An unusual case of adult-onset still's disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. CASE PRESENTATION: A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). CONCLUSION: Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.

Constipation and hemolytic uremic syndrome.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) classically presents with diarrhea. Absence of diarrheal prodrome increases suspicion for atypical HUS (aHUS). Inability to obtain a fecal specimen for culture or culture-independent testing limits the ability to differentiate STEC-HUS and aHUS. CASE-DIAGNOSIS/TREATMENT: Our patient presented with abdominal pain and constipation, and evaluation of pallor led to a diagnosis of HUS. There was a complete absence of diarrhea during the disease course. Lack of fecal specimen for several days delayed testing for STEC. Treatment for atypical HUS was initiated with complement-blockade therapy. PCR-testing for Shiga toxin from fecal specimen later returned positive. Alternative complement-pathway testing did not identify a causative genetic variant or anti-Factor H antibody. A diagnosis of STEC-HUS was assigned, and complement-blockade therapy was stopped. CONCLUSION: Diagnosis of aHUS remains a diagnosis of exclusion, whereby other causes of HUS are eliminated with reasonable certainty. Exclusion of STEC is necessary and relies on testing availability and recognition of testing limitations. Diarrhea-negative STEC-HUS remains a minority of cases, and future research is needed to explore the clinical characteristics of these patients.

Atypical haemolytic uraemic syndrome in a postpartum patient.

A postpartum patient presented 1 week following uncomplicated pregnancy and elective repeat caesarean section with acute hypertension, severe anaemia and acute kidney injury. Her workup demonstrated microangiopathic anaemia, thrombocytopenia and liver enzyme elevations. Differential diagnoses included postpartum haemolysis-elevated liver enzyme-low platelet (HELLP) syndrome, haemolytic uraemic syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP). She was treated initially with systemic corticosteroids, haemodialysis and plasmapheresis for presumed TTP while awaiting the results of ADAMSTS13 assay performed at an outside laboratory. When reported back as normal, the diagnosis of atypical HUS was established. Eculizumab was administered with rapid improvement of her condition.

Coronavirus disease 2019-associated thrombotic microangiopathy treated with plasma exchange and antihypertensive therapy in a patient with HIV: A case report with literature review.

RATIONALE: Coronavirus disease 2019 (COVID-19) is an infectious disease that often causes complications in multiple organs and thrombosis due to abnormal blood coagulation. This case report aimed to describe the clinical course of COVID-19-associated thrombotic microangiopathy (TMA) and reviewed the comprehensive information on TMA, thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome associated with COVID-19 in the past literature. PATIENT CONCERNS: A 46-year-old Japanese man was diagnosed with human immunodeficiency virus infection 10 years ago and treated with antiretroviral therapy. The patient presented with fever, malaise, hematuria, and bilateral upper abdominal discomfort for the past 4 days. DIAGNOSES: COVID-19-associated TMA was diagnosed based on a positive polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 and laboratory findings such as thrombocytopenia, acute kidney injury, and hemolytic anemia. Malignant hypertension and human immunodeficiency virus infection were also considered as differential diagnoses of TMA. INTERVENTIONS: Considering the possibility of TTP, plasma exchange was performed, and glucocorticoids were administered. Hemodialysis was performed for acute kidney injury. Antihypertensive drugs were administered to control the high blood pressure. OUTCOMES: Platelet count and renal function improved, and hemodialysis was no longer required. The patient was in good general condition and was discharged from the hospital. LESSONS: COVID-19-associated TMA should be considered as a differential diagnosis during the COVID-19 epidemic. Excessive inflammation and severe COVID-19 are not essential for TMA development. Early intervention using conventional TMA treatments, such as plasma exchange and corticosteroids, might be important in improving prognosis while differentiating between TTP and atypical hemolytic uremic syndrome. Antihypertensive therapy may be helpful in the treatment of COVID-19-associated TMA.

Clinical features of women with thrombotic microangiopathy in pregnancy: A case series from a single Japanese tertiary perinatal care center.

AIM: Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. METHODS: We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. RESULTS: Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. CONCLUSIONS: Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

Ischemic cerebrovascular complications with initial presentation of genetic atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease, with scarce reports of neurologic manifestations in the acute setting. Ischemic cortical infarcts concurrently with aHUS presentation have not been described in adult patients. CASE DESCRIPTION: A 46-year-old male presented with acutely declining mental status and progressive weakness, in the setting of longstanding hypertension and known type B aortic dissection. Urgent neuroimaging showed bilateral multifocal multiterritorial ischemic infarcts, concerning for an embolic source or hypercoagulable state. Systemic workup was notable for microangiopathic hemolytic anemia and acute kidney injury. Empiric plasmapheresis was initiated for presumed thrombotic thrombocytopenic purpura. Broad workup did not support such a diagnosis, and kidney biopsy showed findings compatible with aHUS. Additional blood testing showed increased complement pathway activity. Shiga toxin was negative, and overall clinical picture fit with aHUS as diagnosis. Treatment with complement inhibitor was started and patient gradually recovered. Genetic testing confirmed a pertinent pathogenic mutation, CFHR1 homozygous deletion. CONCLUSION: Acute multifocal multiterritorial ischemic infarcts and systemic thrombotic microangiopathy may be a manifestation of aHUS, and with associated genetic mutation, even in adult population.

Purtscher-Like Retinopathy Associated With Atypical Hemolytic Uremic Syndrome.

This case report discusses a diagnosis of atypical hemolytic uremic syndrome in a woman aged 38 years who presented with progressively blurry vision in both eyes over a period of 10 days.

Eculizumab use in patients with pneumococcal-associated hemolytic uremic syndrome and kidney outcomes.

BACKGROUND: Streptococcus pneumoniae-associated hemolytic uremic syndrome (P-HUS) is a rare and severe disease. Only a few reports have been published about eculizumab use in P-HUS. METHODS: We analyzed demographic, clinical, and laboratory data of patients with P-HUS from our center. RESULTS: The cohort consisted of 4 females and 3 males. All patients had pneumonia. Four were given eculizumab (days 1-3). The eculizumab group required a shorter duration of dialysis and mechanical ventilation (medians 20 vs. 28.5 and 30 vs 38.5 days, respectively) compared with the non-eculizumab group, but this was still much longer than normally reported; the thrombocytopenia resolution was similar in both groups (medians 10 vs. 8 days). Chronic kidney disease (CKD) was correlated with the duration of dialysis and mechanical ventilation duration at 1 year (r = 0.797, P = 0.032 and r = 0.765, P = 0.045) and last follow-up (r = 0.807, P = 0.028 and r = 0.814, P = 0.026, respectively); our scoring system showed even stronger correlations (r = 0.872, P = 0.011 and r = 0.901, P = 0.0057, respectively). The eculizumab group showed slightly better 1-year and last follow-up CKD stage (2.75 vs. 3, P = 0.879 and 2.5 vs. 3.67, P = 0.517). CONCLUSIONS: Despite the fact that the eculizumab group showed better outcomes, eculizumab does not seem to improve the course of P-HUS compared with previous reports. Kidney outcomes are strongly correlated with the duration of dialysis and mechanical ventilation duration. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial.

SIGNIFICANCE STATEMENT: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) is a serious condition, characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis. So far, no specific treatment has been proven efficient in STEC-HUS. The use of eculizumab, a monoclonal antibody inhibiting terminal complement complex, has demonstrated remarkable success in atypical hemolytic uremic syndrome, but its use in uncontrolled studies to treat STEC-HUS has yielded inconsistent results. In this Phase 3 randomized, placebo-controlled trial in 100 pediatric patients with STEC-HUS, the findings did not show efficacy of eculizumab during the acute phase of the disease. However, the results indicated a reduction of renal sequelae in eculizumab-treated patients at 1-year follow-up. Larger prospective studies would be needed to further explore eculizumab as a potential treatment. BACKGROUND: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT. Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority. METHODS: We conducted a Phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. The primary end point was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement. RESULTS: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04). No safety concern was reported. CONCLUSIONS: In pediatric patients with STEC-HUS, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae. CLINICAL TRIALS REGISTRATIONS: EUDRACT (2014-001169-28) ClinicalTrials.gov ( NCT02205541 ).

Why has plasma exchange failed in TRACK syndrome? Lessons from a new variant of the atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare and life-threatening form of thrombotic microangiopathy, associated with high mortality and morbidity. Most cases present with hemolytic anemia, thrombocytopenia, and renal insufficiency. However, it can have unusual multiple end-organ injuries including extrarenal organ and system involvements such as neurologic, cardiac, gastrointestinal, and respiratory systems. We describe a 4-year-old girl who developed aHUS due to the TSEN2 mutation and had cardiac involvement. She did not benefit from plasma exchange, as stated in previous cases. It should be kept in mind that therapeutic plasma exchange may not be beneficial in some cases of aHUS, especially due to genetic mutations.

Atypical haemolytic uremic syndrome with refractory multiorgan involvement and heterozygous CFHR1/CFHR3 gene deletion.

BACKGROUND: We present this challenging case report of Atypical Haemolytic Uremic Syndrome (aHUS) presenting with multi-organ involvement in a patient and heterozygous CFHR1/CFHR3 gene variant, which was refractory to initial eculizumab therapy. CASE PRESENTATION: A forty-three year old female presented with aHUS and had heterozygous disease-associated deletions in the complement genes CFHR1/CFHR3. She had progressive kidney failure and severe extra-renal manifestations including cardiomyopathy and haemorrhagic cystitis; as well as pulmonary, gastrointestinal and neurological involvement. The initial kidney biopsy revealed thrombotic microangiopathy (TMA) changes involving all glomeruli. Clinical improvement was initially seen during eculizumab initiation with suppressed CH50 level, but a new rhinovirus/enterovirus upper respiratory tract infection triggered further severe multi-organ disease activity. The extra-renal manifestations stabilised, then ultimately improved after a period of eculizumab dose intensification. However, the impact on dose intensification on this improvement is unclear. Despite the extra-renal clinical improvement, she ultimately progressed to end-stage kidney disease (ESKD), commencing peritoneal dialysis for three years before undergoing a successful uncomplicated cadaveric kidney transplant without prophylactic eculizumab. Two years after transplant, she has excellent transplant graft function without any further disease recurrence. CONCLUSIONS: This case highlights the concept of extra-renal manifestations in aHUS initially resistant to eculizumab, which potentially responded to dose intensification. Whilst organ injuries are potentially reversible with timely targeted treatment, it appears that the kidneys are most vulnerable to injury.

Hemolytic Uremic Syndrome: A Case Report.

Thrombotic microangiopathy is a pathological condition comprised of microvascular thrombosis involving any body organ leading to thrombocytopenia, coombs-negative hemolytic anemia, and end-organ damage. The clinical presentation of the case shows typical hemolytic uremic syndrome, however, lab reports show atypical hemolytic uremic syndrome (low C3). Pain abdomen and loose stool with some signs of dehydration were initial presentations. Early initiation of renal replacement therapy and management of dehydration was done. Simple diarrhea can also manifest as acute kidney injury with the hemolytic uremic syndrome. Hence we should keep hemolytic uremic syndrome as the differential diagnosis of diarrhea. Irrespective of lab parameters, early management in line with the typical hemolytic uremic syndrome should be done for better outcomes. Keywords: anemia; case reports; dehydration; renal replacement therapy.

Bilateral Proliferative Retinopathy as the Initial Presentation of Atypical Hemolytic Uremic Syndrome: A Case Report.

In this case report, we describe a 34-year-old male patient who presented with vision loss and was found to have profound occlusive retinal vasculopathy. His initial laboratory studies were unremarkable, but five weeks after his ocular symptoms began, he developed acute multi-organ failure and was ultimately diagnosed with atypical hemolytic uremic syndrome (aHUS). His course was complicated by a stroke, respiratory distress requiring intubation, long-term hemodialysis, and eventually death. Occlusive retinal vasculopathy may be the presenting finding in aHUS, although thrombotic microangiopathy syndromes typically present with acute kidney injury and or failure, hemolytic anemia, and thrombocytopenia. [Ophthalmic Surg Lasers Imaging Retina 2023;54:297-300.].

Atypical Hemolytic Uremic Syndrome in a Pregnant Patient with a Thrombomodulin Gene Variant Treated with Plasma Exchange and Eculizumab.

BACKGROUND Hemolytic uremic syndrome (HUS) includes the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The atypical form of HUS is a rare disease characterized by complement overactivation, and it can be from genetic or acquired causes. Genetic causes involve mutation in one of the factors in the alternative complement pathway or inhibitors. Malignant hypertension and pregnancy are the most important acquired causes. The optimal management of patients with aHUS is with eculizumab, which is recombinant antibody against human complement component C5. CASE REPORT This report describes the case of a 25-year-old woman with frequent hospitalizations for poorly controlled hypertension who presented at 20 weeks of gestation with headache, vomiting, and a blood pressure of 230/126 mmHg. The patient had acute kidney injury with hematuria and proteinuria, and kidney biopsy showed hypertensive arteriolar nephrosclerosis and fibrinoid arteriolar necrosis consistent with thrombotic microangiopathy. Further work-up with a genetic panel showed heterozygosity for the thrombomodulin (THBD) gene. She was started on treatment with plasma exchange and eculizumab, a recombinant monoclonal antibody that inhibits terminal complement activation at the C5 protein. The patient responded well to the treatment at the time of her initial outpatient follow-up. CONCLUSIONS This case shows the potential of severe renal manifestation of aHUS, and the need for a kidney biopsy in cases of severe uncontrolled hypertension presenting with kidney injury. If evidence of aHUS is found, prompt treatment with plasma exchange and eculizumab should be initiated.

The Role of Complement in Autoimmune Disease-Associated Thrombotic Microangiopathy and the Potential for Therapeutics.

The complement system is a tightly regulated, cascading protein network representing a key component linking the innate and humoral immune systems. However, if misdirected or dysregulated, it can be similarly damaging to host-tissue. The role of complement dysregulation on vascular endothelial cells has been well established in atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and target organ injury. Yet, a great deal of complexity exists around the role of complement in TMA associated with other diseases. A further complicating factor is the cross-talk between complement, neutrophils, and coagulation pathways in the pathophysiology of TMA. Advancements in the understanding of the etiopathogenesis of aHUS paved the way for the successful development of anticomplement therapies (complement C5 inhibitors), which have revolutionized the treatment of aHUS. Therefore, a clearer understanding of the role of the complement system in TMA associated with other conditions will help to identify patients who would benefit from these therapies. This review aims to provide an assessment of the nature and extent of complement involvement in TMA associated with autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and scleroderma renal crisis. Defining the role of complement in TMA in these conditions will help to guide timely diagnosis and management.

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.

Haemolytic Uremic Syndrome: A Study Cohort over 10-Year Period in a Paediatric Tertiary Centre Hospital.

BACKGROUND: Haemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by haemolytic anaemia, thrombocytopenia, and acute kidney injury. It represents the most frequent cause of acute kidney failure in paediatric age. HUS includes acquired types, such as post-infectious forms, and inherited types. If not promptly recognized, HUS still has high mortality and morbidity, with disabling long-term sequelae. METHODS: Children diagnosed with HUS hospitalized between January 2010 and July 2021 at Meyer Children's Hospital were retrospectively studied. RESULTS: We selected 33 patients (M:F = 15:18) with a median age of 40 months (range 12-180 months). Twenty-eight cases (84.8%) were classified as acquired HUS: Shiga-like toxin Escherichia coli-related-HUS (STEC-HUS) was diagnosed in 26 patients (78.8%), while other 2 patients had HUS secondary to Streptococcus pneumoniae infections (3%) and hematopoietic stem cell transplantation (3%), each one. Five cases (15.1%) were classified as hereditary HUS: 4 patients (12.1%) presented inherited complement disorders (atypical HUS); 1 patient (3%) was diagnosed with cobalamin C deficiency. Diarrhoea was the most rated symptom (72.7%), mainly in STEC-HUS forms. In hereditary HUS, kidney involvement manifestations prevailed. Hypertension was present in 54.5% of total cases. Hypocomplementemia was present in 48.5% of patients; 30.3% of patients needed hospitalization in paediatric intensive care unit (PICU). Early hypertension and hypocomplementemia resulted to be related to the disease severity for either acute phase or long-term outcome. Leucocytosis, thrombocytopenia, and worsen renal function indices were related to PICU hospitalization. Overall, the outcome was good: long-term complications persisted in 18.2% of cases; 1 patient developed kidney failure; no patient died. CONCLUSIONS: HUS is a multifactorial disease mostly affecting children between 3 and 5 years old. Hypertension, leucocytosis, hypocomplementemia, thrombocytopenia, increased renal function indices, and extrarenal manifestations are risk factors for the worst outcome.

Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab.

BACKGROUND: Clinically validated biomarkers for monitoring of patients with complement-mediated thrombotic microangiopathy (CM-TMA) including atypical hemolytic uremic syndrome (aHUS) are unavailable. Improved characterization of biomarkers in patients with aHUS may inform treatment and monitoring for patients with CM-TMA. METHODS: This analysis used data collected from 55/56 (98.2 %) adult patients with aHUS enrolled in the global Phase III study of ravulizumab (NCT02949128). Baseline (pre-treatment) patient serum, plasma and urine biomarker levels were compared with the maximum observed levels in normal donors and evaluated for associations with pre-treatment plasma exchange/infusion and dialysis status. Biomarkers were also assessed for associations with key clinical measures at baseline and with changes at 26 and 52 weeks from treatment initiation via linear regression analyses. RESULTS: Complement-specific urine levels (factor Ba and sC5b-9) were elevated in >85 % of patients and are significantly associated with pre-treatment kidney dysfunction. Baseline levels of other evaluated biomarkers were elevated in >70 % of patients with aHUS, except for plasma sC5b-9 and serum sVCAM-1. Lower levels of urine complement markers at baseline are significantly associated with improvements in total urine protein and estimated glomerular filtration rate at 26 and 52 weeks of treatment. Clinical assessment of complement activation by a receiver operating characteristic analysis of Ba and sC5b-9 was more sensitive and specific in urine matrix than plasma. CONCLUSION: This analysis identified a set of biomarkers that may show utility in the prognosis of CM-TMA, including their potential for measuring and predicting response to anti-C5 therapy. Further studies are required to enhance patient risk stratification and improve management of these vulnerable patients. CLINICAL TRIALS REGISTRATION: NCT02949128, ClinicalTrials.gov.