Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) that can lead to end organ damage and death without treatment. The ability to rapidly distinguish aHUS from other forms of TMA is key for optimal patient management. The PLASMIC Score was developed to identify individuals with thrombotic thrombocytopenic purpura (TTP), a TMA subtype characterized by severe ADAMTS13 deficiency (< 10%), using 7 commonly available laboratory variables and aspects of the patient's medical history. This study aimed to assess the distribution of PLASMIC Scores in patients with known aHUS, and evaluate the utility of the PLASMIC Score in the diagnostic pathway of aHUS in patients with confirmed TMA.

Data from eculizumab (NCT01194973) and ravulizumab (NCT02949128) clinical trials were utilized to calculate and evaluate PLASMIC Score distribution in aHUS patients. Real-world patient-level data from the PINC AI™ Healthcare Database (PHD) were used to evaluate the performance of the PLASMIC Score in identifying aHUS in patients with documented TMA diagnoses and renal impairment (primary analysis population; n = 110), and subsequent sensitivity analyses were performed in alternative populations.

A total of 94 aHUS patients from the eculizumab and ravulizumab clinical trials dataset were evaluated; 18/36 (50.0%) and 27/58 (46.6%) patients in the eculizumab and ravulizumab trials, respectively, had a PLASMIC Score of 4, and most patients (~ 85%) had PLASMIC Scores ≤ 5 (range: 3-5), which were distributed similarly between the trials. Among the 110 patients with undifferentiated TMA (primary analysis) from the PHD, a PLASMIC Score cutoff of ≤ 5 yielded sensitivity, specificity and positive predictive value (PPV) and negative predictive values (NPV) of 86.5%, 71.4%, 92.8% and 55.6%, respectively, for identifying probable aHUS. Similar diagnostic performance was observed at a cutoff value of ≤ 5 in further sensitivity analyses. A cutoff value of ≤ 4 yielded a lower PPV (62.9%), yet a higher NPV (85.7%), with only 3 patients misclassified as TTP.

Application of the PLASMIC Score in the aHUS diagnostic pathway may support clinical judgement and ascertain confidence in the earlier identification and subsequent treatment of patients with aHUS, thereby improving patient outcomes.

Atypical Haemolytic Uremic Syndrome (aHUS) is a rare but life-threatening thrombotic microangiopathy. If inadequately managed, aHUS can lead to progressive kidney failure, cardiovascular complications and multiorgan dysfunction, resulting in high healthcare costs and a substantial impact on patients' quality of life. Novel complement inhibitors offer potential advantages, yet comprehensive evidence comparing their efficacy and safety is limited. This protocol elaborates the systematic review plans to evaluate the effectiveness and the drug safety of complement inhibitors in aHUS.

A systematic search will be conducted across PubMed, Embase, Cochrane Library, Web of Science and Scopus to identify relevant studies. Eligible studies include randomised controlled trials (RCTs), observational studies and case series with at least three aHUS patients treated with novel complement inhibitors. Two independent reviewers will perform data extraction and quality assessment using standardised tools, including the Risk of Bias Tool 2 for RCTs and the Newcastle-Ottawa Scale for observational studies. A meta-analysis will be conducted if feasible, utilising a random-effects model to account for study heterogeneity.

Ethical approval is not required as only previously published data will be used. Results will be disseminated via peer-reviewed journals and conferences, targeting healthcare professionals and policymakers to support evidence-based decision-making in aHUS management.

CRD42025629879.

Thrombotic microangiopathy (TMA) is a challenging and serious complication of kidney transplantation that significantly affects graft and patient survival, occurring in 0.8%-15% of transplant recipients. TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to endothelial damage and microthrombi formation in small vessels. However, clinical features can range from a renal-limited form, diagnosed only on a kidney biopsy, to full-blown systemic manifestations, which include neurologic, gastrointestinal, and cardiovascular injury. TMA can arise because of genetic or acquired defects such as in complement-mediated TMA or can occur in the context of other conditions like infections, autoimmune diseases, or immunosuppressive drugs, where complement activation may also play a role. Recurrent TMA after kidney transplant is almost always complement-mediated, although complement overactivation may also play a role in de novo post-transplant TMAs associated with ischemia-reperfusion injury, immunosuppressive drugs, antibody-mediated rejection, viral infections, and relapse of autoimmune diseases, such as antiphospholipid antibody syndrome. Differentiating between a complement-mediated process and one triggered by other factors is often challenging but critical to minimize allograft damage because the former is nonresponsive to supportive therapy, needs long-term anticomplement therapy, and has a high risk of recurrence. Given the central role of complement and effect of genetic defects on the risk of recurrence in many forms of post-transplant TMA, genetic testing for complement disorders is key for proper diagnosis and management. Given that complement activation may also play a role in a subset of TMAs associated with other conditions, prompt recognition and timely initiation of anticomplement therapy is equally important. In addition, TMA associated with noncomplement genes, often part of a broader syndromic process with distinct clinical features, has also been described. Early identification and treatment are essential to prevent graft failure and other severe complications. This review explores the pathophysiologic mechanisms underlying various post-transplant TMAs.

Cytomegalovirus (CMV) infection poses a significant risk to kidney transplant recipients. CMV immunoglobulin shows promising prophylactic effect, particularly in the context of ABO-incompatible transplants. However, its efficacy in preventing CMV viremia remains underexplored.

In this retrospective study, we enrolled patients who underwent ABO-incompatible living donor kidney transplantation between May 2021 and September 2023. Prophylactic CMV immunoglobulin was administered at 100 mg/kg weekly for one month in the combined prophylaxis group, while no prophylactic medication was applied in the preemptive therapy group. The primary outcome was measured as the incidence of clinically relevant CMV viremia (CMV DNA >10,000 copies/mL) within one year after transplantation. Both groups received standard preemptive therapy with ganciclovir or valganciclovir after diagnosed with clinically relevant CMV viremia.

Prophylactic CMV immunoglobulin significantly reduced clinically relevant viremia incidence compared to preemptive therapy group (16.0% vs. 34.0%, P = 0.04). At the end of the follow-up, the combined prophylaxis group showed higher eGFR (56.40 ± 14.19 vs. 47.30 ± 13.01 mL/min/1.73m², P = 0.0014) and lower serum creatinine (146.5 ± 57.07 vs. 171.2 ± 51.48 µmol/L, P = 0.0274). However, no significant differences in renal function were observed between the groups at1,3, or 6 months post-transplantation.

CMV immunoglobulin represents a promising prophylactic option for reducing clinically relevant CMV viremia incidence and delaying infection onset in ABO-incompatible kidney transplant recipients.

Atypical hemolytic uremic syndrome (aHUS) is a severe rare disease characterized by microvascular hemolytic anemia, thrombocytopenia, and acute renal failure.

A 10-year-old male presented with symptoms of weakness, jaundice, pallor, swollen eyelids, and no significant lower limb swelling. Laboratory investigations revealed critical hemoglobin levels, fragmented red blood cells, thrombocytopenia, and acute kidney injury.

The patient was diagnosed with aHUS based on the clinical trial of microvascular hemolytic anemia, thrombocytopenia, and organ damage due to thrombosis, as well as laboratory findings.

The patient was treated with a combination of plasma exchange and the drug Eculizumab. Comprehensive nursing care was provided, including the establishment and maintenance of blood purification pipelines, management of complications (such as coagulation, allergic reactions, hypotension, and bleeding), and psychological support for the patient and family.

The patient successfully completed a 3-month treatment regimen with Eculizumab and has been followed up for an additional 10 months without any recurrence of the condition, demonstrating favorable treatment outcomes.

The novel approach of combining plasma exchange with Eculizumab in pediatric aHUS presents significant nursing challenges, but the case demonstrates the potential benefits of this combination therapy, particularly in the pediatric population in China where Eculizumab has recently become available. Comprehensive nursing care, including managing complications and providing psychological support, is crucial to the successful treatment of aHUS.

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Owing to its diverse and nonspecific clinical manifestations, early diagnosis of the condition is challenging and typically requires excluding other TMA-related conditions, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome caused by Escherichia coli infection. Accurate diagnosis relies on the recognition of typical TMA symptoms, laboratory testing, and the exclusion of other conditions. Treatments typically include plasma exchange, supportive care, and complement-targeted therapy. Eculizumab, a complement component 5 inhibitor, plays a crucial role in aHUS treatment in severe cases as well as when traditional interventions fail. In this case report, we described a female Han Chinese patient who developed aHUS following an upper respiratory tract infection, initially presented with intermittent seizures, and received treatment with eculizumab, plasma exchange, and hemodialysis. The patient ultimately remained dialysis-dependent; however, they achieved complete remission for other systemic complications of aHUS. We emphasized in this case report the importance of timely diagnosis and treatment of aHUS as well as the potential value of eculizumab in improving patient outcomes. Furthermore, successful treatment and follow-up results provide insights into the management of this rare disease, including long-term dialysis requirements and disease monitoring after remission. Thus, clinicians can better understand the clinical manifestations of aHUS and its associated diagnostic challenges, treatment strategies, and long-term management needs.

Eculizumab, a terminal complement inhibitor, prevents thrombotic microangiopathy (TMA) and multiorgan damage in hemolytic uremic syndrome (HUS). We evaluated its efficacy and safety in pediatric patients with TMA sub-types: atypical HUS (aHUS), Shiga toxin-producing Escherichia coli (STEC)-HUS, and transplant-associated TMA (TA-TMA).

This retrospective study included all pediatric patients treated with eculizumab for HUS at Schneider Children's Medical Center (2011-2020), including those with pre-existing end-stage kidney disease. Clinical and laboratory parameters were analyzed over 28 weeks. The primary endpoint was achievement of complete TMA response, defined by sustained normalization of hematologic parameters and renal function. Secondary endpoints included TMA event-free status and additional clinical improvements.

Twenty-four pediatric patients (median age 5.8 years) were included: 13 with aHUS, 5 with STEC-HUS, and 6 with TA-TMA. A complete TMA response was achieved in 12 (50%) of the patients overall: 7 (54%) with aHUS, 3 (60%) with STEC-HUS, and 2 (33%) with TA-TMA. TMA event-free status was reached in 15 (63%) patients. Significant improvements were observed in platelet count (63%), lactate dehydrogenase levels (76% within the first week), hemoglobin (60%), and estimated glomerular filtration rate (79%); while CH-50 levels decreased. No severe adverse events were attributed to eculizumab. Chronic kidney disease stage improved for 17 (90%).

The efficacy and safety of eculizumab for three TMA subtypes in pediatric patients potentially expands its therapeutic applications. The complete TMA response rate in aHUS supports eculizumab as a first-line use, while the response rate in STEC-HUS suggests potential efficacy beyond eculizumab's primary indication. The early hematologic responses and reduced CH-50 levels confirm the role of eculizumab complement-mediated HUS and underscore the need for further research in TA-TMA.

Although terminal complement inhibitors transformed the prognosis of atypical haemolytic uraemic syndrome (aHUS) from dismal to favourable, treatment approaches vary due to the intermittent disease nature and high costs. Occasionally, complement inhibition is applied in infectious (i)HUS. We aimed to examine real-world C5 inhibitor use and its impact on patient outcomes.

This retrospective cohort study used longitudinal data from the European Rare Kidney Disease Registry, collected from 76 nephrology centres across 24 European countries between January 1, 2019 and January 31, 2024. Eligible patients had aHUS or iHUS with onset after January 1, 2011, and/or documented C5 inhibitor use. Exclusions included complement-unrelated HUS, post-transplant HUS, and prophylactic C5 inhibitor use around kidney transplantation. Data, derived from medical records and focused queries, were used to assess C5 inhibitor duration, via time-to-event analysis, and kidney function based on annual creatinine levels.

A total of 238 aHUS and 472 patients with iHUS were included in the analysis. C5 inhibition was applied in 76.5% of aHUS and 18.4% of iHUS, with major utilisation differences between countries (p < 0.0001) and less common use in female patients with aHUS (p = 0.0022). Median (interquartile range) treatment duration was 16.1 (3.6-41.2) months in aHUS and 9 (7-32) days in iHUS. After five years, 56% of genetic, 28% of anti-complement factor H (anti-CFH) antibody-mediated, and 23% of aHUS cases with no identified cause remained on treatment. The long-term (>7 years) risk of treatment resumption was 35% in genetic, 15% in aHUS of no identified cause, and 0% in anti-CFH antibody-mediated aHUS. Post-withdrawal aHUS relapses were mostly mild and did not lead to permanent kidney function impairment, ultimately leading to long-term treatment withdrawal in 92.5% of discontinued cases.

Currently, C5 inhibitors are administered in three-quarters of newly diagnosed patients with aHUS in Europe, with varied utilisation and discontinuation practices. Treatment withdrawal is common and safe, although relapses may occur, particularly in genetic aHUS. However, baseline disease severity, selective use in expert centres, and indication bias affect outcome comparability. Findings must be considered in the context of patient-specific factors and disease severity at the time of treatment decisions.

This research was supported by the European Reference Network for Rare Kidney Diseases, funded by the European Union within the framework of the "EU4Health Programme 2021-2027".

A loss-of-functional mutation (W1183R) in human complement factor H (CFH) is associated with complement-associated hemolytic uremic syndrome; mice carrying a similar mutation (W1206R) in CFH also develop thrombotic microangiopathy but its plasma von Willebrand factor (VWF) multimer sizes were dramatically reduced. The mechanism underlying such a dramatic change in plasma VWF multimer distribution in these mice is not fully understood.

To determine the VWF and CFH interaction and how CFH proteins affect VWF multimer distribution.

We employed recombinant protein expression, purification, and various biochemical and biophysical tools.

Purified recombinant W1183R-CFH but not wild-type (WT) CFH protein enhanced the proteolytic cleavage of both peptidyl and multimeric VWF substrates by recombinant ADAMTS-13 in a concentration-dependent manner. Microscale thermophoresis assay demonstrated that both W1183R-CFH and WT-CFH proteins bound various VWF fragments (eg, AIM-A1, A1-A2-A3, D'D3, D'D3-A1, and D'D3-A1-A2) with high affinities. Optical tweezer experiments further showed a concentration-dependent alteration in the contour length (Lc) and the persistent length (Lp) following pulling VWF-A2 domain in the presence of W1183R-CFH or WT-CFH protein. AlphaFold experiments revealed conformational changes in the VWF-A2, particularly the central region where the cleavage bond resides following addition of W1183R-CFH or WT-CFH protein.

These results demonstrate for the first time that W1183R-CFH but not WT-CFH protein enhances the proteolytic cleavage of VWF by ADAMTS-13 under shear. This may be achieved by mechanic-induced conformational changes of the central A2 domain, leading to an enhanced cleavage of Tyr1605-Met1606 bond by ADAMTS-13 under pathophysiological conditions.

Introduction of complement (C) inhibition into clinical practice has revolutionized the treatment of patients with complement-mediated atypical hemolytic syndrome (aHUS). Our C3D1115N mouse model, engineered around a gain of function point mutation in C3, is associated with complement mediated aHUS in man, allowing us to study the clinical disease in a preclinical model. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled further determination of the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on kidney disease. C7 deficiency completely abolished both clinical and histological evidence of disease. Removing C5aR1 (CD88) attenuated the risk of developing clinical disease, but mice still developed thrombotic microangiopathy. Therapeutic inhibition strengthened our genetic findings showing both anti-C7 therapy and an oral C5aR1 antagonist, when used before evidence of significant kidney injury, prevented mice from succumbing to disease. However, there was ongoing histological disease within mice treated with the C5aR1 antagonist. Our data suggest that both C5aR1 and C7 play a role in the development of the conditions required for thrombotic microangiopathy of the kidney. While disrupting the C5a-C5aR1 axis is beneficial, our genetic and therapeutic studies showed that thrombotic microangiopathy of the kidney can still develop and ultimately our data confirm that the membrane attack complex is required to develop thrombotic microangiopathy of the kidney. Overall, our study shows that in addition to requiring alternative pathway dysregulation, local generation of membrane attack complex within the kidney is also critical to drive disease pathology in complement-mediated aHUS.

Catastrophic thrombosis is a severe condition characterized by a hypercoagulable tendency, leading to multiple thromboembolic events in different blood vessels, usually within a short timeframe. Several conditions have been associated with the development of catastrophic thrombosis, including the catastrophic antiphospholipid syndrome, thrombotic anti-platelet factor 4 immune disorders, thrombotic microangiopathies, cancers, the hyper-eosinophilic syndrome, pregnancy, infections, trauma, and drugs. Thrombotic storm represents a medical emergency whose management represents a serious challenge for physicians. Besides the prompt start of anticoagulation, a patient's prognosis depends on early recognition and possible treatment of the underlying condition. In this narrative review, we summarize the main characteristics of catastrophic thrombosis, analyzing the various conditions triggering such life-threatening complication. Finally, an algorithm with the diagnostic workup and the initial management of patients with catastrophic thrombosis is presented.

Haemolytic uremic syndrome (HUS) is a life-threatening disease with a historically poor prognosis in children receiving maintenance kidney replacement therapy (KRT). This study aimed to analyse the incidence and outcome of chronic kidney disease stage 5 (CKD5) due to Escherichia coli-HUS (STEC-HUS) and complement-mediated HUS (CM-HUS) in children, compared with controls with non-HUS CKD5 over the last 24 years.

The study included 1488 children undergoing KRT in Poland between 2000 and 2023. Thirty-nine patients with CM-HUS and 18 with STEC-HUS were identified and analysed for incidence, KRT modality and survival.

The incidence rate of CKD5 was 0.09 cases/million age-related population (marp) for STEC-HUS and 0.23/marp for CM-HUS, while no new cases have been observed in recent years. CKD5 due to CM-HUS developed significantly earlier from initial HUS manifestation than in STEC-HUS (median 0.2 vs. 9.8 years). CM-HUS was associated with younger age at initiation of KRT compared to STEC-HUS and non-HUS controls (median 6.0 years vs. 10.9 and 10.9 years), with higher risk of death (Hazard Ratio 1.92, 95% confidence interval 0.9-4.13) and worse 5-year kidney graft survival at 77%, 93% and 90%, respectively (p < 0.001).

In recent years, both CM-HUS and STEC-HUS have become increasingly rare causes of CKD5 in children. CKD5 due to CM-HUS in the eculizumab era and due to STEC-HUS after improving supportive treatment is exceptional. Children on KRT due to STEC-HUS had a significantly better survival, shorter waiting time for kidney transplantation and better kidney graft survival compared to the CM-HUS group.

Anal cancer is a rare disease where malignant cells originate in the tissues of the anal canal. This form of cancer is classically treated with a combination of radiation therapy and a chemotherapy regimen that includes mitomycin C. This case illustrates an unusual presentation of thrombotic microangiopathy associated with mitomycin C. A 57-year-old woman with a history of anal carcinoma treated with capecitabine/mitomycin C and radiation was sent to the emergency department by her oncologist for an incidental finding of worsening kidney function noted on a complete metabolic panel done prior to getting radiographic imaging. The patient was admitted to the hospital for suspected acute kidney injury from suspected ureteral obstruction and stent occlusion; however, despite reversal of the stents, renal function did not improve. Renal biopsy confirmed thrombotic microangiopathy and diagnosis of drug-induced thrombotic microangiopathy. This case discusses a side effect of thrombotic microangiopathy from mitomycin C and successful treatment with eculizumab.

Aortic disease encompasses life-threatening conditions such as aortic aneurysm and dissection, which are associated with high prevalence, morbidity, and mortality. The complement system, a key component of innate immunity, not only defends against pathogens but also maintains tissue homeostasis. Recent discoveries have expanded its role beyond immunity, linking complement dysregulation to numerous diseases and positioning it as a target for pharmacotherapy. Complement-based treatments for precision medicine are emerging, with several pharmaceuticals either already approved or under investigation. In aortic disease, complement activation and dysregulation have unveiled novel mechanisms and clinical implications. Human and experimental studies suggest that all three complement pathways contribute to disease pathophysiology. The complement system induces direct cellular damage via the membrane attack complex, as well as matrix-metalloproteinase (MMP)-associated tissue damage by promoting MMP-2 and MMP-9 expression. The anaphylatoxins C3a and C5a exacerbate disease by recruiting immune cells and triggering proinflammatory responses. Examples include neutrophil extracellular trap formation and cytokine release by polymorphonuclear neutrophils. These findings highlight the complement system as a promising novel diagnostic and therapeutic target in aortic disease with potential for individualized treatment. However, gaps remain, emphasizing the need for standardized multisite preclinical studies to improve reproducibility and translation. Biomarker studies must also be validated across diverse patient cohorts for clinical applicability. This review examines current knowledge regarding complement in aortic disease, aiming to evaluate its potential for innovative diagnostic and personalized treatment strategies.

Complement-mediated thrombotic microangiopathies (CM-TMA) are rare and life-threatening disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. These conditions result from dysregulation of the alternative complement pathway, often due to genetic variants or autoantibodies. The clinical spectrum is broad, comprising varied presentations and triggers, including infections, malignancies, and pregnancy-related complications. Advances in understanding the genetic and immunological basis of CM-TMA have improved diagnosis and treatment. Diagnosis requires exclusion of other thrombotic microangiopathies like thrombotic thrombocytopenic purpura and secondary causes, with genetic testing recommended to identify underlying susceptibilities. The introduction of C5 inhibitors has transformed the management of CM-TMA, significantly improving outcomes compared to the pre-2011 era when therapeutic plasma exchange was the primary therapy. Despite these advances, challenges remain in determining the optimal duration of therapy. Prophylactic measures against infections, particularly meningococcal disease, are mandatory for patients receiving C5 inhibitors. This article underscores the need for a personalized, multidisciplinary approach in the diagnosis and management of CM-TMA. Advances in genetics and complement biology have led to improved therapeutic strategies, however ongoing research is essential to address unanswered questions regarding relapse risk, treatment duration, and long-term outcomes.

The complement cascade and Neutrophil Extracellular Traps (NETs) represent fundamental tools in protecting the host from foreign pathogens. Complement components and relative fragments, classically assigned to the innate immunity, represent a key link with the humoral immune response. NETs are a crucial component of the innate immune response, consisting of chromatin release from activated neutrophils. These web-like structures facilitate pathogen entrapment and elimination through proteolytic degradation and antimicrobial effectors. Previous findings suggested complement components and NETs have a significant role in the pathogenesis of several diseases characterized by inflammation, such as autoimmune and infectious diseases. However, the crosstalk between NETs and the complement cascade has only recently been investigated, and several aspects still need to be fully clarified. Recent evidence seems to suggest a bidirectional link between the complement cascade and NETosis. We here present the interaction between complement components and NETs in specific autoimmune diseases that mostly affect the kidney, such as systemic lupus erythematosus, Antineutrophilic Cytoplasmic Antibody (ANCA)-associated vasculitis and antiphospholipid syndrome. The mechanisms reported here may represent specific targets for the development of possible therapeutic strategies.

The advent of more affordable genomic analytical pipelines has facilitated the expansion of genetic studies in kidney transplantation. Advances in genetic sequencing have allowed for a greater understanding of the genetic basis of chronic kidney disease, which has helped to guide transplant management and address issues related to living donation in specific disease settings. Recent efforts have shown significant effects of genetic ancestry and donor APOL1 risk genotypes in determining worse allograft outcomes and increased donation risks. Genetic studies in kidney transplantation outcomes have started to assess the effects of donor and recipient genetics in primary disease recurrence and transplant-related comorbidities, while genome-wide donor-recipient genetic incompatibilities have been shown to represent an important determinant of alloimmunity. Future large-scale comprehensive studies will shed light on the clinical utility of integrative genomics in the kidney transplantation setting.

Atypical hemolytic uremic syndrome is a thrombotic microangiopathy caused by the abnormal activation of the alternative complement pathway. Mutations in complement-related genes and autoantibodies against complement regulators are involved in the pathogenesis of this condition; the frequency of, and prognosis of patients harbouring, each genetic mutation varies based on the region and race. Complement factor I (CFI) mutations have been observed in 4%-8% of cases in Europe; however, they have not yet been reported in Japan. We present the first Japanese case of atypical hemolytic uremic syndrome in a patient harbouring a CFI mutation. An 83-year-old female patient presented with severe acute kidney injury, thrombocytopenia, and hemolytic anaemia following a femoral neck fracture. Plasma exchange and haemodialysis were initiated, resulting in improved kidney function and platelet count. However, the platelet count decreased when plasma exchange was discontinued. Therefore, we administered ravulizumab, an anti-complement 5 monoclonal antibody, which led to the maintenance of stable kidney function and platelet count. Genetic analysis revealed a CFI mutation, and the patient was treated with ravulizumab for 2 years without relapse. Individuals diagnosed with atypical hemolytic uremic syndrome harbouring CFI mutations experience poor outcomes, including low rates of remission, high rates of mortality, and progression to end-stage kidney disease. Our case serves as a crucial example demonstrating how prompt identification and appropriate management can lead to better patient outcomes.

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients' access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.

Enteroviruses cause nearly 1 billion global infections annually and are associated with a diverse array of human illnesses. Among these, myocarditis and the resulting chronic inflammation have been recognized as major contributing factors to virus-induced heart failure. Despite our growing understanding, very limited therapeutic strategies have been developed to address the pathological consequences of virus-induced chronic innate immune activation. Coxsackievirus B3 (CVB3) was used as a model cardiotropic enterovirus. We leveraged in vitro cell-based studies to investigate cardiomyocyte and macrophage interaction during CVB3 infection, as well as animal studies and unique human cardio specimens to evaluate mechanisms of viral heart injury. We present evidence that viral myocarditis is in part exacerbated by pathological activation of the complement pathway in cells, mice, and human cardiac tissues. We demonstrate unique cell type-specific responses to viral infection that are exacerbated by mitochondrial injury in cardiomyocytes and NFκB-dependent pro-inflammatory response in macrophages. Macrophages are robustly activated by damage-associated mitochondrial components, including mitochondrial proteins and lipid extracts. Mechanistically, we identify complement protective factors CD59/protectin and CD55/DAF as novel targets of viral proteinase that acts to release the brakes on complement-mediated autoinjury. Collectively, our study highlights a novel mechanism that can act as a potential contributor to CVB3 pathogenesis through mitochondrial injury-mediated autoimmunity.

This study sheds light on how enteroviruses, specifically coxsackievirus B3, may contribute to heart failure by triggering harmful immune responses in the heart. We discovered that viral infections in heart cells cause mitochondrial damage, which in turn activates a destructive immune response involving the complement system. This immune activation is one of the significant contributors that lead to further injury of heart tissues, worsening the damage caused by the virus. Additionally, we identified key protective molecules that are targeted and disrupted by the virus, allowing the immune system to attack the heart even more aggressively. Understanding these mechanisms may provide additional insights into how viral infections can lead to chronic heart conditions and suggests potential therapeutic targets to prevent or reduce heart damage in patients affected by viral myocarditis.

Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care.

Multicenter retrospective study conducted on pediatric patients (< 18 years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal).

A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation.

Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

Atypical hemolytic uremic syndrome (aHUS) is an important differential diagnosis in thrombotic microangiopathy (TMA). The absence of definitive biomarkers usually allows for aHUS to be diagnosed only through a process of exclusion. Due to the unfavorable prognosis if adequate therapy is delayed or not provided, differential diagnostic considerations and initiation of treatment must occur promptly. The presented guideline is intended to serve as an aid in this process.

Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare, life-threatening condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, elevated liver enzymes, and acute kidney injury. Prompt diagnosis and therapy are crucial due to the high risk of progression to chronic kidney disease (CKD), end-stage kidney disease (ESKD), and dialysis dependency, as well as significant maternal and fetal morbidity and mortality.

A comprehensive literature search was conducted across EMBASE, MEDLINE, and the Cochrane CENTRAL from January 2000 to March 2024. Studies reporting on pregnancy and kidney outcomes in women diagnosed with p-aHUS were included.

Ten studies involving 386 pregnancies in 380 patients met the inclusion criteria for the final analysis. Renal outcomes varied, with mean creatinine levels ranging from 0.72 to 8.734 mg/dL. Dialysis was required in 66.6% of patients, and 25% developed ESKD. Maternal complications included preeclampsia (36.4%) and hemolysis, elevated liver enzymes, and low platelets syndrome (29.7%), with a 5% maternal mortality rate. Fetal complications included intrauterine fetal demise (n = 25), intrauterine growth restriction, low birth weight, and prematurity. Treatment with eculizumab significantly reduced the risk of CKD and ESKD, with a pooled risk ratio of 0.20 (95% confidence interval: 0.09-0.44) and low heterogeneity (I² = 0%, P = .43).

This analysis highlights the severe kidney and pregnancy outcomes associated with p-aHUS. Eculizumab treatment is significantly beneficial in reducing the risk of CKD and ESKD.

Kidney diseases are widespread and represent a considerable medical, social and economic burden. However, there has been marked progress in understanding the immunological aspects of kidney disease. This includes the identification of distinct intrarenal immunological niches and characterization of kidney disease endotypes according to the underlying molecular immunopathology, as well as a better understanding of the pathological roles for T cells, mononuclear phagocytes and B cells and the renal elements they target. These insights have improved the diagnosis of kidney disease. Here, we discuss new developments in our understanding of kidney immunology, focusing on immune mechanisms of disease and their translational implications for the diagnosis and treatment of kidney disease. We also describe the immune-mediated crosstalk between the kidney and other organs that influences kidney disease and extrarenal inflammation.

The complement system includes soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates proteins with inflammatory and vasoactive activities. Although complement is crucial to host defense and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. Glomerulopathy encompasses a spectrum of diseases with diverse etiologies, clinical presentations, and outcomes. Among the intricate web of factors contributing to glomerulopathies pathogenesis, the role of complement activation has emerged as a focal point of research interest and therapeutic intervention. The pioneer drug was eculizumab, which made it possible to drastically change the prognosis of atypical hemolytic uremic syndrome, an otherwise fatal disease. This comprehensive review aims to elucidate the multifaceted interplay between complement pathways and glomerulopathies, shedding light on potential pathways for targeted therapies and improved patient care.

When haemolytic anaemia, thrombocytopenia and renal failure are present, a thrombotic microangiopathic (TMA) condition should be suspected. We describe the various differential diagnoses of primary TMA syndromes, their clinical findings, clinical workup and treatment.

A previously healthy man in his fifties was hospitalised with anaemia, thrombocytopenia, bilirubinaemia and acute renal failure. He was in good general condition without neurological symptoms. Due to suspicion of thrombotic microangiopathy (mainly thrombotic thrombocytopenic purpura (TTP)), he was referred to a university clinic for immediate plasma exchange. His renal failure deteriorated and haemodialysis was initiated. However, ADAMTS13 level was normal. Thus, complement-mediated thrombotic microangiopathy was suspected and eculizumab was administered. Due to previous abdominal discomfort a faecal sampling was performed, detecting enterohaemorrhagic E. coli (EHEC) DNA (Shigatoxin 2f). Hence, the diagnosis was Shigatoxin-induced haemolytic uraemic syndrome (ST-HUS). Supportive care was continued and renal function normalised.

When thrombotic microangiopathy is suspected, an assessment is made whether to initiate plasmapheresis and immunomodulatory treatment. A thorough workup is needed to differentiate between the various primary TMA syndromes. Thus, treatment with expensive and possibly harmful drugs can be avoided. The various primary TMA syndromes have overlapping clinical features, and the diagnosis can be difficult.

Transplantation is the treatment of choice in most patients with kidney failure. The complement system plays a vital role in transplantation. The complement system forms a major part of innate immunity and acts as a bridge between innate and acquired immunity. Many diseases, particularly concerning the kidneys, result from complement system dysregulation, like atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3GN), systemic lupus erythematosus (SLE and some other immune complex diseases. The complement system activation is a very important part of post-transplant events like ischemia-reperfusion injury (IRI), delayed graft function (DGF), antibody-mediated rejection (ABMR) and thrombotic microangiopathy (TMA). A better understanding of the complement cascade can help to plan strategies to prevent and manage complement-related problems before and after kidney transplantation. Many newer molecules are either being developed or in the pipeline, which target the complement system at various stages. These novel therapeutics are now considered additional measures to improve graft survival. This review summarises the complement cascade, its role in kidney diseases and kidney transplantation, and possible areas of target and novel therapeutics.

Complement-mediated thrombotic microangiopathy (CM-TMA) or hemolytic uremic syndrome, previously identified as atypical hemolytic uremic syndrome, is a TMA characterized by germ line variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors" by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-TMA and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies immunoglobulin M (IgM)-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ∼50% of patients with CM-TMA who lack an alternative pathway "driving" variant and suggests at least a subset of CM-TMA is characterized by a breakdown of IgM immunologic tolerance.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy typically characterized by anemia, thrombocytopenia, and end-organ injury. aHUS occurs due to endothelial injury resulting from overactivation of the alternative pathway of the complement system. The etiology of the dysregulated complement system is either a genetic mutation in 1 or more complement proteins or an acquired deficiency due to autoantibodies. Over the past decade, advancements in our understanding of the role of complement in the pathophysiology of aHUS as well as the availability of anticomplement drugs has been a game-changer for our patients. These drugs have revolutionized the clinical course, outcome, and prognosis of this disease. Therefore, all patients in whom aHUS is suspected should undergo testing for complement genetic variants and autoantibodies. In approximately 30% to 40% of patients, a genetic variant of uncertain significance (VUS) may be identified. Such patients should undergo further testing to define the significance of the VUS. A combination of antigenic, functional, and biomarker analyses can assist in establishing the significance of the variants and thereby define the etiology in most patients. These analyses will also help to determine the duration of treatment based on the individual's genetic alteration. This review aims to shed light on the diagnosis and management of aHUS and discusses how to stratify patients to determine who can safely discontinue anticomplement therapy.

Hemolytic uremic syndromes (HUSs) are a heterogeneous group of conditions, only some of which are mediated by complement (complement-mediated HUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included the nomenclature of HUS, novel complement testing strategies, identification of biomarkers, genetic predisposition to atypical HUS, optimal dosing and withdrawal strategies for C5 inhibitors, treatment of kidney transplant recipients, disparity of access to treatment, and the next generation of complement inhibitors in complement-mediated HUS. The current rationale for optimal patient management is described.

Aptamers are short, single-stranded oligonucleotides that selectively bind to target biomolecules. Although they generally exhibit good binding specificity, their affinities are often limited because of the relative lack of hydrophobic groups in nucleic acids. Chemically modified nucleotides incorporating hydrophobic structures into uracil have been synthesized to address this obstacle. Modified DNA aptamers containing such nonstandard nucleotides have been developed for >20 different complement proteins. These modified aptamers show increased affinity and enhanced serum stability and have potential value as therapeutic agents. We recently conducted a structure/function study on a family of modified DNA aptamers that bind specifically to complement Factor B (FB). This work revealed that these aptamers selectively inhibit the complement alternative pathway (AP) by preventing the formation of the AP complement component C3 (C3) proconvertase complex, C3bB. Certain patients with atypical hemolytic uremic syndrome express gain-of-function variants of FB that enhance the formation of the proconvertase complex and/or decrease the efficacy of endogenous regulators against the C3 convertases they form. To investigate whether these FB-binding aptamers could override the effects of disease-causing mutations in FB, we examined how they interacted with several FB variants, including D279G, F286L, K323E, and K350N, in various assays of complement function. We found that the inhibitory effect of the FB-binding aptamers superseded the gain-of-function mutations in FB, although the aptamers could not dissociate preformed C3 convertases. These findings suggest that FB-binding aptamers could be further developed as a potential treatment for certain atypical hemolytic uremic syndrome patients or those with other diseases characterized by excessive complement activity.

The introduction of safe and effective rare/ultra-rare disease treatments is a focus of many biotherapeutic enterprises. Despite this increased activity, a significant unmet need remains, and the responsibility to meet this need is augmented by enhanced genomic, biologic, medical, analytical, and informatic tools. It is recognized that the development of an effective and safe rare/ultra-rare disease therapeutic faces a number of challenges with an important role noted for clinical pharmacology. Clinical pharmacology is foundationally an integrative discipline which must be embedded in and is interdependent upon understanding the pathogenic biology, clinical presentation, disease progression, and end-point assessment of the disease under study. This manuscript presents an overview and two case examples of this integrative approach, the development of C5-targeted therapeutics for the treatment of generalized myasthenia gravis and asfotase alpha for the treatment of hypophosphatasia. The two presented case examples show the usefulness of understanding the biological drivers and clinical course of a rare disease, having relevant animal models, procuring informative natural history data, importing assessment tools from relevant alternative areas, and using integrated applied clinical pharmacology to inform target engagement, dose, and the cascade of pharmacodynamic and clinical effects that follow. Learnings from these programs include the importance of assuring cross-validation of assays throughout a development program and continued commitment to understanding the relationship among the array of Pd end points and clinical outcomes. Using an integrative approach, substantive work remains to be done to meet the unmet needs of patients with rare/ultra-rare disease.

Carfilzomib, a new proteasome inhibitor indicated for patients with relapsed/refractory myeloma, has been associated with cases of thrombotic microangiopathy (CFZ-TMA). The role of variants in the complement alternative pathway and therapeutic potential of complement blockade with eculizumab remain to be determined.

We report 37 cases of CFZ-TMA recorded in the French reference center for TMA with their clinical characteristics, genetic analysis and outcome according to treatments.

A trigger was identified in more than half of cases, including eight influenza and five severe acute respiratory syndrome coronavirus-2 cases. All patients presented with acute kidney injury (AKI) [KDIGO stage 3 in 31 (84%) patients] while neurological (n = 13, 36%) and cardiac (n = 7, 19%) damage were less frequent. ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) and complement activity were normal (n = 28 and 18 patients tested) and no pathogenic variant in the alternative complement pathway was found in 7 patients tested. TMA resolved in most (n = 34, 94%) patients but 12 (44%) still displayed stage 3 AKI at discharge. Nineteen (51%) patients were treated with therapeutic plasma exchange, 14 (38%) patients received corticosteroids and 18 (50%) were treated with eculizumab. However, none of these treatments demonstrated a significant impact on outcomes.

This study is the largest case series of CFZ-TMA since its approval in 2012. Patients present with severe AKI and experience frequent sequelae. Complement variants and blockade therapy do not seem to play a role in the pathophysiology and prognosis of the disease.

Gene therapies hold significant promise for treating previously incurable diseases. A number of gene therapies have already been approved for clinical use. Currently, gene therapies are mostly limited to the use of adeno-associated viruses and the herpes virus. Viral vectors, particularly those derived from human viruses, play a critical role in this therapeutic approach due to their ability to efficiently deliver genetic material to target cells. Despite their advantages, such as stable gene expression and efficient transduction, viral vectors face numerous limitations that hinder their broad application. These limitations include small cloning capacities, immune and inflammatory responses, and risks of insertional mutagenesis. This review explores the current landscape of viral vectors used in gene therapy, discussing the different types of DNA- and RNA-based viral vectors, their characteristics, limitations, and current medical and potential clinical applications. The review also highlights strategies to overcome existing challenges, including optimizing vector design, improving safety profiles, and enhancing transgene expression both using molecular techniques and nanotechnologies, as well as by approved drug formulations.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) related to congenital mutations impeding control of the alternative pathway of complement. Following approval of the complement C5 inhibitor eculizumab by the European Medicines Agency and the US Food and Drug Administration, initial guidelines suggested lifelong therapy. Yet, growing evidence indicates that discontinuation of eculizumab, or its long-acting form ravulizumab, is possible for many patients. This mixed-methods study sought to explore international experts' perspectives and experiences related to treatment duration in adult patients with aHUS, while also estimating the financial and potential health consequences of early discontinuation.

Between January and December 2023, we conducted 10 qualitative interviews with experts in the treatment of aHUS, based upon which we constructed a quantitative decision tree, designed to estimate time on treatment and treatment- and disease-related adverse events.

Thematic analysis of the interview data identified four main themes: (1) Concerns and prior experience; (2) High-risk vs. low-risk groups; (3) Patient preference and adherence; and (4) Funding for monitoring and re-treatment. Although most interviewees were in favour of considering treatment discontinuation for many patients (citing the high cost, burden, and potential side effects of lifelong treatment as key reasons), a prior negative experience of discontinuation seemed to make others more reluctant to stop. Deciding which patients required lifelong treatment and which not involved consideration of a wide range of factors, including patient- and system-related factors. Cost-consequence analysis demonstrated the financial savings associated with early treatment discontinuation at the expense of increased risk of recurrent TMA events. Close monitoring for these events had the potential to minimise any long-term injury, primarily renal, with an estimated one event per 100 patient years. For patients at high risk of TMA and with poor adherence to monitoring, rates of renal injury rose to three events per 100 patient years.

aHUS treatment protocols are changing globally in response to new clinical evidence. Against this backdrop, our mixed-methods study provides compelling evidence on the complexity of factors influencing treatment discontinuation decisions in aHUS, as well as the financial and health consequences of early discontinuation.

The complement cascade is an ancient and highly conserved arm of the immune system. The accumulating evidence highlights elevated activity of the complement cascade in cancer microenvironment and emphasizes its effects on the immune, cancer, and cancer stroma cells, pointing to a role in inflammation-mediated etiology of neoplasms. The role the cascade plays in development, progression, and relapse of solid tumors is increasingly recognized, however its role in hematological malignancies, especially those of myeloid origin, has not been thoroughly assessed and remains obscure. As the role of inflammation and autoimmunity in development of myeloid malignancies is becoming recognized, in this review we focus on summarizing the links that have been identified so far for complement cascade involvement in the pathobiology of myeloid malignancies. Complement deficiencies are primary immunodeficiencies that cause an array of clinical outcomes including an increased risk of a range of infectious as well as local or systemic inflammatory and thrombotic conditions. Here, we discuss the impact that deficiencies in complement cascade initiators, mid- and terminal-components and inhibitors have on the biology of myeloid neoplasms. The emergent conclusions indicate that the links between complement cascade, inflammatory signaling, and the homeostasis of hematopoietic system exist, and efforts should continue to detail the mechanistic involvement of complement cascade in the development and progression of myeloid cancers.

Eculizumab has been approved for atypical haemolytic-uraemic syndrome (aHUS) in Japan since 2013. Post-marketing surveillance enrolled patients with aHUS who received ≥ 1 dose of eculizumab to assess eculizumab safety and effectiveness.

We evaluated serious adverse events and effectiveness endpoints, i.e., haematologic normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, and complete thrombotic microangiopathy (TMA) response in adult patients with aHUS without other underlying diseases. In addition, the difference of baseline characteristics between patients who did and did not meet effectiveness endpoints was examined.

In this safety and effectiveness analysis, 79 adult patients were included; median age was 54.0 years, median treatment duration was 30 weeks. Total exposure time of eculizumab was 75.51 patient-years, and 94 serious adverse events were reported in 39 patients. No unexpected safety signals were identified in this population. Mean platelet count, lactate dehydrogenase and estimated glomerular filtration rate significantly improved after 7 days of treatment. Complete TMA response, haematologic normalization and the improvement of sCr levels were met by 35.3%, 40.4% and 51.3% of patients, respectively. Median treatment duration was shorter in patients who did not achieve complete TMA response (6 weeks) than in patients who did (114 weeks). Multivariate analysis suggested that the time from the most recent TMA episode to start of eculizumab treatment was negatively associated with kidney function improvement.

No unexpected safety signals of eculizumab were identified in Japanese patients with aHUS in a real-world setting. Renal outcomes were negatively associated with the time from the most recent TMA episode to the initiation of eculizumab treatment.

Between 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.

In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens.

Patients 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.

Eculizumab 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.