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Abstract: SA-PO457

Coexisting Variations in Complement Regulatory Genes Increase Risk of Relapse in Anti-Factor H (FH) Antibodies Associated Atypical Hemolytic Uremic Syndrome (aHUS)

Session Information

  • Pediatric Nephrology - II
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1600 Pediatric Nephrology

Authors

  • Khandelwal, Priyanka, All India Institute of Medical Sciences, New Delhi, India
  • Faruq, Mohammed, Institute of Genomics and Integrative Biology, New Delhi, India
  • Puraswani, Mamta, All India Institute of Medical Sciences, New Delhi, India
  • Sinha, Aditi, All India Institute of Medical Sciences, New Delhi, India
  • Bagga, Arvind, All India Institute of Medical Sciences, New Delhi, India

Group or Team Name

  • Indian HUS database
Background

Patients with anti-FH antibodies, comprising one-half of children with aHUS in India, are managed by PEX and immunosuppression (IS). While deficiency of FH related protein-1 (CFHR1) is strongly associated, prevalence of additional variations and their impact on outcomes is unclear.

Methods

Of 435 children with anti-FH aHUS in the nationwide database, 93 (21%) were screened by targeted sequencing of 27 genes, comprising full length CFH, CFI, CFB, C3, CD46, THBD, DGKE, coding regions of CFHR1-5, PLG, ADAMTS13 and lectin & terminal pathway. Genotype-phenotype correlation and risk-factors for relapse & adverse outcomes (eGFR <30 mL/min/1.73 m<font size="1">2</font> or death) were evaluated.

Results

Patients aged 9±3 yr had high anti-FH titers (median 4684 AU/ml) that persisted >1000 AU/ml during remission in one-third. At 44-mo follow up, adverse outcome was seen in 20% and relapses in 30% (17% and 30% in database, respectively; P=0.02 and <0.001). Sequencing at mean depth of 123X (96% coverage) showed variants of unknown significance (VUS) in 6.5% (Table). MLPA showed homozygous deletion (90%) or duplication (N=1) of CFHR1. Severity of renal and extrarenal manifestations were independent of genetic variations. Prompt PEX (Hazard ratio, HR=1.03; P=0.009), lower anti-FH titers (HR=1.00; P=0.06) and lower peak creatinine (HR=1.2; P=0.008) were associated with improved outcomes. MASP1 (c.*822C>T) polymorphism protected against relapses (allele frequency relapsers 0.015; non- relapsers 0.11; P=0.02). Maintenance IS (odds ratio, OR=10; P=0.02), no coexisting variations (OR=13; P=0.03); low C3 at onset (OR=5; P=0.03) and MASP1 polymorphism (OR=8; P=0.06) independently reduced the risk of relapses.

Conclusion

Prompt PEX & IS improves long-term outcomes and prevents relapses in patients with anti-FH aHUS. Coexisting variations in regulatory genes might predispose to relapses.

Variant (all heterozygous)PathogenicityAge yrC3 mg/dlAnti-FH AU/mlRelapse, at mo-eGFR & outcome at follow-up
CFI;
c.148C>G, p.P50A
Pathogenic^4748800One, 24-mo82 at 14 yr,
ambulatory HPT
THBD;
c.127G>A, p.A43T
Likely pathogenic^64216133One, 6-moESRD
DGKE;
c.685G>A, p.G229R
VUS, rare9894260None89 at 21-mo;
HPT, proteinuria
CFI;
c.193T>C, p.Y65H
VUS, rare9407956One, 6-mo43 at 11-mo;
HPT
THBD;
c.596C>A, p.A199D
VUS, novel44026741One, 9-mo84 at 44-mo;
HPT, proteinuria
C3;
c.1402G>A,p.G468R
VUS, novel74332152,6 & 24 mo-64 at 66-mo;
HPT

^reported functional assay; HPT, hypertension

Funding

  • Government Support - Non-U.S.