aHUS Relapse Research Articles

Генетически-фенотипический профиль детей с атипичным гемолитико-уремическим синдромом

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease caused by dysregulation of the alternative complement pathway as a result of mutations in complement genes or the formation of antibodies (AB) to some of the complement factors. Identification of the gene mutations incidence and the corresponding phenotypic features in pediatric patients with aHUS in Russia is aimed at improving the diagnosis and prognosis of the disease as well as treatment tactics planning for patient management. The purpose of this research was to determine the patterns of progression, prognosis and outcomes of aHUS in children depending on their genetic profile. Materials and methods used: the Article represents data from a retro- and prospective analyses of the characteristics of the course of aHUS in 172 children depending on their genetic profile performed in Jan. 2012-Feb. 2022. The sporadic form of aHUS was diagnosed after exclusion of the other forms of thrombotic microangiopathy (TMA), the familial form (in cases with the familial records), the acquired (CFH-Ab HUS) in cases with AB increase to factor H. AutoAb against factor H was determined by enzyme-linked immunosorbent assay (ELISA-VIDITEST anti-complement factor H). The search for mutations (n=167) was carried out using Next-generation Sequencing (NGS) and Sanger sequencing methods. Results: the sporadic form of aHUS was diagnosed in 96.9% of cases, familial in 3.1% and CFH-Ab HUS in 23.8%. The genetic nature of aHUS was confirmed in 53.4% of cases. Pathogenic mutations were detected in 8.6% of cases, probably pathogenic in 42.8% and those with unclear clinical significance in 46.8%. The complement genes mutations were detected in 88.5% of cases and mutations of genes not related to the complement system (ADAMTS13, DGKE, INF2) in 11.5%. The most frequently identified mutations were in the CFH (17.1%), C3 (12.9%) and CD46 (12.9%) genes and less frequently in CFI (7.1%), THBD (5.7%), CFHR5 (5.7%) and CFB (1.4%). In children with CFH-Ab HUS, the CFHR1/CFHR3 deletion was detected in 87.8% of cases, including in 19.4% in combination with mutations of unknown clinical significance. Multiple organ failure syndrome had developed in 77.8% of cases in children with pathogenic/probably pathogenic mutations, in 85.3% in patients with mutations of unknown clinical significance, in 91.8% in patients without mutations and in 83.3% in patients with CFHR1/CFHR3 deletion. Chronic kidney disease (CKD) stages 3 to 5 in sporadic/familial aHUS, regardless of genetic profile, had counted for 14.5% and 16.7% in CFH-Ab HUS. Lethal outcome occurred in 4.3% of cases in the presence of mutations, in 4.9% in the absence of mutations and in 2.8% in cases of CFHR1/CFHR3 deletion. Relapses of aHUS prior to the Eculizumab treatment had developed more often in the presence of CFHR1/CFHR3 mutations and deletion in comparison with children without mutations (31.4% v. 13.1%, p=0.0313 and 44.4% v. 13.1%, p= 0.004). Relapse of aHUS after discontinuation of the Eculizumab therapy had developed in 16.4% of cases. Risk factors for the relapse of aHUS were as follows: patient’s age above 12 months old at the time of the development of aHUS, severe arterial hypertension in the acute period, the use of Eculizumab at the fourth week after the onset of the disease and/or later, recurrent course of aHUS and the presence of CKD prior to the start of the Eculizumab therapy. Conclusion: The genetic profile of patients does not determine the severity and outcome of aHUS though it does affect the relapse rate. The prognosis and survival of patients with aHUS are determined by the severity of the acute period and the timeliness of the complement blocking therapy management.

Systematic Review of Individual Patient Data COVID-19 Infection and Vaccination–Associated Thrombotic Microangiopathy

Sporadic cases of atypical hemolytic uremic syndrome (aHUS) have been described in the literature in association with COVID-19 infection and vaccination in adults and pediatric patients. The exact mechanisms underlying COVID-19-associated thrombotic microangiopathies (TMAs) remain incompletely understood. Herein, we present a detailed meta-analysis of the clinical characteristics, outcomes, and management strategies of COVID-19-associated aHUS and thrombotic thrombocytopenic purpura (TTP). This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses updated guidelines. PubMed was utilized for searching for case reports and series. Adverse outcome at last follow-up was defined as estimated glomerular filtration rate< 30 ml/min per 1.73 m2 (patients with aHUS), no remission with therapy, or patient death. Data were analyzed using Wilcoxon rank and Chi-square tests. Our analysis cohort included 118 studies reporting on 170 patients. These included 84 cases of aHUS and 86 cases of TTP resulting from COVID-19 infection (n= 92) or vaccination (n= 78). Significantly more cases of aHUS were reported after infection (n= 65) than immunization (n= 19), compared to TTP, where the reverse was true (n= 27 and n= 59, respectively; P< 0.001). In patients with aHUS with stage 3 acute kidney injury (AKI), requirement of kidney replacement therapy (KRT) was seen in three-fourths of the cohort for a median of 15. In patients with TTP, severe COVID-19 infection (P= 0.04) predicted nonremission or death at last follow-up. Administration of i.v., rituximab and caplacizumab were protective (P= 0.03 and P= 0.06, respectively). Immune TTP (iTTP) was reported more often than HUS following mRNA vaccines (81% vs. 58%; P= 0.06). COVID-19 infection and vaccination are a potential trigger for onset or relapse of aHUS and TTP, especially in patients who are not on maintenance complement inhibitors or immunosuppression.

Recurrent Atypical Hemolytic Uremic Syndrome: A Masquerade of Antibody-Mediated Rejection?

Abstract Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy (TMA) resulting from uncontrolled activation of the alternate complement pathway. It is necessary to distinguish a recurrent aHUS posttransplant from de novo aHUS, as the former is usually associated with complement abnormalities and has a poorer prognosis. Furthermore, COVID-19 is believed to unmask underlying complement defects triggering a relapse of aHUS. In this report, we present one such unique histologic presentation of recurrent TMA following a COVID-19 infection, which was not just a diagnostic challenge but could easily have been misdiagnosed as an antibody-mediated rejection.

Ravulizumab facilitates reduced burden of vascular access, a major benefit in paediatric atypical haemolytic uraemic syndrome.

Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy resulting from dysregulation of the alternative complement pathway, leading to multi-organ dysfunction and chronic kidney disease. Eculizumab is an anti-C5 monoclonal antibody therapy that has significantly improved aHUS disease control and patient outcomes, however it requires fortnightly intravenous dosing. This often necessitates long term central access and a high hospital attendance burden. Ravulizumab is a novel, next-generation anti-C5 monoclonal antibody engineered from eculizumab to reduce endosomal degradation of the antibody, increasing the dosing interval up to 8 weeks. In this retrospective case series we present the transition of three children with aHUS from eculizumab to ravulizumab from a single tertiary paediatric nephrology service. All patients underwent genomic and immunological work up for aHUS, with no cause found. After stabilisation with eculizumab, two patients developed macrovascular thrombotic complications associated with indwelling central vascular catheters, ultimately leading to central access failure. All patients were transitioned from eculizumab to ravulizumab without relapse of aHUS. One patient successfully underwent deceased donor kidney transplantation with ravulizumab for complement inhibition. All patients have transitioned to peripheral access for infusions given the reduced frequency of dosing, maintaining good control of aHUS for 2-4 years. Ravulizumab permits sufficiently reduced frequency of infusion to allow for administration by peripheral cannulation - removing the risks of long term central vascular access often required to deliver eculizumab to paediatric patients.

The use of the drug Elizaria – a biosimilar of the original eculizumab in atypical hemolytic-uremic syndrome due to mutation of the С3 gene in children: clinical observation and literature review

This article presents the features of atypical haemolytic-uremic syndrome (ORPHA 544472) in children. Atypical haemolytic-uremic syndrome (aHUS) is defined by a triad: haemolytic anaemia, thrombocytopenia and acute kidney injury in pediatric and adult patients. The OMIM catalogue presents the phenotypic series of aHUS with mutations of the C3, CFB, CFH, CFHR1, CFHR3, DGKE, MCP, THBD genes. Atypical haemolytic-uremic syndrome is often associated with gene mutations in proteins and activators that regulate complement. We report the case of a girl who had a manifestation of aHUS at 8 years 5 months of age and a severe relapse at 8 years 10 months of age. The relapse was characterised by manifestations of haemolytic anaemia, thrombocytopenia, acute renal damage, severe arterial hypertension, high lactate dehydrogenase and membrane attack complex levels and low C3 component. After 5 courses of haemodialysis, 3 haemodiafiltration, diuresis increased and biochemical parameters improved. We presented with ASUS in a child associated with a p.Cys1101Tyr C3 gene mutation. We used a complement inhibitor, Elizaria®, a biosimilar to the original drug eculizumab, to treat a child with atypical haemolytic-uremic syndrome due to the C3 gene mutation. The complement system inhibitor therapy with Elizaria preserved the health and life of a sick girl with a severe relapse of aHUS.

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

Atypical hemolytic uremic syndrome (aHUS) is a rare disease that manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, and is associated with dysregulation of the alternative complement pathway. The chromosomal region including CFH and CFHR1-5 is rich in repeated sequences, favoring genomic rearrangements that have been reported in several patients with aHUS. However, there are limited data on the prevalence of uncommon CFH-CFHR genomic rearrangements in aHUS and their impact on disease onset and outcomes. In this study, we report the results of CFH-CFHR Copy Number Variation (CNV) analysis and the characterization of resulting structural variants (SVs) in a large cohort of patients, including 258 patients with primary aHUS and 92 with secondary forms. We found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving CFH alone or CFH and CFHR (group A; n=14), while 30% exhibited rearrangements including only CFHRs (group B; n=6). In group A, 6 patients presented CFH::CFHR1 hybrid genes, 7 patients carried duplications in the CFH-CFHR region that resulted either in the substitution of the last CFHR1 exon(s) with those of CFH (CFHR1::CFH reverse hybrid gene) or in an internal CFH duplication. In group A, the large majority of aHUS acute episodes not treated with eculizumab (12/13) resulted in chronic ESRD; in contrast, anti-complement therapy induced remission in 4/4 acute episodes. aHUS relapse occurred in 6/7 grafts without eculizumab prophylaxis and in 0/3 grafts with eculizumab prophylaxis. In group B, 5 subjects had the CFHR31-5::CFHR410 hybrid gene and one had 4 copies of CFHR1 and CFHR4. Compared with group A, patients in group B exhibited a higher prevalence of additional complement abnormalities and earlier disease onset. However, 4/6 patients in this group underwent complete remission without eculizumab treatment. In secondary forms we identified uncommon SVs in 2 out of 92 patients: the CFHR31-5::CFHR410 hybrid and a new internal duplication of CFH. In conclusion, these data highlight that uncommon CFH-CFHR SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the CFH are associated with a poor prognosis but carriers respond to anti-complement therapy.

COVID-19 vaccination and Atypical hemolytic uremic syndrome.

COVID-19 vaccination has been associated with rare but severe complications characterized by thrombosis and thrombocytopenia. Here we present three patients who developed de novo or relapse atypical hemolytic uremic syndrome (aHUS) in native kidneys, a median of 3 days (range 2-15) after mRNA-based (Pfizer/BioNTech's, BNT162b2) or adenoviral (AstraZeneca, ChAdOx1 nCoV-19) COVID-19 vaccination. All three patients presented with evident hematological signs of TMA and AKI, and other aHUS triggering or explanatory events were absent. After eculizumab treatment, kidney function fully recovered in 2/3 patients. In addition, we describe two patients with dubious aHUS relapse after COVID-19 vaccination. To assess the risks of vaccination, we retrospectively evaluated 29 aHUS patients (n=8 with native kidneys) without complement-inhibitory treatment, who received a total of 73 COVID-19 vaccinations. None developed aHUS relapse after vaccination. In conclusion, aHUS should be included in the differential diagnosis of patients with vaccine-induced thrombocytopenia, especially if co-occuring with mechanical hemolytic anemia (MAHA) and acute kidney injury (AKI). Still, the overall risk is limited and we clearly advise continuation of COVID-19 vaccination in patients with a previous episode of aHUS, yet conditional upon clear patient instruction on how to recognize symptoms of recurrence. At last, we suggest monitoring serum creatinine (sCr), proteinuria, MAHA parameters, and blood pressure days after vaccination.

Atypical hemolytic-uremic syndrome: evolution of treatment and impact of clinical and genetic characteristics on possibility of eculizumab withdrawal

Atypical hemolytic uremic syndrome (aHUS) is a rare variant of thrombotic microangiopathy (TMA) associated with uncontrolled activation of alternative complement pathway due to mutations in complement regulatory protein genes or antibodies formation to regulators. Clinical manifestations of aHUS can be triggered by infections, sepsis, pregnancy, autoimmune diseases, organ transplantation, and other complement-activating conditions. Previously, the only treatment option for aHUS was plasma therapy – fresh frozen plasma infusions or plasma exchange, but its effectiveness was insufficient. Currently, targeted treatment available – recombinant monoclonal antibodies against complement C5 protein – eculizumab with high efficiency in achieving aHUS remission, renal function recovery, and preventing TMA at kidney transplantation. For a long time, the question of the optimal duration of treatment and the possibility of eculizumab discontinuing remained unresolved. It was shown that aHUS relapses developed in 20-35 % of patients after discontinuation of complement-blocking therapy. The article presents an overview of a large number of studies of eculizumab treatment outcomes and the possibility of its withdrawal, including a French prospective multicenter study that identified risk factors for aHUS relapse after eculizumab discontinuation: the presence of rare variants of complement genes, female gender, increased soluble C5b-9 plasma level. In patients who did not have rare genetic variants, the risk of relapse was less than 5 %. In general, eculizumab discontinuation after achieving complete remission of aHUS and renal function recovery in patients with low risk of recurrence can provide better tolerability of maintenance treatment, and decrease the incidence of infectious complications and the financial burden on the healthcare system.

POS-044 ECULIZUMAB INTERRUPTION IN KIDNEY TRANSPLANT RECIPIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME: ANALYSIS OF A BRAZILIAN SHORTAGE

IntroductionAfter a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted.MethodsWe screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy.ResultsWe analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%.ConclusionsThis study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.No conflict of interest IntroductionAfter a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted. After a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted. MethodsWe screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy. We screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy. ResultsWe analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%. We analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%. ConclusionsThis study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.No conflict of interest This study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Eculizumab in low-middle income countries: how much does a life cost?

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease and eculizumab was approved as first line therapy in 2011 by the Food and Drug Administration. Access to eculizumab in low-middle income countries is challenging. We discuss access to eculizumab in Brazil that was made possible by judicialization or compassionate use. We showed a nationwide cohort of unplanned eculizumab interruptions resulted in higher rates of aHUS relapse. Similar to the French cohort, the use of eculizumab after transplantation showed superior graft survival compared to conventional treatment. We speculate a possible solution to the higher cost of eculizumab in which the government negotiates with the manufacturers. In this process, the government should compromise to ensure validated protocols of drug use, and the pharmaceutical companies, on the other hand, should reduce prices, especially in low-income countries. We also suggest a price adjustment based on gross domestic product.

Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study

The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.

Kidney transplant in patients with atypical hemolytic uremic syndrome in the anti-C5 era: single-center experience with tailored Eculizumab

Patients with atypical hemolytic uremic syndrome (aHUS) have long been considered ineligible for kidney transplantation (KTx) in several centers due to the high risk of disease recurrence, graft loss and life-threatening complications. The availability of Eculizumab (ECU) has now overcome this problem. However, the best approach towards timing, maintenance schedule, the possibility of discontinuation and patient monitoring has not yet been clearly established. This is a single center case series presenting our experience with KTx in aHUS. This study included 26 patients (16 females) with a diagnosis of aHUS, who spent a median of 5.5years on kidney replacement therapy before undergoing KTx. We compared the aHUS relapse rate in three groups of patients who underwent KTx: patients who received no prophylaxis, patients who underwent plasma exchange, those who received Eculizumabprophylaxis. Complement factor H-related disease was by far the most frequent etiology (n = 19 patients). Untreated patients and patients undergoing pre-KTx plasma exchange prophylaxis had a relapse rate of 0.81 (CI 0.30-1.76) and 3.1 (CI 0.64-9.16) events per 10years cumulative observation, respectively, as opposed to 0 events among patients receiving Eculizumabprophylaxis. The time between Eculizumabdoses was tailored based on classic complement pathway activity (target to< 30%). Using this strategy, 12 patients are currently receiving Eculizumab every 28days, 5 every 24-25days, and 3 every 21days. Our experience supports the prophylactic use of Eculizumabin patients with a previous history of aHUS undergoing KTx, especially when complement dysregulation is well documented by molecular biology.

Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome

Terminal complement inhibition is the standard of care for atypical hemolytic uremic syndrome (aHUS). The optimal duration of complement inhibition is unknown, although indefinite therapy is common. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 31 patients that started eculizumab for acute aHUS (and without a history of renal transplant). Twenty-five (80.6%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (interquartile range: 1.06, 9.70) months. Eighteen patients discontinued per protocol and 7 because of nonadherence. Of these, 5 (20%) relapsed; however, relapse rate was higher in the case of nonadherence (42.8%) vs clinician-directed discontinuation and monitoring (11.1%). Four of 5 patients who relapsed were successfully retreated without a decline in renal function. One patient died because of recurrent aHUS and hypertensive emergency in the setting of nonadherence. Nonadherence to therapy (odds ratio, 8.25; 95% confidence interval, 1.02-66.19; P = .047) was associated with relapse, whereas the presence of complement gene variants (odds ratio, 1.39; 95% confidence interval, 0.39-4.87; P = .598) was not significantly associated with relapse. Relapse occurred in 40% (2 of 5) with a CFH or MCP variant, 33.3% (2 of 6) with other complement variants, and 0% (0 of 6) with no variants (P = .217). There was no decline in mean glomerular filtration rate from the date of stopping eculizumab until end of follow-up. In summary, eculizumab discontinuation with close monitoring is safe in most patients, with low rates of aHUS relapse and effective salvage with eculizumab retreatment in the event of recurrence.

Haemoglobinuria for the early identification of aHUS relapse: data from the ItalKId-HUS Network.

Atypicalhaemolytic uremic syndrome(aHUS) is at high risk of relapse at any time, therefore patients require lifelong monitoring. The most appropriate way to monitor patientsis not yet clear. Patients could be monitored for relapse by urine dipstick testing for haemoglobinuria based on thehypothesisthat thrombotic microangiopathy involving the glomerulus and associated with renal damage (like aHUS) cannot occur without haematuria. The aim of this retrospective study is to analyse our experience with this approach in aHUS patients who have never previously been treated, who are currently on treatment or who have discontinued C5 inhibition.The records of all aHUS patients (children and adults) managed by or referred to our Centre from January 2009 to March 2020 were included and the analysisfor the presence of haemoglobinuriawas restricted to the period followingprimary remission. A positive test was defined as haemoglobin ≥ 1 + .Patients reporting positive urine dipstick tests underwent laboratory investigations to rule in or out the diagnosis of aHUS relapse. Eighty-four patients were included with 1517 determinations of haemoglobinuria during a cumulative observation period of 8904 patient-months. Haemoglobinuria for the early diagnosis of ongoing aHUS relapse shows a sensitivity of 100% and a specificity of 87.4% with a positive predictive value (PPV) of 10.5% and a negative predictive value (NPV) of100%. The accuracy of the test was 87.6%. Haemoglobinuria is a very sensitive and acceptably specific marker of aHUS relapse. This finding and its validation may have a positive impact on patients' quality of life and on the outcome of this life threatening disease via early diagnosis of relapse.

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

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

Outcome of atypical haemolytic uraemic syndrome relapse after eculizumab withdrawal.

BackgroundThe introduction of eculizumab has significantly improved the outcome of patients with atypical haemolytic uraemic syndrome (aHUS). Because of the risk of relapse after discontinuation, eculizumab was proposed as life-long therapy. However, data on the outcome of relapse are limited. In the Netherlands, patients with aHUS are treated with a restrictive eculizumab regime and are included in a national observational study (CUREiHUS, Dutch Trial Register NTR5988/NL5833).MethodsFor this interim safety analysis, we evaluated the outcome of all adult patients with a suspected relapse, defined as the need to intensify eculizumab after tapering or withdrawal of therapy.ResultsWe describe 11 patients who received renewed eculizumab therapy because of suspected relapse. In three patients with aHUS in native kidneys, estimated glomerular filtration rate (eGFR) returned to baseline value and remained stable without overt proteinuria after follow-up. Six out of eight transplanted patients responded to eculizumab therapy with improvement in eGFR. After a median follow-up of 24.6 months, a reduction of eGFR ≥25% was observed in three of these transplanted patients, which was attributed to the aHUS relapse in only one patient.ConclusionsThis interim analysis suggests that re-treatment with eculizumab after relapse is safe and feasible. We will continue to use our restrictive treatment strategy.

Atypical hemolytic uremic syndrome in Brazil: clinical presentation, genetic findings and outcomes of a case series in adults and children treated with eculizumab.

BackgroundAtypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and kidney injury caused by a dysregulation of the alternative complement pathway.MethodsWe conducted a multicenter nonregistry study aimed at collecting clinical, laboratory and genetic information of patients with aHUS in Brazil. Demographic data, genetic findings, treatments and outcomes are presented.ResultsThirty-four patients were included, 62% were female and 67% were Caucasian. Half of the patients had the first manifestation of aHUS before the age of 18 years (pediatric group). Among the 17 patients who had the first manifestation after the age of 18 years (adult group), 6 were kidney transplant patients. Overall, 22 patients (65%) received plasma exchange/plasma infusion (PE/PI) and 31 patients (91%) received eculizumab. Eculizumab was started later in the adult group compared with the pediatric group. Two patients stopped dialysis after PE/PI and 19 patients stopped dialysis after eculizumab despite a late start. A pathogenic/likely pathogenic variant was found in 24.3% of patients. A coexisting condition or trigger was present in 59% of patients (infections, pregnancy, hypertension, autoimmune disease and transplant), especially in the adult group. There was a 30% relapse rate after stopping eculizumab, irrespective of genetic status.ConclusionThis is the largest case series of aHUS in Brazil involving a wide range of patients for which eculizumab was the main treatment. Although eculizumab was started later than advised in the guidelines, most patients were able to stop dialysis at variable intervals. Discontinuation of eculizumab was associated with a 30% relapse of aHUS.

Atypical Hemolytic Uremic Syndrome Successfully Treated with Eculizumab

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, which results from uncontrolled complement activation. Delayed diagnosis and treatment of aHUS may result in end-stage renal disease (ESRD) and an associated dependence on dialysis. In extreme cases, it may cause death due to multi-organ failure. Eculizumab, a humanized monoclonal antibody against C5, inhibits the formation of the terminal membrane attack complex and is used to treat aHUS. Here, we report a 46-year-old male patient who suffered from aHUS relapse, despite prior treatment with repeated plasma exchange and hemodialysis. Eculizumab therapy improved his hematologic findings without use of hemodialysis.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.