Case report: A family of atypical hemolytic uremic syndrome involving a CFH::CFHR1 fusion gene and CFHR3-1-4-2 gene duplication.

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband's parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH-CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH-CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS.

Management of pediatric hemolytic uremic syndrome.

Classical clinical triad of hemolytic uremic syndrome (HUS) is microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury associated with endothelial cell injury. Several situations, including infections, medications, malignancies, and transplantation can trigger endothelial damage. On the HUS spectrum, atypical hemolytic uremic syndrome (aHUS) deserves special attention in pediatric patients, as it can cause endstage kidney disease and mortality. A dysfunction in the alternative complement pathway, either acquired or genetic, has been shown to be the main underlying cause. In the last decades, breathtaking advances have been made in understanding the pathophysiology of this rare disease, which has led to more efficient treatment. Recent studies have implicated genes in pathways beyond the alternative complement system, such as DGKE, TSEN2, and INF2 highlighting the importance of personalized management. Eculizumab has brought about dramatic improvements in the treatment of aHUS. Beyond eculizumab, there are many alternative therapeutics in the pipeline that target the complement system. Because of the rarity of aHUS, data from multiple patient registries are very important. The present report aimed to summarize the most important aspects of diagnosing and treating aHUS based on the Turkish national registry and the literature so as to improve clinical practice.

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.

A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Anti-factor B antibodies in atypical hemolytic uremic syndrome.

BACKGROUND: The etiology of atypical hemolytic uremic syndrome (aHUS) is unknown in 30-40% of patients. Anti-factor B (FB) antibodies are reported in C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN), though not in aHUS. METHODS: We screened patients < 18-year-old from cohorts of aHUS and C3G/idiopathic IC-MPGN. Anti-FB IgG antibodies were measured by ELISA and confirmed by Western blot. Normative levels were based on antibody levels in 103 healthy blood donors. RESULTS: Prevalence of anti-FB antibodies was 9.7% (95% CI 6.1-14.5%; n = 21) in 216 patients with aHUS, including 11.5% (95% CI 6.4-18.5%; n = 14) in anti-FH associated aHUS and 11.8% (95% CI 4.4-23.9%; n = 6) in patients without a definitive genetic or autoimmune etiology. Patients with significant genetic variants did not show anti-FB antibodies. In patients with concomitant anti-FB and anti-FH antibodies, median anti-FH titers were higher (11,312 AU/mL vs. 4920 AU/mL; P = 0.04). Anti-FB antibody titer correlated with disease severity (hemoglobin and platelets; P < 0.05), declined following plasma exchange and increased during relapse. While 4/64 patients with C3G (6.3%) and 1/17 with IC-MPGN showed anti-FB antibodies, titers were higher in aHUS (544.8 AU/mL vs. 1028.8 AU/mL; P = 0.003). CONCLUSION: Anti-FB antibodies are present in 6-10% of patients with aHUS and C3G/IC-MPGN, with higher titers in the former. The diagnostic and therapeutic implication of anti-FB antibodies in aHUS needs confirmation and further studies. The study shows propensity for autoantibody generation and co-existence of multiple risk factors for aHUS in Indian children.

[Translated article] Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (standard deviation (SD) 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) can be associated with mutations, deletions, or hybrid genes in factor H-related (FHR) proteins. METHODS: A child with aHUS was investigated. Genetics was assessed by Sanger and next generation sequencing. Serum FHR5 was evaluated by immunoblotting, ELISA, and by induction of rabbit red blood cell hemolysis in the presence/absence of recombinant human rFHR5. Mutagenesis was performed in HEK cells. RESULTS: A heterozygous genetic variant in factor H-related protein 5 (CFHR5), M514R, was found in the child, who also had a homozygous deletion of CFHR3/CFHR1, and antibodies to factor H, as well as low levels of C3. Patient serum exhibited low levels of FHR5. In the presence of rabbit red blood cells, patient serum induced hemolysis which decreased when rFHR5 was added at physiological concentrations. Similar results were obtained using serum from the father, bearing the CFHR5 variant without factor H antibodies. Patient FHR5 formed normal dimers. The CFHR5 M514R variant was expressed in HEK cells and minimal secretion was detected whereas the protein level was elevated in cell lysates. CONCLUSIONS: Decreased secretion of the product of the mutant allele could explain the low FHR5 levels in patient serum. Reduced hemolysis when rFHR5 was added to serum suggests a regulatory role regarding complement activation on red blood cells. As such, low levels of FHR5, as demonstrated in the patient, may contribute to complement activation.

Complement-mediated thrombotic microangiopathy treated with anticomplement protein 5 therapy, a retrospective study.

BACKGROUND: Complement-mediated thrombotic microangiopathy (CM-TMA), also called atypical hemolytic uremic syndrome (aHUS), is a difficult-to-diagnose rare disease that carries severe morbidity and mortality. Anti-C5 monoclonal antibodies (aC5-mab) are standard treatments, but large studies and long-term data are scarce. Here, we report our single institution experience to augment the knowledge of CM-TMA treated with aC5-mab therapy. METHODS: We aimed to assess the short and long-term effects of aC5-mab in patients diagnosed with CM-TMA treated outside of a clinical trial. This was a retrospective study. We included all patients diagnosed with CM-TMA and treated with aC5-mab at our institution. There were no exclusion criteria. Endpoints included complete TMA response (CR) defined as normalization of hematological parameters and ≥25% improvement in serum creatinine (Cr) from baseline in patients with renal disease, relapse defined as losing the previously achieved CR, morbidity, adverse events, and survival. RESULTS: We found 28 patients with CM-TMA treated with aC5-mab. The median age was 50 years. Baseline laboratories: platelet counts 93 × 109 /L, hemoglobin 8.6 g/dL, lactate dehydrogenase 1326 U/L, serum Cr 4.7 mg/dL, and estimated glomerular filtration rate 19 mL/min. One individual was on renal replacement therapy (RRT) and 10 initiated RRT within 5 days of the first dose of aC5-mab. Genetic variants associated with CM-TMA included mutations in C3, CFB, CFH, CFHR1/3, CFI, and MCP. The mean duration of hospitalization was 24 days. The median time to initiation of aC5-mab was 10 days. Sixteen subjects received RRT. At the time of hospital discharge, 27 were alive, 14 remained on RRT, and 4 had a CR. At 6 months, 23 patients were alive, 18 continued aC5-mab, 8 remained on RRT, and 9 had a CR. At the last follow-up visit past 6 months, 20 were alive, 14 continued aC5-mab, 5 remained on RRT, 12 had a CR, and 1 was lost to follow-up. CONCLUSIONS: Our study provides real-world experience and insight into the long-term outcomes of CM-TMA treated with aC5-mab. Our findings validate that CM-TMA is an aggressive disease with significant morbidity and mortality, and confirm that aC5-mab is a relatively effective therapy for CM-TMA. Our study adds practical, real-world experience to the literature, but future research remains imperative.

Renin and renin blockade have no role in complement activity.

Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.

Concurrent Cobalamin C and Plasminogen Deficiencies in a Patient with Chronic Thrombotic Microangiopathy.

BACKGROUND: Although most patients with atypical hemolytic uremic syndrome (aHUS) have variants in genes participating in alternative complement pathways, rare variants in non-complement pathway-related genes, including DGKE, INF2, MMACHC, PLG, and THBD, have also been described. CASE PRESENTATION: We report an 18-year-old male patient with renal biopsy-proven chronic thrombotic microangiopathy that raised suspicion of aHUS. Whole-exome sequencing revealed a novel pathogenic homozygous MMACHC c.484G>T (p.Gly162Trp) variant. Subsequently, clinical and laboratory findings confirmed cobalamin C (Cbl C) deficiency. Also, homozygous missense c.1112C>T PLG (p.Thr371Ile) variant was detected (it had been reported as a variant of unknown significance). However, the low serum plasminogen (PLG) activity proved the pathogenicity of c.1112C>T. Hence, the patient was diagnosed with concurrent Cbl C and PLG deficiencies. Segregation analysis revealed that the mother and father had the same heterozygous PLG and MMACHC variants. PLG variants have generally been described in aHUS patients concomitant with complement gene variants in the literature; therefore, the association between aHUS and PLG variants is controversial. The possible contribution of PLG deficiency to thrombotic microangiopathy was also discussed in this case. CONCLUSION: Non-complement-mediated aHUS is an exceptional disorder. A limited number of genes are involved in this entity. To our knowledge, this is the first aHUS patient diagnosed with both Cbl C and PLG deficiencies in the literature.

Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy. / Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (SD 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Defective C3d caused by C3 p.W1034R in inherited atypical hemolytic uremic syndrome.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy. Personal genome analyses have revealed numerous aHUS-causing variants, mainly complement-related genes. However, not all aHUS-causing variants have been functionally validated. METHODS: An exome sequence analysis of a Japanese multiplex family composed of three patients diagnosed with aHUS in infancy and showing frequent relapses clustered in a dominant transmission mode was performed. Protein interaction between the C3d and C-terminal domains of factor H was analyzed using a quartz crystal microbalance. RESULTS: Following filtering by heterozygous variants, amino acid substitutions, and allele frequency, the analysis revealed eight rare variants shared by the affected individuals. Variant prioritization listed C3 p.W1034R as the most likely candidate gene mutation in the affected individuals, despite being classified as a variant of uncertain significance. Binding of recombinant C3d harboring 1034R to recombinant short consensus repeats 15 to 20 of factor H was significantly suppressed compared with that of C3 with 1034W. CONCLUSION: C3 p.W1034R results in an inherited form of aHUS that often presents with recurrent episodes, possibly because of impaired interactions between the C3d and C-terminal domains of factor H. Following comprehensive genomic analysis, functional validation of C3 p.W1034R strengthens the molecular basis for aHUS pathophysiology.

Constipation and hemolytic uremic syndrome.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) classically presents with diarrhea. Absence of diarrheal prodrome increases suspicion for atypical HUS (aHUS). Inability to obtain a fecal specimen for culture or culture-independent testing limits the ability to differentiate STEC-HUS and aHUS. CASE-DIAGNOSIS/TREATMENT: Our patient presented with abdominal pain and constipation, and evaluation of pallor led to a diagnosis of HUS. There was a complete absence of diarrhea during the disease course. Lack of fecal specimen for several days delayed testing for STEC. Treatment for atypical HUS was initiated with complement-blockade therapy. PCR-testing for Shiga toxin from fecal specimen later returned positive. Alternative complement-pathway testing did not identify a causative genetic variant or anti-Factor H antibody. A diagnosis of STEC-HUS was assigned, and complement-blockade therapy was stopped. CONCLUSION: Diagnosis of aHUS remains a diagnosis of exclusion, whereby other causes of HUS are eliminated with reasonable certainty. Exclusion of STEC is necessary and relies on testing availability and recognition of testing limitations. Diarrhea-negative STEC-HUS remains a minority of cases, and future research is needed to explore the clinical characteristics of these patients.

End stage renal disease in patient with microscopic polyangiitis and atypical hemolytic-uremic syndrome arose 3 weeks after the third dose of anti-SARS-CoV2 vaccine mRNA-1273: A case report with literature revision.

RATIONALE: Immune system deregulation, including AAV, is a key event that may potentially evolve into ESRD. Abnormal activation of the cAP is also a cardinal feature of TMA, particularly aHUS. The kidney is the most frequently involved organ, and renal-limited forms of TMA are often encountered in clinical practice. Isolated case reports described the occurrence of renal TMA in AAV patients. Some cases of both de novo and relapses of AAV and/or TMAs after anti-SARS-CoV2 vaccination have been reported. We reported, for the 1st time, a case of patients with new-onset MPA and aHUS occurring 3 weeks after the third dose of mRNA-1273 vaccine anti-SARS-CoV2. PATIENT CONCERNS: We present a 67-year-old man, affected by arterial hypertension, reported, after mRNA-1273 vaccine anti-SARS-CoV2, anuria, fatigue, anorexia and nausea. Laboratory data revealed acute renal failure. DIAGNOSIS: Positivity of MPO-ANCA was observed. 7 days after admission, we observed a worsening of anemia and thrombocytopenia with haptoglobin reduction, LDH increase and presence of schistocytes. Plasma levels of ADAMTS-13 were normal. A renal biopsy was performed, and findings were consistent with microscopic polyangiitis, with features of micro-thrombotic glomerulopathy. Genetic tests revealed absence of hybrid genes associated with the increased risk of aHUS. INTERVENTIONS AND OUTCOMES: We started renal replacement treatment, including hemodialysis, and pulsed methylprednisolone, with no improvement of laboratory parameters. Then, plasma exchange was performed leading to partial haematological response. Only with Eculizumab, a human C5 inhibitor, we observed a normalization of haptoglobin levels and platelets' count. However, three months after discharge, the patient still required hemodialysis. LESSONS: To our knowledge we observed the first case aHUS, without genetic predisposition, associated with MPA occurring after the third dose of anti-SARS-CoV2 vaccine. This case report highlights the potential link between anti-SARS-CoV2 vaccine as a trigger of MPA and aHUS. This systematic review offers additional perspectives. It is plausible to hypothesize that the vaccine was the trigger for the development of these 2 diseases.Solid evidence on the mechanisms of interaction between vaccine and immune system, the role of genetic predisposition, and other variables, will shed additional light on the controversial link between anti-SARS-CoV2 vaccine and autoimmunity.

[Comparative characteristics of the complement system in patients with C3-glomerulopathy and atypical hemolytic uremic syndrome of chronic course who suffered an acute episode of thrombotic microangiopathy].

AIM: To compare changes in the complement system in C3-glomerulopathy (C3-GP) and atypical hemolytic uremic syndrome (aHUS) after the relief of an acute episode of thrombotic microangiopathy. MATERIALS AND METHODS: The study included 8 patients diagnosed with C3-GP and 8 with aHUS in remission. The blood levels of the complement system components were determined: C3, C4, C3a, C5a, factor H (CFH), factor B (CFB), membrane-attacking complex (MAC), antibodies to C3b (anti-C3b-AT), the level of hemolytic activity (CH50), the content of factor D (CFD) in the urine. RESULTS: C3 and CH50 levels were within the reference range in both groups, however, in the C3-GP group they were at the lower limit, and C3 level was significantly lower than in the aHUS group: 0.56 [0.44; 0.96] vs 1.37 [1.16; 2.52] (p=0.003). CFB increased level was detected in both groups, but in the C3-GP group it was significantly lower than in the aHUS group - 275.1 [222.1; 356.6] vs 438.7 [323.3; 449.3] (p=0.010). C3a, C5a and MAC levels were increased in both groups, but the maximum was in the C3-GP group, and the MAC level in the C3-GP group was 2 times higher than that in aHUS, and these differences reached statistical significance - 123 555±6686 vs 5603±1294 (p=0.036). CFH and CFD levels was increased in both groups, but their highest values was in the aHUS group. CONCLUSION: Alternative complement pathway activation signs were present in both groups of patients with complement-mediated nephropathies, regardless the stage of the disease. In C3-GP, alternative complement pathway activation was more pronounced than in aHUS after the relief of an acute episode of thrombotic microangiopathy.

[Various phenotypes of postpartum atypical hemolytic uremic syndrome: the role of genetic testing in determining prognosis. Case report].

We report a case of atypical hemolytic uremic syndrome (aHUS) that occurred after childbirth in a patient with a history of numerous recurrent episodes of TMA with nephrotic proteinuria and impaired renal function. At 33 weeks of the first spontaneous pregnancy, proteinuria up to 0.8 g/l was first registered, at 38 weeks she was hospitalized with proteinuria, reaching a maximum of 13 g/l, she was delivered promptly, after which progressive thrombocytopenia was noted over the next few days (up to 44×109/l) and anemia and severe arterial hypertension, which could not be corrected by several groups of antihypertensive drugs. Initiated plasma therapy had no effect. After exclusion of all other causes of TMA, therapy with eculizumab was initiated, which made it possible to quickly and completely stop the phenomena of TMA. The presented observation demonstrates the successful treatment of recurrent course of aHUS with eculizumab with the achievement of complete recovery of kidney function in a patient with a homozygous mutation in the MCP gene. It is worth noting the importance of genetic research even in those situations where clinically aHUS is beyond doubt.

Atypical hemolytic and uremic syndrome in Algeria: diagnostic difficulties and therapeutic constraints / Syndrome hémolytique et urémique atypique en Algérie : difficultés diagnostiques et contraintes thérapeutiques

Atypical Hemolytic Uremic Syndrome (aHUS) is a systemic disease due to dysregulation of the alternate complement pathway, mortality is estimated at 10% and more than 50% of patients progress to end-stage renal disease. The aim of this study was to summarize the clinical data and biological results as well as the evolution and management of patients with aHUS seen over a period of four years in one specialized department in Algeria. Our study was observational and longitudinal. The inclusion criteria were: the clinical-biological triad of aHUS and age ≤ 16 years. The type of treatment, the presence of complement mutation or anti-complement factor autoantibodies were not eligibility conditions. On inclusion and every six months, demographic data, clinical and biological history and results after treatment were collected prospectively. Our workforce consisted of 21 children with aHUS. Thirteen patients benefited from a complement study; among them, 7 had complement abnormalities. Eleven children had familial HUS; among them 8 died and 6 were less than one year old. Plasma exchanges were performed in two children. Six patients received eculizumab, with an average age of 3.6 years. After the acute phase, 9 children recovered their kidney function, one child had developed a chronic kidney disease (CKD), and 11 died, among them 8 belong to aHUS families. Fifty percent of deaths occurred in the first 3 months. At 2 years of evolution, out of 7 children having reached this stage, five had renal sequelae and four of them had CKD. The severe prognosis of this disease makes early diagnosis and treatment essential.

Le syndrome hémolytique et urémique atypique (SHUa) est une maladie systémique due à une dérégulation de la voie alterne du complément. La mortalité est estimée à 10 % et plus de 50 % des patients évoluent vers l'insuffisance rénale terminale. Le but de la présente étude était de résumer les données cliniques et les résultats biologiques ainsi que l'évolution et la prise en charge des patients atteints de SHUa vus sur une durée de quatre ans dans un service spécialisé en Algérie. Notre étude était observationnelle et longitudinale. Les critères d'inclusion étaient : la triade clinico-biologique du SHUa et l'âge ≤ 16 ans. Le type de traitement, la présence de mutation du complément ou d'auto-anticorps anti-facteur du complément ne constituaient pas des conditions d'éligibilité. À l'inclusion et tous les six mois, les données démographiques, l'histoire clinique, biologique et les résultats après traitement étaient collectés prospectivement. Notre effectif était formé de 21 enfants avec SHUa. Treize patients ont bénéficié d'une étude du complément ; parmi eux sept avaient des anomalies du complément. Onze enfants avaient un SHU familial ; parmi eux huit sont décédés et six avaient moins d'un an. Des échanges plasmatiques ont été réalisés chez deux enfants. Six patients ont bénéficié d'éculizumab, avec un âge moyen de 3,6 ans. Après la phase aiguë, neuf enfants avaient récupéré leur fonction rénale, un enfant avait gardé une insuffisance rénale chronique (IRC), et 11 enfants étaient décédés dont huit appartenaient à des familles de SHUa. Cinquante pourcent des décès étaient survenus durant les trois premiers mois. À deux ans d'évolution, sur sept enfants ayant atteint ce stade, cinq avaient des séquelles rénales et quatre d'entre eux étaient en IRC. Le pronostic sévère de cette maladie rend la précocité du diagnostic et de la prise en charge primordiales.