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COL4A3 mutation is an independent risk factor for poor prognosis in children with Alport syndrome

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Abstract

Background

Alport syndrome (AS) is an inherited glomerular disease caused by mutations in COL4A3, COL4A4, or COL4A5. Associations between clinical manifestations and genotype are not yet well defined. Our study aimed to define clinical and genetic characteristics, establish genotype–phenotype correlations, and determine prognosis of AS in children.

Methods

A total of 87 children with AS from 10 pediatric nephrology centers, whom had genetic analyses performed at the Hacettepe University Nephrogenetics Laboratory between February 2017 and February 2019, were included. Data regarding demographics, family history, clinical and laboratory characteristics, histopathological and genetic test results, treatments, and yearly follow-up results were retrospectively analyzed.

Results

Of 87 patients, 16% presented with nephrotic syndrome. In patients with nephrotic syndrome, kidney biopsy findings showed focal segmental glomerulosclerosis (FSGS) in 79%, and COL4A3 mutations were the leading genetic abnormality (50%). Twenty-four percent of all patients progressed to chronic kidney disease (CKD). The rate of progression to CKD and the decline in the glomerular filtration rate of the patients with COL4A3 mutation were higher than other mutation groups (p < 0.001 and p = 0.04, respectively). In kidney survival analysis, nephrotic syndrome presentation, histopathology of FSGS, COL4A3 mutations, and autosomal recessive inheritance were found as independent risk factors for earlier progression to CKD. Cyclosporin A treatment did not improve kidney survival.

Conclusions

We emphasize that genetic testing is important for patients suspected as having AS. Furthermore, COL4A mutations should be considered in patients with FSGS and steroid-resistant nephrotic syndrome. This approach will shed light on the prognosis of patients and help with definitive diagnosis, preventing unnecessary and potentially harmful medications.

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Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

English revision was provided by a native speaker from the Hacettepe University Technology Transfer Center (Job code HTTTM_529).

Author information

Authors and Affiliations

  1. Division of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, 06230, Ankara, Turkey

    Gulsah Ozdemir, Bora Gulhan, Ali Duzova, Fatih Ozaltin & Rezan Topaloglu

  2. Division of Pediatric Nephrology, Nephrogenetics Laboratory, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Emine Atayar & Fatih Ozaltin

  3. Division of Pediatric Nephrology, Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    Seha Saygılı

  4. Division of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey

    Oguz Soylemezoglu

  5. Division of Pediatric Nephrology, Faculty of Medicine, Ankara University, Ankara, Turkey

    Zeynep Birsin Ozcakar

  6. Division of Pediatric Nephrology, Dr. Sami Ulus Maternity and Children’s Health Hospital, Ankara, Turkey

    Fehime Kara Eroglu

  7. Division of Pediatric Nephrology, Göztepe Training and Research Hospital, Istanbul Medeniyet University, Istanbul, Turkey

    Cengiz Candan

  8. Division of Pediatric Nephrology, Tepecik Training and Research Hospital, Izmir, Turkey

    Belde Kasap Demir

  9. Division of Pediatric Nephrology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey

    Alper Soylu

  10. Division of Pediatric Nephrology, Faculty of Medicine, Pamukkale University, Denizli, Turkey

    Selçuk Yüksel

  11. Division of Pediatric Nephrology, Faculty of Medicine, Marmara University, Istanbul, Turkey

    Harika Alpay

  12. Division of Pediatric Nephrology, Haseki Training and Research Hospital, Istanbul, Turkey

    Ayse Agbas

  13. Department of Preventive Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Mutlu Hayran

Authors
  1. Gulsah Ozdemir
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  2. Bora Gulhan
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  6. Zeynep Birsin Ozcakar
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  7. Fehime Kara Eroglu
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Contributions

RT, BG, FO, and AD: Research formulation and study design

RT, GO, SS, OS, ZBO, FKE, CC, BKD, AS, SY, HA, and AA: Data acquisition

RT, BG, FO, AD, GO, and MH: Data analysis/interpretation

FO and EA: Genetic analysis

MH, BG, and GO: Statistical analysis

RT: Supervision/mentorship

Each of the authors contributed important intellectual content during manuscript drafting and/or revision and approved the final version. Furthermore, they all accept responsibility for the overall work, including the accuracy and integrity of all portions of the work.

Corresponding author

Correspondence to Rezan Topaloglu.

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The authors declare that they have no conflict of interest.

Ethics approval

The study protocol was approved by the Non-Interventional Clinical Researches Ethics Board of Hacettepe University (KA 19073).

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Written informed consent was provided by the patients’ parents, as well as by patients aged > 10 years.

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Patients signed informed consent regarding publishing their data.

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Ozdemir, G., Gulhan, B., Atayar, E. et al. COL4A3 mutation is an independent risk factor for poor prognosis in children with Alport syndrome. Pediatr Nephrol 35, 1941–1952 (2020). https://doi.org/10.1007/s00467-020-04574-8

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  • DOI: https://doi.org/10.1007/s00467-020-04574-8

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