Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Renin Angiotensin Aldosterone Syst. Author manuscript; available in PMC 2010 March 31.
Published in final edited form as:
PMCID: PMC2848168

Disordered aldosterone-volume relationship in end-stage kidney disease



Sodium loading, and subsequent volume expansion, suppresses aldosterone levels in individuals with normal renal function. We hypothesised that loss of renal function impairs this volume-aldosterone relationship.

Materials and methods

With multifrequency bioimpedance spectroscopy, we measured total body water (TBW), extracellular volume (ECV), and intracellular volume in five haemodialysis patients at varied states of hydration and in five healthy volunteers during low-, normal-, and high-salt diets. Serum aldosterone, potassium, and C-reactive protein were measured simultaneously. Scatterplots and general estimating equations were used to examine the relationship among these variables.


In healthy volunteers with salt loading, and in haemodialysis subjects with increased inter-dialytic weight gain, expansion of ECV led to reciprocal declines in serum aldosterone concentrations. The relationship was more profound in healthy volunteers (p<0.001) than in haemodialysis subjects (p=0.1). Notably, haemodialysis subjects posted consistently higher levels of ECV (median 49.6% TBW, IQR 43.9–51.8% compared to 41.1%, 39.9–42.8% in volunteers) and serum aldosterone (median 26.7 ng/dl, IQR 19.8–29.6 compared to 12.4 ng/dl, 8.8–16.0 in volunteers). Serum potassium did not appear to influence aldosterone concentration (p=0.9).


The shift of the volume-aldosterone curve in haemodialysis subjects suggests that end-stage kidney disease is a state of high volume and inappropriately high aldosterone. These data have important clinical implications, as dialysis patients may benefit from both volume reduction and mineralocorticoid receptor blockade.

Keywords: aldosterone, chronic kidney disease, extracellular volume, haemodialysis, mineralocorticoid receptor blockers


Advances in non-invasive bioimpedance techniques allow accurate measurements of extracellular volume (ECV) among subjects with and without chronic kidney disease, including dialysis-dependent patients.1-3 The ability to objectively assess ECV should provide opportunities to improve the health of end-stage kidney disease (ESKD) patients by attaining physiologic dry weight and optimising blood pressure targets.4-6 Bioimpedance measurements can also serve as important research tools.7

In a seminal study performed more than 30 years ago, Brunner et al. demonstrated that 24-hour urine aldosterone levels were suppressed in subjects with high 24-hour urine sodium levels.8 These measurements – and their resultant aldosterone-sodium curves (figure 1A) – proved crucial for diagnosing hyperaldosterone states in which sodium loading did not result in appropriately suppressed aldosterone levels. An inherent assumption in these curves, which has yet to be formally tested, is that sodium excretion, a valid marker of sodium intake during steady state, also serves as a marker of ECV.

Figure 1
The relationship between aldosterone and sodium intake predicts similar curves for aldosterone and extracellular volume (ECV) measurements. The aldosterone-sodium curves (A) are adapted from the study by Brunner et al.,8 and serve as a model for our proposed ...

Using whole body bioimpedance, we studied healthy volunteers on low-, normal-, and high-salt diets, and maintenance haemodialysis subjects pre-ultrafiltration at varying degrees of inter-dialytic weight gain, to replace the classic sodium-aldosterone curves with ECV-aldosterone curves. We hypothesised that ECV elevations would lead to reductions in serum aldosterone for both healthy volunteers and haemodialysis subjects, but that this relationship would occur at higher volumes and higher aldosterone concentrations for the haemodialysis subjects. In other words, we hypothesised that the volume-aldosterone curve would ‘shift to the right’ as renal function declined (figure 1B).9



Five clinically-stable, long-term (i.e. vintage ≥ one year) haemodialysis patients from the outpatient dialysis units of the University of North Carolina Kidney Center, believed to be at variable levels of hydration, were enrolled in this study. Exclusion criteria were age < 10 or > 80 years, significant residual renal function (defined as urine output > 250 ml/day), hospitalisation within the last three months, myocardial infarction or stroke in the preceding six months, congestive heart failure (defined by ejection fraction < 40%), simultaneous participation in another clinical study, pregnancy, amputation of a limb, and presence of a pacemaker, implantable defibrillator, or artificial joint.

Five healthy volunteers were simultaneously enrolled. Inclusion criteria for entering the volunteer study protocol were age ≥ 18 and ≤ 65 years, no known past medical history, no chronic prescription medications, and ability to collect three 24-hour urine samples over a 10-day period. We excluded volunteers with systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg, estimated glomerular filtration rate (calculated from serum creatinine) < 60 ml/min/1.73 m2, and body mass index > 30 kg/m2. All haemodialysis subjects and healthy volunteers provided informed consent for study procedures approved by the Institutional Review Board of the University of North Carolina.

Study procedures

We measured total body water (TBW), ECV, and intracellular volume (ICV) on five haemodialysis patients, every other week for 12 weeks, using a whole body (wrist to ankle) multifrequency bioimpedance spectroscopy (BIS) system (Xitron 4200). The measurements were done within the first five minutes of a routine haemodialysis session, before initiating ultrafiltration, and followed established methods of whole body BIS measurement; extracellular and intracellular resistance were calculated based on the Cole-Cole model with the raw data of resistance and reactance from 5 kHz to 1000 kHz as described elsewhere.1,10,11 Xitron software then converted resistance values to ECV and ICV; TBW was the sum of ECV and ICV values. Measurements of ECV and ICV were then converted to a percentage of TBW; measurements in litres are not considered a valid outcome without an internal, directly measured referent (TBW), as body habitus between subjects is variable. Blood samples were drawn concomitantly with half of the BIS analyses (approximately every four weeks). Serum was frozen for aldosterone assays but immediately sent for potassium and C-reactive protein measurements. No dietary or inter-dialytic weight gain recommendations were made for the dialysis subjects. No changes were made to the subjects' dialysis prescriptions, including no change in ultrafiltration goals or rates (beyond holding ultrafiltration until after completion of the bioimpedance measurements). Dialysate sodium concentration was standard (rather than modelled) for all subjects during the study period.

We performed similar BIS measurements for TBW, ECV, and ICV alongside aldosterone collections on five healthy volunteers during a 10-day period. The first measurements were done after a 24-hour period of urine collection for sodium excretion to establish baseline dietary salt intake and presumed euvolaemic measurements. The second measurements were done after a four-day period of low-salt intake during which subjects were encouraged to consume < 50 mmol/d (1.2 g/d) sodium. The third measurements were done after a four-day period of high-salt intake during which subjects were encouraged to consume > 150 mmol/d (3.6 g/d) sodium. Twenty-four-hour urine collections for sodium excretion were performed during the fourth day of low- and high-salt diets. The degree of salt loading in our healthy volunteers was milder than that employed in the experiments by Titze and colleagues that suggested osmotically inactive sodium storage in the skin or bone.12-14 Therefore, salt loading in the volunteers should be confined to the extracellular space and reflected in the BIS measurements of ECV.

All blood collections for aldosterone were done prior to 10 a.m. after subjects had been supine for a minimum of five minutes. Two serum samples for each study session were prepared and frozen at −20°C. Serum aldosterone concentrations (ng/dl) were determined by enzyme immunoassay according to the manufacturer's instructions (Alpco Diagnostics, available at

Data analyses

All analyses and plots were performed separately for healthy volunteers and haemodialysis subjects using STATA version 9.2 (StataCorp, Texas, USA). Scatterplots were created to visually compare changes in aldosterone concentrations versus changes in ECV measurements. To account for repeated measurements, we used generalised estimating equation (GEE) models with robust standard error and an exchangeable correlation matrix to evaluate the degree of influence ECV had on aldosterone values. Because the original sodium-aldosterone curves and our own scatterplots for ECV-volume did not perfectly follow linear relationships, we repeated our GEE models using power transformations of aldosterone (aldosterone0.5 and aldosterone2). Scatterplots and GEE modelling were similarly used to examine the effect of serum potassium on aldosterone levels, and the effect of ECV and aldosterone on C-reactive protein levels. Two-sided hypotheses tests with a 5% type I error were adopted for all statistical inferences.


All subjects completed the study protocol without interruption or complications. The healthy volunteers were all male, with median age 38 years (range 32–62). The mean 24-hour urine sodium for the healthy volunteers was 28.6±25.2 mmol/d during the low-salt phase and 173.0±60.3 mmol/d during the high-salt phase. The dialysis subjects consisted of two males and three females, with median age 50 years (range 11–80). None were diabetic, and all had body mass indices below 30 kg/m2. Inter-dialytic weight gain during the study period for these subjects ranged from 0.7 to 4.1 kg (median 2.7, IQR 2.0–3.3).

ECV (expressed as % of TBW) increased in healthy volunteers with greater amounts of salt in the diet (range 32.6–46.8% TBW) and in haemodialysis subjects with greater amounts of inter-dialytic weight gain (range 41.7–54.5% TBW) (Table 1). In healthy volunteers, ECV expansion clearly led to reductions in serum aldosterone concentrations (figure 2A). We ran three GEE models of aldosterone, aldosterone0.5, and aldosterone2 versus ECV. These yielded beta-coefficients (95% CIs, p values) of −130.7 (−167.7731, −93.53762, p<0.001), −18.2 (−26.3, −10.0, p<0.001), and −4,040.8 (−4,653.5, −3,428.1, p<0.001), respectively. In haemodialysis subjects, a similar trend towards lower aldosterone levels at higher states of ECV was observed (figure 2B). GEE models of aldosterone, aldosterone0.5, and aldosterone2 versus ECV yielded beta-coefficients (95% CIs, p values) of −99.4 (−218.1, 19.4, p=0.1), −10.1 (−22.6, 2.3, p=0.1), and −4,952.6 (−10,670.6, 765.4, p=0.09), respectively. Overall, compared to the healthy volunteers, haemodialysis subjects clearly demonstrated both higher ECV (median 49.6% TBW, IQR 43.9–51.8% TBW versus median 41.1% TBW, IQR 39.9–42.8%) and serum aldosterone measurements (median 26.7 ng/dl, IQR 19.8–29.6 ng/dl versus median 12.4 ng/dl, IQR 8.8–16.0 ng/dl) (figures 2C and 2D).

Figure 2
Scatterplots of serum aldosterone levels and extracellular volume (ECV) measurements in healthy volunteers and haemodialysis subjects. Volume expansion during high-salt diets clearly suppressed aldosterone levels in the healthy volunteers (A), and a similar ...
Table 1
Whole body bioimpedance measurements of healthy volunteers (A) and haemodialysis subjects (B) at time of aldosterone measurements.

Serum potassium was generally well controlled in the haemodialysis subjects (median 5.0 mmol/L, range 3.8–6.2 mmol/L) and did not, in GEE models, influence aldosterone concentrations (p=0.9) (figure 3). Approximately 75% of C-reactive protein levels in the haemodialysis subjects were above 1.0 mg/L, the upper limit of normal for this assay, and were more influenced by aldosterone concentrations (p<0.001) than ECV measurements (p=0.2) (figure 4).

Figure 3
In haemodialysis subjects, serum potassium did not appear to influence serum aldosterone levels.
Figure 4
In haemodialysis subjects, C-reactive protein tended to increase with volume expansion but decrease with elevations in aldosterone. In the setting of expanded volume, aldosterone's actions at non-epithelial mineralocorticoid receptors are pro-inflammatory. ...


In this study, we used multifrequency BIS to measure ECV in five healthy volunteers on low-, normal-, and high-salt diets and in five haemodialysis subjects at various states of inter-dialytic weight gain. Serum aldosterone concentrations were drawn simultaneously, allowing us to construct volume-aldosterone curves that updated similar sodium-aldosterone curves created more than 30 years ago. The curves confirm that in individuals with normal renal function, 24-hour urinary sodium excretion is a reasonable surrogate marker for ECV status, and ECV expansion leads to suppression of aldosterone secretion. More importantly, the shift of the volume-aldosterone curve seen in the haemodialysis subjects suggests that ESKD is a state of high volume and inappropriately high aldosterone for this degree of volume expansion. These results have significant clinical implications.

Despite advances in the diagnosis and management of kidney disease, mortality rates for patients on haemodialysis remains as high as 20–25% at one year and 50–60% at five years.15 Cardiovascular disease accounts for the majority of these deaths, with sudden cardiac death being the leading cause.16,17 In the last decade, two landmark clinical trials have demonstrated that mineralocorticoid receptor blockade with spironolactone or eplerenone significantly reduces mortality in patients with advanced congestive heart failure.18,19 Notably, the mineralocorticoid receptor blockade doses used in these trials were relatively low, suggesting that the benefits of therapy were due not to blood pressure reduction or diuresis, but rather due to blockade of aldosterone's non-epithelial, pro-inflammatory, pro-fibrotic effects on the heart.20,21 These non-epithelial effects of aldosterone are exaggerated in conditions, such as congestive heart failure, of elevated aldosterone levels and expanded ECV.22

We hypothesised that patients with chronic and ESKD similarly manifest relative hyperaldosteronaemic and hypervolaemic states, which become more pronounced as renal function deteriorates.9 The volume-aldosterone curves constructed in this study support this hypothesis. While volume (and apparently not potassium) influences aldosterone concentrations to a similar, albeit less rigorous, degree in ESKD as it does in normal renal function, the suppression is nonetheless inadequate and incomplete. Despite clear and objective evidence of volume expansion, the haemodialysis subjects posted only five of 30 (16.7%) serum aldosterone concentrations under 15 ng/dl, generally considered the upper limit of normal serum aldosterone measurements.23 In other words, haemodialysis subjects may be seen as chronically failing volume suppression tests (as would be used to diagnose primary aldosteronism). In ESKD, hyperaldosteronism in the high volume state leads to activation of non-epithelial mineralocorticoid receptors, promoting vascular inflammation and fibrosis.24,25

A recent study using bioimpedance to measure ECV found that overhydration was an important and independent predictor of mortality in maintenance dialysis patients.26 This study comes almost two decades after hypertension control without medication was shown to be the best single marker of survival in haemodialysis patients.27 Therefore, nephrologists are keenly aware that expanded ECV is a major contributor to the high rates of cardiovascular morbidity and mortality in ESKD. Yet the discussion has heretofore centred primarily on blood pressure.28,29 In our opinion, this has led to an unfortunate neglect of the inflammatory role of aldosterone in these high volume states.

This is not the first study to demonstrate that ESKD patients have abnormally high aldosterone levels.30-35 Our study, however, is the first to objectively measure ECV alongside these aldosterone levels, and thus the first to demonstrate that expansion of ECV does suppress aldosterone concentration in ESKD, albeit suboptimally and to still inappropriately high levels. The resultant high volume-high aldosterone state may be a pro-inflammatory condition that explains, in part, the large burden of cardiovascular disease in this population.33 In this study, we used C-reactive protein levels as a crude marker of inflammation. While C-reactive protein levels tended to increase with ECV expansion, they clearly decreased with higher aldosterone concentration; we thus propose that volume status plays a larger role than aldosterone concentration in determining the pro-inflammatory activation of non-epithelial mineralocorticoid receptors.

Obviously, these results are meant to fuel discussion about potential therapeutic decisions. The expanded ECV measurements demonstrated here and in other studies of haemodialysis patients clearly argue for a re-evaluation of current practice patterns regarding dietary sodium counselling, ultrafiltration goals, and overall estimation of dry weight.6,26,36 Moreover, the markedly elevated aldosterone levels seen in ESKD suggest that mineralocorticoid receptor blockade could emerge as a crucial therapeutic intervention.37 Indeed, already a number of small studies (and at least three more ongoing or recently completed studies) have looked at whether low doses of mineralocorticoid receptor blockade are safe in ESKD patients, for whom the intratubular potassium-sparing effects should be scant (in oliguria) to none (in anuria).34,38-41

Our study, which is limited by its small size and exploratory design, should be interpreted as a hypothesis-forwarding rather than hypothesis-confirming experiment. Of note, had we enrolled diabetic and/or obese subjects, we may have seen more extreme levels of aldosterone (both low and high) given the potential for hyporeninaemia in diabetes and hyperaldosteronism in obesity and the metabolic syndrome.42-44 Further investigations are needed that incorporate a larger number of dialysis subjects, with and without known congestive heart failure, and a more sensitive marker of inflammation and cardiovascular disease risk than C-reactive protein levels. Nonetheless, we feel that the ECV-aldosterone curves constructed in this study should have major clinical implications, providing a new route by which nephrologists can approach the tremendous burden of cardiovascular disease in the haemodialysis population. This study begins to lay the groundwork for clinical trials testing whether low-dose mineralocorticoid receptor blockade, a widely used and effective therapy in congestive heart failure, can reduce mortality in haemodialysis patients.


We are grateful to David Barrow, PhD, and the Bioanalytical Core Labs of the UNC Clinical and Translational Research Center for assistance with the aldosterone measurements. We also thank Stephen Marshall, PhD, for guidance with statistical analyses in this study.

Disclosures: Funding for this study was provided by a pilot grant from the Renal Research Institute, LLC (New York, NY, USA).



1. De Lorenzo A, Andreoli A, Matthie J, Withers P. Predicting body cell mass with bioimpedance by using theoretical methods: a technological review. J Appl Physiol. 1997;82:1542–58. [PubMed]
2. Levin NW, Zhu F, Seibert E, Ronco C, Kuhlmann MK. Use of segmental multifrequency bioimpedance spectroscopy in hemodialysis. Contrib Nephrol. 2005;149:162–7. [PubMed]
3. Zhu F, Wystrychowski G, Kitzler T, Thijssen S, Kotanko P, Levin NW. Application of bioimpedance techniques to peritoneal dialysis. Contrib Nephrol. 2006;150:119–28. [PubMed]
4. Kotanko P, Levin NW, Zhu F. Current state of bioimpedance technologies in dialysis. Nephrol Dial Transplant. 2008;23:808–12. [PubMed]
5. Kuhlmann MK, Zhu F, Seibert E, Levin NW. Bioimpedance, dry weight and blood pressure control: new methods and consequences. Curr Opin Nephrol Hypertens. 2005;14:543–9. [PubMed]
6. Wabel P, Chamney P, Moissl U, Jirka T. Importance of whole-body bioimpedance spectroscopy for the management of fluid balance. Blood Purif. 2009;27:75–80. [PMC free article] [PubMed]
7. Tattersall J. Bioimpedance analysis in dialysis: state of the art and what we can expect. Blood Purif. 2009;27:70–4. [PubMed]
8. Brunner HR, Laragh JH, Baer L, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972;286:441–9. [PubMed]
9. Klemmer PJ, Bomback AS. Extracellular volume and aldosterone interaction in chronic kidney disease. Blood Purif. 2009;27:92–8. [PubMed]
10. Cole KS, Cole RH. Dispersion and absorption in dielectrics. I: Alternating current characteristics. J Chem Phys. 1941;9:341–51.
11. Piccoli A, Pastori G, Guizzo M, Rebeschini M, Naso A, Cascone C. Equivalence of information from single versus multiple frequency bioimpedance vector analysis in hemodialysis. Kidney Int. 2005;67:301–13. [PubMed]
12. Titze J, Shakibaei M, Schafflhuber M, et al. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol. 2004;287:H203–08. [PubMed]
13. Titze J, Lang R, Ilies C, et al. Osmotically inactive skin Na+ storage in rats. Am J Physiol Renal Physiol. 2003;285:F1108–17. [PubMed]
14. Titze J, Maillet A, Lang R, et al. Long-term sodium balance in humans in a terrestrial space station simulation study. Am J Kidney Dis. 2002;40:508–16. [PubMed]
15. US Renal Data System, USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda, MD: 2006.
16. Ritz E, Wanner C. The challenge of sudden death in dialysis patients. Clin J Am Soc Nephrol. 2008;3:920–9. [PubMed]
17. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305. [PubMed]
18. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17. [PubMed]
19. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21. [PubMed]
20. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345:1689–97. [PubMed]
21. Brown NJ. Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens. 2005;14:235–41. [PubMed]
22. Sato A, Saruta T. Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res. 2004;27:303–10. [PubMed]
23. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:3266–81. [PubMed]
24. Struthers AD. Aldosterone-induced vasculopathy. Mol Cell Endocrinol. 2004;217:239–41. [PubMed]
25. Struthers AD. Aldosterone in heart failure: pathophysiology and treatment. Curr Heart Fail Rep. 2004;1:171–5. [PubMed]
26. Wizemann V, Wabel P, Chamney P, et al. The mortality risk of overhydration in haemodialysis patients. Nephrol Dial Transplant. 2009;24:1574–9. [PMC free article] [PubMed]
27. Charra B, Calemard E, Ruffet M, et al. Survival as an index of adequacy of dialysis. Kidney Int. 1992;41:1286–91. [PubMed]
28. Charra B, Chazot C. Volume control, blood pressure and cardiovascular function. Lessons from hemodialysis treatment. Nephron Physiol. 2003;93:94–101. [PubMed]
29. Agarwal R, Alborzi P, Satyan S, Light RP. Dry-weight reduction in hypertensive hemodialysis patients (DRIP): a randomized, controlled trial. Hypertension. 2009;53:500–07. [PMC free article] [PubMed]
30. Cooke CR, Horvath JS, Moore MA, Bledsoe T, Walker WG. Modulation of plasma aldosterone concentration by plasma potassium in anephric man in the absence of a change in potassium balance. J Clin Invest. 1973;52:3028–32. [PMC free article] [PubMed]
31. Cooke CR, Ruiz-Maza F, Kowarski A, Migeon CJ, Walker WG. Regulation of plasma aldosterone concentration in anephric man and renal transplant recipients. Kidney Int. 1973;3:160–6. [PubMed]
32. Hene RJ, Boer P, Koomans HA, Mees EJ. Plasma aldosterone concentrations in chronic renal disease. Kidney Int. 1982;21:98–101. [PubMed]
33. Sato A, Funder JW, Saruta T. Involvement of aldosterone in left ventricular hypertrophy of patients with end-stage renal failure treated with hemodialysis. Am J Hypertens. 1999;12:867–73. [PubMed]
34. Gross E, Rothstein M, Dombek S, Juknis HI. Effect of spironolactone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric hemodialysis patients. Am J Kidney Dis. 2005;46:94–101. [PubMed]
35. Kohagura K, Higashiuesato Y, Ishiki T, et al. Plasma aldosterone in hypertensive patients on chronic hemodialysis: distribution, determinants and impact on survival. Hypertens Res. 2006;29:597–604. [PubMed]
36. Lin YP, Yu WC, Hsu TL, Ding PY, Yang WC, Chen CH. The extracellular fluid-to-intracellular fluid volume ratio is associated with large-artery structure and function in hemodialysis patients. Am J Kidney Dis. 2003;42:990–9. [PubMed]
37. Covic A, Gusbeth-Tatomir P, Goldsmith DJ. Is it time for spironolactone therapy in dialysis patients? Nephrol Dial Transplant. 2006;21:854–8. [PubMed]
38. McLaughlin N, Gehr TW, Sica DA. Aldosterone-receptor antagonism and end-stage renal disease. Curr Hypertens Rep. 2004;6:327–30. [PubMed]
39. Saudan P, Mach F, Perneger T, et al. Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol Dial Transplant. 2003;18:2359–63. [PubMed]
40. Nitta K, Akiba T, Nihei H. Aldosterone blockade and vascular calcification in hemodialysis patients. Am J Med. 2003;115:250. [PubMed]
41. Hussain S, Dreyfus DE, Marcus RJ, Biederman RW, McGill RL. Is spironolactone safe for dialysis patients? Nephrol Dial Transplant. 2003;18:2364–8. [PubMed]
42. Perez GO, Lespier L, Jacobi J, et al. Hyporeninemia and hypoaldosteronism in diabetes mellitus. Arch Intern Med. 1977;137:852–5. [PubMed]
43. Krug AW, Ehrhart-Bornstein M. Aldosterone and metabolic syndrome: is increased aldosterone in metabolic syndrome patients an additional risk factor? Hypertension. 2008;51:1252–8. [PubMed]
44. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, et al. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A. 2003;100:14211–16. [PubMed]