Clinical-Laboratory- Genetic Profile and Outcomes of Patients with Atypical Hemolytic Uremic Syndrome and Restrictive Use of Eculizumab: A Single Center Experience and a Brief Review

Background Atypical HUS (aHUS) is a rare thrombotic microangiopathy (TMA) caused by complement dysregulation. Eculizumab is a humanized monoclonal antibody targeting against complement factor C5. Ravulizumab, a longer acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for treatment of aHUS in 2019. Here we describe the clinical presentation, laboratory, genetic profile, treatment along with long-term sequelae of patients diagnosed with aHUS. The outcomes of restrictive use of eculizumab and the use of ravulizumab were also studied. Materials and Methods We conducted a single center retrospective cohort study, searching electronic medical records of patients diagnosed and treated for aHUS at University of Arkansas for Medical Sciences, from January 1, 2013 to January 31, 2021, after IRB approval. Inclusion criteria :1) Presence of microangiopathic hemolytic anemia (MAHA) with thrombocytopenia 2) ADAMTS13 activity > 10 % 3) Age > 18. Exclusion criteria: 1) Age < 18 years 2) TMA associated with hemolytic uremic syndrome, scleroderma renal crises, anti-phospholipid syndrome. Results Seventeen patients meeting the inclusion criteria were enrolled in the study. The mean age at diagnosis was 47.4 ± 17.9 years. Most of the patients were Caucasians (n=10, 58%) and females (n= 14, 82%). All the patients except one had acute kidney injury (AKI) at presentation (n=16, 94.1%), the most frequent extra-renal presentation was CNS involvement -seizures, confusion and altered mental status (n= 7, 41.2 %) followed by Gastrointestinal- non-bloody diarrhea, nausea and vomiting (n=5, 29.4 %) [Figure 1]. Lab investigations are described in [Table 1]. Complement genetic testing was done in 100% of study population. Factor H related genes 1/3 (CFHR1/3) and complement factor H (CFH) were the most commonly found pathogenic mutations [Table 2]. In this study, pregnancy and infection (n= 4, 23.5% each) were identified as the most common triggers [Figure 2]. For two of the patients, it was the first pregnancy and for the other two, it was their second and third pregnancies. They presented at the second, sixth, and sixteenth week postpartum respectively. Eleven (64.70%) patients developed chronic kidney disease (CKD) with six (35.29%) patients progressing to end stage renal disease (ESRD). Two (11.76 %) pregnant patients developed cardiomyopathy, two (11.76%) patients developed pulmonary complications (pneumonia and pulmonary hypertension) and three (17.64%) patients developed epilepsy. All the postpartum females in our study were able to breastfeed while on eculizumab with no long-term complications in the neonates. One patient had two subsequent deliveries with no ante, intra, or post-partum consequences or repeated triggers of aHUS. Fourteen patients (82.3%) received therapeutic plasma exchange, four (23.5%) patients received iv methyl prednisone (1mg/kg) and two (11.7%) patients received IVIg prior to initiating eculizumab. Over time, five (29.41%) patients opted to completely stop drug therapy and four patients (23.52%) chose to shift to ravulizumab because of the ease of treatment duration (every 8 weeks rather than every 2 weeks for eculizumab). All these nine patients remained in remission with stable hematologic and renal parameters on subsequent follow-ups [Table 3]. Three patients (17.6 % mortality) died in our study due to causes unrelated to aHUS. Conclusions: The clinical diagnosis of atypical HUS can be challenging especially with extra-renal manifestations. Females were four times more affected than males. PCMs were present in 11 patients. Early diagnosis and treatment with C5 inhibitors improves morbidity and mortality. The decision to discontinue or switch eculizumab to ravulizumab will likely decrease healthcare costs and improve patient compliance but should be based on disease severity. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The Syndromes of Thrombotic Microangiopathy: A Critical Appraisal on Complement Dysregulation

Thrombotic microangiopathy (TMA) is a rare and potentially life-threatening condition that can be caused by a heterogeneous group of diseases, often affecting the brain and kidneys. TMAs should be classified according to etiology to indicate targets for treatment. Complement dysregulation is an important cause of TMA that defines cases not related to coexisting conditions, that is, primary atypical hemolytic uremic syndrome (HUS). Ever since the approval of therapeutic complement inhibition, the approach of TMA has focused on the recognition of primary atypical HUS. Recent advances, however, demonstrated the pivotal role of complement dysregulation in specific subtypes of patients considered to have secondary atypical HUS. This is particularly the case in patients presenting with coexisting hypertensive emergency, pregnancy, and kidney transplantation, shifting the paradigm of disease. In contrast, complement dysregulation is uncommon in patients with other coexisting conditions, such as bacterial infection, drug use, cancer, and autoimmunity, among other disorders. In this review, we performed a critical appraisal on complement dysregulation and the use of therapeutic complement inhibition in TMAs associated with coexisting conditions and outline a pragmatic approach to diagnosis and treatment. For future studies, we advocate the term complement-mediated TMA as opposed to the traditional atypical HUS-type classification.

Differential diagnosis of obstetric thrombotic microangiopathy: a review

Thrombotic microangiopathy (TMA) is a clinical and morphological syndrome, which is based on damage of the endothelium. Clinically, TMA is characterized by a triad of symptoms: thrombocytopenia, microangiopathic hemolytic anemia, and target organ damage. In obstetric practice, TMA most often occurs with preeclampsia or HELLP syndrome, atypical HUS, TTP. The review presents the basic differential criteria for the diagnosis of TMA during pregnancy and after childbirth, as well as the management of patients.

Atypical hemolytic uremic syndrome & treatment: case study

Atypical Hemolytic Uremic Syndrome (aHUS) is considered as an uncommon pathology that usually affects young adults and causes acute kidney injury which can further lead to End Stage Renal Disease (ESRD). Atypical HUS usually occurs due to impairment in alternate pathway of complement system. aHUS are usually sporadic and less than 20% cases are familial. About 50% aHUS cases show no clear initiating factors. Mortality rate has been reduced in atypical HUS over the years due to progress in intensive care and dialysis facility. First treatment option should be PE, with exchange of 1.5 plasma volumes (60-75 ml/kg) per session, under the cover of fresh frozen plasma (FFP). PE needs to be performed on daily basis while waiting for the results of platelet count, LDH and Hb levels to be normal and renal functions showing improvement. Here we present a case in 15-year-old boy who was healthy previously. Continuous...

Living Related Donor Kidney Transplantation in Atypical HUS: When should it be considered?

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