IgA Nephropathy: Clinical Significance of Urinary Proteins/Polypeptides Characterization

Claudio      Bazzi

Abstract

IgA nephropathy (IgAN), the most frequent type of glomerulonephritis, is characterized at biopsy by a wide variability of functional, proteinuric and histologic features; about 30% of patients progress to end stage renal disease (ESRD). Baseline proteinuria is one of the main predictors of progression. Few studies evaluated whether some components of proteinuria improve prediction of the outcome and may identify patients for whom different therapeutic approaches are indicated (no treatment, renin-angiotensin system (RAS) inhibition, immunosuppression). The composition of proteinuria was assessed by classical methods (SDS-PAGE, immunonephelometry); recently new technologies [mainly capillary electrophoresis coupled to mass spectrometry (CE-MS)] were able to analyze the whole spectrum of urinary proteins/ polypeptides. Low molecular weight proteins in SDS-PAGE pattern predicted progression. Urinary excretion of IgG, a reliable marker of selectivity of glomerular capillary wall, predicted progression better than proteinuria/day and other markers by univariate and multivariate analysis. Fractional Excretion of IgG identified patients responsive to ACEinhibitors (ACEi) in non-crescentic IgAN and patients responsive to immunosuppression in crescentic-IgAN. CE-MS identified a specific “IgAN polypeptide pattern” significantly different from controls and from other glomerular diseases with high sensitivity and specificity. In patients treated with ACEi the analysis with 2-D PAGE coupled to nano-HPLCESI- MS/MS identified 3 proteins [kininogen, inter-α-trypsin inhibitor heavy chain H4 and transthyretin] whose excretion was significantly different in ACEi-responders vs non-responders. Baseline low kininogen excretion predicted inadeguate/ absent response to ACEi. Conclusions: urinary excretion of IgG is to date the best proteinuric predictor of progression and responsiveness to ACEi in non-crescentic IgAN and to immunosuppression in crescentic IgAN . Urinary profile assessed by proteome analysis identifies a polypeptide pattern that distinguishes IgAN from healthy controls and other glomerular diseases and some proteins whose value predicts ACEi-responsiveness. Future developments of urinary proteome characterization in larger cohorts of patients may further improve diagnosis, prognostication and therapeutic approach.

Keywords: IgA nephropathy, proteinuria characterization, urine proteomics, outcome, therapy responsiveness

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