Small vessels, big trouble in the kidneys and beyond: Hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Divisions of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Blood (Impact Factor: 10.45). 05/2011; 118(6):1452-62. DOI: 10.1182/blood-2011-02-321315
Source: PubMed


Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenging diagnosis after hematopoietic stem cell transplantation. Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. Potential causes include infections, chemotherapy, radiation, and calcineurin inhibitors. Recent literature addresses the roles of cytokines, graft-versus-host disease, the coagulation cascade, and complement in the pathogenesis of TA-TMA. Current diagnostic criteria are unsatisfactory, because patients who have received a transplant can have multiple other reasons for the laboratory abnormalities currently used to diagnose TA-TMA. Moreover, our lack of understanding of the exact mechanism of disease limits the development and evaluation of potential treatments. Short- and long-term renal complications contribute to TA-TMA's overall poor prognosis. In light of these challenges, future research must validate novel markers of disease to aid in early diagnosis, guide current and future treatments, prevent long-term morbidity, and improve outcomes. We focus on TA-TMA as a distinct complication of hematopoietic stem cell transplantation, emphasizing the central role of the kidney in this disease.

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    • "Transplantation-associated thrombotic microangiopathy (TA-TMA) represents a challenge after allogeneic hematopoietic progenitor cell transplantation because of diagnostic uncertainties, lack of established treatment, and an overall poor prognosis [1]. Eculizumab, which is a monoclonal antibody against terminal complement, has been used successfully in atypical hemolytic and uremic syndrome and TA-TMA associated with solid organ transplantation. "
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    ABSTRACT: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenge after allogeneic hematopoietic progenitor cell transplantation, considering the diagnostic uncertainties and lack of established treatment. We report a 43-year-old male patient who was diagnosed as TA-TMA after allogeneic progenitor cell transplantation for a progressive ALK negative anaplastic large cell lymphoma and responded to eculizumab with dramatically improving neurological status and renal function. Rapid neurological and renal recovery achieved after eculizumab could support a possible relationship between complement activation and TA-TMA. Eculizumab should be a reasonable treatment approach in patients with TA-TMA after allogeneic hematopoietic progenitor cell transplantation.
    Full-text · Article · Feb 2015
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    • "The incidence of TA-TMA is 10–35% as reported in the largest retrospective reviews and studies examining renal and other tissues [22]. In our prospective TA-TMA study, 39% of patients met published diagnostic criteria for TA-TMA, but 18% had severe disease likely affecting overall post-transplant outcomes [4]. "
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is now a well-recognized and potentially severe complication of HSCT that carries a high risk of death. In those who survive, TA-TMA may be associated with long-term morbidity and chronic organ injury. Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA. Specifically, TA-TMA can manifest as a multi-system disease occurring after various triggers of small vessel endothelial injury, leading to subsequent tissue damage in different organs. While the kidney is most commonly affected, TA-TMA involving organs such as the lung, bowel, heart, and brain is now known to have specific clinical presentations. We now review the most up-to-date research on TA-TMA, focusing on the pathogenesis of endothelial injury, the diagnosis of TA-TMA affecting the kidney and other organs, and new clinical approaches to the management of this complication after HSCT. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Nov 2014 · Blood Reviews
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    • "Glomerular endothelial injury associated with the atypical hemolytic-uremic syndrome frequently leads to end stage kidney failure [5]. Similarly, transplant-associated TMA is a significant cause of morbidity, mortality, and kidney allograft loss [6,7]. "
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    ABSTRACT: The microvascular endothelium of the kidney glomerulus is injured in Shiga-like toxigenic bacterial infection, genetic or acquired loss of complement regulatory protein function, and allo-immune responses of solid-organ or bone marrow transplantation. Existing models of diseases with glomerular endothelial cell (EC) injury, collectively grouped as thrombotic microangiopathies, are problematic, impeding investigation of the mechanisms of microvascular defense and repair. To develop a model of glomerular endothelial injury in the mouse, we conjugated the M. oreades lectin to the cytotoxin, saporin, (LS) to selectively injure the glomerular endothelium. Injury of the microvasculature was evaluated by light, immunofluorescence, and electron microscopy, and by quantitative RT-PCR of cell-type specific transcripts. Renal function was evaluated by quantitation of serum creatinine. The toxin conjugate induced apoptosis of microvascular ECs in vitro, and subtle histologic features of thrombotic microangiopathy in vivo that were enhanced by co-injection of 50 μg/kg LPS. Among LS/LPS-treated animals, loss of glomerular EC staining correlated with decreased expression of EC-specific transcripts, and impaired kidney function. Selective injury of the glomerular microvasculature with LS toxin conjugate and LPS elicits histologic features of thrombotic microangiopathy and acute kidney failure.
    Full-text · Article · Oct 2013 · PLoS ONE
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