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Development of albuminuria and enhancement of oxidative stress during chronic renin–angiotensin system suppression

Ruiz-Hurtado, Gemaa,b,*; Condezo-Hoyos, Luisc; Pulido-Olmo, Helenaa,b; Aranguez, Isabeld; del Carmen Gónzalez, Mariac; Arribas, Silviac; Cerezo, Césara; Segura, Juliána; Praga, Manuele; Fernández-Alfonso, Maria S.b; Ruilope, Luis Miguela,*

doi: 10.1097/HJH.0000000000000292
ORIGINAL PAPERS: Therapeutic aspects

Objective: Albuminuria has been recently described in hypertensive patients under chronic renin-angiotensin system (RAS) suppression. We investigated whether this fact could be related to an increase in oxidative stress.

Methods: We examined normoalbuminuric and albuminuric patients in stage 2 chronic kidney disease, both with more than 2 years of RAS blockade. The relationship between albuminuria and circulating biomarkers for both oxidative damage, that is carbonyl and malondialdehyde, as well as antioxidant defense, that is reduced glutathione, thiol groups, uric acid, bilirubin, or catalase, and superoxide scavenging activity, was assessed.

Results: We found that only patients with albuminuria showed an important increase in carbonyls (P < 0.001) and malondialdehyde (P < 0.05) compared to normoalbuminuric patients. This increase in oxidative damage was also accompanied by a rise in catalase activity (P < 0.05) and low-molecular-weight antioxidants only when they were measured as total antioxidant capacity (P < 0.01). In order to establish the specific oxidative status of each group, new indexes of oxidative damage and antioxidant defense were calculated with all these markers following a mathematical and statistical approach. Although both pro-oxidant and antioxidant indexes were significantly increased in patients with albuminuria, only the oxidative damage index positively correlated with the increase of albumin/creatinine ratio (P = 0.0024).

Conclusions: We conclude that albuminuria is accompanied by an amplified oxidative damage in patients in early stages of chronic kidney disease. These results indicate that chronic RAS protection must be directed to avoid development of albuminuria and oxidative damage.

aUnidad de Hipertensión. Instituto de Investigación imas12. Hospital Universitario 12 de Octubre

bInstituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense de Madrid

cDepartamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid

dDepartamento de Bioquímica, Facultad de Farmacia, Universidad Complutense de Madrid

eDivision of Nephrology, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain

*Gema Ruiz-Hurtado and Luis Miguel Ruilope contributed equally to the writing of this article.

Correspondence to Gema Ruiz-Hurtado, Unidad de Hipertensión, Hospital Universitario 12 de Octubre, Avenida de Córdoba s/n, 28041 Madrid, Spain. Tel: +34 913908198; fax: +34 915765644; e-mail:

Abbreviations: ABPM, ambulatory blood pressure monitoring; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AUC, area under curve; BP, blood pressure; CKD, chronic kidney disease; CTZ, coelenterazine; DNPH, 2,4-dinitrophenylhydrazine; DTNB, 5,5’-dithiobis(2-nitrobenzoic acid); eGFR, estimated glomerular filtration rate; GSH, reduced glutathione; MDA, malondialdehyde; MWF, Munich Wistar Frömter; O2, superoxide; OPA, o-phthaldehyde; PAC, plasma aldosterone concentration; PRC, plasma renin concentration; QTL, quantitative trait loci; RAS, renin–angiotensin system; ROC, receiver-operating characteristics; ROS, reactive oxygen species; SHR, spontaneously hypertensive rat; SOD, superoxide dismutase; SOSA, superoxide scavenging activity; TAC, total antioxidant capacity; TBA, thiobarbituric acid

Received 31 March, 2014

Revised 29 May, 2014

Accepted 29 May, 2014

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