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) | Pathogenicity | Age yr | C3 mg/dl | Anti-FH AU/ml | Relapse, at mo- | eGFR & outcome at follow-up |
| CFI; c.148C>G, p.P50A | Pathogenic^ | 4 | 74 | 8800 | One, 24-mo | 82 at 14 yr, ambulatory HPT |
| THBD; c.127G>A, p.A43T | Likely pathogenic^ | 6 | 42 | 16133 | One, 6-mo | ESRD |
| DGKE; c.685G>A, p.G229R | VUS, rare | 9 | 89 | 4260 | None | 89 at 21-mo; HPT, proteinuria |
| CFI; c.193T>C, p.Y65H | VUS, rare | 9 | 40 | 7956 | One, 6-mo | 43 at 11-mo; HPT |
| THBD; c.596C>A, p.A199D | VUS, novel | 4 | 40 | 26741 | One, 9-mo | 84 at 44-mo; HPT, proteinuria |
| C3; c.1402G>A,p.G468R | VUS, novel | 7 | 43 | 3215 | 2,6 & 24 mo- | 64 at 66-mo; HPT |
^reported functional assay; HPT, hypertension
Funding
- Government Support - Non-U.S.