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.

Automated summary

We constructed a quantitative proteome atlas for IgA nephropathy (IgAN) and identified three subtypes based on proteomic profiles. We found differences in protein expression, subcellular injury, and extracellular accumulation among the subtypes. The complement mitochondrial extracellular (CME) pathway showed high diagnostic potential in distinguishing IgAN subtypes. Moreover, proteins related to glial cells, endothelial cells, and tubular interstitial fibrosis were highly expressed in certain subtypes and associated with worse prognosis.