Proteomic profiling of IgA nephropathy reveals distinct molecular prognostic subtypes

IgA nephropathy (IgAN) is a heterogeneous disease, which poses a series of lenges to accurate diagnosis and personalized therapy. Herein, we constructed systematic quantitative proteome atlas from 59 IgAN and 19 normal control nors. Consensus sub-clustering of proteomic profiles divided IgAN into three types (IgAN-C1, C2, and C3). IgAN-C2 had similar proteome expression patterns with normal control, while IgAN-C1/C3 exhibited higher level of complement vation, more severe mitochondrial injury, and significant extracellular accumulation. Interestingly, the complement mitochondrial extracellular (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 gial cells, endothelial cells, and tubular interstitial fibrosis were highly expressed in IgAN-C1/C3. Most critically, IgAN-C1/C3 had a worse prognosis compared IgAN-C2 (30% eGFR decline, p = 0.02). Altogether, we proposed a molecular typing and prognostic system which could help to understand IgAN heterogene-ity and improve the treatment in the clinic.