Santiago-Hernandez, AranzazuMartin-Lorenzo, MartaMartínez, Paula JGómez-Serrano, MaríaLopez, Juan AntonioCannata, PabloEsteban, VanesaHeredero, AngelesAldamiz-Echevarria, GonzaloVázquez, JesúsRuiz-Hurtado, GemaBarderas, Maria GSegura, JulianRuilope, Luis MAlvarez-Llamas, Gloria2026-07-152026-07-152021-11-01J Hypertens. 2021 Nov 1;39(11):2220-2231.https://hdl.handle.net/20.500.12105/27588A continuous association between albuminuria and cardiorenal risk exists further below moderately increased albuminuria ranges. If only based in albumin to creatinine ratio (ACR) higher than 30 mg/g, a significant percentage of individuals may be out of the scope for therapeutic management. Despite epidemiological outcomes, the identification of biochemical changes linked to early albuminuria is underexplored, and normoalbuminuric individuals are usually considered at no risk in clinical practice. Here, we aimed to identify early molecular alterations behind albuminuria development. Hypertensive patients under renin-angiotensin system (RAS) suppression were classified as control, (ACR < 10 mg/g) or high-normal (ACR = 10-30 mg/g). Urinary protein alterations were quantified and confirmed by untargeted and targeted mass spectrometry. Coordinated protein responses with biological significance in albuminuria development were investigated. Immunohistochemistry assays were performed in human kidney and arterial tissue to in situ evaluate the associated damage. A total of 2663 identified proteins reflect inflammation, immune response, ion transport and lipids metabolism (P value ≤ 0.01). A1AT, VTDB and KNG1 varied in high-normal individuals (P value < 0.05), correlated with ACR and associated with the high-normal condition (odds ratio of 20.76, 6.00 and 7.04 were found, respectively (P value < 0.001)). After 12 months, protein variations persist and aggravate in progressors to moderately increased albuminuria. At tissue level, differential protein expression was found in kidney from individuals with moderately increased albuminuria and atherosclerotic aortas for the three proteins, confirming their capacity to reflect subclinical organ damage. Early renal and vascular damage is molecularly evidenced within the normoalbuminuria condition.Authors acknowledge Lucía Guerrero and Marisa López from Hypertension Unit, Hospital 12 de Octubre and FJDBiobank. This work was supported by the Instituto de Salud Carlos III co-supported by FEDER grants (PI16/01334, PI20/01103, PI17/01093, PI17/01193, PI18/00348, IF08/3667-1, CPII15/00027, CP15/00129, CPII20/00022, PT13/0001/0013 and PRB3 [IPT17/0019-ISCIII-SGEFI/ERDF]); Spain Ministry of Science, Innovation and Universities (PGC2018-097019-BI00); REDinREN (RD16/0009, ARADyAL (RD/0006/0013), Fundación SENEFRO/SEN, CAM (2018-T2/BMD-11561, CM_P2018/BAAA-4574), SEAIC (19_ADB), Fundación Conchita Rábago de Jiménez Díaz, Alfonso X el Sabio University Foundations and `la Caixa' Banking Foundation (project code HR17-00247).engNAhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International34261953JOURNAL OF HYPERTENSIONopen access