Background:C3 glomerulopathy (C3G) is a rare kidney disease caused by uncontrolled activation of the complement alternative pathway (AP), frequently driven by nephritic factors (NeFs) that stabilize the AP C3 and C5 convertases. NeFs are detected in up to 80% of patients and exhibit heterogeneous stabilizing activity, contributing to variable degrees of complement dysregulation. Current complement-targeted therapies reduce complement activation but may compromise immune surveillance by blocking key components of the pathway. Supplementation with the physiological AP regulator factor H (FH) represents an alternative strategy aimed at restoring complement homeostasis while preserving essential immune functions. CPV-104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G. Objectives and Methods:We evaluated the ability of CPV-104 to antagonize NeF-mediated stabilization of the AP C3 convertase (C3bBb) in eight C3G patients enrolled in the Italian MPGN/C3G Registry. Patients were classified as C3NeF+ or C5NeF+ based on properdin dependence in convertase stabilization assays. NeF activity was analyzed using solid-phase assays in which C3bBb decay and formation were assessed in the presence of CPV-104 or serum-derived FH (sd-FH). The impact of CPV-104 ex vivo was tested in fluid-phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA. Results:CPV-104 accelerated decay of NeF-stabilized C3bBb with efficacy comparable to sd-FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV-104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV-104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd-FH. In fluid-phase assays, using patient sera, CPV-104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd-FH across patient samples. Conclusions:CPV-104 effectively limits both stabilization and formation of AP C3 convertases in NeF-positive C3G, demonstrating superior functional activity compared with sd-FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV-104 represents a promising and potentially safer therapeutic strategy for NeF-driven C3G and warrants further clinical investigation.

INTRODUCTION:Membranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate. METHODS:Here, we applied hierarchical clustering to a much larger cohort of patients with C3G/IC-MPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable. RESULTS:Five clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches. CONCLUSIONS:Our proposed strategy may possibly guide anti-complement treatment.

KEY POINTS:This retrospective study analyzed clinical, histological, and biochemical data from a large cohort of participants with biopsy-proven primary C3 glomerulopathy/immune complex-mediated membranoproliferative GN. C3 glomerulopathy and immune complex-mediated membranoproliferative GN subjects shared most baseline and longitudinal features; 10-year kidney survival did not differ across histological subtypes. Older age at onset and higher proteinuria levels at 1 year from biopsy were the strongest predictors of kidney failure. BACKGROUND:Membranoproliferative glomerulonephritides (MPGNs) are defined by a typical glomerular histopathological pattern including C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). The overall prognosis is poor and the treatment options remain limited. Outcome predictors and reliable surrogate endpoints are critically needed for interventional trials. Herein, we described the natural history and analyzed clinical, histological and biochemical data from a large cohort of patients with primary C3G/IC-MPGN. METHODS:This is a retrospective analysis of patients with biopsy-proven primary C3G or IC-MPGN from the Italian Registry of MPGN. Demographic, clinical and histopathological data, molecular complement profiles, treatment patterns, and outcomes were collected. We performed univariable and multivariable Cox regressions and Kaplan-Meier survival analyses to assess risk associations with kidney disease progression. The composite endpoint included ESKD (defined by either eGFR <15 ml/min per 1.73 m 2 , initiation of chronic dialysis or kidney transplantation), doubling of serum creatinine at the last available follow-up, or death by kidney-related causes. RESULTS:Of the 349 patients identified, 208 had C3G and 141 IC-MPGN. Females were 41%, and over half were younger than 18 years old at time of biopsy. C3G and IC-MPGN patients shared most baseline and longitudinal features, with IC-MPGN patients presenting with higher baseline proteinuria (median 4.0 versus 2.3 g/24 hours, P < 0.001). Median eGFR at presentation was 83 ml/min per 1.73 m 2 . Twenty-six percent of patients progressed to ESKD over a median follow-up of 5 years from diagnosis. Higher proteinuria levels at 1 year from biopsy, particularly ≥1 g/24 hours, were significantly associated with a higher risk of adverse kidney outcomes. Pediatric onset was associated with better kidney survival, whereas kidney survival at 10 years did not statistically differ across histological subtypes. Complement dysregulation and rare functional variants in complement genes were not associated with outcomes. CONCLUSIONS:Our findings from a large and well-characterized cohort of individuals with primary C3G/IC-MPGN identify age at onset and proteinuria levels as associations with kidney survival, a finding that should inform future interventional trials.

IntroductionComplement factor H (FH) is a major regulator of the complement alternative pathway, its mutations predispose to an uncontrolled activation in the kidney and on blood cells and to secondary C3 deficiency. Plasma exchange has been used to correct for FH deficiency and although the therapeutic potential of purified FH has been suggested by in vivo experiments in animal models, a clinical approved FH concentrate is not yet available. We aimed to develop a purification process of FH from a waste fraction rather than whole plasma allowing a more efficient and ethical use of blood and plasma donations.MethodsWaste fractions from industrial plasma fractionation (pooled human plasma) were analyzed for FH content by ELISA. FH was purified from unused fraction III and its decay acceleration, cofactor, and C3 binding capacity were characterized in vitro. Biodistribution was assessed by high-resolution dynamic PET imaging. Finally, the efficacy of the purified FH preparation was tested in the mouse model of C3 glomerulopathy (Cfh−/− mice).ResultsOur purification method resulted in a high yield of highly purified (92,07%), pathogen-safe FH. FH concentrate is intact and fully functional as demonstrated by in vitro functional assays. The biodistribution revealed lower renal and liver clearance of human FH in Cfh-/- mice than in wt mice. Treatment of Cfh-/- mice documented its efficacy in limiting C3 activation and promoting the clearance of C3 glomerular deposits.ConclusionWe developed an efficient and economical system for purifying intact and functional FH, starting from waste material of industrial plasma fractionation. The FH concentrate could therefore constitute possible treatments options of patients with C3 glomerulopathy, particularly for those with FH deficiency, but also for patients with other diseases associated with alternative pathway activation.

BackgroundBetween 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed.MethodsIn this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens.ResultsPatients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients.ConclusionsEculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Membranoproliferative glomerulonephritis (MPGN) is a rare chronic nephropathy, affecting predominantly children and young adults and defined by a typical glomerular histopathological pattern of mesangial hypercellularity, endocapillary proliferation and duplication of the glomerular basement membrane. While clinical presentation and outcome are variable, the overall prognosis is poor, with progression to end-stage renal disease (ESRD) in about 40% of cases.

Uncontrolled activation of the alternative pathway (AP) of complement, due to genetic and/or acquired defects, plays a primary pathogenetic role in C3 glomerulopathy (C3G), a rare and heterogeneous disease characterised by predominant C3 fragment deposition within the glomerulus, as well as glomerular damage. There are currently no approved disease-specific treatments for C3G, but new drugs that directly counteract AP dysregulation, targeting components of the pathway, have opened promising new perspectives for managing the disease. Complement factor B (FB), which is primarily synthesised by hepatocytes, is a key component of the AP, as it drives the central amplification loop of the complement system. In this study we used a GalNAc (N-Acetylgalactosamine)-conjugated siRNA to selectively target and suppress liver FB expression in two mouse models characterised by the complete (Cfh-/- mice) or partial (Cfh+/-) loss of function of complement factor H (FH). Homozygous deletion of FH induced a severe C3G phenotype, with strong dysregulation of the AP of complement, glomerular C3 deposition and almost complete C3 consumption. Mice with a heterozygous deletion of FH had intermediate C3 levels and exhibited slower disease progression, resembling human C3G more closely. Here we showed that FB siRNA treatment did not improve serum C3 levels, nor limit glomerular C3 deposition in Cfh-/- mice, while it did normalise circulating C3 levels, reduce glomerular C3 deposits, and limit mesangial electron-dense deposits in Cfh+/- mice. The present data provide important insights into the potential benefits and limitations of FB-targeted inhibition strategies and suggest RNA interference-mediated FB silencing in the liver as a possible therapeutic approach for treating C3G patients with FH haploinsufficiency.

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenia purpura (TTP) are rare diseases sharing a common pathological feature, thrombotic microangiopathy (TMA). TMA is characterized by microvascular thrombosis with consequent thrombocytopenia, microangiopathic hemolytic anemia and/or multiorgan dysfunction. In the past, the distinction between HUS and TTP was predominantly based on clinical grounds. However, clinical presentation of the two syndromes often overlaps and, the differential diagnosis is broad. Identification of underlying pathogenic mechanisms has enabled the classification of these syndromes on a molecular basis: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS or complement-mediated TMA (aHUS/CM-TMA) associated with genetic or acquired defects leading to dysregulation of the alternative pathway (AP) of complement; and TTP that results from a severe deficiency of the von Willebrand Factor (VWF)-cleaving protease, ADAMTS13. The etiology of TMA differs between pediatric and adult patients. Childhood TMA is chiefly caused by STEC-HUS, followed by CM-TMA and pneumococcal HUS (Sp-HUS). Rare conditions such as congenital TTP (cTTP), vitamin B12 metabolism defects, and coagulation disorders (diacylglycerol epsilon mutation) present as TMA chiefly in children under 2 years of age. In contrast secondary causes and acquired ADAMT13 deficiency are more common in adults. In adults, compared to children, diagnostic delays are more frequent due to the wide range of differential diagnoses. In this review we focus on the three major forms of TMA, STEC-HUS, aHUS and TTP, outlining the clinical presentation, diagnosis and management of the affected patients, to help highlight the salient features and the differences between adult and pediatric patients which are relevant for management.

Background. Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidney. It occurs in adulthood but is also rarely diagnosed in early childhood. The majority of the disease-causing variants observed in ADPKD patients are in two genes: PKD1 and PKD2. Methods. 237 patients from 198 families with a clinical diagnosis of ADPKD were screened for PKD1 and PKD2 genetic variants using Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) analysis. Results. Disease-causing (diagnostic) variants were identified in 173 families (211 patients), 156 on PKD1 and 17 on PKD2. Variants of unknown significance (VUS) were detected in 6 additional families, while no mutations were found in the remaining 19 families. Among the diagnostic variants detected, 51 were novel. In ten families, seven large rearrangements were found and the molecular breakpoints of 3 rearrangements were identified. Renal survival was significantly worse for PKD1 mutated patients, particularly those carrying truncating mutations. In patients with PKD1 truncating ( PKD1-T) mutations, disease onset was significantly earlier than in patients with PKD1 non-truncating (PKD1-NT) variants or PKD2 mutated patients. Conclusions. Comprehensive genetic testing confirms its utility in diagnosing patients with ADPKD and contributes to explaining the clinical heterogeneity observed in this disease. Moreover, the genotype-phenotype correlation can allow a more accurate disease prognosis.

Introduction:Atypical hemolytic uremic syndrome (aHUS) is a rare disease that manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, and is associated with dysregulation of the alternative complement pathway. The chromosomal region including CFH and CFHR1-5 is rich in repeated sequences, favoring genomic rearrangements that have been reported in several patients with aHUS. However, there are limited data on the prevalence of uncommon CFH-CFHR genomic rearrangements in aHUS and their impact on disease onset and outcomes.Methods:In this study, we report the results of CFH-CFHR Copy Number Variation (CNV) analysis and the characterization of resulting structural variants (SVs) in a large cohort of patients, including 258 patients with primary aHUS and 92 with secondary forms.Results:We found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving CFH alone or CFH and CFHR (group A; n=14), while 30% exhibited rearrangements including only CFHRs (group B; n=6). In group A, 6 patients presented CFH::CFHR1 hybrid genes, 7 patients carried duplications in the CFH-CFHR region that resulted either in the substitution of the last CFHR1 exon(s) with those of CFH (CFHR1::CFH reverse hybrid gene) or in an internal CFH duplication. In group A, the large majority of aHUS acute episodes not treated with eculizumab (12/13) resulted in chronic ESRD; in contrast, anti-complement therapy induced remission in 4/4 acute episodes. aHUS relapse occurred in 6/7 grafts without eculizumab prophylaxis and in 0/3 grafts with eculizumab prophylaxis. In group B, 5 subjects had the CFHR31-5::CFHR410 hybrid gene and one had 4 copies of CFHR1 and CFHR4. Compared with group A, patients in group B exhibited a higher prevalence of additional complement abnormalities and earlier disease onset. However, 4/6 patients in this group underwent complete remission without eculizumab treatment. In secondary forms we identified uncommon SVs in 2 out of 92 patients: the CFHR31-5::CFHR410 hybrid and a new internal duplication of CFH.Discussion:In conclusion, these data highlight that uncommon CFH-CFHR SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the CFH are associated with a poor prognosis but carriers respond to anti-complement therapy.

Abstract Background Five to 50% of atypical hemolytic and uremic syndrome (aHUS) in children are caused by autoantibodies against complement Factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. Methods In this multicenter, retrospective study, we report the outcome of 12 children with anti-CFH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. Results Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received plasma exchange (PE) or IgG adsorption. Three patients received MMF alone, 1 patient received an association of MMF and steroids, 1 patient received an association of MMF and rituximab, 3 patients received MMF/steroids and rituximab and 4 patients did not receive any immunosuppression. Anti-CFH ab levels significantly decreased but no difference was observed based on the immunosuppressive regimen. ECZ was discontinued in 7/10 patients after 11 [7.5–15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-CFH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70mL/min/1.73m2 in all patients. Conclusion Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-CFH antibodies and renders anti-CFH titers reduction less urgent. Anti-CFH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of associating eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-CFH antibody-associated HUS.

Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage. Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA. In vitro experiments were performed on human microvascular endothelial cells from the derma and lung exposed to SARS-CoV-2-derived spike protein 1 (S1). The expression of adhesive molecules was studied by immunofluorescence and leukocyte adhesion and platelet aggregation were assessed under flow conditions. Angiotensin converting enzyme 2 (ACE2) and AMPK expression were investigated by Western Blot analysis. In addition, S1-treated endothelial cells were incubated with anti-ACE2 blocking antibody, AMPK agonist, or complement inhibitors. Our results show that significant levels of spike protein were found in the 30.4% of severe COVID-19 patients. In vitro, the activation of endothelial cells with S1 protein, via ACE2, impaired AMPK signalling, leading to robust leukocyte recruitment due to increased adhesive molecule expression and thrombomodulin loss. This S1-induced pro-inflammatory phenotype led to exuberant C3 and C5b-9 deposition on endothelial cells, along with C3a and C5a generation that further amplified S1-induced complement activation. Functional blockade of ACE2 or complement inhibition halted S1-induced platelet aggregates by limiting von Willebrand factor and P-selectin exocytosis and expression on endothelial cells. Overall, we demonstrate that SARS-CoV-2-derived S1 is sufficient in itself to propagate inflammatory and thrombogenic processes in the microvasculature, amplified by the complement system, recapitulating the thromboembolic complications of COVID-19.

IntroductionPregnancy and postpartum are triggers for various forms of thrombotic microangiopathy (TMA), a lesion characterized by endothelial injury and thrombosis in the microcirculation of various organs. These forms include thrombotic thrombocytopenic purpura (TTP), caused by ADAMTS13 deficiency, and atypical hemolytic uremic syndrome (aHUS), most often associated with genetically determined dysregulation of complement system. HUS is the most common form of TMA in the post-partum period. The diagnosis of pregnancy-associated HUS can be difficult because preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome may present with clinical and laboratory features of TMA that however commonly resolve spontaneously after delivery.Here, we report the biochemical and genetic characterization of a 22 years old primigravida of African origin who presented at 38 weeks of gestation with severe hypertension, nephrotic syndrome (NS) and elevated liver enzymes, consistent with a diagnosis of HELLP. However, after an emergency delivery, the patient developed post-partum HUS with thrombocytopenia, hemolytic anemia, increased LDH and acute kidney injury.The patient received antihypertensives, fresh frozen plasma and packed red cell transfusions. From day 11 post-partum the patient also received antibiotics for sepsis by Klebsiella pneumoniae.Within day 18 post-partum blood pressure normalized and TMA resolved. However, NS persisted and renal biopsy (performed 13 days after delivery) disclosed a focal segmental glomerulosclerosis (FSGS) pattern with the collapsing variant.MethodsGenetic analyses included Next Generation Sequencing, to evaluate the presence of rare genetic variants in complement aHUS-associated genes (CFH, CD46, CFI, CFB, C3, THBD, and DGKE), and Multiplex Ligation-dependent probe amplification (MLPA), to investigate the copy number variations (CNVs) in the genomic region of CFH-CFHR1-5 genes. Proband serum (collected 14 days post-partum) was used to evaluate the FHR protein pattern by Western blot (WB) and to test C5b-9 deposition on human microvascular endothelial cells (HMEC-1), as marker of complement activation.ResultsAt the time of sample collection, platelet count and s-creatinine were normal, but anemia was still present, LDH was elevated, leucocytes were increased and proteinuria was still in nephrotic range. Complement profile showed normal C3 and C4 levels but elevated plasma sC5b-9 (615 ng/ml, nv <400). ADAMTS13 was normal.Proband serum caused higher than normal C5b-9 deposits on HMEC-1 (179%; nv <150%) indicating endothelial complement activation. Genetic results provided abnormal CNVs in the CFHR5 gene with deletion of coding regions from exon 4 to exon 9. WB analysis revealed a shorter than normal FHR5 protein (~20 kDa) consistent with the predicted product of the CFHR5 deleted gene.ConclusionsWe hypothesize that mutant FHR5 protein contributed to complement dysregulation predisposing to post-partum HUS. CFHR5 abnormalities were found in aHUS and also in other glomerulopathies (IgA nephropathy and C3 glomerulopathy). Cases with combined FSGS and HUS have been previously reported, but none in association with pregnancy. Functional studies are required to elucidate the pathogenic role of the FHR5 abnormality in the complex clinical picture here presented.No conflict of interest IntroductionPregnancy and postpartum are triggers for various forms of thrombotic microangiopathy (TMA), a lesion characterized by endothelial injury and thrombosis in the microcirculation of various organs. These forms include thrombotic thrombocytopenic purpura (TTP), caused by ADAMTS13 deficiency, and atypical hemolytic uremic syndrome (aHUS), most often associated with genetically determined dysregulation of complement system. HUS is the most common form of TMA in the post-partum period. The diagnosis of pregnancy-associated HUS can be difficult because preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome may present with clinical and laboratory features of TMA that however commonly resolve spontaneously after delivery.Here, we report the biochemical and genetic characterization of a 22 years old primigravida of African origin who presented at 38 weeks of gestation with severe hypertension, nephrotic syndrome (NS) and elevated liver enzymes, consistent with a diagnosis of HELLP. However, after an emergency delivery, the patient developed post-partum HUS with thrombocytopenia, hemolytic anemia, increased LDH and acute kidney injury.The patient received antihypertensives, fresh frozen plasma and packed red cell transfusions. From day 11 post-partum the patient also received antibiotics for sepsis by Klebsiella pneumoniae.Within day 18 post-partum blood pressure normalized and TMA resolved. However, NS persisted and renal biopsy (performed 13 days after delivery) disclosed a focal segmental glomerulosclerosis (FSGS) pattern with the collapsing variant.

Hemolytic uremic syndrome (HUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia, and renal impairment mostly triggered by strains of Shiga-like toxin-producing Escherichia coli (STEC-HUS). A rarer form of HUS, defined as atypical HUS (aHUS), is associated with genetic or acquired dysregulation of the alternative pathway of the complement system and presents a poorer prognosis than STEC-HUS. Factor H autoantibodies (anti-FHs) have been reported in aHUS in 5-11% of cases and are strongly associated with the homozygous deletion of CFHR3-CFHR1 genes. In the large majority of patients, anti-FH-associated aHUS is commonly preceded by gastrointestinal or respiratory tract infections. Here, we described the clinical case of a 3-year-old boy who was hospitalized for aHUS preceded by Mycoplasma pneumoniae (MP) infection. He resulted positive for anti-FHs and carried the homozygous deletion of CFHR3-CFHR1. Of relevance, he also showed a variant of unknown significance in the C5 gene. The patient was successfully treated with eculizumab and achieved hematological and renal remission. The anti-FH titer decreased, became negative after 6 months of mycophenolate mofetil (MMF) treatment, and remained negative for 21-month follow-up indicating that immunosuppression was effective and could prevent the reappearance of anti-FHs. We hypothesized that MP, likely through an evasion strategy of immunosurveillance based on binding of pathogen to FH, triggers anti-FH antibody generation and aHUS in a subject genetically predisposed. In conclusion, to the best of our knowledge, here, we reported the first case of anti-FH-mediated aHUS after an MP infection who benefited from eculizumab and immunosuppressive therapy based on MMF. Hence, monitoring of anti-FHs in patients with post-MP infection glomerulonephritis could be recommended, especially in those with low C3 plasma levels.