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1
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Gharaei S, Gharaei J, Ragy O, Kanigicherla DAK. Use of rituximab and plasma exchange in treatment and prophylaxis of recurrent FSGS. Clin Kidney J 2025; 18:sfaf058. [PMID: 40123963 PMCID: PMC11928785 DOI: 10.1093/ckj/sfaf058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Indexed: 03/25/2025] Open
Abstract
Background Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and renal failure, requiring transplantation. However, FSGS can often recur after transplantation resulting in graft failure. The most used therapeutic intervention for rFSGS is plasma exchange (PE), with variable success. Recently, rituximab has found increasing use in both treatment and prevention of recurrent FSGS. Methods We undertook a systematic review of therapeutic ± preventative plasma exchange, rituximab or a combination of both for recurrent FSGS. Studies published between 2017 and 2024 were included, to reflect the most contemporary clinical practice. Results Twenty-seven studies with a total of 475 patients received treatment for recurrence post-transplantation and/or for prevention of recurrent FSGS. Of 221 patients who received plasma exchange on its own as therapy, 156 (71%) achieved either complete or partial remission. Rituximab alone was used in only four patients (75% remission rate), while 67% achieved remission with a combination of both. One hundred and forty-two patients received pre/peri-transplantation treatment to prevent recurrence in the graft. Fifty-one patients (36%) experienced recurrence despite prophylaxis. Recurrence rates were 35% with plasma exchange alone and 38% with rituximab alone. Conclusion We conclude that rituximab did not add significant benefit to plasma exchange when used as initial therapeutic intervention in post-transplant recurrent FSGS. The modest benefit of prophylactic therapies highlights the need for risk stratification to identify patients most likely to benefit from such interventions. Larger prospective studies with standardized approaches to treatment are essential in improving outcomes in rFSGS.
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Affiliation(s)
- Sophie Gharaei
- Manchester Medical School, University of Manchester, Manchester, UK
- Manchester Institute of Nephrology and Transplantation, Manchester, UK
| | - Julia Gharaei
- School of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
| | - Omar Ragy
- Manchester Institute of Nephrology and Transplantation, Manchester, UK
- University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Durga A K Kanigicherla
- Manchester Institute of Nephrology and Transplantation, Manchester, UK
- University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
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2
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Shah MM, Crane C, Steiner RW. Successful use of deceased donors with medically complex kidneys. Transplant Rev (Orlando) 2025; 39:100888. [PMID: 39608040 DOI: 10.1016/j.trre.2024.100888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/15/2024] [Accepted: 11/16/2024] [Indexed: 11/30/2024]
Abstract
The number of patients waiting for kidney transplants from deceased organ donors continues to increase. In this context, non-transplantation of acceptable kidneys is especially regrettable. Here, we review successful transplantation of deceased donor kidneys with anatomic abnormalities, intrinsic kidney diseases, and other ostensibly problematic conditions. These scenarios will be encountered infrequently and, with limited time to decide, uncertainty often results in organ refusal. In general, anatomic abnormalities can be overcome, kidney diseases remit in recipients, and systemic donor conditions such as poisonings do not affect the recipient. Acknowledging the risk of publication bias and need for more long-term outcome data, familiarity with these "once in a lifetime" deceased donor kidneys potentially avoids unwarranted refusals and provides insights into many disease processes.
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Affiliation(s)
- Mita M Shah
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, CA, United States of America.
| | - Clarkson Crane
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, CA, United States of America
| | - Robert W Steiner
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, CA, United States of America
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3
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Altintas MM, Agarwal S, Sudhini Y, Zhu K, Wei C, Reiser J. Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders. ANNUAL REVIEW OF PATHOLOGY 2025; 20:329-353. [PMID: 39854184 PMCID: PMC11875227 DOI: 10.1146/annurev-pathol-051220-092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.
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Affiliation(s)
- Mehmet M Altintas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | | | - Yashwanth Sudhini
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ke Zhu
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Changli Wei
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Jochen Reiser
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
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4
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Salfi G, Casiraghi F, Remuzzi G. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Front Immunol 2023; 14:1247606. [PMID: 37795085 PMCID: PMC10546017 DOI: 10.3389/fimmu.2023.1247606] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/05/2023] [Indexed: 10/06/2023] Open
Abstract
The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential "circulating factors" contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS.
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Affiliation(s)
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
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5
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Angeletti A, Bruschi M, Kajana X, La Porta E, Spinelli S, Caridi G, Lugani F, Verrina EE, Ghiggeri GM. Biologics in steroid resistant nephrotic syndrome in childhood: review and new hypothesis-driven treatment. Front Immunol 2023; 14:1213203. [PMID: 37705972 PMCID: PMC10497215 DOI: 10.3389/fimmu.2023.1213203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/14/2023] [Indexed: 09/15/2023] Open
Abstract
Nephrotic syndrome affects about 2-7 per 100,000 children yearly and accounts for less than 15% of end stage kidney disease. Steroids still represent the cornerstone of therapy achieving remission in 75-90% of the cases The remaining part result as steroid resistant nephrotic syndrome, characterized by the elevated risk of developing end stage kidney disease and frequently presenting disease recurrence in case of kidney transplant. The pathogenesis of nephrotic syndrome is still far to be elucidated, however, efficacy of immune treatments provided the basis to suggest the involvement of the immune system in the pathogenesis of the disease. Based on these substrates, more immune drugs, further than steroids, were administered in steroid resistant nephrotic syndrome, such as antiproliferative and alkylating agents or calcineurin inhibitors. However, such treatments failed in inducing a sustained remission. In last two decades, the developments of monoclonal antibodies, including the anti-CD20 rituximab and inhibitor of B7-1 abatacept, represented a valid opportunity of treatment. However, also the effectiveness of biologics resulted limited. We here propose a new hypothesis-driven treatment based on the combining administration of rituximab with the anti-CD38 monoclonal antibody daratumumab (NCT05704400), sustained by the hypothesis to target the entire B-cells subtypes pool, including the long-lived plasmacells.
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Affiliation(s)
- Andrea Angeletti
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Maurizio Bruschi
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Xhuliana Kajana
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Edoardo La Porta
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Sonia Spinelli
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gianluca Caridi
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Francesca Lugani
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Enrico Eugenio Verrina
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
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6
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Gauckler P, Zitt E, Regele H, Eller K, Säemann MD, Lhotta K, Neumann I, Rudnicki M, Odler B, Kronbichler A, Zschocke J, Windpessl M. [Diagnosis and treatment of focal-segmental glomerulosclerosis-2023]. Wien Klin Wochenschr 2023; 135:638-647. [PMID: 37728649 PMCID: PMC10511576 DOI: 10.1007/s00508-023-02260-x] [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] [Accepted: 07/24/2023] [Indexed: 09/21/2023]
Abstract
The histopathological term focal-segmental glomerulosclerosis comprises different pathogenic processes with the unifying features of a high proteinuria and the name-giving glomerular lesion pattern seen on light microscopy. A differentiation according to the underlying cause into primary, secondary and genetic forms is therefore of utmost importance. The pathogenesis of primary focal-segmental glomerulosclerosis remains unknown but, like minimal-change disease, an autoimmune-mediated process leading to podocyte damage is assumed. Consequently, the unifying term "podocytopathy" is increasingly being used for both entities. Supportive treatment measures to preserve kidney function are important in all subtypes. In contrast, immunosuppressive treatment is only indicated in primary focal-segmental glomerulosclerosis. Steroid-dependence, steroid-resistance and frequently relapsing disease often complicate disease management and necessitate alternative treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides consensus recommendations on how to best diagnose and manage patients with focal-segmental glomerulosclerosis.
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Affiliation(s)
- Philipp Gauckler
- Department Innere Medizin IV (Nephrologie und Hypertensiologie), Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - Emanuel Zitt
- Abteilung für Innere Medizin III (Nephrologie, Dialyse und Hypertensiologie), Akademisches Lehrkrankenhaus Feldkirch, Feldkirch, Österreich
| | - Heinz Regele
- Klinisches Institut für Pathologie, Medizinische Universität Wien, Wien, Österreich
| | - Kathrin Eller
- Klinische Abteilung für Nephrologie, Abteilung für Innere Medizin III (Nephrologie, Dialyse und Hypertensiologie), Medizinische Universität Graz, Graz, Österreich
| | - Marcus D. Säemann
- 6.Medizinische Abteilung mit Nephrologie & Dialyse, Klinik Ottakring, Wien, Österreich
- Medizinische Fakultät, SFU, Wien, Österreich
| | - Karl Lhotta
- Abteilung für Innere Medizin III (Nephrologie, Dialyse und Hypertensiologie), Akademisches Lehrkrankenhaus Feldkirch, Feldkirch, Österreich
| | - Irmgard Neumann
- Vasculitis.at, Wien, Österreich
- Immunologiezentrum Zürich (IZZ), Zürich, Schweiz
| | - Michael Rudnicki
- Department Innere Medizin IV (Nephrologie und Hypertensiologie), Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - Balazs Odler
- Klinische Abteilung für Nephrologie, Abteilung für Innere Medizin III (Nephrologie, Dialyse und Hypertensiologie), Medizinische Universität Graz, Graz, Österreich
| | - Andreas Kronbichler
- Department Innere Medizin 4 (Nephrologie und Hypertensiologie), Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - Johannes Zschocke
- Institut für Humangenetik, Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - Martin Windpessl
- Abteilung für Innere Medizin IV, Klinikum Wels-Grieskirchen, Wels, Österreich
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7
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Hartinger JM, Kratky V, Hruskova Z, Slanar O, Tesar V. Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives. Front Immunol 2022; 13:1024068. [PMID: 36420256 PMCID: PMC9676507 DOI: 10.3389/fimmu.2022.1024068] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/13/2022] [Indexed: 11/09/2022] Open
Abstract
The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.
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Affiliation(s)
- Jan Miroslav Hartinger
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
- *Correspondence: Jan Miroslav Hartinger,
| | - Vojtech Kratky
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
| | - Zdenka Hruskova
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
| | - Ondrej Slanar
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
| | - Vladimir Tesar
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
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8
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Hattori M, Shirai Y, Kanda S, Ishizuka K, Kaneko N, Ando T, Eguchi M, Miura K. Circulating nephrin autoantibodies and posttransplant recurrence of primary focal segmental glomerulosclerosis. Am J Transplant 2022; 22:2478-2480. [PMID: 35472030 PMCID: PMC9790549 DOI: 10.1111/ajt.17077] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Motoshi Hattori
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
| | - Yoko Shirai
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
| | - Shoichiro Kanda
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan,Department of PediatricsThe University of TokyoTokyoJapan
| | - Kiyonobu Ishizuka
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
| | - Naoto Kaneko
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
| | - Taro Ando
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
| | - Makoto Eguchi
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
| | - Kenichiro Miura
- Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
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9
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Sageshima J, Chandar J, Chen LJ, Shah R, Al Nuss A, Vincenzi P, Morsi M, Figueiro J, Vianna R, Ciancio G, Burke GW. How to Deal With Kidney Retransplantation-Second, Third, Fourth, and Beyond. Transplantation 2022; 106:709-721. [PMID: 34310100 DOI: 10.1097/tp.0000000000003888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Kidney transplantation is the best health option for patients with end-stage kidney disease. Ideally, a kidney transplant would last for the lifetime of each recipient. However, depending on the age of the recipient and details of the kidney transplant, there may be a need for a second, third, fourth, or even more kidney transplants. In this overview, the outcome of multiple kidney transplants for an individual is presented. Key issues include surgical approach and immunologic concerns. Included in the surgical approach is an analysis of transplant nephrectomy, with indications, timing, and immunologic impact. Allograft thrombosis, whether related to donor or recipient factors merits investigation to prevent it from happening again. Other posttransplant events such as rejection, viral illness (polyomavirus hominis type I), recurrent disease (focal segmental glomerulosclerosis), and posttransplant lymphoproliferative disease may lead to the need for retransplantation. The pediatric recipient is especially likely to need a subsequent kidney transplant. Finally, noncompliance/nonadherence can affect both adults and children. Innovative approaches may reduce the need for retransplantation in the future.
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Affiliation(s)
- Junichiro Sageshima
- Division of Transplant Surgery, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA
| | - Jayanthi Chandar
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Linda J Chen
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Rushi Shah
- Surgical Transplant Fellow, Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Ammar Al Nuss
- Surgical Transplant Fellow, Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Paolo Vincenzi
- Surgical Transplant Fellow, Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Mahmoud Morsi
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Jose Figueiro
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Rodrigo Vianna
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
- Division of Liver and GI Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Gaetano Ciancio
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
| | - George W Burke
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL
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10
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Jain NG, Chen JK, Mahajan R, Kehoe J, Singer P, Whyte D, Bomback AS. Use of ofatumumab and eplerenone in post-transplant recurrence of FSGS. Pediatr Transplant 2022; 26:e14191. [PMID: 34806263 DOI: 10.1111/petr.14191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/06/2021] [Accepted: 11/08/2021] [Indexed: 01/15/2023]
Abstract
BACKGROUND Focal segmental glomerulosclerosis (FSGS) predisposes patients for risk of recurrent disease in allografts. METHODS We report a case of a recipient of an unrelated living donor renal transplant and discuss considerations for utilization of ofatumumab and eplerenone in treatment for recurrent FSGS. RESULTS The recipient was initially managed with scheduled plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab post-transplant during index hospitalization. With notable recurrence of FSGS noted on kidney transplant biopsy, she was initially treated with additional plasmapheresis sessions leading to downtrend in proteinuria. The patient was then transitioned to LDL-A pheresis, which resulted again in uptrend in proteinuria. This prompted return to scheduled plasmapheresis sessions weekly, leading again to a downtrend in proteinuria. Albumin levels remained within normal range throughout her course. Following initiation of eplerenone and ofatumumab, the patient demonstrated normalization of urine protein:creatinine ratio and remission of FSGS recurrence without need for additional apheresis. CONCLUSIONS With notable risk of recurrence of FSGS in kidney transplants leading to allograft failure, the use of ofatumumab and eplerenone in conjunction should be considered for management to induce remission.
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Affiliation(s)
- Namrata G Jain
- Division of Pediatric Nephrology, Department of Pediatrics, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Justin K Chen
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Ruchi Mahajan
- Division of Pediatric Nephrology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
| | - Jacqueline Kehoe
- Division of Pediatric Nephrology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
| | - Pamela Singer
- Division of Pediatric Nephrology, Department of Pediatrics, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York, USA
| | - Dilys Whyte
- Division of Pediatric Nephrology, Department of Pediatrics, Good Samaritan Hospital and Medical Center, West Islip, New York, USA
| | - Andrew S Bomback
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
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11
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Basu B, Angeletti A, Islam B, Ghiggeri GM. New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are? Front Immunol 2022; 13:805697. [PMID: 35222385 PMCID: PMC8873567 DOI: 10.3389/fimmu.2022.805697] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 01/25/2022] [Indexed: 12/16/2022] Open
Abstract
Nephrotic proteinuria is the hallmark of several glomerulonephritis determined by different pathogenetic mechanisms, including autoimmune, degenerative and inflammatory. Some conditions such as Minimal Change Nephropathy (MCN) and Focal Segmental Glomerulosclerosis (FSGS) are of uncertain pathogenesis. Chimeric anti-CD20 monoclonal antibodies have been used with success in a part of proteinuric conditions while some are resistant. New human and humanized monoclonal anti-CD 20 antibodies offer some advantages based on stronger effects on CD20 cell subtypes and have been already administered in hematology and oncology areas as substitutes of chimeric molecules. Here, we revised the literature on the use of human and humanized anti-CD 20 monoclonal antibodies in different proteinuric conditions, resulting effective in those conditions resistant to rituximab. Literature on the use of human anti-CD 20 monoclonal antibodies in different proteinuric diseases is mainly limited to ofatumumab, with several protocols and doses. Studies already performed with ofatumumab given in standard doses of 1,500 mg 1.73m2 suggest no superiority compared to rituximab in children and young adults with steroid dependent nephrotic syndrome. Ofatumumab given in very high doses (300 mg/1.73m2 followed by five infusion 2,000 mg/1.73 m2) seems more effective in patients who are not responsive to common therapies. The question of dose remains unresolved and the literature is not concordant on positive effects of high dose ofatumumab in patients with FSGS prior and after renal transplantation. Obinutuzumab may offer some advantages. In the unique study performed in patients with multidrug dependent nephrotic syndrome reporting positive effects, obinutuzumab was associated with the anti-CD38 monoclonal antibody daratumumab proposing the unexplored frontier of combined therapies. Obinutuzumab represent an evolution also in the treatment of autoimmune glomerulonephritis, such as membranous nephrotahy and lupus nephritis. Results of randomized trials, now in progress, are awaited to add new possibilities in those cases that are resistant to other drugs. The aim of the present review is to open a discussion among nephrologists, with the hope to achieve shared approaches in terms of type of antibodies and doses in the different proteinuric renal conditions.
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Affiliation(s)
- Biswanath Basu
- Division of Pediatric Nephrology, Department of Pediatrics, Nilratan Sircar (NRS) Medical College and Hospital, Kolkata, India
| | - Andrea Angeletti
- Division of Nephrology, Dialysis, Transplantation, IstitutoGianninaGaslini Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy
- Laboratory on Molecular Nephrology, IstitutoGianninaGaslini Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy
| | - Bilkish Islam
- Department of Pediatrics, Nil Ratan Sircar Medical College and Hospital, Kolkata, India
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, Transplantation, IstitutoGianninaGaslini Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy
- Laboratory on Molecular Nephrology, IstitutoGianninaGaslini Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genoa, Italy
- *Correspondence: Gian Marco Ghiggeri,
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Torres DD, Fontò G, Guastamacchia L, Santangelo L, Carbone V, Piscopo G, Spadaccino F, Ranieri E, Netti GS, Giordano M. Therapeutic Approach for Recurrent Focal Segmental Glomerulosclerosis in Pediatric Renal Transplant Recipients: A Single-Center Experience. Blood Purif 2022; 51:847-856. [DOI: 10.1159/000521311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 12/02/2021] [Indexed: 11/19/2022]
Abstract
<b><i>Introduction:</i></b> Recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KTx) develops in 40% of patients, leading to graft loss in half of cases. Extracorporeal apheretic treatments, combined with immunosuppressive drugs, seem to be the most promising therapies, but at now limited reports are available, mainly in pediatric patients. <b><i>Objective:</i></b> We aimed to assess the efficacy of immunoadsorption (IA) to treat recurrent FSGS in pediatric patients. <b><i>Methods:</i></b> We report a case series of 4 pediatric patients (aged 4–12 years) followed at our institution for early recurrent FSGS after KTx. FSGS recurrence was treated with early and intensive apheretic treatments IA. <b><i>Results:</i></b> After IA initiation, a partial remission (PR) of proteinuria at 24-month follow-up was achieved only in 1 patient. The others showed a mild reduction of nephrotic proteinuria, without PR, but gained a significant improvement in clinical signs of nephrotic syndrome (reduction of edema, increased serum albumin, and total protein levels). After a median follow-up of 38 (22–48) months, renal function was almost stable over time in all patients, except one who returned to hemodialysis after 22 months. No severe IA-related complications occurred. <b><i>Conclusions:</i></b> According to our clinical experience, IA revealed as a safe and effective therapy to treat patients with recurrent FSGS after KTx and it could maintain stable renal function in 75% of patients.
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UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant. Pediatr Nephrol 2022; 37:199-207. [PMID: 34383125 PMCID: PMC8674165 DOI: 10.1007/s00467-021-05248-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/03/2022]
Abstract
BACKGROUND Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). METHODS We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. RESULTS Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission-brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. CONCLUSIONS OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.
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Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med 2021; 11:jcm11010093. [PMID: 35011834 PMCID: PMC8745094 DOI: 10.3390/jcm11010093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Primary focal segmental glomerulosclerosis (FSGS) is associated with a high risk of recurrence after kidney transplantation with a major risk of graft loss despite preventive or curative treatments. Aim: to assess graft survival in FSGS kidney-transplant recipients and to compare those that had a relapse with those that had no relapse. Patients/Methods: we included 17 FSGS kidney-transplant recipients between January 2000 and January 2020, separated retrospectively into two groups (recurrences: n = 8 patients; no recurrences: n = 9 patients). FSGS recurrence was defined as having proteinuria of ≥3 g/g or urinary creatinine of ≥3 g/day. All patients received an induction therapy; maintenance immunosuppressive therapy at post-transplantation relied on tacrolimus/mycophenolate mofetil/steroids. In order to prevent or treat FSGS recurrence, patients received apheresis sessions plus rituximab. Results: FSGS recurrence rate was 47%. All patients that relapsed with a first graft also relapsed with subsequent grafts. Median time to recurrence was 3 (min: 1; max: 4745) days, despite rituximab/apheresis prophylaxis. Mean age was significantly lower in the relapsers (group 1) than in the non-relapsers (group 2); i.e., 47 ± 11 vs. 58 ± 9 years (p = 0.04). Time to progression to stage 5 chronic kidney disease (CKD) and young age at FSGS diagnosis were lower in group 1 compared to group 2; i.e., 5 (min: 1; max: 26) vs. 2 (min: 1; max: 26) years, and 16 (min: 4; max: 55) vs. 34 (min: 6; max 48) years, respectively. There was no difference between the two groups in terms of progression to CKD stage 5 on the native kidneys, averaging 7 years in both groups (p = 0.99). In group 1, seven patients received rituximab/apheresis prophylaxis, although this did not prevent the recurrence of FSGS. Conclusion: pretransplant prophylaxis with plasmapheresis/rituximab did not appear to reduce the risk of recurrence of primary FSGS on the graft, but could allow remission in the event of recurrence.
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De Souza L, Prunster J, Chan D, Chakera A, Lim WH. Recurrent glomerulonephritis after kidney transplantation: a practical approach. Curr Opin Organ Transplant 2021; 26:360-380. [PMID: 34039882 DOI: 10.1097/mot.0000000000000887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW This review will provide a practical approach in the assessment of kidney failure patients with primary glomerulonephritides (GN) being considered for kidney transplantation, focusing on high-risk subtypes of immunoglobulin A nephropathy, focal segmental glomerulosclerosis, idiopathic membranous glomerulonephritis and membranoproliferative glomerulonephritis. RECENT FINDINGS Recurrent glomerulonephritis remains one of the most common causes of allograft loss in kidney transplant recipients. Although the epidemiology and clinical outcomes of glomerulonephritis recurrence occurring after kidney transplantation are relatively well-described, the natural course and optimal treatment strategies of recurrent disease in kidney allografts remain poorly defined. With a greater understanding of the pathophysiology and treatment responses of patients with glomerulonephritis affecting the native kidneys, these discoveries have laid the framework for the potential to improve the management of patients with high-risk glomerulonephritis subtypes being considered for kidney transplantation. SUMMARY Advances in the understanding of the underlying immunopathogenesis of primary GN has the potential to offer novel therapeutic options for kidney patients who develop recurrent disease after kidney transplantation. To test the efficacy of novel treatment options in adequately powered clinical trials requires a more detailed understanding of the clinical and histological characteristics of kidney transplant recipients with recurrent glomerulonephritis.
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Affiliation(s)
- Laura De Souza
- Department of Renal Medicine, Cairns Hospital, Cairns North, Queensland
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns North, Queensland
| | - Doris Chan
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
| | - Aron Chakera
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
| | - Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
- Medical School, University of Western Australia, Crawley, Western Australia, Australia
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Boonpheng B, Hansrivijit P, Thongprayoon C, Mao SA, Vaitla PK, Bathini T, Choudhury A, Kaewput W, Mao MA, Cheungpasitporn W. Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation: A systematic review and meta-analysis. World J Transplant 2021; 11:303-319. [PMID: 34316454 PMCID: PMC8291000 DOI: 10.5500/wjt.v11.i7.303] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/10/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular diseases leading to renal failure. FSGS has a high risk of recurrence after kidney transplantation. Prevention of recurrent FSGS using rituximab and/or plasmapheresis has been evaluated in multiple small studies with conflicting results. AIM To assess the risk of recurrence of FSGS after transplantation using prophylactic rituximab with or without plasmapheresis, and plasmapheresis alone compared to the standard treatment group without preventive therapy. METHODS This meta-analysis and systematic review were performed by first conducting a literature search of the MEDLINE, EMBASE, and Cochrane databases, from inception through March 2021; search terms included 'FSGS,' 'steroid-resistant nephrotic syndrome', 'rituximab,' and 'plasmapheresis,'. We identified studies that assessed the risk of post-transplant FSGS after use of rituximab with or without plasmapheresis, or plasmapheresis alone. Inclusion criteria were: Original, published, randomized controlled trials or cohort studies (either prospective or retrospective), case-control, or cross-sectional studies; inclusion of odds ratio, relative risk, and standardized incidence ratio with 95% confidence intervals (CI), or sufficient raw data to calculate these ratios; and subjects without interventions (controls) being used as comparators in cohort and cross-sectional studies. Effect estimates from individual studies were extracted and combined using a random effects model. RESULTS Eleven studies, with a total of 399 kidney transplant recipients with FSGS, evaluated the use of rituximab with or without plasmapheresis; thirteen studies, with a total of 571 kidney transplant recipients with FSGS, evaluated plasmapheresis alone. Post-transplant FSGS recurred relatively early. There was no significant difference in recurrence between the group that received rituximab (with or without plasmapheresis) and the standard treatment group, with a pooled risk ratio of 0.82 (95%CI: 0.47-1.45, I 2 = 65%). Similarly, plasmapheresis alone was not associated with any significant difference in FSGS recurrence when compared with no plasmapheresis; the pooled risk ratio was 0.85 (95%CI: 0.60-1.21, I 2 = 23%). Subgroup analyses in the pediatric and adult groups did not yield a significant difference in recurrence risk. We also reviewed and analyzed post-transplant outcomes including timing of recurrence and graft survival. CONCLUSION Overall, the use of rituximab with or without plasmapheresis, or plasmapheresis alone, is not associated with a lower risk of FSGS recurrence after kidney transplantation. Future studies are required to assess the effectiveness of rituximab with or without plasmapheresis among specific patient subgroups with high-risk for FSGS recurrence.
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Affiliation(s)
- Boonphiphop Boonpheng
- Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States
| | - Panupong Hansrivijit
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | | | - Shennen A Mao
- Division of Transplant Surgery, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Pradeep K Vaitla
- Division of Nephrology, Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Tarun Bathini
- Department of Internal Medicine, University of Arizona, Tucson, AZ 85721, United States
| | - Avishek Choudhury
- School of Systems and Enterprises, Stevens Institute of Technology, Hoboken, NJ 07030, United States
| | - Wisit Kaewput
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok 10400, Thailand
| | - Michael A Mao
- Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
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17
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Hamroun A, Gibier JB, Maanaoui M, Lionet A, Gnemmi V, Bouyé S, Fantoni JC, Averland B, Antoine C, Lenain R, Hazzan M, Provôt F. Successful Reuse of Kidney Graft After Early Recurrence of Primary Focal and Segmental Glomerulosclerosis. Am J Kidney Dis 2021; 78:897-901. [PMID: 34118304 DOI: 10.1053/j.ajkd.2021.03.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 03/26/2021] [Indexed: 11/11/2022]
Abstract
Primary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine+corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation.
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Affiliation(s)
- Aghilès Hamroun
- Departments of Nephrology, Dialysis, Transplantation, and Apheresis, Lille University, Regional and University Hospital Center of Lille, Lille, France; Paris-Saclay University, Versailles Saint Quentin University, Inserm, Clinical Epidemiology Team, CESP, Centre for Research in Epidemiology and Population Health, Villejuif, France.
| | - Jean-Baptiste Gibier
- Department of Pathology, Pathology Institute, Lille University, Regional and University Hospital Center of Lille, Inserm UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team "Mucins, Epithelial Differentiation and Carcinogenesis," F-59037 Lille, France
| | - Mehdi Maanaoui
- Departments of Nephrology, Dialysis, Transplantation, and Apheresis, Lille University, Regional and University Hospital Center of Lille, Lille, France; INSERM U1190, Translational Research for Diabetes, Lille, France
| | - Arnaud Lionet
- Departments of Nephrology, Dialysis, Transplantation, and Apheresis, Lille University, Regional and University Hospital Center of Lille, Lille, France
| | - Viviane Gnemmi
- Department of Pathology, Pathology Institute, Lille University, Regional and University Hospital Center of Lille, Inserm UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team "Mucins, Epithelial Differentiation and Carcinogenesis," F-59037 Lille, France
| | - Sébastien Bouyé
- Urology, Lille University, Regional and University Hospital Center of Lille, Lille, France
| | | | | | - Corinne Antoine
- Agence de la Biomédecine, Saint-Denis, France; Nephrology and Kidney Transplantation, Hospital Saint Louis, Paris, France
| | - Rémi Lenain
- Departments of Nephrology, Dialysis, Transplantation, and Apheresis, Lille University, Regional and University Hospital Center of Lille, Lille, France; INSERM UMR1246 - SPHERE, Nantes University, Tours University, Nantes, France
| | - Marc Hazzan
- Departments of Nephrology, Dialysis, Transplantation, and Apheresis, Lille University, Regional and University Hospital Center of Lille, Lille, France
| | - François Provôt
- Departments of Nephrology, Dialysis, Transplantation, and Apheresis, Lille University, Regional and University Hospital Center of Lille, Lille, France
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18
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Immune-mediated entities of (primary) focal segmental glomerulosclerosis. Cell Tissue Res 2021; 385:423-434. [PMID: 33907872 PMCID: PMC8523460 DOI: 10.1007/s00441-021-03454-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/19/2021] [Indexed: 12/21/2022]
Abstract
Focal segmental glomerulosclerosis (FSGS) represents a glomerular scar formation downstream of various different mechanisms leading to podocytopathy and podocyte loss. Recently, significant advances were made in understanding genetic factors, podocyte intrinsic mechanisms, and adaptive mechanisms causing FSGS. However, while most cases of nephrotic FSGS are being treated with immunosuppressants, the underlying immune dysregulation, involved immune cells, and soluble factors are only incompletely understood. Thus, we here summarize the current knowledge of proposed immune effector cells, secreted soluble factors, and podocyte response in immune-mediated (primary) FSGS.
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19
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Dudreuilh C, Barbet C, Gatault P, Ferlicot S, Lebranchu Y, Rabot N, Beaudreuil S, Dürrbach A, Büchler M. Response to plasma exchange and graft survival in recurrent focal and segmental glomerulosclerosis after transplantation: does the time of recurrence matter? A retrospective study. Transpl Int 2020; 34:302-312. [PMID: 33275815 DOI: 10.1111/tri.13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/10/2020] [Accepted: 11/30/2020] [Indexed: 11/29/2022]
Abstract
Recurrence of primary focal and segmental glomerulosclerosis following kidney transplantation (rFSGS) is a frequent and severe disease. We studied the time to recurrence of FSGS and its impact on the response to plasma exchange (PE) and graft survival. Between 1990 and 2013, 2730 kidney transplants were performed, including 52 patients with a primary diagnosis of FSGS. Of these patients with primary FSGS, 34 (67%) developed rFSGS. We retrospectively divided these patients into two groups depending on the time to recurrence: early (up to three months after transplantation, n = 26) or late (more than three months after transplantation, n = 8). Survival did not significantly differ between the two groups. In cases of late recurrence, PE was started later and was performed less frequently, and remission was achieved after more PE sessions and longer PE treatment than for the early group (P = 0.01). In early recurrence, resistance to PE at 40 days was associated with no long-term response to PE. PE should be performed as soon as possible after rFSGS. Patients with late rFSGS need to be offered the same treatment regime as those with early rFSGS.
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Affiliation(s)
- Caroline Dudreuilh
- Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.,EA4245 Dendritic Cells, Immunomodulation and Grafts, François-Rabelais University, Tours, France
| | - Christelle Barbet
- Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.,EA4245 Dendritic Cells, Immunomodulation and Grafts, François-Rabelais University, Tours, France
| | - Philippe Gatault
- Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.,EA4245 Dendritic Cells, Immunomodulation and Grafts, François-Rabelais University, Tours, France
| | - Sophie Ferlicot
- Department of Pathology, Bicetre University Hospital, Le Kremlin Bicêtre, France
| | - Yvon Lebranchu
- Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.,EA4245 Dendritic Cells, Immunomodulation and Grafts, François-Rabelais University, Tours, France
| | - Nolwenn Rabot
- Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.,EA4245 Dendritic Cells, Immunomodulation and Grafts, François-Rabelais University, Tours, France
| | - Severine Beaudreuil
- Nephrology Department, Hopitaux Universitaires Paris-Sud, APHP, Le Kremlin-Bicetre, France.,UMR 1197, University Paris Sud, INSERM, Paris-Saclay University, Villejuif, France
| | - Antoine Dürrbach
- Nephrology Department, Hopitaux Universitaires Paris-Sud, APHP, Le Kremlin-Bicetre, France.,UMR 1197, University Paris Sud, INSERM, Paris-Saclay University, Villejuif, France
| | - Matthias Büchler
- Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.,EA4245 Dendritic Cells, Immunomodulation and Grafts, François-Rabelais University, Tours, France
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20
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Abstract
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.
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21
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Afzali S, Salehi S, Shahi A, Amirzargar A. B cell modulation strategies in the improvement of transplantation outcomes. Mol Immunol 2020; 125:140-150. [PMID: 32682148 DOI: 10.1016/j.molimm.2020.06.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/19/2020] [Accepted: 06/30/2020] [Indexed: 01/03/2023]
Abstract
Successful transplantation outcome is the final goal in most end stage and nonfunctional organs; however, despite using different therapeutic strategies, antibody-mediated rejection is still a big obstacle. B cells have a key role in transplant rejection by several functions, such as antibody production, antigen presenting, contribution in T cell activation, forming the germinal center, and tertiary lymphoid organs. Therefore, B cells modulation seems to be very crucial in transplant outcome. A double-edged sword function is considered for B cells during transplantation; On the one hand, antibody production against the transplanted organ induces antibody-mediated rejection. On the other hand, IL10 production by regulatory B (Breg) cells induces graft tolerance. Nowadays, several monoclonal antibodies (mAb) are available for B cell modulation that are routinely used in transplant recipients, among which rituximab (anti-CD20 mAb) act in eliminating B cells. However, there are some other monoclonal antibodies, such as epratuzumab and Inotuzumab ozogamicin (IO), which exert anti-CD22 activity, resulting in disruption of B cell functions and induction of tolerance in autoimmune disease or B cell malignancies; that notwithstanding, these mAbs have not yet been tried in transplantation. In this review, we focus on different methods for modulating the activity of B cells as well as induction of Breg cells, aiming to prevent the allograft rejection.
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Affiliation(s)
- Shima Afzali
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeedeh Salehi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Shahi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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22
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Jyothish M, Berry M, Neil D. Outcomes of renal transplantation in adult patients with primary focal segmental glomerulosclerosis: a single-centre experience over 5 decades. Clin Med (Lond) 2020; 20:s111. [PMID: 32409414 DOI: 10.7861/clinmed.20-2-s111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
| | - Miriam Berry
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Desley Neil
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
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23
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Ofatumumab rescue treatment in post-transplant recurrence of focal segmental glomerulosclerosis. Pediatr Nephrol 2020; 35:341-345. [PMID: 31667616 DOI: 10.1007/s00467-019-04365-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/08/2019] [Accepted: 09/12/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Treatment of post-transplant focal segmental glomerulosclerosis (FSGS) recurrence is still debated. The use of the fully human anti-CD20 monoclonal antibody ofatumumab has been suggested. CASE-DIAGNOSIS/TREATMENT Two boys with FSGS received a kidney transplantation at the age of 15 years from a deceased and a living donor. Maintenance therapy consisted of calcineurin inhibitors, antiproliferative agents, and prednisone. Early post-transplant FSGS recurrence was observed after 2 and 3 days. Rituximab infusion and plasmapheresis sessions were performed with transient clinical improvement in the first patient, and no apparent response in the second patient. Both patients were treated with two ofatumumab infusions, which induced in patient #1 a complete and stable remission for more than 12 months and in patient #2 a partial remission with a progressive reduction of proteinuria and normalization of serum protein levels. CONCLUSIONS Ofatumumab may be a therapeutic option for post-transplant FSGS recurrence in patients who respond poorly to rituximab.
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24
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Lim WH, Shingde M, Wong G. Recurrent and de novo Glomerulonephritis After Kidney Transplantation. Front Immunol 2019; 10:1944. [PMID: 31475005 PMCID: PMC6702954 DOI: 10.3389/fimmu.2019.01944] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/01/2019] [Indexed: 12/13/2022] Open
Abstract
The prevalence, pathogenesis, predictors, and natural course of patients with recurrent glomerulonephritis (GN) occurring after kidney transplantation remains incompletely understood, including whether there are differences in the outcomes and advances in the treatment options of specific GN subtypes, including those with de novo GN. Consequently, the treatment options and approaches to recurrent disease are largely extrapolated from the general population, with responses to these treatments in those with recurrent or de novo GN post-transplantation poorly described. Given a greater understanding of the pathogenesis of GN and the development of novel treatment options, it is conceivable that these advances will result in an improved structure in the future management of patients with recurrent or de novo GN. This review focuses on the incidence, genetics, characteristics, clinical course, and risk of allograft failure of patients with recurrent or de novo GN after kidney transplantation, ascertaining potential disparities between “high risk” disease subtypes of IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. We will examine in detail the management of patients with high risk GN, including the pre-transplant assessment, post-transplant monitoring, and the available treatment options for disease recurrence. Given the relative paucity of data of patients with recurrent and de novo GN after kidney transplantation, a global effort in collecting comprehensive in-depth data of patients with recurrent and de novo GN as well as novel trial design to test the efficacy of specific treatment strategy in large scale multicenter randomized controlled trials are essential to address the knowledge deficiency in this disease.
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Affiliation(s)
- Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia.,School of Medicine, University of Western Australia, Perth, WA, Australia
| | - Meena Shingde
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia.,Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia.,Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, NSW, Australia
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25
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Kienzl-Wagner K, Waldegger S, Schneeberger S. Disease Recurrence-The Sword of Damocles in Kidney Transplantation for Primary Focal Segmental Glomerulosclerosis. Front Immunol 2019; 10:1669. [PMID: 31379860 PMCID: PMC6652209 DOI: 10.3389/fimmu.2019.01669] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/04/2019] [Indexed: 12/21/2022] Open
Abstract
A major obstacle in kidney transplantation for primary focal segmental glomerulosclerosis (FSGS) is the risk of disease recurrence. Recurrent FSGS affects up to 60% of first kidney grafts and exceeds 80% in patients who have lost their first graft due to recurrent FSGS. Clinical and experimental evidence support the hypothesis that a circulating permeability factor is the mediator in the pathogenesis of primary and recurrent disease. Despite all efforts, the causing agent has not yet been identified. Several treatment options for the management of recurrent FSGS have been proposed. In addition to plasma exchange, B-cell depleting antibodies are effective in recurrent FSGS. This indicates, that the secretion and/or activity of the postulated circulating permeability factor(s) may be B-cell related. This review summarizes the current knowledge on permeability factor(s) possibly related to the disease and discusses strategies for the management of recurrent FSGS. These include profound B-cell depletion prior to transplantation, as well as the salvage of an allograft affected by recurrent FSGS by transfer into a second recipient.
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Affiliation(s)
- Katrin Kienzl-Wagner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Siegfried Waldegger
- Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
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26
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Solomon S, Zolotnitskaya A, Del Rio M. Ofatumumab in post-transplantation recurrence of focal segmental glomerulosclerosis in a child. Pediatr Transplant 2019; 23:e13413. [PMID: 30973669 DOI: 10.1111/petr.13413] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/21/2019] [Accepted: 02/28/2019] [Indexed: 12/15/2022]
Abstract
FSGS is a potentially devastating form of nephrotic syndrome. Treatment of SRNS can be difficult, especially post-transplantation. The current therapy of post-transplant SRNS includes plasmapheresis, ACE-I, CNI, and monoclonal antibodies (rituximab). Patients who are refractory to these interventions have limited therapeutic alternatives. We present a case of a patient with SRNS secondary to FSGS. He did not respond to immunosuppressive medications prior to transplant, progressed to ESRD, and was started on chronic hemodialysis. He received a DDKT which was complicated by post-transplant FSGS recurrence. A course of plasmapheresis, rituximab, and CNI were administered with some response. Ofatumumab was then given to the patient. As a result, the patient achieved partial remission. Ofatumumab may be a safe and effective option for post-transplant recurrence of FSGS.
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27
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Kienzl‐Wagner K, Rosales A, Scheidl S, Giner T, Bösmüller C, Rudnicki M, Oberhuber R, Margreiter C, Soleiman A, Öfner D, Waldegger S, Schneeberger S. Successful management of recurrent focal segmental glomerulosclerosis. Am J Transplant 2018; 18:2818-2822. [PMID: 29962080 PMCID: PMC6220932 DOI: 10.1111/ajt.14998] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/20/2018] [Accepted: 06/22/2018] [Indexed: 01/25/2023]
Abstract
Primary focal segmental glomerulosclerosis (FSGS) recurs in up to 55% of patients after kidney transplantation. Herein we report the successful management of recurrent FSGS. A 5-year-old boy with primary FSGS received a deceased donor renal transplant. Immediate and fulminant recurrence of FSGS caused anuric graft failure that was resistant to plasmapheresis and rituximab. After exclusion of structural or immunologic damage to the kidney by repeated biopsies, the allograft was retrieved from the first recipient on day 27 and transplanted into a 52-year-old second recipient who had vascular nephropathy. Immediately after retransplantation, the allograft regained function with excellent graft function persistent now at 3 years after transplant. After 2 years on hemodialysis, the boy was listed for kidney retransplantation. To prevent FSGS recurrence, pretreatment with ofatumumab was performed. Nephrotic range proteinuria still occurred after the second transplantation, which responded, however, to daily plasma exchange in combination with ofatumumab. At 8 months after kidney retransplantation graft function is good. The clinical course supports the hypothesis of a circulating permeability factor in the pathogenesis of FSGS. Successful ofatumumab pretreatment implicates a key role of B cells. Herein we provide a description of successful management of kidney failure by FSGS, carefully avoiding waste of organs.
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Affiliation(s)
- Katrin Kienzl‐Wagner
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
| | - Alejandra Rosales
- Department of PediatricsMedical University of InnsbruckInnsbruckAustria
| | - Stefan Scheidl
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
| | - Thomas Giner
- Department of PediatricsMedical University of InnsbruckInnsbruckAustria
| | - Claudia Bösmüller
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
| | - Michael Rudnicki
- Department of Internal MedicineMedical University of InnsbruckInnsbruckAustria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
| | | | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
| | | | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic SurgeryMedical University of InnsbruckInnsbruckAustria
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