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Molecular basis and outcomes of atypical haemolytic uraemic syndrome in Czech children

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A Correction to this article was published on 11 January 2022

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Abstract

Atypical haemolytic uraemic syndrome is an ultra-rare, life-threatening disease. Causative variants in genes that encode complement factors can be identified in 40–70% of cases. We performed genetic analysis of 21 Czech children with atypical haemolytic uraemic syndrome. Genetic or acquired predisposition to the disease was identified in the majority of our patients: CFHR1 and CFHR3 deletions in 14/21 (67%; 13 of them were positive for anti-complement factor H antibodies), variants in complement genes or DGKE in 13/21 (62%). Multiple genetic findings were identified in eight patients (38%). The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population was estimated to be 0.092 (CI 0.053–0.131) cases per million inhabitants and 0.92 (CI 0.53–1.32) cases per 100,000 births for the entire reporting period. Ten patients were initially treated with plasma exchange and eight with eculizumab or with a combination of eculizumab and plasma exchange. At the last follow-up, 20 patients were alive and one patient had end-stage renal disease.

Conclusion: The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population corresponds to the reported incidence in Europe. We detected the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies in Czech paediatric patients. Treatment by eculizumab led to superior outcomes and prevention of the disease relapses compared with plasma exchange therapy. Our results may help to understand the polygenic nature of atypical haemolytic uraemic syndrome as a disease that results from a combination of various risk factors.

What is Known:

• Atypical haemolytic uraemic syndrome (aHUS) is considered a polygenic and multifactorial disease. Genetic predisposition to aHUS is identified in 40–70% of children.

• Anti-complement factor H antibodies are usually found in 6–25% of affected children.

What is New:

• Potentially causative genetic or acquired factors were confirmed in the majority of patients. The prevailing finding was the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies (62% of patients).

• The incidence of aHUS in Czech children is 0.092 (CI 0.053–0.131) cases per million inhabitants and 0.92 (CI 0.53–1.32) cases per 100,000 births for the entire reporting period.

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Abbreviations

aHUS:

Atypical haemolytic uraemic syndrome

AKI:

Acute kidney injury

AP:

Alternative complement pathway

anti-CFH antibodies:

Anti-complement factor H antibodies

C3:

Complement component 3

CFB:

Complement factor B

CFH:

Complement factor H

CFI:

Complement factor I

CFHR:

Complement factor H-related

CI:

95% confidence interval

CKD:

Chronic kidney disease

DGKE:

Diacylglycerol kinase epsilon

ESRD:

End-stage renal disease

GFR:

Glomerular filtration rate

LDH:

Lactate dehydrogenase

MCP:

Membrane cofactor protein

MLPA:

Multiplex ligation-dependent probe amplification

NGS:

Next-generation sequencing

PLEX:

Plasma exchange

PLG:

Plasminogen

THBD:

Thrombomodulin

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Acknowledgements

We thank Ondřej Cinek for providing laboratory supervision and genetic evaluation, Tomáš Seeman and Michal Malina for blood sample collection and Michal Kulich for the help with statistics and incidence calculations.

Funding

The study was supported by the Ministry of Health of the Czech Republic, grant number 15-31586A, and by the Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences (PPD2018-016/2018).

Author information

Authors and Affiliations

  1. Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic

    Šárka Štolbová, Martin Bezdíčka, Tomas Seeman, Naděžda Šimánková, Štěpánka Průhová & Jakub Zieg

  2. 3rd Department of Medicine and MTA-SE Research Group of Immunology and Haematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

    Zoltán Prohászka & Dorottya Csuka

  3. Institute of Haematology and Blood Transfusion, Prague, Czech Republic

    Ingrid Hrachovinová

  4. Department of Cardiovascular Surgery, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic

    Jan Burkert

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  1. Šárka Štolbová
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Contributions

Šárka Štolbová wrote the initial draft of the manuscript and collected the data.

Martin Bezdíčka performed MLPA and NGS, analysed data and wrote the manuscript.

Zoltán Prohászka revised the manuscript.

Dorottya Csuka revised the manuscript and helped with genetic variants evaluation.

Ingrid Hrachovinová performed MCP expression in cells and tested the presence of anti-CFH antibodies and wrote the manuscript.

Jan Burkert revised the manuscript.

Naděžda Šimánková participated in data collection.

Štěpánka Průhová supervised mutation classification and nomenclature and revised the manuscript.

Jakub Zieg supervised the study and revised the manuscript.

Corresponding author

Correspondence to Martin Bezdíčka.

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Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Ethics Committee for Multi-Centric Clinical Trials of the Motol University Hospital and 2nd Faculty of Medicine, Charles University in Prague) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Communicated by Mario Bianchetti

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The original online version of this article was revised: Tomas Seeman has been added as co-author who contributed significantly to this article.

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Štolbová, Š., Bezdíčka, M., Seeman, T. et al. Molecular basis and outcomes of atypical haemolytic uraemic syndrome in Czech children. Eur J Pediatr 179, 1739–1750 (2020). https://doi.org/10.1007/s00431-020-03666-9

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