Clinical Value of Kidney Immunodeposits and Urinary Complement Activation Fragments in IgAN

Introduction: Ig deposits and complement activation are central in the pathogenesis of IgA nephropathy (IgAN). Whether immunodeposits, assessed by immunofluorescence (IF) and electron microscopy (EM), or the measurement of urinary complement activation fragments, can help determine the likelihood of progression of IgAN is unknown. Methods: In this retrospective analysis of 247 patients of IgAN with pathology assessments and clinical follow-up from the Cure Glomerulonephropathy (CureGN) cohort, we assessed immunodeposits by IF (intensity and localization of IgA, C3, IgG, and IgM) and EM (quantity and localization of deposits and foot process effacement [FPE]), as well as urinary membrane attack complex at enrollment (soluble C5b9 [sC5b9]). We tested associations between immunodeposits and urinary sC5b9 with light microscopy (LM) with proteinuria and survival from kidney failure or a ≥ 40% decline in estimated glomerular filtration rate (eGFR; combined outcome). Results: Mesangial and endocapillary hypercellularity and crescents were associated with IgA and C3 capillary localization by IF. Mesangial and endocapillary hypercellularity also correlated with IgA and C3 staining intensity by IF, and immunodeposits intensity and degree of FPE by EM. In 115 incident subjects enrolled within 6 months of their kidney biopsy, proteinuria and urinary sC5b9 were associated with IgA and C3 capillary deposition by IF, as well as the quantity of subendothelial deposits by EM. Finally, proteinuria and urinary sC5b9 were each independently associated with a combined outcome and showed an interaction when both were elevated. Conclusion: In IgAN, the amount and localization of immunodeposits correlated with proliferative lesions and urinary sC5b9. In turn, the urinary membrane attack complex was independently associated with loss of eGFR.