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01-12-2009 | Review

Role of aldosterone in the progression of chronic kidney disease and potential use of aldosterone blockade in children

Authors: Elaine Ku, Vito M. Campese

Published in: Pediatric Nephrology | Issue 12/2009

Abstract

Much focus has been placed on the role of the renin–angiotensin system as a mediator of the progression of chronic kidney disease. Novel therapeutic strategies to inhibit the negative impact of renin–angiotensin activation, including dual therapy with an angiotensin-converting enzyme inhibitor and an angiotensin-receptor blocker, have been suggested to achieve more complete disruption of the renin–angiotensin system. The role played by aldosterone, a target of angiotensin II, in the progression of chronic kidney disease has become a subject of significant interest over the past decade. Experimental studies in animals have shown that persistently elevated aldosterone levels lead to pathohistological changes in the kidney, along with renal and cardiac fibrosis. Incomplete suppression of aldosterone may, therefore, contribute to the deleterious effects of the renin–angiotensin system in the setting of chronic kidney disease. Clinical trials in adults have shown a potential role for mineralocorticoid receptor blockers to delay further the development of end-stage renal disease by completing renin–angiotensin blockade. In adults, mineralocorticoid receptor blockade produces a significant anti-proteinuric effect and has minimal risk of causing hyperkalemia if the condition of the patients is closely monitored. Further studies will need to be conducted to determine whether mineralocorticoid receptor blockers are equally effective and safe for the treatment of chronic kidney disease in children.

Ardissino G, Dacco V, Testa S, Bonaudo R, Claris-Appiani A, Taioli E, Marra G, Edefonti A, Sereni F (2003) Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics 111:e382–e387PubMed

Keane WF, Lyle PA (2003) Recent advances in management of type 2 diabetes and nephropathy: lessons from the RENAAL study. Am J Kidney Dis 41:S22–S25PubMed

Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G (1998) Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int 53:1209–1216PubMed

Simonetti GD, Santoro L, Ferrarini A, Crosazzo-Franscini L, Fossali E, Bianchetti MG (2007) Systemic hypertension and proteinuria in childhood chronic renal parenchymal disease: role of antihypertensive drug management. Paediatr Drugs 9:413–418PubMed

Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869PubMed

Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462PubMed

Ruggenenti P, Perna A, Remuzzi G (2003) Retarding progression of chronic renal disease: the neglected issue of residual proteinuria. Kidney Int 63:2254–2261PubMed

Ibrahim HN, Rosenberg ME, Hostetter TH (1997) Role of the renin–angiotensin–aldosterone system in the progression of renal disease: a critical review. Semin Nephrol 17:431–440PubMed

Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A (1981) Rise of plasma aldosterone during long-term captopril treatment. N Engl J Med 304:1110PubMed

10.

Shiigai T, Shichiri M (2001) Late escape from the antiproteinuric effect of ace inhibitors in nondiabetic renal disease. Am J Kidney Dis 37:477–483PubMed

11.

Simpson SA, Tait JF, Bush IE (1952) Secretion of a salt-retaining hormone by the mammalian adrenal cortex. Lancet 2:226–228PubMed

12.

Ahmad N, Romero DG, Gomez-Sanchez EP, Gomez-Sanchez CE (2004) Do human vascular endothelial cells produce aldosterone? Endocrinology 145:3626–3629PubMed

13.

Del Vecchio L, Procaccio M, Vigano S, Cusi D (2007) Mechanisms of disease: the role of aldosterone in kidney damage and clinical benefits of its blockade. Nat Clin Pract Nephrol 3:42–49PubMed

14.

Gomez-Sanchez EP, Ahmad N, Romero DG, Gomez-Sanchez CE (2005) Is aldosterone synthesized within the rat brain? Am J Physiol Endocrinol Metab 288:E342–E346PubMed

15.

Silvestre JS, Robert V, Heymes C, Aupetit-Faisant B, Mouas C, Moalic JM, Swynghedauw B, Delcayre C (1998) Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J Biol Chem 273:4883–4891PubMed

16.

Takeda Y, Miyamori I, Yoneda T, Hatakeyama H, Inaba S, Furukawa K, Mabuchi H, Takeda R (1996) Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin. J Clin Endocrinol Metab 81:2797–2800PubMed

17.

Remuzzi G, Cattaneo D, Perico N (2008) The aggravating mechanisms of aldosterone on kidney fibrosis. J Am Soc Nephrol 19:1459–1462PubMed

18.

Nagai Y, Miyata K, Sun GP, Rahman M, Kimura S, Miyatake A, Kiyomoto H, Kohno M, Abe Y, Yoshizumi M, Nishiyama A (2005) Aldosterone stimulates collagen gene expression and synthesis via activation of ERK1/2 in rat renal fibroblasts. Hypertension 46:1039–1045PubMed

19.

Lombes M, Alfaidy N, Eugene E, Lessana A, Farman N, Bonvalet JP (1995) Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart. Circulation 92:175–182PubMed

20.

Gomez-Sanchez EP (2004) Brain mineralocorticoid receptors: orchestrators of hypertension and end-organ disease. Curr Opin Nephrol Hypertens 13:191–196PubMed

21.

Todd-Turla KM, Schnermann J, Fejes-Toth G, Naray-Fejes-Toth A, Smart A, Killen PD, Briggs JP (1993) Distribution of mineralocorticoid and glucocorticoid receptor mRNA along the nephron. Am J Physiol Renal Physiol 264:F781–F791

22.

Brown NJ, Nakamura S, Ma L, Nakamura I, Donnert E, Freeman M, Vaughan DE, Fogo AB (2000) Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 58:1219–1227PubMed

23.

Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, Kondo S, Kiyomoto H, Shokoji T, Kimura S, Kohno M, Abe Y (2004) Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension 43:841–848PubMed

24.

Fullerton MJ, Funder JW (1994) Aldosterone and cardiac fibrosis: in vitro studies. Cardiovasc Res 28:1863–1867PubMed

25.

Lea WB, Kwak ES, Luther JM, Fowler SM, Wang Z, Ma J, Fogo AB, Brown NJ (2009) Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int. doi: 10.1038/ki.2009.9 PubMedPubMedCentral

26.

Chiga M, Rai T, Yang SS, Ohta A, Takizawa T, Sasaki S, Uchida S (2008) Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int 74:1403–1409PubMed

27.

Xue C, Siragy HM (2005) Local renal aldosterone system and its regulation by salt, diabetes, and angiotensin II type 1 receptor. Hypertension 46:584–590PubMed

28.

Ibrahim HN, Hostetter TH (2000) Role of dietary potassium in the hyperaldosteronism and hypertension of the remnant kidney model. J Am Soc Nephrol 11:625–631PubMed

29.

Foster RH, MacFarlane CH, Bustamante MO (1997) Recent progress in understanding aldosterone secretion. Gen Pharmacol 28:647–651PubMed

30.

Miller PL, Rennke HG, Meyer TW (1991) Glomerular hypertrophy accelerates hypertensive glomerular injury in rats. Am J Physiol Renal Physiol 261:F459–F465

31.

Sun Y, Zhang J, Zhang JQ, Ramires FJ (2000) Local angiotensin II and transforming growth factor-beta1 in renal fibrosis of rats. Hypertension 35:1078–1084PubMed

32.

Toto R, Palmer BF (2008) Rationale for combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor treatment and end-organ protection in patients with chronic kidney disease. Am J Nephrol 28:372–380PubMed

33.

Urata H, Nishimura H, Ganten D (1996) Chymase-dependent angiotensin II forming systems in humans. Am J Hypertens 9:277–284PubMed

34.

Sato A, Saruta T (2003) Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens 16:781–788PubMed

35.

Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, Fujita T (2006) Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol 17:3438–3446PubMed

36.

Bomback AS, Klemmer PJ (2007) The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 3:486–492PubMed

37.

Quan ZY, Walser M, Hill GS (1992) Adrenalectomy ameliorates ablative nephropathy in the rat independently of corticosterone maintenance level. Kidney Int 41:326–333PubMed

38.

Greene EL, Kren S, Hostetter TH (1996) Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 98:1063–1068PubMedPubMedCentral

39.

Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr (1998) Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension 31:451–458PubMed

40.

Rocha R, Chander PN, Zuckerman A, Stier CT Jr (1999) Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension 33:232–237PubMed

41.

Naruse M, Tanabe A, Sato A, Takagi S, Tsuchiya K, Imaki T, Takano K (2002) Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 40:28–33PubMed

42.

Taira M, Toba H, Murakami M, Iga I, Serizawa R, Murata S, Kobara M, Nakata T (2008) Spironolactone exhibits direct renoprotective effects and inhibits renal renin–angiotensin–aldosterone system in diabetic rats. Eur J Pharmacol 589:264–271PubMed

43.

MacFadyen RJ, Lee AF, Morton JJ, Pringle SD, Struthers AD (1999) How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 82:57–61PubMedPubMedCentral

44.

Sato A, Hayashi K, Naruse M, Saruta T (2003) Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41:64–68PubMed

45.

Lijnen P, Staessen J, Fagard R, Amery A (1982) Increase in plasma aldosterone during prolonged captopril treatment. Am J Cardiol 49:1561–1563PubMed

46.

Schjoedt KJ, Andersen S, Rossing P, Tarnow L, Parving HH (2004) Aldosterone escape during blockade of the renin–angiotensin–aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 47:1936–1939PubMed

47.

Chrysostomou A, Becker G (2001) Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med 345:925–926PubMed

48.

Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ (2006) Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 1:256–262PubMed

49.

Furumatsu Y, Nagasawa Y, Tomida K, Mikami S, Kaneko T, Okada N, Tsubakihara Y, Imai E, Shoji T (2008) Effect of renin–angiotensin–aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens Res 31:59–67PubMed

50.

Tylicki L, Rutkowski P, Renke M, Larczynski W, Aleksandrowicz E, Lysiak-Szydlowska W, Rutkowski B (2008) Triple pharmacological blockade of the renin–angiotensin–aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial. Am J Kidney Dis 52:486–493PubMed

51.

van den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D, Boomsma F (2006) Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens 24:2285–2292PubMed

52.

Fox CS, Larson MG, Hwang SJ, Leip EP, Rifai N, Levy D, Benjamin EJ, Murabito JM, Meigs JB, Vasan RS (2006) Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample. Kidney Int 69:2064–2069PubMed

53.

Pimenta E, Gaddam KK, Pratt-Ubunama MN, Nishizaka MK, Aban I, Oparil S, Calhoun DA (2008) Relation of dietary salt and aldosterone to urinary protein excretion in subjects with resistant hypertension. Hypertension 51:339–344PubMed

54.

Arima S, Kohagura K, Xu HL, Sugawara A, Abe T, Satoh F, Takeuchi K, Ito S (2003) Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol 14:2255–2263PubMed

55.

Bianchi S, Bigazzi R, Campese VM (2006) Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 70:2116–2123PubMed

56.

Bianchi S, Bigazzi R, Campese VM (2005) Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis 46:45–51PubMed

57.

Sato A, Hayashi K, Saruta T (2005) Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. Am J Hypertens 18:44–49PubMed

58.

Michea L, Vukusich A, Gonzalez M, Zehnder C, Marusic ET (2004) Effect of spironolactone on K(+) homeostasis and ENaC expression in lymphocytes from chronic hemodialysis patients. Kidney Int 66:1647–1653PubMed

59.

Saudan P, Mach F, Perneger T, Schnetzler B, Stoermann C, Fumeaux Z, Rossier M, Martin PY (2003) Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol Dial Transplant 18:2359–2363PubMed

60.

Gross E, Rothstein M, Dombek S, Juknis HI (2005) Effect of spironolactone on blood pressure and the renin–angiotensin–aldosterone system in oligo-anuric hemodialysis patients. Am J Kidney Dis 46:94–101PubMed

61.

Wuhl E, Mehls O, Schaefer F (2004) Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. Kidney Int 66:768–776PubMed

62.

Ardissino G, Vigano S, Testa S, Dacco V, Paglialonga F, Leoni A, Belingheri M, Avolio L, Ciofani A, Claris-Appiani A, Cusi D, Edefonti A, Ammenti A, Cecconi M, Fede C, Ghio L, La Manna A, Maringhini S, Papalia T, Pela I, Pisanello L, Ratsch IM (2007) No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy—report from the ItalKid Project database. Nephrol Dial Transplant 22:2525–2530PubMed

63.

Kaito H, Nozu K, Iijima K, Nakanishi K, Yoshiya K, Kanda K, Przybyslaw Krol R, Yoshikawa N, Matsuo M (2006) The effect of aldosterone blockade in patients with Alport syndrome. Pediatr Nephrol 21:1824–1829PubMed

64.

Buck ML (2005) Clinical experience with spironolactone in pediatrics. Ann Pharmacother 39:823–828PubMed

Title: Role of aldosterone in the progression of chronic kidney disease and potential use of aldosterone blockade in children
Authors: Elaine Ku
Vito M. Campese
Publication date: 01-12-2009
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 12/2009
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-009-1176-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of aldosterone in the progression of chronic kidney disease and potential use of aldosterone blockade in children

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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