Heart Failure Reviews

, Volume 24, Issue 5, pp 709–723 | Cite as

Levels of angiotensin peptides in healthy and cardiovascular/renal-diseased paediatric population—an investigative review

  • F. K. Suessenbach
  • B. B. BurckhardtEmail author


The renin-angiotensin-aldosterone system (RAAS) plays a major role in the regulation of blood pressure and homeostasis. Therefore, it is a commonly used target for pharmacotherapy of cardiovascular diseases in adults. However, the efficacy of this pharmacotherapy can only be limitedly derived into children. Comprehensive knowledge of the humoral parameters acting in the paediatric RAAS (e.g. angiotensin I, angiotensin II, angiotensin 1–7, angiotensin III, and angiotensin IV) might facilitate a more effective and rational pharmacotherapy in children. Therefore, this review aims to provide an overview of the maturing RAAS. Out of 925 identified records, 35 publications were classified as relevant. Physiological and pathophysiological concentrations of angiotensin peptides were compiled and categorised according to European Medicines Agency age groups. Age has a major impact on circulating angiotensin I, angiotensin II, and angiotensin 1–7, which is reflected in an age-dependent decrease during childhood. In contrast to data obtained in adults, no gender-related differences in angiotensin levels were identified. The observed increase in peptide concentrations regarding cardiac- and renal-diseased children is influenced by surgical repair, while evidence for a pharmacological impact is conflicting. A comprehensive set of angiotensin I, angiotensin II, and angiotensin 1–7 values from neonates up to adolescents was compiled. Indicating age as a strong effector. However, evidence about potential promising targets of the RAAS like angiotensin III and angiotensin IV is still lacking in children.


RAAS Angiotensin Paediatric Cardiovascular disease Renal disease 



Angiotensin-converting enzyme inhibitor


Appropriate for gestational age


Antenatal corticosteroids




Atrial septal defect


Bidirectional Glenn


Calcium channel blocker


Chronic renal failure


Cardiovascular disease


Enzyme-linked immunosorbent assay


European Medicines Agency


End-stage renal disease


Gestational age


High-pressure liquid chromatography


Head-up tilt


Interquartile range


Labeling of enalapril up to adolescents


Moderate-low birthweight


Normal birthweight


Renin-angiotensin-aldosterone system


Renal failure




Standard deviation


Standard error


Small for gestational age


Steroid-resistant idiopathic nephrotic syndrome


Ultraviolet/visible spectroscopy


Very low birthweight


Ventricular septal defect



We thank Jutta Tins for the assistance in double-checking the data and Prof. Dr. Stephanie Laeer for conceptual support.

Authors’ contribution

Conception and design of the work were developed in close collaboration by Suessenbach FK and Burckhardt BB. Data collection and analysis were performed by Suessenbach FK. The interpretation and drafting of the article were done by Suessenbach FK and Burckhardt BB. Critical revision and final approval of the version to be published were given by Burckhardt BB.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, Ahmed M, Aksut B, Alam T, Alam K, Alla F, Alvis-Guzman N, Amrock S, Ansari H, Ärnlöv J, Asayesh H, Atey TM, Avila-Burgos L, Awasthi A, Banerjee A, Barac A, Bärnighausen T, Barregard L, Bedi N, Belay Ketema E, Bennett D, Berhe G, Bhutta Z, Bitew S, Carapetis J, Carrero JJ, Malta DC, Castañeda-Orjuela CA, Castillo-Rivas J, Catalá-López F, Choi JY, Christensen H, Cirillo M, Cooper L Jr, Criqui M, Cundiff D, Damasceno A, Dandona L, Dandona R, Davletov K, Dharmaratne S, Dorairaj P, Dubey M, Ehrenkranz R, el Sayed Zaki M, Faraon EJA, Esteghamati A, Farid T, Farvid M, Feigin V, Ding EL, Fowkes G, Gebrehiwot T, Gillum R, Gold A, Gona P, Gupta R, Habtewold TD, Hafezi-Nejad N, Hailu T, Hailu GB, Hankey G, Hassen HY, Abate KH, Havmoeller R, Hay SI, Horino M, Hotez PJ, Jacobsen K, James S, Javanbakht M, Jeemon P, John D, Jonas J, Kalkonde Y, Karimkhani C, Kasaeian A, Khader Y, Khan A, Khang YH, Khera S, Khoja AT, Khubchandani J, Kim D, Kolte D, Kosen S, Krohn KJ, Kumar GA, Kwan GF, Lal DK, Larsson A, Linn S, Lopez A, Lotufo PA, el Razek HMA, Malekzadeh R, Mazidi M, Meier T, Meles KG, Mensah G, Meretoja A, Mezgebe H, Miller T, Mirrakhimov E, Mohammed S, Moran AE, Musa KI, Narula J, Neal B, Ngalesoni F, Nguyen G, Obermeyer CM, Owolabi M, Patton G, Pedro J, Qato D, Qorbani M, Rahimi K, Rai RK, Rawaf S, Ribeiro A, Safiri S, Salomon JA, Santos I, Santric Milicevic M, Sartorius B, Schutte A, Sepanlou S, Shaikh MA, Shin MJ, Shishehbor M, Shore H, Silva DAS, Sobngwi E, Stranges S, Swaminathan S, Tabarés-Seisdedos R, Tadele Atnafu N, Tesfay F, Thakur JS, Thrift A, Topor-Madry R, Truelsen T, Tyrovolas S, Ukwaja KN, Uthman O, Vasankari T, Vlassov V, Vollset SE, Wakayo T, Watkins D, Weintraub R, Werdecker A, Westerman R, Wiysonge CS, Wolfe C, Workicho A, Xu G, Yano Y, Yip P, Yonemoto N, Younis M, Yu C, Vos T, Naghavi M, Murray C (2017) Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 70(1):1–25. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Momper JD, Mulugeta Y, Burckart GJ (2015) Failed pediatric drug development trials. Clin Pharmacol Ther 98(3):245–251. CrossRefPubMedGoogle Scholar
  3. 3.
    De A, Shah P, Szmuszkovicz J, Bhombal S, Azen S, Kato RM (2018) A retrospective review of infants receiving sildenafil. J Pediatr Pharmacol Ther 23(2):100–105. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Basu R, Poglitsch M, Yogasundaram H, Thomas J, Rowe BH, Oudit GY (2017) Roles of angiotensin peptides and recombinant human ACE2 in heart failure. J Am Coll Cardiol 69(7):805–819. CrossRefPubMedGoogle Scholar
  5. 5.
    Yugandhar VG, Clark MA (2013) Angiotensin III: a physiological relevant peptide of the renin angiotensin system. Peptides 46:26–32. CrossRefGoogle Scholar
  6. 6.
    Fiselier TJ, Lijnen P, Monnens L, van Munster P, Jansen M, Peer P (1983) Levels of renin, angiotensin I and II, angiotensin-converting enzyme and aldosterone in infancy and childhood. Eur J Pediatr 141(1):3–7CrossRefGoogle Scholar
  7. 7.
    Miyawaki M, Okutani T, Higuchi R, Yoshikawa N (2006) Plasma angiotensin II concentrations in the early neonatal period. Arch Dis Child Fetal Neonatal Ed 91(5):F359–F362. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Broughton Pipkin F, Smales OR (1977) A study of factors affecting blood pressure and angiotensin II in newborn infants. J Pediatr 91(1):113–119CrossRefGoogle Scholar
  9. 9.
    Miyawaki M, Okutani T, Higuchi R, Yoshikawa N (2008) The plasma angiotensin II level increases in very low-birth weight infants with neonatal chronic lung disease. Early Hum Dev 84(6):375–379. CrossRefPubMedGoogle Scholar
  10. 10.
    Broughton Pipkin F, Smales OR (1975) Proceedings. Blood pressure and angiotensin II in the newborn. Arch Dis Child 50(4):330CrossRefGoogle Scholar
  11. 11.
    Tang Y-J, Zhang Z-Z, Chen S-Q, Chen S-M, Li C-J, Chen J-W, Yuan B, Xia Y, Wang L (2015) Effect of topical propranolol gel on plasma renin, angiotensin II and vascular endothelial growth factor in superficial infantile hemangiomas. J Huazhong Univ Sci Technol Med Sci 35(5):759–762. CrossRefPubMedGoogle Scholar
  12. 12.
    Zaher H, Rasheed H, El-Komy MM, Hegazy RA, Gawdat HI, Abdel Halim DM, Abdel Hay RM, Hegazy RA, Mohy AM (2016) Propranolol versus captopril in the treatment of infantile hemangioma (IH). A randomized controlled trial. J Am Acad Dermatol 74(3):499–505. CrossRefPubMedGoogle Scholar
  13. 13.
    van Acker KJ, Scharpé SL, Lynen PJ, Amery AK (1983) Comparative study of active and inactive plasma renin in healthy infants and adults. J Clin Chem Clin Biochem 21(12):775–778PubMedGoogle Scholar
  14. 14.
    Broughton Pipkin F, Smales OR, O’Callaghan M (1981) Renin and angiotensin levels in children. Arch Dis Child 56(4):298–302CrossRefGoogle Scholar
  15. 15.
    Cruces P, Diaz F, Puga A, Erranz B, Donoso A, Carvajal C, Wilhelm J, Repetto GM (2012) Angiotensin-converting enzyme insertion/deletion polymorphism is associated with severe hypoxemia in pediatric ARDS. Intensive Care Med 38(1):113–119. CrossRefPubMedGoogle Scholar
  16. 16.
    SEM E-DK, Sayed AA, Nassar AY, Mohey-Eldeen ZM, Eldeeb HM, Meki A-RMA (2017) Role of some vasoactive mediators in scorpion envenomed children. Possible relation to envenoming outcome. Toxicon 127:77–84. CrossRefGoogle Scholar
  17. 17.
    Zhang C, Chen S, Zhou G, Jin Y, Zhang R, Yang H, Xi Y, Ren J, Duan G (2018) Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease. PLoS One 13(5):e0197861. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Simões e Silva AC, Diniz JSS, Regueira Filho A, Santos RAS (2004) The renin angiotensin system in childhood hypertension. Selective increase of angiotensin-(1-7) in essential hypertension. J Pediatr 145(1):93–98. CrossRefPubMedGoogle Scholar
  19. 19.
    Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Draz HM (2010) Relationship between resistin and aPAI-1 levels with insulin resistance in Saudi children. Pediatr Int 52(4):551–556. CrossRefPubMedGoogle Scholar
  20. 20.
    Tiosano D, Schwartz Y, Braver Y, Hadash A, Gepstein V, Weisman Y, Lorber A (2011) The renin-angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D-resistance rickets (HVDRR). J Bone Miner Res 26(9):2252–2260. CrossRefPubMedGoogle Scholar
  21. 21.
    Hjortdal VE, Stenbøg EV, Ravn HB, Emmertsen K, Jensen KT, Pedersen EB, Olsen KH, Hansen OK, Sørensen KE (2000) Neurohormonal activation late after cavopulmonary connection. Heart 83(4):439–443CrossRefGoogle Scholar
  22. 22.
    Franco MCP, Casarini DE, Carneiro-Ramos MS, Sawaya AL, Barreto-Chaves MLM, Sesso R (2008) Circulating renin-angiotensin system and catecholamines in childhood. Is there a role for birthweight? Clin Sci 114(5):375–380. CrossRefPubMedGoogle Scholar
  23. 23.
    Mahler B, Kamperis K, Ankarberg-Lindgren C, Djurhuus JC, Rittig S (2015) The effect of puberty on diurnal sodium regulation. Am J Physiol Renal Physiol 309(10):F873–F879. CrossRefPubMedGoogle Scholar
  24. 24.
    Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Yakout SM, Sabico SB, Gibson GC, Chrousos GP, Kumar S (2011) Parent-offspring transmission of adipocytokine levels and their associations with metabolic traits. PLoS One 6(4):e18182. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kamperis K, Rittig S, Radvanska E, Jorgensen KA, Djurhuus JC (2008) The effect of desmopressin on renal water and solute handling in desmopressin resistant monosymptomatic nocturnal enuresis. J Urol 180(2):707–713. CrossRefPubMedGoogle Scholar
  26. 26.
    Mahler B, Kamperis K, Schroeder M, Frøkiær J, Djurhuus JC, Rittig S (2012) Sleep deprivation induces excess diuresis and natriuresis in healthy children. Am J Physiol Renal Physiol 302(2):F236–F243. CrossRefPubMedGoogle Scholar
  27. 27.
    Kamperis K, Rittig S, Bower WF, Djurhuus JC (2012) Effect of indomethacin on desmopressin resistant nocturnal polyuria and nocturnal enuresis. J Urol 188(5):1915–1922. CrossRefPubMedGoogle Scholar
  28. 28.
    Gheissari A, Sabri M, Pirpiran M, Merrikhi A (2013) Possible correlation among echocardiographic measures, serum brain natriuretic peptide, and angiotensin II levels in hypertensive kidney transplanted children. Exp Clin Transplant 11(2):128–133. CrossRefPubMedGoogle Scholar
  29. 29.
    Rittig S, Matthiesen TB, Pedersen EB, Djurhuus JC (2006) Circadian variation of angiotensin II and aldosterone in nocturnal enuresis. Relationship to arterial blood pressure and urine output. J Urol 176(2):774–780. CrossRefPubMedGoogle Scholar
  30. 30.
    South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Snively BM, Shaltout HA, Rose JC, O’Shea TM, Washburn LK (2017) Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm. Pediatr Res 81(1–1):88–93. CrossRefPubMedGoogle Scholar
  31. 31.
    Washburn LK, Brosnihan KB, Chappell MC, Diz DI, Gwathmey TM, Nixon PA, Russell GB, Snively BM, O’Shea TM (2015) The renin-angiotensin-aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia. J Renin-Angiotensin-Aldosterone Syst 16(3):529–538. CrossRefPubMedGoogle Scholar
  32. 32.
    Miller JA, Anacta LA, Cattran DC (1999) Impact of gender on the renal response to angiotensin II. Kidney Int 55(1):278–285. CrossRefPubMedGoogle Scholar
  33. 33.
    Legato MJ, Johnson PA, Manson JE (2016) Consideration of sex differences in medicine to improve health care and patient outcomes. JAMA 316(18):1865–1866. CrossRefPubMedGoogle Scholar
  34. 34.
    Simões e Silva AC, Diniz JSS, Pereira RM, Pinheiro SVB, Santos RAS (2006) Circulating renin angiotensin system in childhood chronic renal failure. Marked increase of angiotensin-(1-7) in end-stage renal disease. Pediatr Res 60(6):734–739. CrossRefPubMedGoogle Scholar
  35. 35.
    Yi Z, Li Z, Wu X-C, He Q-N, Dang X-Q, He X-J (2006) Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol 21(7):967–972. CrossRefPubMedGoogle Scholar
  36. 36.
    Nakagawa Y, Toya K, Natsume H, Nasuda K, Takeuchi H, Kubota A, Ogawa H, Igarashi Y (1997) Long-term follow-up of a girl with the neonatal form of Bartter’s syndrome. Endocr J 44(2):275–281CrossRefGoogle Scholar
  37. 37.
    Mainwaring RD, Lamberti JJ, Moore JW, Billman GF, Nelson JC (1994) Comparison of the hormonal response after bidirectional Glenn and Fontan procedures. Ann Thorac Surg 57(1):59–63CrossRefGoogle Scholar
  38. 38.
    Saiki H, Kuwata S, Kurishima C, Masutani S, Senzaki H (2016) Vulnerability of coronary circulation after Norwood operation. Ann Thorac Surg 101(4):1544–1551. CrossRefPubMedGoogle Scholar
  39. 39.
    Tokiwa K, Iwai N, Nakamura K, Shiraishi I, Hayashi S, Onouchi Z (1993) Pulmonary hypertension as a fatal complication of extrahepatic portal hypertension. Eur J Pediatr Surg 3(6):373–375. CrossRefPubMedGoogle Scholar
  40. 40.
    Friedman A, Chesney RW, Ball D, Goodfriend T (1980) Effective use of captopril (angiotensin I-converting enzyme inhibitor) in severe childhood hypertension. J Pediatr 97(4):664–667CrossRefGoogle Scholar
  41. 41.
    Seguias L, Zilleruelo G, Strauss J, Abitbol C, Montane B (2001) Angiotensin-II and endothelin-1 levels in children with renoprival hypertension. Pediatr Nephrol 16(6):493–496CrossRefGoogle Scholar
  42. 42.
    Wagoner AL, Shaltout HA, Fortunato JE, Diz DI (2016) Distinct neurohumoral biomarker profiles in children with hemodynamically defined orthostatic intolerance may predict treatment options. Am J Physiol Heart Circ Physiol 310(3):H416–H425. CrossRefPubMedGoogle Scholar
  43. 43.
    Jankowski V, Vanholder R, van der Giet M, Tölle M, Karadogan S, Gobom J, Furkert J, Oksche A, Krause E, Tran TNA, Tepel M, Schuchardt M, Schlüter H, Wiedon A, Beyermann M, Bader M, Todiras M, Zidek W, Jankowski J (2007) Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol 27(2):297–302. CrossRefPubMedGoogle Scholar
  44. 44.
    Jankowski V, Tölle M, Santos RAS, Günthner T, Krause E, Beyermann M, Welker P, Bader M, Pinheiro SVB, Sampaio WO, Lautner R, Kretschmer A, van der Giet M, Zidek W, Jankowski J (2011) Angioprotectin. An angiotensin II-like peptide causing vasodilatory effects. FASEB J 25(9):2987–2995. CrossRefPubMedGoogle Scholar
  45. 45.
    Komukai K, Mochizuki S, Yoshimura M (2010) Gender and the renin-angiotensin-aldosterone system. Fundam Clin Pharmacol 24(6):687–698. CrossRefPubMedGoogle Scholar
  46. 46.
    Ferrario CM, Strawn WB (2006) Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 98(1):121–128. CrossRefPubMedGoogle Scholar
  47. 47.
    Gore R, Chugh PK, Tripathi CD, Lhamo Y, Gautam S (2017) Pediatric off-label and unlicensed drug use and its implications. Curr Clin Pharmacol 12(1):18–25. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Institute of Clinical Pharmacy and PharmacotherapyHeinrich Heine UniversityDusseldorfGermany

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