J Hypertens. 2022 Feb 01;40(2):348-355. doi: 10.1097/HJH.0000000000003018.
Urine N-acetyl-Ser-Asp-Lys-Pro measurement as a versatile biomarker to assess adherence to angiotensin-converting enzyme inhibitors.
Journal of hypertension
Benjamin Kably, Eliane M Billaud, Audrey Derobertmasure, Anne Blanchard, Pierre Boutouyrie, Michel Azizi
Affiliations
Affiliations
- Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Pharmacology Unit and DMU BIOPHYGEN.
- INSERM UMRS970.
- Université de Paris, INSERM, CIC1418.
- Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Department and DMU CARTE, Paris, France.
PMID: 34508023
DOI: 10.1097/HJH.0000000000003018
Abstract
BACKGROUND: Poor adherence to treatment is a major health issue in hypertension. The large number of drugs to be detected limits the implementation of chemical adherence testing by liquid chromatography/mass spectrometry (LC-MS/MS). AcSDKP, a peptide accumulating in the presence of angiotensin-converting-enzyme inhibitor (ACEI) treatment, has been validated as a proven marker of adherence by enzyme-linked immunosorbent assay. Our aim was to validate urine measurements of AcSDKP compared with active metabolites of various ACEI, measured simultaneously by LC-MS/MS.
METHOD: We first studied the time-dependent relationships between urinary perindoprilat and AcSDKP in a pharmacokinetic/pharmacodynamic study in healthy volunteers. We then compared the sensitivity and specificity of urinary AcSDKP vs. three ACEI active metabolites (enalaprilat, perindoprilat, ramiprilat) taken as reference to detect nonadherence in spot urine samples from a prospective cohort of hypertensive outpatients.
RESULTS: The urinary excretion profiles of AcSDKP and perindoprilat were similar, exhibited a significant correlation, and showed excellent agreement in healthy volunteers. In patients, we found a similar agreement between AcSDKP and the three ACEI metabolites urinary concentrations. The sensitivity and specificity for adherence assessment of urine AcSDKP was 92.2 and 100%, respectively. We observed a difference in the evaluation of good adherence between ACEI metabolites (85.7%) and AcSDKP (79.0%) because of discrepancies in samples where AcSDKP reached undetectability quicker than ACEI metabolites. This characteristic of AcSDKP is of particular interest and could better reflect the true adherence status of patients.
CONCLUSION: Overall, spot urine AcSDKP measurement by LC-MS/MS is a reliable marker of the intake of ACEI treatment and could substitute ACEI metabolites detection.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
References
- Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Reduction of proteinuria by angiotensin converting enzyme inhibition. Kidney Int 1987; 32:78–83. - PubMed
- Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145–153. - PubMed
- James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507–520. - PubMed
- Silvariño R, Rios P, Baldovinos G, Chichet MA, Perg N, Sola L, et al. Is Chronic kidney disease progression influenced by the type of renin-angiotensin-system blocker used? Nephron 2019; 143:100–107. - PubMed
- Zhang Y, Ding X, Hua B, Liu Q, Chen H, Zhao X-Q, et al. Real-world use of ACEI/ARB in diabetic hypertensive patients before the initial diagnosis of obstructive coronary artery disease: patient characteristics and long-term follow-up outcome. J Transl Med 2020; 18:150. - PubMed
- Kini V, Ho PM. Interventions to improve medication adherence: a review. JAMA 2018; 320:2461–2473. - PubMed
- Hameed MA, Dasgupta I. Medication adherence and treatment-resistant hypertension: a review. Drugs Context 2019; 8:212560. - PubMed
- Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens 2018; 36:1953–2041. - PubMed
- WHO: adherence to long term therapies: evidences for action. WHO. Available at: http://www.who.int/chp/knowledge/publications/adherence_report/en/. [Accessed 2 June 2019] - PubMed
- Gupta P, Patel P, Tomaszewski M. Measurements of antihypertensive medications in blood and urine. Drug adherence in hypertension and cardiovascular protection. Springer International Publishing; 2018; 29–41. - PubMed
- Kably B, Billaud EM, Boutouyrie P, Azizi M. Is there any hope for monitoring adherence in an efficient and feasible way for resistant hypertension diagnosis and follow-up? Curr Hypertens 2020; 22:96. - PubMed
- Hamdidouche I, Jullien V, Boutouyrie P, Billaud E, Azizi M, Laurent S. Routine urinary detection of antihypertensive drugs for systematic evaluation of adherence to treatment in hypertensive patients. J Hypertens 2017; 35:1891–1898. - PubMed
- Tomaszewski M, White C, Patel P, Masca N, Damani R, Hepworth J, et al. High rates of nonadherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart Br Card Soc 2014; 100:855–861. - PubMed
- Gupta P, Patel P, Štrauch B, Lai FY, Akbarov A, Gulsin GS, et al. Biochemical screening for nonadherence is associated with blood pressure reduction and improvement in adherence. Hypertension 19792017; 70:1042–1048. - PubMed
- Lawson AJ, Shipman KE, George S, Dasgupta I. A novel ‘Dilute-and-Shoot’ liquid chromatography-tandem mass spectrometry method for the screening of antihypertensive drugs in urine. J Anal Toxicol 2016; 40:17–27. - PubMed
- De Nicolò A, Avataneo V, Rabbia F, Bonifacio G, Cusato J, Tomasello C, et al. UHPLC-MS/MS method with protein precipitation extraction for the simultaneous quantification of ten antihypertensive drugs in human plasma from resistant hypertensive patients. J Pharm Biomed Anal 2016; 129:535–541. - PubMed
- Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International Society of Hypertension global hypertension practice guidelines. J Hypertens 2020; 38:982–1004. - PubMed
- Société Francaise d’Hypertension Artérielle. Call for action - Agir pour l’observance dans l’Hypertension Artérielle. 2017. - PubMed
- Azizi M, Ezan E, Reny JL, Wdzieczak-Bakala J, Gerineau V, Ménard J. Renal and metabolic clearance of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) during angiotensin-converting enzyme inhibition in humans. Hypertension 1999; 33:879–886. - PubMed
- Azizi M, Ezan E, Nicolet L, Grognet JM, Ménard J. High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition. Hypertension 1997; 30:1015–1019. - PubMed
- Monge M, Paquet V, Bergerot D, Zhygalina V, Blanchard A. Dose-effect relationship of perindopril 10, 14 and 20 mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers. Int J Cardiol 2016; 222:648–653. - PubMed
- Azizi M, Ménard J, Peyrard S, Lièvre M, Marre M, Chatellier G. Assessment of patients’ and physicians’ compliance to an ACE inhibitor treatment based on urinary N-acetyl Ser-Asp-Lys-Pro determination in the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study. Diabetes Care 2006; 29:1331–1336. - PubMed
- Beaussier H, Boutouyrie P, Bobrie G, Frank M, Laurent S, Coudoré F, Azizi M. True antihypertensive efficacy of sequential nephron blockade in patients with resistant hypertension and confirmed medication adherence. J Hypertens 2015; 33:2526–2533. - PubMed
- Azizi M, Pereira H, Hamdidouche I, Gosse P, Monge M, Bobrie G. DENERHTN Investigators. Adherence to antihypertensive treatment and the blood pressure-lowering effects of renal denervation in the Renal Denervation for Hypertension (DENERHTN) Trial. Circulation 2016; 134:847–857. - PubMed
- Struthers AD, MacFadyen R, Fraser C, Robson J, Morton JJ, Junot C, Ezan E. Nonadherence with angiotensin-converting enzyme inhibitor therapy: a comparison of different ways of measuring it in patients with chronic heart failure. J Am Coll Cardiol 1999; 34:2072–2077. - PubMed
- Dugues P, Fabresse N, Mégarbane B, Alvarez J, Larabi IA. Validation d’une méthode de dosage de sept inhibiteurs de l’enzyme de conversion (IEC) et trois métabolites actifs dans le plasma par CL-SM/SM. Application à une toxicocinétique du ramipril et du périndopril au cours de deux intoxications aiguës. Toxicol Anal Clin 2020; 32:12–22. - PubMed
- Patijn J. Reproducibility protocol for diagnostic procedures in manual/musculoskeletal medicine. Man Med 2019; 57:451–479. - PubMed
- Thompson WD, Walter SD. A reappraisal of the kappa coefficient. J Clin Epidemiol 1988; 41:949–958. - PubMed
- European Medicines Agency. EMEA-Annex III Summary Of Product Characteristics-Coversyl [Internet]. European Medicines Agency, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/coversyl. [Accessed 1 June 2021] - PubMed
- Junot C, Pruvost A, Créminon C, Grognet JM, Benech H, Ezan E. Characterization of immunoreactive acetyl-Ser-Asp-Lys-Pro in human plasma and urine by liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci App 2001; 752:69–75. - PubMed
- European Medicines Agency. EMEA-Annex III Summary of product characteristics-ecazide [Internet]. European Medicines Agency; 2018. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/ecazide. [Accessed 1 June 2021] - PubMed
- Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM, et al. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest 1996; 97:839–844. - PubMed
- Azizi M, Massien C, Michaud A, Corvol P. In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor. Hypertension 2000; 35:1226–1231. - PubMed
- Azizi M, Lamarre-Cliche M, Labatide-Alanore A, Bissery A, Guyene TT, Ménard J. Physiologic consequences of vasopeptidase inhibition in humans: effect of sodium intake. J Am Soc Nephrol JASN 2002; 13:2454–2463. - PubMed
- Azizi M, Bissery A, Peyrard S, Guyene TT, Ozoux M-L, Floch A, Ménard J. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans. Clin Pharmacol Ther 2006; 79:49–61. - PubMed
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