Abstract
As part of the extended renin-angiotensin-aldosterone system, active renin and its precursor prorenin have been an area of research interest for decades. Although several studies showed a correlation with disease, other studies found no significant association, e.g. attributed to limited sample size or pharmacological effects of antihypertensive drugs. Since the measurement of both proteins has typically been carried out in adult populations, the data in paediatrics is limited. This review aimed to collate the current data on plasma renin and prorenin levels in children and compare the levels of healthy vs. the diseased state. A literature search using Medline resulted in 213 publications of which 15 studies were classified as relevant. In the extant studies in the literature, an age-dependent decline of renin plasma concentration was observed in newborns compared to adolescents. For children with cardiovascular disease, five studies were identified that provide limited insight into the pathophysiological regulation of renin. In general, sample handling is still a crucial step, which might particularly affect measured active renin concentrations due to conformational changes of its precursor prorenin. A reliable assessment for prorenin levels in the maturating population is yet not possible due to the low number of available publications. Three different approaches to quantify prorenin were found and raise the question on the comparability of these methods. The review emphazised several weaknesses and highlights the need for an accurate procedure to determine levels of active renin as well as prorenin in its closed and open form.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
References
1. Schroten, NF, Gaillard, CAJM, Van Veldhuisen, DJ, Szymanski, MK, Hillege, HL, De Boer, RA. New roles for renin and prorenin in heart failure and cardiorenal crosstalk. Heart Fail Rev 2012; 17: 191–201. https://doi.org/10.1007/s10741-011-9262-2. Search in Google Scholar
2. Nguyen, G. Renin, (pro)renin and receptor: an update. Clin Sci 2011; 120: 169–78. https://doi.org/10.1042/cs20100432. Search in Google Scholar
3. Berge, C, Courand, PY, Harbaoui, B, Paget, V, Khettab, F, Bricca, G, et al. Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications. J Hypertens 2015; 33: 118–25. https://doi.org/10.1097/hjh.0000000000000367. Search in Google Scholar
4. Tomaschitz, A, Pilz, S, Ritz, E, Morganti, A, Grammer, T, Amrein, K, et al. Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure. Eur Heart J 2011; 32: 2642–9. https://doi.org/10.1093/eurheartj/ehr150. Search in Google Scholar
5. Paternostro, R, Reiberger, T, Mandorfer, M, Schwarzer, R, Schwabl, P, Bota, S, et al. Plasma renin concentration represents an independent risk factor for mortality and is associated with liver dysfunction in patients with cirrhosis. J Gastroenterol Hepatol 2017; 32: 184–90. https://doi.org/10.1111/jgh.13439. Search in Google Scholar
6. Stoicescu, M, Csepento, C, Muţiu, G, Bungǎu, S. The role of increased plasmatic renin level in the pathogenesis of arterial hypertension in young adults. Rom J Morphol Embryol 2011; 52: 419–23. 21424086. Search in Google Scholar
7. Maas, MH, Cransberg, K, van Grotel, M, Pieters, R, van den Heuvel-Eibrink, MM. Renin-induced hypertension in Wilms tumor patients. Pediatr Blood Cancer 2007; 48: 500–3. https://doi.org/10.1002/pbc.20938. Search in Google Scholar
8. Ichihara, A, Sakoda, M, Kurauchi-Mito, A, Kaneshiro, Y, Itoh, H. Renin, prorenin and the kidney: a new chapter in an old saga. J Nephrol 2009; 22: 306–11. 19557706. Search in Google Scholar
9. Nguyen, G, Blanchard, A, Curis, E, Bergerot, D, Chambon, Y, Hirose, T, et al. Plasma soluble (Pro)Renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity. Hypertension 2014; 63: 297–302. https://doi.org/10.1161/hypertensionaha.113.02217. Search in Google Scholar
10. Campbell, DJ, Nussberger, J, Stowasser, M, Danser, AHJ, Morganti, A, Frandsen, E, et al. Activity assays and immunoassays for plasma renin and prorenin: information provided and precautions necessary for accurate measurement. Clin Chem 2009; 55: 867–77. https://doi.org/10.1373/clinchem.2008.118000. Search in Google Scholar
11. Tu, W, Eckert, GJ, Pratt, JH, Jan Danser, AH. Plasma levels of prorenin and renin in blacks and whites: their relative abundance and associations with plasma aldosterone concentration. Am J Hypertens 2012; 25: 1030–4. https://doi.org/10.1038/ajh.2012.83. Search in Google Scholar
12. Krop, M, Van Gool, JMG, Day, D, Hollenberg, NK, Danser, AHJ. Evaluation of a direct prorenin assay making use of a monoclonal antibody directed against residues 32-39 of the prosegment. J Hypertens 2011; 29: 2138–46. https://doi.org/10.1097/hjh.0b013e32834b1978. Search in Google Scholar
13. Blazy, I, Guillot, F, Laborde, K, Dechaux, M. Comparison of plasma renin and prorenin in healthy infants and children as determined with an enzymatic method and a new direct immunoradiometric assay. Scand J Clin Lab Invest 1989; 49: 413–8. https://doi.org/10.3109/00365518909089115. Search in Google Scholar
14. Yoshida, G, Kawasaki, M, Murata, I, Hayakawa, Y, Aoyama, T, Miyazaki, N, et al. Higher plasma prorenin concentration plays a role in the development of coronary artery disease. Biomark Res 2015; 3: 1–7. https://doi.org/10.1186/s40364-015-0044-1. Search in Google Scholar
15. Human renin ELISA kit (renin III generation) by Cisbo bioassays; 2016. Available from: https://www.cisbio.eu/media/asset/c/i/cisbio_ivd_pi_renine_mod020_eng.pdf. Search in Google Scholar
16. Lamarre-Cliche, M, De Champlain, J, Lacourcière, Y, Poirier, L, Karas, M, Larochelle, P. Effects of circadian rhythms, posture, and medication on renin-aldosterone interrelations in essential hypertensives. Am J Hypertens 2005; 18: 56–64. https://doi.org/10.1016/j.amjhyper.2004.08.025. Search in Google Scholar
17. Glinicki, P, Jeske, W, Gietka-Czernel, M, Bednarek-Papierska, L, Kruszyńska, A, Słowińska-Srzednicka, J, et al. The effect of blood collection procedure on plasma renin activity (PRA) and concentrations of direct renin (DRC) and aldosterone. J Renin Angiotensin Aldosterone Syst 2015; 16: 339–43. https://doi.org/10.1177/1470320313494434. Search in Google Scholar
18. Tu, W, Eckert, GJ, Pratt, JH, Jan Danser, AH. Plasma levels of prorenin and renin in blacks and whites: their relative abundance and associations with plasma aldosterone concentration. Am J Hypertens 2012; 25: 1030–4. https://doi.org/10.1038/ajh.2012.83. Search in Google Scholar
19. Tomaschitz, A, Pilz, S, Ritz, E, Morganti, A, Grammer, T, Amrein, K, et al. Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure. Eur Heart J 2011; 32: 2642–9. https://doi.org/10.1093/eurheartj/ehr150. Search in Google Scholar
20. Buchhorn, R, Hammersen, A, Bartmus, D, Bursch, J. The pathogenesis of heart failure in infants with congenital heart disease. Cardiol Young 2001; 11: 498–504. https://doi.org/10.1017/s1047951101000725. Search in Google Scholar
21. Funder, JW, Carey, RM, Mantero, F, Murad, MH, Reincke, M, Shibata, H, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2016; 101: 1889–916. https://doi.org/10.1210/jc.2015-4061. Search in Google Scholar
22. Abdel Ghafar, MT. Association of aldosterone synthase CYP11B2 (-344C/T) gene polymorphism with essential hypertension and left ventricular hypertrophy in the Egyptian population. Clin Exp Hypertens 2019; 41: 779–86. https://doi.org/10.1080/10641963.2018.1557679. Search in Google Scholar
23. Derkx, FHM, Alberda, AT, De Jong, FH, Zeilmaker, FH, Makovitz, JW, Schalekamp, MADH. Source of plasma prorenin in early and late pregnancy: observations in a patient with primary ovarian failure. J Clin Endocrinol Metab 1987; 65: 349–54. https://doi.org/10.1210/jcem-65-2-349. Search in Google Scholar
24. Franken, AAM, Derkx, FHM, In’t Veld, AJM, Hop, WCJ, Rens, GHV, Peperkamp, E, et al. High plasma prorenin in diabetes mellitus and its correlation with some complications. J Clin Endocrinol Metab 1990; 71: 994–1002. https://doi.org/10.1210/jcem-71-4-1008. Search in Google Scholar
25. Chiarelli, F, Pomilio, M, De Luca, FA, Vecchiet, J, Verrotti, A. Plasma prorenin levels may predict persistent microalbuminuria in children with diabetes. Pediatr Nephrol 2001; 16: 116–20. https://doi.org/10.1007/s004670000514. Search in Google Scholar
26. Allen, TJ, Cooper, ME, Gilbert, RE, Winikoff, J, Skinner, SL, Jerums, G. Serum total renin is increased before microalbuminuria in diabetes. Kidney Int 1996; 50: 902–7. https://doi.org/10.1038/ki.1996.390. Search in Google Scholar
27. Buchhorn, R, Bartmus, D, Siekmeyer, W, Hulpke-Wette, M, Schulz, R, Bursch, J. Beta-blocker therapy of severe congestive heart failure in infants with left to right shunts. Am J Cardiol 1998; 81: 1366–8. https://doi.org/10.1016/s0002-9149(98)00175-1. Search in Google Scholar
28. Daneman, D, Crompton, CH, Balfe, JW, Sochett, EB, Chatzilias, A, Cotter, BR, et al. Plasma prorenin as an early marker of nephropathy in diabetic (IDDM) adolescents. Kidney Int 1994; 46: 1154–9. https://doi.org/10.1038/ki.1994.379. Search in Google Scholar
29. Gangnus, T, Burckhardt, BB. Potential and limitations of atrial natriuretic peptide as biomarker in pediatric heart failure—a comparative review. Front Pediatr 2019;6:420. Search in Google Scholar
30. Harris, TH, Gossett, JG. Diagnosis and diagnostic modalities in pediatric patients with elevated troponin. Pediatr Cardiol 2016; 37: 1469–74. https://doi.org/10.1007/s00246-016-1459-7. Search in Google Scholar
31. Cantinotti, M, Law, Y, Vittorini, S, Crocetti, M, Marco, M, Murzi, B, et al. The potential and limitations of plasma BNP measurement in the diagnosis, prognosis, and management of children with heart failure due to congenital cardiac disease: an update. Heart Fail Rev 2014; 19: 727–42. https://doi.org/10.1007/s10741-014-9422-2. Search in Google Scholar
32. Chronische Herzinsuffizienz [Internet] Leitlinie Pädiatrische Kardiologie: 2015. 1–10 p. Available from: https://www.awmf.org/uploads/tx_szleitlinien/023-006l_S2k_Chronische_Herzinsuffizienz_Kinder_Jugendliche_2015-10.pdf. Search in Google Scholar
33. Schütz, S, Le Moullec, JM, Corvol, P, Gasc, JM. Early expression of all the components of the renin-angiotensin-system in human development. Am J Pathol 1996; 149: 2067–79.8952539. Search in Google Scholar
34. Kruger, C, Hoper, K, Weissortel, R, Hensen, J, Dorr, HG. Value of direct measurement of active renin concentrations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Pediatr 1996; 155: 858–61. https://doi.org/10.1007/bf02282834. Search in Google Scholar
35. Ohyama, K, Ohta, M, Fujimoto, M, Nakagomi, Y, Yamori, T, Kato, K. Plasma active renin concentration in children. Endocrinol Jpn 1989; 36: 605–10. https://doi.org/10.1507/endocrj1954.36.605. Search in Google Scholar
36. Martinerie, L, Pussard, E, Foix-L’Hélias, L, Petit, F, Cosson, C, Boileau, P, et al. Physiological partial aldosterone resistance in human newborns. Pediatr Res 2009; 66: 323–8. https://doi.org/10.1203/PDR.0b013e3181b1bbec. Search in Google Scholar
37. Sigirci, A, Hallac, T, Akyncy, A, Temel, I, Gulcan, H, Aslan, M, et al. Renal interlobar artery parameters with duplex Doppler sonography and correlations with age, plasma renin, and aldosterone levels in healthy children. AJR Am J Roentgenol 2006; 186: 828–32. https://doi.org/10.2214/AJR.04.1445. Search in Google Scholar
38. Hjortdal, VE, Stenbog, EV, Ravn, HB, Emmertsen, K, Jensen, KT, Pedersen, EB, et al. Neurohormonal activation late after cavopulmonary connection. Heart 2000; 83: 439–43. https://doi.org/10.1136/heart.83.4.439. Search in Google Scholar
39. Mahler, B, Kamperis, K, Schroeder, M, Frøkiær, J, Djurhuus, JC, Rittig, S. Sleep deprivation induces excess diuresis and natriuresis in healthy children. Am J Physiol Ren Physiol 2012; 302: 236–43. https://doi.org/10.1152/ajprenal.00283.2011. Search in Google Scholar
40. Shamsuzzaman, A, Szczesniak, RD, Fenchel, MC, Amin, RS. Plasma renin levels and renin-blood pressure relationship in normal-weight and overweight children with obstructive sleep apnea and matched controls. Sleep Med 2015; 16: 101–6. https://doi.org/10.1016/j.sleep.2014.05.022. Search in Google Scholar
41. Buchhorn, R, Ross, RD, Bartmus, D, Wessel, A, Hulpke-Wette, M, Bursch, J. Activity of the renin-angiotensin-aldosterone and sympathetic nervous system and their relation to hemodynamic and clinical abnormalities in infants with left-to-right shunts. Int J Cardiol 2001; 78: 221–5. https://doi.org/10.1016/s0167-5273(01)00398-9. Search in Google Scholar
42. Buchhorn, R, Hulpke-Wette, M, Nothroff, J, Paul, T. Heart rate variability in infants with heart failure due to congenital heart disease: reversal of depressed heart rate variability by propranolol. Med Sci Monit 2002; 8: 661–7.12388917. Search in Google Scholar
43. Buchhorn, R, Hulpke-Wette, M, Hilgers, R, Bartmus, D, Wessel, A, Bürsch, J. Propranolol treatment of congestive heart failure in infants with congenital heart disease: the CHF-PRO-INFANT Trial. Int J Cardiol 2001; 79: 167–73. https://doi.org/10.1016/S0167-5273(01)00413-2. Search in Google Scholar
44. Buchhorn, R, Hulpke-Wette, M, Ruschewski, W, Ross, RD, Fielitz, J, Pregla, R, et al. Effects of therapeutic beta blockade on myocardial function and cardiac remodelling in congenital cardiac disease. Cardiol Young 2003; 13: 36–43. https://doi.org/10.1017/s1047951103000076. Search in Google Scholar
45. Blumenfeld, JD, Sealey, JE, Mann, SJ, Bragat, A, Marion, R, Pecker, MS, et al. β-Adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. Am J Hypertens 1999; 12: 451–9. https://doi.org/10.1016/s0895-7061(99)00005-9. Search in Google Scholar
46. Terada, T, Urushihara, M, Saijo, T, Nakagawa, R, Kagami, S. (Pro)renin and (pro)renin receptor expression during kidney development in neonates. Eur J Pediatr 2017; 176: 183–9. https://doi.org/10.1007/s00431-016-2820-9. Search in Google Scholar
47. Nicolaidou, P, Georgouli, H, Matsinos, Y, Psychou, F, Messaritaki, A, Gourgiotis, D, et al. Endothelin-1 in children with acute poststreptococcal glomerulonephritis and hypertension. Pediatr Int 2003; 45: 35–8. https://doi.org/10.1046/j.1442-200x.2003.01661.x. Search in Google Scholar
48. Kruger, C, Rauh, M, Dorr, HG. Immunoreactive renin concentrations in healthy children from birth to adolescence. Clin Chim Acta 1998; 274: 15–27. https://doi.org/10.1016/s0009-8981(98)00044-8. Search in Google Scholar
49. Gomez, RA, Lynch, KR, Sturgill, BC, Elwood, JP, Chevalier, RL, Carey, RM, et al. Distribution of renin mRNA and its protein in the developing kidney. Am J Physiol Physiol 1989; 257: F850–8. https://doi.org/10.1152/ajprenal.1989.257.5.f850. Search in Google Scholar
© 2020 Walter de Gruyter GmbH, Berlin/Boston