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Chen Y, Zhi Y, Zhong H, Ma L, Gu X, Cai Y, Huang J, Yi X, Wu X, Yung KKL, Zhou P. Inhibition of Kv1.3 channel restrains macrophage M2 polarization and ameliorates renal fibrosis via regulating STAT6 phosphorylation. Pharmacol Res 2025; 213:107623. [PMID: 39870185 DOI: 10.1016/j.phrs.2025.107623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 01/04/2025] [Accepted: 01/20/2025] [Indexed: 01/29/2025]
Abstract
Macrophages play crucial roles in regulating both homeostatic and inflammatory responses, with classical activated (M1) and alternatively activated (M2) subsets defined by the surrounding micro-environment. Renal fibrosis, developed from persistent inflammation, is worsened by M2 macrophages, yet the precise mechanisms underlying macrophage M2 polarization remain unclear. In this study, we investigated the role of Kv1.3, one of the primary potassium channels which is expressed in both innate and adaptive immunity, on macrophage M2 polarization and renal fibrosis. Our findings demonstrated that genetic or pharmacological inhibition of Kv1.3 significantly suppressed the expression of M2 markers and STAT6 phosphorylation. Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model. Mechanistically, we revealed that Kv1.3 was required for STAT6 phosphorylation in a mitochondria membrane potential dependent manner. Collectively, this study suggests that Kv1.3 is essential for macrophage M2 polarization and highlights the potential of Kv1.3 blockers as therapeutic agents for renal fibrosis and other M2 polarization-related diseases.
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Affiliation(s)
- Yanshan Chen
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Yuanxing Zhi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Hailin Zhong
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Liang Ma
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Xinpei Gu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Yijing Cai
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Jingjing Huang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Xin Yi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China
| | - Xiaoyan Wu
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, China
| | - Ken Kin Lam Yung
- Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, Department of Science and Environmental Studies, the Education University of Hong Kong, Hong Kong, China
| | - Pingzheng Zhou
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences,Southern Medical University, Guangzhou 510515, China; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China.
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Di Vincenzo A, Granzotto M, Trevellin E, Purificati C, Vecchiato M, Foletto M, Pesavento M, Vettor R, Rossato M. Bariatric surgery modulates plasma levels of antibodies against angiotensin II type 1 and endothelin 1 type A receptor in severe obesity. J Endocrinol Invest 2025; 48:191-199. [PMID: 38900373 DOI: 10.1007/s40618-024-02412-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/10/2024] [Indexed: 06/21/2024]
Abstract
PURPOSE The contribution of endothelial-targeted autoantibodies against the angiotensin II type 1 receptor (anti-AT1R) and the anti-endothelin 1 type A receptor (anti-ETAR1) has been proposed in the development of cardiovascular diseases. However, no data have been reported yet in obesity. In this observational study we evaluated the relationship between anthropometric and metabolic parameters and anti-AT1R and anti-ETAR1 concentrations in a cohort of patients with severe obesity and associated comorbidities undergoing bariatric surgery. METHODS Clinical evaluation and metabolic assessment were performed in 36 subjects referring to our Center for the Study and Integrated Treatment of Obesity at the University Hospital of Padova. Circulating inflammatory adipocytokines and the endothelial dysfunction marker asymmetric dimethylarginine (ADMA) were evaluated; plasma levels of anti-AT1R and anti-ETAR1 were also determined. 10 normal-weight subjects were considered as a control group. 29 patients out of 36 were re-evaluated after surgery. RESULTS With respect to normal-weight controls patients showed significantly higher plasma levels of anti-AT1R (28 ± 20.4 vs 13.5 ± 2.8 U/mL, p < 0.005) and ADMA (0.8 ± 0.1 vs 0.54 ± 0.08 uM/L, p < 0.0001) but not anti-ETAR1 (14.2 ± 1.3 vs 13.3 ± 2 U/mL, p = 0.1). Anti-AT1R concentration showed an increasing trend with the worsening of glycemic status, while the presence of arterial hypertension among the patients did not affect autoantibodies levels. One year after surgery, a significant improvement in body weight and metabolic and inflammatory parameters was observed, along with a significant reduction of anti-AT1R (28.1 ± 20.4 U/mL vs 22.6 ± 16 U/mL, p < 0.05) and anti-ETAR1 (14.2 ± 1.3 U/L vs 13 ± 1.6 U/L, p < 0.01). CONCLUSIONS Subjects with obesity present higher plasma levels of anti-AT1R which are more related to glycemic profile than blood pressure levels, and are reduced by bariatric surgery. Considering the detrimental effects of these autoantibodies on vascular health, they should be assessed as potential biomarkers in obesity and metabolic diseases.
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Affiliation(s)
- A Di Vincenzo
- Internal Medicine 3, Department of Medicine, University-Hospital of Padova, Padua, Italy.
- Endocrine-Metabolic Laboratory, Department of Medicine, University-Hospital of Padova, Padua, Italy.
| | - M Granzotto
- Endocrine-Metabolic Laboratory, Department of Medicine, University-Hospital of Padova, Padua, Italy
| | - E Trevellin
- Endocrine-Metabolic Laboratory, Department of Medicine, University-Hospital of Padova, Padua, Italy
| | - C Purificati
- Internal Medicine 3, Department of Medicine, University-Hospital of Padova, Padua, Italy
| | - M Vecchiato
- Sports and Exercise Medicine Division, Department of Medicine, University-Hospital of Padova, Padua, Italy
| | - M Foletto
- Week Surgery Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University-Hospital of Padova, Padua, Italy
| | - M Pesavento
- Internal Medicine 3, Department of Medicine, University-Hospital of Padova, Padua, Italy
| | - R Vettor
- Internal Medicine 3, Department of Medicine, University-Hospital of Padova, Padua, Italy
- Endocrine-Metabolic Laboratory, Department of Medicine, University-Hospital of Padova, Padua, Italy
| | - M Rossato
- Internal Medicine 3, Department of Medicine, University-Hospital of Padova, Padua, Italy
- Endocrine-Metabolic Laboratory, Department of Medicine, University-Hospital of Padova, Padua, Italy
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Torres Sánchez MJ, Ruiz Fuentes MC, Clavero García E, Rísquez Chica N, Espinoza Muñoz K, Espigares Huete MJ, Caba Molina M, Osuna A, Wangensteen R. Hydroxyproline in Urine Microvesicles as a Biomarker of Fibrosis in the Renal Transplant Patient. Biomedicines 2024; 12:2836. [PMID: 39767742 PMCID: PMC11673537 DOI: 10.3390/biomedicines12122836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Interstitial fibrosis/tubular atrophy in kidney transplantation is an unspecific lesion induced by immune and non-immune factors, which determines the progression of chronic kidney disease. Hydroxyproline is an imino acid that is part of the molecule of collagen. The aim of this study was to assess hydroxyproline in urine microvesicles as a marker of fibrosis in the renal transplant patient. Patients and Methods: An observational cross-sectional study was conducted on 46 renal transplant patients who had undergone renal biopsy with diagnostic intention, as well as 19 healthy controls. Clinical, histological, and laboratory variables were collected at the time of marker determination and renal function was analyzed 2 years later. Hydroxyproline was measured in urine microvesicles. Results: Renal transplant patients showed a higher microvesicular concentration of hydroxyproline compared to the control group, with the following medians (interquartile range (IQR)): 28.024 (5.53) ng/mL vs. 2.51 (1.16) ng/mL, p < 0.001. In the transplanted patients, patients in whom biopsy showed some score of total cortical parenchymal inflammation (ti) displayed a significantly higher concentration of hydroxyproline in urine microvesicles than those patients who did not score for cortical parenchymal inflammation (29.91 ± 2.797 ng/mL vs. 22.72 ± 8.697 ng/mL, p = 0.034). No significant correlation was observed between urinary markers and serum creatinine, calcium, and parathyroid hormone (PTH). Conclusions: The concentration of hydroxyproline in urinary microvesicles increased in renal transplant patients relative to healthy controls. Hydroxyproline in urinary microvesicles is a marker of chronic renal inflammation in transplanted patients, and further studies are required to confirm this finding in other pathologies, as well as the association with fibrosis and the evolution of renal function.
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Affiliation(s)
- María José Torres Sánchez
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - María Carmen Ruiz Fuentes
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
- Department of Medicine, University of Granada, 18071 Granada, Spain;
| | - Elena Clavero García
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - Noelia Rísquez Chica
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - Karla Espinoza Muñoz
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - María José Espigares Huete
- Nephrology Department, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain; (M.J.T.S.); (E.C.G.); (N.R.C.); (K.E.M.); (M.J.E.H.)
| | - Mercedes Caba Molina
- Department of Pathological Anatomy, Provincial Unit of Pathological Anatomy of Granada (UPIGAP), Instituto de Investigación Biosanitaria, Ibs Granada, University of Granada, 18071 Granada, Spain;
| | - Antonio Osuna
- Department of Medicine, University of Granada, 18071 Granada, Spain;
| | - Rosemary Wangensteen
- Area of Physiology, Department of Health Sciencies, University of Jaen, 23071 Jaen, Spain;
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Li Y, Zhang J, Qiu X, Zhang Y, Wu J, Bi Q, Sun Z, Wang W. Diverse regulated cell death patterns and immune traits in kidney allograft with fibrosis: a prediction of renal allograft failure based on machine learning, single-nucleus RNA sequencing and molecular docking. Ren Fail 2024; 46:2435487. [PMID: 39632251 PMCID: PMC11619039 DOI: 10.1080/0886022x.2024.2435487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 11/02/2024] [Accepted: 11/23/2024] [Indexed: 12/07/2024] Open
Abstract
Objectives: Post-transplant allograft fibrosis remains a challenge in prolonging allograft survival. Regulated cell death has been widely implicated in various kidney diseases, including renal fibrosis. However, the role of different regulated cell death (RCD) pathways in post-transplant allograft fibrosis remains unclear. Methods and Results: Microarray transcriptome profiling and single-nuclei sequencing data of post-transplant fibrotic and normal grafts were obtained and used to identify RCD-related differentially expressed genes. The enrichment activity of nine RCD modalities in tissue and cells was examined using single-sample gene set enrichment analysis, and their relations with immune infiltration in renal allograft samples were also assessed. Parenchymal and non-parenchymal cells displayed heterogeneity in RCD activation. Additionally, cell-cell communication analysis was also conducted in fibrotic samples. Subsequently, weighted gene co-expression network analysis and seven machine learning algorithms were employed to identify RCD-related hub genes for renal fibrosis. A 9-gene signature, termed RCD risk score (RCDI), was constructed using the least absolute shrinkage and selection operator and multivariate Cox regression algorithms. This signature showed robust accuracy in predicting 1-, 2-, and 3-year allograft survival status (area under the curve for 1-, 2-, and 3-year were 0.900, 0.877, 0.858, respectively). Immune infiltration analysis showed a strong correlation with RCDI and the nine model genes. Finally, molecular docking simulation suggested rapamycin, tacrolimus and mycophenolate mofetil exhibit strong interactions with core RCD-related receptors. Conclusions: In summary, this study explored the activation of nine RCD pathways and their relationships with immune traits, identified potential RCD-related hub genes associated with renal fibrosis, and highlighted potential therapeutic targets for renal allograft fibrosis.
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Affiliation(s)
- Yuqing Li
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Jiandong Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Xuemeng Qiu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Yifei Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Jiyue Wu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Qing Bi
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Zejia Sun
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
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Robertson H, Kim HJ, Li J, Robertson N, Robertson P, Jimenez-Vera E, Ameen F, Tran A, Trinh K, O'Connell PJ, Yang JYH, Rogers NM, Patrick E. Decoding the hallmarks of allograft dysfunction with a comprehensive pan-organ transcriptomic atlas. Nat Med 2024; 30:3748-3757. [PMID: 38890530 PMCID: PMC11645273 DOI: 10.1038/s41591-024-03030-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 04/29/2024] [Indexed: 06/20/2024]
Abstract
The pathogenesis of allograft (dys)function has been increasingly studied using 'omics'-based technologies, but the focus on individual organs has created knowledge gaps that neither unify nor distinguish pathological mechanisms across allografts. Here we present a comprehensive study of human pan-organ allograft dysfunction, analyzing 150 datasets with more than 12,000 samples across four commonly transplanted solid organs (heart, lung, liver and kidney, n = 1,160, 1,241, 1,216 and 8,853 samples, respectively) that we leveraged to explore transcriptomic differences among allograft dysfunction (delayed graft function, acute rejection and fibrosis), tolerance and stable graft function. We identified genes that correlated robustly with allograft dysfunction across heart, lung, liver and kidney transplantation. Furthermore, we developed a transfer learning omics prediction framework that, by borrowing information across organs, demonstrated superior classifications compared to models trained on single organs. These findings were validated using a single-center prospective kidney transplant cohort study (a collective 329 samples across two timepoints), providing insights supporting the potential clinical utility of our approach. Our study establishes the capacity for machine learning models to learn across organs and presents a transcriptomic transplant resource that can be employed to develop pan-organ biomarkers of allograft dysfunction.
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Affiliation(s)
- Harry Robertson
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Hani Jieun Kim
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia
- Kinghorn Cancer Centre and Cancer Research Theme, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Jennifer Li
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Nicholas Robertson
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China
| | - Paul Robertson
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Elvira Jimenez-Vera
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Farhan Ameen
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Andy Tran
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Katie Trinh
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Philip J O'Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Jean Y H Yang
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Ellis Patrick
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia.
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia.
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia.
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China.
- Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
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Jiang Y, Zhu X, Jordan K, Li Y, Conley S, Tang H, Lerman A, Eirin A, Ou T, Lerman LO. Dyslipidemia-induced renal fibrosis related to ferroptosis and endoplasmic reticulum stress. J Lipid Res 2024; 65:100610. [PMID: 39094771 PMCID: PMC11401224 DOI: 10.1016/j.jlr.2024.100610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/18/2024] [Accepted: 07/20/2024] [Indexed: 08/04/2024] Open
Abstract
Dyslipidemia may induce chronic kidney disease and trigger both ferroptosis and endoplasmic reticulum (ER) stress, but the instigating factors are incompletely understood. We tested the hypothesis that different models of dyslipidemia engage distinct kidney injury mechanisms. Wild-type (WT) or proprotein-convertase subtilisin/kexin type-9 (PCSK9)-gain-of-function (GOF) Ossabaw pigs were fed with a 6-month normal diet (ND) or high-fat diet (HFD) (n = 5-6 each). Renal function and fat deposition were studied in vivo using CT, and blood and kidney tissue studied ex-vivo for lipid profile, systemic and renal vein FFAs levels, and renal injury mechanisms including lipid peroxidation, ferroptosis, and ER stress. Compared with WT-ND pigs, both HFD and PCSK9-GOF elevated triglyceride levels, which were highest in WT-HFD, whereas total and LDL cholesterol levels rose only in PCSK9-GOF pigs, particularly in PCSK9-GOF/HFD. The HFD groups had worse kidney function than the ND groups. The WT-HFD kidneys retained more FFA than other groups, but all kidneys developed fibrosis. Furthermore, HFD-induced ferroptosis in WT-HFD indicated by increased free iron, lipid peroxidation, and decreased glutathione peroxidase-4 mRNA expression, while PCSK9-GOF induced ER stress with upregulated GRP94 and CHOP protein expression. In vitro, pig kidney epithelial cells treated with palmitic acid and oxidized LDL to mimic HFD and PCSK9-GOF showed similar trends to those observed in vivo. Taken together, HFD-induced hypertriglyceridemia promotes renal FFA retention and ferroptosis, whereas PCSK9-GOF-induced hypercholesterolemia elicits ER stress, both resulting in renal fibrosis. These observations suggest different targets for preventing and treating renal fibrosis in subjects with specific types of dyslipidemia.
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Affiliation(s)
- Yamei Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xiangyang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Kyra Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Yongxin Li
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Sabena Conley
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Tongwen Ou
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
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Peng L, Wang C, Yu S, Li Q, Wu G, Lai W, Min J, Chen G. Dysregulated lipid metabolism is associated with kidney allograft fibrosis. Lipids Health Dis 2024; 23:37. [PMID: 38308271 PMCID: PMC10837934 DOI: 10.1186/s12944-024-02021-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 01/17/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Interstitial fibrosis and tubular atrophy (IF/TA), a histologic feature of kidney allograft destruction, is linked to decreased allograft survival. The role of lipid metabolism is well-acknowledged in the area of chronic kidney diseases; however, its role in kidney allograft fibrosis is still unclarified. In this study, how lipid metabolism contributes to kidney allografts fibrosis was examined. METHODS A comprehensive bioinformatic comparison between IF/TA and normal kidney allograft in the Gene Expression Omnibus (GEO) database was conducted. Further validations through transcriptome profiling or pathological staining of human recipient biopsy samples and in rat models of kidney transplantation were performed. Additionally, the effects of enhanced lipid metabolism on changes in the fibrotic phenotype induced by TGF-β1 were examined in HK-2 cell. RESULTS In-depth analysis of the GEO dataset revealed a notable downregulation of lipid metabolism pathways in human kidney allografts with IF/TA. This decrease was associated with increased level of allograft rejection, inflammatory responses, and epithelial mesenchymal transition (EMT). Pathway enrichment analysis showed the downregulation in mitochondrial LC-fatty acid beta-oxidation, fatty acid beta-oxidation (FAO), and fatty acid biosynthesis. Dysregulated fatty acid metabolism was also observed in biopsy samples from human kidney transplants and in fibrotic rat kidney allografts. Notably, the areas affected by IF/TA had increased immune cell infiltration, during which increased EMT biomarkers and reduced CPT1A expression, a key FAO enzyme, were shown by immunohistochemistry. Moreover, under TGF-β1 induction, activating CPT1A with the compound C75 effectively inhibited migration and EMT process in HK-2 cells. CONCLUSIONS This study reveal a critical correlation between dysregulated lipid metabolism and kidney allograft fibrosis. Enhancing lipid metabolism with CPT1A agonists could be a therapeutic approach to mitigate kidney allografts fibrosis.
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Affiliation(s)
- Linjie Peng
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Chang Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Shuangjin Yu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Qihao Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Guobin Wu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Weijie Lai
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Jianliang Min
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China
| | - Guodong Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China.
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8
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Lu T, Chen S, Xu J. RGS1 mediates renal interstitial fibrosis through activation of the inflammatory response. Arch Biochem Biophys 2023; 750:109744. [PMID: 37696381 DOI: 10.1016/j.abb.2023.109744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/05/2023] [Accepted: 09/08/2023] [Indexed: 09/13/2023]
Abstract
Renal interstitial fibrosis (RIF) is considered as a common pathway for all patients with chronic kidney disease (CKD) to progress to end-stage kidney disease (ESRD). The basic pathological manifestation is the increase of matrix component in the tubular interstitium, while the injury of tubular epithelial cells in the renal interstitium and the excessive accumulation of matrix will eventually lead to tubular atrophy and obstruction, loss of effective renal units, and finally impaired renal filtration function. The relevant mechanism of RIF remains unclear. The present study will investigate the function and relevant mechanism of RGS1 in RIF. The RIF-related microarrays GSE22459 and GSE76882 were downloaded and analyzed. Renal parenchymal atrophic calyx tissues were collected from clinical RIF patients. Cellular inflammation, fibrosis and animal RIF models were constructed using Lipopolysaccharide (LPS), TGF-β1 and unilateral ureteral occlusion (UUO). HE and Masson staining were performed to detect morphological alterations of renal tissue samples. qRT-PCR, Western blot and ELISA were carried out to detect the expression of relevant genes/proteins. RGS1 is a gene co-differentially expressed by GSE22459 and GSE76882. RGS1 expression was elevated in renal tissues of RIF patients, cells and animal RIF models. Knockdown of RGS1 inhibited renal cell inflammatory response, fibrosis and renal fibrosis in RIF mice. Overexpression of RGS1 plays the opposite role. Knockdown of RGS1 inhibited the inflammatory response in the RIF cell and mouse model. Targeting RGS1 might be a potential therapeutic strategy for RIF treatment.
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Affiliation(s)
- Tefei Lu
- Department of Urology, Ningbo Medical Central Lihuili Hospital, Ningbo, 315040, Zhejiang, China
| | - Sheng Chen
- Department of Urology, Ningbo Medical Central Lihuili Hospital, Ningbo, 315040, Zhejiang, China
| | - Jianting Xu
- Department of Urology, Ningbo Medical Central Lihuili Hospital, Ningbo, 315040, Zhejiang, China.
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9
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Zhang TY, Yan J, Wu J, Yang W, Zhang S, Xia J, Che X, Li H, Li D, Ying L, Yuan X, Zhou Y, Zhang M, Mou S. Shear wave elastography parameters adds prognostic value to adverse outcome in kidney transplantation recipients. Ren Fail 2023; 45:2235015. [PMID: 37462113 DOI: 10.1080/0886022x.2023.2235015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/05/2023] [Accepted: 07/05/2023] [Indexed: 07/20/2023] Open
Abstract
INTRODUCTION The tissue stiffness of donor kidneys in transplantation may increase due to pathological changes such as glomerulosclerosis and interstitial fibrosis, and those changes associate worse outcomes in kidney transplantation recipients. Ultrasound elastography is a noninvasive imaging examination with the ability to quantitatively reflect tissue stiffness. Aim of this study was to evaluate the prognostic value of ultrasound elastography for adverse kidney outcome in kidney transplantation recipients. METHODS Shear wave elastography (SWE) examinations were performed by two independent operators in kidney transplantation recipients. The primary outcome was a composite of kidney graft deterioration, all-cause re-hospitalization, and all-cause mortality. Survival analysis was calculated by Kaplan-Meier curves with the log-rank test and Cox regression analysis. RESULTS A total of 161 patients (mean age 46 years, 63.4% men) were followed for a median of 20.1 months. 27 patients (16.77%) reached the primary endpoint. The mean and median tissue stiffness at the medulla (hazard ratio: 1.265 and 1.229, respectively), estimated glomerular filtration rate (eGFR), and serum albumin level were associated with the primary outcome in univariate Cox regression. Adding mean or median medulla SWE to a baseline model containing eGFR and albumin significantly improved its discrimination (C-statistics: 0.736 for the baseline, 0.766 and 0.772 for the model added mean and median medulla SWE, respectively). CONCLUSION The medullary tissue stiffness of kidney allograft measured by shear wave elastography may provide incremental prognostic value to adverse outcomes in kidney transplantation recipients. Including SWE parameters in kidney transplantation recipients management could be considered to improve risk stratification.
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Affiliation(s)
- Tian-Yi Zhang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayi Yan
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiajia Wu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenqi Yang
- Department of Ultrasound, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Shijun Zhang
- Department of Ultrasound, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Jia Xia
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiajing Che
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongli Li
- Department of Ultrasound, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Dawei Li
- Department of Urology, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Liang Ying
- Department of Urology, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Xiaodong Yuan
- Department of Urology, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Yin Zhou
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Zhang
- Department of Urology, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Shan Mou
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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10
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Yin Y, Chen C, Zhang D, Han Q, Wang Z, Huang Z, Chen H, Sun L, Fei S, Tao J, Han Z, Tan R, Gu M, Ju X. Construction of predictive model of interstitial fibrosis and tubular atrophy after kidney transplantation with machine learning algorithms. Front Genet 2023; 14:1276963. [PMID: 38028591 PMCID: PMC10646529 DOI: 10.3389/fgene.2023.1276963] [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: 08/13/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Background: Interstitial fibrosis and tubular atrophy (IFTA) are the histopathological manifestations of chronic kidney disease (CKD) and one of the causes of long-term renal loss in transplanted kidneys. Necroptosis as a type of programmed death plays an important role in the development of IFTA, and in the late functional decline and even loss of grafts. In this study, 13 machine learning algorithms were used to construct IFTA diagnostic models based on necroptosis-related genes. Methods: We screened all 162 "kidney transplant"-related cohorts in the GEO database and obtained five data sets (training sets: GSE98320 and GSE76882, validation sets: GSE22459 and GSE53605, and survival set: GSE21374). The training set was constructed after removing batch effects of GSE98320 and GSE76882 by using the SVA package. The differentially expressed gene (DEG) analysis was used to identify necroptosis-related DEGs. A total of 13 machine learning algorithms-LASSO, Ridge, Enet, Stepglm, SVM, glmboost, LDA, plsRglm, random forest, GBM, XGBoost, Naive Bayes, and ANNs-were used to construct 114 IFTA diagnostic models, and the optimal models were screened by the AUC values. Post-transplantation patients were then grouped using consensus clustering, and the different subgroups were further explored using PCA, Kaplan-Meier (KM) survival analysis, functional enrichment analysis, CIBERSOFT, and single-sample Gene Set Enrichment Analysis. Results: A total of 55 necroptosis-related DEGs were identified by taking the intersection of the DEGs and necroptosis-related gene sets. Stepglm[both]+RF is the optimal model with an average AUC of 0.822. A total of four molecular subgroups of renal transplantation patients were obtained by clustering, and significant upregulation of fibrosis-related pathways and upregulation of immune response-related pathways were found in the C4 group, which had poor prognosis. Conclusion: Based on the combination of the 13 machine learning algorithms, we developed 114 IFTA classification models. Furthermore, we tested the top model using two independent data sets from GEO.
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Affiliation(s)
- Yu Yin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Congcong Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dong Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qianguang Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhengkai Huang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Fei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaobing Ju
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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11
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Coronel MM, Linderman SW, Martin KE, Hunckler MD, Medina JD, Barber G, Riley K, Yolcu ES, Shirwan H, García AJ. Delayed graft rejection in autoimmune islet transplantation via biomaterial immunotherapy. Am J Transplant 2023; 23:1709-1722. [PMID: 37543091 PMCID: PMC10837311 DOI: 10.1016/j.ajt.2023.07.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 07/31/2023] [Accepted: 07/31/2023] [Indexed: 08/07/2023]
Abstract
The induction of operational immune tolerance is a major goal in beta-cell replacement strategies for the treatment of type 1 diabetes. Our group previously reported long-term efficacy via biomaterial-mediated programmed death ligand 1 (PD-L1) immunotherapy in islet allografts in nonautoimmune models. In this study, we evaluated autoimmune recurrence and allograft rejection during islet transplantation in spontaneous nonobese diabetic (NOD) mice. Graft survival and metabolic function were significantly prolonged over 60 days in recipients of syngeneic islets receiving the biomaterial-delivered immunotherapy, but not in control animals. The biomaterial-mediated PD-L1 immunotherapy resulted in delayed allograft rejection in diabetic NOD mice compared with controls. Discrimination between responders and nonresponders was attributed to the enriched presence of CD206+ program death 1+ macrophages and exhausted signatures in the cytotoxic T cell compartment in the local graft microenvironment. Notably, draining lymph nodes had similar remodeling in innate and adaptive immune cell populations. This work establishes that our biomaterial platform for PD-L1 delivery can modulate immune responses to transplanted islets in diabetic NOD mice and, thus, can provide a platform for the development of immunologic strategies to curb the allo- and autoimmune processes in beta-cell transplant recipients.
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Affiliation(s)
- María M Coronel
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Stephen W Linderman
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA
| | - Karen E Martin
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Michael D Hunckler
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Juan D Medina
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Graham Barber
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Kayle Riley
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Esma S Yolcu
- Department of Child Health and Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Haval Shirwan
- Department of Child Health and Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
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12
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Lee HK, Jung NH, Lee DE, Lee H, Yang J, Kim YS, Han SS, Han N, Kim IW, Oh JM. Discovery of Biomarkers Related to Interstitial Fibrosis and Tubular Atrophy among Kidney Transplant Recipients by mRNA-Sequencing. J Pers Med 2023; 13:1242. [PMID: 37623492 PMCID: PMC10455123 DOI: 10.3390/jpm13081242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/26/2023] Open
Abstract
Interstitial fibrosis and tubular atrophy (IF/TA) after kidney transplantation causes a chronic deterioration of graft function. IF/TA can be diagnosed by means of a graft biopsy, which is a necessity as non-invasive diagnostic methods are unavailable. In this study, we identified IF/TA-related differentially expressed genes (DEGs) through next-generation sequencing using peripheral blood mononuclear cells. Blood samples from kidney transplant recipients undergoing standard immunosuppressive therapy (tacrolimus/mycophenolate mofetil or mycophenolate sodium/steroid) and diagnosed as IF/TA (n = 41) or normal (controls; n = 41) at their one-year protocol biopsy were recruited between January of 2020 and August of 2020. DEGs were derived through mRNA sequencing and validated by means of a quantitative real-time polymerase chain reaction. We identified 34 DEGs related to IF/TA. ADAMTS2, PLIN5, CLDN9, and KCNJ15 demonstrated a log2(fold change) of >1.5 and an area under the receiver operating characteristic curve (AUC) value of >0.6, with ADAMTS2 showing the largest AUC value and expression levels, which were 3.5-fold higher in the IF/TA group relative to that observed in the control group. We identified and validated DEGs related to IF/TA progression at one-year post-transplantation. Specifically, we identified ADAMTS2 as a potential IF/TA biomarker.
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Affiliation(s)
- Hyun Kyung Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; (H.K.L.)
| | - Na Hyun Jung
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; (H.K.L.)
| | - Da Eun Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; (H.K.L.)
| | - Hajeong Lee
- Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea (Y.S.K.)
- Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jaeseok Yang
- Transplantation Center, Seoul National University Hospital, Seoul 03080, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Yon Su Kim
- Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea (Y.S.K.)
- Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Seung Seok Han
- Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea (Y.S.K.)
- Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Nayoung Han
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; (H.K.L.)
- College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea
| | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; (H.K.L.)
| | - Jung Mi Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; (H.K.L.)
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13
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Hua C, Qiu L, Zhou L, Zhuang Y, Cai T, Xu B, Hao S, Fang X, Wang L, Jiang H. Value of multiparametric magnetic resonance imaging for evaluating chronic kidney disease and renal fibrosis. Eur Radiol 2023; 33:5211-5221. [PMID: 37148348 DOI: 10.1007/s00330-023-09674-1] [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: 10/08/2022] [Revised: 01/12/2023] [Accepted: 02/13/2023] [Indexed: 05/08/2023]
Abstract
OBJECTIVES To identify optimized MRI markers for evaluating chronic kidney disease (CKD) and renal interstitial fibrosis (IF). MATERIALS AND METHODS This prospective study included 43 patients with CKD and 20 controls. The CKD group was divided into mild and moderate-to-severe subgroups based on pathological results. Scanned sequences included T1 mapping, R2* mapping, intravoxel incoherent motion imaging, and diffusion-weighted imaging. One-way analyses of variance were used to compare MRI parameters among groups. Correlations of MRI parameters with estimated glomerular filtration rate (eGFR) and renal IF were analyzed using age as covariates. The support vector machine (SVM) model was used to evaluate the diagnostic efficacy of multiparametric MRI. RESULTS Compared to control values, renal cortical apparent diffusion coefficient (cADC), medullary ADC (mADC), cortical pure diffusion coefficient (cDt), medullary Dt (mDt), cortical shifted apparent diffusion coefficient (csADC), and medullary sADC (msADC) values gradually decreased in the mild and moderate-to-severe groups, while cortical T1 (cT1) and medullary T1 (mT1) values gradually increased. Values of cADC, mADC, cDt, mDt, cT1, mT1, csADC, and msADC were significantly associated with eGFR and IF (p < 0.001). The SVM model indicated that multiparametric MRI combining cT1 and csADC can distinguish patients with CKD from controls with high accuracy (0.84), sensitivity (0.70), and specificity (0.92) (AUC: 0.96). Multiparametric MRI combining cT1 and cADC exhibited high accuracy (0.91), sensitivity (0.95), and specificity (0.81) for evaluating IF severity (AUC: 0.96). CONCLUSION Multiparametric MRI combining T1 mapping and diffusion imaging may be of clinical utility in non-invasive assessment of CKD and IF. CLINICAL RELEVANCE STATEMENT This study shows that multiparametric MRI combining T1 mapping and diffusion imaging may be clinically useful in the non-invasive assessment of chronic kidney disease (CKD) and interstitial fibrosis; this could provide information for risk stratification, diagnosis, treatment, and prognosis. KEY POINTS • Optimized MRI markers for evaluating chronic kidney disease and renal interstitial fibrosis were investigated. • Renal cortex/medullary T1 values increased as interstitial fibrosis increased; cortical shifted apparent diffusion coefficient (csADC) correlated significantly with eGFR and interstitial fibrosis. • Support vector machine (SVM) combining cortical T1 (cT1) and csADC/cADC effectively identifies chronic kidney disease and accurately predicts renal interstitial fibrosis.
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Affiliation(s)
- Chenchen Hua
- Diagnostic Radiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
- Department of Diagnostic Radiology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Lu Qiu
- Department of Diagnostic Radiology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Leting Zhou
- Department of Nephrology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Yi Zhuang
- Department of Diagnostic Radiology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Ting Cai
- Department of Nephrology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Bin Xu
- Diagnostic Radiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Shaowei Hao
- Siemens Healthineers Digital Technology (Shanghai) CO., Ltd, Shanghai, China
| | - Xiangming Fang
- Diagnostic Radiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China
| | - Liang Wang
- Department of Nephrology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China.
| | - Haoxiang Jiang
- Department of Diagnostic Radiology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, China.
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14
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Zhang H, Yang Y, Liu Z, Xu H, Zhu H, Wang P, Liang G. Significance of methylation-related genes in diagnosis and subtype classification of renal interstitial fibrosis. Hereditas 2023; 160:32. [PMID: 37496082 PMCID: PMC10373342 DOI: 10.1186/s41065-023-00295-8] [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: 04/04/2023] [Accepted: 07/16/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND RNA methylation modifications, such as N1-methyladenosine/N6-methyladenosine /N5-methylcytosine (m1A/m6A/m5C), are the most common RNA modifications and are crucial for a number of biological processes. Nonetheless, the role of RNA methylation modifications of m1A/m6A/m5C in the pathogenesis of renal interstitial fibrosis (RIF) remains incompletely understood. METHODS Firstly, we downloaded 2 expression datasets from the GEO database, namely GSE22459 and GSE76882. In a differential analysis of these datasets between patients with and without RIF, we selected 33 methylation-related genes (MRGs). We then applied a PPI network, LASSO analysis, SVM-RFE algorithm, and RF algorithm to identify key MRGs. RESULTS We eventually obtained five candidate MRGs (WTAP, ALKBH5, YTHDF2, RBMX, and ELAVL1) to forecast the risk of RIF. We created a nomogram model derived from five key MRGs, which revealed that the nomogram model may be advantageous to patients. Based on the selected five significant MRGs, patients with RIF were classified into two MRG patterns using consensus clustering, and the correlation between the five MRGs, the two MRG patterns, and the genetic pattern with immune cell infiltration was shown. Moreover, we conducted GO and KEGG analyses on 768 DEGs between MRG clusters A and B to look into their different involvement in RIF. To measure the MRG patterns, a PCA algorithm was developed to determine MRG scores for each sample. The MRG scores of the patients in cluster B were higher than those in cluster A. CONCLUSIONS Ultimately, we concluded that cluster A in the two MRG patterns identified on these five key m1A/m6A/m5C regulators may be associated with RIF.
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Affiliation(s)
- Hanchao Zhang
- Department of Urology, The Affilated Hospital and Clinical Medical College of Chengdu University, Chengdu, Sichuan, China
- Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yue Yang
- Department of Urology, The Affilated Hospital and Clinical Medical College of Chengdu University, Chengdu, Sichuan, China
- Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Zhengdao Liu
- Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Hong Xu
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Han Zhu
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Peirui Wang
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Guobiao Liang
- Medical College of Soochow University, Suzhou, Jiangsu, China.
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
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Maralescu FM, Vaduva A, Schiller A, Petrica L, Sporea I, Popescu A, Sirli R, Dema A, Bodea M, Grosu I, Bob F. Relationship between Novel Elastography Techniques and Renal Fibrosis-Preliminary Experience in Patients with Chronic Glomerulonephritis. Biomedicines 2023; 11:365. [PMID: 36830901 PMCID: PMC9953735 DOI: 10.3390/biomedicines11020365] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
INTRODUCTION A renal biopsy represents the gold standard in the diagnosis, prognosis, and management of patients with glomerulonephritis. So far, non-invasive elastographic techniques have not confirmed their utility in replacing a biopsy; however, the new and improved software from Hologic Supersonic Mach 30 is a promising method for assessing the renal tissue's stiffness and viscosity. We investigated whether this elastography technique could reveal renal tissue fibrosis in patients with chronic glomerulonephritis. MATERIALS AND METHODS Two-dimensional-shear wave elastography (SWE) PLUS and viscosity plane-wave ultrasound (Vi PLUS) assessments were performed in 40 patients with chronic glomerulopathies before being referred for a renal biopsy. For each kidney, the mean values of five stiffness and viscosity measures were compared with the demographic, biological, and histopathological parameters of the patients. RESULTS In total, 26 men and 14 women with a mean age of 52.35 ± 15.54 years, a mean estimated glomerular filtration rate (eGFR) of 53.8 ± 35.49 mL/min/1.73m2, and a mean proteinuria of 6.39 ± 7.42 g/24 h were included after providing their informed consent. Out of 40 kidney biopsies, 2 were uninterpretable with inappropriate material and were divided into four subgroups based on their fibrosis percentage. Even though these elastography techniques were unable to differentiate between separate fibrosis stages, when predicting between the fibrosis and no-fibrosis group, we found a cut-off value of <20.77 kPa with the area under the curve (AUC) of 0.860, a p < 0.001 with 88.89% sensitivity, and a 75% specificity for the 2D SWE PLUS measures and a cut-off value of <2.8 Pa.s with an AUC of 0.792, a p < 0.001 with 94% sensitivity, and a 60% specificity for the Vi PLUS measures. We also found a cut-off value of <19.75 kPa for the 2D SWE PLUS measures (with an AUC of 0.789, p = 0.0001 with 100% sensitivity, and a 74.29% specificity) and a cut-off value of <1.28 Pa.s for the Vi PLUS measures (with an AUC 0.829, p = 0.0019 with 60% sensitivity, and a 94.29% specificity) differentiating between patients with over 40% fibrosis and those with under 40%. We also discovered a positive correlation between the glomerular filtration rate (eGFR) and 2D-SWE PLUS values (r = 0.7065, p < 0.0001) and Vi PLUS values (r = 0.3637, p < 0.0211). C reactive protein (CRP) correlates with the Vi PLUS measures (r = -0.3695, p = 0.0189) but not with the 2D SWE PLUS measures (r = -0.2431, p = 0.1306). CONCLUSION Our findings indicate that this novel elastography method can distinguish between individuals with different stages of renal fibrosis, correlate with the renal function and inflammation, and are easy to use and reproducible, but further research is needed for them to be employed routinely in clinical practice.
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Affiliation(s)
- Felix-Mihai Maralescu
- Division of Nephrology, Department of Internal Medicine II, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
| | - Adrian Vaduva
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
- ANAPATMOL Research Centre, Discipline of Morphopathology, Department of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Discipline of Morphopathology, Department of Microscopic Morphology, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Adalbert Schiller
- Division of Nephrology, Department of Internal Medicine II, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
| | - Ligia Petrica
- Division of Nephrology, Department of Internal Medicine II, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
| | - Ioan Sporea
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
- Department of Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Alina Popescu
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
- Department of Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Roxana Sirli
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
- Department of Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Alis Dema
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
- ANAPATMOL Research Centre, Discipline of Morphopathology, Department of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Discipline of Morphopathology, Department of Microscopic Morphology, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Madalina Bodea
- Division of Nephrology, Department of Internal Medicine II, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
| | - Iulia Grosu
- Division of Nephrology, Department of Internal Medicine II, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
| | - Flaviu Bob
- Division of Nephrology, Department of Internal Medicine II, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Victor Babeș University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Emergency Hospital, L. Rebreanu Street, Nr. 156, 300723 Timisoara, Romania
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16
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Haas M, Mirocha J, Huang E, Najjar R, Peng A, Sethi S, Vo A, Anglicheau D, Jordan SC, Rabant M. A Banff-based histologic chronicity index is associated with graft loss in patients with a kidney transplant and antibody-mediated rejection. Kidney Int 2023; 103:187-195. [PMID: 36332728 PMCID: PMC11466365 DOI: 10.1016/j.kint.2022.09.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/19/2022] [Accepted: 09/16/2022] [Indexed: 11/15/2022]
Abstract
Antibody-mediated rejection (AMR) is the major cause of graft loss in kidney transplant recipients. The Banff classification defines two classes of AMR, active and chronic active but over time this classification has become increasingly complex. To simplify the approach to AMR, we developed activity and chronicity indices based on kidney transplant biopsy findings and examined their association with graft survival in 147 patients with active or chronic active AMR, all of whom had donor-specific antibodies and were treated for AMR. The activity index was determined as the sum of Banff glomerulitis (g), peritubular capillaritis (ptc), arteritis (v) and C4d scores, with a maximum score of 12. The chronicity index was the sum of interstitial fibrosis (ci), tubular atrophy (ct), chronic vasculopathy (cv), and chronic glomerulopathy (cg) scores, the latter doubled, with a maximum score of 15. While the activity index was generally not associated with graft loss, the chronicity index was significantly associated with graft loss with an optimal threshold value of 4 or greater for predicting graft loss. The association of the chronicity index of 4 or greater with graft loss was independent of other parameters associated with graft loss, including the estimated glomerular filtration rate at the time of biopsy, chronic active (versus active) AMR, AMR with de novo (versus persistent/rebound) donor-specific antibodies, Banff (g+ptc) scores, concurrent T cell-mediated rejection and donor-specific antibody reduction post-biopsy. The association of the chronicity index of 4 or greater with graft loss was confirmed in an independent cohort of 61 patients from Necker Hospital, Paris. Thus, our findings suggest that the chronicity index may be valuable as a simplified approach to decision-making in patients with AMR.
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Affiliation(s)
- Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
| | - James Mirocha
- General Clinical Research Center, Clinical & Translational Science Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Edmund Huang
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Reiad Najjar
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Alice Peng
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Supreet Sethi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ashley Vo
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dany Anglicheau
- Deparment of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, AP-HP, INSERM U1151, Université Paris Cite, Paris, France
| | - Stanley C Jordan
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Marion Rabant
- Department of Pathology, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cite, Paris, France
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17
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van der Elst G, Varol H, Hermans M, Baan CC, Duong-van Huyen JP, Hesselink DA, Kramann R, Rabant M, Reinders MEJ, von der Thüsen JH, van den Bosch TPP, Clahsen-van Groningen MC. The mast cell: A Janus in kidney transplants. Front Immunol 2023; 14:1122409. [PMID: 36891297 PMCID: PMC9986315 DOI: 10.3389/fimmu.2023.1122409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
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Affiliation(s)
- G van der Elst
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - H Varol
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M Hermans
- Department of Internal Medicine, Division of Allergy and Clinical Immunology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - C C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | - D A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - R Kramann
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.,Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - M Rabant
- Department of Pathology, Necker Hospital, APHP, Paris, France
| | - M E J Reinders
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - J H von der Thüsen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - T P P van den Bosch
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M C Clahsen-van Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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18
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Hernández D, Vázquez-Sánchez T, Sola E, Lopez V, Ruiz-Esteban P, Caballero A, Salido E, Leon M, Rodriguez A, Serra N, Rodriguez C, Facundo C, Perello M, Silva I, Marrero-Miranda D, Cidraque I, Moreso F, Guirado L, Serón D, Torres A. Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study. BMC Nephrol 2022; 23:357. [PMCID: PMC9639260 DOI: 10.1186/s12882-022-02989-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/24/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Subclinical inflammation, including borderline lesions (BL), is very common (30–40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function.
Methods
The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression.
Discussion
This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL.
Trial registration
clinicaltrials.gov: NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1. Protocol Version 2 of 21 January 2022. Sponsor: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org.
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19
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The Progression of Interstitial Fibrosis and Tubular Atrophy at 6 Months Is an Independent Predictor of Poor Graft Outcomes in Kidney Transplant Recipients. Transplant Direct 2022; 8:e1375. [PMID: 36505898 PMCID: PMC9722773 DOI: 10.1097/txd.0000000000001375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/15/2022] Open
Abstract
Interstitial fibrosis and tubular atrophy (IFTA) found on 1-y surveillance biopsies has been associated with poor graft outcomes. However, its progression over time and relationship to outcomes are less well defined. Methods We studied implantation and 6-mo surveillance biopsies and examined the association between the progression of IFTA (ΔIFTA) and a composite of censored graft loss or doubling of serum creatinine in 248 adult kidney recipients. Results The percentage of patients with ΔIFTA of 1 or ≥2 was 35% and 22%, respectively. Positive ΔIFTA was a risk factor for the composite endpoint (hazard ratio, 1.36; 95% confidence interval, 1.03-1.79). This estimate was robust to adjustment for recipient and donor baseline characteristics, baseline IFTA, tacrolimus levels, and rejection status. ΔIFTA was associated with decreased estimated glomerular filtration rate at 3 and 5 y. IFTA+i was a predictor in the cohort; however, IFTA progression was not limited to those with a mononuclear cell interstitial inflammation (Banff "i") score above zero. Notably, donor age was a predictor of IFTA at 6 mo, but not of ΔIFTA, whereas rejection, donor diabetes, and recipient smoking status were. Conclusions Progression of IFTA at 6 mo can predict outcomes. ΔIFTA was not related to donor age but may be linked to other risk factors influencing decision-making for donor versus recipient selection.
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20
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Chen Y, Zhang B, Liu T, Chen X, Wang Y, Zhang H. T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation. Front Immunol 2022; 13:895762. [PMID: 35844542 PMCID: PMC9283858 DOI: 10.3389/fimmu.2022.895762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
In kidney transplantation, deteriorated progression of rejection is considered to be a leading course of postoperative mortality. However, the conventional histologic diagnosis is limited in reading the rejection status at the molecular level, thereby triggering mismatched pathogenesis with clinical phenotypes. Here, by applying uniform manifold approximation and projection and Leiden algorithms to 2,611 publicly available microarray datasets of renal transplantation, we uncovered six rejection states with corresponding signature genes and revealed a high-risk (HR) state that was essential in promoting allograft loss. By identifying cell populations from single-cell RNA sequencing data that were associated with the six rejection states, we identified a T-cell population to be the pathogenesis-triggering cells associated with the HR rejection state. Additionally, by constructing gene regulatory networks, we identified that activated STAT4, as a core transcription factor that was regulated by PTPN6 in T cells, was closely linked to poor allograft function and prognosis. Taken together, our study provides a novel strategy to help with the precise diagnosis of kidney allograft rejection progression, which is powerful in investigating the underlying molecular pathogenesis, and therefore, for further clinical intervention.
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Affiliation(s)
- Yihan Chen
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- The Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Bao Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- The Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Tianliang Liu
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- The Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xiaoping Chen
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- The Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yaning Wang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- The Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Yaning Wang, ; Hongbo Zhang,
| | - Hongbo Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- The Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Yaning Wang, ; Hongbo Zhang,
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21
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Seron D, Rabant M, Becker JU, Roufosse C, Bellini MI, Böhmig GA, Budde K, Diekmann F, Glotz D, Hilbrands L, Loupy A, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation. Transpl Int 2022; 35:10135. [PMID: 35669975 PMCID: PMC9163314 DOI: 10.3389/ti.2022.10135] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 12/14/2022]
Abstract
The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.
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Affiliation(s)
- Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
| | - Marion Rabant
- Department of Pathology, Hôpital Necker–Enfants Malades, Paris, France
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Candice Roufosse
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | | | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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22
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Revealing Potential Diagnostic Gene Biomarkers Associated with Immune Infiltration in Patients with Renal Fibrosis Based on Machine Learning Analysis. J Immunol Res 2022; 2022:3027200. [PMID: 35497880 PMCID: PMC9045970 DOI: 10.1155/2022/3027200] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/02/2022] [Accepted: 04/07/2022] [Indexed: 11/22/2022] Open
Abstract
Chronic kidney disease is characterized by the development of renal fibrosis. The basic mechanisms of renal fibrosis have not yet been fully investigated despite significant progress in understanding the etiology of the disease. In this work, the researchers sought to identify potential diagnostic indicators for renal fibrosis. From the GEO database, we were able to acquire two gene expression profiles with publically available data (GSE22459 and GSE76882, respectively) from human renal fibrosis and control samples. 215 renal fibrosis specimens and 124 normal specimens were examined for differentially expressed genes (DEGs). The SVM-RFE and LASSO regression models were used to discover potential markers. CIBERSORT was applied to estimate the combined cohorts' immune cell fraction compositional trends in renal fibrosis. RT-PCR was used to examine the expression of ISG20 in renal fibrosis and healthy samples. In vitro experiments were applied to examine the function of ISG20 knockdown on the progression of renal fibrosis. In this study, we identified 24 DEGs. The result of LASSO and SVM-RFE identified nine critical genes. ROC assays confirmed the diagnostic value of the above nine genes for renal fibrosis. Immune cell infiltration analysis revealed that ISG20 and SERPINA3 were both found to be correlated with T cell follicular helper, neutrophils, T cell CD4 memory activated, eosinophils, T cell CD8, dendritic cell activated, B cell memory, monocytes, macrophage M2, plasma cells, T cell CD4 naïve, mast cell resting, B cell naïve, T cell regulatory, and NK cell activated. Finally, we observed that the expression of ISG20 and SERPINA3 was distinctly increased in renal fibrosis samples compared with normal samples. ISG20 siRNA significantly suppressed the progression of renal fibrosis in vitro. Overall, this study identified nine diagnostic biomarkers for renal fibrosis. ISG20 may be a novel therapeutic target of renal fibrosis.
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23
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Ho J, Okoli GN, Rabbani R, Lam OLT, Reddy V, Askin N, Rampersad C, Trachtenberg A, Wiebe C, Nickerson P, Abou‐Setta AM. Effectiveness of T cell-mediated rejection therapy: A systematic review and meta-analysis. Am J Transplant 2022; 22:772-785. [PMID: 34860468 PMCID: PMC9300092 DOI: 10.1111/ajt.16907] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/22/2021] [Accepted: 11/26/2021] [Indexed: 01/25/2023]
Abstract
The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised, and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), and Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with the National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2 statistic. From 2875 screened citations, we included 12 studies (1255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95% CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.
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Affiliation(s)
- Julie Ho
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - George N. Okoli
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Rasheda Rabbani
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada,Department of Community Health SciencesMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Otto L. T. Lam
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Viraj K. Reddy
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Nicole Askin
- Neil John Maclean Health Sciences LibraryUniversity of ManitobaWinnipegManitobaCanada
| | - Christie Rampersad
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Aaron Trachtenberg
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Chris Wiebe
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Peter Nickerson
- Department of Internal MedicineMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
| | - Ahmed M. Abou‐Setta
- George and Fay Yee Centre for Healthcare InnovationMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada,Department of Community Health SciencesMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaCanada
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24
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Mine KL, de Marco R, Raimundo TRF, Ernesto JV, Medina-Pestana JO, Tedesco-Silva H, Gerbase-DeLima M. High soluble HLA-DQB2 levels in posttransplant serum are associated with kidney graft dysfunction. Int J Immunogenet 2022; 49:63-69. [PMID: 35083872 DOI: 10.1111/iji.12569] [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: 07/17/2021] [Revised: 12/20/2021] [Accepted: 01/08/2022] [Indexed: 11/27/2022]
Abstract
HLA-DQB2 is a gene of limited polymorphism, with unknown function that presents at least two transcript variants: v1, which encodes the full-length beta-chain, and v2, which lacks exon 4 and could give rise to a soluble protein. We previously showed a strong correlation between high v2 expression in preimplantation biopsies (PIB) of kidneys from young (18- to 49-year olds) but not from old, deceased donors and 1-year posttransplant low (estimated glomerular filtration rate < 45 ml/min/1.73 m2 ) graft function (GF). In this study, we aimed to investigate the impact of posttransplant soluble HLA-DQB2 (sDQB2) serum levels, v1 expression in PIB, and recipient HLA-DQB2 rs7453920 A/G polymorphism on GF. sDQB2 was evaluated by enzyme-linked immunosorbent assay in sera from 114 recipients, collected at least 1 year (median 2.1 years) after transplantation. Higher sDQB2 levels were observed in recipients of kidneys from young, but not from old, donors that had a ≥30% decline in GF within 1 year after blood collection for sDQB2 determination. Among the 15 recipients of kidneys from young donors with sDQB2 ≥ 1.52 ng/ml, 40% presented a ≥30% decline in GF, whereas this occurred in none of the 43 recipients with lower sDQB2 levels (p = 0.007; OR: 36.5). Expression of HLA-DQB2 variant 1, measured by reverse transcription-polymerase chain reaction (RT-PCR) in 92 PIB from young or old donors, did not significantly differ between transplants with high or low 4-year GF. HLA-DQB2 rs7453920 single nucleotide polymorphism (SNP) frequencies did not significantly differ between recipients with low or high 4-year GF. We conclude that HLA-DQB2 variant 1 expression in PIB and recipient rs7453920 SNP polymorphism are not associated with graft outcome. On the other hand, the association, in transplants of kidneys from young donors, between high posttransplant serum sDQB2 levels and decline in GF is a very interesting finding that deserves a validation study in a larger cohort.
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Affiliation(s)
- Karina L Mine
- Instituto de Imunogenética, Associação Fundo de Incentivo à Pesquisa, São Paulo, Brazil
| | - Renato de Marco
- Instituto de Imunogenética, Associação Fundo de Incentivo à Pesquisa, São Paulo, Brazil
| | - Tamiris R F Raimundo
- Instituto de Imunogenética, Associação Fundo de Incentivo à Pesquisa, São Paulo, Brazil
| | - Julia V Ernesto
- Instituto de Imunogenética, Associação Fundo de Incentivo à Pesquisa, São Paulo, Brazil
| | - José O Medina-Pestana
- Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Hélio Tedesco-Silva
- Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Maria Gerbase-DeLima
- Instituto de Imunogenética, Associação Fundo de Incentivo à Pesquisa, São Paulo, Brazil
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25
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Lee YH, Sato Y, Saito M, Fukuma S, Saito M, Yamamoto S, Komatsuda A, Fujiyama N, Satoh S, Lee SH, Boor P, Habuchi T, Floege J, Yanagita M. Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients. J Am Soc Nephrol 2022; 33:186-200. [PMID: 34725107 PMCID: PMC8763171 DOI: 10.1681/asn.2021050715] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 09/13/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the effects of TLTs on future graft function using our histologic TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs. METHODS Serial protocol biopsy samples (0 hour, 1, 6, and 12 months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. RESULTS Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy, and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared with patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pretransplantation rituximab treatment dramatically attenuated the development of stage II TLTs. CONCLUSIONS TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation.
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Affiliation(s)
- Yu Ho Lee
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Yuki Sato
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Mitsuru Saito
- Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Shingo Fukuma
- Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masaya Saito
- Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Shigenori Yamamoto
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Medical Innovation Center TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Komatsuda
- Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Nobuhiro Fujiyama
- Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
| | - Shigeru Satoh
- Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Peter Boor
- Institute of Pathology, RWTH University of Aachen, Germany, Aachen, Germany,Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany,Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany
| | - Tomonori Habuchi
- Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Jürgen Floege
- Division of Nephrology, RWTH University of Aachen, Germany, Aachen, Germany
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
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26
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Abstract
With the incremental improvements in long-term kidney transplant survival, there is renewed focus on what causes failure of the transplanted allograft. Over the past decade, our understanding of the injuries that lead to loss of graft function over time has evolved. Chronic allograft injury includes both immune-mediated and nonimmune-mediated injuries, which may involve the organ donor, the recipient, or both. The targets of injury include the kidney tubular epithelium, the endothelium, and the glomerulus. As a response to injury, there are the expected tissue remodeling and repair processes. However, if inflammation persists, which is not uncommon in the transplant setting, the resulting maladaptive response is matrix deposition and/or fibrosis. This ultimately leads to declining graft function and, finally, failure. With our advancing knowledge of the multiple etiologies and mechanisms, enhanced by more recent cohort studies in humans, there is an opportunity to identify those at greater risk to initiate new strategies to ameliorate the process. Although the most recent studies focus on immune-mediated injuries, there is a critical need to identify both markers of injury and mechanisms of injury. In this review, we highlight the findings of recent studies, highlight the potential therapeutic targets, and identify the continued unmet need for understanding the mechanisms of late graft failure.
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Affiliation(s)
- Eric Langewisch
- Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Roslyn B. Mannon
- Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Medical Service, VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska
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27
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Park WD, Kim DY, Mai ML, Reddy KS, Gonwa T, Ryan MS, Herrera Hernandez LP, Smith ML, Geiger XJ, Turkevi-Nagy S, Cornell LD, Smith BH, Kremers WK, Stegall MD. Progressive decline of function in renal allografts with normal 1-year biopsies: Gene expression studies fail to identify a classifier. Clin Transplant 2021; 35:e14456. [PMID: 34717009 DOI: 10.1111/ctr.14456] [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: 04/30/2021] [Revised: 07/23/2021] [Accepted: 08/04/2021] [Indexed: 11/29/2022]
Abstract
Histologic findings on 1-year biopsies such as inflammation with fibrosis and transplant glomerulopathy predict renal allograft loss by 5 years. However, almost half of the patients with graft loss have a 1-year biopsy that is either normal or has only interstitial fibrosis. The goal of this study was to determine if there was a gene expression profile in these relatively normal 1-year biopsies that predicted subsequent decline in renal function. Using transcriptome microarrays we measured intragraft mRNA levels in a retrospective Discovery cohort (170 patients with a normal/minimal fibrosis 1-year biopsy, 54 with progressive decline in function/graft loss and 116 with stable function) and developed a nested 10-fold cross-validated gene classifier that predicted progressive decline in renal function (positive predictive value = 38 ± 34%%; negative predictive value = 73 ± 30%, c-statistic = .59). In a prospective, multicenter Validation cohort (270 patients with Normal/Interstitial Fibrosis [IF]), the classifier had a 20% positive predictive value, 85% negative predictive value and .58 c-statistic. Importantly, the majority of patients with graft loss in the prospective study had 1-year biopsies scored as Normal or IF. We conclude predicting graft loss in many renal allograft recipients (i.e., those with a relatively normal 1-year biopsy and eGFR > 40) remains difficult.
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Affiliation(s)
| | - Dean Y Kim
- Henry Ford Hospital, Detroit, Michigan, USA
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28
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The Effects of Sex and Body Weight on Renal Graft Function-The Role of CCL2. J Clin Med 2021; 10:jcm10214951. [PMID: 34768469 PMCID: PMC8584442 DOI: 10.3390/jcm10214951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 11/22/2022] Open
Abstract
There are reports on the effects of excessive recipient body weight on renal graft function. Increased CCL2 (chemokine CC-mortif ligand 2) production is observed in patients with excessive body weight. CCL2 also exacerbates the inflammatory process in the renal graft. A total of 49 renal graft recipients of both sexes having undergone renal biopsy within the last 18 months were retrospectively reviewed. At their most recent appointment the patients’ plasma concentrations of CCL2 were evaluated. Renal function was assessed retrospectively. CCL2 concentrations were higher in men than women (p < 0.047), while higher CCL2 levels were associated with a decrease in eGFR (estimated glomerular filtration rate) during the first year post Tx (kidney transplantation). CCL2 negatively correlated with eGFR at 5 years (R = −0.45, p < 0.040997) and positively correlated with the degree of tubular atrophy in renal biopsy specimens (R = 0.43, p < 0.027293) and with systolic pressure. Men showed significantly higher BMI (body mass index) values at the time of Tx and at their last appointment than women did (p < 0.000403; p < 0.000613, respectively). Men showed poorer long-term renal graft function, with significantly lower eGFR values at 4 and 5 years into the post-transplantation period. The male sex and excessive body weight have adverse effects on short- and long-term renal graft function, which is associated with increased levels of CCL2.
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29
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Ricaurte Archila L, Denic A, Mullan AF, Narasimhan R, Bogojevic M, Thompson RH, Leibovich BC, Sangaralingham SJ, Smith ML, Alexander MP, Rule AD. A Higher Foci Density of Interstitial Fibrosis and Tubular Atrophy Predicts Progressive CKD after a Radical Nephrectomy for Tumor. J Am Soc Nephrol 2021; 32:2623-2633. [PMID: 34531177 PMCID: PMC8722813 DOI: 10.1681/asn.2021020267] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/22/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. METHODS We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000-2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6-12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. RESULTS Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m2), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. CONCLUSIONS Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.
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Affiliation(s)
| | - Aleksandar Denic
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Aidan F. Mullan
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Ramya Narasimhan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Marija Bogojevic
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | | | | | | | - Maxwell L. Smith
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Mariam P. Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona
| | - Andrew D. Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota,Division of Epidemiology, Mayo Clinic, Rochester, Minnesota
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30
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Handschin J, Wehmeier C, Amico P, Hopfer H, Dickenmann M, Schaub S, Hirt-Minkowski P. Urinary CXCL10 Measurement in Late Renal Allograft Biopsies Predicts Outcome Even in Histologically Quiescent Patients. Transplant Proc 2021; 53:2168-2179. [PMID: 34419254 DOI: 10.1016/j.transproceed.2021.07.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 06/27/2021] [Accepted: 07/19/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND CXCL10 is a promising early noninvasive diagnostic marker for allograft rejection and predictive for long-term outcomes. However, its value when measured later in the posttransplant course has not yet been accurately analyzed. METHODS We investigated urinary CXCL10 in 141 patients from a prospective, observational renal transplant cohort with 182 clinically indicated allograft biopsies performed >12 months posttransplant and corresponding urines. Urinary CXCL10 was retrospectively quantified on stored urines using the MSD V-Plex Chemokine Panel 1 sandwich immunoassay (Meso Scale Discovery). The primary outcome was a composite of allograft loss/renal function decline (>30% estimated glomerular filtration rate [eGFR]-decrease between index biopsy and last follow-up). RESULTS Seventy-two patients (51%) reached the primary outcome, and their urinary CXCL10 levels were significantly higher at the time of their biopsy compared with patients with stable allograft function (median 9.3 ng/mmol vs 3.3 ng/mmol, P < .0001). Time-to-endpoint analyses according to high/low urinary CXCL10 demonstrated that low urinary CXCL10 (≤7.0 ng/mmol) was associated with 73% 5-year event-free graft survival compared with 48% with high urinary CXCL10 (>7.0 ng/mmol; P = .0001). Even in histologically quiescent patients, high urinary CXCL10 was associated with inferior endpoint-free graft survival (P = .003), and it was an independent predictor of the primary outcome (P = .03). CONCLUSIONS This study demonstrates that urinary CXCL10 has a promising diagnostic performance for detection of late allograft rejection and is an independent predictor of long-term renal allograft outcomes, even in histologically quiescent patients.
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Affiliation(s)
- Joelle Handschin
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Caroline Wehmeier
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patrizia Amico
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Helmut Hopfer
- lnstitute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Michael Dickenmann
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland; Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland; HLA-Diagnostic and lmmunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Patricia Hirt-Minkowski
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
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31
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Chandran S, Leung J, Hu C, Laszik ZG, Tang Q, Vincenti FG. Interleukin-6 blockade with tocilizumab increases Tregs and reduces T effector cytokines in renal graft inflammation: A randomized controlled trial. Am J Transplant 2021; 21:2543-2554. [PMID: 33331082 DOI: 10.1111/ajt.16459] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 11/11/2020] [Accepted: 12/11/2020] [Indexed: 01/25/2023]
Abstract
Interleukin-6 (IL-6) is a proinflammatory cytokine and key regulator of Treg: T effector cell (Teff) balance. We hypothesized that IL-6 blockade with tocilizumab, a monoclonal antibody to IL-6R, would increase Tregs, dampen Teff function, and control graft inflammation. We conducted a randomized controlled clinical trial (2014-2018) of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first year posttransplant. Subjects received tocilizumab (8 mg/kg IV every 4 weeks; 6 doses; n = 16) or no treatment (controls; n = 14) on top of usual maintenance immunosuppression. Kidney biopsies pre- and post-treatment were analyzed using Banff criteria. Blood was analyzed for serum cytokines, Treg frequencies, and T cell effector molecule expression (IFN-γ, IL-17, granzyme B) post-stimulation ex vivo. Tocilizumab-treated subjects were more likely to show improved Banff ti-score (62.5% vs. 21.4%, p = .03), increased Treg frequency (7.1% ± 5.55% vs. 3.6% ± 1.7%, p = .0168), and a blunted Teff cytokine response compared to controls. Changes in Banff i- and t-scores were not significantly different. The treatment was relatively well tolerated with no patient deaths or graft loss. Blockade of IL-6 is a novel and promising treatment option to regulate the T cell alloimmune response in kidney transplant recipients. NCT02108600.
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Affiliation(s)
- Sindhu Chandran
- Department of Medicine, University of California, San Francisco, California, USA
| | - Joey Leung
- Department of Surgery, University of California, San Francisco, California, USA
| | - Crystal Hu
- Department of Surgery, University of California, San Francisco, California, USA
| | - Zoltan G Laszik
- Department of Pathology, University of California, San Francisco, California, USA
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, California, USA
| | - Flavio G Vincenti
- Department of Medicine, University of California, San Francisco, California, USA.,Department of Surgery, University of California, San Francisco, California, USA
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32
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Abstract
Interstitial fibrosis with tubule atrophy (IF/TA) is the response to virtually any sustained kidney injury and correlates inversely with kidney function and allograft survival. IF/TA is driven by various pathways that include hypoxia, renin-angiotensin-aldosterone system, transforming growth factor (TGF)-β signaling, cellular rejection, inflammation and others. In this review we will focus on key pathways in the progress of renal fibrosis, diagnosis and therapy of allograft fibrosis. This review discusses the role and origin of myofibroblasts as matrix producing cells and therapeutic targets in renal fibrosis with a particular focus on renal allografts. We summarize current trends to use multi-omic approaches to identify new biomarkers for IF/TA detection and to predict allograft survival. Furthermore, we review current imaging strategies that might help to identify and follow-up IF/TA complementary or as alternative to invasive biopsies. We further discuss current clinical trials and therapeutic strategies to treat kidney fibrosis.Supplemental Visual Abstract; http://links.lww.com/TP/C141.
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33
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Puthumana J, Thiessen-Philbrook H, Xu L, Coca SG, Garg AX, Himmelfarb J, Bhatraju PK, Ikizler TA, Siew ED, Ware LB, Liu KD, Go AS, Kaufman JS, Kimmel PL, Chinchilli VM, Cantley LG, Parikh CR. Biomarkers of inflammation and repair in kidney disease progression. J Clin Invest 2021; 131:139927. [PMID: 33290282 PMCID: PMC7843225 DOI: 10.1172/jci139927] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 12/01/2020] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.
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Affiliation(s)
- Jeremy Puthumana
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Leyuan Xu
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Steven G. Coca
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Amit X. Garg
- Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada
| | | | - Pavan K. Bhatraju
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - T. Alp Ikizler
- Division of Nephrology & Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Edward D. Siew
- Division of Nephrology & Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Tennessee Valley Health Services, Nashville Veterans Affairs Hospital, Nashville, Tennessee, USA
| | - Lorraine B. Ware
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kathleen D. Liu
- Division of Nephrology, UCSF School of Medicine, San Francisco, California, USA
| | - Alan S. Go
- Division of Nephrology, UCSF School of Medicine, San Francisco, California, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
| | - James S. Kaufman
- Division of Nephrology, Veterans Affairs New York Harbor Health Care System, New York University School of Medicine, New York, New York, USA
| | - Paul L. Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | - Vernon M. Chinchilli
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Lloyd G. Cantley
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Chirag R. Parikh
- Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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A Rejection Gene Expression Score in Indication and Surveillance Biopsies Is Associated with Graft Outcome. Int J Mol Sci 2020; 21:ijms21218237. [PMID: 33153205 PMCID: PMC7672640 DOI: 10.3390/ijms21218237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 11/26/2022] Open
Abstract
Rejection-associated gene expression has been characterized in renal allograft biopsies for cause. The aim is to evaluate rejection gene expression in subclinical rejection and in biopsies with borderline changes or interstitial fibrosis and tubular atrophy (IFTA). We included 96 biopsies. Most differentially expressed genes between normal surveillance biopsies (n = 17) and clinical rejection (n = 12) were obtained. A rejection-associated gene (RAG) score was defined as its geometric mean. The following groups were considered: (a) subclinical rejection (REJ-S, n = 6); (b) borderline changes in biopsies for cause (BL-C, n = 13); (c) borderline changes in surveillance biopsies (BL-S, n = 12); (d) IFTA in biopsies for cause (IFTA-C, n = 20); and (e) IFTA in surveillance biopsies (IFTA-S, n = 16). The outcome variable was death-censored graft loss or glomerular filtration rate decline ≥ 30 % at 2 years. A RAG score containing 109 genes derived from normal and clinical rejection (area under the curve, AUC = 1) was employed to classify the study groups. A positive RAG score was observed in 83% REJ-S, 38% BL-C, 17% BL-S, 25% IFTA-C, and 5% IFTA-S. A positive RAG score was an independent predictor of graft outcome from histological diagnosis (hazard ratio: 3.5 and 95% confidence interval: 1.1–10.9; p = 0.031). A positive RAG score predicts graft outcome in surveillance and for cause biopsies with a less severe phenotype than clinical rejection.
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Steines L, Poth H, Herrmann M, Schuster A, Banas B, Bergler T. B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats. Int J Mol Sci 2020; 21:ijms21218045. [PMID: 33126753 PMCID: PMC7662293 DOI: 10.3390/ijms21218045] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/23/2020] [Accepted: 10/25/2020] [Indexed: 12/22/2022] Open
Abstract
Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either therapeutic immunosuppression (no rejection, NR) or subtherapeutic immunosuppression (chronic rejection, CR) and were sacrificed on d56. One group additionally received an anti-BAFF antibody (CR + AB). Intra-renal T (CD3+) and B (CD20+) cells, their proliferation (Ki67+), and IgG+ plasma cells were analyzed by immunofluorescence microscopy. Formation of T and B cell zones and TLOs was assessed. Intra-renal expression of TLO-promoting factors, molecules of T:B crosstalk, and B cell differentiation was analyzed by qPCR. Intra-renal B and T cell zones and TLOs were detected in CR and were associated with elevated intra-renal mRNA expression of TLO-promoting factors, including CXCL13, CCL19, lymphotoxin-β, and BAFF. Intra-renal plasma cells were also elevated in CR. Anti-BAFF treatment significantly decreased intra-renal B cell zones and TLO, as well as intra-renal B cell-derived TLO-promoting factors and B cell differentiation markers. We conclude that BAFF-dependent intra-renal B cells promote TLO formation and advance local adaptive alloimmune responses in chronic rejection.
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Affiliation(s)
- Louisa Steines
- Correspondence: ; Tel.: +49-941-9447301; Fax: +49-941-9447302
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Treg expansion with trichostatin A ameliorates kidney ischemia/reperfusion injury in mice by suppressing the expression of costimulatory molecules. Transpl Immunol 2020; 63:101330. [PMID: 32896615 DOI: 10.1016/j.trim.2020.101330] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 01/14/2023]
Abstract
Innate immune reactions are believed to be associated with ischemia/reperfusion injury (IRI), and IRI might be treatable by expanding regulatory T cells (Tregs), which can suppress the excessive responses of the immune system. Organ IRI is known to be closely involved in the expression of costimulatory molecules. The present study aimed to assess whether Tregs endogenously expanded by the administration of trichostatin A (TsA), a histone deacetylase inhibitor, could reduce renal IRI and to clarify their association with the expression of costimulatory molecules in a murine model. In this study, the wild-type mice used for an IRI model were randomly divided into the following four treatment groups: TsA group, DMSO group (control), DMSO+PC61 group, and TsA + PC61 group. Renal injury in the early phase after IRI was ameliorated in the TsA group (increased Tregs) when compared with the other groups. After renal IRI, both the mRNA and the protein levels of anti-inflammatory cytokines, IL-10 and TGF-β in the kidney and spleen were significantly higher in the TsA group than in the other groups, whereas the IL-6 levels were significantly lower in the TsA group than in the other groups. These results were offset by the administration of PC61, supporting that the renoprotective effect of TsA in this study is Treg dependent. mRNA expression levels of CD80, CD86, and ICAM-1 were lower in the TsA group, consistent with Treg control of injury through costimulatory molecules. Our findings suggest that endogenously expanded Tregs coordinate postischemic immune responses and decrease the expression of costimulatory molecules after renal IRI, and thus, they might ameliorate renal IRI. TsA administration for expanding Tregs is a promising therapeutic strategy for renal IRI.
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Yu YM, Ni QQ, Wang ZJ, Chen ML, Zhang LJ. Multiparametric Functional Magnetic Resonance Imaging for Evaluating Renal Allograft Injury. Korean J Radiol 2020; 20:894-908. [PMID: 31132815 PMCID: PMC6536799 DOI: 10.3348/kjr.2018.0540] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/19/2018] [Indexed: 02/06/2023] Open
Abstract
Kidney transplantation is the treatment of choice for patients with end-stage renal disease, as it extends survival and increases quality of life in these patients. However, chronic allograft injury continues to be a major problem, and leads to eventual graft loss. Early detection of allograft injury is essential for guiding appropriate intervention to delay or prevent irreversible damage. Several advanced MRI techniques can offer some important information regarding functional changes such as perfusion, diffusion, structural complexity, as well as oxygenation and fibrosis. This review highlights the potential of multiparametric MRI for noninvasive and comprehensive assessment of renal allograft injury.
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Affiliation(s)
- Yuan Meng Yu
- Department of Medical Imaging, Jinling Hospital, Clinical School of Southern Medical University, Nanjing, China
| | - Qian Qian Ni
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Zhen Jane Wang
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Meng Lin Chen
- Medical Imaging Teaching and Research Office, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Long Jiang Zhang
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
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Fu Q, Liao M, Feng C, Tang J, Liao R, Wei L, Yang H, Markmann JF, Chen K, Deng S. Profiling of mRNA of interstitial fibrosis and tubular atrophy with subclinical inflammation in recipients after kidney transplantation. Aging (Albany NY) 2020; 11:5215-5231. [PMID: 31343413 PMCID: PMC6682514 DOI: 10.18632/aging.102115] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 07/16/2019] [Indexed: 12/18/2022]
Abstract
Interstitial fibrosis and tubular atrophy (IFTA) with inflammation (IFTA-I) is strongly correlated with kidney allograft failure. Diagnosis of IFTA-I accurately and early is critical to prevent graft failure and improve graft survival. In the current study, through analyzing the renal allograft biopsy in patients with stable function after kidney transplantation (STA), IFTA and IFTA-I group with semi-supervised principal components methods, we found that CD2, IL7R, CCL5 based signature could not only distinguish STA and IFTA-I well, but predict IFTA-I with a high degree of accuracy with an area under the curve (AUC) of 0.91 (P = 0.00023). Additionally, IRF8 demonstrated significant differences among STA, IFTA and IFTA-I groups, suggesting that IRF8 had the capacity to discriminate the different classifications of graft biopsies well. Also, with Kaplan-Meier and log-rank methods, we found that IRF8 could serve as the prognostic marker for renal graft failure in those biopsies without rejection (AUC = 0.75) and the recipients expressing high had a higher risk for renal graft loss (P < 0.0001). This research may provide new targets for therapeutic prevention and intervention for post-transplantation IFTA with or with inflammation.
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Affiliation(s)
- Qiang Fu
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine of University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.,Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02148, USA.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China
| | - Minxue Liao
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine of University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China.,North Sichuan Medical College, Nanchong 637100, Sichuan, China
| | - Cheng Feng
- Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China.,Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Jichao Tang
- Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China.,Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Rui Liao
- Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China.,Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Liang Wei
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine of University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China
| | - Hongji Yang
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine of University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China.,North Sichuan Medical College, Nanchong 637100, Sichuan, China.,Southwest Medical University, Luzhou 646000, Sichuan, China
| | - James F Markmann
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02148, USA
| | - Kai Chen
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine of University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China
| | - Shaoping Deng
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine of University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.,Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02148, USA.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan, China.,North Sichuan Medical College, Nanchong 637100, Sichuan, China.,Southwest Medical University, Luzhou 646000, Sichuan, China
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Shaw BI, Cheng DK, Acharya CR, Ettenger RB, Lyerly HK, Cheng Q, Kirk AD, Chambers ET. An age-independent gene signature for monitoring acute rejection in kidney transplantation. Theranostics 2020; 10:6977-6986. [PMID: 32550916 PMCID: PMC7295062 DOI: 10.7150/thno.42110] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. Methods: To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. Results: We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. Conclusion: We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.
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Affiliation(s)
- Brian I Shaw
- Department of Surgery, Duke University Medical Center, Durham, United States
| | - Daniel K. Cheng
- Department of Pediatrics, Duke University Medical Center, Durham, United States
| | | | - Robert B Ettenger
- Department of Pediatrics, UCLA Mattel Children's Hospital, Los Angeles, United States
| | - Herbert Kim Lyerly
- Department of Surgery, Duke University Medical Center, Durham, United States
| | - Qing Cheng
- Department of Surgery, Duke University Medical Center, Durham, United States
| | - Allan D Kirk
- Department of Surgery, Duke University Medical Center, Durham, United States
- Department of Pediatrics, Duke University Medical Center, Durham, United States
| | - Eileen T Chambers
- Department of Surgery, Duke University Medical Center, Durham, United States
- Department of Pediatrics, Duke University Medical Center, Durham, United States
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40
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Moreso F, Sellarès J, Soler MJ, Serón D. Transcriptome Analysis in Renal Transplant Biopsies Not Fulfilling Rejection Criteria. Int J Mol Sci 2020; 21:ijms21062245. [PMID: 32213927 PMCID: PMC7139324 DOI: 10.3390/ijms21062245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/11/2020] [Accepted: 03/20/2020] [Indexed: 01/02/2023] Open
Abstract
The clinical significance of renal transplant biopsies displaying borderline changes suspicious for T-cell mediated rejection (TCMR) or interstitial fibrosis and tubular atrophy (IFTA) with interstitial inflammation has not been well defined. Molecular profiling to evaluate renal transplant biopsies using microarrays has been shown to be an objective measurement that adds precision to conventional histology. We review the contribution of transcriptomic analysis in surveillance and indication biopsies with borderline changes and IFTA associated with variable degrees of inflammation. Transcriptome analysis applied to biopsies with borderline changes allows to distinguish patients with rejection from those in whom mild inflammation mainly represents a response to injury. Biopsies with IFTA and inflammation occurring in unscarred tissue display a molecular pattern similar to TCMR while biopsies with IFTA and inflammation in scarred tissue, apart from T-cell activation, also express B cell, immunoglobulin and mast cell-related genes. Additionally, patients at risk for IFTA progression can be identified by genes mainly reflecting fibroblast dysregulation and immune activation. At present, it is not well established whether the expression of rejection gene transcripts in patients with fibrosis and inflammation is the consequence of an alloimmune response, tissue damage or a combination of both.
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Berchtold L, Crowe LA, Friedli I, Legouis D, Moll S, de Perrot T, Martin PY, Vallée JP, de Seigneux S. Diffusion magnetic resonance imaging detects an increase in interstitial fibrosis earlier than the decline of renal function. Nephrol Dial Transplant 2020; 35:1274-1276. [PMID: 32160279 DOI: 10.1093/ndt/gfaa007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 12/30/2019] [Indexed: 11/14/2022] Open
Affiliation(s)
- Lena Berchtold
- Service and Laboratory of Nephrology, Department of Internal Medicine Specialties and of Physiology and Metabolism, University and University Hospital of Geneva, Geneva, Switzerland
| | - Lindsey A Crowe
- Service of Radiology, Department of Radiology and Medical Informatics, University Hospital of Geneva and University of Geneva, Geneva, Switzerland
| | - Iris Friedli
- Service of Radiology, Department of Radiology and Medical Informatics, University Hospital of Geneva and University of Geneva, Geneva, Switzerland
| | - David Legouis
- Intensive Care Unit, Department of Anaesthesiology, Pharmacology and Intensive Care, University of Geneva, Geneva, Switzerland
| | - Solange Moll
- Institute of Clinical Pathology, Department of Clinical Pathology, University Hospital of Geneva, Geneva, Switzerland
| | - Thomas de Perrot
- Service of Radiology, Department of Radiology and Medical Informatics, University Hospital of Geneva and University of Geneva, Geneva, Switzerland
| | - Pierre-Yves Martin
- Service and Laboratory of Nephrology, Department of Internal Medicine Specialties and of Physiology and Metabolism, University and University Hospital of Geneva, Geneva, Switzerland
| | - Jean-Paul Vallée
- Service of Radiology, Department of Radiology and Medical Informatics, University Hospital of Geneva and University of Geneva, Geneva, Switzerland
| | - Sophie de Seigneux
- Service and Laboratory of Nephrology, Department of Internal Medicine Specialties and of Physiology and Metabolism, University and University Hospital of Geneva, Geneva, Switzerland
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42
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Schaadt NS, Schönmeyer R, Forestier G, Brieu N, Braubach P, Nekolla K, Meyer-Hermann M, Feuerhake F. Graph-based description of tertiary lymphoid organs at single-cell level. PLoS Comput Biol 2020; 16:e1007385. [PMID: 32084130 PMCID: PMC7055921 DOI: 10.1371/journal.pcbi.1007385] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 03/04/2020] [Accepted: 09/09/2019] [Indexed: 01/17/2023] Open
Abstract
Our aim is to complement observer-dependent approaches of immune cell evaluation in microscopy images with reproducible measures for spatial composition of lymphocytic infiltrates. Analyzing such patterns of inflammation is becoming increasingly important for therapeutic decisions, for example in transplantation medicine or cancer immunology. We developed a graph-based assessment of lymphocyte clustering in full whole slide images. Based on cell coordinates detected in the full image, a Delaunay triangulation and distance criteria are used to build neighborhood graphs. The composition of nodes and edges are used for classification, e.g. using a support vector machine. We describe the variability of these infiltrates on CD3/CD20 duplex staining in renal biopsies of long-term functioning allografts, in breast cancer cases, and in lung tissue of cystic fibrosis patients. The assessment includes automated cell detection, identification of regions of interest, and classification of lymphocytic clusters according to their degree of organization. We propose a neighborhood feature which considers the occurrence of edges with a certain type in the graph to distinguish between phenotypically different immune infiltrates. Our work addresses a medical need and provides a scalable framework that can be easily adjusted to the requirements of different research questions.
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Affiliation(s)
| | | | | | | | - Peter Braubach
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | | | - Michael Meyer-Hermann
- Systems Immunology and Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Institute for Biochemistry, Biotechnology and Bioinformatics, TU Braunschweig, Braunschweig, Germany
| | - Friedrich Feuerhake
- Institute for Pathology, Hannover Medical School, Hannover, Germany
- Institute for Neuropathology, University Clinic Freiburg, Freiburg, Germany
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43
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A Novel, Dose-Adjusted Tacrolimus Trough-Concentration Model for Predicting and Estimating Variance After Kidney Transplantation. Drugs R D 2019; 19:201-212. [PMID: 31073875 PMCID: PMC6544741 DOI: 10.1007/s40268-019-0271-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background and Objective Given that a high intrapatient variability (IPV) of tacrolimus whole blood concentration increases the risk for a poor kidney transplant outcome, some experts advocate routine IPV monitoring for detection of high-risk patients. However, attempts to estimate the variance of tacrolimus trough concentrations (TTC) are limited by the need for patients to receive a fixed dose over time and/or the use of linear statistical models. A goal of this study is to overcome the current limitations through the novel application of statistical methodology generalizing the relationship between TTC and dose through the use of nonparametric functional regression modeling. Methods With TTC as a response and dose as a covariate, the model employs an unknown bivariate function, allowing for the potentially complex, nonlinear relationship between the two parameters. A dose-adjusted variance of TTC is then derived based on standard functional principal component analysis (FPCA). To assess the model, it was compared against an FPCA-based model and linear mixed-effects models using prediction error, bias, and coverage probabilities for simulated data as well as phase III data from the Astellas new drug application studies for extended-release tacrolimus. Results Our numerical investigation indicates that the new model better predicts dose-adjusted TTCs compared with the prediction of linear mixed effects models. Estimated coverage probabilities also indicate that the new model accurately accounts for the variance of TTC during the periods of large fluctuation in dose, whereas the linear mixed effects model consistently underestimates the coverage probabilities because of the inaccurate characterization of TTC fluctuation. Conclusion This is the first known application of a functional regression model to assess complex relationships between TTC and dose in a real clinical setting. This new method has applicability in future clinical trials including real-world data sets due to flexibility of the nonparametric modeling approach. Electronic supplementary material The online version of this article (10.1007/s40268-019-0271-2) contains supplementary material, which is available to authorized users.
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Pathak V, Madhavan D, Narayanasamy K, Kumar S, Ramalingam V, Sengodagounder B, Bodonyi-Kovacs G. Low-dose Rituximab and Thymoglobulin Induction With Steroid-free Maintenance Immunosuppression and Protocol Biopsies Improves Long-term Patient and Graft Survival After Kidney Transplantation: Survival and Safety Outcomes in More Than 1100 Patients From a Single Center. Transplant Direct 2019; 5:e475. [PMID: 31576371 PMCID: PMC6708634 DOI: 10.1097/txd.0000000000000923] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 06/04/2019] [Accepted: 06/11/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Steroid-free maintenance immunosuppression after kidney transplantation provides acceptable patient and graft survival and minimizes steroid-associated side effects among recipients with a low immunological risk. However, the long-term outcomes of such protocols, incorporating low-dose rituximab and thymoglobulin induction along with protocol biopsies, in non-European populations remains underreported. METHODS We retrospectively analyzed 1142 consecutive kidney transplantations conducted at our center from July 2005 to October 2017. Immunosuppression protocol included induction with thymoglobulin and low-dose preoperative rituximab. Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil; prednisolone was discontinued on postoperative day 5. Protocol biopsies were carried out at 3 months and at 1, 5, and 10 years after transplantation-in addition to the indicated biopsies. The 12-year patient and graft survival and posttransplantation complications were studied. RESULTS The analysis of outcomes was conducted for 1111 transplant recipients. Patients (70.59%) remained steroid-free at 12 years after transplantation. The patient survival rates at 1, 5, and 12 years were 97.7%, 94.8%, and 92.4%, respectively. The corresponding graft survival rates were 97.2%, 90.9%, and 86.1%, respectively. Biopsy-proven acute rejection occurred in 12.7% of recipients, including 3.5% subclinical rejections. The cumulative incidence of graft loss was 6.56% at 12.3 years. The overall incidence of death was 5.3%. CONCLUSIONS Steroid-free maintenance immunosuppression was associated with excellent long-term patient and graft survival rates and reduced incidence of prednisolone-related side effects, despite acceptable rejection rates. Low-dose rituximab with thymoglobulin induction with immediate steroid withdrawal and surveillance biopsies resulted in excellent long-term outcomes in our single-center experience.
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Affiliation(s)
- Vivek Pathak
- Consultant Nephrologist, Kovai Medical Center, Coimbatore, India
| | - Devdas Madhavan
- Consultant Urologist, Kovai Medical Center, Coimbatore, India
| | | | - Sampath Kumar
- Consultant Urologist, Kovai Medical Center, Coimbatore, India
| | | | | | - Gabor Bodonyi-Kovacs
- Assistant Professor, Division of Nephrology, MFA, George Washington University, Washington, DC
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Philogene MC, Johnson T, Vaught AJ, Zakaria S, Fedarko N. Antibodies against Angiotensin II Type 1 and Endothelin A Receptors: Relevance and pathogenicity. Hum Immunol 2019; 80:561-567. [PMID: 31010696 PMCID: PMC8015780 DOI: 10.1016/j.humimm.2019.04.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/16/2019] [Accepted: 04/16/2019] [Indexed: 12/25/2022]
Abstract
Antibodies against two G-protein coupled receptors (GPCRs), angiotensin II type 1 receptor (AT1R) and endothelin A receptor (ETAR) are among a growing number of autoantibodies that are found to be associated with allograft dysfunction. AT1R antibodies (AT1Rabs) and ETAR antibodies (ETARabs) have been shown to activate their target receptors and affect signaling pathways. Multiple single center reports have shown an association between presence of these antibodies and acute or chronic rejection and graft loss in kidney, heart, liver, lung and composite tissue transplantations. However, the characteristics of patients that are most likely to develop adverse outcomes, the phenotypes associated with graft damage solely due to these antibodies, and the antibody titer required to cause dysfunction are areas that remain controversial. This review compiles existing knowledge on the effect of antibodies against GPCRs in other diseases in order to bridge the gap in knowledge within transplantation biology. Future areas for research are highlighted and include the need for functional assays and treatment protocols for transplant patients who present with AT1Rabs and ETARabs. Understanding how antibodies that activate GPCRs influence transplantation outcome will have direct clinical implications for preemptive evaluation of transplant candidates as well as the post-transplant care of organ recipients.
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Affiliation(s)
- Mary Carmelle Philogene
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Tory Johnson
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Arthur Jason Vaught
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Sammy Zakaria
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Neal Fedarko
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Jiang K, Ferguson CM, Lerman LO. Noninvasive assessment of renal fibrosis by magnetic resonance imaging and ultrasound techniques. Transl Res 2019; 209:105-120. [PMID: 31082371 PMCID: PMC6553637 DOI: 10.1016/j.trsl.2019.02.009] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/12/2019] [Accepted: 02/20/2019] [Indexed: 02/06/2023]
Abstract
Renal fibrosis is a useful biomarker for diagnosis and guidance of therapeutic interventions of chronic kidney disease (CKD), a worldwide disease that affects more than 10% of the population and is one of the major causes of death. Currently, tissue biopsy is the gold standard for assessment of renal fibrosis. However, it is invasive, and prone to sampling error and observer variability, and may also result in complications. Recent advances in diagnostic imaging techniques, including magnetic resonance imaging (MRI) and ultrasonography, have shown promise for noninvasive assessment of renal fibrosis. These imaging techniques measure renal fibrosis by evaluating its impacts on the functional, mechanical, and molecular properties of the kidney, such as water mobility by diffusion MRI, tissue hypoxia by blood oxygenation level dependent MRI, renal stiffness by MR and ultrasound elastography, and macromolecule content by magnetization transfer imaging. Other MR techniques, such as T1/T2 mapping and susceptibility-weighted imaging have also been explored for measuring renal fibrosis. Promising findings have been reported in both preclinical and clinical studies using these techniques. Nevertheless, limited specificity, sensitivity, and practicality in these techniques may hinder their immediate application in clinical routine. In this review, we will introduce methodologies of these techniques, outline their applications in fibrosis imaging, and discuss their limitations and pitfalls.
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Affiliation(s)
- Kai Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | | | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
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Cockfield SM, Wilson S, Campbell PM, Cantarovich M, Gangji A, Houde I, Jevnikar AM, Keough‐Ryan TM, Monroy‐Cuadros F, Nickerson PW, Pâquet MR, Ramesh Prasad GV, Senécal L, Shoker A, Wolff J, Howell J, Schwartz JJ, Rush DN. Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts. Am J Transplant 2019; 19:1730-1744. [PMID: 30582281 PMCID: PMC6590452 DOI: 10.1111/ajt.15225] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 12/10/2018] [Accepted: 12/12/2018] [Indexed: 01/25/2023]
Abstract
Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.
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Affiliation(s)
| | - Sam Wilson
- Astellas Pharma Global DevelopmentNorthbrookIllinois
| | | | | | - Azim Gangji
- St. Joseph's Healthcare HamiltonHamiltonOntarioCanada
| | | | | | | | | | | | | | | | | | | | | | - John Howell
- Astellas Pharma Global Development, Inc.MarkhamOntarioCanada
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Paoletti E, Bussalino E, Bellino D, Tagliamacco A, Bruzzone M, Ravera M, Parodi A, Fontana I, Gaggero G, Garibotto G, Ravetti JL. Early interstitial macrophage infiltration with mild dysfunction is associated with subsequent kidney graft loss. Clin Transplant 2019; 33:e13579. [PMID: 31034645 DOI: 10.1111/ctr.13579] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 04/15/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post-transplant year. Banff score, CD68+ count (score 0-3) by immunohistochemistry, and 1-year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68+ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow-up, four patients (11%) suffered from biopsy-proven T-cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68+ group). Graft survival was lower in KTRs with grade 3 CD68+ infiltration (P = 0.0074; log-rank test). Grade 3 CD68+ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74-16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57-16; P < 0.001). We conclude that grade 3 CD68+ interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors.
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Affiliation(s)
- Ernesto Paoletti
- Nephrology, Dialysis, and Transplantation, University of Genova, Ospedale Policlinico San Martino, Genova, Italy
| | - Elisabetta Bussalino
- Nephrology, Dialysis, and Transplantation, University of Genova, Ospedale Policlinico San Martino, Genova, Italy
| | - Diego Bellino
- Nephrology, Dialysis, and Transplantation, University of Genova, Ospedale Policlinico San Martino, Genova, Italy
| | | | - Marco Bruzzone
- Clinical Epidemiology Unit, Ospedale Policlinico San Martino, Genova, Italy
| | - Maura Ravera
- Nephrology, Dialysis, and Transplantation, University of Genova, Ospedale Policlinico San Martino, Genova, Italy
| | - Angelica Parodi
- Nephrology, Dialysis, and Transplantation, University of Genova, Ospedale Policlinico San Martino, Genova, Italy
| | - Iris Fontana
- Renal Transplantation Unit, Ospedale Policlinico San Martino, Genova, Italy
| | | | - Giacomo Garibotto
- Nephrology, Dialysis, and Transplantation, University of Genova, Ospedale Policlinico San Martino, Genova, Italy
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49
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Ho J, Sharma A, Kroeker K, Carroll R, De Serres S, Gibson IW, Hirt-Minkowski P, Jevnikar A, Kim SJ, Knoll G, Rush DN, Wiebe C, Nickerson P. Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients. BMJ Open 2019; 9:e024908. [PMID: 30975673 PMCID: PMC6500325 DOI: 10.1136/bmjopen-2018-024908] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
INTRODUCTION Subclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients. METHODS AND ANALYSIS This is a phase ii/iii multicentre, international randomised controlled parallel group trial to determine if the early treatment of rejection, as detected by urine CXCL10, will improve kidney allograft outcomes. Incident adult kidney transplant patients (n~420) will be enrolled to undergo routine urine CXCL10 monitoring postkidney transplant. Patients at high risk of rejection, defined as confirmed elevated urine CXCL10 level, will be randomised 1:1 stratified by centre (n=250). The intervention arm (n=125) will undergo a study biopsy to check for subclinical rejection and biopsy-proven rejection will be treated per protocol. The control arm (n=125) will undergo routine post-transplant monitoring. The primary outcome at 12 months is a composite of death-censored graft loss, clinical biopsy-proven acute rejection, de novo donor-specific antibody, inflammation in areas of interstitial fibrosis and tubular atrophy (Banff i-IFTA, chronic active T-cell mediated rejection) and subclinical tubulitis on 12-month surveillance biopsy. The secondary outcomes include decline of graft function, microvascular inflammation at 12 months, development of IFTA at 12 months, days from transplantation to clinical biopsy-proven rejection, albuminuria, EuroQol five-dimension five-level instrument, cost-effectiveness analysis of the urine CXCL10 monitoring strategy and the urine CXCL10 kinetics in response to rejection therapy. ETHICS AND DISSEMINATION The study has been approved by the University of Manitoba Health Research Ethics Board (HS20861, B2017:076) and the local research ethics boards of participating centres. Recruitment commenced in March 2018 and results are expected to be published in 2023. De-identified data may be shared with other researchers according to international guidelines (International Committee of Medical Journal Editors [ICJME]). TRIAL REGISTRATION NUMBER NCT03206801; Pre-results.
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Affiliation(s)
- Julie Ho
- Internal Medicine, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada
- Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Atul Sharma
- Data Science, George and Fay Yee Centre for Healthcare Innovation, Winnipeg, Manitoba, Canada
| | - Kristine Kroeker
- Data Science, George and Fay Yee Centre for Healthcare Innovation, Winnipeg, Manitoba, Canada
| | - Robert Carroll
- Transplant Nephrology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Sacha De Serres
- Internal Medicine & Nephrology, Universite Laval, Québec, Québec, Canada
| | - Ian W Gibson
- Pathology, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Anthony Jevnikar
- Internal Medicine & Nephrology, Western University, London, Ontario, Canada
| | - S Joseph Kim
- Internal Medicine & Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - Greg Knoll
- Internal Medicine & Nephrology, University of Ottawa, Ottawa, Ontario, Canada
| | - David N Rush
- Internal Medicine, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada
| | - Chris Wiebe
- Internal Medicine, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada
| | - Peter Nickerson
- Internal Medicine, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada
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50
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Sparkes T, Ravichandran B, Opara O, Ugarte R, Drachenberg CB, Philosophe B, Bromberg JS, Barth RN. Alemtuzumab induction and belatacept maintenance in marginal pathology renal allografts. Clin Transplant 2019; 33:e13531. [PMID: 30866104 DOI: 10.1111/ctr.13531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 03/04/2019] [Indexed: 12/28/2022]
Abstract
We performed a prospective, 12-month, single-center, nonrandomized, open-label pilot study to investigate the use of belatacept therapy combined with alemtuzumab induction in renal allografts with preexisting pathology, as these kidneys may be more susceptible to additional toxicity when exposed to calcineurin inhibitors posttransplant. Nineteen belatacept recipients were matched retrospectively to a cohort of tacrolimus recipients on the basis of preimplantation pathology. The estimated glomerular filtration rate was not significantly different between belatacept and tacrolimus recipients at either 3 or 12 months posttransplant (59 vs 45, P = 0.1 and 56 vs 48 mL/min/1.72/m2 , P = 0.3). Biopsy-proven acute rejection rates at 12 months were 26% in belatacept recipients and 16% in tacrolimus recipients (P = 0.7). Graft survival at 1 year was 89% in both groups. Alemtuzumab induction combined with either calcineurin inhibitor or costimulatory blockade therapies resulted in similar acceptable one-year outcomes in kidneys with preexisting pathologic changes. Longer-term follow-up may be necessary to identify preferential strategies to improve outcomes of kidneys at a higher risk for poor function (ClinicalTrials.gov-NCT01496417).
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Affiliation(s)
- Tracy Sparkes
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, Maryland
| | - Bharath Ravichandran
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, Maryland
| | - Onumara Opara
- Department of Transplant, University of Maryland School of Medicine, Baltimore, Maryland
| | - Richard Ugarte
- Department of Transplant, University of Maryland School of Medicine, Baltimore, Maryland
| | - Cinthia B Drachenberg
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Benjamin Philosophe
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jonathan S Bromberg
- Department of Transplant, University of Maryland School of Medicine, Baltimore, Maryland
| | - Rolf N Barth
- Department of Transplant, University of Maryland School of Medicine, Baltimore, Maryland
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