Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy

Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Tortajada, A
- Gutierrez, E
- Goicoechea de Jorge E
- Anter, J
- Segarra, A
- Espinosa, M
- Blasco, M
- Marco, H
- Quintana, LF
- Gutierrez, J
- Pinto, S
- Lopez-Trascasa, M
- Praga, M
- Rodriguez de Córdoba S
Abstract
IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (Delta(CFHR3-CFHR1)). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, Delta(CFHR3-CFHR1) homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR-1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR-1 in IgAN pathogenesis is to compete with complement regulation by FH.
Datos de la publicación
- ISSN/ISSNe:
- 0085-2538, 1523-1755
- Tipo:
- Article
- Páginas:
- 953-963
- PubMed:
- 28637589
- Factor de Impacto:
- 3,238 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
KIDNEY INTERNATIONAL ELSEVIER SCIENCE INC
Citas Recibidas en Web of Science: 66
Documentos
- No hay documentos
Filiaciones
Keywords
- CFH mutation; complement alternative pathway; factor H; factor H-related proteins; IgAN
Proyectos y Estudios Clínicos
DIAGNÓSTICO GENÉTICO MOLECULAR DE LAS CILIOPATÍAS RENALES MEDIANTE SECUENCIACIÓN MASIVA DE NUEVA GENERACIÓN (NGS).
Investigador Principal: MARIA JOSE APARISI NAVARRO
GV/2016/057 . 2016
REGISTRO NACIONAL DE RECHAZO HUMORAL: ESTUDIO EPIDEMIOLOGICO MULTICENTRICO OBSERVACIONAL PROSPECTIVO PARA EVALUAR LAS CARACTERISTICAS CLINICAS, SEROLOGICAS E HISTOLOGICAS Y LA EVOLUCION A 5 AÑOS DEL RECHAZO HUMORAL POST-TRASPLANTE RENAL EN ESPAÑA
Investigador Principal: ISABEL BENEYTO CASTELLO
HUMORAL-KTX . 2011
UN ESTUDIO OBSERVACIONAL, NO INTERVENCIONISTA, MULTICÉNTRICO Y MULTINACIONAL DE PACIENTES CON SÍNDROME HEMOLÍTICO URÉMICO ATÍPICO (REGISTRO DE SHUA).
Investigador Principal: ELENA ROMÁN ORTIZ
ALE-ECU-2012-01 . 2013
Cita
Tortajada A,Gutierrez E,Goicoechea de Jorge E,Anter J,Segarra A,Espinosa M,Blasco M,ROMAN E,Marco H,Quintana LF,Gutierrez J,Pinto S,Lopez M,Praga M,Rodriguez de Córdoba S. Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy. Kidney Int. 2017. 92. (4):p. 953-963. IF:8,429. (1).