Proteomic profiling of IgA nephropathy reveals distinct molecular prognostic subtypes

IgA nephropathy (IgAN) is a heterogeneous disease, which poses a series of challenges to accurate diagnosis and personalized therapy. Herein, we constructed a systematic quantitative proteome atlas from 59 IgAN and 19 normal control donors. Consensus sub-clustering of proteomic profiles divided IgAN into three subtypes (IgAN-C1, C2, and C3). IgAN-C2 had similar proteome expression patterns with normal control, while IgAN-C1/C3 exhibited higher level of complement activation, more severe mitochondrial injury, and significant extracellular matrix accumulation. Interestingly, the complement mitochondrial extracellular matrix (CME) pathway enrichment score achieved a high diagnostic power to distinguish IgAN-C2 from IgAN-C1/C3 (AUC>0.9). In addition, the proteins related to mesangial cells, endothelial cells, and tubular interstitial fibrosis were highly expressed in IgAN-C1/C3. Most critically, IgAN-C1/C3 had a worse prognosis compared to IgAN-C2 (30% eGFR decline, p = 0.02). Altogether, we proposed a molecular subtyping and prognostic system which could help to understand IgAN heterogeneity and improve the treatment in the clinic.