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1
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Hansen CM, Bachmann S, Su M, Budde K, Choi M. Calcineurin Inhibitor Associated Nephrotoxicity in Kidney Transplantation-A Transplant Nephrologist's Perspective. Acta Physiol (Oxf) 2025; 241:e70047. [PMID: 40243357 PMCID: PMC12005075 DOI: 10.1111/apha.70047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 03/29/2025] [Accepted: 03/29/2025] [Indexed: 04/18/2025]
Abstract
AIM Calcineurin inhibitors (CNIs) have revolutionized transplant medicine, improving allograft survival but posing challenges like calcineurin inhibitor-induced nephrotoxicity (CNT). Acute CNT, often dose-dependent, leads to vasoconstriction and acute kidney injury, with treatment focusing on CNI exposure reduction. Chronic CNT manifests as progressive allograft function decline, with challenges in distinguishing it from nonspecific allograft nephropathy. METHODS This narrative review provides a concise overview of the clinical management of CNT, covering acute and chronic CNT. We reviewed original articles, landmark papers, and meta-analyses on CNT mitigation strategies, including CNI-sparing approaches. RESULTS Preventive measures include co-medications, CNI exposure monitoring, and CNI sparing strategies, such as reducing target trough levels and converting to mTOR inhibitors (mTORi) or belatacept. Despite improvements in graft function, challenges persist in demonstrating significant differences in allograft survival with CNI-sparing regimens. The paradigm shift from chronic CNT as the main cause of chronic allograft nephropathy toward rather immunologic triggered injuries and/or comorbidities as relevant contributors to allograft deterioration over time must be kept in mind. CONCLUSION CNIs have significantly improved kidney transplant outcomes, but their associated nephrotoxicity necessitates mitigation strategies. The decision to implement such regimens is always an individual choice balancing against the risk of immunologic injuries. Further long-term studies are needed to optimize immunosuppressive approaches and refine CNT management.
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Affiliation(s)
- Carla M. Hansen
- Department of Nephrology and Medical Intensive CareCharité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu BerlinBerlinGermany
| | - Sebastian Bachmann
- Department of Nephrology and Medical Intensive CareCharité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu BerlinBerlinGermany
| | - Mingzhen Su
- Department of Nephrology and Medical Intensive CareCharité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu BerlinBerlinGermany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive CareCharité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu BerlinBerlinGermany
| | - Mira Choi
- Department of Nephrology and Medical Intensive CareCharité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu BerlinBerlinGermany
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Leong ZCW, Kong JHL, Khor SY, Liew YF. Everolimus-Associated Thrombotic Microangiopathy Following Renal Transplant: A Case Report. Cureus 2024; 16:e71535. [PMID: 39544564 PMCID: PMC11562689 DOI: 10.7759/cureus.71535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2024] [Indexed: 11/17/2024] Open
Abstract
Thrombotic microangiopathy (TMA) is a serious complication that may affect post-renal transplant recipients. De novo TMA has been linked to the use of transplant immunosuppressive agents, including calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORi). We report a case of a 41-year-old female renal transplant recipient who presented with hemolytic anemia, thrombocytopenia, and acute allograft dysfunction. Before her presentation, she was on immunosuppression with oral tacrolimus, oral prednisolone, and oral everolimus. Her renal biopsy showed features of TMA, which led to extensive workup to identify the underlying cause. Eventually, everolimus was recognized as the cause of secondary TMA as her hemolytic parameters and renal allograft function recovered following discontinuation of this drug. This case report highlights the association of everolimus with TMA in a post-renal transplant patient. Early recognition and drug withdrawal can prevent allograft loss.
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Affiliation(s)
| | | | - See Yee Khor
- Pathology, Hospital Seberang Jaya, Permatang Pauh, MYS
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3
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Dessaix K, Bontoux C, Aubert O, Grünenwald A, Sberro Soussan R, Zuber J, Duong Van Huyen JP, Anglicheau D, Legendre C, Fremeaux Bacchi V, Rabant M. De novo thrombotic microangiopathy after kidney transplantation in adults: Interplay between complement genetics and multiple endothelial injury. Am J Transplant 2024; 24:1205-1217. [PMID: 38320731 DOI: 10.1016/j.ajt.2024.01.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/24/2024]
Abstract
De novo thrombotic microangiopathy (dnTMA), after renal transplantation may significantly alter graft outcomes. However, its pathogenesis and the role of complement alternative pathway dysregulation remain elusive. We studied all consecutive adult patients with a kidney allograft biopsy performed between January 2004 and March 2016 displaying dnTMA. Ninety-two patients were included. The median time of occurrence was 166 (IQR 25-811) days. The majority (82.6 %) had TMA localized only in the graft. Calcineurin inhibitor toxicity and antibody-mediated rejection (ABMR) were the 2 most frequent causes (54.3% and 37.0%, respectively). However, etiological factors were multiple in 37% patients. Interestingly, pathogenic variants in the genes of complement alternative pathway were significantly more frequent in the 42 tested patients than in healthy controls (16.7% vs 3.7% respectively, P < .008). The overall graft survival after biopsy was 66.0% at 5 years and 23.4% at 10 years, significantly worse than a matched cohort without TMA. Moreover, graft survival of patients with TMA and ABMR was worse than a matched cohort with ABMR without TMA. The 2 main prognostic factors were a positive C4d staining and a lower estimated glomerular filtration rate at diagnosis. DnTMA is a severe and multifactorial disease, induced by 1 or several endothelium-insulting conditions, mostly calcineurin inhibitor toxicity and ABMR.
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Affiliation(s)
- Kathleen Dessaix
- Service des Maladies du Rein et du Métabolisme, Transplantation et Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France
| | - Christophe Bontoux
- Laboratoire d'Anatomie et Cytologie Pathologiques, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France; Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Team 4, Institute of Research on Cancer and Aging of Nice, InsermU1081, CNRS UMR7284, FHU OncoAge, Institut Hospitalo-Universitaire RespirERA, Université Côte d'Azur, Hôpital Pasteur, CHU de Nice, CEDEX 1, Nice, France
| | - Olivier Aubert
- Service des Maladies du Rein et du Métabolisme, Transplantation et Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France; INSERM, PARCC, Paris Translational Reseach for Organ Transplantation, Université Paris Cité, Paris, France
| | - Anne Grünenwald
- INSERM, UMRS 1138, Inflammation, Complement and Cancer Team, Centre de recherche des Cordeliers, Sorbonne Universités, Université Paris Cité, Paris, France
| | - Rebecca Sberro Soussan
- Service des Maladies du Rein et du Métabolisme, Transplantation et Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France
| | - Julien Zuber
- Service des Maladies du Rein et du Métabolisme, Transplantation et Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France
| | - Jean-Paul Duong Van Huyen
- Laboratoire d'Anatomie et Cytologie Pathologiques, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France; INSERM, PARCC, Paris Translational Reseach for Organ Transplantation, Université Paris Cité, Paris, France
| | - Dany Anglicheau
- Service des Maladies du Rein et du Métabolisme, Transplantation et Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France; Necker-Enfants Malades Institute, INSERM U1151, Université de Paris Cité, Paris, France
| | - Christophe Legendre
- Service des Maladies du Rein et du Métabolisme, Transplantation et Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France
| | - Veronique Fremeaux Bacchi
- INSERM, UMRS 1138, Inflammation, Complement and Cancer Team, Centre de recherche des Cordeliers, Sorbonne Universités, Université Paris Cité, Paris, France; Service d'Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Université Paris Cité, Paris, France
| | - Marion Rabant
- Laboratoire d'Anatomie et Cytologie Pathologiques, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants maladies, Université Paris Cité, Paris, France; Necker-Enfants Malades Institute, INSERM U1151, Université de Paris Cité, Paris, France.
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4
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Acharya R, Clapp W, Upadhyay K. Safety and Efficacy of Very Early Conversion to Belatacept in Pediatric Kidney Transplantation with Transplant-Associated Thrombotic Microangiopathy: Case Study and Review of Literature. Clin Pract 2024; 14:882-891. [PMID: 38804401 PMCID: PMC11130864 DOI: 10.3390/clinpract14030069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024] Open
Abstract
The inhibition of co-stimulation during T-cell activation has been shown to provide effective immunosuppression in kidney transplantation (KT). Hence, the conversion from calcineurin inhibitor (CNI) to belatacept is emerging as a potential alternate maintenance immunosuppressive therapy in those with transplant-associated thrombotic microangiopathy (TA-TMA) or in the prevention of TA-TMA. We present a 17-year-old male who presented with biopsy-proven CNI-associated TA-TMA immediately post-KT. The administration of eculizumab led to the reversal of TMA. Tacrolimus was converted to belatacept with excellent efficacy and safety during a short-term follow-up of one year. Further larger controlled studies are required to demonstrate the efficacy of this approach in children who present with early-onset TMA post-KT.
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Affiliation(s)
- Ratna Acharya
- Department of Pediatrics, Nemours Children’s Hospital, Orlando, FL 32827, USA
| | - William Clapp
- Division of Anatomic Pathology, Department of Pathology, University of Florida, Gainesville, FL 32610, USA
| | - Kiran Upadhyay
- Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
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5
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Hsiung CY, Chen HY, Wang SH, Huang CY. Unveiling the Incidence and Graft Survival Rate in Kidney Transplant Recipients With De Novo Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis. Transpl Int 2024; 37:12168. [PMID: 38323071 PMCID: PMC10844394 DOI: 10.3389/ti.2024.12168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 01/09/2024] [Indexed: 02/08/2024]
Abstract
De novo thrombotic microangiopathy (TMA) is a rare and challenging condition in kidney transplant recipients, with limited research on its incidence and impact on graft survival. This study conducted a systematic review and meta-analysis of 28 cohorts/single-arm studies and 46 case series/reports from database inception to June 2022. In meta-analysis, among 14,410 kidney allograft recipients, de novo TMA occurred in 3.20% [95% confidence interval (CI): 1.93-4.77], with systemic and renal-limited TMA rates of 1.38% (95% CI: 06.5-2.39) and 2.80% (95% CI: 1.27-4.91), respectively. The overall graft loss rate of de novo TMA was 33.79% (95% CI: 26.14-41.88) in meta-analysis. This study provides valuable insights into the incidence and graft outcomes of de novo TMA in kidney transplant recipients.
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Affiliation(s)
- Chien-Ya Hsiung
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Fu Jen Catholic University, New Taipei City, Taiwan
| | - Hsin-Yu Chen
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Han Wang
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Ying Huang
- Department of Pharmacy, Kaohsiung Veteran General Hospital, Kaohsiung, Taiwan
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6
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Drug-induced de novo thrombotic microangiopathy diagnosed 2 years after renal transplantation: a case report and literature review. RENAL REPLACEMENT THERAPY 2023. [DOI: 10.1186/s41100-022-00453-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Abstract
Background
Post-transplant de novo thrombotic microangiopathy (TMA) is a rare yet serious complication that generally can develop in renal transplant recipients immediately after reperfusion or several months after transplantation. Here, we report a case of systemic tacrolimus-associated TMA in a patient diagnosed 2 years after renal transplantation.
Case presentation
A 49-year-old woman presented with severe anemia 18 months after undergoing renal transplantation. Anemia was refractory to recombinant human erythropoietin and was suspected to be due to excessive menstruation. Anemia persisted even after hysterectomy, and thereafter, pancytopenia developed. A bone marrow biopsy was performed and showed no evidence of myeloproliferative neoplasms. Furthermore, an increase in serum lactate dehydrogenase level and the appearance of schistocytes on peripheral blood smear was noted 24 months post-transplant. Other possible causes of de novo TMA were excluded, and an allograft biopsy was performed. Pathological findings of the allograft biopsy showed that some afferent arterioles had formed thrombi. Suspecting tacrolimus to be the cause of TMA, 25 months after the transplant, we switched treatment to cyclosporine. Pancytopenia and renal function improved after switching to this calcineurin inhibitor. Subsequently, her allograft renal function stabilized for three years after renal transplantation.
Conclusion
We encountered a case of secondary drug-induced TMA in the late stages of renal transplantation. Therefore, TMA should be suspected when anemia with hemolysis is observed in recipients of kidney transplant.
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Oh YJ, Lee J, Kim Y, Jun H, Sim J, Kim MG, Jung CW. Eculizumab as rescue therapy in a kidney transplant recipient with atypical hemolytic uremic syndrome: a case report. KOREAN JOURNAL OF TRANSPLANTATION 2022; 36:283-288. [PMID: 36704807 PMCID: PMC9832595 DOI: 10.4285/kjt.22.0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/18/2022] [Accepted: 10/05/2022] [Indexed: 11/12/2022] Open
Abstract
A 61-year-old female patient with chronic kidney disease due to diabetes mellitus and hypertension-induced nephropathy received a deceased donor kidney transplant in March 2020. In July 2020, she was transferred from a local hospital due to the exacerbation of general weakness and diarrhea. Upon her arrival, we noticed a high level of serum creatinine (sCr) of 1.5 mg/dL and a decrease in urine output. Her laboratory results indicated significant hemolysis, with a hemoglobin level of 7.0 g/dL, platelet count of 20 ×103/μL, and a lactate dehydrogenase level of 3,207 IU/L. Kidney biopsy showed severe thrombotic microangiopathy without any evidence of acute rejection. Under the impression of atypical hemolytic uremic syndrome (aHUS), we immediately started plasmapheresis and hemodialysis for anuria. Eculizumab was considered as a kidney graft rescue therapy since her sCr level was not effectively decreased, and her anuria continued despite hemodialysis and plasmapheresis. Eculizumab (900 mg) was administered weekly for 4 weeks. An additional 600 mg of eculizumab was administered on the day of plasmapheresis. Since the patient's laboratory data gradually improved, hemodialysis and plasmapheresis were ceased on admission day 37. After that, eculizumab was administered biweekly (1,200 mg) two more times. The patient's sCr and platelet count normalized after 2 months of eculizumab treatment. Based on our experience, a shorter interval between the clinical diagnosis of aHUS and administration of eculizumab increases the likelihood of rescuing the kidney.
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Affiliation(s)
- Young Ju Oh
- Department of Surgery, Korea University Anam Hospital, Seoul, Korea
| | - Joohyun Lee
- Department of Surgery, Korea University Anam Hospital, Seoul, Korea
| | - Yeonmi Kim
- Department of Rehabilitation Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Heungman Jun
- Department of Surgery, Korea University Anam Hospital, Seoul, Korea
| | - Jongmin Sim
- Department of Pathology, Korea University Anam Hospital, Seoul, Korea
| | - Myung-Gyu Kim
- Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Cheol Woong Jung
- Department of Surgery, Korea University Anam Hospital, Seoul, Korea,Corresponding author: Cheol Woong Jung Department of Surgery, Korea University Anam Hospital, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea, Tel: +82-2-920-6385, Fax: +82-2-928-1631, E-mail:
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8
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Wu Q, Tian X, Gong N, Zheng J, Liang D, Li X, Lu X, Xue W, Tian P, Wen J. Early graft loss due to acute thrombotic microangiopathy accompanied by complement gene variants in living-related kidney transplantation: case series report. BMC Nephrol 2022; 23:249. [PMID: 35836191 PMCID: PMC9284761 DOI: 10.1186/s12882-022-02868-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 06/29/2022] [Indexed: 11/10/2022] Open
Abstract
Background Recently, early graft loss has become very rare in living-related kidney transplantation (LKT) as a result of decreased risk of hyperacute rejection and improvements in immunosuppressive regimens. Post-transplant acute thrombotic microangiopathy (TMA) is a rare, multi-factorial disease that often occurs shortly after kidney transplantation and is usually resistant to treatment with dismal renal outcomes. The complement genetic variants may accelerate the development of TMA. However, the complement genetic test was seldom performed in unknown native kidney disease recipients scheduled for LKT. Case presentation We reported three cases of unknown native kidney diseases who had fulminant TMA in the allograft shortly after LKT. Both the donors and the recipients were noted to carry complement genetic variants, which were identified by genetic testing after transplantation. However, all recipients were refractory to treatment and had allograft loss within 3 months after LKT. Conclusion This case series highlights the suggestion to screen complement gene variants in both the donors and the recipients with unknown native kidney diseases scheduled for LKT. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-022-02868-7.
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Affiliation(s)
- Qianqian Wu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xiaohui Tian
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jin Zheng
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Dandan Liang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xue Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xia Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wujun Xue
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Puxun Tian
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China.
| | - Jiqiu Wen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.
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9
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Abbas F, Abbas SF. De Novo and Recurrent Thrombotic Microangiopathy After Renal Transplantation: Current Concepts in Management. EXP CLIN TRANSPLANT 2021; 20:549-557. [PMID: 34546154 DOI: 10.6002/ect.2021.0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Thrombotic microangiopathy is a well-recognized complication of kidney transplantation that leads frequently to allograft failure. This serious outcome can greatly depend on the underlying etiology and on the timing of therapeutic interventions. Thrombotic microangiopathy syndrome may occur with no previous history of thrombotic microangiopathy (that is, de novo thrombotic microangiopathy), mostly due to medica tions or infections. More frequently, it may recur after kidney transplant in patients with endstage renal failure due to atypical hemolytic uremic syndrome. However, for patients with Shiga-toxininduced hemolytic uremic syndrome, particularly pediatric patients, there is a favorable prognosis. A fundamental tool for management of this disease is genetic screening for abnormal mutations; this can recognize the suggested approach of therapy and may determine the outcome of the disease to a large extent. Although patients with complement factor H and I mutations have worse prognosis, other patients with membrane cofactor protein mutations, for example, have a more favorable prognosis. Accordingly, the plan of therapy can be tailored with a better chance of cure. Unfortunately, the successful use of the biological agent eculizumab, an anti-C5 agent, in some of these syndromes is largely impeded by its high cost, which is linked to its use as a life-long therapy. However, newly suggested therapeutic options may ameliorate this drawback.
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Affiliation(s)
- Fedaei Abbas
- From the Nephrology Department, Jaber El Ahmed Military Hospital, Safat, Kuwait.,the Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool, United Kingdom
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10
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Ávila A, Gavela E, Sancho A. Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity. Front Med (Lausanne) 2021; 8:642864. [PMID: 33898482 PMCID: PMC8063690 DOI: 10.3389/fmed.2021.642864] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/22/2021] [Indexed: 01/25/2023] Open
Abstract
Thrombotic microangiopathy is a rare but serious complication that affects kidney transplant recipients. It appears in 0.8–14% of transplanted patients and negatively affects graft and patient survival. It can appear in a systemic form, with hemolytic microangiopathic anemia, thrombocytopenia, and renal failure, or in a localized form, with progressive renal failure, proteinuria, or arterial hypertension. Post-transplant thrombotic microangiopathy is classified as recurrent atypical hemolytic uremic syndrome or de novo thrombotic microangiopathy. De novo thrombotic microangiopathy accounts for the majority of cases. Distinguishing between the 2 conditions can be difficult, given there is an overlap between them. Complement overactivation is the cornerstone of all post-transplant thrombotic microangiopathies, and has been demonstrated in the context of organ procurement, ischemia-reperfusion phenomena, immunosuppressive drugs, antibody-mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome. Although treatment of the causative agents is usually the first line of treatment, this approach might not be sufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve renal function. Complement blockade with eculizumab has been shown to be an effective therapy in post-transplant thrombotic microangiopathy, but it is necessary to define which patients can benefit from this therapy and when and how eculizumab should be used.
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Affiliation(s)
- Ana Ávila
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
| | - Eva Gavela
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
| | - Asunción Sancho
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
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11
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Saikumar Doradla LP, Lal H, Kaul A, Bhaduaria D, Jain M, Prasad N, Thammishetti V, Gupta A, Patel M, Sharma RK. Clinical profile and outcomes of De novo posttransplant thrombotic microangiopathy. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2021; 31:160-168. [PMID: 32129209 DOI: 10.4103/1319-2442.279936] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Thrombotic microangiopathy (TMA) after kidney transplant is rather uncommon but an important reversible cause of graft loss. This retrospective study of biopsy-proven posttransplant TMA was done to identify the important etiological factors, clinical features, and outcomes of post transplant TMA in a tertiary care referral hospital in northern India. This retrospective study was conducted among all renal transplant recipients who presented with graft dysfunction between 1989 and 2015. All the cases were looked for their etiology, clinical course, treatment modalities, and renal outcomes. The study was conducted in accord with prevailing ethical principles and reviewed by our own institutional review board. Seventeen patients out of 2000 (0.008%) transplants done during the study period had posttransplant TMA, out of which all the patients had de novo TMA, and the median time of presentation after transplantation was four months. Systemic TMA was noted in only four patients. Biopsy revealed associated rejection in five patients and associated calcineurin inhibitor (CNI) toxicity in 12 patients. Patients with TMA due to CNI toxicity were managed with CNI reduction or switching to alternate CNI or mammalian target of rapamycin inhibitors. In addition, antithymocyte globulin and plasma exchange were used in rejection-associated TMA. While four out of 12 patients (33%) in CNI-related TMA developed end-stage renal disease (ESRD), all patients in rejection-associated TMA developed ESRD. The overall one-year graft survival was 47%, whereas five- and 10-year survival was 35%. There was no significant difference in graft survival between localized and systemic TMAs (P = 0.4). Posttransplant TMA should be suspected even if there are no systemic features of hemolysis and early graft biopsy and prompt action is needed. The occurrence of TMA in the setting of rejection is associated with grave prognosis.
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Affiliation(s)
- L P Saikumar Doradla
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - H Lal
- Departmenta of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anupma Kaul
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - D Bhaduaria
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - M Jain
- Departmenta of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - N Prasad
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - V Thammishetti
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - A Gupta
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - M Patel
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - R K Sharma
- Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Teixeira CM, Tedesco Silva Junior H, de Moura LAR, Proença HMDS, de Marco R, Gerbase de Lima M, Cristelli MP, Viana LA, Felipe CR, Medina Pestana JO. Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes. PLoS One 2020; 15:e0227445. [PMID: 31923282 PMCID: PMC6953866 DOI: 10.1371/journal.pone.0227445] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/18/2019] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Thrombotic microangiopathy (TMA) in post-transplant setting has heterogeneous clinical manifestations. METHODS We retrospectively studied data of 89 patients with post-transplant TMA, which was characterized by thrombi in at least one glomerulus and/or arteriole. Systemic TMA was defined by thrombocytopenia and microangiopathic anemia and early onset TMA, when occurred less than 90 days post transplant. RESULTS The cumulative incidence was 0.93%. The majority of the recipients were young (mean age 39 years), female (52%) and Caucasian (48%) with primary kidney disease of unknown etiology (37%). Early TMA occurred in 51% of the patients and systemic TMA, in 25%. Underlying precipitating factors were: infection (54%), acute rejection (34%), calcineurin inhibitor toxicity (13%) and pregnancy (3%). 18% of the patients had several triggers. Glomerular TMA was observed in 50% of the biopsies and endothelial cell activation, in 61%. The 1-year patient survival was 97% and corresponding graft survival, 66%. Allograft survival was inferior when acute antibody mediated rejection (ABMR) occurred (with 41%; without 70%, p = 0.01), however no differences were determined by hemolysis, time of onset, thrombi location or endothelial cell activation. CONCLUSIONS Our results suggest that post-transplant TMA is a rare but severe condition, regardless of its clinical and histological presentation, mainly when associated to ABMR.
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13
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Lee H, Kang E, Kang HG, Kim YH, Kim JS, Kim HJ, Moon KC, Ban TH, Oh SW, Jo SK, Cho H, Choi BS, Hong J, Cheong HI, Oh D. Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome. Korean J Intern Med 2020; 35:25-40. [PMID: 31935318 PMCID: PMC6960041 DOI: 10.3904/kjim.2019.388] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 12/04/2019] [Indexed: 12/13/2022] Open
Abstract
Thrombotic microangiopathy (TMA) is defined by specific clinical characteristics, including microangiopathic hemolytic anemia, thrombocytopenia, and pathologic evidence of endothelial cell damage, as well as the resulting ischemic end-organ injuries. A variety of clinical scenarios have features of TMA, including infection, pregnancy, malignancy, autoimmune disease, and medications. These overlapping manifestations hamper differential diagnosis of the underlying pathogenesis, despite recent advances in understanding the mechanisms of several types of TMA syndrome. Atypical hemolytic uremic syndrome (aHUS) is caused by a genetic or acquired defect in regulation of the alternative complement pathway. It is important to consider the possibility of aHUS in all patients who exhibit TMA with triggering conditions because of the incomplete genetic penetrance of aHUS. Therapeutic strategies for aHUS are based on functional restoration of the complement system. Eculizumab, a monoclonal antibody against the terminal complement component 5 inhibitor, yields good outcomes that include prevention of organ damage and premature death. However, there remain unresolved challenges in terms of treatment duration, cost, and infectious complications. A consensus regarding diagnosis and management of TMA syndrome would enhance understanding of the disease and enable treatment decision-making.
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Affiliation(s)
- Hajeong Lee
- Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Eunjeong Kang
- Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Hee Gyung Kang
- Division of Pediatric Nephrology, Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
| | - Young Hoon Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Seok Kim
- Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hee-Jin Kim
- Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Chul Moon
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Tae Hyun Ban
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Se Won Oh
- Division of Nephrology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Sang Kyung Jo
- Division of Nephrology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Heeyeon Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Bum Soon Choi
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Junshik Hong
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Hae Il Cheong
- Division of Pediatric Nephrology, Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
| | - Doyeun Oh
- Department of Internal Medicine, CHA University School of Medicine, Seongnam, Korea
- Correspondence to Doyeun Oh, M.D. Department of Internal Medicine, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea Tel: +82-31-780-5217, Fax: +82-31-780-5221, E-mail:
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Gatz JD, Spangler R. Evaluation of the Renal Transplant Recipient in the Emergency Department. Emerg Med Clin North Am 2019; 37:679-705. [PMID: 31563202 DOI: 10.1016/j.emc.2019.07.008] [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: 11/26/2022]
Abstract
Renal transplants are becoming more and more frequent in the United States and worldwide. Studies demonstrate that these patients inevitably end up visiting an emergency department. In addition to typical medical and surgical problems encountered in the general population, this group of patients has unique problems arising from their immunocompromised state and also due to side effects of the medications required. This article discusses these risks and management decisions that the emergency department physician should be aware of in order to prevent adverse outcomes for the patient and transplanted kidney.
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Affiliation(s)
- John David Gatz
- Department of Emergency Medicine, University of Maryland School of Medicine, 110 South Paca Street, Sixth Floor, Suite 200, Baltimore, MD 21201, USA
| | - Ryan Spangler
- Department of Emergency Medicine, University of Maryland School of Medicine, 110 South Paca Street, Sixth Floor, Suite 200, Baltimore, MD 21201, USA.
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15
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Ramachandran R, Sood V, Kashif A, Nada R, Sharma A. Hyperacute rejection in a blood group incompatible renal transplant recipient – enigma of unfathomable thrombotic microangiopathy! INDIAN JOURNAL OF TRANSPLANTATION 2019. [DOI: 10.4103/ijot.ijot_51_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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16
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Abbas F, El Kossi M, Kim JJ, Shaheen IS, Sharma A, Halawa A. Complement-mediated renal diseases after kidney transplantation - current diagnostic and therapeutic options in de novo and recurrent diseases. World J Transplant 2018; 8:203-219. [PMID: 30370231 PMCID: PMC6201327 DOI: 10.5500/wjt.v8.i6.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/09/2018] [Accepted: 08/28/2018] [Indexed: 02/05/2023] Open
Abstract
For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy (a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases. Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.
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Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ihab Sakr Shaheen
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Royal Hospital for Children, Glasgow G51 4TF, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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17
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Abbas F, El Kossi M, Kim JJ, Sharma A, Halawa A. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant 2018; 8:122-141. [PMID: 30211021 PMCID: PMC6134269 DOI: 10.5500/wjt.v8.i5.122] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 02/05/2023] Open
Abstract
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.
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Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Renal Unit, Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Transplant Surgery, Royal Liverpool University Hospitals, Liverpool UK L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplantation Surgery, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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18
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Román E, Mendizábal S, Jarque I, de la Rubia J, Sempere A, Morales E, Praga M, Ávila A, Górriz JL. Secondary thrombotic microangiopathy and eculizumab: A reasonable therapeutic option. Nefrologia 2018; 37:478-491. [PMID: 28946961 DOI: 10.1016/j.nefro.2017.01.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 01/03/2017] [Accepted: 01/14/2017] [Indexed: 12/16/2022] Open
Abstract
Understanding the role of the complement system in the pathogenesis of atypical haemolytic uraemic syndrome and other thrombotic microangiopathies (TMA) has led to the use of anti-complement therapy with eculizumab in these diseases, in addition to its original use in patients with paroxysmal nocturnal haemoglobinuria andatypical haemolytic uraemic syndrome. Scientific evidence shows that both primary and secondary TMAs with underlying complement activation are closely related. For this reasons, control over the complement system is a therapeutic target. There are 2scenarios in which eculizumab is used in patients with TMA: primary or secondary TMA that is difficult to differentiate (including incomplete clinical presentations) and complement-mediated damage in various processes in which eculizumab proves to be efficacious. This review summarises the evidence on the role of the complement activation in the pathophysiology of secondary TMAs and the efficacy of anti-complement therapy in TMAs secondary to pregnancy, drugs, transplant, humoral rejection, systemic diseases and glomerulonephritis. Although experience is scarce, a good response to eculizumab has been reported in patients with severe secondary TMAs refractory to conventional treatment. Thus, the role of the anti-complement therapy as a new treatment option in these patients should be investigated.
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Affiliation(s)
- Elena Román
- Servicio de Nefrología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, España.
| | - Santiago Mendizábal
- Servicio de Nefrología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Isidro Jarque
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Javier de la Rubia
- Servicio de Hematología, Hospital Universitario Dr. Peset, Valencia, España
| | - Amparo Sempere
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Enrique Morales
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Manuel Praga
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Ana Ávila
- Servicio de Nefrología, Hospital Universitario Dr. Peset, Valencia, España
| | - José Luis Górriz
- Servicio de Nefrología, Hospital Universitario Dr. Peset, Valencia, España
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Kawanishi T, Hasegawa J, Kono M, Ishiwatari A, Ogawa T, Abe Y, Endo M, Ishigooka H, Okumi M, Tanabe K, Wakai S, Shirakawa H. Thrombotic microangiopathy after kidney transplantation successfully treated with eculizumab: A case report. TRANSPLANTATION REPORTS 2018. [DOI: 10.1016/j.tpr.2018.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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20
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Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K. De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev (Orlando) 2017; 32:58-68. [PMID: 29157988 DOI: 10.1016/j.trre.2017.10.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 10/22/2017] [Accepted: 10/23/2017] [Indexed: 12/14/2022]
Abstract
Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post-transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS. Here, we review the etio-pathogenesis, diagnosis and treatment options for de novo post-transplant TMA. It is usually in the setting of calcineurin inhibitor use, mammalian target of rapamycin inhibitor use, or antibody mediated rejection; recently genetic mutations in complement regulatory genes for Factor H and Factor I similar to those described in aHUS have been reported in up to a third of these patients. Systemic signs of TMA are frequently absent, and a renal allograft biopsy is often needed to establish the diagnosis. Although withdrawal of the offending agents is usually the first line of treatment and resolution of laboratory abnormalities has been documented with this approach in several case reports and case series, available retrospective data demonstrate lack of benefit in long-term graft outcomes. Co-stimulation blockage with belatacept provides an effective alternate immunosuppressive strategy for these patients. Anti-complement therapy with eculizumab is effective in some cases; further work is required to define which patients with TMA (with and without concomitant antibody-mediated rejection) would benefit from receiving this treatment, and what biomarkers can be used to identify them.
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Affiliation(s)
- Neetika Garg
- Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, United States.
| | - Helmut G Rennke
- Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, United States
| | - Martha Pavlakis
- Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, United States
| | - Kambiz Zandi-Nejad
- Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, United States
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21
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Saha M, McDaniel JK, Zheng XL. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics. J Thromb Haemost 2017; 15:1889-1900. [PMID: 28662310 PMCID: PMC5630501 DOI: 10.1111/jth.13764] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Indexed: 01/07/2023]
Abstract
Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS-13. In general, severe deficiency of plasma ADAMTS-13 activity (< 10 IU dL-1 ) with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP. A patient usually presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS-13 activity (> 10 IU dL-1 ) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. Although plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS-13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with demonstrable autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide and splenectomy, etc., should be considered to eliminate autoantibodies for a sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS-13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS-13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis and diagnosis of, and current and potential novel therapies for, hereditary and acquired TTP.
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Affiliation(s)
- Manish Saha
- Division of Nephrology, Departments of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35249
| | - Jenny K. McDaniel
- Division of Hematology/Oncology, Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL 35249
| | - X. Long Zheng
- Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35249
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Brocklebank V, Kavanagh D. Complement C5-inhibiting therapy for the thrombotic microangiopathies: accumulating evidence, but not a panacea. Clin Kidney J 2017; 10:600-624. [PMID: 28980670 PMCID: PMC5622895 DOI: 10.1093/ckj/sfx081] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 06/21/2017] [Indexed: 02/07/2023] Open
Abstract
Thrombotic microangiopathy (TMA), characterized by organ injury occurring consequent to severe endothelial damage, can manifest in a diverse range of diseases. In complement-mediated atypical haemolytic uraemic syndrome (aHUS) a primary defect in complement, such as a mutation or autoantibody leading to over activation of the alternative pathway, predisposes to the development of disease, usually following exposure to an environmental trigger. The elucidation of the pathogenesis of aHUS resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. In other TMAs, although complement activation may be seen, its role in the pathogenesis remains to be confirmed by an interventional trial. Although many case reports in TMAs other than complement-mediated aHUS hint at efficacy, publication bias, concurrent therapies and in some cases the self-limiting nature of disease make broader interpretation difficult. In this article, we will review the evidence for the role of complement inhibition in complement-mediated aHUS and other TMAs.
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Affiliation(s)
- Vicky Brocklebank
- The National Renal Complement Therapeutics Centre (NRCTC), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - David Kavanagh
- The National Renal Complement Therapeutics Centre (NRCTC), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Epperla N, Hemauer K, Hamadani M, Friedman KD, Kreuziger LB. Impact of treatment and outcomes for patients with posttransplant drug-associated thrombotic microangiopathy. Transfusion 2017; 57:2775-2781. [PMID: 28836275 DOI: 10.1111/trf.14263] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/17/2017] [Accepted: 06/17/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Drug-induced transplant-associated thrombotic microangiopathy (DTA-TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition. STUDY DESIGN AND METHODS Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases. RESULTS There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group. CONCLUSION While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings.
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Affiliation(s)
| | | | | | - Kenneth D Friedman
- Division of Hematology and Oncology.,BloodCenter of Wisconsin, Milwaukee, Wisconsin
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Clinical dissection of thrombotic microangiopathy. Ann Hematol 2017; 96:1715-1726. [PMID: 28752391 DOI: 10.1007/s00277-017-3063-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/04/2017] [Indexed: 10/19/2022]
Abstract
Differential treatment strategies are applied in thrombotic microangiopathy (TMA) according to the sub-classifications. Hence, it is worthwhile to overview clinical manifestations and outcomes of overall TMA patients according to sub-classifications. We analyzed TMA patients whose serum lactate dehydrogenase levels >250 IU/L, with the presence of schistocytes in their peripheral blood smear, or with typical vascular pathologic abnormalities in their renal biopsy. We compared clinical manifestations including overall survival (OS) and renal survival according to TMA causes. A total of 117 TMA patients (57 primary and 60 secondary TMA) were analyzed. Renal symptom was the most common manifestation in whole patients, while renal function at diagnosis was worst in pregnancy-related TMA group. Primary TMA patients had more frequent CNS symptom and hematologic manifestation compared to secondary TMAs. Among secondary TMAs, pregnancy- and HSCT-related TMA patients showed prevalent hemolytic features. During 150.2 months of follow-up, 5-year OS rate was 64.8%. Poor prognostic factors included older age, combined hematologic and solid organ malignancies, lower hemoglobin levels, and lower serum albumin levels. There was no significant difference in OS between primary and secondary TMAs. Seventy-eight percent of patients experienced AKI during TMA. Five-year death-censored renal survival rate was poor with only 69.2%. However, excellent renal outcome was observed in pregnancy-associated TMA. TMA showed various clinical manifestations according to their etiology. Notably, both OS and renal survival were poor regardless of their etiologies except pregnancy-associated TMA. Physicians should differentiate a variety of TMA categories and properly manage this complex disease entity.
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Kumar D, LeCorchick S, Gupta G. Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants. Front Med (Lausanne) 2017; 4:60. [PMID: 28580358 PMCID: PMC5437176 DOI: 10.3389/fmed.2017.00060] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/01/2017] [Indexed: 12/28/2022] Open
Abstract
The goal of immunosuppression in transplantation has shifted to improving long-term outcomes, reducing drug-induced toxicities while preserving the already excellent short-term outcomes. Long-term gains in solid organ transplantation have been limited at least partly due to the nephrotoxicity and metabolic side effects of calcineurin inhibitors (CNIs). The alloimmune response requires activation of the costimulatory pathway for T cell proliferation and amplification. Belatacept is a molecule that selectively blocks T cell costimulation. In June 2011, the U.S. Food and Drug Administration approved it for maintenance immunosuppression in kidney transplantation based on two open-label, randomized, phase III trials. Since its introduction, belatacept has shown promise in both short- and long-term renal transplant outcomes in several other trials. It exhibits a superior side effect profile compared to CNIs with a comparable efficacy. Across all solid organ transplants, the burden of chronic kidney disease, its associated cardiovascular morbidity, mortality, and inferior patient/allograft survival is a well-documented problem. In this review, we aim to discuss the evidence behind the use of belatacept in solid organ transplants as an effective alternative to CNIs for renal rescue in patients with acute and/or chronic kidney injury.
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Affiliation(s)
- Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA, USA
| | - Spencer LeCorchick
- Division of Transplant Surgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA, USA
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Yamamoto T, Watarai Y, Futamura K, Okada M, Tsujita M, Hiramitsu T, Goto N, Narumi S, Takeda A, Kobayashi T. Efficacy of Eculizumab Therapy for Atypical Hemolytic Uremic Syndrome Recurrence and Antibody-Mediated Rejection Progress After Renal Transplantation With Preformed Donor-Specific Antibodies: Case Report. Transplant Proc 2017; 49:159-162. [PMID: 28104125 DOI: 10.1016/j.transproceed.2016.10.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Atypical hemolytic uremic syndrome (aHUS) develops as the result of unregulated complement progression and precipitates de novo thrombotic microangiopathy. Plasma therapy is used to control the progression of the complement cascade, but that therapy is not effective in all patients and is accompanied by risk of infection and/or allergy. Eculizumab has been reported as an efficient therapy for aHUS. We report the case of a 35-year old woman who underwent effective eculizumab therapy for aHUS recurrence and antibody-mediated rejection (AMR) progress after renal transplantation with preformed donor-specific antibodies (DSA). She developed end-stage renal disease due to suspicious IgA nephropathy at age 33 years. Kidney transplantation was performed at age 35 years, and aHUS recurred 2 weeks later, leading to the progressive hemolytic anemia and renal dysfunction. Therefore, she underwent plasma therapy several times. Because it was difficult to continue to plasma therapy for severe allergy, eculizumab was proposed as an alternate therapy. Treatment with eculizumab was initiated 36 days after renal transplantation. After 3 years of eculizumab treatment, and without plasma therapy, schistocytes decreased, haptoglobin increased to within normal limits, creatinine levels stabilized, and no further episodes of diarrhea were reported. At protocol biopsy 1 year after transplantation, she was diagnosed with C4d-negative subclinical AMR. However, her pathologic findings at follow-up biopsy 3 years after transplantation were recovered. We conclude that eculizumab alone, without plasma therapy, is sufficient to treat recurrence of aHUS and AMR due to DSA after renal transplantation and to maintain long-term graft function.
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Affiliation(s)
- T Yamamoto
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
| | - Y Watarai
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - K Futamura
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - M Okada
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - M Tsujita
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - T Hiramitsu
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - N Goto
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - S Narumi
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - A Takeda
- Department of Nephrology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - T Kobayashi
- Department of Kidney Transplant Surgery, Aichi Medical University, Nagakute, Japan
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Hayashi Y, Nagahara A, Kawashima A, Kakuta Y, Ujike T, Abe T, Fukuhara S, Fujita K, Uemura M, Kiuchi H, Imamura R, Miyagawa Y, Ichimaru N, Maeda T, Nonomura N. [A CASE OF SUCCESSFUL RECOVERY OF RENAL ALLOGRAFT FUNCTION FOLLOWING A DIAGNOSIS OF THROMBOTIC MICROANGIOPATHY CLINICALLY MADE IN THE IMMEDIATE POST-TRANSPLANT PERIOD]. Nihon Hinyokika Gakkai Zasshi 2017; 108:166-169. [PMID: 30033982 DOI: 10.5980/jpnjurol.108.166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
A 57-year-old female patient on hemodialysis with chronic renal failure due to chronic glomerular nephritis received deceased donor kidney transplantation. Induction immunosuppressive therapy was combination of tacrolimus, mycophenolate mofetil, everolimus, prednisolone, and basiliximab. She was diagnosed with secondary thrombotic microangiopathy (TMA) by clinical findings such as hemolytic anemia, thrombocytopenia and acute kidney injury not by pathological findings on the 4th post-operative date. Plasma exchange was performed with suspension of tacrolimus. General conditions recovered, and the graft function was preserved.
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Affiliation(s)
- Yujiro Hayashi
- Department of Urology, Osaka University Graduate School of Medicine
| | - Akira Nagahara
- Department of Urology, Osaka University Graduate School of Medicine
| | | | - Yoichi Kakuta
- Department of Urology, Osaka University Graduate School of Medicine
| | - Takeshi Ujike
- Department of Urology, Osaka University Graduate School of Medicine
| | - Toyofumi Abe
- Department of Urology, Osaka University Graduate School of Medicine
| | | | - Kazutoshi Fujita
- Department of Urology, Osaka University Graduate School of Medicine
| | - Motohide Uemura
- Department of Urology, Osaka University Graduate School of Medicine
| | - Hiroshi Kiuchi
- Department of Urology, Osaka University Graduate School of Medicine
| | - Ryoichi Imamura
- Department of Urology, Osaka University Graduate School of Medicine
| | - Yasushi Miyagawa
- Department of Urology, Osaka University Graduate School of Medicine
| | - Naotsugu Ichimaru
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine
| | - Tetsuo Maeda
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine
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Ibrahim H, Al Qurashi S, Abdullah M, Hajeer A, Alsaad KO, Al Sayyari A. Antibody-mediated rejection and aHUS in renal graft recipient. COGENT MEDICINE 2016. [DOI: 10.1080/2331205x.2016.1215014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Hafez Ibrahim
- Department of Medicine, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11426, Saudi Arabia
| | - Salem Al Qurashi
- Department of Medicine, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11426, Saudi Arabia
| | - Mubarak Abdullah
- Department of Medicine, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11426, Saudi Arabia
| | - Ali Hajeer
- Department of Laboratory Medicine, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11426, Saudi Arabia
| | - Khaled O. Alsaad
- Department of Laboratory Medicine, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11426, Saudi Arabia
| | - Abdulla Al Sayyari
- Department of Medicine, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 22490, Riyadh 11426, Saudi Arabia
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Yun SH, Lee JH, Oh JS, Kim SM, Sin YH, Kim YJ, Kim JK. Overcome of Drug Induced Thrombotic Microangiopathy after Kidney Transplantation by Using Belatacept for Maintenance Immunosuppression. KOREAN JOURNAL OF TRANSPLANTATION 2016. [DOI: 10.4285/jkstn.2016.30.1.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Seong Han Yun
- Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Korea
| | - Jin Ho Lee
- Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Korea
| | - Joon Seok Oh
- Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Korea
| | - Seong Min Kim
- Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Korea
| | - Yong Hun Sin
- Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Korea
| | - Yong-Jin Kim
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Joong Kyung Kim
- Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Korea
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30
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Wu K, Budde K, Schmidt D, Neumayer HH, Lehner L, Bamoulid J, Rudolph B. The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy. Clin Transplant 2016; 30:105-17. [PMID: 26448478 DOI: 10.1111/ctr.12645] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. METHODS Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. RESULTS The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. CONCLUSION The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.
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Affiliation(s)
- Kaiyin Wu
- Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - Klemens Budde
- Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - Danilo Schmidt
- Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - Hans-Hellmut Neumayer
- Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - Lukas Lehner
- Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - Jamal Bamoulid
- Medizinische Klinik mit Schwerpunkt Nephrologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - Birgit Rudolph
- Institut für Pathologie, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
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31
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De novo thrombotic microangiopathy after non-renal solid organ transplantation. Blood Rev 2014; 28:269-79. [DOI: 10.1016/j.blre.2014.09.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 09/02/2014] [Indexed: 12/14/2022]
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Paz M, Roberti J, Mos F, Cicora F. Conversion to Belatacept-Based Immunosuppression Therapy in Renal Transplant Patients. Transplant Proc 2014; 46:2987-90. [DOI: 10.1016/j.transproceed.2014.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Differing tales of two patients after receiving a kidney transplant from a donor with disseminated intravascular coagulation. Case Rep Transplant 2014; 2014:754256. [PMID: 25061532 PMCID: PMC4100278 DOI: 10.1155/2014/754256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 05/31/2014] [Accepted: 06/16/2014] [Indexed: 11/17/2022] Open
Abstract
In order to decrease the time on the deceased donor kidney wait list and to have more organs available, criteria for acceptable organs for transplant could be made less stringent. There are reports of successful recipient outcomes using kidney donors presenting with disseminated intravascular coagulation (DIC). We report a unique circumstance where two patients received kidneys from the same deceased donor who had DIC; one patient developed thrombotic microangiopathy (TMA) while the other did not. This difference in outcome may indicate that both donor and recipient factors contribute to the development of posttransplant TMA.
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35
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Prasad D, Agarwal D, Malhotra V, Mathur M, Garsa R, Gandhi K, Beniwal P. Successful outcome of tacrolimus-associated thrombotic microangiopathy in renal transplant recipient with plasmapharesis. INDIAN JOURNAL OF TRANSPLANTATION 2014. [DOI: 10.1016/j.ijt.2014.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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36
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Ali MN, Ali MNA, Syed A, Syed AB, Bhandari S, Bhandari SC. Case series: hemolytic uremic syndrome--another cause of transplant dysfunction. Transplant Proc 2014; 45:3284-8. [PMID: 24182801 DOI: 10.1016/j.transproceed.2013.07.060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 07/14/2013] [Accepted: 07/17/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND Renal transplantation is the optimal treatment for suitable patients with end-stage renal disease (ESRD). However, acute graft dysfunction occurs in 5%-35% of patients. This is commonly due to acute rejection, drug toxicity, ureteric obstruction, or infection. Atypical hemolytic uremic syndrome (aHUS), either recurrent or de novo, is uncommon after transplantation. CASES We highlight three cases of acute transplant dysfunction in which transplant biopsy revealed HUS without associated clinical or hematologic clues to the etiology. Two cases had recurrent HUS and 1 had de novo HUS secondary to tacrolimus therapy. Screenings for ADAMTS-13 and gene mutations of complement regulatory proteins were negative. Thrombocytopenia and red blood cell fragments on blood film appeared some days later. TREATMENT Treatment comprised a combination of plasma exchange with fresh-frozen plasma and switching immunosuppressive therapy, which led to the recovery of the above hematologic features but salvaged graft function in only 1 case. CONCLUSIONS Classical hematologic findings of HUS appeared late in these cases. HUS should be considered in cases of allograft dysfunction where there is no obvious cause, and biopsy should be performed. This enables early initiation of therapy to gain rapid recovery of hematologic parameters and potentially of transplant function.
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Affiliation(s)
| | - M N A Ali
- Department of Renal Medicine, Hull and East Yorkshire Hospitals, NHS Trust, and Hull and York Medical School, Hull, East Yorkshire, United Kingdom
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Ponticelli C, Moroni G, Glassock RJ. De novo glomerular diseases after renal transplantation. Clin J Am Soc Nephrol 2014; 9:1479-87. [PMID: 24700797 DOI: 10.2215/cjn.12571213] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glomerular diseases developing in the kidney allograft are more often recurrences of the original disease affecting the native kidneys. However, in an undefined number of cases de novo, glomerular diseases unrelated to the original disease in the native kidneys can develop in the transplanted kidney. The clinical presentation and histologic features of de novo diseases are often similar to those features observed in patients with primary or secondary GN in the native kidneys. However, in transplanted kidneys, the glomerular, vascular, and tubulointerstitial changes are often intertwined with structural abnormalities already present at the time of transplant or caused by antibody- or cell-mediated allograft rejection, immunosuppressive drugs, or superimposed infection (most often of a viral nature). The pathophysiology of de novo glomerular diseases is quite variable. In rare cases of de novo minimal change disease, circulating factors increasing the glomerular permeability likely participate. Maladaptive hemodynamic changes and tissue fibrosis caused by calcineurin inhibitors or other factors may be involved in the pathogenesis of de novo FSGS. The exposure of cryptic podocyte antigens may favor the development of de novo membranous nephropathy. Many cases of de novo membranoproliferative GN are related to hepatitis C virus infection. Patients with Alport syndrome lacking antigenic epitopes in their glomerular basement membrane may develop antibodies against these glomerular basement membrane antigens expressed in the transplanted kidney. Infection may cause acute GN to have a heterogeneous clinical presentation and outcome. De novo pauci-immune GN in renal transplant is rare. Preexisting or acquired intolerance to glucose may, in the long term, cause diabetic nephropathy. The prognosis of de novo diseases depends on the type of GN, the severity of lesions caused by the alloimmune response, or the efficacy of immunosuppressive therapy. In most cases, the management of de novo glomerular diseases is empirical or elusive.
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Affiliation(s)
- Claudio Ponticelli
- Division of Nephrology, Humanitas Scientific Institute, Rozzano, Milan, Italy;
| | - Gabriella Moroni
- Division of Nephrology, Fondazione Ca' Granda Ospedale Maggiore Istituto Scientifico, Milan, Italy; and
| | - Richard J Glassock
- Department of Medicine, Geffen School of Medicine at the University of California at Los Angeles, Laguna Niguel, California
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Koppula S, Yost SE, Sussman A, Bracamonte ER, Kaplan B. Successful conversion to belatacept after thrombotic microangiopathy in kidney transplant patients. Clin Transplant 2014; 27:591-7. [PMID: 23923969 DOI: 10.1111/ctr.12170] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2013] [Indexed: 12/11/2022]
Abstract
Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation. TMA may occur de novo or as recurrent disease post-transplant. De novo disease is usually associated with immunosuppressive drugs or can be seen as a part of endothelial damage that accompanies antibody-mediated rejection. Treatment for de novo TMA is limited to plasma exchange and change in immunosuppression. We report two cases of de novo TMA post-transplant that were successfully treated by converting to belatacept for maintenance immunosuppression.
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Affiliation(s)
- Sireesha Koppula
- Department of Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA
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Radha S, Tameem A, Sridhar G, Aiyangar A, Rajaram KG, Prasad R, Kiran K. Thrombotic microangiopathy in renal allografts. Indian J Nephrol 2014; 24:24-7. [PMID: 24574627 PMCID: PMC3927186 DOI: 10.4103/0971-4065.125052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Thrombotic microangiopathy (TMA) is a serious complication of renal transplantation. It is a morphological expression of various etiological factors. In a renal allograft, TMA can occur de novo or be a recurrent disease. The aim of this study was to analyze the etiological factors and observe the changing trends of TMA with respect to emerging new etiological factors. We evaluated 131 graft biopsies over a period of 2½ years (2010-2012). All the renal biopsies were formalin fixed, paraffin embedded. Twenty serial sections were studied. Stains routinely used were Hematoxylin and Eosin, Periodic Acid Schiff, Massons Trichrome and Silver Methenamine stains. C4d by immunohistochemical method was done on all graft biopsies. Incidence of TMA in our series was 9.1%. Out of the 12 cases, five were associated with calcineurin inhibitor toxicity, three were diagnosed as acute antibody-mediated rejection, and two were recurrent haemolytic uremic syndrome. One patient developed haemolytic uremic syndrome on treatment with sirolimus and one patient was cytomegalovirus positive on treatment with ganciclovir, developed haemolytic uremic syndrome during treatment course. This study describes a spectrum of etiological factors for thrombotic mciroangiopathy ranging from common cause like calcineurin inhibitor toxicity to rare cause like ganciclovir induced TMA.
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Affiliation(s)
- S Radha
- Consultant, Department of Pathology, Aware Global Hospitals, Visakhapatnam, India
| | - Afroz Tameem
- Consultant, Department of Pathology, Aware Global Hospitals, Visakhapatnam, India
| | - G Sridhar
- Department of Nephrology, Aware Global Hospitals, Consultant, Visakhapatnam, India
| | - A Aiyangar
- Department of Nephrology, Aware Global Hospitals, Consultant, Visakhapatnam, India
| | - K G Rajaram
- Consultant, Department of Nephrologist, Hyderabad Kidney and Laparoscopic Centre, Visakhapatnam, India
| | - R Prasad
- Professor of Nephrology, Andhra Medical College and King George Hospital, Visakhapatnam, India
| | - K Kiran
- Consultant Nephrologist, Kamineni Hospitals, Hyderabad, India
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40
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Use of belatacept as alternative immunosuppression in three renal transplant patients with de novo drug-induced thrombotic microangiopathy. Case Rep Med 2013; 2013:260254. [PMID: 24198835 PMCID: PMC3806345 DOI: 10.1155/2013/260254] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 09/09/2013] [Accepted: 09/15/2013] [Indexed: 12/23/2022] Open
Abstract
Thrombotic microangiopathy (TMA), a severe complication of renal transplantation, is a pathological process involving microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia. It generally appears within the first weeks after transplantation, when immunosuppressive drugs are used at high doses. De novo TMA may also be drug-induced when calcineurin inhibitors or proliferation signal inhibitors are used. We report three cases of de novo drug-induced TMA in renal transplant patients who were managed by replacing calcineurin inhibitors or proliferation signal inhibitors with belatacept, a primary maintenance immunosuppressive drug, which blocks the CD28 costimulation pathway, preventing the activation of T lymphocytes. To identify the cause of TMA, we ruled out HUS, hepatitis C serology, HIV serology, parvovirus B19, cytomegalovirus, anti-HLA antibodies, and prolonged activated partial thromboplastin time. We suspect that the TMA was caused by the calcineurin inhibitors or proliferation signal inhibitors. Belatacept treatment was initiated at a dose of 10 mg/kg on days 1, 5, 14, 28, 60, and 90; maintenance treatment was 5 mg/kg once a month for 1 year. Belatacept, in combination with other agents, prevented graft rejection in three patients.
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Abstract
Hemolytic uremic syndromes can have devastating consequences in childhood. The common feature of a microangiopathic hemolytic anemia and thrombocytopenia associated with varying degrees of renal injury often creates diagnostic confusion. The inability to arrive at a definitive diagnosis quickly can lead to a delay in initiating renal-preserving and sometimes life-saving treatment. Currently, both the treatment plan and the prognosis vary substantially according to the presumed diagnosis. The availability of anti-complement therapy makes differentiating the cause of the hemolytic uremic syndrome particularly critical. Therefore, it is imperative that consideration be given to each of the possible syndromes at presentation in order to facilitate correct diagnosis and development of an appropriate treatment strategy for both the acute phase and for the long-term care of the patient.
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Affiliation(s)
- Carla M Nester
- Departments of Internal Medicine and Pediatrics, Rare Renal Disease Clinic, University of Iowa, Iowa City, IA 52242-1081, USA.
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42
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Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant 2012; 27:2673-85. [PMID: 22802583 PMCID: PMC3398067 DOI: 10.1093/ndt/gfs279] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Accepted: 04/07/2012] [Indexed: 12/17/2022] Open
Abstract
Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS.
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Affiliation(s)
- Thomas Barbour
- Imperial College, Centre for Complement and Inflammation Research, London, UK.
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43
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Clark W. Plasma exchange for renal disease: Evidence and use 2011. J Clin Apher 2012; 27:112-6. [DOI: 10.1002/jca.21221] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2012] [Accepted: 02/21/2012] [Indexed: 11/06/2022]
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Abstract
Thrombotic microangiopathies encompass a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia associated with hyaline thrombi (comprised primarily of platelet aggregates in the microcirculation), and varying degrees of end-organ failure. Many primary (genetic) and secondary etiological predisposing factors have been described-namely pregnancy, autoimmune disorders, cancer, drugs and antineoplastic therapy, bone marrow transplantation/solid organ transplantation, and infections. In the setting of infectious diseases, the association with Shiga or Shiga-like exotoxin of Escherichia coli 0157:h7 or Shigella dysenteriae type 1-induced typical hemolytic uremic syndrome is well known. Recently however, an increasing body of evidence suggests that viruses may also play an important role as trigger factors in the pathogenesis of thrombotic microangiopathies. This is a comprehensive review focusing on the current understanding of viral associated/induced endothelial stimulation and damage that ultimately leads to the development of this life-threatening multisystemic disorder.
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Affiliation(s)
- Rodrigo Lopes da Silva
- Hospital Santo António dos Capuchos, Centro Hospitalar Lisboa Center, Alameda Capuchos, Lisboa, Portugal.
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45
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Chandran S, Baxter-Lowe L, Olson JL, Tomlanovich SJ, Webber A. Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation--a case report. Transplant Proc 2011; 43:2097-101. [PMID: 21693335 DOI: 10.1016/j.transproceed.2011.02.064] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Accepted: 02/16/2011] [Indexed: 01/02/2023]
Abstract
A 34-year-old female recipient of a simultaneous pancreas-kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia. Renal biopsy revealed acute antibody-mediated rejection (AMR) and acute thrombotic microangiopathy (TMA). Clinical and laboratory manifestations, which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin, resolved rapidly and completely to eculizumab (Soliris, Alexion Pharmaceuticals, Inc., Cheshire, Conn), a complement factor C5 antibody. De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases. This is the first report of successful treatment of de novo TMA with eculizumab, which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR. Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA, especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease.
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Affiliation(s)
- S Chandran
- Department of Medicine, Division of Nephrology, Kidney Transplant Service, University of California San Francisco, California, USA
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46
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Troxell ML, Norman D, Mittalhenkle A. Glomerular fibrin thrombi in ABO and crossmatch compatible renal allograft biopsies. Pathol Res Pract 2011; 207:15-23. [DOI: 10.1016/j.prp.2010.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2009] [Revised: 09/12/2010] [Accepted: 10/04/2010] [Indexed: 11/29/2022]
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Transplantation-associated thrombotic microangiopathy after steroid pulse therapy for polyserositis related to graft-versus-host disease. Clin Exp Nephrol 2010; 15:179-83. [PMID: 21120571 DOI: 10.1007/s10157-010-0376-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Accepted: 10/21/2010] [Indexed: 10/18/2022]
Abstract
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a rare but devastating syndrome that occurs in allogeneic hematopoietic stem cell transplant recipients, and is associated with a variety of transplantation-related factors, including conditioning regimens, immunosuppressive agents, graft-versus-host disease (GVHD) and opportunistic infections. TA-TMA has an unfavorable prognosis and responds poorly to conventional treatment including plasma exchange (PE). We present a case of a 37-year-old man with membranous nephropathy (MN) and polyserositis caused by GVHD after hematopoietic stem cell transplantation. He developed TA-TMA after steroid pulse therapy for polyserositis. We treated the patient with PE and mycophenolate mofetil (MMF) after which the TA-TMA successfully improved and the MN underwent complete remission. The present case suggests that corticosteroids with severe GVHD might increase the risk of TA-TMA, and that PE in combination with MMF may be a valuable therapy to improve the prognosis.
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48
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49
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Satoskar AA, Pelletier R, Adams P, Nadasdy GM, Brodsky S, Pesavento T, Henry M, Nadasdy T. De novo thrombotic microangiopathy in renal allograft biopsies-role of antibody-mediated rejection. Am J Transplant 2010; 10:1804-1811. [PMID: 20659088 DOI: 10.1111/j.1600-6143.2010.03178.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody-mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR-associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR-related TMA because plasmapheresis treatment may be beneficial.
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Affiliation(s)
- A A Satoskar
- Department of Pathology, Ohio State University, Columbus, OH, USA.
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50
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Noris M, Remuzzi G. Genetics and genetic testing in hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Semin Nephrol 2010; 30:395-408. [PMID: 20807612 DOI: 10.1016/j.semnephrol.2010.06.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are rare diseases that manifest with thrombocytopenia and microangiopathic hemolytic anemia accompanied by renal and neurologic dysfunction. Most childhood cases of HUS are caused by Shiga-toxin-producing bacteria and have a good prognosis. The other form, atypical HUS (aHUS), accounts for 10% of cases. Prognosis of aHUS and TTP has changed over time from fatal disorders to 60% to 80% survival in the plasma therapy era. In the past 10 years the molecular bases of aHUS and TTP have been discovered that mostly lead to uncontrolled activation of the complement system in aHUS and to abnormal von Willebrand factor processing in TTP. Identification of the underlying abnormality in an individual patient can provide prognostically significant information in predicting long-term outcome, response to therapies, and transplant outcome. It also paves the way for the use of specific new therapies in the near future.
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Affiliation(s)
- Marina Noris
- Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Villa Camozzi, Ranica, Bergamo, Italy.
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