Abstract
BackgroundFactor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.MethodsA total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).ResultsEight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.ConclusionsOur observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.
Highlights
Membranoproliferative glomerulonephritis (MPGN) is a welldescribed histological pattern on light microscopy characterized by the pathological presence of capillary wall thickening with double-contour formation, mesangial hypercellularity, and endocapillary proliferation on kidney biopsies [1]
C3, C4, alternative pathway (AP), and classical pathway (CP) activity were decreased in patients with immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN)/C3 glomerulopathy (C3G) compared to those in healthy subjects (Table 1)
We have examined the distribution of serum Factor H-related protein 5 (FHR-5) levels across the previously described clusters [4, 19] and observed a clear association: patients in cluster 3 and cluster 4 had significantly higher FHR-5 levels when compared to cluster 1 (1.47 mg/L, 1.25–1.98, p < 0.05, Dunn’s post-hoc test, p = 0.0003, ANOVA; Figure 9A)
Summary
Membranoproliferative glomerulonephritis (MPGN) is a welldescribed histological pattern on light microscopy characterized by the pathological presence of capillary wall thickening with double-contour formation, mesangial hypercellularity, and endocapillary proliferation on kidney biopsies [1]. Mutant FHR-5 was described as a pathogenic factor in a subtype of C3G [27,28,29] This hereditary endemic form in Cyprus was named CFHR5nephropathy, which is caused by an internal duplication of exons 2 and 3 of the CFHR5 gene [28]. Detailed functional and genetic analysis of CFHR5 along with the parallel measurement of serum levels of the protein in comparison with patients’ clinical, complement, and genetic data has not been performed in a large number of IC-MPGN and C3G patients. We report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data
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