sirolimus and Hemolytic-Uremic-Syndrome

Pulmonary alveolar proteinosis (PAP) has been associated with the immunosuppressant sirolimus in transplant patients. PAP is a progressive lung disease characterized by the accumulation of surfactant-like material in the lungs leading to decreased pulmonary function with shortness of breath and cough as common symptoms. We report a rare case of sirolimus-associated PAP in a kidney transplant recipient with a history of end-stage renal disease secondary to haemolytic uraemic syndrome (HUS) and review of the literature. Discontinuation of sirolimus and initiation of tacrolimus led to resolution of PAP without recurrence of HUS.

Topics: Female; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pulmonary Alveolar Proteinosis; Recurrence; Sirolimus; Tacrolimus

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Administration Schedule; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Postoperative Complications; Sirolimus

Acute and chronic nephrotoxicity frequently limits the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications. The clinical aspects, pathophysiology, and relevant pharmacology of current and future immunosuppressive drugs are reviewed in this paper. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented.

Topics: Acute Kidney Injury; Animals; Cyclosporins; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polyenes; Sirolimus; Tacrolimus

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.

Topics: Adult; Calcineurin Inhibitors; Cause of Death; Chronic Disease; Creatinine; Drug Therapy, Combination; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemolytic-Uremic Syndrome; Humans; Middle Aged; Patient Compliance; Prednisone; Recurrence; Sirolimus; Treatment Outcome

Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation.. The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy.. From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC+(cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC+(C2/100) was performed for patients exposed to mTORi.. Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n=19) and drug-related TMA (n=17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P=.006).. Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)]>12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.

Topics: Adult; Aged; Cyclosporine; Everolimus; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Sirolimus; Thrombotic Microangiopathies; TOR Serine-Threonine Kinases

Post-transplant haemolytic uraemic syndrome (HUS) is a rare but serious disease with a high mortality rate, when left untreated. Immunosuppressive drugs like calcineurin inhibitors as well as mammalian target of rapamycin inhibitors have been reported as causative agents for post-transplant HUS.. A retrospective observational study was performed in lung transplant recipients, who took part in an interventional study, in two centres. Haemoglobin, platelets, creatinine and lactate dehydrogenase levels were monitored during routine follow-up and patients with deteriorating kidney function were screened for post-transplant HUS. All cases of post-transplant HUS were identified by clinical and laboratory findings. Outcome was recorded until 6 months after diagnosis.. A total of 2188 visits in 512 lung transplant recipients (outpatients) were analysed. Out of those, 126 patients took part in an interventional study. In this study, 67 were switched to everolimus in combination with calcineurin inhibitors 4 weeks after transplantation, 59 patients remained on standard immunosuppression (calcineurin inhibitors, mycophenolate mofetil and prednisolone). Five cases of post-transplant HUS were identified in the everolimus group. None of the patients had evidence of gastrointestinal infection or preexisting renal disease. Post-transplant HUS was treated with therapeutic plasma exchange and methylprednisolone pulse therapy. Everolimus was discontinued in all five patients. This treatment regimen led to normalization of haemoglobin, platelets and improved renal function. Two patients developed end-stage renal failure and were maintained on haemodialysis. One patient died due to multiorgan failure. Improvement of renal function was seen in two patients. No further cases were recorded in patients without everolimus during the study period.. Our data should raise the awareness of post-transplant HUS in lung transplant recipients. Post-transplant HUS is a rare disease, but it is a serious cause of acute renal failure in lung transplant recipients treated with a combination of everolimus and calcineurin inhibitors.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Everolimus; Female; Follow-Up Studies; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Sirolimus; Survival Rate

Topics: Cyclosporine; Heart Transplantation; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus

Hemolytic uremic syndrome (HUS) is a rare complication following solid organ transplantation. We report on a patient who underwent renal transplantation using Campath-1H induction and tacrolimus maintenance therapy who developed HUS, which was managed by plasma exchange and switch to Rapamycin. However, graft function could not be restored.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Plasma Exchange; Sirolimus; Tacrolimus

A 34-year old male renal transplant recipient developed thrombotic microangiopathy (Hemolytic Uremic Syndrome) in the early post-transplant period following combined immuno-suppressive therapy with tacrolimus and everolimus. The management consisted of discontinuation of tacrolimus and substitution with mycophenolate mofetil. His renal functions improved, the hematological abnormalities reversed and he continues to have good graft function one year later.

Topics: Adult; Biopsy; Drug Therapy, Combination; Everolimus; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Prodrugs; Sirolimus; Tacrolimus

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.

Topics: Adolescent; Adult; Cohort Studies; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Retrospective Studies; Sirolimus; Transplantation Conditioning; Transplantation, Homologous

Among the numeruos adverse side effects of tacrolimus (TAC), de novo thrombotic microangiopathy stands out as an infrecuente but severe complication. Renal dysfunction is the only alteration that should lead to suspicion of thrombotic microangiopathy, because the clinical features of intravascular hemolysis are not always found. The definitive diagnosis can usually be made with kidney biopsy. Patientes with TAC induced thrombotic microangiopathy usually promptly recover after treatment withdrawal or reduction in the dose of TAC and a short course of plasma therapy, but the risk of rejection increases. Switching from TAC to cyclosporine has also been tried with resolution of the hemolysis but thrombotic microangiopathy has been noted with both and this condition may later recur. We present a 29-year-old man who received a kidney-pancreas transplant for end-stage diabetic nephropathy. After initial induction with basiliximab, the immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil. Twenty four days posttransplantation his renal function declined with a peak creatine level of 2.35 mg/dl. Laboratory studies showed thrombocytopenia and features of intravascular hemolysis. TAC associated hemolytic uremic syndrome was suspected and drug was immediately stopped and converted to sirolimus. Also he was treated with plasma infusion. The allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection. Our experience demostrate that switching from tacrolimus to sirolimus could be an adecuate strategy for patients who develop FK506-associated de novo thrombotic microangiopathy without increase risk of acute rejection.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Duodenostomy; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Jejunostomy; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Mycophenolic Acid; Pancreas Transplantation; Pancreatic Fistula; Plasma; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

We sought to examine factors that predisposed 1.5% (10/672) of renal transplant recipients treated with a cyclosporine (CsA)/sirolimus (SRL)/steroid immunosuppressive regimen to develop hemolytic uremic syndrome (HUS).. Two cohorts of recipients were treated for 1-212 months (mean: 25.0+/-26.4, median: 18.1) with concentration-control CsA regimens based upon either area under the concentration-time curve (AUC; n=412 patients) or trough measurements (C0; n=260 patients).. The only demographic feature more common to affected patients was an original glomerulopathic disease in 7 patients, 4 of whom had displayed IgA glomerulonephritis. All 10 affected patients showed a clinical picture of hemolysis with schistocytes, thrombocytopenia (nadir: 35,000+/-19,600 platelets/mm3), as well as elevated serum levels of lactate dehydrogenase (1697+/-1427 IU) and creatinine (Scr; 2.05+/-1.52 mg/dL prediagnosis to 5.13+/-2.43 mg/dL at diagnosis). Seven patients experienced adverse events concomitant with the bout of HUS, namely, acute rejection episodes prior to (n=2) or during (n=3), and 2 patients, infections (Herpes simplex and pancolitis). The mean values of daily steroid dose and the immunosuppressive drug C0 values were above the putative therapeutic targets: namely, CsA C0=294.9+/-153.2 ng/ml versus 150+/-50 ng/ml and SRL C0=20.1+/-14.0 ng/ml versus 10+/-5 ng/ml, respectively. The therapeutic approach included discontinuation of CsA in 9/10, which was transient in 6/9; discontinuation of SRL in all 10, which was transient in 3, OKT3 for concurrent rejection in 3, and plasmapheresis in 5 patients. At 24 weeks postdiagnosis 9/10 patients have well-functioning kidneys with a mean Scr value of 1.6+/-0.59 mg/dL. One patient who underwent transplant nephrectomy subsequently succumbed due to a cluster of refractory thrombocytopenia, Aspergillus infection, and multiorgan failure.. This initial experience suggests that a time-limited and reversible de novo HUS syndrome may be less frequent and milder among renal transplant recipients treated with SRL-based immunosuppression.

Topics: Adult; Cyclosporine; Drug Therapy, Combination; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus

Topics: Adult; Cytomegalovirus Infections; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Sirolimus; Tacrolimus