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This Article Abstract Full Text (PDF) Free All Versions of this Article: 102/1/445    most recent 00614.2006v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nguyen, M. K. Articles by Kurtz, I. Search for Related Content PubMed PubMed Citation Articles by Nguyen, M. K. Articles by Kurtz, I.

Is the osmotically inactive sodium storage pool fixed or variable?

Division of Nephrology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California

Submitted 1 June 2006 ; accepted in final form 3 August 2006

ABSTRACT

Recently, there is renewed interest in the role of osmotically inactive Na⁺ storage during Na⁺ retention. Although it is well accepted that a portion of the total exchangeable Na⁺ reservoir is osmotically inactive, there is current controversy as to whether the osmotically inactive Na⁺ storage pool is fixed or variable during Na⁺ retention. In this article, we analyze the current scientific evidence to assess whether the osmotically inactive Na⁺ storage pool can be dynamically regulated. Our analysis supports the assertion that the osmotically inactive Na⁺ storage pool is fixed rather than variable.

exchangeable sodium

Although it is well accepted that a portion of Na_e is osmotically inactive, there is current controversy as to whether the osmotically inactive Na⁺ storage pool is fixed or variable in clinical conditions characterized by Na⁺ retention. Indeed, Heer et al. (6) demonstrated positive Na⁺ balance in healthy subjects on a metabolic ward without increases in body weight, expansion of the extracellular space, or plasma Na⁺ concentration ([Na⁺]). These authors, therefore, suggested that there is osmotic inactivation of Na_e. However, determination of osmotically inactive Na⁺ storage must be based not only on Na⁺ and H₂O balance, but also on K⁺ balance, because changes in Na_e are often accompanied by changes in exchangeable K⁺ (10). In the study of Heer et al., these investigators accounted for Na⁺ and H₂O balance but they failed to account for K⁺ balance. Therefore, their observation that Na⁺ retention was not accompanied by osmotically adequate water retention can potentially be explained by concomitant negative K⁺ balance. Likewise, Farber and colleagues (1, 4) demonstrated that edematous patients with heart disease have a higher total body Na⁺/H₂O ratio than do edematous patients with hepatic or renal disease and suggested the existence of an osmotically inactive Na⁺ storage pool in patients with heart disease. However, Farber and colleagues also did not account for the modulating effect of K⁺ on water retention.

Similarly, Titze et al. (14) suggested the existence of an osmotically inactive Na⁺ reservoir that exchanges Na⁺ with the extracellular space in human subjects in a terrestrial space station simulation study. In addition, Titze et al. (13) postulated that skin is an osmotically inactive Na⁺ reservoir that accumulates Na⁺ when dietary NaCl is excessive. However, these studies also failed to account for K⁺ balance. In a subsequent study, Titze et al. (12) did take into consideration the fact that K⁺, as with Na⁺, exerts osmotic activity and contributes to water retention. Titze et al. (12) reported that skin Na⁺ retention in deoxycorticosterone acetate (DOCA)-salt rats was not balanced by K⁺ loss, indicating osmotically inactive skin Na⁺ storage (12). In this study, Titze et al. (12) suggested that parallel increases in the skin Na⁺/H₂O ratio and skin (Na⁺ + K⁺)/H₂O ratio indicated Na⁺ abundance relative to water and hence osmotically inactive Na⁺ storage in the tissue. However, the assumption that an increased skin (Na⁺ + K⁺)/H₂O ratio is indicative of osmotically inactive Na⁺ storage, fails to account for the modulating effect of non-Na⁺ and non-K⁺ solutes on the skin (Na⁺ + K⁺)/H₂O ratio. The skin (Na⁺ + K⁺)/H₂O ratio is a function of the Na⁺, K⁺, and H₂O content of the tissue. Although the skin Na⁺ and K⁺ content is modulated by only the mass balance of Na⁺ and K⁺, the skin water content is a function of the amount of osmotically active Na⁺ and K⁺ as well as osmotically active non-Na⁺ and non-K⁺ solutes. To the extent that osmotically active non-Na⁺ and non-K⁺ solutes determine the amount of water retained in the skin tissue, the quantity of osmotically active non-Na⁺ and non-K⁺ solutes will modulate the skin (Na⁺ + K⁺)/H₂O ratio by altering the denominator in this ratio. Therefore, an increased skin (Na⁺ + K⁺)/H₂O ratio may simply reflect changes in the mass balance of skin osmotically active non-Na⁺ and non-K⁺ solutes relative to that of Na⁺ and K⁺. More importantly, to determine the portion of the total skin water content that is due to the osmotically active Na⁺ and K⁺, one must first quantify the amount of skin water that is retained by the osmotically active non-Na⁺ and non-K⁺ solutes. However, Titze et al. (12, 13) did not account for the amount of osmotically active non-Na⁺ and non-K⁺ solutes in the skin tissue. Therefore, in the presence of non-Na⁺ and non-K⁺ solutes, an increment in the skin (Na⁺ + K⁺)/H₂O ratio may simply be a reflection of the input and output of Na⁺, K⁺, and H₂O at the tissue level rather than an indication of osmotically inactive skin Na⁺ storage.

In the study of Titze et al. (12), these investigators demonstrated that skin Na⁺ retention resulted in an increased skin (Na⁺ + K⁺)/H₂O ratio in saline-treated rats compared with water-treated rats in both control and DOCA rats (Table 1). Given that the serum [Na⁺] remained unchanged (Table 1; Ref. 12), if a significant amount of Na⁺ were to accumulate in an osmotically inactive form in the skin, then a concomitant increment in the total body (Na⁺ + K⁺)/H₂O ratio must also occur (7, 8). However, as shown in Table 1, the increased skin (Na⁺ + K⁺)/H₂O ratio in saline-treated rats was not accompanied by an increment in the total body (Na⁺ + K⁺)/H₂O ratio (12). Indeed, the total body (Na⁺ + K⁺)/H₂O ratio remained constant in saline-treated rats compared with water-treated rats in both control and DOCA rats without a change in the serum [Na⁺], thereby arguing against significant osmotically inactive Na⁺ storage in skin or any other tissues during Na⁺ retention (7, 8). Interestingly, there was an increment in the total body (Na⁺ + K⁺)/H₂O ratio in DOCA rats compared with control rats, but this increased total body (Na⁺ + K⁺)/H₂O ratio was associated with an increment in the serum [Na⁺] (Table 1; Ref. 12). Therefore, the increased total body (Na⁺ + K⁺)/H₂O ratio in DOCA rats compared with control rats, likely resulted from osmotically active (not osmotically inactive) Na⁺ retention in excess of H₂O, thereby leading to a concomitant increase in the serum [Na⁺].

where TBW is total body water, Vol is volume, and total body Na⁺ + K⁺ represents the total body osmotically active Na⁺ + K⁺.

If one were to assume that [Na⁺ + K⁺]_serum = [Na⁺ + K⁺]_ISF = [Na⁺ + K⁺]_ICF, then:

Therefore,

However, the determination of osmotically active Na⁺ + K⁺ retention based on the serum [Na⁺ + K⁺] is inaccurate because it is well known that the [Na⁺ + K⁺] is not equal in the serum, ISF, and ICF (5, 9). Indeed, the serum [Na⁺ + K⁺] is greater than the interstitial fluid [Na⁺ + K⁺] due to the Gibbs-Donnan equilibrium (9, 11). Additionally, the interstitial fluid [Na⁺ + K⁺] is different from the intracellular [Na⁺ + K⁺] due to differences in the concentration of non-Na⁺ and non-K⁺ osmoles in these two compartments (5). Moreover, it is also not known whether alterations in the mass balance of Na⁺, K⁺, and H₂O will result in equivalent changes in the plasma, interstitial fluid, and intracellular [Na⁺ + K⁺]. Therefore, on the basis of these studies (6, 12–14), it cannot be concluded that the osmotically inactive Na⁺ pool is variable during states of Na⁺ retention.

Recently, Seeliger et al. (10) performed Na⁺, K⁺, and H₂O balance studies of 4-days duration in dogs. Seeliger et al. demonstrated that changes in exchangeable Na⁺ were often accompanied by changes in exchangeable K⁺ and that Na⁺ storage was osmotically active during Na⁺ retention. Indeed, these investigators demonstrated that the changes in total body Na⁺ and K⁺ were proportional to the changes to total body water (10). Therefore, by considering the mass balance of Na⁺, K⁺, and H₂O, these researchers demonstrated that Na⁺ accumulation occurs in an osmotically active form during Na⁺ retention.

In summary, there is clear-cut evidence in the literature that the total exchangeable Na⁺ exists in both osmotically active and inactive forms. Whether the osmotically inactive exchangeable Na⁺ pool can be dynamically regulated has not been demonstrated experimentally thus far. Indeed, current evidence supports the assertion that the osmotically inactive Na⁺ storage pool is fixed rather than variable.

FOOTNOTES

Address for reprint requests and other correspondence: M. K. Nguyen, Div. of Nephrology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Rm. 7–155 Factor Bldg., Los Angeles, CA 90095 (e-mail: mtnguyen{at}mednet.ucla.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 102/1/445    most recent 00614.2006v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nguyen, M. K. Articles by Kurtz, I. Search for Related Content PubMed PubMed Citation Articles by Nguyen, M. K. Articles by Kurtz, I.