QJM Advance Access published online on August 24, 2008
QJM, doi:10.1093/qjmed/hcn104
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Effect of serum albumin on serum sodium: necessity to consider the Donnan effect
Sir,In a recent issue of QJM, Kengne et al. defined the association between mild asymptomatic hyponatremia and bone fracture.1 However, the defined association might reflect the effect of hypoalbuminemia on bone fracture and incidental fall, because hyponatremia frequently associates with hypoalbuminemia and the association is probably causal.2,3 Depletion of effective circulatory volume in hypoalbuminemia triggers secretion of antidiuretic hormone, which can induce hyponatremia.3,4 Despite this causal association, not only the study by Kengne et al. but also several studies dealing with serum sodium did not include serum albumin as a variable in the analysis.1,5–7
Hyponatremia in association with hypoalbuminemia could be considered appropriate, if it were ‘ordered’ for the Donnan effect. In the Donnan equilibrium, the distribution of permeable ions between the vascular and interstitial compartments is affected by the impermeable ions, largely negative-charged albumin. Therefore, change of serum sodium proportional to change of serum albumin by the Donnan effect will not affect the ionic milieu in the interstitial compartment (Appendix 1). Interstitium is the compartment that surrounds the cells in each organ, and the proportional change of serum sodium could be considered ‘ordered’ rather than ‘disordered’, because it would not change the ionic milieu for the cells in each organ. The ‘ordered’ hyponatremia is not thought to induce attention and gait deficits. To judge whether the change is ‘ordered’ or ‘disordered’, complementation of serum sodium might be useful; addition and reduction of 2 mmol/l for serum sodium per 1 g/dl decrease and increase of serum albumin, respectively. The complemented serum sodium could indicate the real tonicity in interstitium.
In summary, serum sodium should be interpreted in association with serum albumin. The ‘ordered’ hyponatremia for hypoalbuminemia is thought to be not an electrolyte ‘disorder’ for the cells in each organ. It could be considered ‘ordered’, if change of serum sodium is proportional to change of serum albumin. The complemented serum sodium could indicate whether hyponatremia is ‘ordered’ or ‘disordered’.
According to the Donnan equilibrium, permeable ions between the vascular and interstitial compartments should be in the equation of
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To keep the ionic milieu of the interstitial compartment constant (C):
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Since sodium is the most abundant cationic ion in the vascular compartment, and 1 g/dl serum albumin is assumed to hold 
4 mEq/l of negative charge (plasma anion gap is 16 mEq/l when serum albumin concentration is 4 g/dl):
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Division of Nephrology, Hypertension &
Endocrinology
Department of Medicine
Tohoku University Graduate School of Medicine
Sendai, Miyagi
Japan
email: mtanemoto-tky{at}umin.ac.jp
References
1. Gankam KF, Andres C, Sattar L, Melot CDG. Mild hyponatremia and risk of fracture in the ambulatory elderly. Q J Med (2008) 101:583–8.[Web of Science]
2. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med (2006) 119:S30–5.[CrossRef][Web of Science][Medline]
3. Dandona P, Fonseca V, Baron DN. Hypoalbuminaemic hyponatraemia: a new syndrome? Br Med J (Clin Res Ed) (1985) 291:1253–5.[Medline]
4. Ferreira da Cunha D, Pontes MJ, Modesto dos Santos V, Araujo Oliveira F, Freire de Carvalho da Cunha S. Hyponatremia in acute-phase response syndrome patients in general surgical wards. Am J Nephrol (2000) 20:37–41.[CrossRef][Web of Science][Medline]
5. Shea AM, Hammill BG, Curtis LH, Szczech LA, Schulman KA. Medical costs of abnormal serum sodium levels. J Am Soc Nephrol (2008) 19:764–70.
6. Klein L, O'Connor CM, Leimberger JD, Gattis-Stough W, Pina IL, Felker GM, et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation (2005) 111:2454–60.
7. Goldberg A, Hammerman H, Petcherski S, Nassar M, Zdorovyak A, Yalonetsky S, et al. Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction. Arch Intern Med (2006) 166:781–6.
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