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Hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with high-risk malignant and nonmalignant conditions. Nevertheless, various post-allogeneic HCT (allo-HCT) complications with diverse chronology, etiology, and pathophysiological background can develop, including general and organ-specific complications, such as graft dysfunction, infectious, and non-infectious etiologies, as well as non-infectious pulmonary complications (NIPCs). Post-transplant complications can also be related to conditioning intensity and drug-specific side effects. However, treatment options for these complications are suboptimal at present. Poor graft function (PGF) is a potentially life-threatening post-allo-HCT complication and is reported in 5-30% of patients. Nevertheless, consensus guidelines to define and treat PGF are not available. Most therapies are symptomatic with variable success rates. NIPCs are diverse and difficult to diagnose. The pathophysiology of NIPCs remains ill-defined, and effective treatment approaches have not been standardized, with mortality exceeding 50% for some conditions, such as idiopathic pneumonia syndrome (IPS). Modification of the conditioning regimen intensity and introduction of novel agents have been used to decrease post-allo-HCT complications, including infections, non-infectious complications, graft-versus-host disease (GvHD), as well as cardiopulmonary, neurological, hepatorenal, and other complications. Transplant-associated thrombotic microangiopathy (TA-TMA) is a lethal post-allo-HCT complication that may be associated with functional and genetic abnormalities in complement activation and related to the use of calcineurin inhibitors, such as cyclosporine and tacrolimus. The introduction of complement inhibitors has transformed TA-TMA from a lethal complication to a treatable syndrome.Keywords:
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Cyclosporine and tacrolimus are calcineurin inhibitors that are used to prevent acute rejection in renal transplant recipients. The lymphocyte immunosuppressant sensitivity test (LIST) can predict the pharmacological efficacy of these immunosuppressive agents for renal transplant recipients. There is a correlation between cyclosporine and tacrolimus pharmacological efficacy as evaluated by LIST by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay procedure prior to renal transplantation. However, the LIST can also evaluate patients before and after the transplantation.The present study examined the relationship between cyclosporine and tacrolimus pharmacological efficacy by LIST using the MTT assay in 16 renal transplant recipients at 1, 3 and 12 months after transplantation, as well as before the operation.The relationship of cyclosporine and tacrolimus pharmacological efficacy gave a significant Kendall and Spearman's coefficient correlation in these transplant recipients by the LIST using the MTT assay procedure immediately prior to renal transplantation (rk = 0.711, rs = 0.877, p < 0.01). Furthermore, correlations between the cyclosporine and tacrolimus IC50 values were also observed with a significant Kendall and Spearman's coefficient correlation at 1 and 12 months after transplantation (rk1month = 0.65, rs1month = 0.829, p < 0.01, and k12month = 0.433, rs12month = 0.603, p < 0.01, respectively). However, no statistically significant relationship was observed between the pharmacological efficacies of the calcineurin inhibitors at 3 months after transplantation (rk3month = 0.117, rs3month = 0.1, p > 0.05).Both cyclosporine and tacrolimus exhibit pharmacological efficacy by the inhibition of calcineurin. However, the correlation between cyclosporine and tacrolimus pharmacological efficacies may be altered, due to immunosuppressive therapy or clinical events at 3 months after renal transplantation.
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Calcineurin inhibitors (CNI) have been clearly associated with posttransplant thrombotic microangiopathy (PTTMA). We report a case of de novo PT-TMA involving predominantly small arteries and arterioles of a renal allograft in a patient receiving tacrolimus. Serial biopsies demonstrate the natural history of this lesion through the chronic nonspecific phase. The case is discussed in the context of a literature review of PT-TMA in general and CNI use in particular.
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Thrombotic microangiopathy
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Calcineurin inhibitor induced thrombotic microangiopathy is a rare but well recognized complication of a renal transplantation that occurs in 1% of the patients who are on tacrolimus immunosuppression. Among the other aetiological factors of the "de-novo" Thrombotic Microangiopathy (TMA), the condition especially has to be differentiated from an antibody mediated rejection, as both have different pathogenesis, therapeutic connotations and outcomes.We report a case of a middle aged female renal transplant recipient treated with tacrolimus, who developed localised thrombotic microangiopathy in the early post transplantation period. Despite the normal trough levels of tacrolimus, a diagnosis of "Tacrolimus induced TMA" was rendered after excluding other causes of the "de-novo" TMA, which included an antibody mediated rejection, a meticulous clinico-pathological correlation and serological studies. The treatment included the substitution of tacrolimus by rapamycin, with the subsequent normalization of the renal function.
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Takeda A, Ohtsuka Y, Horike K, Inaguma D, Goto N, Watarai Y, Uchida K, Morozumi K. A case of tacrolimus‐associated thrombotic microangiopathy after ABO‐blood‐type‐incompatible renal transplantation. Clin Transplant 2011: 25 (Suppl. 23): 15–18. © 2011 John Wiley & Sons A/S. Abstract: De novo thrombotic microangiopathy(TMA) is most commonly triggered by calcineurin inhibitors (CNI) and the prognosis is less severe than with recurrent TMA. However, it is difficult to distinguish de novo TMA from CNI toxicity and acute antibody‐mediated rejection(AMR) soon after renal transplantation. We present a case of tacrolimus‐associated TMA soon after ABO blood type incompatible renal transplantation that was difficult to differentiate from acute AMR. On day 9 his urine output decreased dramatically and the Scr level increased. His anti‐blood type A antibody titer increased to ×16 postopratively and the tacrolimus trough level was higher than in our immunosuppressive regimen. Although we gave priority to anti‐AMR treatment, adequate dose adjustment of tacrolimus after tacrolimus nephrotoxicity was diagnosed from graft biopsy could correct allograft dysfunction.
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Tacrolimus (FK 506) is a calcineurin inhibitor and is commonly used as an immunosuppressant after a solid organ transplant. One of the serious adverse effects of tacrolimus is thrombotic microangiopathy (TMA) which has a high mortality rate. TMA leads to vascular thrombosis, eventually leading to ischemia of end organs. It is diagnosed clinically and based on the laboratory parameters. Early detection of TMA and prompt treatment can change the course. Drug-induced TMA has a poor prognosis as compared to idiopathic TMA. We present here the case of a 47-year-old male who developed tacrolimus-induced TMA after an orthotopic heart transplant and he was treated with the currently available treatment. He ultimately died after 40 days of hospitalization.
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PThrombotic microangiopathy (TMA) is a rare serious adverse reaction of calcineurin inhibitors, tacrolimus and cyclosporin. We report a case of a young male renal transplant recipient treated with tacrolimus, who developed TMA. Treatment included discontinuation of tacrolimus, increasing the dose of mycophenolate mofetil and infusion of fresh-frozen plasma. This was followed by normalization of renal function and dis-appearance of proteinuria. The remission has been sustained after a follow-up of nine months.
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Calcineurin inhibitor-induced thrombotic microangiopathy (TMA) has been described in up to 14% of solid-organ transplant recipients. Sirolimus has recently been described in two reports in association with TMA. Sirolimus is known to potentiate cyclosporine-induced nephrotoxicity, but such effect has not been shown with tacrolimus. We report two intestinal transplant patients who developed TMA while on a tacrolimus and sirolimus immunosuppressive regimen. This syndrome appeared soon after institution of or increase in sirolimus dosage and improved only after this medication was discontinued.
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Background. Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function.
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