Thrombotic microangiopathy after living-donor liver transplantation

Thrombotic microangiopathy (TMA) is an infrequent but severe life-threatening disorder in solid organ transplant recipients. Few studies of TMA in living donor liver transplant (LDLT) recipients, however, have been reported. We investigated the clinical characteristics and prognostic factors of TMA after LDLT. Among 393 adult LDLT recipients, 30 patients (7.6%) were identified to have TMA. The 1-, 3- and 5-year survival rates of these patients were lower (60.6%, 52.5% and 47.7%, respectively) than those of patients without TMA (93.0%, 89.0% and 87.3%, respectively). Multivariate analysis confirmed that reduced administration of fresh frozen plasma and sensitization against HLA are closely related with TMA (odds ratio [OR]: 2.6 and 16.1, respectively). However, a review of the cases revealed that individual responses to treatment varied considerably and the main etiologies were difficult to determine. A comparison of the clinical factors suggested that late onset (>30 days), poor response to treatment and delayed diagnosis and/or treatment are associated with a poor outcome. Because the prevention of TMA in LDLT patients is difficult, early diagnosis and initiation of intensive therapies may be crucial to improve the prognosis.     

Thrombotic microangiopathy following pancreas after kidney transplants

Abstract:  Advances in immunosuppressive therapy and refinement in surgical techniques have allowed pancreas after kidney (PAK) transplantation to become a viable therapeutic option for patients with brittle type I diabetic recipients of a living donor or previous deceased kidney alone transplant. Although maintenance immunosuppressive therapy is not significantly changed after the addition of a pancreas, a temporary booster in immunosuppressive therapy and an increase in the dose of calcineurin inhibitor (CNI) are required after PAK transplantation. The latter has been implicated in the observed variable decline in kidney allograft function. We herein report two cases of kidney allograft dysfunction following PAK transplant due to biopsy-proven transplant, thrombotic microangiopathy (TMA). Whether PAK transplantation pre-disposes a subset of patients to the development of post-transplant TMA is not known. Diagnostic kidney biopsies should be considered in PAK transplant recipients with worsening kidney allograft function.     

Partial venous thrombosis of the pancreatic allografts after simultaneous pancreas-kidney transplantation

Despite new advances in transplantation, complete venous thrombosis (VT) of the pancreas after simultaneous pancreas kidney (SPK) transplantation usually results in graft loss. Data are limited regarding the outcome and treatment of partial VT of the pancreas allograft. From July 1994 to December 1999, 126 patients with IDDM/end-stage renal disease underwent SPK with systemic bladder drainage at the University of Miami. We retrospectively reviewed our experience regarding the outcome and treatment options of partial VT of the pancreas allografts. From July 1994 to April 1997, partial VT was not seen in the first 66 SPK patients induced with anti-CD3 rnAb and oral or intravenous (i.v.) tacrolimus (TAC) in the operating room. From May 1997 to June 1999, 14 (29%) out of 48 patients had VT. These cases were identified following the i.v. use of TAC with anti-IL-2R antibody-induction therapy (7/15) or without (7/33). Partial thrombosis of the splenic vein (PTSV) was documented in 10 patients, 2 had complete thrombosis of the splenic vein (CTSV), 1 had partial thrombosis of the superior mesenteric vein (PTSMV), and 1 patient had PTSV and PTSMV. These were identified incidentally during routine color Doppler ultrasonography (CDU). None of these SPK recipients demonstrates a change in clinical parameters. The first 8 patients were systemically heparinized, followed by oral anticoagulation, except 1 patient with CTSV. He progressed to complete thrombosis of the pancreas allograft and was treated with percutaneous thrombectomy and urokinase infusion, followed by heparinization and oral anticoagulation. One patient required exploration for bleeding. In an attempt to reduce the morbidity of heparinization, we treated the next 6 patients with PTSV with aspirin followed by serial CDU. All 14 patients had preservation of the endocrine and exocrine pancreatic functions. CDU showed resolution with recanalization of the thrombosed vein(s). From July 1999 to December 1999, 12 SPK recipients were administered TAC orally with or without induction therapy with anti-IL-2R antibody. So far, in this group, VT has not been identified. In summary, a total of 14 out of 126 patients (11%) had isolated VT with a mean follow-up of 36.4 months. Based on our experience, we suggest that extensive VT after pancreas transplantation, including splenic and superior mesenteric VT, be treated with heparin and subsequent oral anticoagulation for 3 months. For more limited, partial splenic VT, aspirin may be sufficient. Follow-up CDU is critical for a successful outcome. The i.v. use of TAC appears to be a risk factor for the increased incidence of VT. Currently, using IL-2rmAb as induction, TAC is started orally on postoperative days 3 or 4 and aspirin on postoperative day 2.     

Post renal transplant thrombotic microangiopathy: A single centre experience

SUMMARY: Thrombotic microangiopathy (TMA) is a rare complication of renal transplantation. This study is a review of our experience of seven cases of TMA occurring between 1986 and 1995, an incidence of 0.8%. One patient had a recurrence of TMA in her graft having an episode of haemolytic uraemic syndrome as the cause of her original kidney failure. the other six patients had a rejection episode either at the time of diagnosis of TMA or a mean of 12 days prior to the diagnosis of TMA. All patients were treated with plasma exchange and those on cyclosporin had their dose reduced. Two patients had graft loss while the remainder had successful outcomes with stable graft function 3–11 years post diagnosis of TMA. We conclude that, in our experience rejection played a prominent role in the disease pathogenesis and that cyclosporin could be continued successfully albeit at a reduced dosage.     

Heparin-induced thrombocytopenia antibody and the pathogenesis of thrombotic microangiopathy after stem cell transplantation

Thrombotic microangiopathy (TMA) that occurs after stem cell transplantation (SCT) is generally regarded as being different from thrombotic thrombocytopenic purpura (TTP), because it is reportedly not associated with deficiency of von Willebrand factor-cleaving protease, whereas this enzyme is deficient in TTP. However, better understanding of the pathogenesis of this condition is still required. Accordingly, we investigated the relationship between TMA occurring after SCT and heparin-induced thrombocytopenia (HIT), a condition related to low-dosed heparin therapy that features thrombocytopenia and generalized thrombotic disorders. Thirty-nine consecutive patients who underwent bone marrow transplantation were divided into a TMA group and a non-microangiopathy group (10 and 29 patients, respectively). Before SCT, the serum platelet factor 4 (PF4) levels of the TMA and non-microangiopathy groups were 0.123 +/- 0.023 and 0.132 +/- 0.025, respectively (p = NS). One week after recovery of the white blood cell count following transplantation, the TMA group (0.2902 +/- 0.0678) had a significantly higher PF4 level than the non-microangiopathy group (0.1548 +/- 0.0312) (p < 0.001, t-test). Thus, PF4 increased after engraftment of the transplanted stem cells in the patients who developed TMA. In patients who developed TMA, there was a significant correlation between the PF4 level and the grade of angiopathy according to the Zeigler grading system (p < 0.01 by linear regression analysis). These results suggest that a HIT antibody produced by donor cells may be involved in the development of TMA after SCT.     

胰肾联合移植的排斥反应

目的　探讨胰肾联合移植术后的排斥反应。方法　对我院施行的 3例胰肾联合移植的病人 ,采用FK5 0 6 MMF Perid Zenapax四联免疫治疗方案 ,通过床边彩超及Cr、BUN、血糖等来监测移植物的排斥反应。对排斥反应采用激素冲击疗法 ,对激素不敏感者采用OKT3治疗。结果　3例患者中有 2例出现排斥反应 ,其发生率达 6 6 % ;在出现排斥反应时 ,首先表现为低热、全身不适 ,尿量减少 ,血Cr、BUN升高 ,彩超示移植物血流阻抗升高 ,之后才是血糖升高。结论　胰肾联合移植中 ,排斥反应与多种因素有关 ,移植肾对移植胰具有保护作用 ,肾脏可以作为监测胰腺排异的窗口 ,彩超检查可以作为筛选移植物排异反应的手段。     

Thrombotic microangiopathy and graft arteriopathy in pig hearts following transplantation into baboons

BACKGROUND: Acute humoral xenograft rejection (AHXR) is an immunologic barrier in pig-to-baboon organ transplantation (Tx). We report microvascular thrombosis and myocardial necrosis in a series of cardiac xenografts. METHODS: Ten baboons underwent heterotopic heart Tx from pigs transgenic for human decay-accelerating factor. Recipients were treated with soluble Gal glycoconjugates and multiple immunosuppressive agents. Grafts were removed when palpable contractions stopped. Stained tissue sections from harvested grafts were analyzed by light and fluorescence microscopy. RESULTS: Xenograft survival ranged from 4 to 139 (mean 37, median 27) days. Some histology was typical for AHXR (n = 4; median survival 22 days). Hemorrhage and edema were only focal in the longer-surviving grafts (n = 4, median survival 54 days). All grafts had multiple platelet-rich fibrin thrombi occluding myocardial vessels. Ischemic damage was manifested by contraction band necrosis in four grafts, myocytolysis in eight, coagulative necrosis in nine, and patchy myocyte dropout in all grafts. A notable paucity of interstitial mononuclear cells was observed in all grafts. Marked intimal thickening resembling that of allograft vasculopathy was observed in one graft. Immunofluorescence showed immunoglobulin (Ig)G and/or IgM deposition in five grafts. Multivessel C4d deposition appeared in seven grafts. Significant C3 deposition was absent. CONCLUSIONS: Cardiac xenograft survival in the pig-to-baboon model can be significantly prolonged by vigorous immunosuppressive treatment of recipient animals. Additional efforts to block humoral activation of graft endothelial cells and/or to overcome species-specific molecular coagulation pathway incompatibilities may prevent the development of microvascular thrombosis and myocardial infarction. Cardiac xenograft vasculopathy (chronic rejection) can occur with prolonged graft survival.     

Thrombotic microangiopathy after kidney transplantation

Two forms of post-transplant thrombotic microangiopathy (TMA) may be recognized: recurrent TMA and de novo TMA. Recurrent TMA may occur in patients who developed a nondiarrhoeal form of haemolytic uraemic syndrome (HUS) being particularly frequent in patients with autosomal recessive or dominant HUS. The recurrence is almost the rule in patients with mutation in complement factor H gene. Most patients eventually lose the graft. Treatment with plasma infusions or plasmapheresis is often disappointing, but few cases may be rescued. Intravenous immunoglobulins and rituximab have also been successful in anedoctic cases. De novo TMA is rarer. A number of factors including viral infection may be responsible of de novo TMA, but in most cases TMA is triggered by calcineurin inhibitors or mTOR inhibitors. The clinical presentation of de novo TMA may be variable with some patients showing clinical and laboratory features of HUS while others showing only a progressive renal failure. The prognosis is less severe than with recurrent TMA. Complete withdrawal of the offending drug may lead to improvement in many cases. The addition of plasma exchange may result in graft salvage in about 80% of cases.     

Thrombotic Microangiopathy After Kidney Transplantation

Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation that often causes graft failure. TMA may occur de novo, often triggered by immunosuppressive drugs and acute antibody‐mediated rejection, or recur in patients with previous history of hemolytic uremic syndrome (HUS). Recurrent TMA is very rare in patients who had developed end‐stage renal failure following HUS caused by Shiga‐toxin producing E. scherichia coli, whereas disease recurrence is common in patients with atypical HUS (aHUS). The underlying genetic defect greatly impacts the risk of posttransplant recurrence in aHUS. Indeed recurrence is almost the rule in patients with mutations in genes encoding factor H or factor I, whereas patients with a mutation in membrane‐cofactor‐protein gene have a good transplant outcome. Prophylactic and therapeutic options for posttransplant TMA, including plasma therapy, combined kidney and liver transplantation and targeted complement inhibitors are discussed in this review.     

Thrombotic microangiopathy associated with unusual viral sequences in HIV-1-positive patients

Background. Thrombotic microangiopathy (TMA) is a rare disordercaused by endothelial cell damage. TMA has been associated withthe human immunodeficiency virus 1 (HIV-1) infection, yet onlya minority of all HIV-1 patients develops TMA. Since HIV-1 hasbeen shown to interact with endothelial cells, we investigatedwhether certain mutations in the HIV-1 envelope protein areassociated with the development of TMA in HIV-1-infected patients. Methods. Plasma was obtained from nine HIV-1-positive patientswith TMA. Viral loads were determined from the samples and comparedwith the clinical data. Viral envelope protein sequences fromthe regions known to be responsible for viral tropism were isolated,sequenced and compared with known HIV-1 isolates. The isolateswere expressed as synthetic fusion proteins; binding of thesefusion proteins to CD4+ cells as well as to endothelial celllines was investigated. Results. The viral loads in patients with HIV/TMA were highlyvariable with no correlation to the clinical status. Most patientscarried macrophage-tropic viral envelope protein sequences andan unusual insertion was found in the V2 variable region. Theisolates showed increased CD4 binding, but a direct bindingto endothelial cells was not observed. Conclusions. Although TMA is generally diagnosed in patientswith advanced HIV-1 infection, viral loads per se were not predictiveof TMA in this study. While a direct interaction with endothelialcells was not detectable, specific viral envelope mutationswere found in a region known to influence viral tropism. Hence,viral-specific factors might contribute to the pathogenesisof HIV-associated TMA.     

Successful conversion to belatacept after thrombotic microangiopathy in kidney transplant patients

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.     

Thrombotic microangiopathy developing in early stage after renal transplantation with a high trough level of tacrolimus

Thrombotic microangiopathy (TMA) is characterized clinically by hemolytic anemia, thrombocytopenia, and renal failure. Cyclosporine (CyA)-associated TMA is a well-documented complication, but tacrolimus (TAC)-associated TMA is rare. We report the case of a renal transplant recipient who developed TMA in the early stage after renal transplantation with a high trough level of TAC. A 56-year-old female suffering from end-stage renal disease received a living renal graft from a blood-type-identical donor. She had developed hemolytic anemia, thrombocytopenia and acute renal failure 4 days after transplantation (6 days after TAC administration). She was diagnosed as having TMA without rejection by the clinical course and pathological findings. Renal function and hemolytic parameters improved by solely a decrease of the TAC trough level. When TAC-associated TMA develops in renal transplant recipients, we recommend a decrease of the TAC trough level before changing to CyA.     

胰肾联合移植术后死亡原因分析

目的分析肠道引流式胰肾联合移植术后死亡原因。方法回顾分析我院2001年5月至2006年10月开展的10例胰肾联合移植治疗终末期糖尿病并发尿毒症患者的临床资料，分析胰肾联合移植术后死亡的原因。结果3例胰肾联合移植术后死亡，其中2例死于肺部感染，1例死于缺血坏死性胰腺炎。结论胰肾联合移植术风险较大，肺部感染、缺血坏死性胰腺炎是术后死亡的主要原因。     

Thrombotic microangiopathy associated with alpha-interferon therapy for chronic myeloid leukaemia

The association of interferon (IFN) therapy with haemolytic uraemic syndrome in patients with chronic myeloid leukaemia (CML) has been reported infrequently. The pathogenesis of the renal lesion in such cases remains unclear. We report the case of a patient with chronic myeloid leukaemia who developed nephrotic syndrome and renal failure while being treated with hydroxyurea and IFN-alpha. Renal biopsy showed features of chronic thrombotic microangiopathy. The discontinuation of IFN-alpha, and a prompt institution of plasmapheresis and steroids resulted in improvement of the nephrotic syndrome and renal function. These findings suggest that long-term IFN-alpha therapy can induce thrombotic microangiopathy and haemolytic uraemic syndrome in patients with chronic myeloid leukaemia.     

Cyclosporine withdrawal in post-renal transplant thrombotic microangiopathy

INTRODUCTION: Thrombotic microangiopathy (TMA) is a well known complication of cyclosporine (CsA)-treated renal transplantation but optimum treatment strategies are not clearly defined. PATIENTS AND METHODS: All patients transplanted between January 1996 and December 2001 at our center who had biopsy-proven TMA and in whom CsA was withdrawn were studied retrospectively. RESULTS: The TMA was found in nine of 688 patients (1.3%). All except one donor were living related. HLA matching was one haplotype in all except one where both haplotypes were different. There were five males and four females and the mean age was 24.9 +/- 9 yr. All of them developed TMA within 3 months of transplant. Five of nine had evidence of microangiopathic hemolysis on peripheral film. Serum creatinine at the time of diagnosis of TMA was 3.1 +/- 1.3 mg/dL. Cyclosporine was discontinued in all and mycophenolate mofetil was substituted for azathioprine. No episode of acute rejection occurred after CsA withdrawal. Graft function did not improve in four who eventually became dialysis-dependent after a mean duration of 12.6 +/- 8.3 months. Remaining patients showed stabilization or improvement in function and all had serum creatinine below 2 mg/dL after a mean follow up of 24 months. CONCLUSION: The CsA withdrawal in cases with TMA at a stage when significant functional deterioration has not taken place can salvage the graft.     

胰肾联合移植术后排斥反应分析

目的 探讨预防和逆转胰肾联合移植术后排斥反应的方法。方法 回顾性分析1999年9月～2003年9月17例同种异体胰肾联合移植手术患者的临床资料。全部病例采用口服免疫抑制剂：环孢素A、霉酚酸酯或硫唑嘌呤、激素三联用药。其中2例术前及术后第5天应用抗IL-2R单克隆抗体,3例应用OKT3进行免疫诱导。结果 17例患者中1例发生移植胰腺、肾脏加速性排斥反应．经保守治疗无效,切除移植物;8例发生急性排斥反应,其中单纯肾脏排斥反应6例,同时累及胰腺、肾脏的排斥反应2例,经甲泼尼龙或OKT3治疗后均逆转。结论 胰肾联合移植术后合理应用免疫抑制剂。术前采用综合措施降低高危受者的致敏性,是预防和治疗排斥反应的有效方法。     

Thrombotic microangiopathy after lung transplantation

BACKGROUND: Thrombotic microangiopathy (TMA) is a well-recognized complication after transplantation. The purpose of this study was to describe our center's experience with this complication after lung transplantation. METHODS: We retrospectively reviewed cases of TMA among patients who underwent lung transplantation between January 1, 1999 and December 31, 2003 (n = 257). The cases were characterized and the outcomes were analyzed. Univariate and multivariate Cox regression models were constructed to identify potential risk factors for TMA. RESULTS: Twenty-four cases of TMA developed in 20 recipients. Thirteen cases occurred in the setting of another illness and 11 cases were isolated complications. Multivariate Cox regression models identified female gender, history of TMA, and the immunosuppressive regimen as independent predictors of TMA. Maintenance immunosuppression with the combination of a calcineurin inhibitor and sirolimus carried a significantly higher risk of TMA than a calcineurin inhibitor alone. After the diagnosis of TMA, calcineurin inhibitors were stopped in 18 cases; however, in 6 cases in which the onset of TMA coincided with the addition of sirolimus to a calcineurin inhibitor, only sirolimus was discontinued. Plasmapheresis was performed for severe cases (n = 10). TMA remitted in all cases, and an alternate calcineurin inhibitor was introduced in 14 cases. TMA recurred in 4 recipients, a median 253 days after the initial episode. The median survival after the onset of TMA was 377 days. CONCLUSION: TMA is a serious complication after lung transplantation, and the risk is highest when sirolimus is used in combination with a calcineurin inhibitor.