Hyponatremia is a common clinical problem, but the clinical complications and the treatment of this condition have been debated for many years. It is well recognized that hyponatremia can cause neurological complications and, even death, but it is unclear if these complications are the result of the hyponatremia itself or consequences of treatment. In recent years, it has become apparent that the duration of the hyponatremia, acute versus chronic, significantly influences the clinical complications. Acute hyponatremia is defined as hyponatremia that develops in a matter of hours, usually less than 24 hours, whereas chronic hyponatremia takes longer to develop and is more insidious. This clinical distinction has been verified in experimental animals in which the onset of hyponatremia was carefully controlled [1]. In these experimental models it has been shown that an acute decrease in plasma sodium to roughly 106 meq/L in seven hours was associated with seizures and coma, but these clinical features completely resolved with rapid correction of the serum sodium and there was no mortality associated with the treatment. In contrast, in the same study, the investigators observed that chronic hyponatremia, which developed in three days, was not associated with either seizures or coma, despite a lower serum sodium than observed in the acute hyponatremia group. It is of interest to note that rapid treatment of this chronic hyponatremic group was associated with demyelinating lesions in the brain and a high mortality rate.

Careful measurements of electrolyte and water content of the brain were done in these studies and it was shown that the brain adapts to hyponatremia. The initial adaptation is intracellular sodium and potassium loss, maximal after seven hours <[>1], while later on the adaptation is loss of non-electrolyte organic solutes [2,3]. This response of the brain to acute hyponatremia occurs in order to prevent brain cell swelling which is secondary to the osmotic water flow induced by the acute decrease in extracellular osmolality. In this regard, it is of interest to note that in the animal studies noted above, the water content of the brain increased 10 percent in the acute hyponatremia group and less than 5 percent in the chronic hyponatremia group [1]. It is thus clear that the chronic decrease in total brain solute, up to a 30% [1] decline in chronic hyponatremia is an effective way to reduce water flow into the brain cells and thus reduce edema. Recently proton Magnetic Resonance Spectroscopy (MRS) has been used in animal studies to examine the role of non-electrolyte organic osmolytes in the adaptation to hyponatremia [2]. These studies found that the re-accumulation of these organic osmolytes is slow and independent of the rate of correction of the hyponatremia [2,3]. This slow return of organic osmolyte concentrations to normal is believed to be related to the morbidity caused by the rapid correction of hyponatremia.

Although these studies in animals provide compelling evidence that the brain protects itself against chronic hyponatremia, similar studies in humans have been lacking until recently, owing to the methodologic difficulties in quantifying brain solute content during the development and correction of hyponatremia. It is therefore of clinical significance to verify the role of organic osmolytes in the regulation of the cell volume in the human brain during the hypo-osmolar stress of hyponatremia. Additionally, understanding the time frame and magnitude of the shifts in the concentration of the organic osmolytes would be helpful in planning rational management of hyponatremia. This issue of Kidney contains a summary of a paper describing the use of (MRS) to evaluate the changes in the concentration of intracellular organic osmolytes in response to chronic hyponatremia in humans [4].

The study attempts to quantify the changes in the concentration of certain intracellular osmolytes using MRS. The study identified 12 patients with hyponatremia, serum sodium <<125 meq/L, of greater than 1 week duration from both inpatient and outpatient settings. Ten age matched healthy volunteers were chosen as controls. A single small volume, approximately 11-ml, of occipital-parietal gray matter was localized using conventional magnetic resonance imaging (MRI). This volume of tissue or "voxel" was then examined with proton MRS to determine the intracellular concentrations of a variety of organic osmolytes. To obtain proton MRS, effort must be taken to mask the signal from water, the most abundant source of protons in living cells. This is accomplished using sophisticated MRS excitation and measurement schemes that allow observation of non-water protons with minimal interference from the protons of water. The intracellular concentration of the osmolytes was calculated based on the concentrations of the osmolytes in the voxel of tissue, which was then adjusted for the relative abundance of CSF and wet brain tissue in the voxel. The estimations of the CSF and wet brain weight in the voxel were made using separate measurements of the magnetic resonance relaxation characteristics of the water in the voxel. This technique is based upon the difference in the magnetic relaxation, T2 specifically, between CSF and brain tissue [5]. The accuracy of this method in determining true concentrations of the osmolytes is difficult to estimate based on the lack of good standards. The reproducibility, however, is good and this technique is appropriately used for determining differences among two groups.

The study found that the proton resonance signals of creatine, choline and myo-inositol were easily distinguishable and quantifiable in the gray and white matter of both the hyponatremic and control patients. The intracellular concentrations of these osmotically active compounds were found to be significantly decreased in the patients with chronic hyponatremia as compared to the controls. The degree of reduction in the concentrations were larger than could be explained by simple shifts of water into the cells produced by the osmotic water flow secondary to the hyponatremia. These findings suggest that in chronic hyponatremia there is a true decrease in the production, and/or an increase in the degradation, of organic osmolytes. This adaptive response serves to decrease the water flow into the cells during hyponatremia in order to prevent cell swelling. A follow up study with a small subset of the patients showed an increase in the concentrations of the osmolytes associated with partial resolution of the hyponatremia, indicating a reversal of this adaptive response once the pathophysiologic state is corrected. In summary, the study showed a reversible decrease in the concentration of certain intracellular osmolytes during chronic hyponatremia in humans and a trend toward return of these osmolytes to normal with partial resolution of the hyponatremia. Thus the human brain adapts to changes in serum osmolality by varying its solute content to prevent rapid and dangerous changes in cell volume.

The organic osmolytes observed in this study also appear to serve a similar purpose in hypernatremia. Lee et. al. [6] have recently reported a similar study using proton MRS to study the concentration of organic osmolytes in a child with hypernatremia. The study found a significant increase in the concentration of osmolytes during severe hypernatremia in a single child. The changes were followed as a function of correction of the hypernatremia and were reversible.

The study summarized in this issue is of particular interest for both its technical merit and novelty, as well as for the insight it provides into an important homeostatic mechanism. Using MRS to study biochemical changes in the human brain opens up many avenues for future research on the metabolic changes associated with disturbances of extracellular tonicity, using a non-invasive, in vivo technique. Due to the expense and time expenditure required for these studies, it is not likely that studies on individual patients will be used for their management per se, but rather future work may provide a better understanding of the adaptation to changes in tonicity and thus lead to changes in management strategies. The study is among the early studies in what promises to be an exciting new line of in vivo physiologic research. Proton MRS, as well as studies using other nuclei, particularly 31P, is now being used to examine MRI directed, site specific physiology and pathophysiology in vivo.

Future research will likely be focused on determining the kinetics of the changes in the concentration of the organic osmolytes as a function of the changes in the tonicity of the extracellular environment. These studies will have the clinical impact of distinguishing between the responses to acute versus chronic alterations in extracellular tonicity. Once the kinetics of intracellular osmolyte regulation of cell volume are better characterized, the mechanism of this fascinating homeostatic system can be better studied and understood.

References

1. Sterns RH, Thomas DJ, Herndon RM. Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int. 1989;35:69.

2. Lien YH, Shapiro JI, Chan L. Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of Central Pontine Myelinolysis. J. Clin. invest. 1991;88:303.

3. Verbalis JG, Gullans SR. Rapid correction of hyponatremia produces differential effects on brain osmolyte and electrolyte reaccumulation in rats. Brain Res. 1993:606:19.

4. Videen JS, Michaelis T, Pinto P, Ross BD. Human cerebral osmolytes during chronic hyponatremia, A proton Magnetic Resonance Spectroscopy Study. J. Clin. Invest. 1995;95:788.

5. Kreis R, Ernst T, Ross BD. Absolute quantitation of water and metabolite in the human brain. II, Metabolic Concentration, J. Magn. Reson. 1993;B102:9