Complement is a major component of innate immunity. In health, complement activation is kept at a low level and deposition of activated components and further activation of complement is limited to the surface of pathogens, apoptotic cells or immune complexes. In IgA nephropathy, the most frequent cause of chronic kidney disease worldwide, the involvement of complement is sustained by the deposition of complement components in the glomeruli and the strong protection from IgAN development conferred by the deletion of the genes encoding FHR-1 and FHR-3.
In recent publications [Tortajada et al. J. Clin. Invest. 2013], the group of Prof. Rodríguez de Córdoba demonstrated that the FHRs proteins compete complement regulation by Factor H and that an unbalanced ratio of FH and FHR-1 proteins results in complement dysregulation. The work now published in Kidney Int. shows that the normal balance of FHR-1 and FH is altered in IgAN and associates with progression to end terminal kidney disease.
Using a well-characterized patient cohorts consisting of 112 patients with IgAN the authors have shown that levels of FHR-1 are abnormally elevated in IgAN patients and there is a correlation between impaired renal function and increased levels of plasma FHR-1. Also, in a significant number of patients the elevated FHR-1/FH ratio results in CFH mutations causing partial FH deficiencies. All together, the data illustrate the relevance of the competition between FH and FHR-1 in IgAN pathogenesis. The results also suggest that functional FH deficiency are a common cause of progression among IgAN patients and that an early determination of FH and FHR-1 plasma levels may allow a prompt identification of those who are potential candidates for early treatment with complement inhibitors.
Reference: Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy . Tortajada A., Gutiérrez E., Goicoechea de Jorge E., Anter J., Segarra A., Espinosa M., Blasco M., Roman E., Marco H., Quintana LF., Gutiérrez J., Pinto S., Lopez-Trascasa M., Praga M., Rodriguez de Córdoba S. Kidney Int. 2017 Jun 18. pii: S0085-2538(17)30254-5. doi: 10.1016/j.kint.2017.03.041