Glomerular and tubular proteome markers of progressive IgA nephropathy

Background: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, with a clinical course ranging from asymptomatic non-progressive to aggressive and progressive disease to kidney failure. The exact mechanism of progression is not fully understood and further research is needed. Proteomics could help to investigate the mechanism of progression in IgAN and define potential biomarkers. The aims of this study were: -To identify novel tissue biomarkers for progressive IgAN that may be used for prognostication. -To improve understanding of underlying mechanisms in IgAN. -To separately investigate glomerular and tubular biomarkers in IgAN. Methods: Formalin-fixed paraffin-embedded kidney biopsy of patients with IgAN and control from the Norwegian Kidney Biopsy Registry were used. The IgAN group was divided in progressive or non-progressive based on progression to kidney failure over 10 years. Glomerular and tubulointerstitial tissues were microdissected, the proteome was analysed using mass spectrometry and the protein abundance was compared between groups. Results: As compared to IgAN patients without progressive disease, glomeruli from patients with progressive IgAN had significantly higher abundance of components of the classical and the terminal complement pathways (Paper I), and the tubulointerstitial tissue had higher abundance of proteins related to inflammation (Paper III). As compared to controls, glomeruli from patients with IgAN showed significantly higher abundance of extracellular matrix structural proteins and extracellular matrix associated proteins (Paper II). Periostin was the protein with the highest fold change between groups both in glomeruli and tubuli. Conclusions: Microdissection of glomeruli and tubuli allowed for compartment-specific analyses of prognostic markers and a better understanding of underlying mechanisms of progressive IgAN. The most promising marker seem to be periostin which associated with progressive disease both in glomeruli and tubuli.Doktorgradsavhandlin

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.publishedVersio

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.publishedVersio

Glomerular and tubular proteome markers of progressive IgA nephropathy

Background: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, with a clinical course ranging from asymptomatic non-progressive to aggressive and progressive disease to kidney failure. The exact mechanism of progression is not fully understood and further research is needed. Proteomics could help to investigate the mechanism of progression in IgAN and define potential biomarkers. The aims of this study were: -To identify novel tissue biomarkers for progressive IgAN that may be used for prognostication. -To improve understanding of underlying mechanisms in IgAN. -To separately investigate glomerular and tubular biomarkers in IgAN. Methods: Formalin-fixed paraffin-embedded kidney biopsy of patients with IgAN and control from the Norwegian Kidney Biopsy Registry were used. The IgAN group was divided in progressive or non-progressive based on progression to kidney failure over 10 years. Glomerular and tubulointerstitial tissues were microdissected, the proteome was analysed using mass spectrometry and the protein abundance was compared between groups. Results: As compared to IgAN patients without progressive disease, glomeruli from patients with progressive IgAN had significantly higher abundance of components of the classical and the terminal complement pathways (Paper I), and the tubulointerstitial tissue had higher abundance of proteins related to inflammation (Paper III). As compared to controls, glomeruli from patients with IgAN showed significantly higher abundance of extracellular matrix structural proteins and extracellular matrix associated proteins (Paper II). Periostin was the protein with the highest fold change between groups both in glomeruli and tubuli. Conclusions: Microdissection of glomeruli and tubuli allowed for compartment-specific analyses of prognostic markers and a better understanding of underlying mechanisms of progressive IgAN. The most promising marker seem to be periostin which associated with progressive disease both in glomeruli and tubuli

Proteomic signature of tubulointerstitial tissue predicts prognosis in IgAN

Abstract 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 &lt; 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. </jats:sec

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

Proteomic signature of tubulointerstitial tissue predicts prognosis in IgAN

Abstract 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&lt;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.</jats:p