Abstract
IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.
Highlights
I gA nephropathy (IgAN) is the most common primary glomerulopathy worldwide and is an important cause of chronic kidney disease, especially in young people.[1]
The common occurrence of the complete absence of factor H-related protein (FHR)-1 and FHR-3 in healthy individuals with the delCFHR3-1 allele in homozygosity has suggested that these 2 FHR proteins are biologically redundant
Insights into key roles of FHR-1 and FHR-3 in diseases have been derived from the association between delCFHR3-1 alleles and protection from IgA nephropathy (IgAN) and age-related macular degeneration.[25]
Summary
I gA nephropathy (IgAN) is the most common primary glomerulopathy worldwide and is an important cause of chronic kidney disease, especially in young people.[1]. Complement C3 accompanies IgA immunostaining in most diagnostic IgAN biopsies.[5] Evidence of complement alternative pathway activation was identified in the plasma of 30% to 75% of IgAN adults[6,7] and correlated with proteinuria and the rate of renal function loss in a cohort of 50 IgAN patients.[7] An association was demonstrated between mesangial C3 deposition, decreased serum C3 levels, and doubling of serum creatinine or reaching end-stage renal disease in a cohort of 343 IgAN patients.[8] This demonstrated a link between histology and serum markers of complement activation in IgAN pathogenesis. This study did not show associations with markers of clinical outcomes, glomerular MBL and other MBL complement pathway components, including MASP-1/-3 and MASP-2, were found in 25% of a separate cohort of 60 IgAN patients, and these findings correlated with proteinuria and histologic features of severity.[10]
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