Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Complement Factor I Gene Variant in an Atypical Hemolytic Uremic Syndrome Triggered by Hypereosinophilia Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a condition characterized by acute kidney injury (AKI), thrombocytopenia, and microangiopathic hemolytic anemia secondary to complement pathway dysregulation. Several triggers have been identified as causing aHUS in genetically susceptible patients; however, hypereosinophilia syndrome (HES)-triggered aHUS has not been reported. In this article, we present a case of aHUS presented with generalized urticarial rashes and angioedema. The initial investigations revealed hypereosinophilia (maximal absolute eosinophil count of 6,840 cells/µL) with normal bone-marrow analyses; hence, idiopathic HES was diagnosed. During hospitalization, the patient developed convulsion, stuporous, and full-blown thrombotic microangiopathy (TMA), with AKI requiring temporary hemodialysis. A kidney biopsy confirmed the existence of renal TMA. Next-generation sequencing of the coding regions of aHUS-related genes was performed, revealing an underlying complement factor I (CFI) deficiency, a heterozygous variant p.P64L of CFI gene. The patient was successfully treated with high-dose steroids and extended duration of plasmapheresis.

Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan.

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of  ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10 years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

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

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

C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN. FINDINGS: Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months. LIMITATIONS: Small retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches.

Complement-Mediated Thrombotic Microangiopathy with 10 Years of Stable Renal Function After a Year-Long Treatment with Eculizumab with Coincidental Polycystic Kidney Disease.

BACKGROUND Complement-mediated thrombotic microangiopathy (cTMA), is a genetic disease that results when an unchecked alternative complement pathway is triggered by an external factor, resulting in endothelial cell injury with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, though other organ systems may be involved. CASE REPORT A 5-year-old girl presented with non-bloody diarrhea, hemolysis, renal failure, and thrombocytopenia. She was negative for Shiga toxin. She was diagnosed with cTMA, and this diagnosis was confirmed later by a mutation in the complement factor H (CFH) gene. The patient was started on eculizumab 8 weeks after onset of symptoms. A month later, she was able to stop hemodialysis. Eculizumab was given for a year, and then, because of clinical remission, was stopped. At the time of stopping hemodialysis, serum creatinine was 2.07 mg/dL; at the end of eculizumab therapy, it was 1.23 mg/dL. Now, 10 years later, it is 1.10 mg/dL. Glomerular filtration rate by Schwartz equation was 52 mL/min/1.73 m² after eculizumab and 60 mL/min/1.73 m² currently. The cTMA lab parameters normalized after 2 doses of eculizumab and have remained normal for 10 years. Two years ago, on routine ultrasound, renal cysts were noted. Recent genetic testing re-confirmed the CFH mutation and additionally showed a polycystic kidney disease (PKD1) mutation. Notably, there is no family history of either. Currently, the patient has mild proteinuria. CONCLUSIONS Instead of lifelong eculizumab treatment, we successfully managed the patient's condition with a year of eculizumab and intensive followup on sixty occasions over a decade. This approach can work if there are no relapses. Genetic tests revealed mutations for cTMA and autosomal dominant polycystic kidney disease (ADPKD)/PKD1 in the same patient. These have not been reported before, to the best of our knowledge.

Eculizumab, a successful treatment for atypical postpartum hemolytic-uremic syndrome: a case report / Eculizumab, un tratamiento exitoso en el síndrome hemolítico-urémico atípico puerperal: un caso clínico

Atypical hemolytic-uremic syndrome (aHUS) is a rare entity characterized by the association of acute kidney failure, thrombocytopenia and microangiopathic hemolytic anemia due to the dysregulation of the alternative pathway of the complement system. It is included within the thrombotic microangiopathies. The following aHUS was developed in the immediate puerperium in the context of severe preeclampsia. The patient was a primiparous woman of 30+1 weeks who required hospitalization for anticonvulsant and hypotensive treatment, and who underwent an emergency cesarean section due to a pathological cardiotocographic pattern. 36 hours after delivery, the patient presented with sudden dyspnea and cognitive deterioration, progressing in a few hours to renal and multiorgan failure. Blood test showed severe anemia, thrombopenia and hypertransaminemia. In view of the fast evolution and severity, it was decided to treat with Eculizumab, although the scientific evidence was very poor. Aside from the supportive treatment performed in the Intensive Care Unit, the patient was successfully treated with Eculizumab, with favorable evolution over the following months and restoration of kidney function, although need for chronic hypotensive treatment remained.

El síndrome hemolítico-urémico atípico (SHUa) es una entidad rara caracterizada por la asociación de insuficiencia renal aguda, trombocitopenia y anemia hemolítica microangiopática debido a la desregulación de la vía alternativa del sistema del complemento. Se incluye dentro de las microangiopatías trombóticas. Se presenta un SHUa que se desarrolló en el puerperio inmediato en el contexto de una preeclampsia grave. La paciente era una primípara de 30+1 semanas que requirió hospitalización para tratamiento anticonvulsivo e hipotensor, y a la que se le practicó una cesárea de urgencia por un patrón cardiotocográfico patológico. A las 36 horas del parto, la paciente presentó una disnea súbita y un deterioro cognitivo progresivo, que evolucionó en pocas horas a un fallo renal agudo y multiorgánico. La analítica mostró anemia severa, trombopenia e hipertransaminemia. Ante la rápida evolución y gravedad, se decidió tratar con Eculizumab, aunque la evidencia científica era escasa. Aparte del tratamiento de soporte realizado en la Unidad de Cuidados Intensivos, la paciente fue tratada con éxito con Eculizumab, con evolución favorable en los meses siguientes y restablecimiento de la función renal, aunque se mantuvo la necesidad de tratamiento hipotensor crónico.

Recurrent microangiopathic hemolysis after recovery from complement-mediated hemolytic uremia syndrome during chemotherapy for a CFH-mutated patient with T-lymphoblastic lymphoma.

Complement-mediated hemolytic uremic syndrome (CM-HUS) following chemotherapy for pediatric acute lymphoid neoplasms has rarely been reported. We report the case of an 8-year-old boy with T-lymphoblastic lymphoma (T-LBL) who developed CM-HUS with complement factor H (CFH) mutations (S1191L, V1197A) during induction therapy. Safe administration of chemotherapy after CM-HUS recovery was challenging. By closely monitoring hemolytic and renal parameters during the 2-year treatment period, we observed four episodes of microangiopathic hemolytic anemia (MAHA) with hypocomplementemia and low haptoglobin but no renal dysfunction or thrombocytopenia. Here, we describe the MAHA and CM-HUS episodes in the hopes of elucidating the complex pathophysiology of disorders associated with CFH mutation.

Post-Transplant Thrombotic Microangiopathy due to a Pathogenic Mutation in Complement Factor I in a Patient With Membranous Nephropathy: Case Report and Review of Literature.

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ injury occurring due to endothelial cell damage and microthrombi formation in small vessels. TMA is primary when a genetic or acquired defect is identified, as in atypical hemolytic uremic syndrome (aHUS) or secondary when occurring in the context of another disease process such as infection, autoimmune disease, malignancy or drugs. Differentiating between a primary complement-mediated process and one triggered by secondary factors is critical to initiate timely treatment but can be challenging for clinicians, especially after a kidney transplant due to presence of multiple confounding factors. Similarly, primary membranous nephropathy is an immune-mediated glomerular disease associated with circulating autoantibodies (directed against the M-type phospholipase A2 receptor (PLA2R) in 70% cases) while secondary membranous nephropathy is associated with infections, drugs, cancer, or other autoimmune diseases. Complement activation has also been proposed as a possible mechanism in the etiopathogenesis of primary membranous nephropathy; however, despite complement being a potentially common link, aHUS and primary membranous nephropathy have not been reported together. Herein we describe a case of aHUS due to a pathogenic mutation in complement factor I that developed after a kidney transplant in a patient with an underlying diagnosis of PLA2R antibody associated-membranous nephropathy. We highlight how a systematic and comprehensive analysis helped to define the etiology of aHUS, establish mechanism of disease, and facilitated timely treatment with eculizumab that led to recovery of his kidney function. Nonetheless, ongoing anti-complement therapy did not prevent recurrence of membranous nephropathy in the allograft. To our knowledge, this is the first report of a patient with primary membranous nephropathy and aHUS after a kidney transplant.

Clinically Different Presentations of Family Members With the Same Homozygote Diacylglycerol Kinase Epsilon Mutation: Case Report.

Membranoproliferative glomerulonephritis and renal microangiopathies may manifest similar clinical presentations and histology. Many genetic mutations that cause these diseases have been reported. Studies on mutations in the gene encoding diacylglycerol kinase epsilon identified a novel pathophysiologic mechanism leading to atypical hemolytic uremic syndrome and/or membranoproliferative glomerulonephritis. Here, we present the different clinical presentations and treatments in 4 family members who carried the same homozygous diacylglycerol kinase epsilon mutation. The first patient (age 5 years, 3 months old at diagnosis) had nephrotic syndrome. The kidney biopsy was membranoproliferative glomerulonephritis; partial remission was achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil treatment. The second patient (age 5 years, 7 months at diagnosis) presented with overlapping atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis. Remission could not be achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil, and hemodialysis treatment was started. At 10 years from first admission, the patient had end-stage kidney disease, and kidney transplant was performed successfully. The third patient was admitted with the diagnosis of nephrotic syndrome at 13 months of age, kidney biopsy showed membranoproliferative glomerulonephritis, and spontaneous remission developed during followup. He presented with hemolytic uremic syndrome 15 months after the first admission, and dialysis was started. Remission was achieved with plasma infusion and eculizumab treatment. The fourth patient (a 7-month-old boy and brother of patient 3) had no clinical or laboratory findings. All patients had genetic analysis, and mutation in exon 2:c.473G>A(p. W158*) was detected. Our related patients with the same mutation showed different clinical and histological findings. However, we did not observe a clear genotype-phenotype correlation in patients with diacylglycerol kinase epsilon nephropathy, suggesting additional factors mediating phenotypic heterogeneity.

CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome.

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.

Clinico-Histological Features of Thrombotic Microangiopathy in Renal Biopsies: A Retrospective Study.

OBJECTIVE: Thrombotic microangiopathy (TMA) is often first detected on a renal biopsy performed for renal manifestations. Apart from hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura, there are various secondary conditions associated with TMA. This study analyzes the clinico-pathological spectrum, etiological factors and renal outcome of TMA diagnosed on renal biopsy. MATERIAL AND METHOD: A retrospective evaluation of renal biopsies for TMA over 5.5 years was performed. Clinical and laboratory data was collected from patient records. RESULTS: A total of 40 biopsies from 39 patients showed TMA comprising 33 native and 7 transplant biopsies. Malignant hypertension (n=13) was the most common etiology in native biopsies followed by postpartum TMA (n=7), atypical HUS (aHUS) (n=7), and lupus nephritis (n=6). TMA in transplant biopsies was due to acute rejection (n=4) and CNI toxicity (n=3). Serum creatinine was high in most patients (mean 5.6 + 2.5 mg/ dl). aHUS showed the highest mean LDH levels and the lowest average platelet counts. Renal biopsies in malignant hypertension and postpartum TMA showed isolated arterial changes while aHUS and lupus nephritis showed both glomerular and arterial involvement. Postpartum TMA and aHUS had poor renal outcome requiring renal replacement therapy. CONCLUSION: Most postpartum TMA and aHUS had systemic features of TMA while malignant hypertension and lupus nephritis showed 'isolated renal TMA'. This emphasizes the importance of careful evaluation of renal biopsies even in the absence of systemic features of TMA.

Atypical HUS and Crohn's disease-interference of intestinal disease activity with complement-blocking treatment.

BACKGROUND: In atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known. CASE-DIAGNOSIS/TREATMENT: We present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn's disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses. CONCLUSION: In aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.

Eculizumab therapy on a patient with co-existent lupus nephritis and C3 mutation-related atypical haemolytic uremic syndrome: a case report.

BACKGROUND: Thrombotic microangiopathy (TMA), a rare but serious complication of systemic lupus erythematosus (SLE), is associated with poor outcomes to conventional immunosuppressive therapy. Recently, eculizumab, a humanised monoclonal antibody that blocks the complement factor 5, has been known to effectively treat atypical haemolytic uremic syndrome (aHUS). Here, we report a case of aHUS co-existing with lupus nephritis that was successfully treated with eculizumab. CASE PRESENTATION: A 23-year-old man presented with abdominal pain and diarrhoea. Initial laboratory tests have shown thrombocytopaenia, microangiopathic haemolytic anaemia, and acute kidney injury. Immunologic tests were consistent with SLE. Kidney biopsy have revealed lupus nephritis class IV-G with TMA. Genetic analysis have shown complement C3 gene mutations, which hints the co-existence of lupus nephritis with aHUS, a form of complement-mediated TMA. Although initial treatment with haemodialysis, plasma exchange, and conventional immunosuppressive therapy (steroid and cyclophosphamide) did not appreciably improve kidney function and thrombocytopaenia, the patient was able to respond to eculizumab therapy. CONCLUSIONS: Due to the similar features of TMA and SLE, clinical suspicion of aHUS in patients with lupus nephritis is important for early diagnosis and prompt management. Timely administration of eculizumab should be considered as a treatment option for aHUS in lupus nephritis patients to yield optimal therapeutic outcomes.

Carfilzomib-induced atypical haemolytic uraemic syndrome: a diagnostic challenge and therapeutic success.

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) that presents with renal insufficiency, thrombocytopaenia and microangiopathic haemolytic anaemia. Typical HUS is associated with Shiga toxin while atypical HUS (aHUS) is due to overactivation of the alternative complement pathway. aHUS has numerous causes, including drugs, with rare reports of carfilzomib, a proteasome inhibitor used in multiple myeloma, as causative agent. Cases vary in presentation, presenting a diagnostic challenge. Historically, TMAs were treated with plasma exchange. aHUS, however, is considered refractory to plasma exchange and best treated with eculizumab, a monoclonal antibody targeting C5, a terminal complement protein. We report a patient with history of multiple myeloma who presented with headaches, elevated blood pressure, petechiae, ecchymosis and haemolytic anaemia. His condition was determined to be carfilzomib-induced aHUS and he was successfully treated with eculizumab. Early detection and treatment of drug-induced aHUS is vital in reducing morbidity and mortality related to the condition.

Eculizumab interruption in atypical hemolytic uremic syndrome due to shortage: analysis of a Brazilian cohort.

BACKGROUND: The risk of eculizumab therapy discontinuation in patients with atypical hemolytic uremic syndrome (aHUS) is unclear. The main objective of this study was to analyze the risk of aHUS relapse after eculizumab interruption due to drug shortage in Brazil. METHODS: We screened all the registered dialysis centers in Brazil (n = 800), willing to participate in the aHUS Brazilian shortage cohort, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included patients with aHUS whose eculizumab therapy underwent unplanned discontinuation for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy (TMA) in a kidney biopsy. RESULTS: We analyzed 25 episodes of exposure to risk of relapse, from 24 patients. Median age was 33 (6-53) years, 18 (72%) were female, 9 (36%) had a functioning renal graft, 5 (20%) were undergoing dialysis. CFH variant was found in 8 (32%) episodes. There were 11 relapses. The risk of relapse was 34%, 44.5% and 58% at 114, 150 and 397 days, respectively. No baseline variable was related to relapse in Cox multivariate analysis, including CFH variant. CONCLUSIONS: In this study, the cumulative incidence of aHUS relapse at 397 days was 58% after eculizumab interruption. The presence of complement variant does not seem to be associated with a higher relapse rate. The eculizumab interruption was deemed not safe, considering that the rate of relapse was high.

Atypical Hemolytic Uremic Syndrome: New Challenges in the Complement Blockage Era.

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.

[Acute HCV-induced hepatitis in a patient affected by atypical hemolytic uremic syndrome (aHUS) treated with Eculizumab - case report].

Atypical hemolytic uremic syndrome (aHUS) is a rare and heterogenous disease caused by a disregulation of the alternative pathway of the complement cascade. Specifically, microvascular damage is produced that can lead to acute kidney disease, hemolytic anemia and thrombocytopenia. It accounts for 10% of all hemolytic uremic syndromes and can result in death or in end stage renal disease since the first episode. We can differentiate two forms of aHUS: a sporadic form (80%), affecting adult people, and a familial form (20%) that usually became manifest during infancy. In the acute phase of the disease, frequent and severe anemia requires multiple blood transfusions, exposing patients to the risk of catching an infective disease. HCV hepatitis is the most prevalent chronic hepatitis worldwide, with approximately 170 million chronically infected individuals - many of which are unaware of their condition. The evolution of the HCV infection is variable: almost 20% of patients spontaneously clear the infection over time (Anti HCV positive, HCV RNA negative patients); 80% of patients cannot control the virus and develop chronic infection (Anti HCV positive; HCV RNA positive patients) that can evolve into liver cirrhosis and hepatocellular carcinoma. The aim of this paper is to describe a clinical case of acute HCV hepatitis in a patient with aHUS treated with Eculizumab.