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Kidney Week

Abstract: PO2237

Complement Genetic Variants and Hypertensive Diseases of Pregnancy

Session Information

Category: Women’s Health and Kidney Diseases

  • 2000 Women’s Health and Kidney Diseases

Authors

  • Burwick, Richard M., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Govindappagari, Shravya, Loma Linda University Medical Center, Loma Linda, California, United States
  • Dellapiana, Gabriela, Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Smithson, Sarah, Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Java, Anuja, Washington University in St Louis, St Louis, Missouri, United States
Background

Complement genetic variants are associated with thrombotic microangiopathy (TMA). Atypical hemolytic uremic syndrome (aHUS) is a classic complement-mediated TMA characterized by hemolytic anemia, thrombocytopenia and acute kidney injury. Clinical features of aHUS resemble those of preeclampsia and HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syndrome. Therefore, we sought to determine if complement genetic variants also predispose to these hypertensive diseases of pregnancy.

Methods

We conducted genetic testing for 20 complement genes in a cohort of 15 women with HELLP syndrome (Fig 1). Patients were evaluated between April 2018 and September 2019 at our institution; those with a diagnosis of aHUS were excluded. Variants were classified on the basis of clinical significance, according to published American College of Medical Genetics guidelines. Based on these standards, variants are classified as, Level 1: pathogenic; Level 2: likely pathogenic; Level 3: variant of uncertain significance (VUS); Level 4: likely benign; Level 5: benign.

Results

At the time of index pregnancy with HELLP syndrome, patients were 36 ± 5 years old; twelve of 15 (80%) were nulliparous, and delivery occurred at 34 ± 5 weeks gestation. Five of 15 patients (33%) had a pathogenic variant, 9 (60%) had a variant of uncertain significance (VUS), and one (7%) had a benign variant. Homozygous deletion of CFHR1-CFHR3 was detected in four patients. Fifteen unique missense variants were detected in various genes, including C3, CFD, CFH, CFHR2, CFHR5, CFI, MASP2, and PLG. One patient with a pathogenic variant developed recurrent severe preeclampsia and one patient with a VUS developed recurrent HELLP syndrome.

Conclusion

These results reveal that overactivity of the complement system, due to an underlying genetic variant, may define a subset of patients that develop preeclampsia and HELLP syndrome. Long term follow-up of these patients is needed to evaluate the risk for future cardiovascular and kidney disease.

Flow Diagram