Atypical Hemolytic Uremic Syndrome Research Articles

Diacylglycerol kinase-ε is S-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment

Diacylglycerol kinase-ε (DGKε) catalyzes phosphorylation of diacylglycerol to phosphatidic acid with a unique specificity toward 1-stearoyl-2-arachidonoyl-sn-glycerol, which is a backbone of phosphatidylinositol (PI). Owing to this specificity, DGKε is involved in the PI cycle maintaining the cellular level of phosphorylated PI derivatives of signaling activity and was also found crucial for lipid metabolism. DGKε dysfunction is linked with the development of atypical hemolytic uremic syndrome (aHUS) and possibly other human diseases. Despite the DGKε significance, data on its regulation by cotranslational and/or post-translational modifications are scarce. Here, we report that DGKε is S-palmitoylated at Cys38/40 (mouse/human DGKε) located in the cytoplasmic end of its N-terminal putative transmembrane fragment. The S-palmitoylation of DGKε was revealed by metabolic labeling of cells with a palmitic acid analogue followed by click chemistry and with acyl-biotin and acyl-polyethylene glycol exchange assays. The S-acyltransferases zDHHC7 (zinc finger DHHC domain containing) and zDHHC17 and the zDHHC6/16 tandem were found to catalyze DGKε S-palmitoylation, which also increased the DGKε abundance. Mouse DGKε-Myc ectopically expressed in human embryonic kidney 293 cells localized to the endoplasmic reticulum where zDHHC6/16 reside and in small amounts also to the Golgi apparatus where zDHHC7 and zDHHC17 are present. The Cys38Ala substitution upregulated, whereas hyperpalmitoylation of wild-type DGKε reduced the kinase activity, indicating an inhibitory effect of the Cys38 S-palmitoylation. In addition, the substitution of neighboring Pro31 with Ala also diminished the activity of DGKε. Taken together, our data indicate that S-palmitoylation can fine-tune DGKε activity in distinct cellular compartments, possibly by affecting the distance between the kinase and its substrate in a membrane.

A Moderate Decrease in ADAMTS13 Activity Correlates with the Severity of STEC-HUS.

Atypical hemolytic uremic syndrome (HUS) develops as a result of damage to the endothelium of microvasculature vessels by Shiga toxin produced by enterohemorrhagic Escherichia coli (STEC-HUS). STEC-HUS remains the leading cause of acute kidney injury (AKI) in children aged 6 months to 5 years. The pathomorphological essence of the disease is the development of thrombotic microangiopathy (TMA). One of the key causes of TMA is an imbalance in the ADAMTS13-von Willebrand factor (vWF)-platelet system. The goal of the work was to clarify the role of a moderate decrease in ADAMTS13 activity in the pathogenesis of STEC-HUS. The activity of ADAMTS13 was determined in 138 children (4 months-14.7 years) in the acute period of STEC-HUS and the features of the course of the disease in these patients were analyzed. The study revealed a decrease in the activity and concentration of ADAMTS13 in 79.8% and 90.6% of patients, respectively. Measurements of von Willebrand factor antigen content and the activity of von Willebrand factor in the blood plasma of part of these patients were carried out. In 48.6% and 34.4% of cases, there was an increase in the antigen concentration and the activity of the Willebrand factor, respectively. Thrombocytopenia was diagnosed in 97.8% of children. We have demonstrated that moderately reduced ADAMTS13 activity correlates with the risk of severe manifestations of STEC-HUS in children; the rate of developing multiple organ failure, cerebral disorders, pulmonary edema, and acute kidney injury with the need for dialysis increases. It is assumed that reduction in ADAMTS13 activity may serve as a predictor of disease severity.

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

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. 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. 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. 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.

Eculizumab en recién nacido con síndrome hemolitico urémico atípico: a propósito de un caso

Eculizumab en recién nacido con síndrome hemolitico urémico atípico: a propósito de un caso

An abscess formation on the transplanted graft and its successfully treatment in kidney transplantation recipient with de novo atypical hemolytic uremic syndrome treated with eculizumab: a case report

An abscess formation on the transplanted graft and its successfully treatment in kidney transplantation recipient with <i>de novo</i> atypical hemolytic uremic syndrome treated with eculizumab: a case report

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

Atypical hemolytic uremic syndrome (aHUS) can be associated with mutations, deletions, or hybrid genes in factor H-related (FHR) proteins. 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. 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. 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.

Anti-factor H autoantibody-associated hemolytic uremic syndrome in an Argentine pediatric cohort

Aim: To describe the clinical characteristics and frequency of anti-factor H (FH) autoantibody-associated atypical hemolytic uremic syndrome (aHUS) in the first cohort of Argentine patients. Methods: The presence of anti-FH autoantibodies in 70 pediatric patients with suspected aHUS was investigated between 2013 and 2022. Clinical and laboratory parameters were collected and compared between patients who were positive and negative for anti-FH antibodies. Results: The 70 patients screened for anti-FH autoantibodies presented clinical features of non-immune microangiopathic hemolytic anemia, thrombocytopenia and renal injury. Positive titers were found in 14 children [mean: 1,938 arbitrary units per mL (AU/mL), range 179–8,500]. Due to missing clinical data, two patients who tested positive for anti-FH and 20 patients who tested negative for anti-FH were excluded from the data analysis. The laboratory features and clinical manifestations of anti-FH-positive aHUS cases (n = 12) were very similar to those of subjects with no autoantibodies detected (n = 36). Treatment administration was heterogeneous among the 12 patients analyzed. Dialysis was performed in six patients in total. Five children received plasmapheresis, while three patients were treated with plasma exchange followed by administration of eculizumab. Two patients received eculizumab only and one showed significant improvement solely through supportive care. Eight patients in total received immunosuppressive therapy. Follow-up of three patients showed a significant decrease of anti-FH autoantibody titers in 2/3 after treatment and during clinical remission. Conclusions: The cohort of 70 pediatric patients in this study demonstrated that the frequency of anti-FH autoantibody-associated aHUS in Argentina is 20%. The implementation of anti-FH testing in the country can potentially contribute to improved treatment and follow-up for patients with autoimmune aHUS.

A Phase 1 Study to Evaluate the Pharmacokinetics of Single High Doses of Iptacopan

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. At the current clinical dose of 200 mg twice daily, the steady-state area under the concentration curve (AUC) and peak concentration (C max) are 25,600 ng•hr/L and 4,120 ng/mL, respectively. In this randomized, participant-blinded, placebo-controlled phase 1 study, we evaluated the pharmacokinetics (PK) of single high doses of iptacopan. Methods: Iptacopan single doses of 400 mg (n=6), 800 mg (n=9), and 1200 mg (n=9) were included in this study, representing ≤6-fold higher doses than the clinical dose of 200 mg twice daily. The study population included healthy men and women aged 18-55 years. The log-transformed PK parameters AUC and C max were analyzed separately using a linear model with treatment as fixed effect. Results: Twenty-four patients received iptacopan and 8 received placebo. The median age of participants in the 400-, 800-, and 1200-mg groups was 51.5, 35, and 36 years, respectively. Following a single oral administration, iptacopan was rapidly absorbed with C max at 1.06, 2.00, and 2.52 hours for 400-mg, 800-mg, and 1200-mg doses, respectively ( Table). Variability (CV% geometric-mean) in iptacopan plasma concentrations were low to moderate (16.6%-30.6%) at C max. After administration, iptacopan plasma concentration-time profiles increased over the dose range of 400 to 1200 mg and were biphasic, with an inflection point at approximately 12 hours ( Figure). Compared to the 200-mg twice daily steady-state PK, the 1200-mg single dose resulted in C max and AUC exposure multiples of 4.0- and 6.5-fold, respectively. The mean apparent elimination half-life was similar across all doses, ranging from 20 to 21 hours. Iptacopan was well tolerated with no moderate or severe treatment-emergent adverse events reported. Conclusion: Iptacopan was rapidly absorbed after administration of single oral doses ranging from 400 to 1200 mg. Variability in iptacopan plasma concentrations were low to moderate over the dose range studied and half-lives were similar. Supratherapeutic, single doses up to 1200 mg were well tolerated and resulted in substantial multiples of iptacopan systemic exposure.

A Mutation in Complement Factor H (W1183R) Enhances VWF Proteolysis By ADAMTS13 Under Shear

Introduction: Complement factor H (CFH) is the primary negative regulator of complement activation in the alternative pathway in both fluidic phase and on cell surface. Loss of function of CFH such as W1183R is associated with atypical hemolytic uremic syndrome (aHUS). Homozygous mutation W1206R in the murine CFH, corresponding to W1183R in human CFH, results in acute aHUS. Interestingly, in these mice, while plasma VWF antigen levels are significantly increased, plasma VWF multimer size is markedly reduced in ADAMTS13-depedent manner. However, the molecular mechanism underlying such a dramatic effect of the mutant CFH (W1206R) on VWF multimer distribution is not known. The goal of this study is to determine how wild type CFH and mutant CFH W1183R affects VWF proteolysis under shear, and the mechanism of action. Methods: Recombinant WT CFH, CFH W1183R, ADAMTS13, and VWF fragments were expressed in mammalian cells and purified to homogeneity. The effects of WT CFH or CFH W1183R on proteolytic cleavage of VWF73 peptide and full-length multimeric VWF were determined. Additionally, the binding and unfolding events were determined by micro scale thermophoresis (MST) and optical tweezer, respectively. Results : WT CFH showed no effect on the cleavage of peptide VWF73 substrate, but CFH W1183R enhanced the proteolytic cleavage of VWF73 by ADAMTS13 in a dose-dependent manner ( Fig. 1). Counterintuitively, WT CFH appeared to inhibit the proteolytic cleavage of multimeric VWF by ADAMTS13 under arterial shear, but CFH W1183R exhibited an opposite effect, modestly enhancing the proteolytic cleavage of multimeric VWF by ADAMTS13 under the same conditions. The MST binding assay demonstrated that both WT CFH and CFH W1183R bind to a short A1, a long AIM-A1, and A1-A2-A3 fragments with a dissociation constant ( K D) of 6.4 x 10 -7, 3.0 x 10 -9 M, and 3.3 x10 -9 mol/L, respectively. These results suggest that CFH may bind to the AIM, A1-A2 junction, and A2 domain. To further assess the impact of CFH binding to A2, we performed optical tweezer experiments. The results showed that both WT CFH (Lc: from 27.4 nm at 12 nM to 40 nm at 1.0 mM) and CFH W1183R (Lc: from 26 nm at 12 nM to 31.8 nm at 1.0 mM) resulted in significantly extended contour length (Lc) of VWF-A2 domain in a concentration-dependent manner ( Fig. 2), suggesting a dramatic conformational change in the A2 domain upon binding by WT CFH or CFH W1183R. Conclusions : Our results demonstrate that WT CFH at physiological concentrations may exhibit a modest inhibitory activity towards cleavage of VWF by ADAMTS13 under shear, but such an inhibitory activity disappears as the result of a point mutation in the C-terminal end of CFH (e.g., W1183R). Instead, the mutant CFH W1183R appears to enhance the VWF cleavage by ADAMTS13, likely through direct binding to the AIM, A1-A2 junction, and A2 domain of VWF, resulting in conformational changes in the central A2 domain.

Results of Preclinical Animal Studies to Evaluate the Effect of Iptacopan on Pregnancy-Related Outcomes

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several complement-driven diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Here, we report results from the preclinical GLP toxicology studies of iptacopan on embryo-fetal development in rats and rabbits and pre- and postnatal development in rats. Methods: In the definitive embryo-fetal development studies,iptacopan was dosed orally via gavage to pregnant rats at 0, 100, 300, and 1000 mg/kg/day (N=24/group) and to pregnant rabbits at doses of 0, 100, 250, and 450 mg/kg/day (N=20/group) during the period of organogenesis (Gestation Day [GD] 6 to 17 and GD7 to 20, respectively). The progress and outcome of pregnancy were evaluated and fetuses were examined for external, visceral, and skeletal abnormalities. In a pre- and postnatal developmental toxicity study in pregnant rats, iptacopan was dosed orally via gavage at 0, 100, 300, and 1000 mg/kg/day (N=22/group) from GD6 to Lactation Day (LD) 21. The untreated offspring were allowed to mature and the effects on development, behavior, and reproductive performance were assessed. Results: In the rat embryo-fetal development study, maternal administration of iptacopan resulted in no adverse clinical observations, no effects on maternal body weights, and no adverse fetal findings. Non-adverse fetal variations of delayed ossification were observed in the skull. Two fetuses in one out of 22 litters at 1000 mg/kg/day had benign cysts on the left side of the parietal region of the head, with no impact on skeletal (skull), CNS (brain), or any other head-based structure. The no observed adverse effect level (NOAEL) for maternal toxicity and embryo-fetal development was 1000 mg/kg/day. In the definitive rabbit embryo-fetal development study, administration of iptacopan caused reduced maternal body weight gain and food consumption at 450 mg/kg/day. There were no treatment-related fetal malformations or variations. The NOAEL was 250 mg/kg/day for maternal toxicity and 450 mg/kg/day for embryo-fetal development. In the pre- and postnatal development study, no adverse findings were observed in the mated female rats during gestation, parturition, and lactation and there were no adverse effects on development of their offspring, including survival, physical development, behavior, and reproductive performance. The NOAEL for maternal (F0 generation) toxicity, maternal performance, and development of the F1 generation offspring was the highest dose of 1000 mg/kg/day. NOAEL and estimated AUC-based safety margins based on total plasma concentrations for all mentioned studies are shown in the Table. Conclusion: In nonclinical reproductive toxicity studies conducted in pregnant rats and rabbits, iptacopan was found to be generally safe with no teratogenic effects in the rat and rabbit. Estimated AUC-based safety margins were &amp;gt;5-fold for all developmental findings compared to exposure at the clinical dose of 200 mg twice daily. While these preclinical data do not provide definitive conclusions or guidance on the use of iptacopan in pregnant women, they do provide reassurance that there is no overt preclinical signal of embryo-fetal toxicity.

A First-in-Human, Phase 1 Study to Assess the Pharmacodynamic Properties of Single-Dose Iptacopan (CLNP023X2101)

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway (AP). Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Here, we report the exploratory pharmacodynamics of single doses of iptacopan from part 1 of the phase 1 study (CLNP023X2101) in healthy participants. Methods: CLNP023X2101 was a randomized, non-confirmatory, first-in-human assessment of iptacopan in healthy participants. Part 1 was a participant-blinded, placebo-controlled, single-ascending dose (SAD) study. SADs ranged from 5 mg to 400 mg in 56 participants across 7 cohorts. Eight participants per cohort were randomized to receive a single oral dose of iptacopan or placebo in a 3:1 ratio. Inhibition of terminal complex activity of the complement system was assessed using the Wieslab assay which was based on the in vitro formation of the C5b-9 complex, triggered by AP activation. Other soluble biomarkers measured were plasma fragment Bb, a biomarker of AP activation generated by the cleavage of Factor B, and plasma sC5b-9. Results: Demographic data were similar across the treatment groups. Most participants were men with a median age of 45 years. Iptacopan led to dose-dependent suppression of the AP activity as measured by the Wieslab assay ( Figure 1). Following administration, &amp;gt;81% reduction of the AP activity (compared with baseline) was observed at 2 hours post-dose for all dose groups except the 5-mg dose group. Duration of sustained inhibition of AP activity was dose-dependent. Greater than 80% inhibition of the AP activity compared with baseline was maintained beyond 12 hours after 200-mg and 400-mg doses. Wieslab values returned to baseline levels after 48 hours post dose except for the 200-mg and 400-mg cohorts. The decrease in Bb levels from baseline was observed at 2 hours post-dose in all groups and was sustained until 12 hours post-dose before returning to baseline levels by 48 hours ( Figure 2). In the 200-mg and 400-mg cohorts, Bb levels plateaued until 24 hours post-dose and similarly returned to baseline by 48 hours. In contrast, no significant change in Bb level was seen in participants receiving placebo. A trend to decreased sC5b-9 levels was observed until 6 hours post-dose in most cohorts (≥25 mg). Conclusions: Iptacopan achieved rapid, substantial, and sustained dose-dependent suppression of AP activity at 2 hours post-dose for all doses &amp;gt;5 mg. Further validating this result, the decrease in Bb levels at 2 hours post-dose was maintained until 12 hours post-dose, with doses ≥100 mg showing sustained inhibition beyond 12 hours. These pharmacodynamic findings of single-dose iptacopan were part of the rationale for dose selection in clinical Phase 2 and 3 studies contributing to the evidence of 200 mg twice daily being the appropriate dose.

A Phase 1 Study to Assess the Effect of Supratherapeutic Doses of Iptacopan on Cardiac Conduction Parameters and Safety

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The purpose of this randomized, participant-blinded, placebo-controlled phase 1 study was to assess the effect of supratherapeutic doses on the exposure-response relationship of iptacopan concentration and cardiac conduction, and to assess the cardiac safety and tolerability of ascending, supra-therapeutic single doses of iptacopan. Methods: Supratherapeutic doses of iptacopan 400, 800, and 1200 mg were included in this study, representing ≤6-fold higher dose than the planned clinical dose of 200 mg. The primary endpoints were change from baseline in Fridericia-corrected QT interval (QTcF) and safety endpoints. The analyses included data from this study pooled with part 1 data (single dose) from the first-in-human (CLNP023X2101) study (n=86). The study population included healthy men and women aged 18-55 years. The relationship between iptacopan plasma concentration and change from baseline in QTcF was estimated using a linear mixed effects model. Results: Thirty-two patients were randomized and received placebo (n=8) or iptacopan (n=24). The median age of participants in the 400-mg, 800-mg, 1200-mg, and placebo groups was 51.5, 35, 36, and 37 years, respectively. The upper bound of the 2-sided 90% CI for linear mixed effects model-derived placebo-adjusted change from baseline in QTcF at the geometric mean C max was 2.82 ms for 400-mg, 2.94 ms for 800-mg, and 3.22 ms for 1200-mg doses. Hence, there was no evidence of clinically meaningful QTc prolongation ( Table). The exposure-response analysis of PR and QRS intervals showed no iptacopan concentration-related effects. While the pre-specified and more simple exposure-response analysis of heart rate using change from day 1 baseline (0 hour) revealed an increase of 3 to 5 beats per minute, in a post hoc analysis using 24-hour, time-matched comparison for each participant at each time point before and after study treatment (the more common and gold-standard analysis), iptacopan had no effect on heart rate. No deaths, no moderate or severe treatment-emergent adverse events, and no treatment cohort discontinuations due to adverse events were reported. Conclusions: Three supratherapeutic doses were well tolerated and were not associated with any relevant change in QTcF. Iptacopan did not affect PR or QRS intervals and a time-matched post hoc analysis showed no effect on heart rate. These results indicate that the anticipated clinical dose of iptacopan (200 mg twice daily) has no adverse clinical effects on cardiac function.

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Treatment Patterns Associated with Readmission after Index Hospitalization

Introduction Atypical hemolytic uremic syndrome (aHUS) is associated with dysregulation of the alternative complement pathway and causes significant morbidity and mortality when undiagnosed or inappropriately treated. C5 inhibitors (C5i) improve thrombotic microangiopathy (TMA) response and renal recovery, but significant morbidity may remain. This study described the clinical characteristics and treatment patterns associated with readmission after index hospitalization using real-world evidence from one of the largest, most diverse cohorts of presumed incident aHUS in the United States (US). Methods This was a retrospective cohort study of 634 incident cases among hospitalized adult patients with presumed aHUS derived from the US Premier Healthcare Database, an electronic healthcare records database that contains ~25% of all US hospitalizations (January 1, 2011-June 30, 2021). aHUS was defined as the presence of an International Classification of Diseases (ICD)-9-CM/ICD-10-CM diagnostic code for TMA (446.6, M31.1, M31.10, M31.19) or HUS (283.11, D59.3) and a treatment code (standard charge, HCPCS, ICD-10-PCS) for a C5i, in the absence of a diagnostic code for secondary causes of TMA/HUS or other C5i indications. The proportion of patients readmitted following the index hospitalization was assessed at 30 days and 365 days following discharge, among other timepoints. The time from index hospitalization discharge to all-cause hospital readmission was defined as the number of days from the discharge date of the index hospitalization to the date of all-cause readmission. Readmission for aHUS was defined as a hospitalization lasting ≥2 days to avoid the inclusion of in-hospital infusion clinic visits for C5i treatment. Demographic and clinical characteristics were analyzed using a t-test, Wilcoxon rank test, Fisher's exact test, or Chi-squared test, as appropriate. Results Overall, 78/634 patients (12.3%) died during index hospitalization. Among the 556 patients who survived until discharge, 23.4% and 39.7% had a readmission within 30 days and 365 days, respectively. During the first 365 days, 20.1% of patients required multiple hospitalizations. The median time to first readmission was 27.5 days (interquartile range [IQR]: 9-102 days). Infection was a common cause of readmission (25.6%). Readmission within either 30 or 365 days was associated with longer median time between index admission and therapeutic plasmapheresis (TPE) (3 vs 2 days, p=0.0002, and 3 vs 2 days, p&amp;lt;0.0001, respectively), longer median time between index admission and C5i (10 vs 8 days, p=0.0441, and 10 vs 8 days, p=0.0005, respectively), and longer median time between index admission and renal replacement therapy (RRT; 4 vs 2 days, p=0.0030, and 3 vs 2 days, p=0.0053, respectively). Only readmission within 365 days was associated with median age (52 vs 46 years of age, p=0.0124) or a history of hypertension (80.5% vs 64.5%, p&amp;lt;0.0001), atrial fibrillation (9.5% vs 4.8%, p=0.0363), or heart failure (21.7% vs 14.6%, p=0.0395) at index hospitalization. Readmission within 30 or 365 days was not associated with sex, race, ethnicity, insurance type, geographical region, hospital size or location (rural vs urban), diabetes, chronic kidney disease, myocardial infarction history, TPE, TPE duration, corticosteroids (CS), CS duration, time to CS, RRT requirement, or TMA remission at discharge. Conclusions aHUS readmission rates remain high, despite treatment with C5i, and infection is a common cause of readmission. Delayed TPE, RRT, and C5i treatment for aHUS during index hospitalization, even if only for 1-2 days, were associated with increased readmission within 30 and 365 days. Future efforts should be made to examine the causal relationship between treatment delays and outcomes.

Clinical case of recurrent aHUS after allogeneic cadaveric kidney transplantation

Introduction. Atypical hemolytic uremic syndrome (aHUS) is a systemic orphan disease that reproduces as an uncontrolled activation of the alternative pathway of the complement system and is expressed as systemic thrombotic microangiopathy (TMA). The classical triad of aHUS symptoms are hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Currently, diagnosis of aHUS is a diagnosis of exclusion and has no pathognomonic features. It is established based on the clinical presentation of the disease after excluding other forms of TMA, Objective: to increase physicians’ awareness of this rare disease, the diagnosis and treatment of aHUS using a clinical case study.Conclusion. Early diagnosis of aHUS is extremely important, as timely targeted therapy can significantly improve or completely restore the functions of the affected organ.

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Outcomes During Index Hospitalization Diagnosis in the Era of C5 Inhibitor Therapy (C5i)

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Outcomes During Index Hospitalization Diagnosis in the Era of C5 Inhibitor Therapy (C5i)

Atypical Hemolytic Uremic Syndrome with Normal Complement Studies in a Patient with Complement Factor I Deficiency

Atypical Hemolytic Uremic Syndrome with Normal Complement Studies in a Patient with Complement Factor I Deficiency

Use of Anti-C5 Inhibitor Leading to Renal Recovery in Combined Typical and Atypical Hemolytic Uremic Syndrome (HUS)

Use of Anti-C5 Inhibitor Leading to Renal Recovery in Combined Typical and Atypical Hemolytic Uremic Syndrome (HUS)

Anti-Complement Factor H Autoantibodies of the IgM Class and Atypical Hemolytic Uremic Syndrome (aHUS)

Anti-Complement Factor H Autoantibodies of the IgM Class and Atypical Hemolytic Uremic Syndrome (aHUS)

Lupus Nephritis Complicated by Atypical Hemolytic Uremic Syndrome and Heterozygous Deletion in CFHR1-CFHR3 Successfully Treated with Ravulizumab

Lupus Nephritis Complicated by Atypical Hemolytic Uremic Syndrome and Heterozygous Deletion in CFHR1-CFHR3 Successfully Treated with Ravulizumab

Outcome of Kidney Transplantation in Atypical Hemolytic Uremic Syndrome (aHUS): Eculizumab Prophylaxis vs. Rescue Therapy

Outcome of Kidney Transplantation in Atypical Hemolytic Uremic Syndrome (aHUS): Eculizumab Prophylaxis vs. Rescue Therapy