Obesity and obesity-associated kidney injuries have played an important role in the rising prevalence of chronic kidney disease (CKD). The link between obesity and kidney disease begins with obesity’s well-known associations with diabetes and hypertension, the two leading etiologies of CKD. However, a growing body of evidence suggests that elevated aldosterone levels and expanded extracellular volume are key components of obesity-induced renal disease via aldosterone’s non-epithelial effects on the kidney. Highlighting these blood pressure- and diabetes-independent mechanisms of kidney injury in obesity allows an exploration of whether mineralocorticoid receptor blockade, coupled with weight loss and salt restriction, is an optimal treatment for overweight CKD patients.

1.
Centers for Disease Control and Prevention (CDC): Prevalence of chronic kidney disease and associated risk factors – United States, 1999–2004. MMWR Morb Mortal Wkly Rep 2007;56:161–165.
2.
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS: Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038–2047.
3.
Hallan SI, Vikse BE: Relationship between chronic kidney disease prevalence and end-stage renal disease risk. Curr Opin Nephrol Hypertens 2008;17:286–291.
4.
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM: Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295:1549–1555.
5.
Ford ES: Prevalence of the metabolic syndrome defined by the international diabetes federation among adults in the US. Diabetes Care 2005;28:2745–2749.
6.
Anderson JW, Kendall CW, Jenkins DJ: Importance of weight management in type 2 diabetes: review with meta-analysis of clinical studies. J Am Coll Nutr 2003;22:331–339.
7.
Praga M: Obesity – a neglected culprit in renal disease. Nephrol Dial Transplant 2002;17:1157–1159.
8.
Hall JE, Henegar JR, Dwyer TM, Liu J, Da Silva AA, Kuo JJ, Tallam L: Is obesity a major cause of chronic kidney disease? Adv Ren Replace Ther 2004;11:41–54.
9.
Ejerblad E, Fored CM, Lindblad P, Fryzek J, McLaughlin JK, Nyren O: Obesity and risk for chronic renal failure. J Am Soc Nephrol 2006;17:1695–1702.
10.
Wahba IM, Mak RH: Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. Clin J Am Soc Nephrol 2007;2:550–562.
11.
Cignarelli M, Lamacchia O: Obesity and kidney disease. Nutr Metab Cardiovasc Dis 2007;17:757–762.
12.
Griffin KA, Kramer H, Bidani AK: Adverse renal consequences of obesity. Am J Physiol Renal Physiol 2008;294:F685–F696.
13.
Muntner P, Winston J, Uribarri J, Mann D, Fox CS: Overweight, obesity, and elevated serum cystatin C levels in adults in the United States. Am J Med 2008;121:341–348.
14.
Elsayed EF, Sarnak MJ, Tighiouart H, Griffith JL, Kurth T, Salem DN, Levey AS, Weiner DE: Waist-to-hip ratio, body mass index, and subsequent kidney disease and death. Am J Kidney Dis 2008;52:29–38.
15.
Bavbek N, Isik B, Kargili A, Uz E, Uz B, Kanbay M, Turgut F, Karakurt F, Akcay A: Association of obesity with inflammation in occult chronic kidney disease. J Nephrol 2008;21:761–767.
16.
Ryu S, Chang Y, Woo HY, Kim SG, Kim DI, Kim WS, Suh BS, Choi NK, Lee JT: Changes in body weight predict CKD in healthy men. J Am Soc Nephrol 2008;19:1798–1805.
17.
Serra A, Romero R, Lopez D, Navarro M, Esteve A, Perez N, Alastrue A, Ariza A: Renal injury in the extremely obese patients with normal renal function. Kidney Int 2008;73:947–955.
18.
Bagby SP: Obesity-initiated metabolic syndrome and the kidney: a recipe for chronic kidney disease? J Am Soc Nephrol 2004;15:2775–2791.
19.
Rasouli N, Kern PA: Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 2008;93:S64–S73.
20.
Yano Y, Hoshide S, Ishikawa J, Hashimoto T, Eguchi K, Shimada K, Kario K: Differential impacts of adiponectin on low-grade albuminuria between obese and nonobese persons without diabetes. J Clin Hypertens (Greenwich) 2007;9:775–782.
21.
Sharma K, Ramachandrarao S, Qiu G, Usui HK, Zhu Y, Dunn SR, Ouedraogo R, Hough K, McCue P, Chan L, Falkner B, Goldstein BJ: Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008;118:1645–1656.
22.
Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD: Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 2001;59:1498–1509.
23.
Epstein M: Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am J Kidney Dis 2001;37:677–688.
24.
Hostetter TH, Ibrahim HN: Aldosterone in chronic kidney and cardiac disease. J Am Soc Nephrol 2003;14:2395–2401.
25.
Sato A, Saruta T: Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res 2004;27:303–310.
26.
Greene EL, Kren S, Hostetter TH: Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996;98:1063–1068.
27.
Rocha R, Chander PN, Zuckerman A, Stier CT Jr: Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension 1999;33:232–237.
28.
Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler GK: Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology 2000;141:3871–3878.
29.
Hollenberg NK: Aldosterone in the development and progression of renal injury. Kidney Int 2004;66:1–9.
30.
Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mannelli M, Matterello MJ, Montemurro D, Palumbo G, Rizzoni D, Rossi E, Pessina AC, Mantero F: Renal damage in primary aldosteronism: results of the PAPY study. Hypertension 2006;48:232–238.
31.
Pimenta E, Gaddam KK, Pratt-Ubunama MN, Nishizaka MK, Aban I, Oparil S, Calhoun DA: Relation of dietary salt and aldosterone to urinary protein excretion in subjects with resistant hypertension. Hypertension 2008;51:339–344.
32.
Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, Calhoun DA: Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med 2008;168:1159–1164.
33.
Klemmer PJ, Bomback AS: Extracellular volume and aldosterone interaction in chronic kidney disease. Blood Purif 2009;27:92–98.
34.
Goodfriend TL, Egan BM, Kelley DE: Aldosterone in obesity. Endocr Res 1998;24:789–796.
35.
Bochud M, Nussberger J, Bovet P, Maillard MR, Elston RC, Paccaud F, Shamlaye C, Burnier M: Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension 2006;48:239–245.
36.
Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH, Garg R: Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab 2007;92:4472–4475.
37.
Krug AW, Ehrhart-Bornstein M: Aldosterone and metabolic syndrome: is increased aldosterone in metabolic syndrome patients an additional risk factor? Hypertension 2008;51:1252–1258.
38.
Rossi GP, Belfiore A, Bernini G, Fabris B, Caridi G, Ferri C, Giacchetti G, Letizia C, Maccario M, Mannelli M, Palumbo G, Patalano A, Rizzoni D, Rossi E, Pessina AC, Mantero F: Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. J Clin Endocrinol Metab 2008;93:2566–2571.
39.
Mule G, Nardi E, Cusimano P, Cottone S, Seddio G, Geraci C, Palermo A, Andronico G, Cerasola G: Plasma aldosterone and its relationships with left ventricular mass in essential hypertensive patients with the metabolic syndrome. Am J Hypertens 2008;21:1055–1061.
40.
Tuck ML, Sowers J, Dornfeld L, Kledzik G, Maxwell M: The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981;304:930–933.
41.
Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM: Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005;45:356–362.
42.
Engeli S, Sharma AM: The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension. J Mol Med 2001;79:21–29.
43.
Sharma AM, Engeli S, Pischon T: New developments in mechanisms of obesity-induced hypertension: role of adipose tissue. Curr Hypertens Rep 2001;3:152–156.
44.
Goodfriend TL, Ball DL, Egan BM, Campbell WB, Nithipatikom K: Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion. Hypertension 2004;43:358–363.
45.
Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg HS, Barthel A, Hauner H, McCann SM, Scherbaum WA, Bornstein SR: Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci USA 2003;100:14211–14216.
46.
Jeon JH, Kim KY, Kim JH, Baek A, Cho H, Lee YH, Kim JW, Kim D, Han SH, Lim JS, Kim KI, Yoon do Y, Kim SH, Oh GT, Kim E, Yang Y: A novel adipokine CTRP1 stimulates aldosterone production. FASEB J 2008;22:1502–1511.
47.
Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF Jr, Montori VM: Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:3266–3281.
48.
Rocchini AP, Katch V, Kveselis D, Moorehead C, Martin M, Lampman R, Gregory M: Insulin and renal sodium retention in obese adolescents. Hypertension 1989;14:367–374.
49.
Nosadini R, Sambataro M, Thomaseth K, Pacini G, Cipollina MR, Brocco E, Solini A, Carraro A, Velussi M, Frigato F, et al: Role of hyperglycemia and insulin resistance in determining sodium retention in non-insulin-dependent diabetes. Kidney Int 1993;44:139–146.
50.
Chagnac A, Herman M, Zingerman B, Erman A, Rozen-Zvi B, Hirsh J, Gafter U: Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol Dial Transplant 2008;23:3946–3952.
51.
Hall JE, Brands MW, Hildebrandt DA, Mizelle HL: Obesity-associated hypertension. Hyperinsulinemia and renal mechanisms. Hypertension 1992;19:I45–I55.
52.
Vogt B, Bochud M, Burnier M: The association of aldosterone with obesity-related hypertension and the metabolic syndrome. Semin Nephrol 2007;27:529–537.
53.
Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J: End-stage renal disease in African-American and white men. 16-year MRFIT findings. JAMA 1997;277:1293–1298.
54.
Flack JM, Ferdinand KC, Nasser SA: Epidemiology of hypertension and cardiovascular disease in African Americans. J Clin Hypertens (Greenwich) 2003;5:5–11.
55.
Grim CE, Cowley AW Jr, Hamet P, Gaudet D, Kaldunski ML, Kotchen JM, Krishnaswami S, Pausova Z, Roman R, Tremblay J, Kotchen TA: Hyperaldosteronism and hypertension: ethnic differences. Hypertension 2005;45:766–772.
56.
Kidambi S, Kotchen JM, Grim CE, Raff H, Mao J, Singh RJ, Kotchen TA: Association of adrenal steroids with hypertension and the metabolic syndrome in blacks. Hypertension 2007;49:704–711.
57.
Kotchen TA, Kotchen JM, Grim CE, Krishnaswami S, Kidambi S: Aldosterone and alterations of hypertension-related vascular function in African Americans. Am J Hypertens 2009;22:319–324.
58.
Navaneethan SD, Yehnert H, Beddhu S: Bariatric surgery in chronic kidney disease: does it halt progression? J Am Soc Nephrol 2008;19:528A.
59.
Agrawal V, Khan I, Rai B, Krause KR, Chengelis DL, Zalesin KC, Rocher LL, McCullough PA: The effect of weight loss after bariatric surgery on albuminuria. Clin Nephrol 2008;70:194–202.
60.
Agrawal V, Krause KR, Chengelis DL, Zalesin KC, Rocher LL, McCullough PA: Relation between degree of weight loss after bariatric surgery and reduction in albuminuria and C-reactive protein. Surg Obes Relat Dis 2009;5:20–26.
61.
Blanco S, Vaquero M, Gomez-Guerrero C, Lopez D, Egido J, Romero R: Potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in a model of type 2 diabetes mellitus, obesity, and mild hypertension. Am J Hypertens 2005;18:557–565.
62.
de Paula RB, da Silva AA, Hall JE: Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 2004;43:41–47.
63.
Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, Fujita T: Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol 2006;17:3438–3446.
64.
Nagase M, Matsui H, Shibata S, Gotoda T, Fujita T: Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. Hypertension 2007;50:877–883.
65.
Nagase M, Fujita T: Aldosterone and glomerular podocyte injury. Clin Exp Nephrol 2008;12:233–242.
66.
Nowicki M, Muskala P, Bald E, Chwatko G: Nephroprotective effect of combined converting enzyme and aldosterone blockade in hypertensive patients with target organ damage is blood pressure-dependent. J Am Soc Nephrol 2003;14:21A.
67.
Morales E, Huerta A, Gutierrez-Solis E, Gutierrez E, Polanco N, Gutierrez-Millet V, Gonzalez E, Praga M: Antiproteinuric effect of renin-angiotensin-aldosterone system (RAAS) in obese patients. Which is the most effective option? J Am Soc Nephrol 2008;19:549A.
68.
Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, Benjamin EJ, Levy D: Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004;351:33–41.
69.
Frey FJ, Odermatt A, Frey BM: Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens 2004;13:451–458.
70.
Brunner HR, Laragh JH, Baer L, Newton MA, Goodwin FT, Krakoff LR, Bard RH, Buhler FR: Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 1972;286:441–449.
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