A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA.

ABSTRACT: High-risk, complement mediated, untreated transplant-associated thrombotic microangiopathy (hrTMA) has dismal outcomes due to multi-organ dysfunction syndrome (MODS). The complement C5 blocker eculizumab shows promising results in hrTMA, but has not been prospectively studied in hematopoietic stem cell transplant (HCT) recipients. We performed the first multi-institutional prospective study in children and young adults to evaluate eculizumab as an early targeted intervention for hrTMA/MODS. We hypothesized that eculizumab would more than double survival in HCT recipients with hrTMA, compared to our prior study of prospectively screened, untreated hrTMAs serving as historical controls. HrTMA features (elevated terminal complement (sC5b-9) and proteinuria measured by random urine protein/creatinine ratio (≥1mg/mg)) were required for inclusion. The primary endpoint was survival at 6 six-months from hrTMA diagnosis. Secondary endpoints were cumulative incidence of MODS 6 months after hrTMA diagnosis and 1-year posttransplant survival. Eculizumab dosing included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy. All 21 evaluated study subjects had MODS. Primary and secondary study endpoints were met by demonstrating survival of 71% (P < .0001) 6 months after hrTMA diagnosis and 62% 1 year after transplant. Of fifteen survivors, 11 (73%) fully recovered organ function and are well. Our study demonstrates significant improvement in survival and recovery of organ function in hrTMA using an intensified eculizumab dosing and real time biomarker monitoring. This study serves as a benchmark for planning future studies that should focus on preventative measures or targeted therapy to be initiated prior to organ injury. This trial was registered at www.clinicaltrials.gov as #NCT03518203.

BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.

Initial Experience with Telemedicine for Interstage Monitoring in Infants with Palliated Congenital Heart Disease.

Infants with staged surgical palliation for congenital heart disease are at high-risk for interstage morbidity and mortality; home monitoring programs have mitigated these risks. In 2019, we instituted telemedicine (TM) in our established Infant Single Ventricle Monitoring Program. All consecutive patients discharged following neonatal operation/intervention were monitored until subsequent stage 2 surgical palliation. We offered TM (synchronous video) visits as part of regularly scheduled follow-up, replacing at least one in-person primary care visit with a TM cardiologist visit. We tracked emergency department (ED) visits, hospitalizations, how TM identified clinical concerns, and whether use of TM prevented unnecessary ED visits or expedited in-person assessment. We assessed caregiver and clinician satisfaction. Between 8/2019 and 5/2020, we conducted 60 TM visits for 29 patients. Of 31 eligible patients, 2 families (6.9%) declined. Median monitoring time was 199 days (range 75-264) and median number of TM visits/patient was 2 (range 1-5). In 6 visits (10%), significant clinical findings were identified which avoided an ED visit. Five TM visits led to expedited outpatient assessments, of which 1 patient required hospitalization. There were no missed events or deaths. Median ED visits/patient/month were significantly lower compared to the same calendar period of the prior year (0.0 (0-2.5) vs. 0.4 (0-3.7), p = 0.0004). Caregivers and clinicians expressed high levels of satisfaction with TM. TM for this high-risk population is feasible and effective in identifying clinical concerns and preventing unnecessary ED visits. TM was particularly effective during the COVID-19 pandemic, allowing for easy adaptation of care to ensure patient safety in this fragile cohort.

Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.

BK polyomavirus diversity-Why viral variation matters.

BK polyomavirus (BKPyV or BKV) is a non-enveloped, circular double-stranded DNA virus that may exceed 80% seroprevalence in adults. BKV infection typically occurs during childhood, and the majority of adults are latently infected. While BKV infection is rarely associated with clinical disease in most individuals, in immunosuppressed individuals, reactivation may cause kidney (BK-associated nephropathy) or bladder (hemorrhagic cystitis and ureteral stenosis) injury. No antiviral therapies have been approved for the treatment of BKV infection. Reducing immunosuppression is the most effective therapy, although this is not feasible in many patients. Thus, a robust understanding of viral pathogenesis and viral diversity remains important for the development of future therapeutic strategies. Studies of BKV diversity are quite sparse compared to other common viral infections; thus, much of our understanding of BVK variability and evolution relies heavily analogous studies of other viruses such as HIV or viral hepatitis. We provide a comprehensive review of BKV diversity at the population and individual level with careful consideration of how viral variability may impact viral replication, pathogenesis, tropism, and protein function. We also discuss a number of outstanding questions related to BK virus diversity that should be explored rigorously in future studies.

The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation.

BACKGROUND: BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. METHODS: In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1-4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. RESULTS: We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1-4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure. CONCLUSIONS: Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.

Acute Kidney Injury in Children after Hematopoietic Cell Transplantation Is Associated with Elevated Urine CXCL10 and CXCL9.

Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic HCT provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant. Children (>2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at 2 large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value, which was recorded ±1 day from when the research urine sample was obtained, as compared with the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI). A total of 176 patients were included from 2 pediatric centers. Thirty-six patients from 1 center were analyzed as a discovery cohort and the remaining 140 patients from the second center were analyzed as a validation cohort. AKI rates were 18% to 35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (P < .01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-γ and interferon-α. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding. CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population.

Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy.

BACKGROUND: Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT and carries high risk of morbidity and mortality. A lack of consistent non-invasive diagnostic criteria can delay diagnosis and lead to irreversible organ damage. METHODS: Serum samples of 100 patients that underwent HSCT at Cincinnati Children's Hospital were serially collected. Unbiased proteomic profiling by SELDI-TOF-MS was performed on serum from TA-TMA patients at baseline (pre-HSCT), 2 weeks before TMA diagnosis (pre-TMA), and at clinical TMA diagnosis. Two proteins with mass to charge ratios of 12-13 kDa were consistently elevated at the 2 week pre-TMA time point by SELDI-TOF, compared to control samples. Potential peptides were isolated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the Linear Trap Quadropole (LTQ). A MASCOT search identified haptoglobin fragments in the 12-17-kDa range. Western blot was performed to validate haptoglobin fragments as a potential biomarker. RESULTS: Western blot of TA-TMA patients showed haptoglobin fragments at 12, 14, and 17 kDa that varied between baseline, pre-TMA, and TMA time points for each patient. By densitometric analysis, the 17-kDa fragment in the pre-TMA samples differed significantly from TMA diagnosis (p < 0.0001). There was no significant difference in the concentrations of the 12-kDa and 14-kDa fragments. CONCLUSION: The 17-kDa haptoglobin degradation product may represent a novel early serum biomarker for TA-TMA that could potentially allow for earlier diagnosis and intervention.

Short, frequent, 5-days-per-week, in-center hemodialysis versus 3-days-per week treatment: a randomized crossover pilot trial through the Midwest Pediatric Nephrology Consortium.

BACKGROUND: No controlled trials in children with end-stage kidney disease have assessed the benefits of more frequently administered hemodialysis (HD). METHODS: We conducted a multicenter, crossover pilot trial to determine if short, more frequent (5 days per week) in-center HD was feasible and associated with improvements in blood pressure compared with three conventional HD treatments per week. Because adult studies have not controlled for the weekly duration of dialysis, we fixed the total treatment time at 12 h a week of dialysis during two 3-month study periods; only frequency varied from 5 to 3 days per week between study periods. RESULTS: Eight children (median age 16.7 years) consented at three children's hospitals. The prespecified primary composite outcome was a sustained 10% decrease in systolic blood pressure and/or a decrease in antihypertensive medications relative to each study period's baseline. Among the six patients completing both study periods, five (83.3%) experienced the primary outcome during HD performed 5 days per week but not 3 days per week; one of the six (16.7%) achieved that outcome during 3-day but not 5-day (p = 0.22) per week HD. During 5-day HD, all patients had significantly more treatments during which their pre-HD systolic (p = 0.01) or diastolic (p = 0.01) blood pressure was 10% lower than baseline. CONCLUSIONS: We observed that more frequent HD sessions per week was feasible and associated with improved blood pressure control, but barriers to changing thrice-weekly standard of care include financial reimbursement and the time demands associated with more frequent treatments.

Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation.

Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.

Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults.

Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multiorgan injury, and severe cases are associated with poor outcomes after hematopoietic stem cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty-nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher nonrelapse mortality (43.6% vs 7.8%, P < .0001) at 1 year post-HSCT compared with those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30 mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1 year), whereas all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (P < .01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest-risk patients who might benefit from prompt clinical interventions.

New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an understudied complication of HSCT that significantly affects transplant-related morbidity and mortality. Over the past several decades, the cause of TA-TMA has remained unknown, limiting treatment options to non-specific therapies adapted from other diseases. Recent prospective studies dedicated to the study of TA-TMA have provided new insights into the pathogenesis of, and genetic susceptibility to TA-TMA, raising awareness of this important transplant complication and allowing for the identification of potentially novel therapeutic targets. Specifically, many patients with TA-TMA develop multi-organ tissue injury through endothelial damage mediated by the activation of the complement pathway, leading to rational therapeutic strategies including complement blockade. This new knowledge has the potential to favorably influence clinical practice and change the standard of care for how patients with TA-TMA are managed. In this review, we summarize novel approaches to the recognition and management of TA-TMA, using case examples to illustrate key clinical points that hopefully lead to improved short and long-term outcomes for these complex HSCT patients, who remain at significant risk for treatment-related morbidity and mortality.

The mortality risk with graft function has decreased among children receiving a first kidney transplant in the United States.

Mortality has decreased in children with end-stage kidney disease. Decreases in mortality during dialysis and improved graft survival contributed to this improvement. However, it is unknown whether rates of death with graft function have also improved. We measured this in first transplant recipients under 21 years of age registered in the US Renal Data System. Cox models were used with a time-dependent renal replacement therapy modality variable to estimate the hazard ratios (HRs) for death with graft function associated with a 1-year increment in the calendar year of transplant. There were 157,201 person-years of observation among 17,468 recipients, with 82.2% of study time during graft function and 17.8% during dialysis after graft failure. There were 2003 deaths (12.7 deaths per 1000 person-years) overall, of which 985 occurred with graft function (7.6 deaths per 1000 person-years) and 1018 occurred during dialysis after graft failure (36.1 deaths per 1000 person-years). Each 1-year increment in calendar year of first transplant was associated with a significantly lower risk of death, both overall observation (HR 0.97 (0.96, 0.98)) and focusing on time with graft function (HR 0.98 (0.97, 0.99)). Living donation was significantly associated with better survival, whereas dialysis after graft failure was associated with a much higher mortality risk (HR 4.85 (4.40, 5.35)) compared with graft function. Thus, the risk of death with graft function has decreased in children receiving a first kidney transplant. Increasing living donation and minimizing dialysis may further improve outcomes.

Vitamin D Deficiency and Survival in Children after Hematopoietic Stem Cell Transplant.

Vitamin D has endocrine function as a key regulator of calcium absorption and bone homeostasis and also has intracrine function as an immunomodulator. Vitamin D deficiency before hematopoietic stem cell transplantation (HSCT) has been variably associated with higher risks of graft-versus-host disease (GVHD) and mortality. Children are at particular risk of growth impairment and bony abnormalities in the face of prolonged deficiency. There are few longitudinal studies of vitamin D deficient children receiving HSCT, and the prevalence and consequences of vitamin D deficiency 100 days after transplant has been poorly studied. Serum samples from 134 consecutive HSCT patients prospectively enrolled into an HSCT sample repository were tested for 25-hydroxy (25 OH) vitamin D levels before starting HSCT (baseline) and at 100 days after transplantation. Ninety-four of 134 patients (70%) had a vitamin D level < 30 ng/mL before HSCT, despite supplemental therapy in 16% of subjects. Post-transplant samples were available in 129 patients who survived to day 100 post-transplant. Vitamin D deficiency persisted in 66 of 87 patients (76%) who were already deficient before HSCT. Moreover, 24 patients with normal vitamin D levels before HSCT were vitamin D deficient by day 100. Overall, 68% of patients were vitamin D deficient (<30 ng/mL) at day 100, and one third of these cases had severe vitamin D deficiency (<20 ng/mL). Low vitamin D levels before HSCT were not associated with subsequent acute or chronic GVHD, contrary to some prior reports. However, severe vitamin D deficiency (<20 ng/mL) at 100 days post-HSCT was associated with decreased overall survival after transplantation (P = .044, 1-year rate of overall survival: 70% versus 84.1%). We conclude that all pediatric transplant recipients should be screened for vitamin D deficiency before HSCT and at day 100 post-transplant and that aggressive supplementation is needed to maintain sufficient levels.

Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25% to 35% of HSCT recipients and shares histomorphologic similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation, and tissue damage. Although significant advances have been made in understanding the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-TMA and may therefore guide the development of targeted treatment interventions.

Antibodies to BK virus in children prior to allogeneic hematopoietic cell transplant.

BK virus (BKV) is associated with kidney and bladder disease after hematopoietic cell transplantation (HCT) but less is known about the seroprevalence of pre-transplant antibodies to BKV in children. We measured BKV IgG antibody titers in 36 children before HCT. BKV IgG antibodies were detected in all 36 patients, with 28/36 (77.8%) developing BK viremia in the first 100 days. Pre-HCT BKV IgG antibody titers >1:40,960 were protective against later BK viremia ≥10,000 copies/ml. The seroprevalence of antibodies to BKV is high in children undergoing HCT and post-transplant BK viremia, which is associated with bladder and kidney injury, is common.

Neonatal atypical hemolytic uremic syndrome from a factor H mutation treated with eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) results from an inherited dysregulation of the alternative complement pathway leading to thrombotic microangiopathy consisting of hemolytic anemia, thrombocytopenia, and renal injury. The complement inhibitor eculizumab is an approved treatment, but its reported use in neonates - who have an inherently high risk of infection - is limited. CASE DIAGNOSIS/TREATMENT: A 28-day-old female presented with gross hematuria and hypertension. aHUS was suspected based on anemia with schistocytes, thrombocytopenia, low C3, and acute kidney injury requiring peritoneal dialysis. A septic work-up initiated on day 2 for hypothermia and respiratory failure was negative. There was no improvement after 6 days of plasma therapy. Despite being < 6 weeks old she was vaccinated with pneumococcal-13 conjugate, meningococcal (groups C and Y) polysaccharide, and Haemophilus b tetanus toxoid conjugate vaccines and started on penicillin prophylaxis. After 1 dose of eculizumab 300 mg, dialysis was discontinued and her hematological parameters improved. Genetic testing revealed a complement factor H mutation. After 11 months of follow-up, she remains on eculizumab and penicillin without recurrence of aHUS or any infectious complications. CONCLUSIONS: Eculizumab is a safe and effective treatment option for aHUS even in neonates at high risk for infection.