Main Article Content
Renal function declines according to age and vascular risk factors, whereas few data are available regarding genetically-mediated effects of anti-hypertensives over renal function.
To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis).
Consecutive outpatients older than 60 years-old with AD and no history of kidney transplant or dialytic therapy were recruited for prospective correlations regarding variations in fasting blood levels of urea and creatinine in one year, considering ACE genotypes of rs1800764 and rs4291 and their respective haplotypes, and treatment with ACEis along with blood pressure variations.
For 190 patients, 152 had arterial hypertension, and 122 used ACEis. Minor allele frequencies were 0.492 for rs1800764-C and 0.337 for rs4291-T, both in Hardy-Weinberg equilibrium. There were no overall significant yearly variations in levels of urea and creatinine, but their concurrent variations were positively correlated (ρ <0.0001). Each A allele of rs4291 led to an yearly urea increase of 3.074 mg/dL, and an yearly creatinine increase of 0.044 mg/dL, while the use of ACEis was protective regarding creatinine variations. The use of ACEis was also protective for carriers of rs1800764-CT/rs4291-AA, while carriers of rs1800764-CT/rs4291-AT had steeper reductions in creatinine levels, particularly when they were treated with ACEis.
Effects of ACEis over creatinine variations are genetically mediated and independent of blood pressure variations in older people with AD.
Higuchi M, Chen R, Abbott RD, Bell C, Launer L, Ross GW, et al. Mid-life proteinuria and late-life cognitive function and dementia in elderly men: The Honolulu-Asia aging study. Alzheimer Dis Assoc Disord. 2015;29:200–205.
Hadjadj S, Tarnow L, Forsblom C, Kazeem G, Marre M, Groop PH, et al. Association between angiotensin-converting enzyme gene polymorphisms and diabetic nephropathy: Case-control, haplotype, and family-based study in three european populations. J Am Soc Nephrol. 2007;18:1284–1291.
Peters R, Beckett N, Poulter R, Burch L, Narkiewicz K, Fagard R, et al. Kidney function in the very elderly with hypertension: data from the hypertension in the very elderly (HYVET) trial. Age Ageing. 2013;42:253–258.
Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JCM. ACE Polymorphisms. Circ Res. 2006;98:1123–1133.
De Oliveira FF, Bertolucci PHF, Chen ES, Smith MC. Brain-penetrating angiotensin-converting enzyme inhibitors and cognitive change in patients with dementia due to Alzheimer's Disease. J Alzheimers Dis. 2014;42:S321–S324.
Bertram L, Tanzi RE. Thirty years of Alzheimer's disease genetics: The implications of systematic meta-analyses. Nature Rev Neurosci. 2008;9:768–778.
Kehoe PG, Katzov H, Andreasen N, Gatz M, Wilcock GK, Cairns NJ, et al. Common variants of ACE contribute to variable age-at-onset of Alzheimer's disease. Hum Genet. 2004;114:478–483.
Chung C-M, Wang R-Y, Fann CSJ, Chen JW, Jong YS, Jou YS, et al. Fine-mapping angiotensin-converting enzyme gene: Separate QTLs identified for hypertension and for ACE activity. PLoS ONE. 2013;8:e56119.
Martínez-Rodríguez N, Posadas-Romero C, Villareal-Molina T, Vallejo M, Del-Valle-Mondragón L, Ramírez-Bello J, et al. Single nucleotide polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals. PLoS ONE. 2013;8:e65700.
Brugts JJ, Isaacs A, de Maat MPM, Boersma E, van Duijn CM, Akkerhuis KM, et al. A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals. J Hypertens. 2009;29:509–519.
Zhang N, Cui H, Yang L. Effect of angiotensin II type I receptor A1166C polymorphism on benazepril action in hypertensive patients: A family-based association test study. Arch Pharm Res. 2012;35:1817–1822.
Schuch JB, Constantin PC, da Silva VK, Korb C, Bamberg DP, da Rocha TJ, et al. ACE polymorphism and use of ACE inhibitors: effects on memory performance. Age. 2014;36:1515–1522.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement. 2011;7:263–269.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure - the JNC 7 report. JAMA. 2003;289:2560–2572.
Kim TH, Chang HS, Park SM, Nam BY, Park JS, Rhim T, et al. Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin Exp Allergy. 2008;38:1727–1737.
Irvin MR, Lynch AI, Kabagambe EK, Tiwari HK, Barzilay JI, Eckfeldt JH, et al. Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study. J Hypertens. 2010;28:2076–2083.
Stewart R, Xue Q-L, Masaki K, Petrovitch H, Ross GW, White LR, et al. Change in blood pressure and incident dementia: A 32-year prospective study. Hypertension. 2009;54:233–240.
De Oliveira FF, Bertolucci PHF, Chen ES, Smith MC. Risk factors for age at onset of dementia due to Alzheimer's disease in a sample of patients with low mean schooling from São Paulo, Brazil. Int J Geriatr Psychiatry. 2014;29:1033–1039.
De Oliveira FF, Pivi GAK, Chen ES, Smith MC, Bertolucci PHF. Risk factors for cognitive and functional change in one year in patients with Alzheimer's disease dementia from São Paulo, Brazil. J Neurol Sci. 2015;359:127–132.
The copy rights of the articles published in Colombia Médica belong to the Universidad del Valle. The contents of the articles that appear in the Journal are exclusively the responsibility of the authors and do not necessarily reflect the opinions of the Editorial Committee of the Journal. It is allowed to reproduce the material published in Colombia Médica without prior authorization for non-commercial use