tacrolimus and Thrombotic-Microangiopathies

Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare entity with no standard of care and high mortality, despite the use of plasma exchange.. Using specific search terms, all cases having TA-TMA treated with eculizumab and indexed in MEDLINE (English language only) by November 2014 were reviewed.. A total of 26 cases, 53% men, had a median age of 33 years (range 2-61). Transplant-associated thrombotic microangiopathy occurred after stem-cell transplant (35%) or solid-organ transplant (65%), frequently associated with the use of cyclosporine or tacrolimus (96%). A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) level was always >10%. After TA-TMA diagnosis, the following drug adjustments were made: discontinuation of cyclosporine or tacrolimus in 45%, dose reduction in another 27%, continuation of the drugs in 23%, and switch from cyclosporine to tacrolimus in remaining 5%. Plasma exchange was performed in ∼43%. The median interval between transplant and initiation of eculizumab was 63 days (range 11-512). A median of 5.5 doses (range 2-21) of eculizumab was utilized with 92% response occurring after a median of 2 doses (range 1-18). At a median follow-up of 52 weeks (range 3-113), the survivors (92%) were doing well.. Within the limits of this retrospective analysis, our study demonstrates that eculizumab use may result in high response rate and 1-year survival in patients with TA-TMA refractory to discontinuation of calcineurin inhibitor and plasma exchange.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Cyclosporine; Female; Humans; Male; Middle Aged; Organ Transplantation; Plasma Exchange; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Tacrolimus; Thrombotic Microangiopathies; Transplantation; Young Adult

Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5-3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus-induced TMA. We identified four patients with tacrolimus-induced TMA post-OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post-partum thrombotic thrombocytopenic purpura) and hepatitis C virus-related cirrhosis. All patients had tacrolimus post-OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post-TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes.

Topics: Adult; Cohort Studies; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Thrombotic Microangiopathies; Young Adult

Transplant-associated thrombotic microangiopathy (TMA) syndromes are reported to occur with increased frequency in transplant patients treated with siroliumus combined with a calcineurin inhibitor. We performed a retrospective study of all pediatric transplant patients at City of Hope who were administered combined tacrolimus/sirolimus (TAC/SIR) to determine the occurrence of TMA.. This analysis includes 41 consecutive patients between the ages of 2 and 20 (median age 9.1) who received an allogeneic hematopoietic stem cell transplant from any source and also received TAC/SIR for prevention or treatment of GVHD. Of those 41 patients, 20 received TAC/SIR as GVHD prohpylaxis and were designated the preventative group (PG), while 21 received TAC/SIR as treatment for GVHD and were designated the therapy group (TG). TMA occurrence in both groups was documented from day -1 of transplant to day 60 for the PG, and until 30 days after last dose for the TG. TMA was defined according to 2005 consensus criteria.. Five of twenty patients in the PG, and five of twenty one in the TG, experienced TMA, with an overall rate of 23.8% for the population. All ten patients with TMA showed elevated levels of TAC, SIR or both and nine of ten suffered from organ injury due to regimen-related toxicity or GVHD.. Physicians should exercise caution in the use of TAC/SIR in pediatric patients due to a high rate of TMA. It is not recommended for heavily pre-treated patients and peak levels of TAC/SIR must be very carefully controlled.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Time Factors; Transplantation, Homologous

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.

Topics: Adolescent; Adult; Busulfan; Child; Cyclophosphamide; Etoposide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Pilot Projects; Radiation Dosage; Siblings; Sirolimus; Survival Analysis; Tacrolimus; Thrombotic Microangiopathies; Tissue Donors; Transplantation Conditioning; Vidarabine; Young Adult

Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Risk Factors; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Transplantation Conditioning

This report highlights the association of tacrolimus use with acute macular neuroretinopathy (AMN). A 27-year-old woman, a known case of diffuse proliferative membranous glomerulonephritis, developed abnormal body movements, loss of consciousness, and blurring of vision in the left eye, after 3 months of starting tacrolimus. Blood investigations revealed anemia, thrombocytopenia, raised urea and creatinine levels, and raised LDH levels. A diagnosis of tacrolimus induced hemolytic uremic syndrome (HUS) with posterior reversible encephalopathy syndrome (PRES) was made. Ocular examination revealed a reddish-brown petaloid retinal lesion, which was better appreciated on red-free imaging as dark grey area pointing towards the fovea. OCT-A and SD-OCT revealed flow voids in deep retinal plexus, and disruption of ellipsoid and interdigitation zone, respectively, findings consistent with AMN. To the best of our knowledge, it is the first report of association of tacrolimus with AMN.

Topics: Adult; Female; Humans; Posterior Leukoencephalopathy Syndrome; Retina; Retinal Diseases; Tacrolimus; Thrombotic Microangiopathies; White Dot Syndromes

Topics: Humans; Immunosuppressive Agents; Infant; Liver Failure, Acute; Liver Transplantation; Tacrolimus; Thrombotic Microangiopathies

To investigate the clinical features of thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation in children.. A retrospective analysis of continuous clinical data from HSCT received in the Department of Hematology and Oncology of Wuhan Children's Hospital from August 1, 2016 to December 31, 2021.. During this period, 209 patients received allo-HSCT in our department, 20 (9.6%) of whom developed TA-TMA. TA-TMA was diagnosed at a median of 94 (7-289) days post-HSCT. Eleven (55%) patients had early TA-TMA within 100 days post-HSCT, while the other 9 (45%) patients had TA-TMA thereafter. The most common symptom of TA-TMA was ecchymosis (55%), while the main signs were refractory hypertension (90%) and multi-cavity effusion (35%). Five (25%) patients had central nervous system symptoms (convulsions and lethargy). All 20 patients had progressive thrombocytopenia, with 16 patients receiving transfusion of platelets that was ineffective. Ruptured red blood cells were visible in only two patients with peripheral blood smears. Cyclosporine A or Tacrolimus (CNI) dose was reduced once TA-TMA was diagnosed. Nineteen cases were treated with low-molecular-weight heparin, 17 patients received plasma exchange, and 12 patients were treated with rituximab. TA-TMA-related mortality percentage in this study was 45% (9/20).. Platelet decline and/or ineffective transfusion post-HSCT should be considered an early indicator of TA-TMA in pediatric patients. TA-TMA in pediatric patients may occur without evidence of peripheral blood schistocytes. Aggressive treatment is required once diagnosis is confirmed, but the long-term prognosis is poor.

Topics: Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Tacrolimus; Thrombotic Microangiopathies

Atypical hemolytic uremic syndrome (aHUS) is a genetic-based thrombotic microangiopathy (TMA) that is mediated by the activation of the alternative complement pathway. Heterozygous deletion in CFHR3-CFHR1 occurs in 30% of the general population and has not been classically linked to aHUS. Post-transplant aHUS has been associated with a high rate of graft loss. Herein, we report our case series of patients who developed aHUS after solid-organ transplantation.. Five consecutive cases of post-transplant aHUS were identified at our center. Genetic testing was performed in all but one.. One patient had a presumed TMA diagnosis before transplant. One heart and 4 kidney (KTx) transplant recipients were diagnosed with aHUS based on the clinical picture of TMA, acute kidney injury, and normal ADAMTS13 activity. Genetic mutation testing revealed heterozygous deletion in CFHR3-CFHR1 in 2 patients and a heterozygous complement factor I (CFI) variant of uncertain clinical significance (VUCS) (Ile416Leu) in a third. Four patients were on tacrolimus, 1 had anti-HLA-A68 donor-specific antibody (DSA), and another had borderline acute cellular rejection at the time of aHUS diagnosis. Four responded to eculizumab, and 1 out of 2 patients came off renal replacement therapy. One KTx recipient died from severe bowel necrosis in the setting of early post-transplant aHUS.. Calcineurin inhibitors, rejection, DSA, infections, surgery, and ischemia-reperfusion injury are common triggers that could unmask aHUS in solid-organ transplant recipients. Heterozygous deletion in CFHR3-CFHR1 and CFI VUCS may be important susceptibility factors acting as the first hit for alternative complement pathway dysregulation.

Topics: Antilymphocyte Serum; Atypical Hemolytic Uremic Syndrome; Humans; Kidney Transplantation; Mutation; Tacrolimus; Thrombotic Microangiopathies

Tacrolimus (TAC) is essential for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HSCT). We have sometimes observed large fluctuations in TAC concentration. However, links between the variability in the concentration or the concentration/dose (C/D) ratio of TAC and clinical complications remain ambiguous. To clarify relationships between various parameters of TAC and early complications such as pre-engraftment immune reactions/engraftment syndrome, aGVHD, and transplant-associated thrombotic microangiopathy (TA-TMA), a total of 146 patients who underwent allo-HSCT were included. Intrapatient variabilities in the concentration and C/D ratio of TAC were estimated by intrapatient mean absolute deviation (iMAD). The mean concentration and C/D ratio of TAC were not significantly different between with and without complications. A strong association was observed between greater iMAD for TAC C/D ratio from days 15 to 21 and the development of TA-TMA. iMAD values for TAC C/D ratio of 11.4 or greater was a risk factor for TA-TMA and the cumulative incidence of nonrelapse mortality (NRM) was significantly higher in patients with iMAD values for TAC C/D ratio of 11.4 or greater. Intrapatient variability in the C/D ratio of TAC was associated with the incidence of TA-TMA and NRM and might be useful for predicting TA-TMA.

Topics: Acute Disease; Adolescent; Adult; Aged; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Tacrolimus; Thrombotic Microangiopathies; Transplantation, Homologous; Young Adult

The differential diagnosis of thrombotic microangiopathy (TMA) in pregnancy includes common conditions, such as preeclampsia. In women with kidney transplantation, additional causes of TMA must be considered.. A 22-year-old primigravid woman with a transplanted kidney presented with fetal growth restriction, hypertension, acute kidney injury, and hemolysis at 28 weeks gestation. While her clinical presentation was initially consistent with preeclampsia, hemolysis persisted beyond 1 week postpartum. Diagnoses of TMA associated with tacrolimus and antibody-mediated rejection were considered. An elevated tacrolimus level likely contributed to her TMA and a decrease in dosage improved her clinical picture and laboratory markers.. We report the case of a pregnant kidney transplant recipient with TMA. A multidisciplinary approach is required to optimize the maternal health outcomes in this complex population.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Pregnancy; Pregnant Women; Tacrolimus; Thrombotic Microangiopathies; Young Adult

Coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality worldwide in both the general population and kidney transplant recipients. Acute kidney injury is a known complication of COVID-19 and appears to most commonly manifest as acute tubular injury on renal biopsy. Coagulopathy associated with COVID-19 is a known but poorly understood complication that has been reported to cause thrombotic microangiopathy on rare occasions in native kidneys of patients with COVID-19. Here, we report the first case of biopsy-proven thrombotic microangiopathy in a kidney transplant recipient with COVID-19 who developed acute pancreatitis and clinical features of microangiopathic hemolytic anemia. The patient recovered with supportive care alone.

Topics: COVID-19; Creatinine; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreatitis; Platelet Count; SARS-CoV-2; Tacrolimus; Thrombotic Microangiopathies; Transplantation, Homologous

In the past, conventional treatment strategies for transplant-associated thrombotic microangiopathy (TA-TMA) have not proven to be very effective. Recently, eculizumab which is a humanized monoclonal antibody that works as a terminal complement inhibitor has demonstrated promise in the treatment landscape of TA-TMA.. This was a single-center retrospective analysis of 20 consecutive adult patients with TA-TMA: 10 patients who received conventional therapy and 10 patients who received eculizumab-based therapy. These patients had undergone allogeneic HSCT at MD Anderson Cancer Center between August 2011 and September 2016.. When comparing the treatment outcomes in the two cohorts, none of the patients in the conventional therapy group obtained a hematologic or complete response according to our response criteria whereas seven patients in the eculizumab group achieved a hematologic response with one patient achieving a complete response with organ recovery. In addition, overall survival at the end of assessment was 60% in the eculizumab cohort and 30% in the conventional cohort. One major difference in practice at our institution versus previously published studies is the management of immunosuppression. In a majority of patients, tacrolimus was continued or transitioned to sirolimus for GVHD prophylaxis.. Response rates and survival were improved for patients who were transitioned to sirolimus, so a two-pronged approach of inhibiting complement along with providing an alternative effective immunosuppressive agent may be beneficial in the treatment of early onset TA-TMA.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Treatment Outcome; Young Adult

Thrombotic microangiopathy (TMA) is a pathologic condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to microvascular endothelial lesions and thrombosis. It occurs in a variety of diseases and, unless recognized and treated, leads to severe morbidity and mortality. We present the case of a 48-year-old woman who underwent lung transplantation, initially under tacrolimus, mycophenolate mofetil (MMF), and prednisolone. Several complications emerged in the following months, including abdominal aortic and left renal artery thrombosis and cutaneous infections, although her renal function remained normal. Six months after transplant, her renal function began to deteriorate, which was assumed to be due to elevated tacrolimus levels and doses were adjusted. Due to leukopenia, MMF was changed to everolimus. One year after, she was admitted with fatigue, anemia, and renal dysfunction. Complementary exams revealed only iron deficiency, leukopenia, normal platelets, and elevated lactate dehydrogenase; her renal ultrasound was normal. A renal biopsy was performed and thrombotic microangiopathy was subsequently identified as the main cause of the renal dysfunction. Tacrolimus was therefore discontinued and MMF restarted with slow improvement of renal function. Only when everolimus was stopped did the patient's renal function show incremental improvement. TMA may be a serious complication after lung transplantation and the risk is higher when a combination of tacrolimus and everolimus is used. Renal biopsy findings are essential to confirm the final diagnosis of TMA, allowing for a change in immunosuppression to prevent permanent and severe renal damage.

Topics: Everolimus; Female; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Lung Transplantation; Middle Aged; Mycophenolic Acid; Tacrolimus; Thrombotic Microangiopathies

Tacrolimus-associated thrombotic microangiopathy (TA-TMA) is a rare complication. TA-TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage due to thrombus. We report asymptomatic TA-TMA diagnosed by laboratory tests in pig-to-rhesus corneal xenotransplantation. Corneal transplantation had been conducted from a wild-type SNU miniature pig to a rhesus macaque. The veterinary records were retrospectively reviewed in this case. The immunosuppressive regimen consisted of rituximab, basiliximab, and IVIg as inductive therapies, and steroids with tacrolimus (0.1 mg/kg/day) as maintenance therapies. Although there were no clinical symptoms, increased levels of lactate dehydrogenase, total bilirubin, blood urea nitrogen, and creatinine and decreased levels of hemoglobin and platelet were observed in laboratory tests on Day (D) 61. Systemic TA-TMA was tentatively diagnosed. Tacrolimus was discontinued starting on D71. Dalteparin, clopidogrel bisulfate (D77-D99), and IVIg (D72) were administered as a conservative treatment. Abnormal laboratory results were reversed on D99. When low-dose tacrolimus (0.07 mg/kg/day) was re-administered on D131 to prevent rejection of the graft, TMA was detected again by laboratory tests on D161, confirming the initial diagnosis. Discontinuation of tacrolimus on D162 and re-administration of Dalteparin (D161-D196) corrected the laboratory values on D161. This report shows that in pig-to-rhesus corneal xenotransplantation, clinically asymptomatic TMA can be induced by tacrolimus, and the discontinuation of tacrolimus and administration of anticoagulant seems sufficient to correct the laboratory TMA.

Topics: Animals; Heterografts; Immunosuppressive Agents; Kidney Transplantation; Macaca mulatta; Male; Retrospective Studies; Swine; Tacrolimus; Thrombosis; Thrombotic Microangiopathies; Transplantation, Heterologous

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.. 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.. 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.. 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.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Drug-Related Side Effects and Adverse Reactions; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Organ Transplantation; Plasma Exchange; Retrospective Studies; Rituximab; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Treatment Outcome; Young Adult

  A 65-year-old woman with a 17-year history of polymyositis and 8-year history of rheumatoid arthritis who was treated with a low dose of prednisolone and tacrolimus (Tac) was admitted to our hospital because of general malaise and hypertension. Blood tests showed thrombocytopenia, hemolytic anemia with fragmented erythrocytes, and hypercreatinemia. Based on these clinical features, she was diagnosed with thrombotic micro-angiopathy (TMA). Thrombocytopenia and hemolytic anemia with fragmented erythrocytes improved with the discontinuation of Tac and plasma exchange; however, hypertension and renal dysfunction persisted. TMA due to calcineurin inhibitor (CNI) nephropathy was suspected based on the histopathological findings of renal biopsy. However, the condition was atypical of a CNI nephropathy because the trough level of Tac was lower than that reported previously and renal dysfunction persisted after drug discontinuation. She had mild sclerodactylia and Raynaud's symptoms, although the diagnostic criteria for systemic sclerosis (SSc) were not satisfied. Moreover, the patient tested positive for anti PL-7 antibody. The relationship between anti PL-7 antibody and pathogenesis of SSc has been reported. In this case, it was suspected that CNI nephropathy worsened because of the potential basic factors of SSc. These findings indicate that TMA may occur in patients testing positive for anti PL-7 antibody who are treated with Tac.

Topics: Aged; Amino Acyl-tRNA Synthetases; Arthritis, Rheumatoid; Autoantibodies; Biomarkers; Calcineurin Inhibitors; Female; Humans; Plasma Exchange; Polymyositis; Tacrolimus; Thrombotic Microangiopathies; Withholding Treatment

BACKGROUND Thrombotic microangiopathy (TMA) is a severe life-threatening complication associated with solid organ transplantation. We retrospectively investigated the incidence, risk factors, and appropriate treatment of TMA following adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The subjects were 129 adult patients who underwent LDLT in our department from 1997 to 2014. Patients with TMA were identified retrospectively based on diagnostic criteria. We calculated the incidence of TMA and performed a risk factor analysis for TMA occurrence. We also assessed our past treatments for TMA and sought to identify the most appropriate form of treatment. RESULTS Thirteen patients were identified as having TMA. The incidence of TMA in the study cohort was 10.1% but was especially high (37.9%) among ABO-incompatible cases. A univariate analysis revealed that ABO incompatibility, usage of tacrolimus, usage of rituximab, and cold ischemic time ≥50 minutes are risk factors for occurrence of TMA (p<0.10). Multivariate analysis demonstrated that ABO incompatibility was the only independent risk factor for TMA (p=0.009). Initiation of treatment on the day of TMA diagnosis was associated with better survival. CONCLUSIONS ABO incompatibility is an independent risk factor for TMA following adult LDLT. Our results suggest that early initiation of treatment is crucial for improving the outcomes.

Topics: ABO Blood-Group System; Adult; Aged; Blood Group Incompatibility; Female; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Rituximab; Tacrolimus; Thrombotic Microangiopathies; Young Adult

De novo thrombotic microangiopathy (TMA) following renal transplantation is a severe complication associated with high rates of allograft failure. Several immunosuppressive agents are associated with TMA. Conventional approaches to managing this entity, such as withdrawal of the offending agent and/or plasmapheresis, often offer limited help, with high rates of treatment failure and graft loss. We herein report a case of drug induced de novo TMA successfully treated using the C5a inhibitor eculizumab in a renal transplant patient. This report highlights a potentially important role for eculizumab in settings where drug-induced de novo TMA is refractory to conventional therapies.

Topics: Adult; Antibodies, Monoclonal, Humanized; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus; Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is a rare complication associated with the use of calcineurin inhibitors in lung transplantation, irrespective of the underlying disease of the graft recipient. It usually occurs in incomplete forms, complicating and delaying diagnosis until damage is already irreversible. It is unrelated to time from transplantation and often presents with concomitant infection, which tends to confound diagnosis. The cases discussed here have a common causative agent and all present with concomitant infection. Treatment recommendations have changed in recent years with the introduction of plasmapheresis or, more recently, the availability of the antibody eculizumab. Notwithstanding, the most cost-effective measure is withdrawal or switching of the calcineurin inhibitor. TMA is an underdiagnosed clinical entity that should be considered in the management of transplantation patients.

Topics: Abscess; Candida glabrata; Candidiasis; Creatinine; Disease Susceptibility; Drug Substitution; Erythrocytes, Abnormal; Everolimus; Female; Hemoglobins; Humans; Immunosuppressive Agents; L-Lactate Dehydrogenase; Lung Transplantation; Male; Middle Aged; Myositis; Nocardia Infections; Platelet Transfusion; Pneumonia; Postoperative Complications; Tacrolimus; Thrombotic Microangiopathies; Young Adult

Calcineurin inhibitor (CNI)-induced thrombotic microangiopathy (TMA) is a rare complication after renal transplantation. It may be difficult to distinguish from CNI toxicity and acute antibody-mediated rejection (AMR). Its clinical presentation may vary from isolated localised forms up to catastrophic systemic presentations.. We report a case of tacrolimus-induced TMA soon after renal transplantation in an 11-year-old boy who received his second renal transplantation. His first graft was lost because of AMR. On day 12 after his second renal transplantation, his renal function started worsening and a kidney biopsy was performed, which showed histopathological signs of TMA. The diagnosis of tacrolimus-induced TMA was established after excluding AMR and other causes of de novo TMA. Genetic complement investigation disclosed two complement factor H risk polymorphisms as possible modifiers of TMA emergence. Treatment was based on replacing tacrolimus with everolimus, with a subsequent normalisation of renal function.. A prompt diagnosis of de novo TMA by early allograft biopsy is essential for the allograft outcome and genetic investigations for possible complement abnormalities are reasonable, not only for patients with a systemic aspect of their post-transplant TMA. Replacing tacrolimus with everolimus effectively controlled the TMA and stabilised renal function in our patient.

Topics: Calcineurin Inhibitors; Child; Drug Substitution; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus; Thrombotic Microangiopathies

Topics: Adult; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Postoperative Complications; Tacrolimus; Thrombotic Microangiopathies

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n=68) or plus MTX (TAC/MTX)±ATG (n=34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX±ATG (7.4% vs 8.8%, P=0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC >25 ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (P<0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Methotrexate; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Transplantation, Homologous; Young Adult

Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ≥9.9 ng/mL (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.

Topics: Adolescent; Adult; Aged; Child; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Male; Middle Aged; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Young Adult

A 25-year-old woman with a history of bilateral lung transplant secondary to cystic fibrosis presented with non-specific abdominal complaints and was found to have acute kidney injury, thrombocytopaenia and laboratory findings consistent with a microangiopathic haemolytic anaemia. Her thrombotic microangiopathy (TMA) was attributed to tacrolimus, which was discontinued and replaced with cyclosporine with resolution of her TMA and no subsequent complications. This is the fifth reported case of TMA associated with tacrolimus use in a lung transplant patient, and the third to be successfully managed with cyclosporine substitution. Clinicians must be aware of this uncommon, but likely under-reported complication of tacrolimus therapy in lung transplant recipients. Cyclosporine replacement may be used as a successful therapy to treat tacrolimus-associated TMA without increasing the risk of acute rejection that may be associated with other treatment strategies.

Topics: Adult; Cystic Fibrosis; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Tacrolimus; Thrombotic Microangiopathies

TMA is a rare complication of tacrolimus. Disruption of endothelial cells, platelet aggregation, and intravascular mechanical fragmentation of red cells are core mechanisms of injury; however, exact pathways of toxicity are not clear. The clinical presentation may vary but TMA is a potentially life-threatening condition usually demanding aggressive treatment. We present the case of TMA in a child after living-related liver transplantation (LRLTx) on tacrolimus-based immunosuppressive regiment successfully converted to sirolimus.

Topics: Anemia, Hemolytic; Biopsy; Erythrocytes; Female; Graft Survival; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Platelet Aggregation; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Treatment Outcome

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.

Topics: Acute Disease; Aged; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Severity of Illness Index; Tacrolimus; Thrombotic Microangiopathies

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

Topics: Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methotrexate; Middle Aged; Retrospective Studies; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Thrombotic Microangiopathies; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Topics: Acute Disease; Antiviral Agents; Colon; Colonoscopy; DNA, Viral; Enzyme Inhibitors; Ganciclovir; Hepatitis B; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Thrombotic Microangiopathies

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.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prognosis; Tacrolimus; Thrombotic Microangiopathies

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.

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus; Thrombotic Microangiopathies