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Regalia A, Abinti M, Alfieri CM, Campise M, Verdesca S, Zanoni F, Castellano G. Post-transplant glomerular diseases: update on pathophysiology, risk factors and management strategies. Clin Kidney J 2024; 17:sfae320. [PMID: 39664990 PMCID: PMC11630810 DOI: 10.1093/ckj/sfae320] [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: 06/27/2024] [Indexed: 12/13/2024] Open
Abstract
In recent years, advancements in immunosuppressive medications and post-transplant management have led to a significant decrease in acute rejection rates in renal allografts and consequent improvement in short-term graft survival. In contrast, recent data have shown an increased incidence of post-transplant glomerular diseases, which currently represent a leading cause of allograft loss. Although pathogenesis is not fully understood, growing evidence supports the role of inherited and immunological factors and has identified potential pre- and post-transplant predictors. In this review, we illustrate recent advancements in the pathogenesis of post-transplant glomerular disease and the role of risk factors and immunological triggers. In addition, we discuss potential prevention and management strategies.
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Affiliation(s)
- Anna Regalia
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Matteo Abinti
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
- Post-Graduate School of Specialization in Nephrology, University of Milan, Milan, Italy
| | - Carlo Maria Alfieri
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariarosaria Campise
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Simona Verdesca
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Zanoni
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
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Trujillo H, Caravaca-Fontán F, Praga M. Ten tips on immunosuppression in primary membranous nephropathy. Clin Kidney J 2024; 17:sfae129. [PMID: 38915435 PMCID: PMC11195618 DOI: 10.1093/ckj/sfae129] [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: 02/29/2024] [Indexed: 06/26/2024] Open
Abstract
Membranous nephropathy (MN) management poses challenges, particularly in selecting appropriate immunosuppressive treatments (IST) and monitoring disease progression and complications. This article highlights 10 key tips for the management of primary MN based on current evidence and clinical experience. First, we advise against prescribing IST to patients without nephrotic syndrome (NS), emphasizing the need for close monitoring of disease progression. Second, we recommend initiating IST in patients with persistent NS or declining kidney function. Third, we suggest prescribing rituximab (RTX) or RTX combined with calcineurin inhibitors in medium-risk patients. Fourth, we propose cyclophosphamide-based immunosuppression for high-risk patients. Fifth, we discourage the use of glucocorticoid monotherapy or mycophenolate mofetil as initial treatments. Sixth, we underscore the importance of preventing infectious complications in patients receiving IST. Seventh, we emphasize the need for personalized monitoring of IST by closely measuring kidney function, proteinuria, serum albumin and anti-M-type phospholipase A2 receptor levels. Eighth, we recommend a stepwise approach in the treatment of resistant disease. Ninth, we advise adjusting treatment for relapses based on individual risk profiles. Finally, we caution about the potential recurrence of MN after kidney transplantation and suggest appropriate monitoring and treatment strategies for post-transplantation MN. These tips provide comprehensive guidance for clinicians managing MN, aiming to optimize patient outcomes and minimize complications.
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Affiliation(s)
- Hernando Trujillo
- Department of Nephrology, Hospital Universitario, 12 de Octubre, Madrid, Spain
| | - Fernando Caravaca-Fontán
- Department of Nephrology, Hospital Universitario, 12 de Octubre, Madrid, Spain
- Instituto de Investigación Hospital, 12 de Octubre (i+12), Madrid, Spain
| | - Manuel Praga
- Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain
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Li J, Wang X, Jiang S, Li W. Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy. Med Clin (Barc) 2023; 161:417-421. [PMID: 37532619 DOI: 10.1016/j.medcli.2023.06.007] [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: 03/21/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 08/04/2023]
Abstract
BACKGROUND Patients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. METHODS In this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. RESULTS Twenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan-Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). CONCLUSIONS The PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.
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Affiliation(s)
- Jiayi Li
- Department of Nephrology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China; Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Xu Wang
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Shimin Jiang
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Wenge Li
- Department of Nephrology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China; Department of Nephrology, China-Japan Friendship Hospital, Beijing, China.
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Ali A, Al-Taee H, Kadhim TJ. Relapsing De Novo Membranous Nephropathy. Case Rep Transplant 2022; 2022:6754520. [PMID: 35547830 PMCID: PMC9085326 DOI: 10.1155/2022/6754520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/12/2022] [Indexed: 02/07/2023] Open
Abstract
Allograft membranous glomerulopathy can be a recurrent or de novo disease. Both instead have different underlying immune pathophysiology and disease pattern. While the introduction of ANTI-PLAR2 and THS7A brought new insights into the management of Immune/primary MN, the treatment of de novo MN is not clear. Relapsing de novo MN in a kidney transplant was rarely reported. Here, we present a case of relapsing de novo MN without evidence of rejection and a gratifying response to rituximab.
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Affiliation(s)
- Ala Ali
- Nephrology and Renal Transplantation Centre, The Medical City, Baghdad, Iraq
| | - Huda Al-Taee
- Nephrology and Renal Transplantation Centre, The Medical City, Baghdad, Iraq
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De Novo Membranous Nephropathy Associated With Antibody-Mediated Rejection in Kidney Transplant Recipients. Transplant Proc 2022; 54:1270-1277. [DOI: 10.1016/j.transproceed.2021.11.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/19/2021] [Indexed: 01/11/2023]
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Darji PI, Patel HA, Darji BP, Sharma A, Halawa A. Is de novo membranous nephropathy suggestive of alloimmunity in renal transplantation? A case report. World J Transplant 2022; 12:15-20. [PMID: 35096553 PMCID: PMC8771595 DOI: 10.5500/wjt.v12.i1.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Post-transplant nephrotic syndrome (PTNS) in a renal allograft carries a 48% to 77% risk of graft failure at 5 years if proteinuria persists. PTNS can be due to either recurrence of native renal disease or de novo glomerular disease. Its prognosis depends upon the underlying pathophysiology. We describe a case of post-transplant membranous nephropathy (MN) that developed 3 mo after kidney transplant. The patient was properly evaluated for pathophysiology, which helped in the management of the case.
CASE SUMMARY This 22-year-old patient had chronic pyelonephritis. He received a living donor kidney, and human leukocyte antigen-DR (HLA-DR) mismatching was zero. PTNS was discovered at the follow-up visit 3 mo after the transplant. Graft histopathology was suggestive of MN. In the past antibody-mediated rejection (ABMR) might have been misinterpreted as de novo MN due to the lack of technologies available to make an accurate diagnosis. Some researchers have observed that HLA-DR is present on podocytes causing an anti-DR antibody deposition and development of de novo MN. They also reported poor prognosis in their series. Here, we excluded the secondary causes of MN. Immunohistochemistry was suggestive of IgG1 deposits that favoured the diagnosis of de novo MN. The patient responded well to an increase in the dose of tacrolimus and angiotensin converting enzyme inhibitor.
CONCLUSION Exposure of hidden antigens on the podocytes in allografts may have led to subepithelial antibody deposition causing de novo MN.
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Affiliation(s)
- Prakash I Darji
- Department of Nephrology and Renal Transplantation, Zydus Hospitals, Ahmedabad 380059, Gujarat, India
| | - Himanshu A Patel
- Department of Nephrology and Renal Transplantation, Zydus Hospitals, Ahmedabad 380059, Gujarat, India
| | - Bhavya P Darji
- Internship, Department of Medicine, GCS Medical College, Hospital and Research Centre, Ahmedabad 380025, Gujarat, India
| | - Ajay Sharma
- Faculty of Health and Life Science, Institute of Learning and Teaching, University of Liverpool, Liverpool L69 3BX, United Kingdom
- Consultant Transplant Surgeon, Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Life Science, Institute of Learning and Teaching, University of Liverpool, Liverpool L69 3BX, United Kingdom
- Department of Transplantation, Sheffield Teaching Hospitals, Sheffield S10 2JF, United Kingdom
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Zanoni F, Khairallah P, Kiryluk K, Batal I. Glomerular Diseases of the Kidney Allograft: Toward a Precision Medicine Approach. Semin Nephrol 2022; 42:29-43. [PMID: 35618394 PMCID: PMC9139085 DOI: 10.1016/j.semnephrol.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The continual development of potent immunosuppressive regimens has led to a decreased incidence of acute rejection and improvement of short-term kidney allograft survival. In contrast to acute rejection, glomerular diseases of the kidney allograft are being encountered more frequently and are emerging as leading causes of late kidney allograft failure. Although data on the pathogeneses of glomerular diseases in the kidney allograft are sparse, cumulative evidence suggests that post-transplant glomerular diseases may be the result of inherited predispositions and immunologic triggers. Although studying immunologic signals and performing genome-wide association studies are ideal approaches to tackle glomerular diseases in the kidney allograft, such studies are challenging because of the lack of adequately powered cohorts. In this review, we focus on the most commonly encountered recurrent and de novo glomerular diseases in the kidney allograft. We address the important advances made in understanding the immunopathology and genetic susceptibility of glomerular diseases in the native kidney and how to benefit from such knowledge to further our knowledge of post-transplant glomerular diseases. Defining genomic and immune predictors for glomerular diseases in the kidney allograft would support novel donor-recipient matching strategies and development of targeted therapies to ultimately improve long-term kidney allograft survival.
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Affiliation(s)
- Francesca Zanoni
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Krzysztof Kiryluk
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ibrahim Batal
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA,Corresponding Author: Ibrahim Batal MD, Department of Pathology and Cell Biology, Renal Division, Columbia University Irving Medical Center, 630 W 168th street, VC14-238, New York, NY 10032, Phone: 212-305-9669, Fax: 212-342-5380,
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Batal I, Vasilescu ER, Dadhania DM, Adel AA, Husain SA, Avasare R, Serban G, Santoriello D, Khairallah P, Patel A, Moritz MJ, Latulippe E, Riopel J, Khallout K, Swanson SJ, Bomback AS, Mohan S, Ratner L, Radhakrishnan J, Cohen DJ, Appel GB, Stokes MB, Markowitz GS, Seshan SV, De Serres SA, Andeen N, Loupy A, Kiryluk K, D'Agati VD. Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series. Am J Kidney Dis 2020; 76:374-383. [PMID: 32359820 PMCID: PMC7483441 DOI: 10.1053/j.ajkd.2020.01.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 01/07/2020] [Indexed: 12/20/2022]
Abstract
RATIONALE & OBJECTIVES Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN Multicenter case series. SETTING & PARTICIPANTS We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.
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Affiliation(s)
- Ibrahim Batal
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.
| | - Elena-Rodica Vasilescu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Darshana M Dadhania
- Department of Medicine, Nephrology, Weill Cornell Medical College, New York, NY
| | | | - S Ali Husain
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - Rupali Avasare
- Department of Medicine, Nephrology, Oregon Health & Science University, Portland, OR
| | - Geo Serban
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Dominick Santoriello
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Pascale Khairallah
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - Ankita Patel
- Department of Medicine, Nephrology, Hackensack University Medical Center, Hackensack, NJ
| | - Michael J Moritz
- Department of Surgery, Lehigh Valley Health Network, Allentown, PA
| | - Eva Latulippe
- Department of Pathology, University Health Center of Quebec, Laval University, Québec, QC, Canada
| | - Julie Riopel
- Department of Pathology, University Health Center of Quebec, Laval University, Québec, QC, Canada
| | - Karim Khallout
- Paris Translational Research Center for Organ Transplantation, INSERM, UMR-S970, Paris, France
| | | | - Andrew S Bomback
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - Sumit Mohan
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Lloyd Ratner
- Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | - Jai Radhakrishnan
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - David J Cohen
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - Gerald B Appel
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - Michael B Stokes
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Glen S Markowitz
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
| | - Surya V Seshan
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY
| | - Sacha A De Serres
- Renal Division, Department of Medicine, University Health Center of Quebec, Laval University, Québec, QC, Canada
| | - Nicole Andeen
- Department of Pathology, Oregon Health & Science University, Portland, OR
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, INSERM, UMR-S970, Paris, France
| | - Krzysztof Kiryluk
- Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY
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Leon J, Pérez-Sáez MJ, Batal I, Beck LH, Rennke HG, Canaud G, Legendre C, Pascual J, Riella LV. Membranous Nephropathy Posttransplantation: An Update of the Pathophysiology and Management. Transplantation 2019; 103:1990-2002. [PMID: 31568231 DOI: 10.1097/tp.0000000000002758] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Membranous nephropathy (MN) is a common cause of nephrotic syndrome after transplantation and is associated with an increased risk of allograft loss. MN may occur either as a recurrent or as a de novo disease. As in native kidneys, the pathophysiology of the MN recurrence is in most cases associated with antiphospholipid A2 receptor antibodies. However, the posttransplant course has some distinct features when compared with primary MN, including a lower chance of spontaneous remission and a greater requirement for adjuvant immunosuppressive therapy to induce complete remission. Although the efficacy of rituximab in primary MN is now well established, no randomized studies have assessed its effectiveness in MN after transplant, and there are no specific recommendations for the management of these patients. This review aims to synthesize and update the pathophysiology of posttransplant MN, as well as to address unsolved issues specific to transplantation, including the prognostic value of antiphospholipid A2 receptor, the risk of living-related donation, the link between de novo MN and rejection, and different therapeutic strategies so far deployed in posttransplant MN. Lastly, we propose a management algorithm for patients with MN who are planning to receive a kidney transplant, including pretransplant considerations, posttransplant monitoring, and the clinical approach after the diagnosis of recurrence.
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Affiliation(s)
- Juliette Leon
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France
| | - María José Pérez-Sáez
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Nephrology Department, Hospital del Mar, Barcelona, Spain
| | - Ibrahim Batal
- Pathology and Cell Biology, Columbia University Medical Center, New York, NY
| | - Laurence H Beck
- Division of Nephrology, Boston Medical Center, Boston University School of Medicine, Boston, MA
| | - Helmut G Rennke
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Guillaume Canaud
- Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France
| | - Christophe Legendre
- Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France
| | - Julio Pascual
- Nephrology Department, Hospital del Mar, Barcelona, Spain
| | - Leonardo V Riella
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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