Genetic predisposition to infection in a case of atypical hemolytic uremic syndrome

Heuvel, Lambertus van den; Riesbeck, Kristian; Tahir, Omaima El; Gracchi, Valentina; Kremlitzka, Mariann; Morré, Servaas A.; Furth, A. Marceline van; Singh, Birendra; Okrój, Marcin; Kar, Nicole C. A. J. van de; Blom, Anna M.; Volokhina, Elena

doi:10.1038/s10038-017-0356-0

Cited by 4 publications

(4 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However in C3G, none of the RVs were notably more frequent than others. Data on RVs found in the complement inhibitor vitronectin and clusterin genes in the aHUS and C3G datasets were not available for analysis at the time of writing (58, 59).…”

Section: Resultsmentioning

confidence: 99%

Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Osborne

Breno

Borsa

et al. 2018

The Journal of Immunology

Self Cite

145

150

View full text Add to dashboard Cite

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (, ,, ,, ,, ,, ,, , and) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes ,, ,, and than in the Exome Aggregation Consortium (allele frequency< 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.

show abstract

Section: Resultsmentioning

confidence: 99%

Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Osborne

Breno

Borsa

et al. 2018

The Journal of Immunology

Self Cite

145

150

View full text Add to dashboard Cite

show abstract

“…However, Willems et al, 2019 have recently reported that Clu is decreased in plasma of children suffering from bacterial infections. Vn and Clu polymorphisms have also been identified that impair their potency in scavenging and inactivating sMAC precursors ( Ståhl et al, 2009 ; van den Heuvel et al, 2018 ), which could predispose to host cell damage by bystander lysis. For both polymorphisms, patients suffered from recurrent complement-mediated hemolytic uremic syndrome, and in case of the Vn polymorphism, this was even associated with recurrent E. coli infections.…”

Section: Discussionmentioning

confidence: 99%

Soluble MAC is primarily released from MAC-resistant bacteria that potently convert complement component C5

Doorduijn

Lukassen

Wout

et al. 2022

eLife

View full text Add to dashboard Cite

The Membrane Attack Complex (MAC or C5b-9) is an important effector of the immune system to kill invading microbes. MAC formation is initiated when complement enzymes on the bacterial surface convert complement component C5 into C5b. Although the MAC is a membrane-inserted complex, soluble forms of MAC (sMAC, or terminal complement complex (TCC)) are often detected in sera of patients suffering from infections. Consequently, sMAC has been proposed as a biomarker, but it remains unclear when and how it is formed during infections. Here, we studied mechanisms of MAC formation on different Gram-negative and Gram-positive bacteria and found that sMAC is primarily formed in human serum by bacteria resistant to MAC-dependent killing. Surprisingly, C5 was converted into C5b more potently by MAC-resistant compared to MAC-sensitive Escherichia coli strains. In addition, we found that MAC precursors are released from the surface of MAC-resistant bacteria during MAC assembly. Although release of MAC precursors from bacteria induced lysis of bystander human erythrocytes, serum regulators vitronectin (Vn) and clusterin (Clu) can prevent this. Combining size exclusion chromatography with mass spectrometry profiling, we show that sMAC released from bacteria in serum is a heterogeneous mixture of complexes composed of C5b-8, up to 3 copies of C9 and multiple copies of Vn and Clu. Altogether, our data provide molecular insight into how sMAC is generated during bacterial infections. This fundamental knowledge could form the basis for exploring the use of sMAC as biomarker.

show abstract

“…Around 0.5 to seven percent of all acute rhinosinusitis are caused by bacterial microorganism, out of which only five to 15 percent are caused by Moraxella catarrhalis ( 45 , 46 ). A paper by van den Heuvel et al presented a case of Bordetella pertussis associated aHUS which also had simultaneous isolation of both Klebsiella oxytoca and Moraxella catarrhalis , proposing a potential role of those pathogens in the development of HUS, but also stating that exact role of each pathogen in aHUS is not clear ( 47 ). Taking into consideration that our patient did not present with signs or symptoms of acute otitis media or acute bacterial rhinosinusitis ( 48 ), and that he had COVID-19 infection confirmed by PCR and with signs and symptoms to match, we find it less possible that Moraxella catarrhalis could in this particular case be a potential trigger for complement mediated hemolytic uremic syndrome.…”

Section: Discussionmentioning

confidence: 99%

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature

et al. 2023

View full text Add to dashboard Cite

IntroductionAs the global pandemic continues, new complications of COVID-19 in pediatric population have turned up, one of them being hemolytic uremic syndrome (HUS), a complement-mediated thrombotic microangiopathy (CM-TMA) characterized by triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI). With both multisystem inflammatory syndrome in children (MIS-C) and HUS sharing complement dysregulation as one of the key factors, the aim of this case report is to highlight differences between these two conditions and also emphasize the importance of complement blockade as a treatment modality.Case reportWe describe a 21-month-old toddler who initially presented with fever and confirmed COVID-19. His condition quickly deteriorated and he developed oliguria, accompanied with diarrhea, vomiting and oral intake intolerance. HUS was suspected, supported with compelling laboratory findings, including decreased platelets count and C3 levels, elevated LDH, urea, serum creatinine and sC5b-9 and presence of schistocytes in peripheral blood, negative fecal Shiga toxin and normal ADAMTS13 metalloprotease activity. The patient was given C5 complement blocker Ravulizumab and started to display rapid improvement.ConclusionAlthough reports of HUS in the setting of COVID-19 continue to pour in, the questions of exact mechanism and similarities to MIS-C remain. Our case for the first time accentuates the use of complement blockade as a valuable treatment option in this scenario. We sincerely believe that reporting on HUS as a complication of COVID-19 in children will give rise to improved diagnosis and treatment, as well as better understanding of both of these intricating diseases.

show abstract

Genetic predisposition to infection in a case of atypical hemolytic uremic syndrome

Cited by 4 publications

References 10 publications

Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Soluble MAC is primarily released from MAC-resistant bacteria that potently convert complement component C5

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature

Contact Info

Product

Resources

About