Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombotic microangiopathy (TMA) is one of the severe complications after stem cell transplantation (SCT) and is associated with graft-versus-host disease (GVHD) prophylaxis including FK506. In this study, we experimented on rats using FK506 to demonstrate the occurrence of intestinal TMA. FK506 was administrated into Wistar/ST rats intraperitoneally for 7 days. Rats were examined histopathologically after FK506 injection using light and electron microscopy and immunohistochemistry. FK506 concentrations in whole blood were measured by enzyme immunoassay. In the acute phase, hemorrhagic lesions with multifocal erosions and crypt loss were found in the small intestines of all treated rats. Capillary vessels were dilated, and a few platelet thrombi were found. Electron microscopy demonstrated degenerative swelling of endothelial cells and platelet aggregates adhering to the vessel walls. In the later phase, epithelial regenerative failure, characterized by crypt ghosts, was found in the affected mucosa. Apoptotic epithelial cells were increased in number. The extent of intestinal injury was proportional to the whole blood levels of FK506. The intestinal lesions in rats were consistent with TMA and induced by the injection of FK506 alone. Apoptotic enteropathy was also observed and similar to intestinal GVHD. In this study, we established an intestinal TMA model induced by immunosuppressant (Tacrolimus) only without irradiation.
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PMID:Intestinal thrombotic microangiopathy induced by FK506 in rats. 1727 91

The application of myeloablative Allo-SCT is limited by its associated morbidity and mortality. Reduced-intensity conditioning regimens attempt to diminish these, but are associated with a higher risk of disease relapse. Given the evidence of activity of clofarabine and cytarabine in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), we explored a novel reduced-intensity conditioning regimen based on this backbone. Patients received clofarabine 40 mg/m(2) i.v. on days -6 to -2, cytarabine 1 g/m(2) i.v. on days -6 to -2 and anti-thymocyte globulin (ATG) 1 mg/kg on day -4 and 2.5 mg/kg x 2 days on days -3 and -2. Seven patients were enrolled. Their median age was 54 years; three were with MDS and four with AML. The median duration of neutropenia was 14 days and that of thrombocytopenia was 22 days. Toxicities included hand-foot syndrome (57% grade 2), elevated alanine aminotransferase (ALT) (57% grade 3), elevated aspartate aminotransferase (AST) (86% grade 3) and hyperbilirubinemia (29% grade 3-5). No acute GVHD was observed. Enrollment to the trial was halted after three of the first seven patients expired on days +15, +26 and +32. Three of the four surviving patients have relapsed with a median TTP of 152 days. This regimen was not sufficiently immunosuppressive to ensure engraftment, and was associated with substantial morbidity and mortality.
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PMID:Allo-SCT conditioning for myelodysplastic syndrome and acute myeloid leukemia with clofarabine, cytarabine and ATG. 1913 40

Combination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation-based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens:fludarabine-melphalan (n = 46); total body irradiation-etoposide (n = 28), and busulfan-cyclophosphamide (n = 11). The conditioning regimens were completed on day -4. Sirolimus and tacrolimus were started on day -3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P = .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.
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PMID:A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. 2050 74

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.
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PMID:Renal thrombotic microangiopathy associated with chronic humoral graft versus host disease after hematopoietic stem cell transplantation. 2116 41

Allogeneic hematopoietic cell transplantation (HCT) represents a vital procedure for patients with various hematologic conditions. Despite advances in the field, HCT carries significant morbidity and mortality. A rare but potentially devastating complication is transplantation-associated thrombotic microangiopathy (TA-TMA). In contrast to idiopathic TTP, whose etiology is attributed to deficient activity of ADAMTS13, (a member of the A Disintegrin And Metalloprotease with Thrombospondin 1 repeats family of metalloproteases), patients with TA-TMA have > 5% ADAMTS13 activity. Pathophysiologic mechanisms associated with TA-TMA, include loss of endothelial cell integrity induced by intensive conditioning regimens, immunosuppressive therapy, irradiation, infections and graft-versus-host (GVHD) disease. The reported incidence of TA-TMA ranges from 0.5% to 75%, reflecting the difficulty of accurate diagnosis in these patients. Two different groups have proposed consensus definitions for TA-TMA, yet they fail to distinguish the primary syndrome from secondary causes such as infections or medication exposure. Despite treatment, mortality rate in TA-TMA ranges between 60% to 90%. The treatment strategies for TA-TMA remain challenging. Calcineurin inhibitors should be discontinued and replaced with alternative immunosuppressive agents. Daclizumab, a humanized monoclonal anti-CD25 antibody, has shown promising results in the treatment of TA-TMA. Rituximab or the addition of defibrotide, have been reported to induce remission in this patient population. In general, plasma exchange is not recommended.
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PMID:Thrombotic microangiopathy in haematopoietic cell transplantation: an update. 2177 39

Thrombotic microangiopathy (TMA) is a major complication after hematopoietic stem cell transplantation (HSCT). In this study, we examined the clinical and pathologic features of 2 patients and 5 autopsy cases with HSCT-associated renal TMA to clarify the association between graft-versus-host disease (GVHD) and renal TMA. The median interval between HSCT and renal biopsy or autopsy was 7 months (range 3-42 months). Clinically, acute and chronic GVHD occurred in 7 and 4 patients, respectively. Clinical evidence for TMA was detected in 2 patients, while chronic kidney disease developed in all patients. The main histopathological findings were diffuse endothelial injury in glomeruli, peritubular capillaries (PTCs), and small arteries. In addition, all cases showed glomerulitis, renal tubulitis, and peritubular capillaritis with infiltration of CD3+ T cells and TIA-1+ cytotoxic cells, suggesting that GVHD occurred during the development of TMA. Diffuse and patchy C4d deposition was noted in glomerular capillaries and PTCs, respectively, in 2 biopsy and 2 autopsy cases, suggesting the involvement of antibody-mediated renal endothelial injury in more than 50% of renal TMA cases. In conclusion, the kidney is a potential target of chronic GVHD that may induce the development of HSCT-associated TMA. Importantly, some cases are associated with chronic humoral GVHD.
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PMID:Renal thrombotic microangiopathy associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. 2188 1

Stem cell Transplantation-Associated Thrombotic Microangiopathy (TA-TMA) is an awful complication with high morbidity and mortality. The reported incidence varies from 0.5% to 75% due to the difficulty of diagnosis in these patients. They do not respond to plasma exchange and despite new treatments, such as defibrotide and rituximab, mortality rate ranges between 60% and 90%. Rheopheresis is a specific application of membrane differential filtration for extracorporeal hemorheotherapy that has been used in the diabetic foot syndrome, venous leg ulcer, pulmonary hypertension, sudden hearing loss, macula degeneration and peripheral arterial occlusive disease. The main therapeutic basis of Rheopheresis is the reduction of blood and plasma viscosity that results in improvements of microcirculation and blood flow. The physiopathologic mechanism associated with TA-TMA is the loss of endothelial cell integrity with hypercoagulability secondary to infections, immunosuppressive therapy and graft-versus-host disease. Because of this, we believe that treatment with Rheoapheresis may improve microcirculation and resolve TA-TMA. We report two patients diagnosed of severe TA-MA successfully treated with Rheopheresis using a selective fibrinogen adsorption system (Rheosorb) with a LIFE-18 apheresis unit (Miltenyi Biotec), an integrated plasma therapy instrument.
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PMID:Using rheopheresis for stem cell transplantation-associated thrombotic microangiopathy (TA-TMA). 2376 89

Renal injury in hematopoietic cell transplant recipients may be related to a combination of factors including chemotherapy, radiation, infection, immunosuppressive agents, ischemia, and graft-versus-host disease, and can involve glomerular, tubulointerstitial, and vascular structures. We reviewed renal pathology from 67 patients at a single institution (2009-2014), including 14 patients with biopsy for clinical dysfunction, 6 patients with surgical kidney resection for other causes, and 47 autopsy patients. Kidney specimens frequently contained multiple histopathologic abnormalities. Thrombotic microangiopathy, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis were the most common glomerular findings. Pathologies not previously reported in the hematopoietic cell transplant setting included collapsing glomerulopathy, antiglomerular basement membrane disease, fibrillary glomerulonephritis, and in the case of two surgical resections distinctive cellular segmental glomerular lesions that defied classification. Kidney specimens frequently demonstrated acute tubular injury, interstitial fibrosis, arteriolar hyaline, and arteriosclerosis. Other kidney findings at autopsy included leukemia and amyloid (both recurrent), diabetic nephropathy, bacterial infection, fungal invasion, and silver deposition along glomerular and tubular basement membranes. Also in the autopsy cohort, C4d immunohistochemistry demonstrated unexpected membranous nephropathy in two patients, yet C4d also colocalized with arteriolar hyaline. This retrospective hematopoietic cell transplant cohort illustrates multifaceted renal injury in patients with renal dysfunction, as well as in patients without clinically recognized kidney injury.
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PMID:Renal pathology in hematopoietic cell transplant recipients: a contemporary biopsy, nephrectomy, and autopsy series. 2701 34

Acute graft-versus-host disease (aGVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Due to the poor prognosis for patients not responding to first-line steroids treatment, improvements in aGVHD therapy are needed. Everolimus is a promising candidate that combines immunosuppressive properties with anti-neoplastic effects. Here, we retrospectively reviewed the efficacy of everolimus with steroids as primary treatment in 13 patients with grade II to grade IV aGVHD after HSCT. Among them, 12 (92.3%) had complete response to everolimus with steroids without additional immunosuppressive agents. The median duration of therapy was 76 days (range 20-110). Asymptomatic hypertriglyceridemia was the most common therapy complication (69.2%), but treatment interruption was not needed. Thrombotic microangiopathy was rare (7.7%), but can be quickly solved by stopping everolimus and cyclosporine treatment. Other toxicities were manageable. Two patients developed chronic GVHD (15.4%), limited in one and extensive in the other. The overall survival was 76.9% with a median follow-up of 3.4 years after HSCT (range 0.7-5.7). Accordingly, everolimus with steroids were feasible for patients with aGVHD after HSCT as primary treatment. Further large-scale studies are required.
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PMID:Everolimus for pediatric patients with acute graft-versus-host disease after hematopoietic stem cell transplantation: A pilot study. 2909 97

Thrombotic microangiopathy associated with hematopoietic stem cell transplantation (HSCT-TMA) is a well-recognized complication of HSCT that has a high risk for death. Even in patients who survive, HSCT-TMA is associated with long-term morbidity and chronic organ injury. HSCT-TMA is a multisystem disease that often affects the kidneys. Renal manifestations of HSCT-TMA include reduced glomerular filtration rate, proteinuria, and hypertension. Understanding of the pathophysiology of HSCT-TMA has expanded in the last decade. Endothelial injury plays a major role. Recent studies also suggest involvement of complement activation. HSCT-TMA has also been considered by some to be an endothelial variant of graft-versus-host disease. Understanding the pathophysiology of HSCT-TMA and its association with activation of the complement system may aid in developing novel therapeutic options. In this review, we summarize current knowledge focusing on epidemiology and prognosis, evidence of complement activation, and endothelial injury; the possible link to graft-versus-host disease; and treatment options for HSCT-TMA.
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PMID:Emerging Concepts in Hematopoietic Stem Cell Transplantation-Associated Renal Thrombotic Microangiopathy and Prospects for New Treatments. 3050 17


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