human setting. METHODS In a cohort of 134 kidney allograft recipients, we performed protocol-specified renal allograft biopsies at 3 months, 1 year, 2 years and 5 years after transplantation (n = 579 biopsies). We used quantitative real-time polymerase chain reaction to measure intrarenal relative average telomere length (T/S ratio). The association between donor and recipient demographic factors, post-transplant clinical/histological events, renal allograft histological evolution by 5 years post-transplant and intrarenal telomere length at 5 years after transplantation was studied using multiple regression models. RESULTS At 5 years after transplantation, shorter intrarenal telomere length was associated with male donor gender, older donor age, donor history of hypertension and donor cardiovascular risk, which confirms the associations observed in native kidneys. Recipient characteristics and post-transplant events like delayed graft function, acute rejection episodes, presence of donor-specific antibodies, cytomegalovirus disease and immunosuppressive regimen did not associate with alterations of intrarenal telomere length at 5 years. Independent of donor age and donor cardiovascular risk, intrarenal arteriosclerosis in protocol biopsies obtained at 5 years after transplantation and progressive arteriosclerosis over time after transplantation associated with shorter telomere length, while this was not the case for other histological lesions. Moreover, telomere attrition augments the association between older donor age and the presence of severe arteriosclerosis. In the group with the oldest donor age and shortest telomere length, there was significantly more severe arteriosclerosis (43%) in protocol biopsies at 5 years after transplantation, compared with other combinations (13-28%) (P = 0.001). Intrarenal arteriosclerosis at 5 years after transplantation did not associate with post-transplant clinical events. CONCLUSIONS We demonstrate that intrarenal telomere length at 5 years after transplantation, as a marker for replicative senescence, associates with renal arteriosclerosis and reflects kidney donor characteristics, but not post-transplant events.
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Affiliation(s)
- Katrien De Vusser
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dries Martens
- Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Evelyne Lerut
- Department of Imaging and Pathology, KU Leuven - University of Leuven, Leuven, Belgium.,Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Tim S Nawrot
- Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.,Department of Public Health and Primary Care, KU Leuven - University of Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
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23
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Wei X, Valenzuela NM, Rossetti M, Sosa RA, Nevarez-Mejia J, Fishbein GA, Mulder A, Dhar J, Keslar KS, Baldwin WM, Fairchild RL, Hou J, Reed EF. Antibody-induced vascular inflammation skews infiltrating macrophages to a novel remodeling phenotype in a model of transplant rejection. Am J Transplant 2020; 20:2686-2702. [PMID: 32320528 PMCID: PMC7529968 DOI: 10.1111/ajt.15934] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/15/2020] [Accepted: 04/07/2020] [Indexed: 01/25/2023]
Abstract
HLA donor-specific antibodies (DSAs) binding to vascular endothelial cells of the allograft trigger inflammation, vessel injury, and antibody-mediated rejection (AMR). Accumulation of intragraft-recipient macrophages is a histological characteristic of AMR, which portends worse outcome. HLA class I (HLA I) DSAs enhance monocyte recruitment by activating endothelial cells and engaging FcγRs, but the DSA-activated donor endothelial influence on macrophage differentiation is unknown. In this study, we explored the consequence of DSA-activated endothelium on infiltrating monocyte differentiation. Here we show that cardiac allografts from murine recipients treated with MHC I DSA upregulated genes related to monocyte transmigration and Fc receptor stimulation. Human monocytes co-cultured with HLA I IgG-stimulated primary human endothelium promoted monocyte differentiation into CD68+ CD206+ CD163+ macrophages (M(HLA I IgG)), whereas HLA I F(ab')2 stimulated endothelium solely induced higher CD206 (M(HLA I F(ab')2 )). Both macrophage subtypes exhibited significant changes in discrete cytokines/chemokines and unique gene expression profiles. Cross-comparison of gene transcripts between murine DSA-treated cardiac allografts and human co-cultured macrophages identified overlapping genes. These findings uncover the role of HLA I DSA-activated endothelium in monocyte differentiation, and point to a novel, remodeling phenotype of infiltrating macrophages that may contribute to vascular injury.
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Affiliation(s)
- Xuedong Wei
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Nicole M. Valenzuela
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Jessica Nevarez-Mejia
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Gregory A. Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Arend Mulder
- Department of Immunohaematology and Bloodtransfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Jayeeta Dhar
- Lerner Research Institute and Transplant Center, Cleveland Clinic, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Karen S. Keslar
- Lerner Research Institute and Transplant Center, Cleveland Clinic, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - William M. Baldwin
- Lerner Research Institute and Transplant Center, Cleveland Clinic, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Robert L. Fairchild
- Lerner Research Institute and Transplant Center, Cleveland Clinic, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Jianquan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
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24
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Loupy A, Coutance G, Bonnet G, Van Keer J, Raynaud M, Aubert O, Bories MC, Racapé M, Yoo D, Duong Van Huyen JP, Bruneval P, Taupin JL, Lefaucheur C, Varnous S, Leprince P, Guillemain R, Empana JP, Levine R, Naesens M, Patel JK, Jouven X, Kobashigawa J. Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy After Heart Transplantation: A Population-Based Study. Circulation 2020; 141:1954-1967. [PMID: 32363949 DOI: 10.1161/circulationaha.119.044924] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development. METHODS Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality. RESULTS A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age (P<0.001), donor male sex (P<0.001), donor tobacco consumption (P=0.001), recipient dyslipidemia (P=0.009), class II anti-human leukocyte antigen donor-specific antibodies (P=0.004), and acute cellular rejection ≥2R (P=0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality (P<0.001). CONCLUSIONS In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.
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Affiliation(s)
- Alexandre Loupy
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Kidney Transplant Department (A.L., O.A.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Guillaume Coutance
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.)
| | - Guillaume Bonnet
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jan Van Keer
- Departments of Cardiology (J.V.K.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium
| | - Marc Raynaud
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | - Olivier Aubert
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Kidney Transplant Department (A.L., O.A.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Marie-Cécile Bories
- Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Maud Racapé
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | - Daniel Yoo
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | | | - Patrick Bruneval
- Pathology Department (P.B.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jean-Luc Taupin
- Laboratory of Immunology and Histocompatibility, AP-HP, Saint Louis Hospital, Paris, France (J.-L.T.)
| | - Carmen Lefaucheur
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | - Shaida Varnous
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.).,INSERM, UMRS 1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France (S.V., P.L.)
| | - Pascal Leprince
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.).,INSERM, UMRS 1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France (S.V., P.L.)
| | - Romain Guillemain
- Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jean-Philippe Empana
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Ryan Levine
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.)
| | - Maarten Naesens
- Microbiology, Immunology, and Transplantation and of Nephrology(M.N.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium.,Renal Transplantation (M.N.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium
| | - Jigneh K Patel
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.)
| | - Xavier Jouven
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jon Kobashigawa
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.)
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25
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Malfait T, Emonds MP, Daniëls L, Nagler EV, Van Biesen W, Van Laecke S. HLA Class II Antibodies at the Time of Kidney Transplantation and Cardiovascular Outcome: A Retrospective Cohort Study. Transplantation 2020; 104:823-834. [DOI: 10.1097/tp.0000000000002889] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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26
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Van Laecke S, Abramowicz D. Cardiovascular disease in kidney transplant recipients: leave no stone unturned. Nephrol Dial Transplant 2020; 34:727-730. [PMID: 31062030 DOI: 10.1093/ndt/gfz084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Indexed: 12/25/2022] Open
Affiliation(s)
- Steven Van Laecke
- Department of Internal Medicine, Renal Division, University Hospital Ghent, Ghent, Belgium
| | - Daniel Abramowicz
- Department of Nephrology and Hypertension, University Hospital Antwerp, Edegem, Belgium
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27
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Sgambat K, Clauss S, Moudgil A. Circulating de novo Donor Specific Antibodies and Carotid Intima-media Thickness in Pediatric Kidney Transplant Recipients, A Pilot Study. Front Pediatr 2020; 8:17. [PMID: 32083044 PMCID: PMC7006029 DOI: 10.3389/fped.2020.00017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background: The presence of circulating de novo donor specific anti-HLA antibodies (dnDSA) has been implicated in an immune-mediated form of accelerated systemic arteriosclerosis in adult heart and kidney transplant recipients, however this has not been previously investigated in pediatric kidney transplant recipients. Carotid intima-media thickness (CIMT) is a reliable method for detection of arteriosclerosis. We hypothesized that children who develop dnDSA after kidney transplant would have increased CIMT compared with those who remain dnDSA negative. Methods: A prospective, controlled pilot cohort study of 38 transplant patients and 20 healthy controls was conducted to investigate the association between CIMT and development of dnDSA after kidney transplant. CIMT, anthropometrics, blood pressure and lipid panel were measured at 1, 18, and 30 months post-transplant. DSA was checked at 6, 12, 18, 24 and 30 months post-transplant. CIMT of DSA positive transplant recipients was compared to DSA negative and controls. Results: Of the 38 transplant recipients, 7 patients developed dnDSA by 18-30 months post-transplant. Among 5 dnDSA positive patients who did not receive treatment for DSA prior to CIMT measurement (n=6 observations), the median CIMT was 0.505 mm (95% CI 0.454-0.560 mm) at 18-30 months post-transplant, compared to 0.455 mm (95% CI 0.440-0.470) in DSA negative transplant recipients (n = 54 observations of 30 patients) and 0.450 mm (95% CI 0.436-0.460) in the healthy controls (20 observations of 20 patients). Presence of dnDSA was independently associated with a 7.8% increase in CIMT compared to those without dnDSA (p=0.006), after adjusting for race, hypertension, dyslipidemia, and abdominal obesity. Conclusions: Development of dnDSA was associated with increased CIMT, an indicator of arteriosclerosis, in a cohort of dnDSA positive pediatric kidney transplant recipients. The association between dnDSA and CIMT was independent of traditional CV risk factors, including hypertension, dyslipidemia, and abdominal obesity.
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Affiliation(s)
- Kristen Sgambat
- Department of Nephrology, Children's National Hospital, Washington, DC, United States
| | - Sarah Clauss
- Department of Cardiology, Children's National Hospital, Washington, DC, United States
| | - Asha Moudgil
- Department of Nephrology, Children's National Hospital, Washington, DC, United States
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28
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Goldenberg I, Huang DT, Nielsen JC. The role of implantable cardioverter-defibrillators and sudden cardiac death prevention: indications, device selection, and outcome. Eur Heart J 2019; 41:2003-2011. [DOI: 10.1093/eurheartj/ehz788] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/09/2019] [Accepted: 10/26/2019] [Indexed: 12/31/2022] Open
Abstract
Abstract
Multiple randomized multicentre clinical trials have established the role of the implantable cardioverter-defibrillator (ICD) as the mainstay in the treatment of ventricular tachyarrhythmias and sudden cardiac death (SCD) prevention. These trials have focused mainly on heart failure patients with advanced left ventricular dysfunction and were mostly conducted two decades ago, whereas a more recent trial has provided conflicting results. Therefore, much remains to be determined on how best to balance the identification of patients at high risk of SCD together with who would benefit most from ICD implantation in a contemporary setting. Implantable cardioverter-defibrillators have also evolved from the simple, defibrillation-only devices implanted surgically to more advanced technologies of multi-chamber devices, with physiologic bradycardic pacing, including cardiac resynchronization therapy, atrial and ventricular therapeutic pacing algorithms, and subcutaneous ICDs. These multiple options necessitate individualized approach to device selection and programming. This review will focus on the current knowledge on selection of patients for ICD treatment, device selection and programming, and future directions of implantable device therapy for SCD prevention.
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Affiliation(s)
- Ilan Goldenberg
- Division of Cardiology, Department of Medicine, The Clinical Cardiovascular Research Center, University of Rochester Medical Center, 265 Crittenden Blvd CU 420653, Rochester, NY 14642, USA
| | - David T Huang
- Division of Cardiology, Department of Medicine, The Clinical Cardiovascular Research Center, University of Rochester Medical Center, 265 Crittenden Blvd CU 420653, Rochester, NY 14642, USA
| | - Jens Cosedis Nielsen
- Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark
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29
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Crossing low-level donor-specific antibodies in heart transplantation. Curr Opin Organ Transplant 2019; 24:227-232. [DOI: 10.1097/mot.0000000000000628] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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30
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Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation. Transplantation 2018; 102:688-698. [PMID: 29135832 DOI: 10.1097/tp.0000000000002002] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown. METHODS We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment. RESULTS Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect. CONCLUSION The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.
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31
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Van Laecke S, Malfait T, Schepers E, Van Biesen W. Cardiovascular disease after transplantation: an emerging role of the immune system. Transpl Int 2018; 31:689-699. [PMID: 29611220 DOI: 10.1111/tri.13160] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 02/12/2018] [Accepted: 03/22/2018] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease (CVD) after transplantation remains a major concern. Little is known about what drives the increased cardiovascular risk in transplant recipients apart from traditional risk factors. The immune system is involved in the pathogenesis of hypertension, atherosclerosis, and coronary artery disease in the general population. Recently, inhibition of interleukin 1 - β by canakinumab versus placebo decreased the incidence of cardiovascular events. Emerging evidence points to a role of adaptive cellular immunity in the development of CVD. Especially, expansion of pro-inflammatory and antiapoptotic cytotoxic CD4+ CD28null T cells is closely associated with incident CVD in various study populations including transplant recipients. The association of cytomegalovirus exposure with increased cardiovascular mortality might be explained by its capacity to upregulate these cytotoxic cells. Also, humoral immunity seems to be relevant for cardiovascular outcome in transplant recipients. Panel-reactive antibodies at baseline and donor-specific antibodies are independently associated with poor cardiovascular outcome after kidney transplantation. Cardiovascular effects of immunosuppressive drugs and statins do not only imply indirect positive or negative effects on traditional cardiovascular risk factors but also intrinsic immunological effects. How immunosuppressive drugs modify atherosclerosis largely remains elusive.
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Affiliation(s)
| | - Thomas Malfait
- Renal Division, Ghent University Hospital, Ghent, Belgium
| | - Eva Schepers
- Renal Division, Ghent University Hospital, Ghent, Belgium
| | - Wim Van Biesen
- Renal Division, Ghent University Hospital, Ghent, Belgium
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32
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Malheiro J, Santos S, Tafulo S, Dias L, Martins LS, Fonseca I, Almeida M, Pedroso S, Beirão I, Castro-Henriques A, Cabrita A. Correlations between donor-specific antibodies and non-adherence with chronic active antibody-mediated rejection phenotypes and their impact on kidney graft survival. Hum Immunol 2018; 79:413-423. [PMID: 29577962 DOI: 10.1016/j.humimm.2018.03.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/20/2018] [Accepted: 03/21/2018] [Indexed: 11/30/2022]
Abstract
Chronic-active antibody-mediated rejection (CAABMR) is associated with poor kidney graft survival and has no clear effective treatment. Forty-one cases of CAABMR were detected in indication graft biopsies and evaluated according to current Banff classification. We investigated the impact of concurrent donor-specific antibodies (DSA) and their characteristics, together with non-adherence regarding immunosuppression on CAABMR histopathological phenotypes and prognosis. Twenty-four (59%) patients had detectable DSA at biopsy, with 15 of them being considered non-adherent. Graft function at biopsy was similar in DSA (+) and (-) patients. DSA (+) patients had significantly higher tubulointerstitial inflammation (i and ti) and acute humoral (g+ptc+v+C4d) composite score than DSA (-). DSA (+)/non-adherent cases presented additionally with increased microvascular inflammation (ptc and v), besides having a distinctively lower ah score. C1q DSA strength was higher (P = .046) in non-adherent patients and correlated closely with C4d score (P = .002). Lower graft function and ah score, higher proteinuria and ci + ct score, and, separately per each model, DSA (+) (HR = 2.446, P = .034), DSA (+)/non-adherent (HR = 3.657, P = .005) and DSA (+)/C1q (+) (HR = 4.831, P = .003) status were independent predictors of graft failure. CAABMR with concomitant DSA pose a higher risk of graft failure. Adherence should be evaluated, and histopathological phenotyping and DSA characterization may add critical information.
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Affiliation(s)
- Jorge Malheiro
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Porto, Portugal.
| | - Sofia Santos
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal
| | - Sandra Tafulo
- Centro do Sangue e Transplantação do Porto, Portugal
| | - Leonídio Dias
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal
| | - La Salete Martins
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Porto, Portugal
| | - Isabel Fonseca
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Porto, Portugal
| | - Manuela Almeida
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Porto, Portugal
| | - Sofia Pedroso
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal
| | - Idalina Beirão
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Porto, Portugal
| | - António Castro-Henriques
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Investigation in Biomedicine (UMIB), Porto, Portugal
| | - António Cabrita
- Nephrology and Kidney Transplantation Department, Hospital de Santo António, Centro Hospitalar do Porto, Portugal
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Abstract
Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient's immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.
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Affiliation(s)
- Rubin Zhang
- Section of Nephrology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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34
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Evidence for an important role of both complement-binding and noncomplement-binding donor-specific antibodies in renal transplantation. Curr Opin Organ Transplant 2017; 21:433-40. [PMID: 27348472 DOI: 10.1097/mot.0000000000000324] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW The review describes the current clinical relevance of circulating anti-human leukocyte antigen (anti-HLA) antibodies in kidney transplantation and discusses recent improvements in their characterization that provide new insights into the identification and management of important clinical outcomes. RECENT FINDINGS Recent studies addressing the relationships between donor-specific anti-HLA antibody (HLA-DSA) properties (i.e., their strength, complement-binding capacity, and IgG subclass composition) and allograft injury and survival have highlighted their relevance in the prediction of antibody-mediated injury and allograft loss. SUMMARY Antibody-mediated rejection is the leading cause of kidney allograft loss. Although considerable experimental and clinical evidence suggests a causal effect of circulating HLA-DSAs in antibody-mediated rejection and allograft failure, HLA-DSAs induce a wide spectrum of injuries to the allograft that illustrate the need to delineate the characteristics of HLA-DSAs that confer pathogenesis. Current risk stratification is based on HLA-DSA characteristics, including antibody specificity, HLA class, and strength. Recently, the complement-binding capacity of HLA-DSAs has been recognized as a clinically relevant marker for predicting pathogenicity and allograft loss. Emerging data also support a role for HLA-DSA IgG subclass composition in discriminating distinct patterns of antibody-mediated injury. This progress in our understanding of HLA-DSA pathogenicity provides new tools to stratify individual immunological risks. However, specific prospective studies addressing immunological risk stratification in large and unselected populations are required to define the clinical benefit and cost-effectiveness of such a comprehensive assessment of HLA-DSAs before implementation in current clinical practice.
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35
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Halloran PF, Potena L, Van Huyen JPD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A. Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System. J Heart Lung Transplant 2017; 36:1192-1200. [DOI: 10.1016/j.healun.2017.05.029] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 05/25/2017] [Accepted: 05/26/2017] [Indexed: 01/08/2023] Open
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Long-term Outcomes of Kidney Transplantation in Patients With High Levels of Preformed DSA: The Necker High-Risk Transplant Program. Transplantation 2017; 101:2440-2448. [PMID: 28114171 DOI: 10.1097/tp.0000000000001650] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required. METHODS Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization. RESULTS The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively. CONCLUSIONS These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.
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Van Loon E, Lerut E, Naesens M. The time dependency of renal allograft histology. Transpl Int 2017; 30:1081-1091. [DOI: 10.1111/tri.13042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/05/2017] [Accepted: 08/21/2017] [Indexed: 01/27/2023]
Affiliation(s)
- Elisabet Van Loon
- Laboratory of Nephrology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
- Department of Nephrology and Renal Transplantation; University Hospitals Leuven; Leuven Belgium
| | - Evelyne Lerut
- Translational Cell and Tissue Research; Department of Imaging and Pathology; KU Leuven; Leuven Belgium
- Department of Morphology and Molecular Pathology; University Hospitals Leuven; Leuven Belgium
| | - Maarten Naesens
- Laboratory of Nephrology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
- Department of Nephrology and Renal Transplantation; University Hospitals Leuven; Leuven Belgium
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Gosset C, Viglietti D, Rabant M, Vérine J, Aubert O, Glotz D, Legendre C, Taupin JL, Duong Van-Huyen JP, Loupy A, Lefaucheur C. Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis. Kidney Int 2017; 92:729-742. [DOI: 10.1016/j.kint.2017.03.033] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 02/21/2017] [Accepted: 03/16/2017] [Indexed: 11/24/2022]
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Katsuma A, Yamakawa T, Nakada Y, Yamamoto I, Yokoo T. Histopathological findings in transplanted kidneys. RENAL REPLACEMENT THERAPY 2017. [DOI: 10.1186/s41100-016-0089-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
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Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am J Transplant 2017; 17:28-41. [PMID: 27862883 PMCID: PMC5363228 DOI: 10.1111/ajt.14107] [Citation(s) in RCA: 506] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 10/25/2016] [Accepted: 10/28/2016] [Indexed: 01/25/2023]
Abstract
The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.
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Current pathological perspectives on chronic rejection in renal allografts. Clin Exp Nephrol 2016; 21:943-951. [PMID: 27848058 DOI: 10.1007/s10157-016-1361-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 11/08/2016] [Indexed: 01/22/2023]
Abstract
Chronic rejection in renal transplantation clinically manifests as slow deterioration in allograft function and is a major contributor of late renal graft loss. Most cases of chronic rejection involve chronic antibody-mediated rejection (ABMR) triggered by the interaction of donor-specific alloantibodies with endothelial cells of the microcirculation. The evolution of the Banff classification involved a major revision of the ABMR criteria during the 2000s and led to the inclusion of detailed pathological characteristics of chronic ABMR in the 2013 Banff scheme, including microcirculation damage observed as newly formed basement membranes and arterial fibrous intimal proliferation. Inflammation of microvasculature including glomeruli and/or peritubular capillaries is also seen in substantial cases of chronic ABMR, defined as chronic active ABMR. Chronic active T cell-mediated rejection (TCMR) results from chronic T cell-mediated injury involving renal arteries but is less characterized under the current Banff classification, mainly due to the expanding histological criteria of chronic active ABMR. Characteristics shared by these two chronic rejection types can potentially cause diagnostic confusion. Hence, the diagnostic criteria or categories of chronic renal rejection require amendment of the current Banff classification. Assessment of rejection cases with molecular phenotyping advanced the mechanistic understanding of various dysfunctions in renal allograft, including ABMR and TCMR. Identification of disease-specific changes in gene expression by immunohistological studies, especially in chronic ABMR, has already been validated by several studies, warranting potential application to the pathological diagnostic process. This review provides an overview of current pathological perspectives on chronic rejection of renal allografts and future directions.
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Williams R, The Editors. Circulation Research “In This Issue” Anthology. Circ Res 2016. [DOI: 10.1161/res.0000000000000108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Dragun D, Catar R, Philippe A. Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity. Kidney Int 2016; 90:280-288. [PMID: 27188505 DOI: 10.1016/j.kint.2016.03.019] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/12/2016] [Accepted: 03/17/2016] [Indexed: 12/17/2022]
Abstract
Detrimental actions of donor-specific antibodies (DSAs) directed against both major histocompatibility antigens (human leukocyte antigen [HLA]) and specific non-HLA antigens expressed on the allograft endothelium are a flourishing research area in kidney transplantation. Newly developed solid-phase assays enabling detection of functional non-HLA antibodies targeting G protein-coupled receptors such as angiotensin type I receptor and endothelin type A receptor were instrumental in providing long-awaited confirmation of their broad clinical relevance. Numerous recent clinical studies implicate angiotensin type I receptor and endothelin type A receptor antibodies as prognostic biomarkers for earlier occurrence and severity of acute and chronic immunologic complications in solid organ transplantation, stem cell transplantation, and systemic autoimmune vascular disease. Angiotensin type 1 receptor and endothelin type A receptor antibodies exert their pathophysiologic effects alone and in synergy with HLA-DSA. Recently identified antiperlecan antibodies are also implicated in accelerated allograft vascular pathology. In parallel, protein array technology platforms enabled recognition of new endothelial surface antigens implicated in endothelial cell activation. Upon target antigen recognition, non-HLA antibodies act as powerful inducers of phenotypic perturbations in endothelial cells via activation of distinct intracellular cell-signaling cascades. Comprehensive diagnostic assessment strategies focusing on both HLA-DSA and non-HLA antibody responses could substantially improve immunologic risk stratification before transplantation, help to better define subphenotypes of antibody-mediated rejection, and lead to timely initiation of targeted therapies. Better understanding of similarities and dissimilarities in HLA-DSA and distinct non-HLA antibody-related mechanisms of endothelial damage should facilitate discovery of common downstream signaling targets and pave the way for the development of endothelium-centered therapeutic strategies to accompany intensified immunosuppression and/or mechanical removal of antibodies.
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Affiliation(s)
- Duska Dragun
- Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany.
| | - Rusan Catar
- Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany
| | - Aurélie Philippe
- Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany
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Ravindranath MH, Jucaud V, Maehara CY, Terasaki PI. Significance of the differences in the prevalence of anti-HLA antibodies in matched pairs of mother's and cord blood. Immunol Lett 2016; 170:68-79. [PMID: 26721232 DOI: 10.1016/j.imlet.2015.11.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Revised: 10/15/2015] [Accepted: 11/30/2015] [Indexed: 11/15/2022]
Abstract
The presence of IgG against pathogens in the cord blood (CB) of vaccinated mothers is attributed to transplacental transfer. However, previous studies using lymphocytotoxicity assay showed anti-HLA IgG in mother's blood (MB) but not in CB, perhaps due to non-transfer of anti-HLA IgG or assay limitations in detecting anti-HLA IgG. Anti-HLA IgG of native and purified sera of 16 MB and CB pairs were measured using an array of microbeads coated with HLA-I/-II molecules on a Luminex platform. Two cases showed no anti-HLA-I IgG in either MB or CB; four MB cases displayed polyallelic HLA-reactive IgG, with negligible or no reactivity by the corresponding CB sera. Notably, anti-HLA-I reactivity in cases 3-6/11/12 and anti-HLA-II reactivity in cases 1/3/4/6/8/11-13 were restricted to CB, with lower or no HLA-reactivity in MB. Mothers' HLA typing is done for HLA-A*, HLA-B* and DRB1* alleles. The mother in case 14 carried DRB1*11:01, the allele-reactive IgG is seen in both native and the purified fraction of sera of MB but not in CB. Also in cases 15 (DRB1*01:01) and 16 (B*49:01 and DBR1*07:01), the allele-reactive IgGs are seen in both native and purified fractions of MB but not in CB confirming the earlier reports on the absence of materno-fetal transfer of anti-HLA IgG. However, the mother of case 6 is homozygous for DRB1*03:01 and the allele-reactive IgG occurred in both MB and CB, confirming the presence of anti-HLA autoantibodies. In Case 13, the mother (HLA-A*24 and HLA-A*52) and CB carried allele-reactive IgG in both native and purified sera, indicating the possible occurrence of transplacental transfer of the IgG. Further confirmation is restricted by the paucity of detailed molecular HLA typing for both the parents and fetuses. While 37.5% of the native IgG in CB and 18.8% in MB showed DRB3*03:01 reactivity, 100% of purified IgG from both CB and MB showed anti-DRB3*03:01 and anti-DPA1*02:01\ DPB1*23:01 antibodies. Several CB cases showed high-prevalence IgG reacting to a single allele of HLA-I and/or HLA-II with minimal or no cross-reactive IgG in CB or in the MB, suggesting the presence of de novo antibodies, possibly against non-inherited maternal HLA or inherited parental HLA haplotypes by the fetus.
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Affiliation(s)
| | - Vadim Jucaud
- Terasaki Foundation Laboratory, Los Angeles, CA, United States
| | | | - Paul I Terasaki
- Terasaki Foundation Laboratory, Los Angeles, CA, United States
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Liew R. Sudden Cardiac Death Risk Stratification - An Update. Eur Cardiol 2015; 10:118-122. [PMID: 30310436 PMCID: PMC6159393 DOI: 10.15420/ecr.2015.10.2.118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 10/28/2015] [Indexed: 11/04/2022] Open
Abstract
Sudden cardiac death (SCD) remains a major public health problem worldwide, yet current methods to identify those at greatest risk are inadequate. High-risk individuals may benefit from potentially life-saving treatment, such as insertion of an implantable-cardioverter defibrillator (ICD). However, such treatments are expensive and have their own associated risks. Furthermore, most cases of SCD occur in the general adult population who may be relatively asymptomatic but yet have an underlying predisposition to SCD. Hence, there is great interest and clinical need in improving methods for risk stratification of SCD to identify those at greatest risk and implement the most appropriate treatment. This review provides an update on current risk-stratification methods for SCD in high-risk groups, in particular patients with reduced left ventricular function following acute myocardial infarction and those with non-ischaemic dilated cardiomyopathy, and highlights some novel methods that may have a role to play in future risk-stratification schemes. Approaches and challenges for SCD risk stratification among the general public are also discussed.
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Affiliation(s)
- Reginald Liew
- Gleneagles Hospital Singapore, Duke-NUS Graduate Medical School, Singapore
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Affiliation(s)
- Richard N Pierson
- Department of Surgery, University of Maryland School of Medicine, Baltimore (R.N.P., J.S.B.) and VA Maryland Health Care System, Baltimore (R.N.P.).
| | - Jonathan S Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore (R.N.P., J.S.B.) and VA Maryland Health Care System, Baltimore (R.N.P.)
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