Emerging biomarkers in IgA nephropathy, membranous nephropathy, and lupus nephritis

Diabetic kidney disease (DKD) studies have identified circulating proteins linked to progression to kidney function decline. Whether these markers generalize to autoimmune nephritides is unclear. We evaluated DKD-derived biomarkers in IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) for associations with renal pathology and longitudinal kidney function decline.

In a single-center cohort of biopsy-proven IgAN (n = 82), MN (n = 22), and LN (n = 22) with healthy controls (n = 88), serum was obtained immediately before renal biopsy. Seven proteins (KIM1, WFDC2, EPHA2, EFNA4, DLL1, LAYN, PVRL4) were quantified by Olink® proximity-extension assay; MMP7 by ELISA. We compared biomarker levels between diseases and controls, examined associations with clinical measures and disease-specific histopathology, and tested prognostic value for kidney function decline-incident CKD stage 3 or ≥ 30% eGFR loss using Cox proportional hazards models.

Across groups, KIM1, WFDC2, EPHA2, DLL1, LAYN, and PVRL4 exceeded controls; EFNA4 was elevated in IgAN; MMP7 was greatest in IgAN. Proteins generally correlated with eGFR (inverse), proteinuria, and urinary NAG; β2-microglobulin correlated in MN/LN only. In IgAN, WFDC2 independently predicted the composite outcome (adjusted HR 3.63; P < 0.001), whereas others did not. No protein predicted outcomes in MN or LN. In IgAN, WFDC2 associated with tubular atrophy/interstitial fibrosis (T) but not with M, E, or S.

DKD-derived proteins are broadly increased in autoimmune nephritides, but only WFDC2 was independently associated with kidney outcome in IgAN and with tubulointerstitial fibrosis. These findings suggest that disease-specific biomarker panels may be needed and warrant multicenter validation.