Defects in complement and “secondary” hemolytic uremic syndrome

Timmermans, Sjoerd A.M.E.G.; Wérion, Alexis; Morelle, Johann; Paassen, Pieter van

doi:10.1016/j.kint.2019.04.011

Cited by 11 publications

(12 citation statements)

References 4 publications

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“…Rare variants in complement genes were found in half the patients with primary aHUS, identical to findings in two large registries 2,3 . DNA testing of genes encoding complement proteins showed that variants can also be found in women with pre‐eclampsia 4 and HELLP, 5,6 although conflicting results have been reported 27,28 . Most of these studies, however, report on variants in complement genes of either uncertain or no significance, overestimating the prevalence of disease‐causing variants 19 .…”

Section: Discussionsupporting

confidence: 56%

“…2,3 DNA testing of genes encoding complement proteins showed that variants can also be found in women with pre-eclampsia 4 and HELLP, 5,6 although conflicting results have been reported. 27,28 Most of these studies, however, report on variants in complement genes of either uncertain or no significance, overestimating the prevalence of disease-causing variants. 19 Moreover, pre-eclampsia or HELLP may develop in pregnant women on eculizumab treatment.…”

Section: Discussionmentioning

confidence: 99%

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The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives

et al. 2020

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Summary Pregnancy has been linked to various microangiopathies, including primary atypical haemolytic uraemic syndrome (aHUS). Complement dysregulation, often linked to rare variants in complement genes, is key for primary aHUS to manifest and may play a role in pregnancy complications of the mother and fetus. The burden of such complications is unknown, making counselling of women with primary aHUS and asymptomatic relatives difficult. We analyzed the maternal and fetal outcomes of 39 pregnancies from 17 women with primary aHUS and two asymptomatic relatives. Seven out of 39 pregnancies were complicated by pregnancy‐associated aHUS. Five out of 32 pregnancies not linked to pregnancy‐associated aHUS were complicated by pre‐eclampsia or HELLP. Rare genetic variants were identified in 10 women (asymptomatic relatives, n = 2) who had a total of 14 pregnancies, including 10 uncomplicated pregnancies. Thirty‐five out of 39 pregnancies resulted in live birth. Eight out of 19 women had progressed to end‐stage kidney disease, with an incidence of 2·95 (95% confidence interval, 1·37–5·61) per 100 person‐years after the first pregnancy. Thus, we emphasized the frequency of successful pregnancies in women with primary aHUS and asymptomatic relatives. Pregnancies should be monitored closely. Rare genetic variants cannot predict the risk of a given pregnancy.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives

et al. 2020

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“…Therefore, the TMAs in the French cohort likely represent a mixture of distinct causes, only some of which may be linked to complement dysregulation. 19 The phenotype of their cohort resembled our patients with normal ex vivo C5b9 formation: an acute, nonrelapsing form of TMA.…”

Section: Discussionmentioning

confidence: 53%

“…Patients were screened for rare variants, i.e., variants with a minor allele frequency <0.1%, and single- 19 The classification of variants was based on international standards. 20 Pathogenic variants were defined as those with functional studies supporting a defect in complement regulation, including null variants in genes linked to complement regulation, variants located in a mutational hotspot, variants located in a functional domain, or variants that cluster in patients with primary aHUS as demonstrated by Osborne et al 21 Rare variants not fulfilling these criteria have been classified as uncertain significance.…”

Section: Rare Variants In Complement Genes and Factor H Autoantibodiesmentioning

confidence: 99%

Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes

Timmermans

Damoiseaux

Wérion

et al. 2021

Kidney International Reports

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Introduction The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment. Methods We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced ex vivo C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA. Results Massive ex vivo C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome ( n / N = 11/11) and in 59% of patients with TMA and coexisting conditions ( n / N = 30/51). Massive ex vivo C5b9 formation was associated with rare genetic variants (45% [ n / N = 20/44] vs. 0% [ n / N = 0/21] patients with normal ex vivo C5b9 formation; P < 0.001). Massive ex vivo C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [ n / N = 12/14] vs. 31% [ n / N = 5/16] of untreated patients; P < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal ex vivo C5b9 formation had an acute, nonrelapsing form of TMA. Conclusions Ex vivo C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications.

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“…This report, along with rising concern that hypertension-related TMA may in some cases be complement mediated, 14 suggests the need for deeper study into ING. Table 1 lists the characteristics of published cases and studies of ING including interesting pathological correlations with TMA, hypertension, and smoking status.…”

Section: Discussionmentioning

confidence: 96%

Finding of pathological thrombomodulin gene variant in a patient with idiopathic nodular glomerulosclerosis and chronic thrombotic microangiopathy-like changes

Hanna

Zuckerman

Ferrey

et al. 2020

SAGE Open Medical Case Reports

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Idiopathic nodular glomerulosclerosis is an unusual histopathological finding that has commonly been observed in male smokers with hypertension. It has remained an enigmatic condition and is best described as a diabetic pattern of glomerular injury seen in non-diabetic patients. It is also one of the few nicotine (smoking)-associated/smoking-associated patterns of renal injury. We present an even more unusual manifestation of this pathological finding in a 59-year-old Hispanic female who presented with chronic kidney disease approaching need for renal replacement therapy. The patient had idiopathic nodular glomerulosclerosis on kidney biopsy, despite no prior history of diabetes, nor smoking history, including no secondhand smoking exposure. The patient did have hypertension. The renal biopsy also showed evidence of chronic thrombotic-microangiopathic changes within arteries and arterioles. Genetic testing of the alternative pathway revealed an unusual and likely pathological variant of thrombomodulin supporting complement dysfunction as having a role in the presentation.

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Defects in complement and “secondary” hemolytic uremic syndrome

Cited by 11 publications

References 4 publications

The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives

The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives

Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes

Finding of pathological thrombomodulin gene variant in a patient with idiopathic nodular glomerulosclerosis and chronic thrombotic microangiopathy-like changes

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