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Rare Variants in Complement Gene in C3 Glomerulopathy and Immunoglobulin-Mediated Membranoproliferative GN.
- Source :
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Clinical journal of the American Society of Nephrology : CJASN [Clin J Am Soc Nephrol] 2023 Nov 01; Vol. 18 (11), pp. 1435-1445. Date of Electronic Publication: 2023 Aug 24. - Publication Year :
- 2023
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Abstract
- Background: C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative GN (Ig-MPGN) are rare complement-mediated kidney diseases. Inherited forms of C3 glomerulopathy/Ig-MPGN are rarely described.<br />Methods: Three hundred ninety-eight patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102) from a national registry were screened for three complement genes: factor H ( CFH ), factor I ( CFI ), and C3 . Patients with rare variant (minor allele frequency <0.1%) were included. Epidemiologic, clinical, and immunologic data at diagnosis and kidney outcomes of patients were retrospectively collected.<br />Results: Fifty-three different rare variants, including 30 (57%), 13 (24%), and ten (19%) in CFH , CFI , and C3 variants, were identified in 66/398 (17%) patients. Thirty-eight (72%) variants were classified as pathogenic, including 20/30 (66%) and 11/13 (84%) variants in CFH and CFI , respectively, impairing synthesis of factor H or factor I regulators. Fifteen of 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biologic stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 [36%] versus 1/37 [3%] and 0% in the CFH group and C3 group, respectively, P < 0.001), the clinical and histologic features were similar among the three variants groups. The kidney outcome was poor regardless of the age at onset and treatment received. Sixty-five percent (43/66) of patients with rare variant reach kidney failure after a median delay of 41 (19-104) months, compared with 28% (55/195) after a median delay of 34 (12-143) months in the nonvariant group. Among 36 patients who received a kidney transplant, 2-year recurrence was frequent, occurring in 39% (12/31), without difference between variant groups, and led to graft failure in three cases.<br />Conclusions: In our cohort, 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH , CFI , or C3 genes. In most cases, a quantitative deficiency in factor H or factor I was identified. The presence of a rare variant was associated with poor kidney survival.<br />Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;11&#95;08&#95;CJN0000000000000252.mp3.<br /> (Copyright © 2023 by the American Society of Nephrology.)
Details
- Language :
- English
- ISSN :
- 1555-905X
- Volume :
- 18
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Clinical journal of the American Society of Nephrology : CJASN
- Publication Type :
- Academic Journal
- Accession number :
- 37615951
- Full Text :
- https://doi.org/10.2215/CJN.0000000000000252