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Albuminuria development in hypertensive patients is an indicator of higher cardiovascular (CV) risk and renal damage. Chronic renin-angiotensin system (RAS) suppression facilitates blood pressure control but it does not prevent from albuminuria development. We pursued the identification of protein indicators in urine behind albuminuria development in hypertensive patients under RAS suppression. Urine was collected from 100 patients classified in three groups according to albuminuria development: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Quantitative analysis was performed in a first discovery cohort by isobaric labeling methodology. Alterations of proteins of interest were confirmed by target mass spectrometry analysis in an independent cohort. A total of 2416 proteins and 1223 functional categories (coordinated protein responses) were identified. Immune response, adhesion of immune and blood cells, and phagocytosis were found significantly altered in patients with albuminuria compared to normoalbuminuric individuals. The complement system C3 increases, while Annexin A1, CD44, S100A8 and S100A9 proteins showed significant diminishment in their urinary levels when albuminuria is present. This study reveals specific links between immune response and controlled hypertension in patients who develop albuminuria, pointing to potential protein targets for novel and future therapeutic interventions. The authors acknowledge Lucia Guerrero and Maria Cruz Casal from Hospital 12 de Octubre for their participation in samples collection. Instituto de Salud Carlos III co- supported by FEDER grants (PI11/01401, PI13/01873, PI14/01650, PI16/01334, CPII15/00027, PT13/0001/0013, IF08/3667-1, PI11/02239, PI11/02432, PI14/0917, PI14/01841, PIE13/00045, CP15/00129, PI13/01746, REDinREN (RD12/0021/0001, RD12/0042/0071 and RD16/0009)), and Fundacion SENEFRO. These results are lined up with the Spanish initiative on the Human Proteome Project (SpHPP). Sí

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