Proteomic signature of tubulointerstitial tissue predicts prognosis in IgAN.

BACKGROUND: IgA nephropathy (IgAN) is associated with a significant risk of progression to kidney failure. Tubular atrophy is an established important risk factor for progressive disease, but few studies have investigated tubulointerstitial molecular markers and mechanisms of progression in IgAN. METHODS: Based on data from the Norwegian Renal Registry, two groups were included: IgAN patients with (n = 9) or without (n = 18) progression to kidney failure during 10 years of follow-up. Tubulointerstitial tissue without discernible interstitial expansion or pronounced tubular alterations was microdissected, proteome was analysed using tandem mass spectrometry and relative protein abundances were compared between groups. RESULTS: Proteome analyses quantified 2562 proteins with at least 2 unique peptides. Of these, 150 proteins had significantly different abundance between progressive and non-progressive IgAN patients, 67 were more abundant and 83 less abundant. Periostin was the protein with the highest fold change between progressive and non-progressive IgAN (fold change 8.75, p < 0.05) and periostin staining was also stronger in patients with progressive vs non-progressive IgAN. Reactome pathway analyses showed that proteins related to inflammation were more abundant and proteins involved in mitochondrial translation were significantly less abundant in progressive vs non-progressive patients. CONCLUSIONS: Microdissection of tubulointerstitial tissue with only mild damage allowed for identification of proteome markers of early progressive IgAN. Periostin abundance showed promise as a novel and important risk marker of progression.

Characterization of glomerular extracellular matrix in IgA nephropathy by proteomic analysis of laser-captured microdissected glomeruli.

BACKGROUND: IgA nephropathy (IgAN) involves mesangial matrix expansion, but the proteomic composition of this matrix is unknown. The present study aimed to characterize changes in extracellular matrix in IgAN. METHODS: In the present study we used mass spectrometry-based proteomics in order to quantitatively compare protein abundance between glomeruli of patients with IgAN (n = 25) and controls with normal biopsy findings (n = 15). RESULTS: Using a previously published paper by Lennon et al. and cross-referencing with the Matrisome database we identified 179 extracellular matrix proteins. In the comparison between IgAN and controls, IgAN glomeruli showed significantly higher abundance of extracellular matrix structural proteins (e.g periostin, vitronectin, and extracellular matrix protein 1) and extracellular matrix associated proteins (e.g. azurocidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase-9 and matrix metalloproteinase 2). Periostin (fold change 3.3) and azurocidin (3.0) had the strongest fold change between IgAN and controls; periostin was also higher in IgAN patients who progressed to ESRD as compared to patients who did not. CONCLUSION: IgAN is associated with widespread changes of the glomerular extracellular matrix proteome. Proteins important in glomerular sclerosis or inflammation seem to be most strongly increased and periostin might be an important marker of glomerular damage in IgAN.