Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression

Cardiovascular Diabetology

Gloria Alvarez-Llamas⁴  Fernando Vivanco¹  Luis M. Ruilope²  Maria G. Barderas³  Julian Segura²  Helena Pulido-Olmo²  Gema Ruiz-Hurtado⁵  Montserrat Baldan-Martin³  Aroa S. Maroto⁴  Fernando de la Cuesta³  Marta Martin-Lorenzo⁴  Laura Gonzalez-Calero⁴ 

[1] Departamento de Bioquimica y Biologia Molecular I, Universidad Complutense de Madrid, Madrid, Spain;Unidad de Hipertension, Instituto de Investigacion i + 12, Hospital Universitario 12 de Octubre, Avenida de Córdoba s/n, Madrid, 28041, Spain;Laboratorio de Fisiopatologia Vascular, Hospital Nacional de Paraplejicos SESCAM, Toledo, Spain;Departamento de Inmunologia, Laboratorio de Inmunoalergia y Proteomica, IIS-Fundacion Jimenez Diaz, UAM, REDinREN, Avda Reyes Catolicos 2, Madrid, 28040, Spain;Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain

关键词: Markers;    Urine;    Hypertension;    CD59;    Cardiovascular risk;    Alpha-1 antitrypsin;    Albuminuria;   

Others  :  1235395
DOI  :  10.1186/s12933-016-0331-7

 received in 2015-11-25, accepted in 2016-01-08,  发布年份 2016

【 摘 要 】

Background

Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non-diabetic patients.

Methods

1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non-diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied.

Results

CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development.

Conclusions

CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings contribute to early identify patients at risk of developing albuminuria even when this classical predictor is still in the normal range, constituting a novel strategy towards a prompt and more efficient therapeutic intervention with better outcome.

【 授权许可】

   
2016 Gonzalez-Calero et al.

【 图 表 】

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【 参考文献 】

• [1]De Jong PE, Gansevoort RT, Bakker SJ. Macroalbuminuria and microalbuminuria do both predict renal and cardiovascular events with similar strength? J Nephrol. 2007; 20:375-380.
• [2]Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS et al.. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010; 375:2073-2081.
• [3]Cerezo C, Ruilope LM, Segura J, Garcia-Donaire JA, de la Cruz JJ, Banegas JR et al.. Microalbuminuria breakthrough under chronic renin-angiotensin-aldosterone system suppression. J Hypertens. 2012; 30:204-209.
• [4]Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014; 37:867-875.
• [5]Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR et al.. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010; 303:423-429.
• [6]Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G et al.. Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007; 2007(25):1105-1187.
• [7]K/DOQI clinical practice guidelines for chronic kidney disease. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease. Am J Kidney Dis. 2002; 39:S76-S110.
• [8]Pascual JM, Rodilla E, Costa JA, Garcia-Escrich M, Gonzalez C, Redon J. Prognostic value of micoralbuminuria during antihypertensive treatment in essential hypertension. Hypertension. 2014; 64:1228-1234.
• [9]Ruiz-Hurtado G, Condezo-Hoyos L, Pulido-Olmo H, Aranguez I, Del Carmen Gónzalez M, Arribas S et al.. Development of albuminuria and enhancement of oxidative stress during chronic renin-angiotensin system suppression. J Hypertens. 2014; 32:2082-2091.
• [10]Pena MJ, Lambers Heerspink HJ, Hellemons ME, Friedrich T, Dallmann G, Lajer M et al.. Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus. Diabet Med. 2014; 31:1138-1147.
• [11]Hellemons ME, Mazagova M, Gansevoort RT, Henning RH, de Zeeuw D, Bakker SJ et al.. Growth-differentiation factor 15 predicts worsening of albuminuria in patients with type 2 diabetes. Diabetes Care. 2012; 35:2340-2346.
• [12]Smith MP, Banks RE, Wood SL, Lewington AJ, Selby PJ. Application of proteomic analysis to the study of renal diseases. Nat Rev Nephrol. 2009; 5:701-712.
• [13]Konvalinka A, Scholey JW, Diamandis EP. Searching for new biomarkers of renal diseases through proteomics. Clin Chem. 2012; 58:353-365.
• [14]Gu YM, Thijs L, Liu YP, Zhang Z, Jacobs L, Koeck T et al.. The urinary proteome as correlate and predictor of renal function in a population study. Nephrol Dial Transplant. 2014; 29:2260-2268.
• [15]Soggiu A, Piras C, Bonizzi L, Hussein HA, Pisanu S, Roncada P. A discovery-phase urine proteomics investigation in type 1 diabetes. Acta Diabetol. 2012; 49:453-464.
• [16]Thongboonkerd V. Proteomic analysis of renal diseases: unraveling the pathophysiology and biomarker discovery. Expert Rev Proteomics. 2005; 2:349-366.
• [17]Martin-Lorenzo Marta, Zubiri Irene, Maroto Aroa S, Gonzalez-Calero L, Posada-Ayala M, de la Cuesta F et al.. KLK1 and ZG16B proteins and arginine–proline metabolism identified as novel targets to monitor atherosclerosis, acute coronary syndrome and recovery. Metabolomics. 2015; 11:1056-1067.
• [18]Zubiri I, Posada-Ayala M, Sanz-Maroto A, Calvo E, Martin-Lorenzo M, Gonzalez-Calero L et al.. Diabetic nephropathy induces changes in the proteome of human urinary exosomes as revealed by label-free comparative analysis. J Proteomics. 2014; 96:92-102.
• [19]Dennen P, Parikh CR. Biomarkers of acute kidney injury: can we replace serum creatinine? Clin Nephrol. 2007; 68:269-278.
• [20]Posada-Ayala M, Zubiri I, Martin-Lorenzo M, Sanz-Maroto A, Molero D, Gonzalez-Calero L et al.. Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease. Kidney Int. 2014; 85:103-111.
• [21]Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS et al.. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol. 2007; 18:913-922.
• [22]Martin-Lorenzo M, Gonzalez-Calero L, Zubiri I, Diaz-Payno PJ, Sanz-Maroto A, Posada-Ayala M et al.. Urine 2DE proteome analysis in healthy condition and kidney disease. Electrophoresis. 2014; 35:2634-2641.
• [23]de la Cuesta F, Alvarez-Llamas G, Maroto AS, Donado A, Zubiri I, Posada M et al.. A proteomic focus on the alterations occurring at the human atherosclerotic coronary intima. Mol Cell Proteomics. 2011; 10(M110):003517.
• [24]Dardé VM, de la Cuesta F, Dones FG, Alvarez-Llamas G, Barderas MG, Vivanco F. Analysis of the plasma proteome associated with acute coronary syndrome: does a permanent protein signature exist in the plasma of ACS patients? J Proteome Res. 2010; 9:4420-4432.
• [25]Sechi S, Chait BT. Modification of cysteine residues by alkylation. A tool in peptide mapping and protein identification. Anal Chem. 1998; 70:5150-5158.
• [26]Picotti P, Aebersold R. Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat Methods. 2012; 9:555-566.
• [27]Arnlöv J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D et al.. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation. 2005; 112:969-975.
• [28]De Jong PE, Gansevoort RT. Albuminuria in non-primary renal disease: risk marker rather than risk factor. Nephrol Dial Transplant. 2010; 25:656-658.
• [29]Shlomai G, Grassi G, Grossman E, Mancia G. Assessment of target organ damage in the evaluation and follow-up of hypertensive patients: where do we stand? J Clin Hypertens (Greenwich). 2013; 15:742-747.
• [30]Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD et al.. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012; 367:2204-2213.
• [31]Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V et al.. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 359:2417-2428.
• [32]Schmieder RE, Mann JF, Schumacher H, Gao P, Mancia G, Weber MA et al.. Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol. 2011; 22:1353-1364.
• [33]Sehestedt T, Jeppesen J, Hansen TW, Wachtell K, Ibsen H, Torp-Pedersen C et al.. Risk prediction is improved by adding markers of subclinical organ damage to SCORE. Eur Heart J. 2010; 31:883-891.
• [34]Murai S, Tanaka S, Dohi Y, Kimura G, Ohte N. The prevalence, characteristics, and clinical significance of abnormal albuminuria in patients with hypertension. Sci Rep. 2014; 4:3884.
• [35]Matafora V, Zagato L, Ferrandi M, Molinari I, Zerbini G, Casamassima N et al.. Quantitative proteomics reveals novel therapeutic and diagnostic markers in hypertension. BBA Clin. 2014; 2:79-87.
• [36]Tamano M, Ohi H. Evaluation of urinary decay accelerating factor and CD59 in renal damage. Clin Exper Nephrol. 1998; 2:155-161.
• [37]Nafar M, Kalantari S, Samavat S, Rezaei-Tavirani M, Rutishuser D, Zubarev RA. The novel diagnostic biomarkers for focal segmental glomerulosclerosis. Int J Nephrol. 2014; 2014:574261.
• [38]Coles B, Lewis R, Anning PB, Morton J, Baalasubramanian S, Morgan BP et al.. CD59 or C3 are not requred for angiotensin II-dependent hypertension or hypertrophy in mice. Immunology. 2007; 121:518-525.
• [39]Castagna F, Wang J, Emit M, Wang G, Jelic S, Parati G. Protection against complement activity is reduced in arterial hypertension. J Hypertens. 2015; 33:e119.
• [40]Wu G, Hu W, Shahsafaei A, Song W, Dobarro M, Sukhova GK et al.. Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res. 2009; 104:550-558.
• [41]Lewis RD, Jackson CL, Morgan BP, Hughes TR. The membrane attack complex of complement drives the progression of atherosclerosis in apolipoprotein E knockout mice. Mol Immunol. 2010; 47:1098-1105.
• [42]Alkhalaf A, Zürbig P, Bakker SJ, Bilo HJ, Cerna M, Fischer C et al.. Multicentric validation of proteomic biomarkers in urine specific for diabetic nephropathy. PLoS One. 2010; 5:e13421.
• [43]Rao PV, Lu X, Standley M, Pattee P, Neelima G, Girisesh G et al.. Proteomic identification of urinary biomarkers of diabetic nephropathy. Diabetes Care. 2007; 30:629-637.
• [44]Jin J, Ku YH, Kim Y, Kim Y, Kim K, Lee JY et al.. Differential proteome profiling using iTRAQ in microalbuminuric and normoalbuminuric type2 diabetic patients. Exp Diabetes Res. 2012; 2012:168602.
• [45]Lisowska-Myjak B, Zboinska A, Muszynski J, Pachecka J. Comparison of urinary albumin and alpha-1-antitrypsin (AAT) excretion in consecutive stages of proteinuria in patients with diabetes mellitus. Clin Exp Med Lett. 2010; 51:83-87.
• [46]Swiatkowska-Stodulska R, Babińska A, Skibowska-Bielińska A, Sworczak K. Assessment of alpha1-antitrypsin and alpha2-macroglobulin levels in obese patients. Pol Arch Med Wewn. 2008; 118:713-718.
• [47]Lisowska-Myjak B, Pachecka J, Witak P, Radowicki S. Comparison of urinary excretion of albumin and alpha-1-antitrypsin in patients with arterial hypertension. Scand J Clin Lab Invest. 1999; 59:93-97.
• [48]Rodriguez-Iturbe B, Pons H, Quiroz Y, Johnson RJ. The immunological basis of hypertension. Am J Hypertens. 2014; 27:1327-1337.
• [49]Catena C, Zingaro L, Casaccio D, Sechi LA. Abnormalities of coagulation in hypertensive patients with reduced creatinine clearance. Am J Med. 2000; 109(7):556-561.
• [50]Derhaschnig U, Testori C, Riedmueller E, Aschauer S, Wolzt M, Jilma B. Hypertensive emergencies are associated with elevated markers of inflammation, coagulation, platelet activation and fibrinolysis. Hypertension. 2013; 27:368-373.
• [51]Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004; 109:2698-2704.
• [52]Yin X, Subramanian S, Hwang SJ, O’Donnell CJ, Fox CS, Courchesne P et al.. Protein biomarkers of new-onset cardiovascular disease: prospective study from the systems approach to biomarker research in cardiovascular disease initiative. Arterioscler Thromb Vasc Biol. 2014; 34:939-945.
• [53]Simon DI, Simon NM. Plasminogen activator inhibitor-1: a novel therapeutic target for hypertension? Circulation. 2013; 128:2286-2288.
• [54]Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007; 116:85-97.