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The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pathway component C2 leading to the formation of hyperactive classical convertases. We now report the identification of the same mutation and another C2 GoF mutation R249C in two other patients with a glomerulopathy of uncertain etiology. Both mutations stabilize the classical C3 convertases by a similar mechanism. The presence of R249C and S250C variants in serum increases complement-dependent cytotoxicity (CDC) in antibody-sensitized human cells and elevates deposition of C3 on ELISA plates coated with C-reactive protein (CRP), as well as on the surface of glomerular endothelial cells. Our data justify the inclusion of classical pathway genes in the genetic analysis of patients suspected of complement-driven renal disorders. Also, we point out CRP as a potential antibody-independent trigger capable of driving excessive complement activation in carriers of the GoF mutations in complement C2. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal damage. Its presentation as nephrotic syndrome (NS) during first year of life is uncommon; we describe a child with clinical and laboratory findings of NS whose renal biopsy revealed thrombotic microangiopathy (TMA). A previously healthy 4-month-old male was admitted with severe dehydration, diarrhea and anuria. Laboratory results showed electrolyte disturbances, increased serum creatinine, anemia without schistocytes, thrombocytosis, normal lactic dehydrogenase (LDH) levels, hypoalbuminemia hypercholesterolemia and decreased C3 levels. After rehydration hematuria and massive proteinuria were also documented and an initial diagnosis of NS of the first year was established. Studies seeking for infectious agents were negative. During hospitalization he continued to be oligo-anuric needing dialysis and a renal biopsy was performed, which showed TMA findings. We here considered the diagnosis of aHUS and started plasma infusions as a bridge until starting eculizumab. After two infusions urine output improved leading to discontinuation dialysis. The diagnoses of STEC infection and thrombocytopenic thrombotic purpura were ruled out. Factor B, H, I and properdin levels were normal. Antibodies against CFH negative were negative. Screening for genes causative of aHUS detected a heterozygous variant in CFHR3 of uncertain significance. On day 20, treatment was switched to eculizumab, which induced a progressive remission of the NS. This case outlines the need for a heightened diagnosis suspicion of this already rare disease since early initiation of eculizumab therapy improves its prognosis. [ABSTRACT FROM AUTHOR]

The article presents answers to a clinical quiz about a rare complication of a pauci-immune crescentic glomerulonephritis in a child.

aHUS is caused by the over‐activation and dysregulation of the alternative complement pathway. Data regarding outcomes of pediatric aHUS patients after kidney transplantation are still very scarce. Accordingly, the aim of this study was to describe the clinical findings and outcomes of pediatric aHUS patients after renal transplantation. This is a retrospective, multicenter study including 12 patients from the national registry system. Among the 12 patients, eight had received prophylactic eculizumab and none of those patients (except one) had experienced aHUS recurrence during a median follow‐up period of 58.5 (min‐max, 4‐94) months. Although eculizumab had been started on the day before transplantation in one of them, aHUS recurrence occurred during the transplantation procedure. Eculizumab had been stopped in only one patient who had no complement gene mutation after 35 months of therapy, and recurrence had not been observed during the 19 months of follow‐up. In three patients, maintenance doses had been spaced out without any recurrence. One additional patient with anti‐CFH antibody received only two doses of eculizumab for transplantation and had been followed for 46 months without aHUS recurrence. The remaining three patients had not received anti‐C5 therapy and none of those patients experienced aHUS recurrence during a median follow‐up period of 21 (min‐max, 9‐42) months. Prophylactic eculizumab is a safe and effective treatment for the prevention of aHUS recurrence. Eculizumab interval prolongation, discontinuation, and transplantation without eculizumab prophylaxis can be tried in selected patients with close follow‐up. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease due to a dysregulation of the complement alternative pathway. Complement factor I (CFI) negatively regulates the alternative pathway and CFI gene rare variants have been associated to aHUS with a low disease penetrance. We report 10 unrelated cases of HUS associated to a rare CFI variant, p.Ile357Met (c.1071T>G). All patients with isolated p.Ile357Met CFI missense variant were retrospectively identified among patients included between January 2007 and January 2022 in the French HUS Registry. We identified 10 unrelated patients (70% women; median age at HUS diagnosis, 36.5 years) who carry the same rare variant p.Ile357Met in the CFI gene. Seven patients (cases 1-7) presented with aHUS in the native kidney associated with malignant hypertension in 5 patients. None received a C5 inhibitor. Two of these cases occurred in the peripartum period with complete recovery of kidney function, while 5 of these patients reached kidney failure requiring replacement therapy (KFRT). Four patients with KFRT subsequently underwent kidney transplantation. Three later developed C3 glomerulopathy in their kidney graft, but none had aHUS recurrence. Three other patients (cases 8-10) experienced de novo thrombotic microangiopathy after kidney transplantation, precipitated by various triggers. The rare CFI variant p.Ile357Met appears to be a facilitating genetic factor for HUS and for some forms of secondary HUS., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy that presents with a triad of hemolytic anemia, thrombocytopenia, and acute kidney impairment. It can be attributed to mutations in an array of different complement proteins leading to the overactivation of the complement system, the most impacted being the alternative pathway. Though rare, influenza B has been documented as a potential trigger to the development of aHUS., Case Presentation: We discuss a 10-year-old girl with a history of aHUS who was found to have a repeat episode of aHUS following an influenza B infection. There have only been a few reports of aHUS triggered by influenza B, making this a unique case. Given the recurrence and atypical features present in this case, a genetic workup was obtained, which showed a heterozygous mutation of complement protein CD46. The presence of mutations in CD46 is a known predisposing factor to aHUS, but influenza B infection is rarely implicated as a trigger to aHUS. The prognosis of aHUS varies and is dependent on the complement mutation specific to the individual., Conclusion: Patients with CD46 mutations have been shown to have high rates of relapse but less long-term kidney damage, as seen in this case. Clinicians should be aware of the association between influenza B and aHUS to improve patient outcomes., Competing Interests: Conflicts of Interest: The authors declare they have no conflicts of interest., (© 2024 HCA Physician Services, Inc. d/b/a Emerald Medical Education.)

A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.

Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1–4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients.

BackgroundWith the introduction of eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment.Case PresentationA nowadays 18-year-old male with a severe, frequently relapsing form of atypical HUS due to a hybrid CFH/CFHR1 gene in combination with the homozygous factor H haplotype, required chronic plasma therapy (PT), including periods with plasma infusion, from the age of onset at 5 months until initiation of eculizumab at the age of 11 years. A mild but stable chronic kidney disease (CKD) and 9 years of disease remission enabled prolongation of eculizumab interval. At the age of 15 years, a sudden yet multifactorial progression of chronic kidney disease (CKD) was observed, without any signs of disease recurrence. However, an acquired glomerulocystic disease, a reduced left kidney function, and abnormal abdominal venous system of unknown etiology were found. In addition, after an aHUS relapse, an unexpected increase in intra-patient variability of eculizumab concentrations was seen. Retrospective pharmacokinetic analysis revealed a change in eculizumab clearance, associated with a simultaneous increase in proteinuria.ConclusionHigh intra-patient variability of eculizumab pharmacokinetics were observed over time, emphasizing the necessity for adequate and continuous therapeutic drug monitoring in aHUS patients. Eculizumab serum trough levels together with complement activation markers (CH50) should be frequently assessed, especially during tapering of drug therapy and/or changing clinical conditions in the patient. In addition, an increase in proteinuria could result in urinary eculizumab loss, indicating that urinary monitoring of eculizumab may be important in aHUS patients with an unexplained decline in serum concentrations.

Objective: Although the definitive diagnosis of atypical hemolytic uremic syndrome (aHUS) depends on a genetic analysis for the complement factors, such a genetic analysis is time-consuming and expensive. We examined the usefulness of a diagnostic scoring system for aHUS. Methods: The thrombotic microangiopathy (TMA) scoring system consists of hemoglobin, the platelet count, creatinine levels and organ failure, and the aHUS scoring system consists of past history and family history of TMA, age at onset, prodromal symptoms and “red or brownish urine”, and these scoring system were both evaluated in patients with aHUS, thrombotic thrombocytopenic purpura or secondary TMA. Results: In a receiver operating characteristics analysis, an adequate cut-off value for diagnosing aHUS, TTP, other TMA or all TMA versus patients without TMA was 7 points for both TMA screening scores. The area under the curve was 0.965 for the TMA screening score and 0.966 for the aHUS score. An adequate cut-off value for diagnosing aHUS was 2 points for a positive aHUS score, - 3 points for an exclusion aHUS score and 0 points for the total aHUS score. Conclusion: The TMA screening and aHUS score systems are useful for making a diagnosis of aHUS without performing specific laboratory tests.

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

The complement system alternative pathway (AP) can be activated excessively in inflammatory diseases, particularly when there is defective complement regulation. For instance, deficiency in complement regulators CD55 and CD59, leads to paroxysmal nocturnal hemoglobinuria (PNH), whereas Factor H mutations predispose to atypical hemolytic uremic syndrome (aHUS), both causing severe thrombohemolysis. Despite eculizumab being the treatment for these diseases, benefits vary considerably among patients. Understanding the molecular mechanisms involved in complement regulation is essential for developing new treatments. Properdin, the positive AP regulator, is essential for complement amplification by stabilizing enzymatic convertases. In this study, the role of properdin in red blood cell (RBC) lysis and endothelial cell opsonization in these AP-mediated diseases was addressed by developing in vitro assays using PNH patient RBCs and human primary endothelial cells, where the effects of inhibiting properdin, using novel monoclonal antibodies (MoAbs) that we generated and characterized, were compared to other complement inhibitors. In in vitro models of PNH, properdin inhibition prevented hemolysis of patient PNH type II and III RBCs more than inhibition of Factor B, C3, and C5 (>17-fold, or >81-fold, or >12-fold lower molar IC90 values, respectively). When tested in an in vitro aHUS hemolysis model, the anti-properdin MoAbs had 11-fold, and 86-fold lower molar IC90 values than inhibition of Factor B, or C3, respectively (P < 0.0001). When comparing target/inhibitor ratios in all hemolysis assays, inhibiting properdin was at least as efficient as the other complement inhibitors in most cases. In addition, using in vitro endothelial cell assays, the data indicate a critical novel role for properdin in promoting complement activation on human endothelial cells exposed to heme (a hemolysis by-product) and rH19-20 (to inhibit Factor H cell-surface protection), as occurs in aHUS. Inhibition of properdin or C3 in this system significantly reduced C3 fragment deposition by 75%. Altogether, the data indicate properdin is key in promoting RBC lysis and complement activation on human endothelial cells, contributing to the understanding of PNH and aHUS pathogenesis. Further studies to determine therapeutic values of inhibiting properdin in complement-mediated diseases, in particular those that are characterized by AP dysregulation, are warranted.

The unexpected occurrence of thrombotic microangiopathy (TMA), characterised by microangiopathic haemolytic anaemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA in patients with metastatic cancer can be a manifestation of the malignancy itself or a therapeutic complication. Distinguishing the cause of TMA is complicated but clinically important to initiate appropriate treatment of metastatic cancer and avoid potential drug toxicity. Eculizumab, which inhibits alternative complement pathway activation, has been shown to be effective in chemotherapy-induced TMA. We report the case of a 69-year-old woman with breast cancer who experienced a mitomycin-C-induced TMA manifestation. TMA did not respond to conservative therapy, plasmapheresis or rituximab and rapidly lead to dialysis dependency. Despite disease progression and metastases, eculizumab treatment was associated with recovered renal function and enabled the patient to avoid dialysis, improving her quality of life.

Preeclampsia is a pregnancy-specific disorder affecting ca 3% of all pregnant women. Preeclampsia is the source of severe pregnancy complications. Later life consequences for mother and infant include increased risk of cardiovascular disease. Preeclampsia is caused by the dysfunction of the endothelium with subsequent activation of complement and coagulation systems. HELLP syndrome is considered to be an extreme complication of preeclampsia but it can also present independently. Diagnostic symptoms in HELLP syndrome are Hemolysis, Elevated Liver enzymes, and Low Platelets. Similar phenotype is present in thrombotic microangiopathies (TMAs) and HELLP syndrome is considered part of the TMA spectrum. Here, we present a case of severe preeclampsia and HELLP syndrome, which exacerbated rapidly and eventually led to need of intensive care, plasma exchange, and hemodialysis. The patient showed signs of hemolysis, disturbance in the coagulation, and organ damage in liver and kidneys. After comprehensive laboratory testing and supportive care, the symptoms did not subside and treatment with complement C5 inhibitor eculizumab was started. Thereafter, the patient started to recover. The patient had pregnancy-induced aHUS. Earlier initiation of eculizumab treatment may potentially shorten and mitigate the disease and hypothetically decrease future health risks of preeclamptic women.

Abstract Background Cobalamin C (cblC) defect is the most common inborn error of Vitamin B12 metabolism often causing severe neurological, renal, gastrointestinal and hematological symptoms. Onset with pulmonary hypertension (PAH) and atypical hemolytic-uremic syndrome (aHUS) is rare. Case presentation We describe the case of a 2-years old child, previously in good health, admitted to the hospital with severe respiratory symptoms, rapid worsening of clinical conditions, O2 desaturation and palmo-plantar edema. The patient showed PAH and laboratory findings compatible with aHUS. cblC defect, an inborn error of metabolism, was identified as the cause of all the symptoms described (cardiac, respiratory and renal involvement). Results of neonatal screening for inborn errors of metabolism had been negative. Administration of IM OHCbl (intramuscular hydroxocobalamin), oral betaine and symptomatic treatment with diuretics and anti-hypertensive systemic and pulmonary drugs induced dramatic improvement of both cardiac and systemic symptoms. Conclusions In this case of cblC defect the metabolic treatment completely reverted symptoms of aHUS and PAH. The course was favorable, and the prognosis is what we foresee for the future.

Background: With the introduction of eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment. Case Presentation: A nowadays 18-year-old male with a severe, frequently relapsing form of atypical HUS due to a hybrid CFH/CFHR1 gene in combination with the homozygous factor H haplotype, required chronic plasma therapy (PT), including periods with plasma infusion, from the age of onset at 5 months until initiation of eculizumab at the age of 11 years. A mild but stable chronic kidney disease (CKD) and 9 years of disease remission enabled prolongation of eculizumab interval. At the age of 15 years, a sudden yet multifactorial progression of chronic kidney disease (CKD) was observed, without any signs of disease recurrence. However, an acquired glomerulocystic disease, a reduced left kidney function, and abnormal abdominal venous system of unknown etiology were found. In addition, after an aHUS relapse, an unexpected increase in intra-patient variability of eculizumab concentrations was seen. Retrospective pharmacokinetic analysis revealed a change in eculizumab clearance, associated with a simultaneous increase in proteinuria. Conclusion: High intra-patient variability of eculizumab pharmacokinetics were observed over time, emphasizing the necessity for adequate and continuous therapeutic drug monitoring in aHUS patients. Eculizumab serum trough levels together with complement activation markers (CH50) should be frequently assessed, especially during tapering of drug therapy and/or changing clinical conditions in the patient. In addition, an increase in proteinuria could result in urinary eculizumab loss, indicating that urinary monitoring of eculizumab may be important in aHUS patients with an unexplained decline in serum concentrations. [ABSTRACT FROM AUTHOR]

Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1–4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients. [ABSTRACT FROM AUTHOR]

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented. [ABSTRACT FROM AUTHOR]

Objectives:DGKE mutations can lead to hemolysis and thrombus in patients with atypical hemolytic uremic syndrome (aHUS). However, the sequence variants of DGKE in Chinese patients with aHUS have not been reported, and the protein function and crystal structure of DGKE remain unresolved. Methods: Targeted exome sequencing was accomplished in one affected patient from each family using the Illumina NextSeq 500 platform. Protein modeling and functional analysis in DGKE were also performed to understand the impact of identified variants on the phenotype. Results: We report a novel compound heterozygous mutation in the DGKE gene in a Chinese consanguineous family in which a child was diagnosed with aHUS, which includes a c.231C>G missense mutation and a c.790_791delTG frameshift mutation derived from his father and mother, respectively. Our bioinformatic analysis suggested that the allelic mutations at different sites in DGKE yield abnormal crystal structures and conformations, leading to dysregulation of its downstream signaling. Conclusions: Our study further expands the spectrum of the sequence variants reported in the DGKE gene and also indicates that different races may have different DGKE variants. Moreover, the altered structures and conformations, caused by DGKE mutations, disrupt the binding of DGKE with its partners, and leading to the occurrence of aHUS. [ABSTRACT FROM AUTHOR]

Ravulizumab, engineered from eculizumab, provides sustained C5 inhibition in atypical hemolytic uremic syndrome (aHUS) while reducing dosing frequency (every 8 vs 2 weeks, respectively). Treatment choice often carries significant financial implications. This study compared the economic consequences of ravulizumab and eculizumab for treating aHUS. A cost-minimization model compared direct medical costs for ravulizumab and eculizumab in treating aHUS, assuming equivalent efficacy and safety, and took a US payer perspective, a lifetime horizon, and a 3.0% cost discount rate. The base case modeled adult and pediatric treatment-naïve populations, with characteristics based on clinical trials, and treatment patterns (duration, discontinuation, re-initiation) derived from eculizumab studies with long-term follow-up. Treatment costs (2019 US$) were based on wholesale drug acquisition costs, Centers for Medicare & Medicaid fee schedules, and published disease management studies. Sensitivity analyses were conducted by adjusting relevant variables. Ravulizumab provided lifetime per-patient cost reductions (discounted) of 32.4% and 35.5% vs eculizumab in adult and pediatric base cases, respectively. Total costs for ravulizumab vs eculizumab were $12,148,748 and $17,979,007, respectively, for adults, and $11,587,832 and $17,959,814, respectively, for children. Pre-discontinuation treatment contributed the largest proportion of total costs for ravulizumab (94.8% and 88.0%) and eculizumab (94.8% and 87.8%) in adults and children, respectively. Across sensitivity analyses, ravulizumab provided cost reductions vs eculizumab. The model included several typical assumptions. Base case patients with more severe stages of chronic kidney disease were assumed not to discontinue treatment, nor to experience an excess mortality risk in either treatment arm, which may not reflect real-world clinical observations. Additionally, rebates and discounts on medication acquisition or administration were not considered. In US patients with aHUS, ravulizumab provided cost reductions of 32.4–35.5% vs eculizumab, with a reduced dosing frequency for ravulizumab. The magnitude of reductions was consistent across sensitivity analyses. [ABSTRACT FROM AUTHOR]

The complement system alternative pathway (AP) can be activated excessively in inflammatory diseases, particularly when there is defective complement regulation. For instance, deficiency in complement regulators CD55 and CD59, leads to paroxysmal nocturnal hemoglobinuria (PNH), whereas Factor H mutations predispose to atypical hemolytic uremic syndrome (aHUS), both causing severe thrombohemolysis. Despite eculizumab being the treatment for these diseases, benefits vary considerably among patients. Understanding the molecular mechanisms involved in complement regulation is essential for developing new treatments. Properdin, the positive AP regulator, is essential for complement amplification by stabilizing enzymatic convertases. In this study, the role of properdin in red blood cell (RBC) lysis and endothelial cell opsonization in these AP-mediated diseases was addressed by developing in vitro assays using PNH patient RBCs and human primary endothelial cells, where the effects of inhibiting properdin, using novel monoclonal antibodies (MoAbs) that we generated and characterized, were compared to other complement inhibitors. In in vitro models of PNH, properdin inhibition prevented hemolysis of patient PNH type II and III RBCs more than inhibition of Factor B, C3, and C5 (>17-fold, or >81-fold, or >12-fold lower molar IC90 values, respectively). When tested in an in vitro aHUS hemolysis model, the anti-properdin MoAbs had 11-fold, and 86-fold lower molar IC90 values than inhibition of Factor B, or C3, respectively (P < 0.0001). When comparing target/inhibitor ratios in all hemolysis assays, inhibiting properdin was at least as efficient as the other complement inhibitors in most cases. In addition, using in vitro endothelial cell assays, the data indicate a critical novel role for properdin in promoting complement activation on human endothelial cells exposed to heme (a hemolysis by-product) and rH19-20 (to inhibit Factor H cell-surface protection), as occurs in aHUS. Inhibition of properdin or C3 in this system significantly reduced C3 fragment deposition by 75%. Altogether, the data indicate properdin is key in promoting RBC lysis and complement activation on human endothelial cells, contributing to the understanding of PNH and aHUS pathogenesis. Further studies to determine therapeutic values of inhibiting properdin in complement-mediated diseases, in particular those that are characterized by AP dysregulation, are warranted. [ABSTRACT FROM AUTHOR]

Background: Medical investigation is a favorite application of Ockham's razor, in virtue of which when presented with competing hypotheses, the solution with the fewest assumptions should be privileged. Hemolytic uremic syndrome (HUS) encompasses diseases with distinct pathological mechanisms, such as HUS due to shiga-like toxin-producing bacteria (STEC-HUS) and atypical HUS, linked to defects in the alternate complement pathway. Other etiologies such as Parvovirus B19 infection are exceptional. All these causes are rare to such extent that we usually consider them mutually exclusive. We report here two cases of HUS that could be traced to multiple causes.Cases Presentation: Case 1 presented as vomiting and diarrhea. All biological characteristics of HUS were present. STEC was found in stool (by PCR and culture). After initial remission, a recurrence occurred and patient was started on Eculizumab. Genetic analysis revealed the heterozygous presence of a CFHR1/CFH hybrid gene. The issue was favorable under treatment. In case 2, HUS presented as fever, vomiting and purpura of the lower limbs. Skin lesions and erythroblastopenia led to suspect Parvovirus B19 primo-infection, which was confirmed by peripheral blood and medullar PCR. Concurrently, stool culture and PCR revealed the presence of STEC. Evolution showed spontaneous recovery.Conclusions: Both cases defy Ockham's razor in the sense that multiple causes could be traced to a single outcome; furthermore, they invite us to reflect on the physiopathology of HUS as they question the classical distinction between STEC-HUS and atypical HUS. We propose a two-hit mechanism model leading to HUS. Indeed, in case 1, HUS unfolded as a result of the synergistic interaction between an infectious trigger and a genetic predisposition. In case 2 however, it is the simultaneous occurrence of two infectious triggers that led to HUS. In dissent from Ockham's razor, an exceptional disease such as HUS may stem from the sequential occurrence or co-occurrence of several rare conditions. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathies (TMA) are a heterogeneous group of red cell fragmentation syndromes characterized by a tendency for thrombosis and pathognomonic red cell fragments in peripheral blood, which results in thrombosis in the microvasculature due to endothelial damage. Genomic investigations into inherited TMAs are of diagnostic, prognostic and therapeutic value. Here, we present two cases that capture the importance of performing genomic testing in rare disorders. Treatment options for these conditions, such as plasma exchange and monoclonal antibodies against complement factors, are intensive and expensive health care interventions. The results of genomic investigation into rare TMAs can better inform the clinicians and their patients of prognosis and suitable personalized treatment options. [ABSTRACT FROM AUTHOR]

Preeclampsia is a pregnancy-specific disorder affecting ca 3% of all pregnant women. Preeclampsia is the source of severe pregnancy complications. Later life consequences for mother and infant include increased risk of cardiovascular disease. Preeclampsia is caused by the dysfunction of the endothelium with subsequent activation of complement and coagulation systems. HELLP syndrome is considered to be an extreme complication of preeclampsia but it can also present independently. Diagnostic symptoms in HELLP syndrome are Hemolysis, Elevated Liver enzymes, and Low Platelets. Similar phenotype is present in thrombotic microangiopathies (TMAs) and HELLP syndrome is considered part of the TMA spectrum. Here, we present a case of severe preeclampsia and HELLP syndrome, which exacerbated rapidly and eventually led to need of intensive care, plasma exchange, and hemodialysis. The patient showed signs of hemolysis, disturbance in the coagulation, and organ damage in liver and kidneys. After comprehensive laboratory testing and supportive care, the symptoms did not subside and treatment with complement C5 inhibitor eculizumab was started. Thereafter, the patient started to recover. The patient had pregnancy-induced aHUS. Earlier initiation of eculizumab treatment may potentially shorten and mitigate the disease and hypothetically decrease future health risks of preeclamptic women. [ABSTRACT FROM AUTHOR]

Complement convertases are enzymatic complexes, which play a critical role in propagation and amplification of the complement cascade. Under physiological conditions, convertases decay shortly after being formed in either spontaneous or inhibitor-driven process. Prolongation of their half-life by C3NeF autoantibodies that prevent convertase dissociation results in pathogenic condition often manifested by renal diseases. However, the diagnosis of convertase abnormalities is difficult due to the labile nature of these enzymes and low credibility of existing methods. Only recently, two-step functional assays employing C5-depleted serum or C5 inhibitors were introduced. Their advantage is convertase formation in the physiological milieu of whole serum and the drawback is inter-assay variability due to variations in rabbit erythrocytes used for the haemolysis-based readout. Abovementioned problems demand the application of the internal standard in each experiment. Obtaining a defined preparation of autoantibodies is complicated due to ethical and practical considerations. We found that recombinant, his-tagged factor B (fB) variant K323E retains full hemolytic activity and possess the ability to form convertases with prolonged half-life either in fB-depleted serum or when mixed with normal human serum. Such dominant character of K323E mutation allows using recombinant protein as a reference in functional convertase assays, not limited to these using rabbit erythrocytes. Additionally, our results demonstrate that gain of function mutations in complement components mimic the phenotype of C3NeF. Hence, patients with such “genetic C3NeF” would not benefit from B-cell depletion (e.g. by rituximab) and therefore should be properly diagnosed in order to choose suitable therapeutic intervention.

Abstract Background The differential diagnosis of thrombotic microangiopathy (TMA) is complex however the rapid diagnosis of the underlying condition is vital to inform urgent treatment decisions. A survey was devised with the objective of understanding current practices across Europe and the Middle East, and of challenges when diagnosing the cause of TMA. Methods Over 450 clinicians, from 16 countries were invited to complete an online survey. Results Of 254 respondents, the majority were nephrologists, had >10 years’ experience in their specialty, and had diagnosed a patient with TMA. The triad of thrombocytopenia, haemolytic anaemia and acute kidney injury are the main diagnostic criteria used. Responses indicate that a differential diagnosis of TMA is usually made within 1–2 (53%) or 3–4 days (26%) of presentation. Similarly, therapy is usually initiated within the first 4 days (74%), however 13% report treatment initiation >1-week post-presentation. Extrarenal symptoms and a panoply of other conditions are considered when assessing the differential diagnosis of TMA. While 70 and 78% of respondents stated they always request complement protein levels and ADAMTS13 activity, respectively. Diagnostic considerations of paediatric and adult nephrologists varied. A greater proportion of paediatric than adult nephrologists consider extrarenal manifestations clinically related to a diagnosis of TMA; pulmonary (45% vs. 18%), gastrointestinal (67% vs. 50%), CNS (96% vs. 84%) and cardiovascular (54% vs. 42%), respectively. Variability in the availability of guidelines and extent of family history taken was also evident. Conclusions This survey reveals the variability of current practices and the need for increased urgency among physicians in the differential diagnosis of TMA, despite their experience. Above all, the survey highlights the need for international clinical guidelines to provide systematically developed recommendations for understanding the relevance of complement protein levels, complement abnormalities and ADAMTS13 testing, in making a differential diagnosis of TMA. Such clinical guidelines would enable physicians to make a more rapid and informed diagnosis of TMA, therefore initiate effective treatment earlier, with a consequent improvement in patient outcomes.

An 11-year-old patient presented with the primary complaint of hematuria and vomiting. On further investigation and a series of diagnostic tests, including a biopsy and thrombotic microangiopathy (TMA) profile, the patient was diagnosed with thrombotic microangiopathy. TMA is a pathological process involving endothelial cell injury, leading to thrombocytopenia and microangiopathic hemolytic anemia. This case highlights the importance of considering TMA in pediatric patients presenting with nonspecific symptoms, such as loss of appetite. Further research is needed to understand the pathophysiology and optimal management strategies for pediatric TMA. This case adds to the growing body of literature on pediatric TMA and underscores the need for a high index of suspicion in similar clinical scenarios., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Singh et al.)

Introduction: The complement system serves as a crucial defense mechanism against invading pathogens; however, dysregulation of this system can result in harmful consequences. Central to the complement cascade are the classical pathway (CP) or lectin pathway (LP) and the alternative pathway (AP) convertases. Aberrant regulation of the convertases is often implicated in the development of rare complement-related diseases. However, analyzing convertase activity poses a significant challenge due to their labile nature and intricate interactions with serum proteins., Methods: In this study, we propose a novel assay for the functional evaluation of these complexes. Our approach leverages a widely available human lymphoma cell line, which when sensitized with antibodies, triggers activation of the CP with a substantial amplification by the AP. The combined action of 2, C5 blockers eculizumab and crovalimab let the cascade proceed up to the level of convertases but not further. In the next step, C5 inhibitors were washed away and guinea pig serum in ethylenediamine tetraacetic acid (EDTA) buffer supported the development of lytic sites on the platform of preexisting convertases., Results: The assay detects recombinant gain-of-function (GoF) components of both convertase types within human serum or plasma. Furthermore, we demonstrate the assay's practical utility in analyzing nephrological patients harboring C3 genetic variants and illustrate its capacity to distinguish between patients and asymptomatic relatives carrying the same pathogenic C3 variant., Conclusion: We provided a proof-of-concept of a new assay that detects convertase overactivity in individuals carrying variants of both pathogenic character or those of unknown significance in ubiquitous complement proteins such as C3., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Atypical hemolytic uremic syndrome (aHUS) poses a significant health challenge due to its rarity and severity within the spectrum of thrombotic microangiopathy. Despite efforts to optimize and personalize health care for patients with aHUS, understanding the individual experiences, needs, and desires of patients with aHUS and their relatives remains limited., Methods: Here, we present a nationwide, exploratory, qualitative interview study with a direct content analysis approach. In-depth interviews and a 6-week evaluation were audio-recorded and conducted using a semistructured topic guide, based on the Institute for Positive Health (IPH) model., Results: Analysis of 10 interviews involving 6 patients with aHUS and 13 relatives revealed the prevalence of long-term disease symptoms in adult patients, notably fatigue, which significantly impacted daily functioning. Moreover, the resilience demonstrated by patients and their relatives was noteworthy; however, the acute phase of aHUS and the unpredictable nature of disease recurrence could profoundly affect mental well-being. The emotional toll of aHUS is pervasive, with feelings of fear, guilt, and trauma persisting across disease phases in both patients and relatives. Challenges in medical care, including delays in diagnosis and the need for personalized and uniform protocols, were highlighted. Support was deemed crucial, indicating the necessity for enhancements in the accessibility to comprehensible disease information and psychological counseling. Finally, complexities surrounding genetic testing and carriership were discussed., Conclusion: This study underscores the profound, enduring, and multifaced impact of aHUS. The insights gleaned from the experiences and needs of patients with aHUS and their relatives could lay the foundation for development and implementation of more personalized innovations in aHUS health care., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a complement system (CS)-mediated ultrarare disease that manifests as thrombotic microangiopathy (TMA) with preferential small kidney vessels involvement. Transient CS activation is also observed in secondary TMA or in patients at risk of developing aHUS. There is no gold standard test to monitor disease activity; however, the ex vivo C5b-9 deposition test seems to be a good approach., Methods: We assessed the C5b-9 deposition induced by serum samples of patients with aHUS ( n  = 8) and with TMA associated with kidney ( n  = 2), lung ( n  = 1) or hematopoietic stem cell (HSC) transplantation (HSCT, n  = 2) during the acute phase of the disease or in remission. As control for transplant-associated TMA (TA-TMA), we analyzed samples of clinically stable kidney and HSC-transplanted patients without signs of TMA. In addition, we studied 1 child with genetic risk of aHUS during an acute infection., Results: In the acute disease phase or in patients with disease activity despite C5 blockade, a significant increase of C5b-9 deposition was detected. In all patients with clinical response to C5 blockade but one, levels of C5b-9 deposition were within the normal range. Finally, we detected increased C5b-9 deposition levels in an asymptomatic child with genetic risk of aHUS when a concomitant otitis episode was ongoing., Conclusion: The ex vivo C5b-9 deposition test is an auspicious tool to monitor CS activity in aHUS and TA-TMA. In addition, we demonstrate that the test may be useful to detect subclinical increase of CS activity, which expands the spectrum of patients that would benefit from a better CS activity assessment., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis in terms of frequent relapses. Although eculizumab is an effective treatment for this type of aHUS, the method of eculizumab discontinuation is not yet established. Herein, we report a case of anti-CFH Ab-associated aHUS in a 6-year-old boy. Eculizumab induction therapy following plasma exchange improved his condition. After 14 months, eculizumab was discontinued because of meningococcal bacteremia. After 6 months of eculizumab cessation, prednisolone (20 mg/alternate days) and mycophenolate mofetil (500 mg/day) were initiated. There were no relapses or increases in anti-CFH Ab titers for 26 months after treatment initiation. We believe that eculizumab induction therapy, following plasma exchange and maintenance therapy with immunosuppressants after eculizumab discontinuation are effective treatments for anti-CFH Ab-related aHUS. [ABSTRACT FROM AUTHOR]

Background: Eculizumab has caused a revolution in the treatment and prognosis of atypical hemolytic uremic syndrome. Early initiation of treatment is recommended to increase chances of renal recovery. Case-diagnosis/treatment: We describe a boy with atypical hemolytic uremic syndrome who started eculizumab therapy after being on dialysis for 4.5 months, with complete anuria. With treatment, he was weaned off dialysis. Conclusion: We review the evidence in the literature and discuss the possible mechanism by which eculizumab induces renal recovery even in patients already on prolonged dialysis. This case report highlights the importance of a treatment trial with eculizumab, even in patients already on prolonged dialysis. [ABSTRACT FROM AUTHOR]

Defective complement action is a cause of several human glomerular diseases including atypical hemolytic uremic syndrome (aHUS), anti-neutrophil cytoplasmic antibody mediated vasculitis (ANCA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, ischemic reperfusion injury, lupus nephritis, membranous nephropathy, and chronic transplant mediated glomerulopathy. Here we summarize ongoing clinical trials of complement inhibitors in nine glomerular diseases and show which inhibitors are used in trials for these renal disorders (http://clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Summary: The complement inhibitor, eculizumab, has revolutionised the management of atypical haemolytic uraemic syndrome (aHUS), although the optimum treatment duration is debated. Twenty‐two cases of acute aHUS managed with eculizumab were retrospectively reviewed, including outcomes after eculizumab withdrawal. Although 41% had an associated complement genetic abnormality, mutation status did not affect severity of clinical presentation. Sixty‐four percent required renal replacement acutely, with a high incidence of nephrotic range proteinuria (47%). Eculizumab followed a median of 6 days of plasma exchange. After a median duration of therapy of 11 weeks (range 1–227), haematological recovery was seen in 100%, while 81% achieved at least partial renal recovery (median increase in estimated glomerular filtration rate (eGFR) 49 ml/min/1·73 m2). At median duration of follow‐up of 85 weeks (range 4–255), 54·5% had eGFR ≥ 60 ml/min/1·73 m2, 27% had CKD, 14% were on dialysis, and 4·5% had died. Eculizumab was withdrawn in 59% (13/22) cases following complete haematological and renal recovery. Three of these 13 patients (23%) subsequently relapsed, with defined triggers in 2/3, but all made a full recovery with rapid resumption of eculizumab. There was a significant association between higher presenting creatinine and poorer renal outcomes. A strategy of eculizumab withdrawal in selected cases is both safe and cost effective. [ABSTRACT FROM AUTHOR]

Highlights from the article: AHUS that renders the appellation aHUS misleading. Prognosis of these patients without aHUS-specific therapy or Patients with aHUS died, required renal replacement therapy or Trials in the use of plasmapheresis in aHUS, aHUS arising The presence of aHUS in a complement amplifying disease is from an unmasking of a primary aHUS or from a complement storm in the setting of direct endothelial.

The human complement system is an important part of the immune system responsible for lysis and elimination of invading microorganisms and apoptotic body cells. Improper activation of the system due to deficiency, mutations, or autoantibodies of complement regulators, mainly factor H (FH) and FH-related proteins (FHRs), causes severe kidney and eye diseases. However, there is no recombinant FH therapeutic available on the market. The first successful recombinant production of FH was accomplished with the moss bioreactor, Physcomitrella patens. Recently, a synthetic regulator, MFHR1, was designed to generate a multitarget complement inhibitor that combines the activities of FH and the FH-related protein 1 (FHR1). The potential of MFHR1 was demonstrated in a proof-of-concept study with transiently transfected insect cells. Here, we present the stable production of recombinant glyco-engineered MFHR1 in the moss bioreactor. The key features of this system are precise genome engineering via homologous recombination, Good Manufacturing Practice-compliant production in photobioreactors, high batch-to-batch reproducibility, and product stability. Several potential biopharmaceuticals are being produced in this system. In some cases, these are even biobetters, i.e., the recombinant proteins produced in moss have a superior quality compared to their counterparts from mammalian systems as for example moss-made aGal, which successfully passed phase I clinical trials. Via mass spectrometry-based analysis of moss-produced MFHR1, we now prove the correct synthesis and modification of this glycoprotein with predominantly complex-type N-glycan attachment. Moss-produced MFHR1 exhibits cofactor and decay acceleration activities comparable to FH, and its mechanism of action on multiple levels within the alternative pathway of complement activation led to a strong inhibitory activity on the whole alternative pathway, which was higher than with the physiological regulator FH. [ABSTRACT FROM AUTHOR]

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Abstract Background Patients are becoming increasingly involved in research which can promote innovation through novel ideas, support patient-centred actions, and facilitate drug development. For rare diseases, registries that collect data from patients can increase knowledge of the disease’s natural history, evaluate clinical therapies, monitor drug safety, and measure quality of care. The active participation of patients is expected to optimise rare-disease management and improve patient outcomes. However, few reports address the type and frequency of interactions involving patients, and what research input patient groups have. Here, we describe a collaboration between an international group of patient organisations advocating for patients with atypical haemolytic uraemic syndrome (aHUS), the aHUS Alliance, and an international aHUS patient registry (ClinicalTrials.gov NCT01522183). Results The aHUS Registry Scientific Advisory Board (SAB) invited the aHUS Alliance to submit research ideas important to patients with aHUS. This resulted in 24 research suggestions from patients and patient organisations being presented to the SAB. The proposals were classified under seven categories, the most popular of which were understanding factors that cause disease manifestations and learning more about the clinical and psychological/social impact of living with the disease. Subsequently, aHUS Alliance members voted for up to five research priorities. The top priority was: “What are the outcomes of a transplant without eculizumab and what non-kidney damage is likely in patients with aHUS?”. This led directly to the initiation of an ongoing analysis of the data collected in the Registry on patients with kidney transplants. Conclusion This collaboration resulted in several topics proposed by the aHUS Alliance being selected as priority activities for the aHUS Registry, with one new analysis already underway. A clear pathway was established for engagement between a patient advocacy group and an international research network. This should ensure the development of a long-term partnership which clearly benefits both groups.

The aim of the experiment was to confirm the hypothesis about the possibility of Scandinavian bead makers crafting complex mosaic glass beads. For this purpose, raw glass material and tools from archaeological sites were examined. Metal tools and glass mosaic canes were made, for the purpose of the experiment, based on archaeological finds. All the glass beads were made during the experiment on a specially constructed open hearth. As a result of the experiments, the possibility of making mosaic glass beads on an open hearth was confirmed. A theoretical and practical procedure for making complex glass beads has been proposed.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA), which copresents with microangiopathic hemolytic anemia, thrombocytopenia, and kidney injury. While typical HUS is normally preceded by infections such as Shiga-toxin-producing  Escherichia coli,  atypical HUS (aHUS) has a genetic component that leads to dysregulation of the alternative complement pathway. We report a case of a 69-year-old female who developed aHUS after undergoing an elective knee surgery. Genetic testing revealed novel mutations affecting diacylglycerol kinase epsilon (DGKE) protein and complement factor I (CFI) that were not reported before as pathogenic. The patient was treated with eculizumab, leading to the complete resolution of TMA with no lasting organ damage., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Abughanimeh et al.)

The complement system is an important component of innate immunity, which is part of the first line of defense against infections. In addition, complement plays an important role in the removal of apoptotic and damaged endogenous cells and, according to recent discoveries, contributes significantly to the homeostasis of the organism. The complement system includes several dozen soluble and membrane-bound proteins, which, after activation, function as a cascade, at the end of which is the elimination of the infectious agent. Complement activation occurs through one of 3 pathways (classical, lectin, and alternative) and all 3 pathways lead to the central C3 component. The cleavage of C3 starts the activation of the so-called effector terminal cascade, which participates in the elimination of pathogens through pro-inflammatory mechanisms, opsonization and, at the end, the creation of a channel in the basement membrane. The systematic control of complement activation plays an important role, because that represents prevention against damage to one's own tissues. Especially, the alternative pathway, which provides more than 80% of the activity of the terminal complement cascade, requires tight control. Dysregulation of complement and especially its alternative pathways is behind many acute and chronic diseases.

Atypical hemolytic uremic syndrome (aHUS) treatment consists of eculizumab. Severe acute respiratory syndrome coronavirus 2 causes severe pneumonia and endothelial injury that leads to a prothrombotic state that may be complicated by macrovascular and microvascular thrombosis. Complement activation is thought to contribute to endothelial injury and there are at least seven ongoing clinical trials testing six different anti-complement strategies for coronavirus disease 2019 (COVID-19), including eculizumab. We herein report on a kidney transplant patient with aHUS on chronic eculizumab therapy that developed severe COVID-19 despite eculizumab administration early in the course of the disease. Although eculizumab was unable to prevent the development of severe endothelial cell injury, as assessed by increasing D-dimer levels from 292 to 10 586 ng/mL, the patient eventually recovered following dexamethasone and convalescent plasma administration. [ABSTRACT FROM AUTHOR]