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Background Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement dysregulation is pivotal for the disease to develop. Here, we studied this premise in seven patients with TMA and coexisting MG. Methods Patients with TMA on kidney biopsy and/or peripheral blood were recruited from the prospective COMPETE cohort (NCT04745195) and Limburg Renal Registry. Patients were screened for complement dysregulation, including genetics/factor H autoantibodies (FHAA) and functional ex vivo testing on microvascular endothelial cells. Results Seven (8%) out of 84 patients with TMA presented with a coexisting MG. MG clustered in patients aged over 50 years (n/N  = 6/32, 19%). C4 and/or C3 levels were low in three patients, while four patients presented with normal complement levels. None of the patients carried rare variants in complement genes. Massive ex vivo C5b9 formation on the endothelium was noted in one patient; purified IgG from this patient caused massive ex vivo C5b9 formation via the alternative pathway of complement activation, pointing to complement dysregulation in the fluid phase. Kidney biopsies from other nephropathies linked to MG rarely exhibited concurrent TMA (n/ N = 1/27, 4%). Conclusions MG clustered in patients with TMA aged over 50 years. TMA and coexisting MG represents a heterogeneous disease spectrum, including a small subset of patients who may present with complement dysregulation. [ABSTRACT FROM AUTHOR]

Background IgA vasculitis (IgAV) is the most common form of childhood vasculitis. Nephritis (IgAVN) occurs in 50% of patients and 1–2% progress to chronic kidney disease stage 5. The pathophysiology of nephritis remains largely unknown, but recent evidence suggests that the complement system may be involved. The aim of this cross-sectional study was to explore whether there is evidence of alternative and/or lectin complement pathway activation in children with IgAVN. Methods Children with IgAV were recruited and grouped according to proteinuria: IgAVN or IgAV without nephritis (IgAVwoN). Age and sex-matched healthy controls (HCs) were also recruited. Cross-sectional urine and plasma concentrations of complement factor D (CFD), factor B (CFB), and MBL-associated protease 1 (MASP-1) were performed using commercially available enzyme-linked immunoassays. Results A total of 50 children were included (IgAVN, n  = 15; IgAVwoN, n  = 20, HCs, n  = 15). The mean age was 8.5 ± 3.7 years old, male:female ratio was 1:1. Urinary CFD and CFB concentrations were statistically significantly increased in children with IgAVN (3.5 ± 5.4 μg/mmol; 25.9 ± 26.5 μg/mmol, respectively) compared to both IgAVwoN (0.4 ± 0.4 μg/mmol, P  = 0.002; 9.2 ± 11.5 μg/mmol, P  = 0.004) and HCs (0.3 ± 0.2 μg/mmol, P  < 0.001; 5.1 ± 6.0 μg/mmol, P  < 0.001). No statistically significant difference was reported for the plasma concentrations of CFD and CFB. Urinary MASP-1 concentrations were statistically significantly increased in IgAVN (116.9 ± 116.7 ng/mmol) compared to HCs (41.4 ± 56.1 ng/mmol, P  = 0.006) and plasma MASP-1 concentrations were increased in IgAVwoN (254.2 ± 23.3 ng/mL) compared to HCs (233.4 ± 6.6 ng/mL, P  = 0.046). Conclusion There is evidence of complement pathway products in the urine of children with IgAVN that warrants further investigation. [ABSTRACT FROM AUTHOR]

A recent study conducted at the Mayo Clinic by Benjamin Madden and Sanjeev Sethi has shed light on the pathophysiology of dense deposit disease (DDD), a subtype of C3 glomerulopathy (C3G). The researchers used laser capture microdissection and mass spectrometry to analyze the major components of deposits in DDD and compared them to C3 glomerulonephritis (C3GN) and control cases. They found that DDD was enriched with apolipoprotein E (apoE) compared to C3GN and control cases, suggesting that apoE staining could be a useful alternative to electron microscopy for diagnosing DDD. However, further research is needed to understand the biological implications of apoE in DDD. [Extracted from the article]

Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease. Therefore, studies involving large samples are scarce, making registries powerful tools to evaluate cases. We present herein the first analysis of the Brazilian aHUS Registry (BRaHUS). Methods Analysis of clinical, laboratory, genetic and treatment data from patients inserted in the BRaHUS, from 2017 to 2020, as an initiative of the Rare Diseases Committee of the Brazilian Society of Nephrology. Results The cohort consisted of 75 patients (40 adults and 35 pediatric). There was a predominance of women (56%), median age at diagnosis of 20.7 years and a positive family history in 8% of cases. Renal involvement was observed in all cases and 37% had low C3 levels. In the <2 years of age group, males were predominant. Children presented lower levels of hemoglobin (P  = .01) and platelets (P  = .003), and higher levels of lactate dehydrogenase (LDH) (P  = .004) than adults. Genetic analysis performed in 44% of patients revealed pathogenic variants in 66.6% of them, mainly in CFH and the CFHR1 -3 deletion. Plasmapheresis was performed more often in adults (P  = .005) and 97.3% of patients were treated with eculizumab and its earlier administration was associated with dialysis-free after 3 months (P  = .08). Conclusions The cohort of BRaHUS was predominantly composed of female young adults, with renal involvement in all cases. Pediatric patients had lower hemoglobin and platelet levels and higher LDH levels than adults, and the most common genetic variants were identified in CFH and the CFHR1-3 deletion with no preference of age, a peculiar pattern of Brazilian patients. [ABSTRACT FROM AUTHOR]

This document is a puzzle related to IgA nephropathy, a kidney disease. The puzzle includes keywords and clues related to the disease, such as the involvement of podocytes, the role of IgA immune complexes, and the treatment options. It also mentions the complement pathways involved, the source of abnormal IgA, and the influence of local activation on kidney damage. The puzzle is intended to be completed online and is authored by Joyita Bharati, Kiran Munir, and Kenar D. Jhaveri. [Extracted from the article]

Background Eculizumab modifies the course of disease in patients with atypical haemolytic uraemic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated haematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analysed. The primary endpoint was the proportion of patients suffering from thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: estimated glomerular filtration rate changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analysed 151 patients with clinically diagnosed aHUS who had evidence of haematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; seven (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential. [ABSTRACT FROM AUTHOR]

Background The incidence of acute kidney injury (AKI) in patients with acute pancreatitis ranges from 15% to 40% and is associated with poor prognosis. Haemolytic uraemic syndrome (HUS) in the setting of acute pancreatitis is an uncommon association with fewer than 30 cases reported in the literature. Methods A retrospective review of the clinical records at our institution between January 1981 and December 2019 was carried out to identify patients with acute pancreatitis and HUS. Additionally, a literature review was conducted on this topic. The aims of the study were to describe the clinical course and outcomes of patients affected by this condition. Results Four cases of HUS following an acute pancreatitis were identified. The mean (±SD) age of the study group was 30 ± 6 years, all of which were males. Excessive alcohol consumption was the main cause of acute pancreatitis in all four patients. HUS with progressive AKI developed in a median interval of 2 days from the onset of pancreatitis (range 1–3 days). All patients required kidney replacement therapy during the course of follow-up. A kidney biopsy was performed in two patients, showing typical thrombotic microangiopathic features. One case was treated with eculizumab, whereas the rest were treated with supportive care and/or plasma exchange. A normalization of haematological parameters and complete recovery of kidney function were observed in all patients at last follow-up, although this improvement was significantly faster in the patient treated with eculizumab. Conclusions HUS may infrequently develop in patients with acute pancreatitis. An early identification of this complication is mandatory, and complement blockade with eculizumab may be associated with a faster kidney function recovery. [ABSTRACT FROM AUTHOR]

Background The 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). Methods For 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. Results We 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. Conclusions This interim analysis suggests that re-treatment with eculizumab after relapse is safe and feasible. We will continue to use our restrictive treatment strategy. [ABSTRACT FROM AUTHOR]

Background Kidney transplantation (KTx) is a strong trigger for the development of either recurrent or de novo atypical haemolytic uraemic syndrome (aHUS). According to previous studies, eculizumab (ECU) is effective for prophylaxis and for treatment of recurrence. Methods We evaluated the experiences of Spanish patients with recurrent and de novo aHUS associated with KTx, treated or not treated with ECU. In the de novo group, we classified patients as having early de novo (during the first month) or late de novo aHUS (subsequent onset). Results We analysed 36 cases of aHUS associated with KTx. All of the 14 patients with pre-KTx diagnosis of aHUS were considered to have high or moderate risk of recurrence. Despite receiving grafts from suboptimal donors, prophylactic ECU was effective for avoiding recurrence. The drug was stopped only in two cases with low–moderate risk of recurrence and was maintained in high-risk patients with no single relapse. There were 22 de novo aHUS cases and 16 belonged to the early de novo group. The median time of onset in the late group was 3.4 years. The early group had a better response to ECU than the late group, probably due to earlier diagnosis and use of the drug. No genetic pathogenic variant was detected in de novo aHUS cases, suggesting a secondary profile of the disease. ECU was stopped in all de novo patients with no relapses. ECU was well tolerated in all cases. Conclusions Both groups (pre-aHUS and de novo) presented different clinical profiles, management approaches and outcomes. One should consider aHUS regardless of time after KTx. Genetic studies are crucial to stratify risks of relapse and to determine necessary lengths of treatment. We suggest short ECU treatment for de novo cases without pathogenic mutation and that ECU treatment be considered pre-emptively for patients with moderate or high risk of recurrence. [ABSTRACT FROM AUTHOR]

Background Pregnancies in patients with complement gene variant-mediated thrombotic microangiopathy (cTMA) are challenging, and pregnancies in such patients after kidney transplantation (KTX) are even more so. Methods We identified nine pregnancies following KTX of three genetically high-risk cTMA patients enrolled in the Vienna thrombotic microangiopathy cohort. Preventive plasma therapy was used in three pregnancies, and one patient had ongoing eculizumab (ECU) therapy during two pregnancies. Results Seven out of nine pregnancies (78%) resulted in the delivery of healthy children. The other two included one early abortion at gestational Week 12 during ongoing ECU therapy and one late foetal death at gestational Week 33 + 3, most likely not related to complement dysregulation. Kidney transplant function after delivery remained stable in all but one pregnancy. In the aforementioned case, a severe cTMA flare occurred after delivery despite use of preventive plasma infusions. Kidney graft function could be rescued in this patient by ECU. As such, successful pregnancies can be accomplished in kidney transplant recipients (KTRs) with a history of cTMA. We used preemptive plasma therapy or ongoing ECU treatment in selected cases. Conclusions Thus, becoming pregnant can be encouraged in KTRs with native kidney cTMA. Extensive preconception counselling, however, is mandatory in such cases. [ABSTRACT FROM AUTHOR]

Background Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and kidney injury caused by a dysregulation of the alternative complement pathway. Methods We 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. Results Thirty-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. Conclusion This 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. [ABSTRACT FROM AUTHOR]

In this issue of Clinical Kidney Journal , Plasse et al. report on the use of high-dose aliskiren as an adjunct therapy in a patient treated with eculizumab for haemolytic uraemic syndrome (HUS). This follows the recent description of the complement factor 3 (C3) activating activity of the enzyme renin and the successful therapeutic use of the direct renin inhibitor aliskiren in three cases of C3 glomerulopathy/dense deposit disease. We discuss the potential clinical and pathophysiological implications of these reports on nephropathies linked to complement, from HUS to C3 glomerulopathy to immunoglobulin A nephropathy as well as the concept of dual complement inhibition for kidney disease. [ABSTRACT FROM AUTHOR]

Background: Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement dysregulation is pivotal for the disease to develop. Here, we studied this premise in seven patients with TMA and coexisting MG., Methods: Patients with TMA on kidney biopsy and/or peripheral blood were recruited from the prospective COMPETE cohort (NCT04745195) and Limburg Renal Registry. Patients were screened for complement dysregulation, including genetics/factor H autoantibodies (FHAA) and functional ex vivo testing on microvascular endothelial cells., Results: Seven (8%) out of 84 patients with TMA presented with a coexisting MG. MG clustered in patients aged over 50 years ( n/N  = 6/32, 19%). C4 and/or C3 levels were low in three patients, while four patients presented with normal complement levels. None of the patients carried rare variants in complement genes. Massive ex vivo C5b9 formation on the endothelium was noted in one patient; purified IgG from this patient caused massive ex vivo C5b9 formation via the alternative pathway of complement activation, pointing to complement dysregulation in the fluid phase. Kidney biopsies from other nephropathies linked to MG rarely exhibited concurrent TMA ( n/ N = 1/27, 4%)., Conclusions: MG clustered in patients with TMA aged over 50 years. TMA and coexisting MG represents a heterogeneous disease spectrum, including a small subset of patients who may present with complement dysregulation., Competing Interests: S.A.M.E.G.T. participated in TMA expert meetings and received travel/speaker fees from Alexion Pharmaceutical Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

A 17-year-old male presented thrombotic microangiopathy (TMA) at 6 months of age with arterial hypertension, anemia, thrombocytopenia and kidney injury improving with plasma infusions. Fourteen years later, he was diagnosed with severe arterial hypertension, increase in serum creatinine and chronic TMA on kidney biopsy. Eculizumab was started and after 18 months of treatment, he persisted with hypertension, decline in renal function and proteinuria. Genetic analysis demonstrated mutation in diacylglycerol kinase epsilon (DGKe). Complement blockade was stopped. This case of late diagnosis of DGKe nephropathy highlights the importance of genetic testing in patients presenting TMA during the first year of life. [ABSTRACT FROM AUTHOR]

Background Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment. [ABSTRACT FROM AUTHOR]

Haemolytic uraemic syndrome (HUS) is a rare complication of invasive infection by Streptococcus pneumoniae (SP-HUS), especially in adults. Here we report an unusual case of a 53-year-old man presenting SP-HUS with severe multivisceral involvement. After failure of supportive care and plasma exchanges, eculizumab (anti-C5 antibody) resulted in a favourable outcome. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) treatment consists of eculizumab. Severe acute respiratory syndrome coronavirus 2 causes severe pneumonia and endothelial injury that leads to a prothrombotic state that may be complicated by macrovascular and microvascular thrombosis. Complement activation is thought to contribute to endothelial injury and there are at least seven ongoing clinical trials testing six different anti-complement strategies for coronavirus disease 2019 (COVID-19), including eculizumab. We herein report on a kidney transplant patient with aHUS on chronic eculizumab therapy that developed severe COVID-19 despite eculizumab administration early in the course of the disease. Although eculizumab was unable to prevent the development of severe endothelial cell injury, as assessed by increasing D-dimer levels from 292 to 10 586 ng/mL, the patient eventually recovered following dexamethasone and convalescent plasma administration. [ABSTRACT FROM AUTHOR]

Background Membranoproliferative glomerulonephritis (MPGN) with immune complexes and C3 glomerulopathy (C3G) in children are rare and have a variable outcome, with some patients progressing to end-stage renal disease (ESRD). Mutations in genes encoding regulatory proteins of the alternative complement pathway and of complement C3 (C3) have been identified as concausative factors. Methods Three children with MPGN type I, four with C3G, i.e. three with C3 glomerulonephritis (C3GN) and one with dense deposit disease (DDD), were followed. Clinical, autoimmune data, histological characteristics, estimated glomerular filtration rate (eGFR), proteinuria, serum C3, genetic and biochemical analysis were assessed. Results The median age at onset was 7.3 years and the median eGFR was 72 mL/min/1.73 m2. Six children had marked proteinuria. All were treated with renin–angiotensin–aldosterone system (RAAS) blockers. Three were given one or more immunosuppressive drugs and two eculizumab. At the last median follow-up of 9 years after diagnosis, three children had normal eGFR and no or mild proteinuria on RAAS blockers only. Among four patients without remission of proteinuria, genetic analysis revealed mutations in complement regulator proteins of the alternative pathway. None of the three patients with immunosuppressive treatment achieved partial or complete remission of proteinuria and two progressed to ESRD and renal transplantation. Two patients treated with eculizumab revealed relevant decreases in proteinuria. Conclusions In children with MPGN type I and C3G, the outcomes of renal function and response to treatment modality show great variability independent from histological diagnosis at disease onset. In case of severe clinical presentation at disease onset, early genetic and biochemical analysis of the alternative pathway dysregulation is recommended. Treatment with eculizumab appears to be an option to slow disease progression in single cases. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA), characterized by organ injury occurring consequent to severe endothelial damage, can manifest in a diverse range of diseases. In complement-mediated atypical haemolytic uraemic syndrome (aHUS) a primary defect in complement, such as a mutation or autoantibody leading to over activation of the alternative pathway, predisposes to the development of disease, usually following exposure to an environmental trigger. The elucidation of the pathogenesis of aHUS resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. In other TMAs, although complement activation may be seen, its role in the pathogenesis remains to be confirmed by an interventional trial. Although many case reports in TMAs other than complement-mediated aHUS hint at efficacy, publication bias, concurrent therapies and in some cases the self-limiting nature of disease make broader interpretation difficult. In this article, we will review the evidence for the role of complement inhibition in complement-mediated aHUS and other TMAs. [ABSTRACT FROM AUTHOR]

Background: Interferon-beta (IFN-beta) is one of the most widely prescribed medications for relapsing-remitting multiple sclerosis (RRMS). IFN-related thrombotic microangiopathy (TMA) is a rare but severe complication, with a fulminant clinical onset and a possibly life-threatening outcome that may occur years after a well-tolerated treatment with IFN. Most patients evolve rapidly to advanced chronic kidney disease and eventually to renal failure. Methods:We performed a retrospective analysis of TMA cases diagnosed and managed in our Nephrology Department from 2010 to 2015, and performed a literature review of IFN-beta-induced TMA. Results: Three cases of TMA among patients treated with IFN-beta were identified who did not show any renal improvement following conventional therapy: IFN withdrawal and plasma exchange (PE, range 8-18) sessions. All of them responded favourably to eculizumab, with progressive clinical and renal improvement, allowing dialysis discontinuation, without recurrence of TMA during a long-term follow-up (range 1-5 years). Conclusions: TMA is a recognized severe complication in RRMS patients treated with IFN-beta. Withdrawal of IFN and treatment with PE, steroids or rituximab did not improve the poor renal prognosis in our three patients and in all the previously described cases in the literature. In our experience, eculizumab had a strikingly favourable effect on renal recovery, suggesting a role of IFN-beta as a trigger in complement-mediated TMA. Neurologists and nephrologists should be vigilant to this complication to prevent possibly irreversible renal damage. [ABSTRACT FROM AUTHOR]

We present a case of haemolytic uraemic syndrome (HUS) in a 16-year-old female with serological evidence of acute Escherichia coli O157:H7 infection. She progressed to established renal failure and received a deceased donor kidney transplant. Shiga toxin-associated HUS (STEC-HUS) does not recur following renal transplantation, but unexpectedly this patient did experience rapid and severe HUS recurrence. She responded to treatment with the terminal complement inhibitor eculizumab and subsequent genetic analysis revealed a rare variant in a complement gene. This highlights the importance of genetic analysis in patients with STEC-HUS prior to renal transplantation so that management can be individualized. [ABSTRACT FROM AUTHOR]

Background. Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disorder for which eculizumab is the only approved treatment. Life-long treatment is indicated; however, eculizumab discontinuation has been reported. Methods. Unpublished authors' cases and published cases of eculizumab discontinuation are reviewed. We also report eculizumab discontinuation data from five clinical trials, plus long-term extensions and the global aHUS Registry. Results. Of six unpublished authors' cases, four patients had a subsequent thrombotic microangiopathy (TMA) manifestation within 12 months of discontinuation. Case reports of 52 patients discontinuing eculizumab were identified; 16 (31%) had a subsequent TMA manifestation. In eculizumab clinical trials, 61/130 patients discontinued treatment between 2008 and 2015. Median follow-up post-discontinuation was 24 weeks and during this time 12 patients experienced 15 severe TMA complications and 9 of the 12 patients restarted eculizumab. TMA complications occurred irrespective of identified genetic mutation, high risk polymorphism or auto-antibody. In the global aHUS Registry, 76/296 patients (26%) discontinued, 12 (16%) of whom restarted. Conclusions. The currently available evidence suggests TMA manifestations following discontinuation are unpredictable in both severity and timing. For evidence-based decision making, better risk stratification and valid monitoring strategies are required. Until these exist, the risk versus benefit of eculizumab discontinuation, either in specific clinical situations or at selected time points, should include consideration of the risk of further TMA manifestations. [ABSTRACT FROM AUTHOR]

A 7-year-old male with poststreptococcal glomerulonephritis (PSGN) developed hemolytic uremic syndrome (HUS) and achieved remission. Hewas treated with eculizumab for 1 year. The eculizumab was discontinued and the patient remained in remission. This is the 10th reported case of PSGN associated with HUS. The histopathological feature observed at the 1-year follow-up was indistinguishable from the expected findings in an individual with healed PSGN without associated HUS. The relatively good prognosis in most prior cases and the absence of any reported recurrences strongly suggest that this form of atypical HUS does not warrant long-term eculizumab therapy. [ABSTRACT FROM AUTHOR]

A 46-year-old female with interstitial lung disease presented with proximal muscle weakness, worsening hypertension, microangiopathic hemolysis, thrombocytopenia and deteriorating renal function. She had no sclerodactyly, but had abnormal capillaroscopy. She tested positive for PM-Scl antibodies, and a renal biopsy showed an acute thrombotic microangiopathy consistent with scleroderma renal crisis (SRC). She failed to respond to corticosteroids, plasmapheresis and renin-angiotensin pathway inhibitors. She recovered quickly with the anti-C5 antibody, eculizumab. She had no genetic abnormalities associated with atypical hemolytic uremic syndrome except a DNA variant of unknown significance in C3. This case suggests that eculizumab may be effective for SRC. [ABSTRACT FROM AUTHOR]

In this issue of CKJ, four reports address different aspects of a rare condition, thrombotic microangiopathy, including atypical haemolytic uraemic syndrome. For rare diseases, a single case report may provide hypothesis-generating information that may lead to concept-changing research with the potential to influence patient care. The present reports and small series illustrate the following aspects of thromboticmicroangiopathy: (i) the role of whole-exome sequencing and of repeating the family history assessment over time in reducing the number of chronic kidney disease patients with non-specific diagnosis (e.g. focal segmental glomerulosclerosis without any further indication as to aetiology or hypertension-attributed kidney disease) and the need for further studies on the potential for type IV collagen mutations to be associated with thrombotic microangiopathy, i.e. the potential for an expanding genetic spectrum; (ii) the expanding clinical spectrum from an acute catastrophic disease to a chronic, mild, stable condition with unknown long-termconsequences and uncharted therapeutic approaches; (iii) the expanding therapeutic spectrum, with the successful use of eculizumab to treat thrombotic microangiopathy in the context of overlap autoimmune disease and (iv) the huge worldwide inequalities in the implementation of these and other advances. International collaboration is needed to address these issues and should encompass the wider use of already available registries for this rare disease and the worldwide implementation of current effective, yet expensive, therapies. [ABSTRACT FROM AUTHOR]

C3 glomerulopathy (C3G) is characterized by C3 deposits with minimal immunoglobulin deposition caused by alternative complement pathway dysregulation. Unfortunately, no therapeutic intervention has consistently improved outcomes for patients with C3G. Eculizumab, a monoclonal antibody to C5, is currently the only approved complement-specific agent with some efficacy in the treatment of C3 glomerulonephritis (C3GN). Here, we describe a patient with acute crescentic C3GN with no identified complement mutation or family history of renal disease who required dialysis for 6 months. Five months after initiation of eculizumab, she became dialysis independent, showing improvement is possible after adequate time on eculizumab. [ABSTRACT FROM AUTHOR]

Eculizumab is an anti-C5 antibody that inhibits C5 cleavage and prevents the generation of the terminal complement complex C5b-9. Eculizumab is licensed to treat paroxysmal nocturnal haemoglobinuria or atypical haemolytic uraemic syndrome (aHUS). Clinical trials are ongoing for C3 glomerulopathy. Given the unfamiliarity of physicians with these rare diseases and the variability of clinical presentation, a delayed initiation of eculizumab therapy is common. Thus, the question arises as to what extent improvement of kidney function may be expected when patients have been dialysis dependent for weeks or months already when eculizumab is initiated. Furthermore, given the high cost and potential adverse effects of eculizumab, the question arises of when to stop therapy because of futility when patients with kidney-only manifestations remain dialysis dependent. In literature reports, eculizumab was stopped as early as after 3 weeks because the patient remained dialysis dependent. In this issue of CKJ, Inman et al. report on eculizumab-induced reversal of dialysis-dependent kidney failure from C3 glomerulonephritis, illustrating both the potential benefit of eculizumab for this complement-mediated disease and the need for lengthy therapy--dialysis independency was reached after 5 months of eculizumab. Indeed, there are reports of renal function recovery when eculizumab was initiated after 4 months on dialysis and of recovery of renal function 2.0-3.5 months after initiation of eculizumab in dialysis-dependent patients with C3 glomerulopathy or aHUS. [ABSTRACT FROM AUTHOR]

Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by haemolytic microangiopathic anaemia, thrombocytopaenia and acute onset of renal failure, in the absence of Escherichia coli infection. Renal damage usually progresses to end-stage renal disease (ESRD), sometimes being accompanied by signs of extrarenal thrombotic microangiopathy (TMA). We report a case of full neurological and haematological recovery after eculizumab treatment in a patient with ESRD secondary to chronic aHUS refractory to plasmatherapy while she was under dialysis. It highlights the use of eculizumab for controlling extrarenal manifestations of aHUS in this population. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disorder for which prompt diagnosis and eculizumab treatment is indicated. The time for relapse and patients at risk for relapse after eculizumab discontinuation are unknown. While some authors believe there is no clinical evidence supporting eculizumab discontinuation, which may be associated with high collateral risks such as loss of renal function, other authors believe that the drug can be safely discontinued with close patient monitoring. In this editorial, we update the pros and cons for eculizumab discontinuation in aHUS. [ABSTRACT FROM AUTHOR]

We describe the clinical course and response to treatment of atypical haemolytic uraemic syndrome (aHUS) in two sisters presenting to our hospital 6 years apart with a novel complement factor H mutation that has not been described previously in literature and demonstrates the genetic complexity of this ultra-rare disease. The contrast in course and outcome of disease between the two sisters highlights the rapid evolution of management of aHUS, the importance of rapidly establishing a diagnosis, and how minimizing time to eculizumab therapy significantly reduces associated morbidity and mortality. [ABSTRACT FROM AUTHOR]

Whether C5 blocking may improve the outcomes of patients developing chemotherapy-induced thrombotic microangiopathy (TMA) remains elusive. Lung fibrosis is a well-known complication of bleomycin, whereas TMAs are very rare (<20 cases described). Here, we report an exceptional case of a male patient that developed acute respiratory distress syndrome and TMA following administration of bleomycin, cisplatin and etoposide. Refractoriness to plasma exchanges prompted us to use eculizumab as salvage therapy. Eculizumab led to complete remission of the TMA before Day 2. However, the patient progressed towards refractory respiratory failure, suggesting that pathophysiological mechanisms of bleomycin-induced lung fibrosis and TMA differ. [ABSTRACT FROM AUTHOR]

A 2-year-old patient with a neuroblastoma developed haemolytic uraemic syndrome (HUS) following treatment with cisplatin and carboplatin. Following treatment with eculizumab, there was a substantial improvement in renal function with the recovery of the platelet count and the cessation of haemolysis. Subsequent investigations showed a novel, heterozygous CD46 splice site mutation with reduced peripheral blood neutrophil CD46 expression.Withdrawal of eculizumab was followed by the recurrence of disease activity, which resolved with re-introduction of therapy. Abnormal regulation of complement may be associated with other cases of cisplatin-induced HUS and treatment with eculizumab may be appropriate for other affected individuals. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is characterized by a variable clinical course and multifaceted pathophysiology. There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of the disease. Therefore, complement inhibition using the humanized anti-C5 monoclonal antibody eculizumab could be a rational treatment. We report here a 16-year-old male with the vasculitic form of IgAN who failed to respond to aggressive conventional therapy including high-dose steroids, cyclophosphamide and plasma exchange and who was treated with four weekly doses of 900 mg eculizumab followed by a single dose of 1200 mg. He responded rapidly to this treatment and has had a stable creatinine around 150 μmol/L (1.67 mg/dL) for >6 months. However, proteinuria was unabated on maximal conventional anti-proteinuric treatment, and a repeat renal biopsy 11 months after presentation revealed severe chronic changes. We believe this case provides proof of principle that complement inhibition may be beneficial in IgAN but also that development of chronicity may be independent of complement. [ABSTRACT FROM AUTHOR]