Reply to and commentary on the Letter to the Editor by Weschler on the dynamic regulation of the osmotically inactive sodium storage pool

Abstract

### Is the Osmotically Inactive Sodium Storage Pool Regulated at the Total Body Level? to the editor: There is current controversy over whether the osmotically inactive Na+ storage pool is fixed or variable in clinical conditions characterized by changes in Na+ and H2O balance. The experimental studies of Farber and colleagues ([1][1], [4][2]), Heer et al. ([6][3]), and Titze et al. ([14][4]–[16][5]) suggested that the osmotically inactive Na+ storage pool is dynamically regulated during Na+ retention. Indeed, Farber and colleagues ([1][1], [4][2]) have demonstrated that edematous patients with heart disease have a higher ratio of total body Na+ to total body water than do edematous patients with hepatic or renal disease and have suggested the existence of an osmotically inactive Na+ storage pool in patients with heart disease. Likewise, Heer et al. ([6][3]) 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. These authors, therefore, suggested that there is osmotic inactivation of exchangeable Na+ as well. However, there are significant limitations inherent in these studies. Determination of osmotically inactive Na+ storage must be based not only on Na+ and H2O balance, but also on K+ balance, since changes in exchangeable Na+ (Nae) are often accompanied by changes in exchangeable K+ (Ke). In the studies of Farber and colleagues ([1][1], [4][2]) and Heer et al. ([6][3]), these investigators accounted for Na+ and H2O balance, but they failed to account for K+ balance. Similarly, Titze et al. ([16][5]) 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. ([15][6]) postulated that skin is an osmotically inactive Na+ reservoir that accumulates Na+ when dietary NaCl is excessive ([15][6]). Like the previous studies mentioned above, these studies also failed to account for K+ balance. In a subsequent study, Titze et al. ([14][4]) did take into consideration the fact that K+, as with Na+, exerts osmotic activity and contributes to water retention. Titze et al. ([14][4]) reported that skin Na+ retention in DOCA-salt rats was not balanced by K+ loss, indicating osmotically inactive skin Na+ storage. In this study, Titze et al. ([14][4]) 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, thereby suggesting osmotically inactive Na+ storage in the tissue. In the recent study of Schafflhuber et al. ([12][7]), these investigators reported that the skin osmotically inactive Na+ storage pool varies with dietary Na+ deprivation during growth. In their study, Schafflhuber et al. ([12][7]) determined the quantity of Na+ + K+ by the technique of dry ashing. Unfortunately, the determination of Na+ + K+ via dry ashing cannot differentiate between the change in the osmotically inactive Na+ + K+ storage pool due to growth and the change in the osmotically inactive Na+ + K+ storage pool due to the mass balance of Na+, K+, and H2O, which were occurring simultaneously in these growing rats. During growth, the development of new bone and skin tissues will lead to a change in the quantity of nonexchangeable, osmotically inactive Na+ + K+, as well as exchangeable, osmotically inactive Na+ + K+ ([2][8], [14][4]). Importantly, alterations in both the quantity of nonexchangeable, osmotically inactive Na+ + K+ and exchangeable, osmotically inactive Na+ + K+ due to growth of new bone and skin tissues must be distinguished from the change in exchangeable, osmotically inactive Na+ + K+ due the mass balance of Na+, K+, and H2O. These factors were not accounted for in this study. On the contrary, Seeliger et al. ([13][9]) performed Na+, K+, and H2O balance studies of 4 days' duration in dogs and demonstrated that changes in exchangeable Na+ were often accompanied by changes in exchangeable K+, and that Na+ storage was osmotically active during Na+ retention at the total body level. Indeed, these investigators demonstrated that the changes in total body Na+ and K+ were proportional to the changes to total body water ([13][9]). Therefore, by considering the mass balance of Na+, K+, and H2O, these researchers argued that Na+ accumulation occurs in an osmotically active form during Na+ retention. Similarly, Overgaard- Steensen et al. ([11][10]) recently demonstrated that the plasma [Na+] can be predicted on the basis of the mass balance of Na+, K+, and H2O in acute hyponatremia in a porcine model ([11][10]). Consequently, these investigators concluded that there is no substantial osmotic activation or inactivation resulting from changes in the mass balance of Na+, K+, and H2O at the total body level ([11][10]). Together, the previous experimental findings demonstrate that the plasma [Na+] can be predicted on the basis of the mass balance of Na+, K+, and H2O at the total body level despite the paradoxical finding that there are changes in the osmotically inactive Na+ storage pool at the skin tissue level. These seemingly paradoxical findings can be reconciled by examining the major determinants of the plasma [Na+], as reflected in the Edelman equation ([3][11], [8][12], [10][13]): Plasma[Na+]≈Nae+KeTBW−(Naosm inactive+Kosm inactive)TBW (1) where Nae is total exchangeable Na+, Ke is total exchangeable K+, Naosm inactive is osmotically inactive Na+, and Kosm inactive is osmotically inactive K+. The plasma [Na+] is a function of the total amount of osmotically active Na+ and K+ distributed within the total body water (TBW), ignoring the modulating effect of Gibbs-Donnan equilibrium, osmotic coefficient of Na+ salts and non-Na+, non-K+ osmotically active solutes ([8][12], [10][13]). According to [Eq. 1][14] , in order...