Recurrent Hemolytic Uremic Syndrome Research Articles

Successful Use of Eculizumab for Prevention of Atypical Hemolytic Uremic Syndrome Recurrence in a Pregnant Kidney Transplant Recipient with CFH Gene Mutation: A Case Report and Literature Review

Successful Use of Eculizumab for Prevention of Atypical Hemolytic Uremic Syndrome Recurrence in a Pregnant Kidney Transplant Recipient with CFH Gene Mutation: A Case Report and Literature Review

Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future.

Atypical hemolytic uremic syndrome is a thrombotic microangiopathy characterized by hemolysis, thrombocytopenia, and acute kidney injury, usually caused by alternative complement system overactivation due to pathogenic genetic variants or antibodies to components or regulatory factors in this pathway. Previously, a lack of effective treatment for this condition was associated with mortality, end-stage kidney disease, and the risk of disease recurrence after kidney transplantation. Plasma therapy has been used for atypical hemolytic uremic syndrome treatment with inconsistent results. Complement-blocking treatment changed the outcome and prognosis of patients with atypical hemolytic uremic syndrome. Early administration of eculizumab, a monoclonal C5 antibody, leads to improvements in hematologic, kidney, and systemic manifestations in patients with atypical hemolytic uremic syndrome, even with apparent dialysis dependency. Pre- and post-transplant use of eculizumab is effective in the prevention of atypical hemolytic uremic syndrome recurrence. Evidence on eculizumab use in secondary hemolytic uremic syndrome cases is controversial. Recent data favor the restrictive use of eculizumab in carefully selected atypical hemolytic uremic syndrome cases, but close monitoring for relapse after drug discontinuation is emphasized. Prophylaxis for meningococcal infection is important. The long-acting C5 monoclonal antibody ravulizumab is now approved for atypical hemolytic uremic syndrome treatment, enabling a reduction in the dosing frequency and improving the quality of life in patients with atypical hemolytic uremic syndrome. New strategies for additional and novel complement blockage medications in atypical hemolytic uremic syndrome are under investigation.

Atypical Hemolytic Uremic Syndrome Precipitated by Recurrent Pancreatitis

Atypical hemolytic uremic syndrome presents with negative direct antiglobulin test microangiopathic hemolytic anemia, acute kidney injury, and thrombocytopenia in the absence of diarrhea. Atypical hemolytic uremic syndrome may be triggered by drugs, infections, systemic lupus erythematosus, or, rarely, pancreatitis. Furthermore, recurrent hemolytic uremic syndrome should raise suspicion for complement-mediated atypical hemolytic uremic syndrome treated with eculizumab, an anti-C5 monoclonal antibody. Here, we report a case of complement-mediated atypical hemolytic uremic syndrome likely precipitated by recurrent alcohol-induced pancreatitis.

Recurrent hemolytic uremic syndrome caused by DGKE gene mutation: a case report

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury without any association with preceding diarrhea. Dysregulation of the complement system is the most common cause of aHUS, and monoclonal humanized anti-C5 antibodies are now recommended as the first-line treatment for aHUS. However, if the complement pathway is not the cause of aHUS, C5 inhibitors are ineffective. In this study, we report the second reported case of aHUS caused by DGKE mutations in Republic of Korea. The patient was an 11-month-old infant who presented with prodromal diarrhea similar to typical HUS, self-remitted with conservative management unlike complement-mediated aHUS but recurred with fever. While infantile aHUS often implies genetic dysregulation of the complement system, other rare genetic causes, such as DGKE mutation, need to be considered before deciding long-term treatment with C5 inhibitors.

Effective Treatment of a Post-renal Transplantation Patient with Early Recurrent Focal Segmental Glomerulosclerosis and Concomitant Hemolytic Uremic Syndrome, a Case Report

While recurrence of primary Focal Segmental Glomerular Sclerosis (FSGS) is common post renal transplantation (30%-80%), a concomitant presentation of hemolytic uremic syndrome (HUS) and recurrent FSGS has never been reported. In addition, treatment of recurrent FSGS and HUS post-renal transplantation is challenging; and usually individualized based on center's experience. Here, we reported a case of a pediatric patient with early recurrence of FSGS and concomitant HUS post-renal transplantation. This patient had a complete hematological and renal response following the administration of Eculizumab and Rituximab, respectively. Withdrawal of Tacrolimus as well as plasmapheresis did not improve kidney function. Therefore, we concluded that both Eculizumab and Rituximab could achieve remission in comparable cases when administered at fixed intervals.

A case of postpartum AKI: recurrent atypical hemolytic uremic syndrome, HELLP syndrome or paroxysmal nocturnal hemoglobinuria? Lessons for the clinical nephrologist

A case of postpartum AKI: recurrent atypical hemolytic uremic syndrome, HELLP syndrome or paroxysmal nocturnal hemoglobinuria? Lessons for the clinical nephrologist

A97 TACROLIMUS-ASSOCIATED HEMOLYTIC UREMIC SYNDROME IN A PEDIATRIC LIVER TRANSPLANT RECIPIENT

Abstract Background Tacrolimus associated hemolytic uremic syndrome (HUS) has been reported in renal and pediatric cardiac transplantation. Furthermore, in adults receiving liver transplant, there are reports of multiorgan failure, death, and end stage renal failure secondary to tacrolimus induced HUS [J NEPHROL 2003; 16: 580–585]. Although tacrolimus is commonly used in pediatric liver transplantation, there are no reports of the same entity. Aims To describe a case of tacrolimus induced HUS in a pediatric liver transplant patient and subsequent re-initiation of tacrolimus. Methods The patient was followed during his hospital admission and after discharge. Results An 8-year-old male with Progressive Familial Intrahepatic Cholestasis (PFIC) Type III, diagnosed at age 2, presents for living unrelated donor liver transplantation. He was previously well compensated but began to deteriorate in the months leading up to transplant with rising liver enzymes, ascites, and mild encephalopathy after presumed viral gastroenteritis. He receives a left lateral segment liver transplantation and is started on tacrolimus immunosuppression post liver transplant as per protocol. On initiation of tacrolimus, the patient’s hemoglobin trends downward to a trough of 59 g/L four days post transplantation. Concurrently, his haptoglobin is <0.10g/L, total bilirubin peaks at 708 umol/L, creatinine rises to a peak of 71 umol/L, urea peaks at 23.0 mmol/L. Platelets reach a nadir at 27x10^9/L, seven days post transplantation. Direct antibody test was negative, and blood cultures remained negative. Given the constellation of hemolytic anemia, thrombocytopenia, and acute kidney injury following initiation of tacrolimus, a diagnosis of atypical HUS is made. Tacrolimus is discontinued, intravenous methylprednisolone is started and the patient is switched to cyclosporine immunosuppression. Both the hemolysis and kidney injury resolve gradually. The patient develops side effects from cyclosporine including hypertension and excessive hair growth. One month post discontinuation of tacrolimus, he is started on sirolimus, while weaning steroids and cyclosporine. Seven weeks post discontinuation of tacrolimus, he is restarted on tacrolimus and is currently tolerating dual immunosuppression with no signs of HUS recurrence. Conclusions Atypical HUS secondary to tacrolimus post liver transplant in children is a rare entity. In the acute period, discontinuation of tacrolimus is essential to preserve renal function given potentially devastating outcomes seen in adults. Cyclosporine is an alternative immunosuppressive agent used in pediatric solid organ transplantation, although it has also been implicated in causing HUS. Funding Agencies None

Thrombotic microangiopathies postrenal transplantation

Aims: The aim of the study was to describe 12 cases of thrombotic microangiopathy (TMA) postrenal transplantation and study the causes, treatment, and outcomes. Materials and Methods: A retrospective observational study was conducted among renal transplants conducted from 2005 to 2018. Results: Of a total number of 1210 transplants, 12 patients (1%) developed posttransplant thrombotic complications. The mean age of recipients was 36.75 years, and the male-to-female ratio was 9:3. Native kidney diseases included diabetic nephropathy, chronic glomerulonephritis, chronic interstitial nephritis, lupus nephritis, atypical hemolytic uremic syndrome (HUS), and immunoglobulin A nephropathy. Treatment options included plasmapheresis, intravenous immunoglobulin, and everolimus. Seven (58.3%) were associated with an acute rejection, 2 (16.6%) had associated histopathological evidence of calcineurin toxicity, 1 (8.3%) had an unknown etiology, 1 (8.3%) had recurrent HUS in the graft, and 2 (18.2%) patients developed glomerular microthrombi, both of which resolved spontaneously. Graft loss was 50% within the 1st year. Six patients (50%) had a good 1-year graft survival. Two patients succumbed (16.6%). Conclusion: TMA in the posttransplant period may be commonly associated with drug toxicities, antibody-mediated rejection, or recurrent HUS. There is no correlation between drug levels and extent or prognosis of TMA. Empirical plasma exchange may be tried even in cases with no evident cause for TMA. Graft loss is common.

Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country. To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016. The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients. Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.

Hemolytic uremic syndrome in a developing country: Consensus guidelines.

Hemolytic uremic syndrome (HUS) is a leading cause of acute kidney injury in children. Although international guidelines emphasize comprehensive evaluation and treatment with eculizumab, access to diagnostic and therapeutic facilities is limited in most developing countries. The burden of Shiga toxin-associated HUS in India is unclear; school-going children show high prevalence of anti-factor H (FH) antibodies. The aim of the consensus meeting was to formulate guidelines for the diagnosis and management of HUS in children, specific to the needs of the country. Four workgroups performed literature review and graded research studies addressing (i) investigations, biopsy, genetics, and differential diagnosis; (ii) Shiga toxin, pneumococcal, and infection-associated HUS; (iii) atypical HUS; and (iv) complement blockade. Consensus statements developed by the workgroups were discussed during a consensus meeting in March 2017. An algorithm for classification and evaluation was developed. The management of Shiga toxin-associated HUS is supportive; prompt plasma exchanges (PEX) is the chief therapy in patients with atypical HUS. Experts recommend that patients with anti-FH-associated HUS be managed with a combination of PEX and immunosuppressive medications. Indications for eculizumab include incomplete remission with plasma therapy, life-threatening features, complications of PEX or vascular access, inherited defects in complement regulation, and recurrence of HUS in allografts. Priorities for capacity building in regional and national laboratories are highlighted. Limited diagnostic capabilities and lack of access to eculizumab prevent the implementation of international guidelines for HUS in most developing countries. We propose practice guidelines for India, which will perhaps be applicable to other developing countries.

Recurrent Hemolytic Uremic Syndrome: A Case Report

Recurrent Hemolytic Uremic Syndrome: A Case Report

Renal Transplant Immunosuppression in Patients With Hemolytic Uremic Syndrome: Four Case Reports

A high rate of recurrence has been described in atypical hemolytic uremic syndrome renal transplant recipients, favored by certain immunosuppressant drugs that can induce complement activation. We present four case series in which three patients were diagnosed pretransplantation and a fourth who had onset in the very early post-transplantation period. The patients received different immunosuppression schedules, and all had improvement after more than 2-years. We suggest the need to stratify the risk of atypical hemolytic uremic syndrome recurrence using genetic studies and the available drugs as the main factors that allow graft survival improvement today.

Hemolytic Uremic Syndrome in Pregnancy and Postpartum.

Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation. We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome. Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%). Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.

Efficacy of Eculizumab Therapy for Atypical Hemolytic Uremic Syndrome Recurrence and Antibody-Mediated Rejection Progress After Renal Transplantation With Preformed Donor-Specific Antibodies: Case Report

Atypical hemolytic uremic syndrome (aHUS) develops as the result of unregulated complement progression and precipitates de novo thrombotic microangiopathy. Plasma therapy is used to control the progression of the complement cascade, but that therapy is not effective in all patients and is accompanied by risk of infection and/or allergy. Eculizumab has been reported as an efficient therapy for aHUS. We report the case of a 35-year old woman who underwent effective eculizumab therapy for aHUS recurrence and antibody-mediated rejection (AMR) progress after renal transplantation with preformed donor-specific antibodies (DSA). She developed end-stage renal disease due to suspicious IgA nephropathy at age 33 years. Kidney transplantation was performed at age 35 years, and aHUS recurred 2 weeks later, leading to the progressive hemolytic anemia and renal dysfunction. Therefore, she underwent plasma therapy several times. Because it was difficult to continue to plasma therapy for severe allergy, eculizumab was proposed as an alternate therapy. Treatment with eculizumab was initiated 36 days after renal transplantation. After 3 years of eculizumab treatment, and without plasma therapy, schistocytes decreased, haptoglobin increased to within normal limits, creatinine levels stabilized, and no further episodes of diarrhea were reported. At protocol biopsy 1 year after transplantation, she was diagnosed with C4d-negative subclinical AMR. However, her pathologic findings at follow-up biopsy 3 years after transplantation were recovered. We conclude that eculizumab alone, without plasma therapy, is sufficient to treat recurrence of aHUS and AMR due to DSA after renal transplantation and to maintain long-term graft function.

Atypical hemolytic uremic syndrome: a clinical conundrum.

Patients negative for Shiga toxin-producing E. coli (STEC) are categorized as having atypical hemolytic uremic syndrome (HUS) and are associated with an increased risk for complement mutations and poorer prognosis compared with typical HUS. However, STEC identification is limited by the natural history of HUS. The current study is aimed at identifying HUS patients with poor outcomes based on the presence or absence of diarrhea (D) or Shiga toxin (S). A single-center retrospective review (2003-2012) of 42 HUS patients (follow-up 31.3 ± 38.7months) was carried out. HUS was managed clinically with supportive treatments such as dialysis, plasma therapy, and eculizumab. There was no significant difference in the D+S+ (31%), D+S- (50%) and D-S- (19%) groups in the outcome variables of chronic kidney disease stages I-II (100% vs 81% vs 67%) and proteinuria at follow-up (20% vs 12.5% vs 33.3%), hospitalization duration (16.0 ± 8.7 vs 18.1 ± 9.5 vs 23.7 ± 12.9days); dialysis requirement (50% vs 81% vs 66.7%), and dialysis duration (10.2 ± 1.9 vs 33.3 ± 72.8 vs 10.3 ± 8.1days). There was no significant difference in study outcomes in STEC+ (59%) versus STEC- (41%) groups. Genetic testing was performed in 12% of HUS patients based on age, recurrent HUS, familial HUS, persistently low C3, or prolonged dialysis, and 80% of the patients tested were positive for genetic mutations. Our study does not show poorer outcomes in STEC- HUS. Indications and the cost-effectiveness of genetic testing, eculizumab, and plasmapheresis in STEC- HUS need to be evaluated further.

Characteristics and Outcomes of Renal Transplant Recipients with Hemolytic Uremic Syndrome in the United States.

Hemolytic uremic syndrome (HUS) accounts for <1% of renal transplants in the US. There are limited data on the characteristics and outcomes of HUS in pediatric and adult kidney transplant recipients in the US. This study included all renal transplant recipients identified with HUS (N=1,233) as a cause of end-stage renal disease between 1987 and 2013 using the UNOS/OPTN database. The cohort was divided into two age groups: pediatric (N=447) and adult (N=786). Main outcomes were acute rejection rate at one-year, allograft and patient survival, and recurrence of HUS post-transplant. Both age groups were then compared with a propensity score (1:2 ratio) matched control group with an alternative primary kidney disease (non-HUS cohort: pediatric [N= 829] and adult [N=1,547]). In pediatric cohort, when compared to the PS matched controls, acute rejection, death censored allograft and patient survival was similar in the HUS group. However, in the adult cohort, the graft and patient survivals were significantly worse in the HUS group. HUS was associated with allograft loss (HR=1.40, 95%CI 1.14-1.71) in adult recipients. Patients with HUS recurrence had significantly lower allograft and patient survival rates compared to the non-recurrent group in both age groups. Acute rejection was one of the major predictor of HUS recurrence in adults (OR=2.64, 95%CI 1.25-5.60). Calcineurin inhibitors (CNI) were not associated HUS recurrence in both age groups. Pediatric HUS-patients, unlike adult recipients, have similar outcomes compared to the PS matched controls. Recurrence of HUS is associated with poor allograft and patient survival in pediatric and adult patients. Use of CNIs seem to be safe as a part of maintenance immunosuppression post-transplantation. A comprehensive national registry is urgently needed.

Atypical Hemolytic Uremic Syndrome Recurrence after Renal Transplantation: C3-Glomerulonephritis as an Initial Presentation.

Risk for atypical hemolytic uremic syndrome (aHUS) recurrence after renal transplantation is low with an isolated membrane cofactor protein mutation (MCP). We report the case of a 32-year-old woman with a MCP who underwent kidney transplantation with a good evolution at 12 months. At 15 and 35 months, 2 episodes of thrombotic microangiopathy (TMA), after a miscarriage and a preeclampsia, were misinterpreted as triggered by tacrolimus. After each episode however serum creatinine returned to baseline. Five years after transplantation, she had a self-limited rhinosinusitis followed 3 weeks later by an oliguric renal failure. Her complement profile was normal. Graft biopsy showed C3 glomerulonephritis with no “humps” on electron microscopy. No significant renal function improvement followed methylprednisolone pulsing. A second biopsy showed severe acute TMA lesions with C3 glomerular deposits. Despite weekly eculizumab for 1 month, dialysis was resumed. A new workup identified the “at-risk” complement factor H haplotype. Thus, aHUS recurrence should be ruled out in aHUS patients considered at low recurrence risk when a TMA is found in graft biopsy. Prompt eculizumab therapy should be considered to avoid graft loss as aHUS recurrence can first present as a C3 glomerulonephritis.

Atypical hemolytic uremic syndrome recurrence after kidney transplantation.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate after kidney transplantation. In most cases, aHUS are caused by genetic mutations of components of the complement alternative pathway. In this single-center series, we present our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation. In this 10-year retrospective study, we identified 12 patients with aHUS who were managed in our center since 2003. We reviewed clinical data, including genetic testing, posttransplant course and response to therapy including the prophylactic use of eculizumab. Overall, eight patients are women. Six of our patients have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations. Nine patients had at least one previous kidney transplant that failed secondary to recurrent aHUS (75% of our patients). Three patients were treated with eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded to the therapy. Four patients received prophylactic eculizumab; three of them received 6 months and one has been on life long therapy. No signs of recurrence have been observed in these 4 patients so far. Genetic mutations of the complement alternative pathway were confirmed in half of our patients, most of those mutations are in CHF. We demonstrate that treatment or prophylaxis with eculizumab was effective in reversing or preventing aHUS whether or not genetic complement mutations were identified.

De Novo Hemolytic Uremic Syndrome/Thrombotic Microangiopathy After Renal Transplantation: A Single Centre Experience.

Background- Hemolytic uremic syndrome (HUS)/thrombotic microangiopathy (TMA) is a well-recognized serious complication of renal transplantation (RTx), affecting 3% to 14% patients who are administered calcineurin inhibitor-based immunosuppressant. We performed a retrospective study to examine the incidence, etiology, course, and outcome of HUS/TMA in our centre. Patients and Methods- This study included 1538 renal allograft biopsies with confirmed diagnosis of TMA/HUS, performed between 2008 and 2013 in 1175 post RTx patients. Patients with recurrent HUS or antibody-mediated rejections were excluded. Institute Transplant Registry records were reviewed for clinical history, laboratory findings, medications, and outcome. The offending drug was withheld in all subjectswere the first step in the management and if required plasmapheresis was added as an adjuvant. Results- De-novo TMA/HUS was observed in 34 (2.2%) biopsies.Mean age at onset was 32.9 ± 9.8 years, and serum creatinine was 3.4 ± 1.9 mg/dL. 33 were drug-induced (20 with Tacrolimus, 12 with cyclosporine,1 with Sirolimus) and 1 was due to CMV; 25 were TMA; and 9 were HUS. Out of 34 patients, 23 developed HUS/TMA within 3 months, eight developing it within 1 year and developing it after 1 year post transplantation. Presenting features were Graft dysfunction in 34 (100%) patients, anemia (hemoglobin <10 g/dL) in 8 (23.5%) patients, thrombocytopenia in 14 (41.2%), and increased lactate dehydrogenase in 9 (26.5%). and schistocytes in 23.5%. 11 (32.3%) patients received plasmapheresis and FFP.Eleven (32.3%) patients needed dialysis support after TMA diagnosis. Graft function recovered in 26, while six developed ESRD. The HUS group showed 62.5% recovery as compared with 87.5% among the TMA group.After mean follow-up of 2.9 years, patient survival was 82.3% and 96.4% and death-censored graft survival was 60.7% versus 94.6% in TMA/HUS group and control group respectively. Conclusion- De novo TMA/HUS after RTx is a rare but severe condition with poor graft outcomes. Early allograft biopsy with prompt diagnosis and management by drug substitution ±plasmapheresis in posttransplant HUS/TMA plays an important role in allograft outcome. TMA showed better recovery than HUS.

Eculizumab Prior to Third Kidney Transplantation for Factor H Mutation Recurrent Hemolytic Uremic Syndrome (HUS).

Eculizumab Prior to Third Kidney Transplantation for Factor H Mutation Recurrent Hemolytic Uremic Syndrome (HUS).