Complement-mediated Thrombotic Microangiopathy Research Articles

Adolescence-onset atypical hemolytic uremic syndrome: is it different from infant-onset?

Atypical hemolytic uremic syndrome (aHUS) is a rare, mostly complement-mediated thrombotic microangiopathy. The majority of patients are infants. In contrast to infantile-onset aHUS, the clinical and genetic characteristics of adolescence-onset aHUS have not been sufficiently addressed to date. A total of 28 patients (21 girls, 7 boys) who were diagnosed as aHUS between the ages of ≥10years and <18years were included in this study. All available data in the Turkish Pediatric aHUS registry were collected and analyzed. The mean age at diagnosis was 12.8±2.3years. Extra-renal involvement was noted in 13 patients (46.4%); neurological involvement was the most common (32%). A total of 21 patients (75%) required kidney replacement therapy. Five patients (17.8%) received only plasma therapy and 23 (82%) of the patients received eculizumab. Hematologic remission and renal remission were achieved in 25 (89.3%) and 17 (60.7%) of the patients, respectively. Compared with the infantile-onset aHUS patients, adolescent patients had a lower complete remission rate during the first episode (p=0.002). Genetic analyses were performed in all and a genetic variant was detected in 39.3% of the patients. The mean follow-up duration was 4.9±2.6years. At the last visit, adolescent patients had lower eGFR levels (p=0.03) and higher rates of chronic kidney disease stage 5 when compared to infantile-onset aHUS patients (p=0.04). Adolescence-onset aHUS is a rare disease but tends to cause more permanent renal dysfunction than infantile-onset aHUS. These results may modify the management approaches in these patients.

143 Ruvalizumab in the treatment of Complement-mediated Thrombotic microangiopathy (CM-TMA) Post Organ transplant

143 Ruvalizumab in the treatment of Complement-mediated Thrombotic microangiopathy (CM-TMA) Post Organ transplant

Thrombotic microangiopathy in children: Redefining hemolytic uremic syndrome, thrombotic thrombocytopenic purpura and related disorders

Thrombotic microangiopathy (TMA) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and end-organ ischemic damage. The primary mechanism involved is the occurrence of microthrombi due to deficient activity of ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, member 13). The most common types of TMA in children are Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) followed by complement-mediated (CM) TMA, Streptococcus pneumoniae-associated hemolytic uremic syndrome (Sp-HUS) and hereditary thrombotic thrombocytopenic purpura (hTTP) and other rare causes. Since the outcomes are dismal if appropriate treatment is not promptly initiated, there is a need to have a high clinical suspicion. Additionally, urgently performing ADAMTS13 functional activity and autoantibody levels can help differentiate hTTP, immune thrombotic thrombocytopenic purpura (iTTP), and CM-TMA. The etiological differentiation is crucial as eculizumab is a specific therapy with exceedingly good results in CM-TMA. While plasma exchanges are required for iTTP, besides corticosteroids and/or rituximab, plasma infusions suffice for hTTP. This review focuses on the commonly encountered congenital and acquired types of TMA in children and their varied presentations while briefly touching upon the rarer disorders causing TMA.

Предикторы неблагоприятного прогноза атипичного гемолитико-уремического синдрома у детей

Atypical hemolytic-uremic syndrome (aHUS) is an ultra-rare disease based on the development of complement-mediated thrombotic microangiopathy, which has an unfavorable prognosis in its natural course. The purpose — to determine predictors of unfavorable prognosis of aHUS in children. Material and methods. 70 patients (aged 2.5 months — 16 years) were examined at the debut of aHUS and 54 in the catamnesis (1–6 years). The activity of metalloproteinase ADAMTS13 was determined in all children in the acute period by the FRET method. The peculiarities of the course and outcomes of the disease were analyzed. Results. 62.9% of children had decreased ADAMTS13 activity. ADAMTS13 deficiency (57.2 vs 15.6%) was associated with prolonged thrombocytopenia (p = 0.03), development of anuric acute kidney injury (p = 0.0005), increased risk of anuria (OR 8.4; 95% CI 2.2–32.1) with the need for dialysis (OR 5.25; 95% CI 1.77–15.57). In the catamnesis group, 61.1% of cases had CKD, 53.7% had proteinuria, and 38.9% had arterial hypertension. The development of CKD directly correlated with CNS damage (rpb = 0.32, p = 0.02), duration of anuria (R = 0.74, p = 0.001), thrombocytopenia (R = 0.5, p = 0.0009), duration of dialysis (R = 0.45, p = 0.008) and late start of complement-blocking therapy with eculizumab (rpb = 0.54, p = 0.0004). CКD C2-C5 in the distant catamnesis (3–6 years) developed in children who had thrombocytopenia &gt; 10 days at the debut of aНUS (p = 0.0005), anuria &gt; 7 days (p = 0.03) and needed dialysis &gt; 10 days (р = 0.02). Conclusion. ADAMTS13 activity deficiency is associated with a more severe course of acute аHUS episode, but does not affect the long-term prognosis. The risk of developing CKD is associated with the severity of acute aHUS. To improve the prognosis of renal and overall survival of patients with aHUS, long-term monitoring of the condition and preventive measures aimed at ensuring long-term remission are necessary.

Differential contributions of the C5b-9 and C5a/C5aR pathways to microvascular and macrovascular thrombosis in complement-mediated thrombotic microangiopathy patients

To clarify the role of the C5a/C5aR (C5a receptor) and C5b-9 pathways in macrovascular thrombosis (MAT) and renal microthrombosis (MIT), 73 renal biopsy-proven complement-mediated thrombotic microangiopathy (C-TMA) patients were enrolled; 9 patients with pure MAT and 13 patients with pure MIT were selected for further study. Twenty-five external C-TMA patients were selected as the validation cohort. Plasma C5a and sC5b-9 (soluble C5b-9) levels were significantly higher in patients with MAT than in those with MIT (P = 0.008, P = 0.041, respectively). The mean optical density of C5aR1 in the kidney was significantly higher in MAT patients than in those with MIT (P < 0.001). Both urinary sC5b-9 levels (MIT: P < 0.001, MAT: P = 0.004) and renal deposition of C5b-9 (MIT: P < 0.001, MAT: P = 0.001) were significantly higher in C-TMA patients compared to normal control, but were similar between MAT and MIT groups. In the correlation analysis within 22C-TMA patients, urinary sC5b-9 levels and renal deposition of C5b-9 were positively correlated to renal MIT formation (P = 0.009 and P = 0.031, respectively). Furthermore, the renal citrullinated histone H3 (CitH3)- and neutrophil elastase (NE)-positive area ratios were both significantly higher in the MAT group than in the MIT group (P = 0.006 and P = 0.020, respectively). Therefore, the local C5b-9 and C5a/C5aR1 pathways might have differential contributions to MIT and MAT formation in the disease.

Genetic Landscape of Thrombotic Microangiopathies with Focus on Plasminogen Mutation Variants

Background: Complement-mediated thrombotic microangiopathy (CM-TMA) or atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a triad of thrombocytopenia, hemolytic anemia, and kidney injury, presumably caused by dysregulation of the complement system. Around 50-60% of all the patients carry a genetic mutation that predisposes them to CM-TMA and influences primarily their risk of recurrence if therapy is stopped. While most of these mutations are in the complement pathway, other genes beyond the complement system have also been recognized. Plasminogen (PLG) gene encodes for plasminogen and plays a role in the coagulation pathway. Bu et al screened 36 patients with clinical diagnosis of aHUS and found 4 patients with variants in the PLG gene ( Bu et al. J Am Soc Nephrol 2014). However, phenotypic correlation with PLG gene mutations and comparisons to other CM-TMAs have not been reported. Aims: 1) To summarize the genetic variants identified in individuals with CM-TMA from a single center cohort and compare the clinical characteristics of individuals with complement mutation versus coagulation pathway mutation 2) Describe the unique phenotypic features of patients with PLG mutations. Methods: This was a single center retrospective study of patients referred or presenting to the Ohio State University for evaluation for an initial clinical diagnosis of CM-TMA that had TMA gene panel testing performed from 2011 until February 2023. Patients were excluded if the diagnosis of CM-TMA was inconclusive or information regarding their initial presentation or treatment were not available. For individuals who met the criteria, data were collected regarding demographics, clinical features at their first presentation, management, renal outcomes, genetic test findings and disease recurrence. Results: We initially identified 121 individuals who met the study criteria. Final analysis included 105 individuals. Median age at diagnosis was 42 years. Two-thirds of the cohort was female. About half of the patients had no identifiable mutation (n=59, 58.6%). Of those with an identifiable mutation (n=46), 66% (n=30) had a complement mutation and 21% (n=9) had a coagulation pathway mutation. When comparing the presentation at diagnosis, individuals with a coagulation pathway mutation had a comparable degree acute kidney injury (AKI) as reflected by elevated creatinine at presentation, but less thrombocytopenia and hemolysis compared to patients with complement pathway mutations (Table 1). Within the coagulation pathway gene variants cohort, there were initially 6 individuals with PLG mutation and 4 with THBD mutation. We excluded one individual with PLG mutation from this cohort since he also had MCP mutation, and his clinical course was well explained by the presence of MCP mutation. The 5 patients with PLG mutation were females (Table 2). Compared to THBD and complement gene variants, patients with PLG mutation had less AKI, thrombocytopenia, and hemolysis at presentation. These individuals demonstrated quicker recovery of renal function within a few weeks to a month, even in the absence of complement blockade therapy, and most were independent of hemodialysis by 3 months after diagnosis. 2 of the 5 (40%) had recurrent TMA and one of had recurrent TMA episodes despite being on long-term complement blockade therapy which was started after a future relapse. These recurrent events resolved completely with supportive therapy that included plasmapheresis. Three patients are on long-term anticoagulation therapy. None have had any aHUS recurrences while on anticoagulation. None of the patients with PLG mutations developed postpartum presentations despite multiple pregnancies in this limited cohort. Conclusions: Our cohort of CM-TMA subjects shows that patients with PLG mutation associated TMAs have a distinct clinical presentation and possible a lack of response to complement blockade therapy compared with complement gene variants in this cohort. Larger multicenter studies are needed to further validate our findings. Given the role of plasminogen in the coagulation pathway, studies are indicated to explore the role of anticoagulation to prevent recurrence in this subset of patients. Additionally, functional studies of these disease specific PLG variants are vital to identify the pathogenic mechanisms for what might be a distinct form of TMA from CM-TMA.

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.

A Rare Presentation of Genetic Complement-Mediated Thrombotic Microangiopathy

A Rare Presentation of Genetic Complement-Mediated Thrombotic Microangiopathy

13 Differential contributions of C5b-9 and C5a/C5aR pathways to microvascular and macrovascular thrombosis in complement-mediated thrombotic microangiopathy patients

13 Differential contributions of C5b-9 and C5a/C5aR pathways to microvascular and macrovascular thrombosis in complement-mediated thrombotic microangiopathy patients

#4033 RAPID COMPLEMENT INHIBITION WITH THE C5 INHIBITOR CROVALIMAB: A TIMING ANALYSIS USING ANIMAL MODEL AND COMPOSER TRIAL DATA

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS) is a life-threatening disease, characterised by acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia due to complement dysregulation. Currently approved treatments for aHUS include the anti-complement C5 monoclonal antibodies eculizumab and ravulizumab. Although currently approved therapeutic options are effective at both inhibiting complement-mediated thrombotic microangiopathy (TMA) and improving renal function, the regular intravenous (IV) infusion dosing regimens impose a significant treatment burden, particularly in paediatric patients (pts) with aHUS, who may need dialysis in the future due to chronic kidney injury and would benefit from preservation of vascular access. Crovalimab is a novel monoclonal antibody developed against complement C5, engineered to allow for small volume subcutaneous (SC) self-injection every 4 weeks, in a weight-based dosing regimen [1]. In the adaptive Phase I/II COMPOSER trial (NCT03157635) evaluating crovalimab in pts with paroxysmal nocturnal haemoglobinuria (PNH), that, like aHUS, is a complement disorder characterised by uncontrolled complement activation, crovalimab has shown maintained disease control and was well tolerated after a median exposure of 3 years. Further, a Phase III study evaluating crovalimab in previously untreated pts met its primary efficacy endpoints [2]. The efficacy and safety of crovalimab are currently being evaluated in adult and paediatric pts with aHUS, either treatment-naive or switching from another complement inhibitor, in the ongoing Phase III single-arm COMMUTE-a and COMMUTE-p trials [3]. Due to the rapidly progressing nature of aHUS, pts experiencing a TMA require rapid suppression of complement activation upon diagnosis to shut down the complement cascade and avoid further kidney deterioration and organ damage. Here, data from in vivo models and the COMPOSER trial were used to determine the time to complete complement inhibition after first crovalimab IV dose. Method Crovalimab's ability to suppress C5 function and complement activity rapidly was initially studied in in vivo models of cynomolgus monkeys. This study assessed the pharmacokinetics and pharmacodynamics of crovalimab in these monkeys after a single IV or SC dose. As part of this study, four animals per group were evaluated with single 4 mg/kg IV and 20 mg/kg IV doses. Crovalimab was also evaluated in the four-part, Phase I/II COMPOSER trial. Part 2 (n = 10) and Part 4A (n = 8) enrolled pts with PNH who were naive to complement inhibition. Pts in Part 2 received crovalimab 375 mg IV on Day 1, 500 mg IV on Day 8, 1000 mg IV on Day 22 and 170 mg SC weekly from Day 36 for 20 weeks. Pts in Part 4A received an optimised crovalimab dosing regimen of 1000 mg IV on Day 1, 340 mg SC on Days 2, 8, 15, and 22 and 680 mg SC Q4W from Day 29 onwards for 20 weeks. Crovalimab concentration, free C5 and complement activity were measured using validated assays in cynomolgus monkeys and in pts with PNH. Results Compared with baseline values in cynomolgus monkeys, a single crovalimab IV dose of 4 mg/kg reduced mean free C5 concentration by 99.6% and terminal complement activity by 81.4%, within 5 minutes after administration. In treatment-naive pts from COMPOSER Parts 2 and 4, mean free C5 concentration dropped to below 1 μg/mL, indicating a high level of target engagement within 1–6 hours from the first IV dose (Figure 1). Correspondingly, inhibition of terminal complement activity was reached within 1 hour, with values near or below the lower limit of quantification (10 U/mL; Figure 2). Complete complement blockade was generally maintained long-term, up to Week 20, in both Parts 2 and 4, regardless of dose. Conclusion Crovalimab induced a complete, rapid, and sustained blockade of terminal complement activity in both non-human primates and pts with PNH, within hours from first dose. The dosing schedule of crovalimab included an initial IV loading dose, allowing for a rapid onset of action, followed by a convenient long-term SC maintenance regimen.

Ravulizumab (Ultomiris)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses ravulizumab (Ultomiris) 10 mg/mL solution for IV infusion.&#x0D; Indication: For the treatment of adults and pediatric patients with atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy.&#x0D;

Pregnancy in Complement-Mediated Thrombotic Microangiopathy: Maternal and Neonatal Outcomes

Pregnancy, delivery, and neonatal outcomes in women with complement-mediated thrombotic microangiopathy (cTMA) have not been well described. A better understanding of these outcomes is necessary to provide women with competent pregnancy counseling. Cohort study. Women with a history of cTMA and pregnancies enrolled into the Vienna thrombotic microangiopathy cohort. New onset or relapses of cTMA. Pregnancy, delivery, and neonatal outcomes of pregnancies in women (a) before cTMA manifestation, (b) complicated by pregnancy-associated cTMA (P-cTMA), and (c) after first manifestation of cTMA or P-cTMA. Mixed models were used to adjust the comparison of pregnancy, delivery, and neonatal outcomes between conditions (before, with, and after cTMA) for repeated pregnancies using the mother's ID as random factor. In addition, the fixed factors, mother's age and neonate's sex, were used for adjustment. For (sex-adjusted and age-adjusted) centile outcomes, only the mother's age was used. Adjusted odds ratios were derived from a generalized linear mixed model with live birth as the outcome. Least squares means and pairwise differences between them were derived from the linear mixed models for the remaining outcomes. 28 women reported 74 pregnancies. Despite higher rates of fetal loss before the diagnosis of P-cTMA and preterm births with P-cTMA, most of the women were able to conceive successfully. Neonatal development in all 3 conditions of pregnancies was excellent. Pregnancy and neonatal outcomes were better in women with a pregnancy after the diagnosis of cTMA. Although our data set comprises a considerable number of 74 pregnancies, the effective sample size is lower because only 28 mothers with multiple pregnancies were observed. The statistical power for detecting clinically relevant effects was probably low. A recall bias for miscarriages cannot be ruled out. Prepregnancy counseling of women with a history of cTMA can be supportive of their desire to become pregnant.

Genetic, clinical, and pathological study of patients with severe hypertension-associated renal microangiopathy.

Severe hypertension may be a prominent manifestation of complement-mediated thrombotic microangiopathy. Furthermore, patients with severe hypertension-associated thrombotic microangiopathy may present with concurrent hematologic abnormalities that mimic complement-mediated thrombotic microangiopathy. Whether or not severe hypertension-associated thrombotic microangiopathy is associated with genetic susceptibility in complement- and/or coagulation-pathway genes remains unclear, and there is thus a need to identify clinicopathological clues to distinguish between these entities. Forty-five patients with concomitant severe hypertension and thrombotic microangiopathy on kidney biopsy were identified retrospectively. Whole-exome sequencing was performed to identify rare variants in 29 complement- and coagulation-cascade genes. Clinicopathological features were compared between patients with severe hypertension-associated thrombotic microangiopathy and complement-mediated thrombotic microangiopathy with severe hypertension. Three patients with pathogenic variants diagnostic of complement-mediated thrombotic microangiopathy and two with anti-factor H antibody positivity were diagnosed with complement-mediated thrombotic microangiopathy with severe hypertension. Among the 40 patients with severe hypertension-associated thrombotic microangiopathy, 53 rare variants of uncertain significance were found in the analyzed genes in 34 (34/40, 85%) patients, of whom 12 patients harbored two or more variants. Compared with complement-mediated thrombotic microangiopathy patients with severe hypertension, patients with severe hypertension-associated thrombotic microangiopathy were more likely to have left ventricular wall thickening (p < 0.001), less-severe acute glomerular thrombotic microangiopathy lesions including mesangiolysis and subendothelial space widening (both p < 0.001), and less arteriolar thrombosis formation (p < 0.001). Rare genetic variants involving complement and coagulation pathways can be found in patients with severe hypertension-associated thrombotic microangiopathy; their role needs further investigation. Cardiac remodeling and acute glomerular TMA lesions may help to differentiate between severe hypertension-associated thrombotic microangiopathy and complement-mediated thrombotic microangiopathy with severe hypertension.

Characterization for the Similarity Assessment between Proposed Biosimilar SB12 and Eculizumab Reference Product Using a State-of-the-Art Analytical Method.

SB12 is being developed as a proposed biosimilar to eculizumab reference product (RP), a humanized monoclonal antibody (IgG2/4 kappa immunoglobulin) that binds to the human C5 complement protein. Binding to this protein inhibits complement-mediated intravascular hemolysis by blocking its cleavage into C5a and C5b. Eculizumab RP is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis, atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy, generalized myasthenia gravis who are anti-acetylcholine receptor antibody-positive, and neuromyelitis optica spectrum disorder in adult patients who are anti-aquaporin-4 antibody-positive. The objective of this study was to demonstrate structural, physicochemical, and biological similarity between eculizumab RP and SB12 using various state-of-the-art analytical methods. Comprehensive analytical characterization was conducted with side-by-side comparison of SB12 with European Union (EU) and United States (US) eculizumab RPs using various analytical methods (more than 40 state-of-the-art assays). Comparisons included purity, product-related impurity, charge heterogeneity, primary structure, post-translational modification, higher-order structure, quantity, Fab-related biological activities (potency and binding activity), and Fc-related biological activities. Based on the analytical similarity assessment, the structural, physicochemical, and biological characterization results demonstrated that SB12 is highly similar to the EU and US eculizumab RP. In the structural aspects, it was confirmed that there is no difference between post-translational modification profiles and higher-order structures of SB12 compared with the eculizumab RP. Product-related impurities in the form of aggregates and charge variants were also confirmed to be similar. Mechanism of action (MoA)-related biological activities showed that SB12 is highly similar to the EU and US eculizumab RP with respect to overall critical and non-critical quality attributes analyzed. Moreover, similarity of comparative binding tendency of SB12 and eculizumab RP to Fc gamma receptors and C1q was confirmed through additional characterization methods. Based on these results, SB12 is expected to have highly similar safety and efficacy compared with eculizumab RP. In summary, the overall analytical characterization and similarity assessment results show that SB12 is highly similar to the EU and US eculizumab RP in terms of structural, physicochemical, biophysical, and biological attributes.

Evaluation of Eculizumab Use in Renal Transplant Recipients.

Introduction: Eculizumab is a monoclonal antibody that binds to complement protein C5, inhibiting complement-mediated thrombotic microangiopathy. It is approved for several indications including atypical hemolytic uremic syndrome. Additionally, eculizumab is used off-label for antibody-mediated rejection and C3 glomerulopathy in renal transplant recipients. Due to limited data available, the purpose of this study was to describe the use of eculizumab treatment in renal transplant recipients. Design: This retrospective single-center study evaluated the safety and efficacy of eculizumab for on- and off-label indications in renal transplant recipients. Adult renal transplant recipients receiving at least 1 dose of eculizumab posttransplant between October 2018 and September 2021 were included. The primary outcome evaluated was graft failure in patients treated with eculizumab. Results: Forty-seven patients were included in analysis. The median age at eculizumab initiation was 51 years [IQR 38-60], with 55% being female. Indications for eculizumab included atypical hemolytic uremic syndrome/thrombotic microangiopathy (63.8%), antibody-mediated rejection (27.7%), C3 glomerulopathy (4.3%), and other (4.3%). Graft failure occurred in 10 patients (21.3%) with a median of 2.4 weeks [IQR 0.5-23.3] from transplant to graft failure. At last follow-up (median 56.1 weeks), 44 (93.6%) patients were alive. After eculizumab initiation, renal function improved at 1 week, 1 month, and last follow-up. Conclusion: Eculizumab treatment demonstrated a benefit on graft and patient survival compared to reported incidence in thrombotic microangiopathy and antibody-mediated rejection. Due to the small sample size and retrospective design, further research is warranted to confirm these results.

Ravulizumab (Ultomiris)

&#x0D; CADTH recommends that Ultomiris be reimbursed by public drug plans for the treatment of adult and pediatric patients at least 1 month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA), if certain conditions are met.&#x0D; Ultomiris should only be covered to treat adults and children (aged 1 month or older) who: have aHUS, evidence of ongoing and progressing TMA (blood clots forming in small blood vessels), and evidence of at least 1 damaged or dysfunctional organ. Ultomiris may be funded for patients who had a kidney transplant, but not for those who have already tried ravulizumab and it did not work.&#x0D; Ultomiris should only be reimbursed if it is prescribed by or in consultation with a nephrologist or hematologist. Its cost should not be more than the least expensive complement inhibitor that is reimbursed for the treatment of aHUS.&#x0D;

Correction to: Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab

Correction to: Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab

Clinical value of the renal pathologic scoring system in complement-mediated thrombotic microangiopathy

Objectives This study was initiated to establish a renal thrombotic microangiopathy (TMA) scoring system based on clinical needs and investigate its predictive value for patients’ long-term outcomes. Methods Kidney biopsy-proven Complement-mediated TMA (C-TMA) patients from January 2000 to December 2017 in Peking University First Hospital were retrospectively studied. Both acute and chronic TMA-related lesions, including 15 pathologic indices, were semiquantitatively scored. The interobserver and intraobserver reproducibility and correlation between the pathologic indices and clinical parameters were analyzed. Furthermore, the patients were divided into 2 groups by dialysis use at baseline, and the association of these pathologic indices with their prognostic outcomes was assessed between the two groups. Results Ninety-two patients with renal biopsy-proven C-TMA were enrolled. All fifteen included pathology indices showed good or moderate interobserver and intraobserver reproducibility and correlated well with several clinical parameters. Several clinicopathological indices were worse in the dialysis group than in the nondialysis group, such as serum creatinine, hemoglobin, platelet count, and estimated glomerular filtration rate. Moreover, morphologic features in the dialysis group presented with more severe vascular lesions. Interstitial fibrosis and chronic tubulointerstitial lesions were related to a trend of high risk of continuous dialysis in the dialysis group. Based on univariate and multivariable Cox regression analysis, more severe glomerular lesions, including glomerular mesangiolysis, glomerular basement membrane double contours and glomerular mesangial proliferation, were identified as risk factors predicting worse prognosis. Conclusions Our renal C-TMA semiquantitative scoring system is reliable with good reproducibility and prognostic value in clinical practice, which needs further validation.

Complement-Mediated Thrombotic Microangiopathy and Spontaneous Splenic Rupture Associated With Cytomegalovirus Infection.

This is a case report of a previously healthy female patient with complement-mediated thrombotic microangiopathy (TMA) caused by a systemic cytomegalovirus infection that was successfully treated with plasmapheresis, steroids, and parenteral valganciclovir. Complement-mediated TMA is the result of various genetic mutations leading to complement abnormalities with overactivation of alternate complement pathway in response to a triggering infection. She also had splenic rupture without splenomegaly and was managed successfully without splenectomy.

A Review on Differential Diagnosis and Diagnostic Criteria of Complement-Mediated Thrombotic Microangiopathy with a PLASMIC Score Below Six and Coexisting Hepatitis B Positivity in a Male Patient

A Review on Differential Diagnosis and Diagnostic Criteria of Complement-Mediated Thrombotic Microangiopathy with a PLASMIC Score Below Six and Coexisting Hepatitis B Positivity in a Male Patient