Abstract
IntroductionIgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.MethodsTo elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.ResultsM-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.ConclusionOur data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.
Highlights
IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment
M-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBLassociated protein (MAp) 19 were increased, whereas plasma MBL-associated serine protease (MASP)-3 levels were decreased in patients with IgAN compared with healthy controls
Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5)
Summary
To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN. Progressive disease was defined by at least 1 of the following criteria: (i) end-stage renal disease without histology evidence of a second pathology causing renal impairment; (ii) biopsy evidence of endocapillary hypercellularity, or (iii) cellular and/or fibrocellular crescents; (iv) treatment with immunosuppression for native IgAN; (v) clinical Henoch-Schonlein purpura, unless spontaneous resolution and >20 years of follow-up with “stable” criteria; or (vi) 50% loss of estimated glomerular filtration rate (eGFR) or average annual loss of eGFR of more than 5 ml/min without evidence of a second pathology causing renal impairment. Stable disease was defined as meeting all of the following: (i) urine protein-creatinine ratio less than 100 units or daily proteinuria of less than 1 g/24 hours; (ii) combined Oxford classification[22] MEST (mesangial hypercellularity [M], endocapillary hypercellularity [E], segmental glomerulosclerosis [S], interstitial fibrosis/tubular atrophy [T]) score of less than 3; and (iii) average annual loss of eGFR of less than 3 ml/min per 1.73 m2. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation.[23]
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