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Paschen C, Koeller MC, Schachner H, Nackenhorst M, Kläger J, Oszwald A, Dörr K, Kammer M, Kozakowski N, Rees A, Kain R, Hecking M, Oberbauer R, Regele H. Association of Podometric Findings in Patients With Hypertension and Type 2 Diabetes: A Retrospective Analysis. Hypertension 2025; 82:1071-1080. [PMID: 40047102 DOI: 10.1161/hypertensionaha.124.24379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/19/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Arterial hypertension (HTN) and type 2 diabetes (T2DM) are contributors to chronic kidney disease leading to glomerulomegaly and podocyte loss. Enlarged glomeruli and podocyte depletion are associated with kidney disease progression. This retrospective study aimed to investigate morphometric changes in patients with HTN and the contribution of coexisting T2DM in HTN. METHODS Glomerular and podocyte structure was estimated stereologically in unaffected areas of tumor nephrectomies in 99 patients. Morphometric features between subjects with HTN (n=47), HTN+T2DM (n=32), and controls without HTN and T2DM (n=20) were compared by ANOVA. Linear regression models evaluated the effect of morphometric parameters on renal compensation after nephrectomy (change of estimated glomerular filtration rate from pre-nephrectomy to 12 months post-nephrectomy). RESULTS In total, 36% of the HTN and 50% of the patients with T2DM exhibited dipstick-positive proteinuria. Glomerular volume in HTN+T2DM was similar compared with controls (2.7±0.8 versus 2.3±0.8×106 µm³; P=0.16) and to HTN only (2.7±0.9×106 µm³; P=0.95). Podocyte density was reduced in HTN+T2DM versus controls (217±66 versus 279±75 per 106 µm³; P=0.02) and not different to HTN only (233±87 per 106 µm³; P=0.67). Podocyte nuclear volume was larger in HTN+T2DM versus controls (230±28 versus 201±32 µm³; P=0.004) and similar to HTN (221±33 µm³; P=0.39). Larger glomerular volume (P=0.009), reduced podocyte density (P=0.003), and nuclear hypertrophy (P=0.01) were associated with impaired compensation. CONCLUSION The patterns of podocyte depletion and nuclear hypertrophy were independently observed in both HTN and HTN+T2DM versus controls. Coexisting T2DM exhibited no additional contribution to glomerular and podocyte alterations.
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Affiliation(s)
- Christopher Paschen
- Division of Nephrology and Dialysis, Department of Medicine III (C.P., K.D., M.K., M.H., R.O.), Medical University of Vienna, Austria
| | - Maximilian C Koeller
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Helga Schachner
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Maja Nackenhorst
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Johannes Kläger
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Andre Oszwald
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Katharina Dörr
- Division of Nephrology and Dialysis, Department of Medicine III (C.P., K.D., M.K., M.H., R.O.), Medical University of Vienna, Austria
| | - Michael Kammer
- Division of Nephrology and Dialysis, Department of Medicine III (C.P., K.D., M.K., M.H., R.O.), Medical University of Vienna, Austria
- Institute for Clinical Biometrics, Center for Medical Data Science (M.K.), Medical University of Vienna, Austria
| | - Nicolas Kozakowski
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Andrew Rees
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Renate Kain
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
| | - Manfred Hecking
- Division of Nephrology and Dialysis, Department of Medicine III (C.P., K.D., M.K., M.H., R.O.), Medical University of Vienna, Austria
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Medicine III (C.P., K.D., M.K., M.H., R.O.), Medical University of Vienna, Austria
| | - Heinz Regele
- Department of Pathology (M.C.K., H.S., M.N., J.K., A.O., N.K., A.R., R.K., H.R.), Medical University of Vienna, Austria
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Margeta D, Noguchi H, Khazaie S, Herlitz LC, Augustine JJ, Heeger PS, Tambur AR, Fairchild RL, Baldwin WM. Spatial transcriptomics of Glomerulo-centric antibody mediated rejection in renal transplants. Clin Immunol 2025; 274:110460. [PMID: 39993695 DOI: 10.1016/j.clim.2025.110460] [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: 01/10/2025] [Revised: 02/20/2025] [Accepted: 02/20/2025] [Indexed: 02/26/2025]
Abstract
In this case study, we used Digital Spatial Profiling to localize transcripts in a series of 4 biopsies from a single patient before, during and after treatment for acute antibody-mediated rejection that was characterized by strong C4d staining of the glomeruli. Spatial resolution demonstrated that molecular signatures of innate immune cells including NK cells and macrophages are located in glomeruli during AMR, and transcripts for HLA class II antigens were upregulated in the glomeruli. In contrast, transcripts of signature genes for podocytes were decreased during rejection. Treatment with IVIg resolved histological evidence of glomerulitis but did not restore expression of podocyte transcripts. These data demonstrate a vulnerability of podocytes in acute AMR with persistent glomerulitis. Additionally, by using a protocol biopsy from the same patient as a baseline, transcript changes for an informative set of genes were uncovered to test for podocyte dysfunction in future patients.
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Affiliation(s)
- Dajana Margeta
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH, USA
| | - Hirotsugu Noguchi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH, USA
| | - Sepideh Khazaie
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH, USA
| | - Leal C Herlitz
- Department of Anatomic Pathology, Cleveland Clinic, OH, USA
| | | | - Peter S Heeger
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anat R Tambur
- Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA
| | - Robert L Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH, USA
| | - William M Baldwin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH, USA.
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Takashima K, Hitosugi M, Uno A, Taniura N, Mukaisho KI, Maruo Y. Continuous increase in podocyte numbers in the first 36 months of life-insights from forensic autopsies in Japanese children. Pediatr Nephrol 2025; 40:1613-1624. [PMID: 39792255 DOI: 10.1007/s00467-024-06644-7] [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: 09/11/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Podocyte depletion is a critical factor in glomerulosclerosis development. While podocyte numbers per glomerulus typically decline with age in adults, they are hypothesized to increase during childhood. However, studies on podocyte number progression in childhood have been limited. METHODS This retrospective analysis examined forensic autopsy cases of Japanese children without kidney disease, aged under 192 months, between April 2010 and March 2023. Podocytes were identified using immunostaining with an anti-transducin-like enhancer of split 4 antibody and p57. Podometric parameters were estimated using the correction factor method, allowing estimation from a single histologic section. RESULTS This study included 68 cases with a median age of 9 months (interquartile range [IQR], 4-78). All podometric parameters correlated with age. Children younger than 36 months displayed significantly fewer podocyte numbers per glomerulus (median, 517; IQR, 483-546) compared to those aged 36 months and older (median, 616; IQR, 595-649; p < 0.001). Regression analysis revealed a significant age-related increase in podocyte numbers per glomerulus in children under 36 months (slope, 3.76; p < 0.001; 95% confidence interval [CI], 2.34-5.19), but not in those aged 36 months and older (slope, 0.25; p = 0.16; 95% CI, - 0.10-0.61). Additionally, the change in the slope at 36 months was significant (p < 0.001; 95% CI, 1.02-2.49); however, this increase did not appear linked to podocyte division. CONCLUSIONS Podocyte numbers per glomerulus increased from birth until 36 months and then stabilized. These findings could facilitate the development of novel treatments for chronic kidney disease caused by glomerulosclerosis and contribute to pediatric kidney health research.
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Affiliation(s)
- Kohei Takashima
- Department of Legal Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan
- Department of Pediatrics, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Masahito Hitosugi
- Department of Legal Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan.
| | - Akari Uno
- Department of Legal Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Naoko Taniura
- Education Center for Medicine and Nursing, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Ken-Ich Mukaisho
- Education Center for Medicine and Nursing, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Shiga, 520-2192, Japan
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Haririan A, Zare Z, Papadimitriou JC, Ugarte R, Ahmed HMA, Niederhaus SV, Drachenberg CB. Association of Ultrastructural Changes in Renal Allograft Biopsies With Diagnostic Elements of Antibody-Mediated Rejection and Graft Outcomes. Transplantation 2025:00007890-990000000-01072. [PMID: 40279545 DOI: 10.1097/tp.0000000000005416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
BACKGROUND The role of electron microscopy (EM) in the diagnosis of kidney allograft pathologies, particularly immunologic injury has not been well studied. METHODS In this retrospective, single-center cohort study, we examined EM features in 796 biopsies from 623 patients at high risk for antibody-mediated rejection, with glomerular abnormalities in light microscopy, presence of donor-specific antibody (DSA), or any degree of albuminuria/proteinuria. RESULTS Glomerular endothelial cell enlargement (GECE) > 50% was present in 29.1%, subendothelial expansion/basement membrane duplication in 24.5%, and peritubular basement membrane multilamellation > 4 (PTCML) in 18.5%. There was an incremental odds of worsening GECE from no DSA to class I DSA (odds ratio [OR], 2.75, P < 0.001; 95% confidence interval [CI], 1.7-4.5), class II DSA (OR, 3.44, P < 0.001, 95% CI, 2.5-4.7) and both classes (OR, 6.3, P < 0.001; 95% CI, 4.1-9.8). Moreover, the increase in number of antibodies was predictive of higher likelihood of worsening GECE (OR, 2.81, P < 0.001; 95% CI, 2.1-3.8 for 1 DSA; OR, 5.29, P < 0.001; 95% CI, 3.5-7.9 for 2-3; and OR, 8.45, P < 0.001; 95% CI, 4.7-15.3 for ≥4). Similar association was observed with PTCML. In multivariate analysis including DSA, subendothelial expansion/basement membrane duplication, and GECE >50%, but not PTCML were independently predictive of graft failure over mean follow-up of 63 mo (hazard ratio [HR], 1.6, P = 0.006, 95% CI, 1.2-2.3; HR, 2.0, P < 0.001; 95% CI, 1.4-2.9, respectively). Among a cohort with g, ptc, cg, and C4d scores 0, GECE >50% was independently associated with graft failure (HR, 2.58, P < 0.001, 95% CI, 1.6-4.3). CONCLUSIONS These observations support the wider use of EM in kidney transplant biopsies to help with earlier diagnosis of antibody-mediated rejection and to risk stratify the graft outcome.
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Affiliation(s)
- Abdolreza Haririan
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Zakieh Zare
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - John C Papadimitriou
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD
| | - Richard Ugarte
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Hiba M A Ahmed
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Silke V Niederhaus
- Division of Transplant Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
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Hanna C, Etry HE, Ibrahim M, Khalife L, Bahous SA, Faour WH. Podocyturia an emerging biomarker for kidney injury. BMC Nephrol 2025; 26:118. [PMID: 40045253 PMCID: PMC11884025 DOI: 10.1186/s12882-025-04039-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/21/2025] [Indexed: 03/09/2025] Open
Abstract
Podocyte injury is an established hallmark of kidney disease progression. Podocyte loss is a widely proven hypothesis to explain, in part, glomerular damage. Regardless of the underlying kidney disease, the pathophysiologic processes frequently involve the glomerulus. A growing body of evidence considered that podocytes detachment (podocytopathy) and their presence in the urine (podocyturia) are the hallmark of glomerular disease progression. As such, developing new tools to monitor disease progression non-invasively is of major clinical importance. Detection of podocytes in the urine as a biomarker of disease progression would be a major achievement toward the development of such tools. This review summarizes current knowledge about podocyturia.
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Affiliation(s)
- Charbel Hanna
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Hady El Etry
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Maroun Ibrahim
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Lynn Khalife
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Sola Aoun Bahous
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon.
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon.
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Cruzado JM, Sola A, Pato ML, Manonelles A, Varela C, Setién FE, Quero-Dotor C, Heald JS, Piñeyro D, Amaya-Garrido A, Doladé N, Codina S, Couceiro C, Bolaños N, Gomà M, Vigués F, Merkel A, Romagnani P, Berdasco M. Severe ischemia-reperfusion injury induces epigenetic inactivation of LHX1 in kidney progenitor cells after kidney transplantation. Am J Transplant 2025; 25:476-488. [PMID: 39521058 DOI: 10.1016/j.ajt.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/16/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
Severe ischemia-reperfusion injury (IRI) causes acute and chronic kidney allograft damage. As therapeutic interventions to reduce damage are limited yet, research on how to promote kidney repair has gained significant interest. To address this question, we performed genome-wide transcriptome and epigenome profiling in progenitor cells isolated from the urine of deceased (severe IRI) and living (mild IRI) donor human kidney transplants and identified LIM homeobox-1 (LHX1) as an epigenetically regulated gene whose expression depends on the IRI severity. Using a mouse model of IRI, we observed a relationship between IRI severity, LHX1 promoter hypermethylation, and LHX1 gene expression. Using functional studies, we confirmed that LHX1 expression is involved in the proliferation of epithelial tubular cells and podocyte differentiation from kidney progenitor cells. Our results provide evidence that severe IRI may reduce intrinsic mechanisms of kidney repair through epigenetic signaling.
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Affiliation(s)
- Josep M Cruzado
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain; Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.
| | - Anna Sola
- Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; Nephrology and Dialysis Unit, Meyer Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Florence, Italy; Department of Biomedical, Experimental and Clinical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Miguel L Pato
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; Epigenetic Therapies Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
| | - Anna Manonelles
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain; Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
| | - Cristian Varela
- Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
| | - Fernando E Setién
- Cancer Epigenetics Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
| | - Carlos Quero-Dotor
- Cancer Epigenetics Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
| | - James S Heald
- Epigenetic Therapies Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
| | - David Piñeyro
- Cancer Epigenetics Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
| | - Ana Amaya-Garrido
- Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
| | - Núria Doladé
- Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
| | - Sergi Codina
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain; Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
| | - Carlos Couceiro
- Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain; Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
| | - Núria Bolaños
- Nephrology and Renal Transplantation Group, Infectious Disease and Transplantation Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain
| | - Montserrat Gomà
- Department of Pathology, Hospital Universitari Bellvitge, Barcelona, Spain
| | - Francesc Vigués
- Department of Clinical Sciences, University of Barcelona, Barcelona, Spain; Department of Urology, Hospital Universitari Bellvitge, Barcelona, Spain
| | - Angelika Merkel
- Bioinformatics Unit, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
| | - Paola Romagnani
- Nephrology and Dialysis Unit, Meyer Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Florence, Italy; Department of Biomedical, Experimental and Clinical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - María Berdasco
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain; Epigenetic Therapies Group, Genesis of Cancer Program, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain.
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Liu X, Fang H, Liang D, Lei Q, Wang J, Xu F, Liang S, Liang D, Yang F, Li H, Chen J, Ni Y, Xie G, Zeng C. Advancing the application of the analytical renal pathology system in allograft IgA nephropathy patients. Ren Fail 2024; 46:2322043. [PMID: 38425049 PMCID: PMC10911252 DOI: 10.1080/0886022x.2024.2322043] [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: 01/17/2024] [Accepted: 02/16/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND The analytical renal pathology system (ARPS) based on convolutional neural networks has been used successfully in native IgA nephropathy (IgAN) patients. Considering the similarity of pathologic features, we aim to evaluate the performance of the ARPS in allograft IgAN patients and broaden its implementation. METHODS Biopsy-proven allograft IgAN patients from two different centers were enrolled for internal and external validation. We implemented the ARPS to identify glomerular lesions and intrinsic glomerular cells, and then evaluated its performance. Consistency between the ARPS and pathologists was assessed using intraclass correlation coefficients. The association of digital pathological features with clinical and pathological data was measured. Kaplan-Meier survival curve and cox proportional hazards model were applied to investigate prognosis prediction. RESULTS A total of 56 biopsy-proven allograft IgAN patients from the internal center and 17 biopsy-proven allograft IgAN patients from the external center were enrolled in this study. The ARPS was successfully applied to identify the glomerular lesions (F1-score, 0.696-0.959) and quantify intrinsic glomerular cells (F1-score, 0.888-0.968) in allograft IgAN patients rapidly and precisely. Furthermore, the mesangial hypercellularity score was positively correlated with all mesangial metrics provided by ARPS [Spearman's correlation coefficient (r), 0.439-0.472, and all p values < 0.001]. Besides, a higher allograft survival was noticed among patients in the high-level groups of the maximum and ratio of endothelial cells, as well as the maximum and density of podocytes. CONCLUSION We propose that the ARPS could be implemented in future clinical practice with outstanding capability.
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Affiliation(s)
- Xumeng Liu
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Huiwen Fang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Dongmei Liang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qunjuan Lei
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | | | - Feng Xu
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Shaoshan Liang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Dandan Liang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Fan Yang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Heng Li
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
| | - Jianghua Chen
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
| | - Yuan Ni
- Ping An Healthcare Technology, Shanghai, China
| | - Guotong Xie
- Ping An Healthcare Technology, Shanghai, China
| | - Caihong Zeng
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
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Chutani A, Guevara-Pineda D, Lerner GB, Menon MC. Re-Evaluating the Transplant Glomerulopathy Lesion-Beyond Donor-Specific Antibodies. Transpl Int 2024; 37:13365. [PMID: 39640250 PMCID: PMC11617188 DOI: 10.3389/ti.2024.13365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 10/29/2024] [Indexed: 12/07/2024]
Abstract
There have been significant advances in short-term outcomes in renal transplantation. However, longer-term graft survival has improved only minimally. After the first post-transplant year, it has been estimated that chronic allograft damage is responsible for 5% of graft loss per year. Transplant glomerulopathy (TG), a unique morphologic lesion, is reported to accompany progressive chronic allograft dysfunction in many cases. While not constituting a specific etiologic diagnosis, TG is primarily considered as a histologic manifestation of ongoing allo-immune damage from donor-specific anti-HLA alloantibodies (DSA). In this review article, we re-evaluate the existing literature on TG, with particular emphasis on the role of non-HLA-antibodies and complement-mediated injury, cell-mediated immune mechanisms, and early podocyte stress in the pathogenesis of Transplant Glomerulopathy.
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Affiliation(s)
- Arun Chutani
- Transplant Nephrology, Yale University of School of Medicine, New Haven, CT, United States
| | | | | | - Madhav C. Menon
- Nephrology, Medicine, Research in Kidney Transplantation, Faculty in Human Translational Immunology and Translational Biomedicine, Yale School of Medicine, New Haven, CT, United States
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Boshart A, Petrovic S, Abovsky M, Pastrello C, Farkona S, Manion K, Neupane S, Allen M, Jurisica I, Konvalinka A. Molecular landscape of kidney allograft tissues data integration portal (NephroDIP): a curated database to improve integration of high-throughput kidney transplant datasets. Front Immunol 2024; 15:1469500. [PMID: 39399491 PMCID: PMC11466753 DOI: 10.3389/fimmu.2024.1469500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/03/2024] [Indexed: 10/15/2024] Open
Abstract
Introduction Kidney transplantation is the optimal treatment for end-stage kidney disease; however, premature allograft loss remains a serious issue. While many high-throughput omics studies have analyzed patient allograft biospecimens, integration of these datasets is challenging, which represents a considerable barrier to advancing our understanding of the mechanisms of allograft loss. Methods To facilitate integration, we have created a curated database containing all open-access high-throughput datasets from human kidney transplant studies, termed NephroDIP (Nephrology Data Integration Portal). PubMed was searched for high-throughput transcriptomic, proteomic, single nucleotide variant, metabolomic, and epigenomic studies in kidney transplantation, which yielded 9,964 studies. Results From these, 134 studies with available data detailing 260 comparisons and 83,262 molecules were included in NephroDIP v1.0. To illustrate the capabilities of NephroDIP, we have used the database to identify common gene, protein, and microRNA networks that are disrupted in patients with chronic antibody-mediated rejection, the most important cause of late allograft loss. We have also explored the role of an immunomodulatory protein galectin-1 (LGALS1), along with its interactors and transcriptional regulators, in kidney allograft injury. We highlight the pathways enriched among LGALS1 interactors and transcriptional regulators in kidney fibrosis and during immunosuppression. Discussion NephroDIP is an open access data portal that facilitates data visualization and will help provide new insights into existing kidney transplant data through integration of distinct studies and modules (https://ophid.utoronto.ca/NephroDIP).
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Affiliation(s)
- Alex Boshart
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Stefan Petrovic
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Mark Abovsky
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Kieran Manion
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Slaghaniya Neupane
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Maya Allen
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Departments of Medical Biophysics and Computer Science, and Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada
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10
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Fukuda A, Sato Y, Shibata H, Fujimoto S, Wiggins RC. Urinary podocyte markers of disease activity, therapeutic efficacy, and long-term outcomes in acute and chronic kidney diseases. Clin Exp Nephrol 2024; 28:496-504. [PMID: 38402504 PMCID: PMC11116200 DOI: 10.1007/s10157-024-02465-y] [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: 12/18/2023] [Accepted: 01/14/2024] [Indexed: 02/26/2024]
Abstract
A critical degree of podocyte depletion causes glomerulosclerosis, and persistent podocyte loss in glomerular diseases drives the progression to end-stage kidney disease. The extent of podocyte injury at a point in time can be histologically assessed by measuring podocyte number, size, and density ("Biopsy podometrics"). However, repeated invasive renal biopsies are associated with increased risk and cost. A noninvasive method for assessing podocyte injury and depletion is required. Albuminuria and proteinuria do not always correlate with disease activity. Podocytes are located on the urinary space side of the glomerular basement membrane, and as they undergo stress or detach, their products can be identified in urine. This raises the possibility that urinary podocyte products can serve as clinically useful markers for monitoring glomerular disease activity and progression ("Urinary podometrics"). We previously reported that urinary sediment podocyte mRNA reflects disease activity in both animal models and human glomerular diseases. This includes diabetes and hypertension which together account for 60% of new-onset dialysis induction patients. Improving approaches to preventing progression is an urgent priority for the renal community. Sufficient evidence now exists to indicate that monitoring urinary podocyte markers could serve as a useful adjunctive strategy for determining the level of current disease activity and response to therapy in progressive glomerular diseases.
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Affiliation(s)
- Akihiro Fukuda
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Yufu City, Oita, 879-5593, Japan.
| | - Yuji Sato
- Division of Nephrology, Department of Internal Medicine, National Health Insurance Takachiho Town Hospital, Takachiho, Miyazaki, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Yufu City, Oita, 879-5593, Japan
| | - Shouichi Fujimoto
- Department of Medical Environment Innovation, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Roger C Wiggins
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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11
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Barsotti GC, Luciano R, Kumar A, Meliambro K, Kakade V, Tokita J, Naik A, Fu J, Peck E, Pell J, Reghuvaran A, Tanvir E, Patel P, Zhang W, Li F, Moeckel G, Perincheri S, Cantley L, Moledina DG, Wilson FP, He JC, Menon MC. Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis. Kidney Int Rep 2024; 9:1354-1368. [PMID: 38707807 PMCID: PMC11068976 DOI: 10.1016/j.ekir.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.
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Affiliation(s)
- Gabriel C. Barsotti
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Randy Luciano
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Ashwani Kumar
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kristin Meliambro
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Vijayakumar Kakade
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Joji Tokita
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Abhijit Naik
- Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Jia Fu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Elizabeth Peck
- Clinical Research Coordinator, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - John Pell
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Anand Reghuvaran
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - E.M. Tanvir
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Prashant Patel
- Investigational Drug Service, Department of Pharmacy Services, Yale New Haven Hospital, Connecticut, USA
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Fan Li
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA
| | - Gilbert Moeckel
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Sudhir Perincheri
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Lloyd Cantley
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Dennis G. Moledina
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - F. Perry Wilson
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - John C. He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Madhav C. Menon
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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12
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Farhat I, Maréchal E, Calmo D, Ansart M, Paindavoine M, Bard P, Tarris G, Ducloux D, Felix SA, Martin L, Tinel C, Gibier JB, Funes de la Vega M, Rebibou JM, Bamoulid J, Legendre M. Recognition of intraglomerular histological features with deep learning in protocol transplant biopsies and their association with kidney function and prognosis. Clin Kidney J 2024; 17:sfae019. [PMID: 38370429 PMCID: PMC10873504 DOI: 10.1093/ckj/sfae019] [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: 10/31/2023] [Indexed: 02/20/2024] Open
Abstract
Background The Banff Classification may not adequately address protocol transplant biopsies categorized as normal in patients experiencing unexplained graft function deterioration. This study seeks to employ convolutional neural networks to automate the segmentation of glomerular cells and capillaries and assess their correlation with transplant function. Methods A total of 215 patients were categorized into three groups. In the Training cohort, glomerular cells and capillaries from 37 patients were manually annotated to train the networks. The Test cohort (24 patients) compared manual annotations vs automated predictions, while the Application cohort (154 protocol transplant biopsies) examined predicted factors in relation to kidney function and prognosis. Results In the Test cohort, the networks recognized histological structures with Precision, Recall, F-score and Intersection Over Union exceeding 0.92, 0.85, 0.89 and 0.74, respectively. Univariate analysis revealed associations between the estimated glomerular filtration rate (eGFR) at biopsy and relative endothelial area (r = 0.19, P = .027), endothelial cell density (r = 0.20, P = .017), mean parietal epithelial cell area (r = -0.38, P < .001), parietal epithelial cell density (r = 0.29, P < .001) and mesangial cell density (r = 0.22, P = .010). Multivariate analysis retained only endothelial cell density as associated with eGFR (Beta = 0.13, P = .040). Endothelial cell density (r = -0.22, P = .010) and mean podocyte area (r = 0.21, P = .016) were linked to proteinuria at biopsy. Over 44 ± 29 months, 25 patients (16%) reached the primary composite endpoint (dialysis initiation, or 30% eGFR sustained decline), with relative endothelial area, mean endothelial cell area and parietal epithelial cell density below medians linked to this endpoint [hazard ratios, respectively, of 2.63 (P = .048), 2.60 (P = .039) and 3.23 (P = .019)]. Conclusion This study automated the measurement of intraglomerular cells and capillaries. Our results suggest that the precise segmentation of endothelial and epithelial cells may serve as a potential future marker for the risk of graft loss.
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Affiliation(s)
- Imane Farhat
- Department of Nephrology, CHU Dijon, Dijon, France
| | | | - Doris Calmo
- Department of Nephrology, CHU Besançon, Besançon, France
| | - Manon Ansart
- LEAD-CNRS, UMR 5022, Université de Bourgogne, Dijon, France
| | | | - Patrick Bard
- LEAD-CNRS, UMR 5022, Université de Bourgogne, Dijon, France
| | | | - Didier Ducloux
- Department of Nephrology, CHU Besançon, Besançon, France
- Etablissement Français du sang, Besançon, France
| | | | | | - Claire Tinel
- Department of Nephrology, CHU Dijon, Dijon, France
- Etablissement Français du sang, Besançon, France
| | | | | | - Jean-Michel Rebibou
- Department of Nephrology, CHU Dijon, Dijon, France
- Etablissement Français du sang, Besançon, France
| | - Jamal Bamoulid
- Department of Nephrology, CHU Besançon, Besançon, France
- Etablissement Français du sang, Besançon, France
| | - Mathieu Legendre
- Department of Nephrology, CHU Dijon, Dijon, France
- LEAD-CNRS, UMR 5022, Université de Bourgogne, Dijon, France
- Etablissement Français du sang, Besançon, France
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13
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Sałaga-Zaleska K, Kuchta A, Bzoma B, Chyła-Danił G, Safianowska A, Płoska A, Kalinowski L, Dębska-Ślizień A, Jankowski M. Nanoparticle Tracking Analysis of Urinary Extracellular Vesicle Proteins as a New Challenge in Laboratory Medicine. Int J Mol Sci 2023; 24:12228. [PMID: 37569604 PMCID: PMC10419144 DOI: 10.3390/ijms241512228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/25/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Urinary extracellular vesicle (uEV) proteins may be used as specific markers of kidney damage in various pathophysiological conditions. The nanoparticle-tracking analysis (NTA) appears to be the most useful method for the analysis of uEVs due to its ability to analyze particles below 300 nm. The NTA method has been used to measure the size and concentration of uEVs and also allows for a deeper analysis of uEVs based on their protein composition using fluorescence measurements. However, despite much interest in the clinical application of uEVs, their analysis using the NTA method is poorly described and requires meticulous sample preparation, experimental adjustment of instrument settings, and above all, an understanding of the limitations of the method. In the present work, we demonstrate the usefulness of an NTA. We also present problems encountered during analysis with possible solutions: the choice of sample dilution, the method of the presentation and comparison of results, photobleaching, and the adjustment of instrument settings for a specific analysis. We show that the NTA method appears to be a promising method for the determination of uEVs. However, it is important to be aware of potential problems that may affect the results.
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Affiliation(s)
- Kornelia Sałaga-Zaleska
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
| | - Agnieszka Kuchta
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
| | - Beata Bzoma
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
- Clinical of Nephrology, Transplantology and Internal Diseases, University Clinical Centre in Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
| | - Gabriela Chyła-Danił
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
| | - Anna Safianowska
- Clinical of Nephrology, Transplantology and Internal Diseases, University Clinical Centre in Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
| | - Agata Płoska
- Department of Medical Laboratory Diagnostic—Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostic—Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland
- BioTechMed Centre, Department of Mechanics of Materials and Structures, Gdansk University of Technology, Narutowicza Street 11/12, 80-233 Gdansk, Poland
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
- Clinical of Nephrology, Transplantology and Internal Diseases, University Clinical Centre in Gdansk, Smoluchowskiego Street 17, 80-214 Gdansk, Poland
| | - Maciej Jankowski
- Department of Clinical Chemistry, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; (K.S.-Z.)
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14
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Lin J, Lv J, Yu X, Xue X, Yu S, Wang H, Chen J. Single-Cell Heterogeneity Restorative Chimeric Engineering Nanoparticles for Alleviating Antibody-Mediated Allograft Injury. ACS APPLIED MATERIALS & INTERFACES 2023; 15:34588-34606. [PMID: 37459593 DOI: 10.1021/acsami.3c06885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
Disturbance of single-cell transcriptional heterogeneity is an inevitable consequence of persistent donor-specific antibody (DSA) production and allosensitization. However, identifying and efficiently clearing allospecific antibody repertoires to restore single-cell transcriptional profiles remain challenging. Here, inspired by the high affinity of natural bacterial proteins for antibodies, a genetic engineered membrane-coated nanoparticle termed as DSA trapper by the engineering chimeric gene of protein A/G with phosphatidylserine ligands for macrophage phagocytosis was reported. It has been shown that DSA trappers adsorbed alloreactive antibodies with high saturation and activated the heterophagic clearance of antibody complexes, alleviating IgG deposition and complement activation. Remarkably, DSA trappers increased the endothelial protective lineages by 8.39-fold, reversed the highly biased cytotoxicity, and promoted the proliferative profiles of Treg cells, directly providing an obligate immune tolerant niche for single-cell heterogeneity restoration. In the mice of allogeneic transplantation, the DSA trapper spared endothelial from inflammatory degenerative rosette, improved the glomerular filtration rate, and prolonged the survival of allogeneic mice from 23.6 to 78.3 days. In general, by identifying the lineage characteristics of rejection-related antibodies, the chimeric engineered DSA trapper realized immunoadsorption and further phagocytosis of alloantibody complexes to restore the single-cell genetic architecture of the allograft, offering a promising prospect for the treatment of alloantibody-mediated immune injury.
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Affiliation(s)
- Jinwen Lin
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China
| | - Junhao Lv
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China
| | - Xianping Yu
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China
| | - Xing Xue
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, P. R. China
| | - Shiping Yu
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China
| | - Huiping Wang
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China
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15
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Zhang L, Chen Z, Gao Q, Liu G, Zheng J, Ding F. Preterm birth leads to a decreased number of differentiated podocytes and accelerated podocyte differentiation. Front Cell Dev Biol 2023; 11:1142929. [PMID: 36936687 PMCID: PMC10018169 DOI: 10.3389/fcell.2023.1142929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Preterm birth was previously identified as a high-risk factor for the long-term development of chronic kidney disease. However, the detailed pattern of podocyte (PD) changes caused by preterm birth and the potential mechanism underlying this process have not been well clarified. In present study, a rat model of preterm birth was established by delivery of pups 2 days early and podometric methods were applied to identify the changes in PDs number caused by preterm birth. In addition, single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatic analysis were performed in the preterm rat kidney to explore the possible mechanism caused by preterm birth. As results, when the kidney completely finished nephrogenesis at the age of 3 weeks, a reduction in the total number of differentiated PDs in kidney sections was detected. In addition, 20 distinct clusters and 12 different cell types were identified after scRNA-seq in preterm rats (postnatal day 2) and full-term rats (postnatal day 0). The numbers of PDs and most types of inherent kidney cells were decreased in the preterm birth model. In addition, 177 genes were upregulated while 82 genes were downregulated in the PDs of full-term rats compared with those of preterm rats. Further functional GO analysis revealed that ribosome-related genes were enriched in PDs from full-term rats, and kidney development-related genes were enriched in PDs from preterm rats. Moreover, known PD-specific and PD precursor genes were highly expressed in PDs from preterm rats, and pseudotemporal analysis showed that PDs were present earlier in preterm rats than in full-term rats. In conclusion, the present study showed that preterm birth could cause a reduction in the number of differentiated PDs and accelerate the differentiation of PDs.
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Affiliation(s)
- Lulu Zhang
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Zhihui Chen
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Qi Gao
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Ge Liu
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Jun Zheng
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
| | - Fangrui Ding
- Department of Neonatology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China
- Department of Neonatology, Nankai University Maternity Hospital, Tianjin, China
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16
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Chancay J, Liu C, Chauhan K, Andersen L, Harris C, Coca S, Delaney V, Tedla F, De Boccardo G, Sehgal V, Moledina D, Formica R, Reghuvaran A, Banu K, Florman S, Akalin E, Shapiro R, Salem F, Menon MC. Role of time from transplantation to biopsy in histologic ABMR: A single center report. Clin Transplant 2022; 36:e14802. [PMID: 36069577 PMCID: PMC10211409 DOI: 10.1111/ctr.14802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/24/2022] [Accepted: 08/19/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Allograft biopsies with lesions of Antibody-Mediated Rejection (ABMR) with Microvascular Inflammation (MVI) have shown heterogeneous etiologies and outcomes. METHODS To examine factors associated with outcomes in biopsies that meet histologic ABMR criteria, we retrospectively evaluated for-cause biopsies at our center between 2011 and 2017. We included biopsies that met the diagnosis of ABMR by histology, along with simultaneous evaluation for anti-Human Leukocyte Antigen (HLA) donor-specific antibodies (DSA). We evaluated death-censored graft loss (DCGL) and used a principal component analysis (PCA) approach to identify key predictors of outcomes. RESULTS Out of the histologic ABMR cohort (n = 118), 70 were DSA-positive ABMR, while 48 had no DSA. DSA(+)ABMR were younger and more often female recipients. DSA(+)ABMR occurred significantly later post-transplant than DSA(-)ABMR suggesting time-dependence. DSA(+)ABMR had higher inflammatory scores (i,t), chronicity scores (ci, ct) and tended to have higher MVI scores. Immunodominance of DQ-DSA in DSA(+)ABMR was associated with higher i+t scores. Clinical/histologic factors significantly associated with DCGL after biopsy were inputted into the PCA. Principal component-1 (PC-1), which contributed 34.8% of the variance, significantly correlated with time from transplantation to biopsy, ci/ct scores and DCGL. In the PCA analyses, i, t scores, DQ-DSA, and creatinine at biopsy retained significant correlations with GL-associated PCs. CONCLUSIONS Time from transplantation to biopsy plays a major role in the prognosis of biopsies with histologic ABMR and MVI, likely due to ongoing chronic allograft injury over time.
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Affiliation(s)
- Jorge Chancay
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Caroline Liu
- Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kinsuk Chauhan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Lisa Andersen
- Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Cynthia Harris
- Transplant Center at Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States
| | - Steven Coca
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Veronica Delaney
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Fasika Tedla
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Graciela De Boccardo
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Vinita Sehgal
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Dennis Moledina
- Yale New Haven Transplantation Center, Yale School of Medicine, New Haven, CT, United States
| | - Richard Formica
- Yale New Haven Transplantation Center, Yale School of Medicine, New Haven, CT, United States
| | - Anand Reghuvaran
- Yale New Haven Transplantation Center, Yale School of Medicine, New Haven, CT, United States
| | - Khadija Banu
- Yale New Haven Transplantation Center, Yale School of Medicine, New Haven, CT, United States
| | - Sander Florman
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Enver Akalin
- Montefiore Einstein Center for Transplantation, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Ron Shapiro
- Transplant Center at Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States
| | - Fadi Salem
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Madhav C Menon
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Yale New Haven Transplantation Center, Yale School of Medicine, New Haven, CT, United States
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17
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McDaniels JM, Shetty AC, Rousselle TV, Bardhi E, Maluf DG, Mas VR. The cellular landscape of the normal kidney allograft: Main players balancing the alloimmune response. FRONTIERS IN TRANSPLANTATION 2022; 1:988238. [PMID: 38994377 PMCID: PMC11235379 DOI: 10.3389/frtra.2022.988238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/22/2022] [Indexed: 07/13/2024]
Abstract
Despite recent advances made in short-term outcomes; minimal improvements have been observed in long-term kidney transplantation outcomes. Due to an imbalance between organ transplant availability and patient waiting list, expanding kidney allograft longevity is a critical need in the field. Prior studies have either focused on early ischemic and immunological conditions affecting kidney allografts (e.g., delayed graft function, acute rejection) or late stage chronic injury when interventions are no longer feasible. However, studies characterizing kidney allografts with normal function by its cellular distribution, cell-cell interactions, and associated molecular pathways are lacking. Herein, we used single nuclei RNA-sequencing to uncover the cellular landscape and transcriptome of the normal kidney allograft. We profiled 40,950 nuclei from seven human kidney biopsies (normal native, N = 3; normal allograft, N = 4); normal allograft protocol biopsies were collected ≥15-months post-transplant. A total of 17 distinct cell clusters were identified with proximal tubules (25.70 and 21.01%), distal tubules (15.22 and 18.20%), and endothelial cells (EC) (4.26 and 9.94%) constituting the major cell populations of normal native and normal allograft kidneys, respectively. A large proportion of cycling cells from normal native kidneys were in G1-phase (43.96%) whereas cells from normal allograft were predominantly in S-phase (32.69%). This result suggests that transcriptional differences between normal native and normal allograft biopsies are dependent on the new host environment, immunosuppression, and injury-affliction. In the normal allograft, EC-specific genes upregulated metabolism, the immune response, and cellular growth, emphasizing their role in maintaining homeostasis during the ongoing alloreactive stress response. Immune cells, including B (2.81%), macrophages (24.96%), monocytes (15.29%), natural killer (NK) (12.83%), neutrophils (8.44%), and T cells (14.41%, were increased in normal allografts despite lack of histological or clinical evidence of acute rejection. Phenotypic characterization of immune cell markers supported lymphocyte activation and proinflammatory cytokines signaling pathways (i.e., IL-15, IL-32). The activation of B, NK, and T cells reveals potential immune cells underlying subclinical inflammation and repair. These single nuclei analyses provide novel insights into kidney and immune cell associated signaling pathways that portray kidney grafts with normal allograft function beyond 2-years post-transplant, revealing a novel perspective in understanding long-term allograft graft survival.
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Affiliation(s)
- Jennifer M McDaniels
- Surgical Sciences Division, Department of Surgery, University of Maryland, Baltimore, MD, United States
| | - Amol C Shetty
- Institute for Genome Sciences, School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Thomas V Rousselle
- Surgical Sciences Division, Department of Surgery, University of Maryland, Baltimore, MD, United States
| | - Elissa Bardhi
- Surgical Sciences Division, Department of Surgery, University of Maryland, Baltimore, MD, United States
| | - Daniel G Maluf
- Program in Transplantation, School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Valeria R Mas
- Surgical Sciences Division, Department of Surgery, University of Maryland, Baltimore, MD, United States
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18
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Menon R, Otto EA, Berthier CC, Nair V, Farkash EA, Hodgin JB, Yang Y, Luo J, Woodside KJ, Zamani H, Norman SP, Wiggins RC, Kretzler M, Naik AS. Glomerular endothelial cell-podocyte stresses and crosstalk in structurally normal kidney transplants. Kidney Int 2022; 101:779-792. [PMID: 34952098 PMCID: PMC9067613 DOI: 10.1016/j.kint.2021.11.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 10/14/2021] [Accepted: 11/15/2021] [Indexed: 12/18/2022]
Abstract
Increased podocyte detachment begins immediately after kidney transplantation and is associated with long-term allograft failure. We hypothesized that cell-specific transcriptional changes in podocytes and glomerular endothelial cells after transplantation would offer mechanistic insights into the podocyte detachment process. To test this, we evaluated cell-specific transcriptional profiles of glomerular endothelial cells and podocytes from 14 patients of their first-year surveillance biopsies with normal histology from low immune risk recipients with no post-transplant complications and compared these to biopsies of 20 healthy living donor controls. Glomerular endothelial cells from these surveillance biopsies were enriched for genes related to fluid shear stress, angiogenesis, and interferon signaling. In podocytes, pathways were enriched for genes in response to growth factor signaling and actin cytoskeletal reorganization but also showed evidence of podocyte stress as indicated by reduced nephrin (adhesion protein) gene expression. In parallel, transcripts coding for proteins required to maintain podocyte adherence to the underlying glomerular basement membrane were downregulated, including the major glomerular podocyte integrin α3 and the actin cytoskeleton-related gene synaptopodin. The reduction in integrin α3 protein expression in surveillance biopsies was confirmed by immunoperoxidase staining. The combined growth and stress response of patient allografts post-transplantation paralleled similar changes in a rodent model of nephrectomy-induced glomerular hypertrophic stress that progress to develop proteinuria and glomerulosclerosis with shortened kidney life span. Thus, even among patients with apparently healthy allografts with no detectable histologic abnormality including alloimmune injury, transcriptomic changes reflecting cell stresses are already set in motion that could drive hypertrophy-associated glomerular disease progression.
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Affiliation(s)
- Rajasree Menon
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
| | - Edgar A Otto
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Celine C Berthier
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Viji Nair
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Evan A Farkash
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Yingbao Yang
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jinghui Luo
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Kenneth J Woodside
- Division of Transplant Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Haniyeh Zamani
- School of Arts and Sciences, University of Michigan, Ann Arbor, Michigan, USA
| | - Silas P Norman
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Roger C Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Matthias Kretzler
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Abhijit S Naik
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
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19
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Zhu Y, Fan Y, Xu F, Liang S, Liang D, Li P, Xia Y, Zhu X, Yang F, Chen J, Zeng C. Focal Segmental Glomerulosclerosis Superimposed on Transplant Glomerulopathy: Implications for Graft Survival. Am J Nephrol 2021; 52:788-797. [PMID: 34749369 DOI: 10.1159/000519648] [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: 07/26/2021] [Accepted: 09/13/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Transplant glomerulopathy (TG) is a morphological lesion resulting from chronic glomerular endothelium injury, and it is strongly associated with poor graft survival. TG coexisting with focal segmental glomerulosclerosis (FSGS) can be found in renal allograft biopsies, but few related studies are available. METHODS Consecutive kidney transplant recipients with biopsy-proven TG were studied retrospectively. Patients concomitant with FSGS were identified and compared with those without FSGS. The influence of FSGS on allograft outcomes was assessed using univariate and multivariate Cox regression models. RESULTS Of the 66 patients with TG, 40 (60.6%) had concomitant FSGS. TG patients with FSGS had higher proteinuria (median, 2.6 vs. 0.8 g/24 h, p < 0.001) and serum creatinine levels (median, 2.5 vs. 2.1 mg/dL, p = 0.04), lower serum albumin levels, higher chronic glomerulopathy (cg) score, larger glomerular tuft area, lower number of podocytes, and higher incidences of podocyte hyperplasia, pseudotubule formation, and diffuse foot process effacement than those without FSGS (all p < 0.05). The kidney allograft loss rate of patients with FSGS was higher than that of patients without FSGS (65.7% vs. 37.5%, p = 0.03). The presence of FSGS was independently associated with allograft loss in TG (hazard ratio (HR) = 3.42, 95% confidence interval (CI): 1.30-8.98, p = 0.01). Other independent predictors were proteinuria (HR = 1.18, 95% CI: 1.02-1.37, p = 0.02), estimated glomerular filtration rate (HR = 0.94, 95% CI: 0.91-0.97, p < 0.001), and panel reactive antibody (HR = 3.99, 95% CI: 1.14-13.99, p = 0.03). Moreover, FSGS (odds ratio (OR) = 4.39, 95% CI: 1.29-14.92, p = 0.02) and cg (OR = 5.36, 95% CI: 1.56-18.40, p = 0.01) were independent risk factors for proteinuria. CONCLUSION In this cohort of patients with TG, the presence of FSGS was strongly associated with more severe clinicopathological features and worse allograft survival.
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Affiliation(s)
- Ying Zhu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Yun Fan
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Feng Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Shaoshan Liang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Dandan Liang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Ping Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Yuanyuan Xia
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaodong Zhu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Fan Yang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Jinsong Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, China
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
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20
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Fukuda A, Minakawa A, Sato Y, Shibata H, Hara M, Fujimoto S. Excretion Patterns of Urinary Sediment and Supernatant Podocyte Biomarkers in Patients with CKD. KIDNEY360 2021; 3:63-73. [PMID: 35368571 PMCID: PMC8967611 DOI: 10.34067/kid.0004772021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/02/2021] [Indexed: 01/10/2023]
Abstract
Background Podocyte depletion causes glomerulosclerosis, and persistent podocyte loss drives progression to ESKD. Urinary sediment podocin (u-sed Pod) mRNA excretion and urinary supernatant podocalyxin (u-sup PCX) protein have been used to monitor disease activity in glomerular diseases. However, the differences in these markers among pathologies have not been investigated. We examined the roles of these markers in kidney diseases. Methods From January 2013 to March 2016, early morning urine samples were collected from 12 healthy controls and 172 patients with kidney disease (n=15 patients with minor glomerular abnormality with mild proteinuria and/or microscopic hematuria, n=15 with minimal change nephrotic syndrome [MCNS], n=15 with membranous nephropathy [MN], n=60 with IgA nephropathy [IgAN], n=19 with crescentic GN [Cres GN], n=10 with lupus nephritis [LN], and n=38 with other kidney diseases). We examined u-sed Pod mRNA excretion, u-sup PCX protein, and the urinary protein-creatinine ratio (u-PCR). Results u-sed Pod mRNA excretion was significantly correlated with u-sup PCX protein (r=0.37, P<0.001). Both u-sed Pod mRNA excretion and u-sup PCX protein were significantly correlated with u-PCR (r=0.53, P<0.001 and r=0.35, P<0.001, respectively). Interestingly, u-sed Pod mRNA excretion was significantly increased in proliferative-type GN-including IgAN with extracapillary proliferative lesions, Cres GN, and LN class IV-and significantly correlated with the rate of crescent formation, whereas u-sup PCX protein was significantly increased only in those with MN and subepithelial dense deposit-type LN compared with controls. Conclusions Higher u-sed Pod mRNA excretion and u-sup PCX protein were associated with proliferative-type GN, indicating podocyte detachment and subepithelial dense deposit-type GN, respectively. The results suggest that u-sed Pod mRNA excretion and u-sup PCX protein have usefulness for the diagnosis and measurement of disease activity with regard to glomerular diseases.
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Affiliation(s)
- Akihiro Fukuda
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Japan,Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Akihiro Minakawa
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yuji Sato
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Japan
| | | | - Shouichi Fujimoto
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
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21
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Banu K, Lin Q, Basgen JM, Planoutene M, Wei C, Reghuvaran AC, Tian X, Shi H, Garzon F, Garzia A, Chun N, Cumpelik A, Santeusanio AD, Zhang W, Das B, Salem F, Li L, Ishibe S, Cantley LG, Kaufman L, Lemley KV, Ni Z, He JC, Murphy B, Menon MC. AMPK mediates regulation of glomerular volume and podocyte survival. JCI Insight 2021; 6:e150004. [PMID: 34473647 PMCID: PMC8525649 DOI: 10.1172/jci.insight.150004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/01/2021] [Indexed: 12/20/2022] Open
Abstract
Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.
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Affiliation(s)
- Khadija Banu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Qisheng Lin
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - John M Basgen
- Morphometry and Stereology Laboratory, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
| | - Marina Planoutene
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chengguo Wei
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Anand C Reghuvaran
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Xuefei Tian
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Hongmei Shi
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Felipe Garzon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aitor Garzia
- Laboratory of RNA Molecular Biology, The Rockefeller University, New York, New York, USA
| | - Nicholas Chun
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Arun Cumpelik
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Andrew D Santeusanio
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Bhaskar Das
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Fadi Salem
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Li Li
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Shuta Ishibe
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lloyd G Cantley
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lewis Kaufman
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kevin V Lemley
- Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Barbara Murphy
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Madhav C Menon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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22
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Naik AS, Wang SQ, Chowdhury M, Aqeel J, O'Connor CL, Wiggins JE, Bitzer M, Wiggins RC. Critical timing of ACEi initiation prevents compensatory glomerular hypertrophy in the remaining single kidney. Sci Rep 2021; 11:19605. [PMID: 34599260 PMCID: PMC8486841 DOI: 10.1038/s41598-021-99124-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/20/2021] [Indexed: 01/05/2023] Open
Abstract
Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy "compensatory" glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.
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Affiliation(s)
- Abhijit S Naik
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
- , F6676 UHS, 1500 E Medical Center Dr, Ann Arbor, MI, 48109-5676, USA.
| | - Su Q Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mahboob Chowdhury
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jawad Aqeel
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Jocelyn E Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Markus Bitzer
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Roger C Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
- , 1570B MSRB2, 1150 W Medical Center Dr, Ann Arbor, MI, 48109-5676, USA.
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23
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Naik AS, Aqeel J, Wang SQ, Chowdhury M, He K, Wiggins RC. Urine marker analysis identifies evidence for persistent glomerular podocyte injury across allograft lifespan. Clin Transplant 2021; 35:e14457. [PMID: 34387906 DOI: 10.1111/ctr.14457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 11/27/2022]
Abstract
Long-term kidney transplant (KT) survival has remained relatively stagnant. Protocol biopsy studies suggest that glomerulosclerosis is a significant contributor to long-term graft failure. We previously demonstrated that podocyte loss in the 1st year post-transplantation predicted long-term allograft survival. However, whether increased podocyte loss continues over the lifespan of a KT remains unclear. We performed a cross-sectional analysis of 1,182 urine samples from 260 KT recipients up to 19-years after transplantation. Urine pellet mRNAs were assayed for podocyte (NPHS2/podocin and nephrin/NPHS1), distal tubule (aquaporin2), and profibrotic cytokine (TGFbeta1). Multivariable generalized estimating equations were used to obtain "population-averaged" effects for these markers over time post-KT. Consistent with early stresses both podocyte and tubular markers increased immediately post-KT. However, only podocyte markers continued to increase long-term. A role for hypertrophic stresses in driving podocyte loss over time is implied by their association with donor BMI, recipient BMI and donor-recipient BMI mismatch at transplantation. Furthermore, urine pellet podocin mRNA was associated with urine TGFbeta1, proteinuria and reduced eGFR, thereby linking podocyte injury to allograft fibrosis and survival. In conclusion we observed that podocyte loss continues long-term post-KT suggesting an important role in driving late graft loss. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Abhijit S Naik
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jawad Aqeel
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Su Q Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mahboob Chowdhury
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Kevin He
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Roger C Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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24
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Haley KE, Elshani M, Um IH, Bell C, Caie PD, Harrison DJ, Reynolds PA. YAP Translocation Precedes Cytoskeletal Rearrangement in Podocyte Stress Response: A Podometric Investigation of Diabetic Nephropathy. Front Physiol 2021; 12:625762. [PMID: 34335284 PMCID: PMC8320019 DOI: 10.3389/fphys.2021.625762] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 05/21/2021] [Indexed: 11/13/2022] Open
Abstract
Podocyte loss plays a pivotal role in the pathogenesis of glomerular disease. However, the mechanisms underlying podocyte damage and loss remain poorly understood. Although detachment of viable cells has been documented in experimental Diabetic Nephropathy, correlations between reduced podocyte density and disease severity have not yet been established. YAP, a mechanosensing protein, has recently been shown to correlate with glomerular disease progression, however, the underlying mechanism has yet to be fully elucidated. In this study, we sought to document podocyte density in Diabetic Nephropathy using an amended podometric methodology, and to investigate the interplay between YAP and cytoskeletal integrity during podocyte injury. Podocyte density was quantified using TLE4 and GLEPP1 multiplexed immunofluorescence. Fourteen Diabetic Nephropathy cases were analyzed for both podocyte density and cytoplasmic translocation of YAP via automated image analysis. We demonstrate a significant decrease in podocyte density in Grade III/IV cases (124.5 per 106 μm3) relative to Grade I/II cases (226 per 106 μm3) (Student's t-test, p < 0.001), and further show that YAP translocation precedes cytoskeletal rearrangement following injury. Based on these findings we hypothesize that a significant decrease in podocyte density in late grade Diabetic Nephropathy may be explained by early cytoplasmic translocation of YAP.
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Affiliation(s)
- Kathryn E Haley
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.,Biomedical Sciences Research Complex (BSRC), University of St Andrews, St Andrews, United Kingdom
| | - Mustafa Elshani
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.,Directorate of Laboratory Medicine, Lothian University Hospitals Trust, Royal Infirmary, Edinburgh, United Kingdom
| | - In Hwa Um
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | - Cameron Bell
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.,Acute Internal Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Peter D Caie
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | - David J Harrison
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.,Directorate of Laboratory Medicine, Lothian University Hospitals Trust, Royal Infirmary, Edinburgh, United Kingdom
| | - Paul A Reynolds
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.,Biomedical Sciences Research Complex (BSRC), University of St Andrews, St Andrews, United Kingdom
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25
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Haruhara K, Sasaki T, de Zoysa N, Okabayashi Y, Kanzaki G, Yamamoto I, Harper IS, Puelles VG, Shimizu A, Cullen-McEwen LA, Tsuboi N, Yokoo T, Bertram JF. Podometrics in Japanese Living Donor Kidneys: Associations with Nephron Number, Age, and Hypertension. J Am Soc Nephrol 2021; 32:1187-1199. [PMID: 33627345 PMCID: PMC8259686 DOI: 10.1681/asn.2020101486] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/11/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Podocyte depletion, low nephron number, aging, and hypertension are associated with glomerulosclerosis and CKD. However, the relationship between podometrics and nephron number has not previously been examined. METHODS To investigate podometrics and nephron number in healthy Japanese individuals, a population characterized by a relatively low nephron number, we immunostained single paraffin sections from 30 Japanese living-kidney donors (median age, 57 years) with podocyte-specific markers and analyzed images obtained with confocal microscopy. We used model-based stereology to estimate podometrics, and a combined enhanced-computed tomography/biopsy-specimen stereology method to estimate nephron number. RESULTS The median number of nonsclerotic nephrons per kidney was 659,000 (interquartile range [IQR], 564,000-825,000). The median podocyte number and podocyte density were 518 (IQR, 428-601) per tuft and 219 (IQR, 180-253) per 106μm3, respectively; these values are similar to those previously reported for other races. Total podocyte number per kidney (obtained by multiplying the individual number of nonsclerotic glomeruli by podocyte number per glomerulus) was 376 million (IQR, 259-449 million) and ranged 7.4-fold between donors. On average, these healthy kidneys lost 5.63 million podocytes per kidney per year, with most of this loss associated with glomerular loss resulting from global glomerulosclerosis, rather than podocyte loss from healthy glomeruli. Hypertension was associated with lower podocyte density and larger podocyte volume, independent of age. CONCLUSIONS Estimation of the number of nephrons, podocytes, and other podometric parameters in individual kidneys provides new insights into the relationships between these parameters, age, and hypertension in the kidney. This approach might be of considerable value in evaluating the kidney in health and disease.
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Affiliation(s)
- Kotaro Haruhara
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia,Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takaya Sasaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Natasha de Zoysa
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | - Yusuke Okabayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Go Kanzaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Izumi Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ian S. Harper
- Monash Micro Imaging, Monash University, Clayton, Australia
| | - Victor G. Puelles
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia,III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Luise A. Cullen-McEwen
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - John F. Bertram
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
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26
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Gibson IW. Transplant Glomerulopathy: Importance of Ultrastructural Examination. GLOMERULAR DISEASES 2021; 1:68-81. [PMID: 36751426 PMCID: PMC9677739 DOI: 10.1159/000513522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/29/2020] [Indexed: 11/19/2022]
Abstract
Background Transplant glomerulopathy (TG) is a morphologic alteration in glomeruli of renal allografts, characterized by glomerular basement membrane reduplications. Summary TG is associated with progressive chronic allograft dysfunction and proteinuria and is a diagnostic feature of chronic antibody-mediated rejection (ABMR) in patients positive for donor-specific antibodies, according to the Banff schema for renal allograft pathology. It is a definitive endpoint in clinical trials and interventional studies for ABMR, but the lesion can also occur in the absence of definitive alloimmune injury, as a consequence of chronic thrombotic microangiopathy, and in some cases in association with hepatitis C infection. This review discusses the pathophysiology and clinical presentation of TG, the diagnostic features by light microscopy, and focuses on the sequential ultrastructural stages of the lesion. The differential diagnosis of TG, and Banff grading of the lesion, are reviewed. Clinicopathological indications for performing routine ultrastructural examination of renal allograft biopsies are discussed. Key Messages TG can be diagnosed at an early stage by electron microscopy, before histological features are apparent, emphasizing the importance of ultrastructural examination of renal allograft biopsies for an early diagnosis, when therapeutic intervention may be beneficial.
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Affiliation(s)
- Ian W. Gibson
- *Ian W. Gibson, Department of Pathology, MS-336C Electron Microscopy Lab, Health Sciences Centre, University of Manitoba, 820 Sherbrook Street, Winnipeg, MB R3A1R9 (Canada),
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27
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Chen DP, Zaky ZS, Schold JD, Herlitz LC, El-Rifai R, Drawz PE, Bruggeman LA, Barisoni L, Hogan SL, Hu Y, O'Toole JF, Poggio ED, Sedor JR. Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation. Clin Transplant 2021; 35:e14234. [PMID: 33511679 DOI: 10.1111/ctr.14234] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/25/2020] [Accepted: 01/20/2021] [Indexed: 01/23/2023]
Abstract
Variants in apolipoprotein L1 (APOL1) gene are associated with nondiabetic kidney diseases in black subjects and reduced kidney transplant graft survival. Living and deceased black kidney donors (n = 107) were genotyped for APOL1 variants. To determine whether allografts from high-risk APOL1 donors have reduced podocyte densities contributing to allograft failure, we morphometrically estimated podocyte number, glomerular volume, and podocyte density. We compared allograft loss and eGFR trajectories stratified by APOL1 high-risk and low-risk genotypes. Demographic characteristics were similar in high-risk (n = 16) and low-risk (n = 91) donors. Podocyte density was significantly lower in high-risk than low-risk donors (108 ± 26 vs 127 ± 40 podocytes/106 um3 , P = .03). Kaplan-Meier graft survival (high-risk 61% vs. low-risk 91%, p-value = 0.049) and multivariable Cox models (hazard ratio = 2.6; 95% CI, 0.9-7.8) revealed higher graft loss in recipients of APOL1 high-risk allografts over 48 months. More rapid eGFR decline was seen in recipients of high-risk APOL1 allografts (P < .001). At 60 months, eGFR was 27 vs. 51 mL/min/1.73 min2 in recipients of APOL1 high-risk vs low-risk kidney allografts, respectively. Kidneys from high-risk APOL1 donors had worse outcomes versus low-risk APOL1 genotypes. Lower podocyte density in kidneys from high-risk APOL1 donors may increase susceptibility to CKD from subsequent stresses in both the recipients and donors.
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Affiliation(s)
- Dhruti P Chen
- Division of Nephrology, UNC Kidney Center, University of North Carolina, Chapel Hill, NC, USA
| | - Ziad S Zaky
- Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jesse D Schold
- Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Leal C Herlitz
- Pathology and Lab Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rasha El-Rifai
- Division of Renal Diseases and Hypertension, University of Minnesota, Minneapolis, MN, USA
| | - Paul E Drawz
- Division of Renal Diseases and Hypertension, University of Minnesota, Minneapolis, MN, USA
| | - Leslie A Bruggeman
- Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Laura Barisoni
- Departments of Pathology and Medicine, Division of Nephrology, Duke University School of Medicine, Durham, NC, USA
| | - Susan L Hogan
- Division of Nephrology, UNC Kidney Center, University of North Carolina, Chapel Hill, NC, USA
| | - Yichun Hu
- Division of Nephrology, UNC Kidney Center, University of North Carolina, Chapel Hill, NC, USA
| | - John F O'Toole
- Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Emilio D Poggio
- Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - John R Sedor
- Glickman Urology and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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28
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Gokhale A, Chancay J, Shapiro R, Randhawa P, Menon MC. Chronic transplant glomerulopathy: New insights into pathogenesis. Clin Transplant 2021; 35:e14214. [PMID: 33389755 DOI: 10.1111/ctr.14214] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/16/2020] [Accepted: 12/18/2020] [Indexed: 01/20/2023]
Abstract
There have been recent significant advances in short-term outcomes in renal transplantation, however, long-term allograft survival remains a challenge. With reported incidences as high of 74.5% of chronic graft loss in patients with biopsies showing transplant glomerulopathy (TG), this syndrome represents an important factor for chronic allograft complications. In this review we show an overview of the novel mechanistic insights into pathogenesis of TG, as well as a brief description of the pathology, diagnosis and newer prognostic indices within TG diagnosis. These data raise intriguing roles for cell-mediated immunity and podocyte stress in TG as well as reinforce previous associations of TG with ABMR. We also delve into management strategies for TG and report the paucity of existing clinical trial data for this prevalent condition in renal transplants.
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Affiliation(s)
- Avantee Gokhale
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jorge Chancay
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ron Shapiro
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Parmjeet Randhawa
- The Thomas E. Starzl Transplantation Institute, Division of Transplantation Pathology at University of Pittsburgh, Pittsburgh, PA, USA
| | - Madhav C Menon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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29
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Bhargava R, Maeda K, Tsokos MG, Pavlakis M, Stillman IE, Tsokos GC. N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury. Am J Transplant 2021; 21:148-160. [PMID: 32531122 PMCID: PMC8188503 DOI: 10.1111/ajt.16140] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 05/29/2020] [Accepted: 06/06/2020] [Indexed: 01/25/2023]
Abstract
Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.
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Affiliation(s)
- Rhea Bhargava
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Kayaho Maeda
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Maria G. Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Martha Pavlakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Isaac E. Stillman
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - George C. Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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30
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Urinary podocyte mRNAs precede microalbuminuria as a progression risk marker in human type 2 diabetic nephropathy. Sci Rep 2020; 10:18209. [PMID: 33097787 PMCID: PMC7584595 DOI: 10.1038/s41598-020-75320-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023] Open
Abstract
Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression. The hypothesis that urinary pellet podocyte mRNA is a more sensitive progression risk marker than microalbuminuria was tested. A cross sectional cohort of 165 type 2 diabetics and 41 age and sex-matched controls were enrolled. Podocyte stress (Urinary pellet podocin:nephrin mRNA ratio), podocyte detachment (Urinary pellet podocin mRNA:creatinine ratio: UPPod:CR) and a tubular marker (Urinary pellet aquaporin 2:creatinine ratio) were measured in macro-albuminuric, micro-albuminuric and norm-albuminuric groups. eGFR was reassessed after 4 years in 124 available diabetic subjects. Urinary pellet podocyte and tubular mRNA markers were increased in all diabetic groups in cross-sectional analysis. After 4 years of follow-up univariable and multivariate model analysis showed that the only urinary markers significantly related to eGFR slope were UPPod:CR (P < 0.01) and albuminuria (P < 0.01). AUC analysis using K-fold cross validation to predict eGFR loss of ≥ 3 ml/min/1.73m2/year showed that UPPod:CR and albuminuria each improved the AUC similarly such that combined with clinical variables they gave an AUC = 0.70. Podocyte markers and albuminuria had overlapping AUC contributions, as expected if podocyte depletion causes albuminuria. In the norm-albuminuria cohort (n = 75) baseline UPPod:CR was associated with development of albuminuria (P = 0.007) and, in the tertile with both normal kidney function (eGFR 84 ± 11.7 ml/min/1.73m2) and norm-albuminuria at baseline, UPPod:CR was associated with eGFR loss rate (P = 0.003). In type 2 diabetics with micro- or macro-albuminuria UPPod:CR and albuminuria were equally good at predicting eGFR loss. For norm-albuminuric type 2 diabetics UPPod:CR predicted both albuminuria and eGFR loss.
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31
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Ellingsen AR, Jørgensen KA, Østerby R, Petersen SE, Juul S, Marcussen N, Nyengaard JR. Human kidney graft survival correlates with structural parameters in baseline biopsies: a quantitative observational cohort study with more than 14 years' follow-up. Virchows Arch 2020; 478:659-668. [PMID: 32986179 DOI: 10.1007/s00428-020-02924-3] [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: 02/28/2020] [Revised: 08/26/2020] [Accepted: 09/02/2020] [Indexed: 01/05/2023]
Abstract
This prospective cohort study evaluates associations between structural and ultrastructural parameters in baseline biopsies from human kidney transplants and long-term graft survival after more than 14 years' follow-up. Baseline kidney graft biopsies were obtained prospectively from 54 consecutive patients receiving a kidney transplant at a single institution. Quantitative measurements were performed on the baseline biopsies by computer-assisted light microscopy and electron microscopy. Stereology-based techniques estimated the fraction of interstitial tissue, the volume of glomeruli, mesangial fraction, and basement membrane thickness of glomerular capillaries. The fraction of occluded glomeruli and scores according to the Banff classification were achieved. Kidney graft survival was analyzed by Kaplan-Meier estimates and Cox regression. Association to long-term kidney function was also analyzed. The long-term surviving kidney transplants were characterized at implantation by less arteriolar hyaline thickening (P < 0.001) and less interstitial fibrosis (P = 0.001), as well as a lower fraction of occluded glomeruli (P = 0.004) and lower glomerular volume (P = 0.03). At the latest follow-up, eGFR was decreased by 12 ml/min/1.73 m2 per unit increase in the score for arteriolar hyalinosis at implantation (P = 0.02), and eGFR was decreased by 19 ml/min/1.73 m2 per 106 μm3 increase in glomerular volume at baseline (P = 0.03). The unbiased Cavalieri estimate of glomerular volume and the ultrastructural parameters are the first to be evaluated in a cohort study with prospective follow-up for more than 14 years. The study shows that baseline biopsies from human kidney grafts contain extraordinary long-term prognostic information, and it highlights the importance of these intrinsic graft factors.
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Affiliation(s)
- Anne R Ellingsen
- Electron Microscopy Laboratory, Aarhus University Hospital, 8200, Aarhus N, Denmark. .,Department of Pathology, Aarhus University Hospital, 8200, Aarhus N, Denmark. .,Department of Clinical Pathology, Odense University Hospital, 5000, Odense C, Denmark. .,Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, 8200, Aarhus N, Denmark.
| | - Kaj A Jørgensen
- Department of Nephrology, Aarhus University Hospital, 8200, Aarhus N, Denmark
| | - Ruth Østerby
- Electron Microscopy Laboratory, Aarhus University Hospital, 8200, Aarhus N, Denmark
| | - Steffen E Petersen
- Department of Urology, Aarhus University Hospital, 8200, Aarhus N, Denmark
| | - Svend Juul
- Department of Public Health, Section for Epidemiology, Aarhus University, 8000, Aarhus C, Denmark
| | - Niels Marcussen
- Department of Clinical Pathology, Odense University Hospital, 5000, Odense C, Denmark
| | - Jens R Nyengaard
- Electron Microscopy Laboratory, Aarhus University Hospital, 8200, Aarhus N, Denmark.,Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, 8200, Aarhus N, Denmark.,Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University, 8000, Aarhus C, Denmark
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32
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Clotet-Freixas S, McEvoy CM, Batruch I, Pastrello C, Kotlyar M, Van JAD, Arambewela M, Boshart A, Farkona S, Niu Y, Li Y, Famure O, Bozovic A, Kulasingam V, Chen P, Kim SJ, Chan E, Moshkelgosha S, Rahman SA, Das J, Martinu T, Juvet S, Jurisica I, Chruscinski A, John R, Konvalinka A. Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study. J Am Soc Nephrol 2020; 31:2705-2724. [PMID: 32900843 DOI: 10.1681/asn.2020030286] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/21/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNFα trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear. METHODS Unbiased proteomic analysis of laser-captured and microdissected glomeruli and tubulointerstitium was performed on 30 for-cause kidney biopsy specimens with early AMR, acute cellular rejection (ACR), or acute tubular necrosis (ATN). RESULTS A total of 107 of 2026 glomerular and 112 of 2399 tubulointerstitial proteins was significantly differentially expressed in AMR versus ACR; 112 of 2026 glomerular and 181 of 2399 tubulointerstitial proteins were significantly dysregulated in AMR versus ATN (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit γ-1 (LAMC1) expression decreased in AMR, as did glomerular nephrin (NPHS1) and receptor-type tyrosine-phosphatase O (PTPRO). The proteomic analysis revealed upregulated galectin-1, which is an immunomodulatory protein linked to the ECM, in AMR glomeruli. Anti-HLA class I antibodies significantly increased cathepsin-V (CTSV) expression and galectin-1 expression and secretion in human glomerular endothelial cells. CTSV had been predicted to cleave ECM proteins in the AMR glomeruli. Glutathione S-transferase ω-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNFα-treated proximal tubular epithelial cells. CONCLUSIONS Basement membranes are often remodeled in chronic AMR. Proteomic analysis performed on laser-captured and microdissected glomeruli and tubulointerstitium identified early ECM remodeling, which may represent a new therapeutic opportunity.
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Affiliation(s)
- Sergi Clotet-Freixas
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Caitriona M McEvoy
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
| | - Ihor Batruch
- Department of Laboratory Medicine and Pathobiology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Chiara Pastrello
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Max Kotlyar
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Julie Anh Dung Van
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Madhurangi Arambewela
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Alex Boshart
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Yun Niu
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Yanhong Li
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Olusegun Famure
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Andrea Bozovic
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Peixuen Chen
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - S Joseph Kim
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
| | - Emilie Chan
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
| | - Sajad Moshkelgosha
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Syed Ashiqur Rahman
- Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Center for Systems Immunology, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jishnu Das
- Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Center for Systems Immunology, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Tereza Martinu
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada.,Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Stephen Juvet
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada.,Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Igor Jurisica
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Andrzej Chruscinski
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Rohan John
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada .,Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
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33
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Naik AS, Le D, Aqeel J, Wang SQ, Chowdhury M, Walters LM, Cibrik DM, Samaniego M, Wiggins RC. Podocyte stress and detachment measured in urine are related to mean arterial pressure in healthy humans. Kidney Int 2020; 98:699-707. [PMID: 32739208 PMCID: PMC10440835 DOI: 10.1016/j.kint.2020.03.038] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 03/04/2020] [Accepted: 03/26/2020] [Indexed: 12/26/2022]
Abstract
Hypertension-associated progressive glomerulosclerosis is a significant driver of both de novo and all-cause chronic kidney disease leading to end-stage kidney failure. The progression of glomerular disease proceeds via continuing depletion of podocytes from the glomeruli into the ultrafiltrate. To non-invasively assess injury patterns associated with mean arterial pressure (MAP), we conducted an observational study of 87 healthy normotensive individuals who were cleared for living kidney donation. Urine pellet podocin and aquaporin2 mRNAs normalized to the urine creatinine concentration (UPod:Creat ratio and UAqp2:Creat ratio) were used as markers of podocyte detachment and tubular injury, respectively. The ratio of two podocyte mRNA markers, podocin to nephrin (UPod:Neph) as well as the ratio of podocin to the tubular marker aquaporin2 (UPod:Aqp2) estimated the relative rates of podocyte stress and glomerular vs. tubular injury. The MAP was positively correlated with the UPod:Neph and UPod:Aqp2, thereby confirming the relationship of MAP with podocyte stress and the preferential targeting of the glomerulus by higher MAP. In multivariable linear regression analysis, both UPod:Neph and UPod:Creat, but not UAqp2:Creat or proteinuria, were both significantly related to a range of normal MAP (70 to 110 mm Hg). Systolic, as opposed to diastolic or pulse pressure was associated with UPod:Creat. Thus, higher podocyte stress and detachment into the urine are associated with MAP even in a relatively "normal" range of MAP. Hence, urine pellet mRNA monitoring can potentially identify progression risk before the onset of overt hypertension, proteinuria or chronic kidney disease.
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Affiliation(s)
- Abhijit S Naik
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA.
| | - Dustin Le
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA
| | - Jawad Aqeel
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA
| | - Su Q Wang
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA
| | - Mahboob Chowdhury
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA
| | - Lisa M Walters
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA
| | - Diane M Cibrik
- Nephrology Division, University of Kansas, Kansas City, Missouri, USA
| | | | - Roger C Wiggins
- Department of Internal Medicine, Nephrology Division, University of Michigan, Ann Arbor, Michigan, USA.
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34
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Kovács G, Devercelli G, Zelei T, Hirji I, Vokó Z, Keown PA. Association between transplant glomerulopathy and graft outcomes following kidney transplantation: A meta-analysis. PLoS One 2020; 15:e0231646. [PMID: 32343692 PMCID: PMC7188300 DOI: 10.1371/journal.pone.0231646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 03/28/2020] [Indexed: 02/07/2023] Open
Abstract
Transplant glomerulopathy (TG), a morphological lesion associated with confluent mechanisms of endothelial injury of renal allografts, may provide a viable predictor of graft failure. This systematic literature review and meta-analysis were performed according to the PRISMA statement to examine evidence describing the association between TG and graft loss or failure and time to these events. The literature review was conducted using the Scopus, EBSCO, and Cochrane Library search engines. Hazard ratios, median survival times, and 95% confidence intervals (CIs) were estimated to evaluate graft survival in the total population and prespecified subgroups. Meta-regression analysis assessed heterogeneity. Twenty-one publications comprising 6,783 patients were eligible for data extraction and inclusion in the meta-analysis. Studies were highly heterogeneous (I2 = 67.3%). The combined hazard ratio of graft loss or failure from random-effects meta-analysis was 3.11 (95% CI 2.44–3.96) in patients with TG compared with those without. Median graft survival in patients with TG was 3.25 (95% CI 0.94–11.21) years—15 years shorter than in those without TG (18.82 [95% CI 10.03–35.32] years). The effect of time from transplantation to biopsy on graft outcomes did not reach statistical significance (p = 0.116). TG was associated with a threefold increase in the risk of graft loss or failure and a 15-year loss in graft survival, indicating viability as a surrogate measure for both clinical practice and studies designed to prevent or reverse antibody-mediated rejection.
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Affiliation(s)
| | | | - Tamás Zelei
- Syreon Research Institute, Budapest, Hungary
| | - Ishan Hirji
- Shire, a Takeda company, Lexington, Massachusetts, United States of America
| | - Zoltán Vokó
- Syreon Research Institute, Budapest, Hungary
- Center for Health Technology Assessment, Semmelweis University, Budapest, Hungary
| | - Paul A. Keown
- Syreon Corporation, Vancouver, British Columbia, Canada
- University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
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35
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Pisarek-Horowitz A, Fan X, Kumar S, Rasouly HM, Sharma R, Chen H, Coser K, Bluette CT, Hirenallur-Shanthappa D, Anderson SR, Yang H, Beck LH, Bonegio RG, Henderson JM, Berasi SP, Salant DJ, Lu W. Loss of Roundabout Guidance Receptor 2 (Robo2) in Podocytes Protects Adult Mice from Glomerular Injury by Maintaining Podocyte Foot Process Structure. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:799-816. [PMID: 32220420 PMCID: PMC7217334 DOI: 10.1016/j.ajpath.2019.12.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 11/24/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023]
Abstract
Roundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes [Robo2 conditional knockout (cKO) mouse] is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is up-regulated after glomerular injury because its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Taken together, these findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and, thus, loss of Robo2 in podocytes could protect from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.
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Affiliation(s)
- Anna Pisarek-Horowitz
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Xueping Fan
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Sudhir Kumar
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Hila M Rasouly
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Richa Sharma
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Hui Chen
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Kathryn Coser
- Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, Massachusetts
| | | | | | - Sarah R Anderson
- Global Pathology, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut
| | - Hongying Yang
- Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, Massachusetts
| | - Laurence H Beck
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Ramon G Bonegio
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Joel M Henderson
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Stephen P Berasi
- Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, Massachusetts
| | - David J Salant
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Weining Lu
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
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36
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Naik AS, Afshinnia F, Aqeel J, Cibrik DM, Samaniego M, Wickman L, Wang SQ, Chowdhury M, Wiggins RC. Accelerated podocyte detachment early after kidney transplantation is related to long-term allograft loss of function. Nephrol Dial Transplant 2020; 34:1232-1239. [PMID: 30500951 DOI: 10.1093/ndt/gfy350] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Kidney allograft half-life has not improved despite excellent short-term survival. Recent long-term surveillance biopsy studies identify accumulating glomerulosclerosis (GS) to be associated with late allograft loss. While podocyte depletion is well known to drive proteinuria and GS in animal models and human glomerular diseases, its role in renal allograft loss of function is generally not recognized. METHODS To address these questions, we collected urine from 125 kidney allograft recipients in the first posttransplant year for urine pellet messenger RNA (mRNA) and protein analysis, with a median follow up of 4.5 years. RESULTS Using multivariable linear models adjusted for proteinuria, transplant, recipient and donor factors, we observed that the average urine pellet podocin mRNA normalized to urine creatinine (UPodCR) in the first posttransplant year was significantly associated with an estimated glomerular filtration rate (eGFR) decline (P = 0.001). The relationship between UPodCR and eGFR decline persisted even among recipients who were nonproteinuric and who had no recurrent or de novo glomerular disease identified on 1-year protocol biopsy. Finally, we identified recipient, donor and recipient:donor body surface area mismatch ratio to be independently associated with UPodCR early after transplantation. A larger donor was protective, while a larger recipient and increased recipient:donor size mismatch ratio were associated with increased UPodCR. CONCLUSIONS These findings support the concept that in kidney allografts, accelerated podocyte loss precedes proteinuria and is associated with inferior long-term allograft outcomes as measured by eGFR decline and may be initiated by recipient:donor size mismatch. Modulating factors driving early podocyte detachment after kidney transplantation may help improve long-term outcomes.
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Affiliation(s)
- Abhijit S Naik
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Farsad Afshinnia
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jawad Aqeel
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, USA
| | - Diane M Cibrik
- Department of Internal Medicine, University of Kansas, Kansas City, KS, USA
| | | | - Larysa Wickman
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA
| | - Su Q Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mahboob Chowdhury
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Roger C Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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37
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Goerlich N, Brand HA, Langhans V, Tesch S, Schachtner T, Koch B, Paliege A, Schneider W, Grützkau A, Reinke P, Enghard P. Kidney transplant monitoring by urinary flow cytometry: Biomarker combination of T cells, renal tubular epithelial cells, and podocalyxin-positive cells detects rejection. Sci Rep 2020; 10:796. [PMID: 31964937 PMCID: PMC6972704 DOI: 10.1038/s41598-020-57524-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 12/31/2019] [Indexed: 01/19/2023] Open
Abstract
Creatinine and proteinuria are used to monitor kidney transplant patients. However, renal biopsies are needed to diagnose renal graft rejection. Here, we assessed whether the quantification of different urinary cells would allow non-invasive detection of rejection. Urinary cell numbers of CD4+ and CD8+ T cells, monocytes/macrophages, tubular epithelial cells (TEC), and podocalyxin(PDX)-positive cells were determined using flow cytometry and were compared to biopsy results. Urine samples of 63 renal transplant patients were analyzed. Patients with transplant rejection had higher amounts of urinary T cells than controls; however, patients who showed worsening graft function without rejection had similar numbers of T cells. T cells correlated with histological findings (interstitial inflammation p = 0.0005, r = 0.70; tubulitis p = 0.006, r = 0.58). Combining the amount of urinary T cells and TEC, or T cells and PDX+ cells, yielded a significant segregation of patients with rejection from patients without rejection (all p < 0.01, area under the curve 0.89–0.91). Urinary cell populations analyzed by flow cytometry have the potential to introduce new monitoring methods for kidney transplant patients. The combination of urinary T cells, TEC, and PDX-positive cells may allow non-invasive detection of transplant rejection.
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Affiliation(s)
| | | | | | | | | | - Benjamin Koch
- Goethe University Hospital Frankfurt, Frankfurt, Germany
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38
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van de Lest NA, Zandbergen M, Wolterbeek R, Kreutz R, Trouw LA, Dorresteijn EM, Bruijn JA, Bajema IM, Scharpfenecker M, Chua JS. Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis. Kidney Int 2019; 96:738-749. [PMID: 31327475 DOI: 10.1016/j.kint.2019.04.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 03/17/2019] [Accepted: 04/22/2019] [Indexed: 01/08/2023]
Abstract
Recent studies suggest that complement plays a role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Moreover, co-localization of IgM and C3 deposits with FSGS lesions has frequently been reported. Here, we investigated whether glomerular complement deposition precedes the development of FSGS and whether it represents local complement activation. Renal biopsies from 40 patients with primary FSGS, 84 patients with minimal change disease, and 10 healthy individuals were stained for C4d, C1q, and mannose-binding lectin. C4d deposits were also measured in renal allograft biopsies from 34 patients with native primary FSGS, 18 of whom subsequently developed recurrent FSGS. Lastly, we measured C4d deposits in the Munich Wistar Frömter rat model of FSGS. The prevalence of C4d-positive glomeruli was significantly higher among patients with FSGS (73%) compared to patients with minimal change disease (21%) and healthy individuals (10%). Moreover, segmental sclerosis was absent in 42% of C4d-positive glomeruli. Glomerular C1q was significantly more prevalent in FSGS compared to minimal change disease or healthy individuals, while mannose-binding lectin was infrequently observed. C4d deposition was significantly more prevalent in recurrent FSGS (72%) before the development of sclerotic lesions compared to control transplant samples (27%). Finally, at the onset of albuminuria but before the development of FSGS lesions, Munich Wistar Frömter rats had a significantly higher percentage of C4d-positive glomeruli (31%) compared to control rats (4%). Thus, glomerular C4d deposition can precede the development of FSGS, suggesting that complement activation may play a pathogenic role in the development of FSGS.
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Affiliation(s)
- Nina A van de Lest
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Malu Zandbergen
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ron Wolterbeek
- Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Reinhold Kreutz
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Germany
| | - Leendert A Trouw
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Eiske M Dorresteijn
- Department of Pediatric Nephrology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Jan A Bruijn
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ingeborg M Bajema
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Jamie S Chua
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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39
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Markell M, Brar A, Bhela S, Patel A, Salifu M. Use of Repository Corticotropin Gel (Acthar) in Progressive Nephrotic Syndrome Secondary to Transplant Glomerulopathy: A Report of Three Cases. Kidney Med 2019; 1:31-35. [PMID: 32734181 PMCID: PMC7380415 DOI: 10.1016/j.xkme.2018.12.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Transplant glomerulopathy is a feared complication of kidney transplantation, often resulting in rapid loss of kidney function and ultimate graft failure. The underlying cause is unclear, with both antibody and cell-mediated immune mechanisms postulated, as well as intrinsic glomerular factors. At the present time, there is no known therapy. We report here 3 cases in which corticotropin gel (Acthar) was used with varying response of proteinuria and stabilization of graft function with continued graft survival as long as 10 years following the diagnosis. Future randomized controlled trials are warranted to examine the efficacy and safety of ACTH gel therapy in nephrotic patients with transplant glomerulopathy.
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Affiliation(s)
| | | | | | | | - Moro Salifu
- SUNY-Downstate School of Medicine, Brooklyn, NY
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40
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Harder JL, Menon R, Otto EA, Zhou J, Eddy S, Wys NL, O'Connor C, Luo J, Nair V, Cebrian C, Spence JR, Bitzer M, Troyanskaya OG, Hodgin JB, Wiggins RC, Freedman BS, Kretzler M. Organoid single cell profiling identifies a transcriptional signature of glomerular disease. JCI Insight 2019; 4:122697. [PMID: 30626756 PMCID: PMC6485369 DOI: 10.1172/jci.insight.122697] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 11/27/2018] [Indexed: 12/13/2022] Open
Abstract
Podocyte injury is central to many forms of kidney disease, but transcriptional signatures reflecting podocyte injury and compensation mechanisms are challenging to analyze in vivo. Human kidney organoids derived from pluripotent stem cells (PSCs), a potentially new model for disease and regeneration, present an opportunity to explore the transcriptional plasticity of podocytes. Here, transcriptional profiling of more than 12,000 single cells from human PSC-derived kidney organoid cultures was used to identify robust and reproducible cell lineage gene expression signatures shared with developing human kidneys based on trajectory analysis. Surprisingly, the gene expression signature characteristic of developing glomerular epithelial cells was also observed in glomerular tissue from a kidney disease cohort. This signature correlated with proteinuria and inverse eGFR, and it was confirmed in an independent podocytopathy cohort. Three genes in particular were further characterized as potentially novel components of the glomerular disease signature. We conclude that cells in human PSC-derived kidney organoids reliably recapitulate the developmental transcriptional program of podocytes and other cell lineages in the human kidney and that transcriptional profiles seen in developing podocytes are reactivated in glomerular disease. Our findings demonstrate an approach to identifying potentially novel molecular programs involved in the pathogenesis of glomerulopathies.
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Affiliation(s)
| | - Rajasree Menon
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Edgar A Otto
- Department of Internal Medicine, Division of Nephrology, and
| | - Jian Zhou
- Flatiron Institute, Simons Foundation, New York, New York, USA
| | - Sean Eddy
- Department of Internal Medicine, Division of Nephrology, and
| | - Noel L Wys
- Department of Internal Medicine, Division of Nephrology, and
| | | | | | - Viji Nair
- Department of Internal Medicine, Division of Nephrology, and
| | - Cristina Cebrian
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jason R Spence
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Markus Bitzer
- Department of Internal Medicine, Division of Nephrology, and
| | - Olga G Troyanskaya
- Flatiron Institute, Simons Foundation, New York, New York, USA.,Lewis-Sigler Institute for Integrative Genomics and.,Department of Computer Science, Princeton University, Princeton, New Jersey, USA
| | | | - Roger C Wiggins
- Department of Internal Medicine, Division of Nephrology, and
| | - Benjamin S Freedman
- Department of Medicine, Division of Nephrology.,Kidney Research Institute.,Institute for Stem Cell and Regenerative Medicine, and.,Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA
| | - Matthias Kretzler
- Department of Internal Medicine, Division of Nephrology, and.,Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
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41
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Manonelles A, Guiteras R, Melilli E, Lazzeri E, Goma M, Crespo E, Bestard O, Sola A, Romagnani P, Cruzado JM. The Presence of Urinary Renal Progenitor Cells in Stable Kidney Transplant Recipients Anticipates Allograft Deterioration. Front Physiol 2018; 9:1412. [PMID: 30364198 PMCID: PMC6191504 DOI: 10.3389/fphys.2018.01412] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 09/18/2018] [Indexed: 12/18/2022] Open
Abstract
Long-term kidney transplant outcomes have reached mild improvements recently. Parietal epithelial cells (PECs) are progenitor cells located along the Bowman’s capsule that can be isolated in urine, and display the capability to replace podocytes, but in certain situations cause glomerulosclerosis. In this study, a cohort of stable kidney transplant recipients with 6 months protocol biopsy was divided in two groups depending on the presence (uPEC+; n = 41) or absence (uPEC-; n = 25) of PECs in urine and followed for 2 years. No differences were found between groups at 6 months after transplantation considering clinical variables, alloimmune response, renal function, albuminuria and graft pathology. However, uPEC+ group showed increased podocyturia and a higher rate of proliferating PECs along the Bowman’s capsule, without concomitant enhancement of the CD44 pro-sclerotic activation marker. Accordingly, 2 years follow up evidenced poorer outcomes in the uPEC+ group with worse renal function, increased albuminuria, wider mesangial expansion and more severe IFTA. In summary, chronic allograft damage can progress in certain stable-supposed grafts by podocyte detachment and reactive PECs proliferation, being the uPEC presence a biomarker of this process. This damage-response regenerative process, if sustained in time, might fail in preserve the allograft function and histology. Our study raises new prospects to overcome current limits on long-term allograft results.
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Affiliation(s)
- Anna Manonelles
- Nephrology Department, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Roser Guiteras
- Experimental Nephrology, Department of Ciències Clíniques, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Universitat de Barcelona, Barcelona, Spain
| | - Edoardo Melilli
- Nephrology Department, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Elena Lazzeri
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
| | - Montse Goma
- Pathology Department, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Elena Crespo
- Experimental Nephrology, Department of Ciències Clíniques, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Universitat de Barcelona, Barcelona, Spain
| | - Oriol Bestard
- Nephrology Department, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain.,Experimental Nephrology, Department of Ciències Clíniques, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Universitat de Barcelona, Barcelona, Spain
| | - Anna Sola
- Experimental Nephrology, Department of Ciències Clíniques, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Universitat de Barcelona, Barcelona, Spain
| | - Paola Romagnani
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
| | - Josep M Cruzado
- Nephrology Department, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain.,Experimental Nephrology, Department of Ciències Clíniques, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Universitat de Barcelona, Barcelona, Spain
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Fukuda A, Minakawa A, Sato Y, Iwakiri T, Iwatsubo S, Komatsu H, Kikuchi M, Kitamura K, Wiggins RC, Fujimoto S. Urinary podocyte and TGF-β1 mRNA as markers for disease activity and progression in anti-glomerular basement membrane nephritis. Nephrol Dial Transplant 2018; 32:1818-1830. [PMID: 28419296 DOI: 10.1093/ndt/gfx047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Accepted: 02/03/2017] [Indexed: 12/11/2022] Open
Abstract
Background Podocyte depletion causes glomerulosclerosis, with persistent podocyte loss being a major factor driving disease progression. Urinary podocyte mRNA is potentially useful for monitoring disease progression in both animal models and in humans. To determine whether the same principles apply to crescentic glomerular injury, a rat model of anti-glomerular basement membrane (anti-GBM) nephritis was studied in parallel with a patient with anti-GBM nephritis. Methods Podocyte loss was measured by Wilms' Tumor 1-positive podocyte nuclear counting and density, glomerular epithelial protein 1 or synaptopodin-positive podocyte tuft area and urinary podocyte mRNA excretion rate. Glomerulosclerosis was evaluated by Azan staining and urinary transforming growth factor (TGF)-β1 mRNA excretion rate. Results In the rat model, sequential kidney biopsies revealed that after a threshold of 30% podocyte loss, the degree of glomerulosclerosis was linearly associated with the degree of podocyte depletion, compatible with podocyte depletion driving the sclerotic process. Urinary podocyte mRNA correlated with the rate of glomerular podocyte loss. In treatment studies, steroids prevented glomerulosclerosis in the anti-GBM model in contrast to angiotensin II inhibition, which lacked a protective effect, and urinary podocyte and TGF-β1 mRNA markers more accurately reflected both the amount of podocyte depletion and the degree of glomerulosclerosis compared with proteinuria under both scenarios. In a patient successfully treated for anti-GBM nephritis, urinary podocyte and TGB-β1 mRNA reflected treatment efficacy. Conclusion These results emphasize the role of podocyte depletion in anti-GBM nephritis and suggest that urinary podocyte and TGF-β1 mRNA could serve as markers of disease progression and treatment efficacy.
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Affiliation(s)
- Akihiro Fukuda
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Akihiro Minakawa
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yuji Sato
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Takashi Iwakiri
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Shuji Iwatsubo
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Hiroyuki Komatsu
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Masao Kikuchi
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Kazuo Kitamura
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
| | - Roger C Wiggins
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - Shouichi Fujimoto
- First Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Hemovascular Medicine and Artificial Organs, University of Miyazaki, Miyazaki, Japan
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Digital pathology in nephrology clinical trials, research, and pathology practice. Curr Opin Nephrol Hypertens 2018; 26:450-459. [PMID: 28858910 DOI: 10.1097/mnh.0000000000000360] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW In this review, we will discuss (i) how the recent advancements in digital technology and computational engineering are currently applied to nephropathology in the setting of clinical research, trials, and practice; (ii) the benefits of the new digital environment; (iii) how recognizing its challenges provides opportunities for transformation; and (iv) nephropathology in the upcoming era of kidney precision and predictive medicine. RECENT FINDINGS Recent studies highlighted how new standardized protocols facilitate the harmonization of digital pathology database infrastructure and morphologic, morphometric, and computer-aided quantitative analyses. Digital pathology enables robust protocols for clinical trials and research, with the potential to identify previously underused or unrecognized clinically useful parameters. The integration of digital pathology with molecular signatures is leading the way to establishing clinically relevant morpho-omic taxonomies of renal diseases. SUMMARY The introduction of digital pathology in clinical research and trials, and the progressive implementation of the modern software ecosystem, opens opportunities for the development of new predictive diagnostic paradigms and computer-aided algorithms, transforming the practice of renal disease into a modern computational science.
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Transplant glomerulopathy. Mod Pathol 2018; 31:235-252. [PMID: 29027535 DOI: 10.1038/modpathol.2017.123] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/28/2017] [Accepted: 08/10/2017] [Indexed: 12/13/2022]
Abstract
In the renal allograft, transplant glomerulopathy represents a morphologic lesion and not a specific diagnosis. The hallmark pathologic feature is glomerular basement membrane reduplication by light microscopy or electron microscopy in the absence of immune complex deposits. Transplant glomerulopathy results from chronic, recurring endothelial cell injury that can be mediated by HLA alloantibodies (donor-specific antibodies), various autoantibodies, cell-mediated immune injury, thrombotic microangiopathy, or chronic hepatitis C. Clinically, transplant glomerulopathy may be silent, detectable on protocol biopsy, or present with overt manifestations, including up to nephrotic range proteinuria, hypertension, and declining glomerular filtration rate. In either case, transplant glomerulopathy is associated with reduced graft survival. This review details the morphologic features of transplant glomerulopathy found on light microscopy, immunofluorescence microscopy, and electron microscopy. The pathophysiology of the causes and risk factors are discussed. Clinical manifestations are emphasized and potential therapeutic modalities are examined.
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Ding F, Wickman L, Wang SQ, Zhang Y, Wang F, Afshinnia F, Hodgin J, Ding J, Wiggins RC. Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome. Kidney Int 2017; 92:1515-1525. [PMID: 28754557 PMCID: PMC5696060 DOI: 10.1016/j.kint.2017.05.017] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/12/2017] [Accepted: 05/04/2017] [Indexed: 01/15/2023]
Abstract
Podocyte depletion is a common mechanism driving progression in glomerular diseases. Alport Syndrome glomerulopathy, caused by defective α3α4α5 (IV) collagen heterotrimer production by podocytes, is associated with an increased rate of podocyte detachment detectable in urine and reduced glomerular podocyte number suggesting that defective podocyte adherence to the glomerular basement membrane might play a role in driving progression. Here a genetically phenotyped Alport Syndrome cohort of 95 individuals [urine study] and 41 archived biopsies [biopsy study] were used to test this hypothesis. Podocyte detachment rate (measured by podocin mRNA in urine pellets expressed either per creatinine or 24-hour excretion) was significantly increased 11-fold above control, and prior to a detectably increased proteinuria or microalbuminuria. In parallel, Alport Syndrome glomeruli lose an average 26 podocytes per year versus control glomeruli that lose 2.3 podocytes per year, an 11-fold difference corresponding to the increased urine podocyte detachment rate. Podocyte number per glomerulus in Alport Syndrome biopsies is projected to be normal at birth (558/glomerulus) but accelerated podocyte loss was projected to cause end-stage kidney disease by about 22 years. Biopsy data from two independent cohorts showed a similar estimated glomerular podocyte loss rate comparable to the measured 11-fold increase in podocyte detachment rate. Reduction in podocyte number and density in biopsies correlated with proteinuria, glomerulosclerosis, and reduced renal function. Thus, the podocyte detachment rate appears to be increased from birth in Alport Syndrome, drives the progression process, and could potentially help predict time to end-stage kidney disease and response to treatment.
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Affiliation(s)
- Fangrui Ding
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Larysa Wickman
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | - Su Q Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yanqin Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Fang Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Farsad Afshinnia
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeffrey Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jie Ding
- Department of Pediatrics, Peking University First Hospital, Beijing, China.
| | - Roger C Wiggins
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
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Trimarchi H. Podocyturia: Potential applications and current limitations. World J Nephrol 2017; 6:221-228. [PMID: 28948159 PMCID: PMC5592426 DOI: 10.5527/wjn.v6.i5.221] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 06/25/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease is a prevalent condition that affects millions of people worldwide and is a major risk factor of cardiovascular morbidity and mortality. The main diseases that lead to chronic kidney disease are frequent entities as diabetes mellitus, hypertension and glomerulopathies. One of the clinical markers of kidney disease progression is proteinuria. Moreover, the histological hallmark of kidney disease is sclerosis, located both in the glomerular and in the interstitial compartments. Glomerulosclerosis underscores an irreversible lesion that is clinically accompanied by proteinuria. In this regard, proteinuria and glomerular sclerosis are linked by the cell that has been conserved phylogenetically not only to prevent the loss of proteins in the urine, but also to maintain the health of the glomerular filtration barrier: The podocyte. It can then be concluded that the link between proteinuria, kidney disease progression and chronic kidney disease is mainly related to the podocyte. What is this situation due to? The podocyte is unable to proliferate under normal conditions, and a complex molecular machinery exists to avoid its detachment and eventual loss. When the loss of podocytes in the urine, or podocyturia, is taking place and its glomerular absolute number decreased, glomerulosclerosis is the predominant histological feature in a kidney biopsy. Therefore, tissular podocyte shortage is the cause of proteinuria and chronic kidney disease. In this regard, podocyturia has been demonstrated to precede proteinuria, showing that the clinical management of proteinuria cannot be considered an early intervention. The identification of urinary podocytes could be an additional tool to be considered by nephrologists to assess the activity of glomerulopathies, for follow-up purposes and also to unravel the pathophysiology of podocyte detachment in order to tailor the therapy of glomerular diseases more appropriately.
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Affiliation(s)
- Hernán Trimarchi
- Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires 1280AEB, Argentina
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Madill-Thomsen KS, Wiggins RC, Eskandary F, Böhmig GA, Halloran PF. The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla. Am J Transplant 2017; 17:2117-2128. [PMID: 28226404 PMCID: PMC5550741 DOI: 10.1111/ajt.14233] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 02/10/2017] [Accepted: 02/12/2017] [Indexed: 01/25/2023]
Abstract
Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes (e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL, and REN). Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the molecular microscope diagnostic system. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had <50% cortex. Molecular scores for antibody-mediated rejection, T cell-mediated rejection, and injury were independent of proportion cortex. Rejection was diagnosed in many biopsies that were mostly or all medulla. Agreement in molecular diagnoses in paired cortex/medulla samples (23/26) was similar to biological replicates (32/37). We conclude that NPHS2 expression can estimate proportion cortex; that proportion cortex has little influence on molecular diagnosis of rejection; and that, although histology cannot assess medulla, rejection does occur in medulla as well as cortex.
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Affiliation(s)
| | - R. C. Wiggins
- Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - F. Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - G. A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - P. F. Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada,Department of Medicine, University of Alberta, Edmonton, AB, Canada,Corresponding author: Philip F. Halloran,
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Podocyte number and density changes during early human life. Pediatr Nephrol 2017; 32:823-834. [PMID: 28028615 PMCID: PMC5368211 DOI: 10.1007/s00467-016-3564-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/30/2016] [Accepted: 11/30/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Podocyte depletion, which drives progressive glomerulosclerosis in glomerular diseases, is caused by a reduction in podocyte number, size or function in the context of increasing glomerular volume. METHODS Kidneys obtained at autopsy from premature and mature infants who died in the first year of life (n = 24) were used to measure podometric parameters for comparison with previously reported data from older kidneys. RESULTS Glomerular volume increased 4.6-fold from 0.13 ± 0.07 μm3 x106 in the pre-capillary loop stage, through 0.35 μm3 x106 at the capillary loop, to 0.60 μm3 x106 at the mature glomerular stage. Podocyte number per glomerulus increased from 326 ± 154 per glomerulus at the pre-capillary loop stage to 584 ± 131 per glomerulus at the capillary loop stage of glomerular development to reach a value of 589 ± 166 per glomerulus in mature glomeruli. Thus, the major podocyte number increase occurs in the early stages of glomerular development, in contradistinction to glomerular volume increase, which continues after birth in association with body growth. CONCLUSIONS As glomeruli continue to enlarge, podocyte density (number per volume) rapidly decreases, requiring a parallel rapid increase in podocyte size that allows podocyte foot processes to maintain complete coverage of the filtration surface area. Hypertrophic stresses on the glomerulus and podocyte during development and early rapid growth periods of life are therefore likely to play significant roles in determining how and when defects in podocyte structure and function due to genetic variants become clinically manifest. Therapeutic strategies aimed at minimizing mismatch between these factors may prove clinically useful.
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Halloran PF, Famulski KS, Reeve J. Molecular assessment of disease states in kidney transplant biopsy samples. Nat Rev Nephrol 2016; 12:534-48. [DOI: 10.1038/nrneph.2016.85] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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50
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Naik AS, Afshinnia F, Cibrik D, Hodgin JB, Wu F, Zhang M, Kikuchi M, Wickman L, Samaniego M, Bitzer M, Wiggins JE, Ojo A, Li Y, Wiggins RC. Quantitative podocyte parameters predict human native kidney and allograft half-lives. JCI Insight 2016; 1:86943. [PMID: 27280173 PMCID: PMC4894348 DOI: 10.1172/jci.insight.86943] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 04/19/2016] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Kidney function decreases with age. A potential mechanistic explanation for kidney and allograft half-life has evolved through the realization that linear reduction in glomerular podocyte density could drive progressive glomerulosclerosis to impact both native kidney and allograft half-lives. METHODS Predictions from podometrics (quantitation of podocyte parameters) were tested using independent pathologic, functional, and outcome data for native kidneys and allografts derived from published reports and large registries. RESULTS With age, native kidneys exponentially develop glomerulosclerosis, reduced renal function, and end-stage kidney disease, projecting a finite average kidney life span. The slope of allograft failure rate versus age parallels that of reduction in podocyte density versus age. Quantitative modeling projects allograft half-life at any donor age, and rate of podocyte detachment parallels the observed allograft loss rate. CONCLUSION Native kidneys are designed to have a limited average life span of about 100-140 years. Allografts undergo an accelerated aging-like process that accounts for their unexpectedly short half-life (about 15 years), the observation that older donor age is associated with shorter allograft half-life, and the fact that long-term allograft survival has not substantially improved. Podometrics provides potential readouts for these processes, thereby offering new approaches for monitoring and intervention. FUNDING National Institutes of Health.
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Affiliation(s)
| | | | | | | | - Fan Wu
- School of Public Health, and
| | | | | | - Larysa Wickman
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | | | - Yi Li
- School of Public Health, and
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