tacrolimus and Atypical-Hemolytic-Uremic-Syndrome

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

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic anemia, thrombocytopenia, and acute kidney injury. HUS is mostly associated with diarrhea (90%). However, 10% of cases are not associated with diarrhea and are thus called as atypical HUS (aHUS); these cases are usually caused by dysregulation of the complement system. Eculizumab, a monoclonal antibody against C5, is the drug of choice for treating aHUS. Herein we aimed to present 8 cases of renal transplantation performed on patients with aHUS.. A total of 8 patients who had been diagnosed with aHUS between the years 2012 to 2018 were enrolled and underwent transplantations. All patients received induction treatment, standard immunosuppresive treatment (tacrolimus, mycophenolic acid, prednisolone), and eculizumab. Eculizumab was administered at a dosage of 900 mg/wk for the first month and 1200 mg every 2 weeks thereafter. Patients were followed up and recorded in terms of demographic features, serum creatinine, lactate dehydrogenase, acute rejection episodes, and allograft outcomes.. Mean age was 34 ± 8 years (Male/Female: 6/2). One of the patients had a second transplantation. Median hemodialysis vintage (25%-75% interquartile range) was 37 (9-63) months. Four patients had pretransplant plasmapheresis and 2 patients had posttransplant plasmapheresis. Induction treatment was ATG in 7 patients, and basiliximab was used only in 1 patient. The median follow-up period was 25 (13-59) months. Mean serum creatinine levels were 1.9 ± .6, 1.2 ± .7, and 1 ± .1 mg/dL for the first day, first month, and last values, respectively. Mean lactate dehydrogenase levels were 286 ± 203, 239 ± 27, and 218 ± 86 U/L for first day, first month, and last values, respectively. None of the patients had an acute rejection episode. Currently, all patients have functioning allografts.. Patients with aHUS may be transplanted successfully with eculizumab with good allograft outcomes.

Topics: Adult; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Combined Modality Therapy; Complement Inactivating Agents; Creatinine; Female; Humans; Kidney Transplantation; Male; Mycophenolic Acid; Plasmapheresis; Postoperative Period; Prednisolone; Tacrolimus; Treatment Outcome

Atypical hemolytic uremic syndrome (aHUS) is a serious hematologic disorder with high mortality if left untreated. A comprehensive literature review revealed only two cases of aHUS post-heart transplantation. In both cases the disease developed after induction of calcineurin inhibitor therapy. We report a case of immediate post-heart transplantation aHUS, manifested before the induction of, and therefore not associated with, calcineurin inhibitors.

Topics: Aged; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Biomarkers; Calcineurin Inhibitors; Creatinine; Dialysis; Early Diagnosis; Female; Haptoglobins; Heart Transplantation; Humans; L-Lactate Dehydrogenase; Plasma Exchange; Platelet Count; Postoperative Complications; Tacrolimus; Time Factors; Treatment Outcome

Dysregulation of complement activation is the most common cause of the atypical haemolytic uraemic syndrome (aHUS). Many patients with aHUS develop end-stage renal disease and consider kidney transplantation. However, the recurrence rate after transplantation ranges from 45-90% in patients with known abnormalities in circulating complement proteins. It was recently proposed that patients with aHUS should be treated prophylactically with plasma exchange or eculizumab to prevent recurrence after transplantation.. A case series describing the successful outcome of kidney transplantation without prophylactic therapy in four adult patients with aHUS and a high risk of disease recurrence. Patients received a living donor kidney and immunosuppression consisting of basiliximab induction, low-dose tacrolimus, prednisone and mycophenolate mofetil. Patients received a statin, and were targeted to a low blood pressure preferably using blockers of the renin-angiotensin system.. After a follow-up of 16-21 months, none of the patients developed recurrent aHUS. Also, no rejection was observed.. Kidney transplantation in adult patients with aHUS can be successful without prophylactic eculizumab, using a protocol that minimises cold ischaemia time, reduces the risk of rejection and provides endothelial protection. Our data suggest that in patients with aHUS, controlled trials are needed to demonstrate the optimal strategy.

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Basiliximab; Cold Ischemia; Drug Therapy, Combination; Female; Hemolytic-Uremic Syndrome; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recombinant Fusion Proteins; Secondary Prevention; Tacrolimus; Young Adult

We report successful kidney transplantation in a 10-yr-old boy with aHUS and heterozygous factor H mutation using the terminal complement inhibitor eculizumab to avoid recurrence of aHUS in the renal graft. Vaccination against meningococcus C (Men C) is essential in patients with dysfunction of the complement system, as induced by eculizumab. In our patient, we report waning SBA titers but maintenance of protective SBA titers (≥1:8) after kidney transplantation under immunosuppressive therapy with mycophenolate mofetil, tacrolimus, steroids, and eculizumab over a 27-month observational period. Our case illustrates that a humoral immune response to conjugate Men C vaccination may be mounted and maintained despite chronic renal disease, kidney transplantation, immunosuppressive drugs, and immunomodulatory therapy with eculizumab. However, it remains unclear whether serologically defined protective SBA titers mediate true protection from invasive meningococcal disease in an immunocompromised patient, particularly under treatment with a complement inhibitor. Thus, close monitoring of SBA titers seems mandatory in this patient.

Topics: Antibodies; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Child; Complement Factor H; Complement Inactivating Agents; Hemolytic-Uremic Syndrome; Heterozygote; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Meningococcal Infections; Meningococcal Vaccines; Mutation; Mycophenolic Acid; Neisseria meningitidis; Peritoneal Dialysis; Recurrence; Renal Insufficiency; Steroids; Tacrolimus; Time Factors

A 33-year-old woman with a history of chronic transplant dysfunction because of repeated bouts of haemolytic uraemic syndrome (HUS) was considered for a second transplant. Extensive genetic investigation of the complement system was executed to rule out known mutations prone to development of HUS. This case illustrates the importance of genetic screening in patients with recurrent HUS.

Topics: Adult; Atypical Hemolytic Uremic Syndrome; Complement Factor H; Disease Progression; Female; Hemolytic-Uremic Syndrome; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Plasma Exchange; Reoperation; Tacrolimus; Unrelated Donors