First, virtually all relevant studies have found that during the development of TIH, Na+ balance is negative Fuisz et al. argued that changes in external Na+ and water balance did not completely account for the fall in serum Na+. Furthermore, chlorothiazide induced hyponatremia in their patients despite Na+ supplementation and positive Na+ balance. These observations led the authors to conclude that a shift of Na+ into the intracellular space contributed to the pathogenesis of hyponatremia. Second, once diuretics are withdrawn, urinary Na+ excretion falls to very low levels. Third, many of these patients are hypokalemic emphasized the importance of K+ depletion in TIH. The great majority of their 25 patients was hypokalemic, and hyponatremia was corrected in 4 of them by K+ repletion despite continued diuretic use and Na+ restriction. These investigators argued that K+ depletion predisposes the patients to hyponatremia because the serum Na+ concentration is dependent upon the ratio of the sum of exchangeable Na+ and K+ to total body water. They also speculated that K+ depletion might cause a shift of Na+ into the intracellular space, thereby further compromising the extracellular volume and stimulating vasopressin release. Na+ and/or K+ depletion alone would not be expected to cause marked hyponatremia because water excretion normally increases as the serum Na+ concentration falls. However, because thiazides interfere with renal water excretion, they impair this normal osmoregulatory response. Thus, as in most patients with hyponatremia, urine osmolality is inappropriately high relative to the osmolality of plasma and often exceeds it