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Buxeda A, Crespo M, Chamoun B, Gimeno J, Torres IB, Redondo-Pachón D, Riera M, Burballa C, Pascual J, Mengel M, Adam BA, Pérez-Sáez MJ. Clinical and molecular spectrum of v-lesion. Am J Transplant 2024; 24:2007-2021. [PMID: 39084462 DOI: 10.1016/j.ajt.2024.07.025] [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: 02/27/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024]
Abstract
Isolated v-lesion presents diagnostic stratification and clinical challenges. We characterized allograft outcomes for this entity based on posttransplant time (early: ≤1 month vs late: >1 month) and compared its molecular phenotype with other v+ rejection forms. Using the NanoString B-HOT panel, we analyzed 92 archival formalin-fixed paraffin-embedded tissue kidney biopsies from 3 centers: isolated v-lesion (n = 23), antibody-mediated rejection (ABMR) v+ (n = 26), T cell-mediated rejection (TCMR) v+ (n = 10), mixed rejection v+ (n = 23), and normal tissue (n = 10). Six gene sets (ABMR, DSAST, ENDAT, TCMR, early/acute injury, late injury) were assessed. Early isolated v-lesions had the poorest 1-year death-censored graft survival compared with late isolated v-lesions or other rejections (P = .034). Gene set analysis showed lower TCMR-related gene expression in isolated v+ groups than TCMR and mixed rejection (P < .001). Both early- and late isolated v-lesions had lower ABMR-related gene expression than ABMR, mixed rejection, and TCMR (P ≤ .022). Late isolated v-lesions showed reduced DSAST and ENDAT gene expression versus ABMR (P ≤ .046) and decreased early/acute injury gene expression than early isolated v+, ABMR, TCMR, and mixed rejection (P ≤ .026). In conclusion, isolated v-lesions exhibit distinct gene expression patterns versus other rejection v+ forms. Early isolated v+ is associated with poorer prognosis and increased early/acute injury gene expression than late isolated v+, suggesting distinct etiologies.
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Affiliation(s)
- Anna Buxeda
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain.
| | - Betty Chamoun
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Department of Nephrology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Javier Gimeno
- Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - Irina B Torres
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | | | - Marta Riera
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Carla Burballa
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Benjamin A Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
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Rabant M, Boullenger F, Gnemmi V, Pellé G, Glowacki F, Hertig A, Brocheriou I, Suberbielle C, Taupin JL, Anglicheau D, Legendre C, Duong Van Huyen JP, Buob D. Isolated v-lesion in kidney transplant recipients: Characteristics, association with DSA, and histological follow-up. Am J Transplant 2018; 18:972-981. [PMID: 29206350 DOI: 10.1111/ajt.14617] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 11/24/2017] [Accepted: 11/25/2017] [Indexed: 01/25/2023]
Abstract
Isolated v-lesion (IvL) represents a rare and challenging situation in renal allograft biopsies because it is unknown whether IvL truly represents rejection, antibody- or T cell-mediated, or not. This multicentric retrospective study describes the clinicopathological features of IvL with an emphasis on the donor-specific antibody (DSA) status, histological follow-up, and graft survival. Inclusion criteria were the presence of v-lesion with minimal interstitial (i ≤ 1) and microvascular inflammation (g + ptc≤1). C4d-positive biopsies were excluded. We retrospectively found 33 IvL biopsies in 33 patients, mainly performed in the early posttransplantation period (median time 27 days) and clinically indicated in 66.7%. A minority of recipients (5/33, 15.2%) had DSA at the time of biopsy. IvL was treated by anti-rejection therapy in 21 cases (63.6%), whereas 12 (36.4%) were untreated. Seventy percent of untreated patients and 66% of treated patients showed favorable histological evolution on subsequent biopsy. Kidney graft survival in IvL was significantly higher than in a matched cohort of antibody-mediated rejection with arteritis. In conclusion, IvL is not primarily antibody-mediated and may show a favorable evolution. The heterogeneity of IvL pathophysiology on early biopsies should prompt DSA testing as well as close clinical and histological follow-up in all patients with IvL.
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Affiliation(s)
- Marion Rabant
- Pathology Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris,, France.,Paris Descartes, Sorbonne Paris Cité University, Paris, France
| | - Fanny Boullenger
- Nephrology department, Centre hospitalier intercommunal André Grégoire, Montreuil, France
| | - Viviane Gnemmi
- Pathology department, CHRU Lille, Lille 2 University, Lille, France
| | - Gaëlle Pellé
- Kidney transplant department, Foch Hospital, Suresnes, France
| | - François Glowacki
- Kidney transplant department, CHRU Lille, Lille 2 University, Lille, France
| | - Alexandre Hertig
- Kidney transplant department, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Isabelle Brocheriou
- Pathology department, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.,Sorbonne Universités, UPMC Paris 06, Paris, France.,Inserm, UMR S 1155, Paris, France
| | - Caroline Suberbielle
- Histocompatibility department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jean-Luc Taupin
- Histocompatibility department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Dany Anglicheau
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Department of Nephrology and Kidney transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Christophe Legendre
- Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Department of Nephrology and Kidney transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jean-Paul Duong Van Huyen
- Pathology Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris,, France.,Paris Descartes, Sorbonne Paris Cité University, Paris, France.,Paris Translational Research Center for Organ Transplantation, INSERM, UMR-S970, Paris, France
| | - David Buob
- Pathology department, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.,Sorbonne Universités, UPMC Paris 06, Paris, France.,Inserm, UMR S 1155, Paris, France
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Parajuli S, Mandelbrot DA, Muth B, Mohamed M, Garg N, Aziz F, Redfield RR, Zhong W, Astor BC, Djamali A. Rituximab and Monitoring Strategies for Late Antibody-Mediated Rejection After Kidney Transplantation. Transplant Direct 2017; 3:e227. [PMID: 29536028 PMCID: PMC5828696 DOI: 10.1097/txd.0000000000000746] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 09/13/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is limited information on treatment strategies and monitoring strategies for late antibody-mediated rejection (ABMR) after kidney transplantation. METHODS In this observational and nonrandomized study, we compared 78 patients diagnosed with late ABMR (>3 months after transplant) who were treated with standard of care steroids/IVIG (n = 38) ± rituximab (n = 40) at our center between March 1, 2013 and December 31, 2016. All patients had follow-up biopsy and donor-specific antibodies (DSA) monitoring within 3 to 12 weeks. RESULTS Patients had biopsy 7.3 ± 7 years after transplant and were followed for 15.9 ± 9.6 months after ABMR was diagnosed. Both treatment strategies were associated with a significant decline in DSA, microvascular inflammation (peritubular capillaritis + glomerulitis), and C4d Banff scores. In univariate regression analyses, rituximab, estimated glomerular filtration rate (eGFR), Banff i, t, v, chronicity (interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy) scores on the first biopsy, and eGFR and Banff v score on follow-up biopsy were associated with graft loss. Multivariate analyses retained only rituximab (hazard ratio, 0.23; 95% confidence interval, 0.06-0.84; P = 0.03) and eGFR at follow-up biopsy (0.84; 95% confidence interval, 0.76-0.92; P < 0.001) as significant predictors of graft loss. Kaplan-Meier analyses demonstrated that the benefit associated with rituximab was apparent after 1 year (15% vs 32% graft loss, P = 0.02). CONCLUSION Treatment of late ABMR with steroids/IVIG ± rituximab was effective in reducing DSA and microcirculation inflammation. The addition of rituximab was associated with better graft survival. Follow-up biopsies could be considered in the management of acute rejection to monitor the effect of therapy. Randomized studies on the best therapeutic options for ABMR are needed.
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Affiliation(s)
- Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Didier A. Mandelbrot
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Brenda Muth
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Maha Mohamed
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Robert R. Redfield
- Division of Transplant Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weixiong Zhong
- Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Brad C. Astor
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
- Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Arjang Djamali
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
- Division of Transplant Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Current status of pediatric renal transplant pathology. Pediatr Nephrol 2017; 32:425-437. [PMID: 27221522 DOI: 10.1007/s00467-016-3381-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 03/07/2016] [Accepted: 03/21/2016] [Indexed: 10/21/2022]
Abstract
Histopathology is still an indispensable tool for the diagnosis of kidney transplant dysfunction in adult and pediatric patients. This review presents consolidated knowledge, recent developments and future prospects on the biopsy procedure, the diagnostic work-up, classification schemes, the histopathology of rejection, including antibody-mediated forms, ABO-incompatible transplants, protocol biopsies, recurrent and de novo disease, post-transplant lymphoproliferative disorder, infectious complications and drug-induced toxicity. It is acknowledged that frequently the correct diagnosis can only be reached in consensus with clinical, serological, immunogenetical, bacteriological and virological findings. This review shall enhance the understanding of the pediatric nephrologist for the thought processes of nephropathologists with the aim to facilitate teamwork between these specialist groups for the benefit of the patient.
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Gwinner W, Metzger J, Husi H, Marx D. Proteomics for rejection diagnosis in renal transplant patients: Where are we now? World J Transplant 2016; 6:28-41. [PMID: 27011903 PMCID: PMC4801803 DOI: 10.5500/wjt.v6.i1.28] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 12/14/2015] [Accepted: 01/05/2016] [Indexed: 02/05/2023] Open
Abstract
Rejection is one of the key factors that determine the long-term allograft function and survival in renal transplant patients. Reliable and timely diagnosis is important to treat rejection as early as possible. Allograft biopsies are not suitable for continuous monitoring of rejection. Thus, there is an unmet need for non-invasive methods to diagnose acute and chronic rejection. Proteomics in urine and blood samples has been explored for this purpose in 29 studies conducted since 2003. This review describes the different proteomic approaches and summarizes the results from the studies that examined proteomics for the rejection diagnoses. The potential limitations and open questions in establishing proteomic markers for rejection are discussed, including ongoing trials and future challenges to this topic.
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Salazar IDR, Merino López M, Chang J, Halloran PF. Reassessing the Significance of Intimal Arteritis in Kidney Transplant Biopsy Specimens. J Am Soc Nephrol 2015; 26:3190-8. [PMID: 25918035 DOI: 10.1681/asn.2014111064] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/10/2015] [Indexed: 12/23/2022] Open
Abstract
Intimal arteritis (the presence of v-lesions) in kidney transplant biopsy specimens is believed to have major prognostic and diagnostic significance. We assessed the relationship of v-lesions to prognosis in 703 indication biopsy specimens and used microarray-based molecular tests to re-examine the relationship of v-lesions to rejection. v-Lesions were noted in 49 specimens (7%) and were usually mild (v1). The presence of v-lesions had no effect on graft survival compared with the absence of v-lesions. Pathologists using current conventions almost always interpreted v-lesions as reflecting T cell-mediated rejection (TCMR), either pure or mixed with antibody-mediated rejection (ABMR). The molecular scores questioned the conventional diagnoses in 29 of 49 specimens (59%), including ten that were conventional TCMR with no molecular rejection and nine that were conventional TCMR mixed with pure ABMR molecularly. The presence of tubulointerstitial inflammation (i-t) meeting TCMR criteria allowed subclassification of v-lesion specimens into 21 i-t-v-lesion specimens and 28 isolated v-lesion specimens. Molecular TCMR scores were positive in 95% of i-t-v-lesion specimens but only 21% of isolated v-lesion specimens. Molecular ABMR scores were often positive in isolated v-lesion biopsies (46%). Time of biopsy after transplantation was critical for understanding isolated v-lesions: most early isolated v-lesion specimens had no molecular rejection and were DSA negative, whereas most isolated >1 year after transplantation had positive DSA and ABMR scores. Therefore, v-lesions in indication biopsy specimens do not affect prognosis and can reflect TCMR, ABMR, or no rejection. Time after transplantation, DSA, and accompanying inflammation provide probabilistic basis for interpreting v-lesions.
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Affiliation(s)
- Israel D R Salazar
- Alberta Transplant Applied Genomics Center, Edmonton, Alberta, Canada; Department of Medicine, Viedma Hospital, Cochabamba, Bolivia; Caja National Health Hospital, Cochabamba, Bolivia; and
| | | | - Jessica Chang
- Alberta Transplant Applied Genomics Center, Edmonton, Alberta, Canada
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Center, Edmonton, Alberta, Canada; Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, Alberta, Canada
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7
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Broecker V, Mengel M. The significance of histological diagnosis in renal allograft biopsies in 2014. Transpl Int 2014; 28:136-43. [PMID: 25205033 DOI: 10.1111/tri.12446] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 06/26/2014] [Accepted: 09/01/2014] [Indexed: 01/20/2023]
Abstract
In 2014, the renal allograft biopsy still represents the best available diagnostic 'gold' standard to assess reasons for allograft dysfunction. However, it is well recognized that histological lesion observed in the biopsy is of limited diagnostic specificity and that the Banff classification as the international diagnostic standard represents mere expert consensus. Here, we review the role of the renal allograft biopsy in different clinical and diagnostic settings. To increase diagnostic accuracy and to compensate for lack of specificity, the interpretation of biopsy pathology needs to be within the clinical context, primarily defined by time post-transplantation and patient-specific risk profile. With this in mind, similar histopathological patterns will lead to different conclusions with regard to diagnosis, disease grading and staging and thus to patient-specific clinical decision-making. Consensus generation for such integrated diagnostic approach, preferably including new molecular tools, represents the next challenge to the transplant community on its way to precision medicine in transplantation.
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Affiliation(s)
- Verena Broecker
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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