The importance of distal delivery of filtrate and residual water permeability in the pathophysiology of hyponatremia.

The purpose of this commentary is to suggest that hyponatremia may develop in some patients in the absence of vasopressin action and to illustrate the possible pathophysiology and its clinical implications. The traditional approach to understanding the pathophysiology of hyponatremia centers on a reduced electrolytefree water excretion due to actions of vasopressin [1, 2]. In some clinical settings, release of vasopressin is thought to be due to decreased effective arterial blood volume (EABV). Notwithstanding, at least in some patients, the degree of decreased EABV does not seem to be large enough to cause the release of vasopressin [3]. Acutely reducing EABV by as much as 7% in healthy adults has little effect on vasopressin levels; a 10–15% reduction in EABV is required to double plasma vasopressin levels [4]. In a series of patients with thiazide-induced hyponatremia reported by Sonnenblick et al. [5], four patients had a plasma vasopressin level measured, and in three of them, it was either low or below the level of detection. Ghose [6] reported measurements of plasma arginine vasopressin in six patients with diuretic-induced hyponatremia. In three of these patients, it was ~0.4 pg/mL and ~1 pg/mL in the other three patients. Urine osmolality was 300 mosmol/kg H2O or less in three of five patients in whom the urine osmolality was reported. Oh et al. reported two patients with what these authors called ‘trickle-down hyponatremia’. Both these patients had a low rate of excretion of osmoles, urine osmolality of close to 325 mosmol/kg H2O and undetectable levels of vasopressin in their plasma [7]. Thaler et al. [8] reported a patient with hyponatremia and low dietary solute intake in whom the urine osmolality was 81 mosmol/ kg H2O and vasopressin level in plasma was below the limits of detection. Of note, 5–10% of hyponatremic patients with the syndrome of inappropriate anti-diuresis have low or undetectable levels of vasopressin in their plasma [9]. Although some patients may have gain-of-function mutations in the V2 vasopressin receptor [10], the pathophysiology of hyponatremia in this subset of patients remains largely undetermined. It is possible that these examples may reflect the levels of vasopressin that are sufficient to produce a biological effect but are under the level of detection by the available assays for vasopressin. This may be the case especially in females who may have more vasopressin V2 receptor expression and greater sensitivity to vasopressin-induced anti-diuresis [11]. In healthy human volunteers undergoing water diuresis, an infusion of vasopressin that resulted in a significant reduction in urine flow rate induced no detectable change in plasma vasopressin concentration [12]. It is of interest to note, however, that the urine osmolality in these subjects rose to ~600 mosmol/ kg H2O. Furthermore, studies by Berliner and Davidson have shown that hypertonic urine can be produced in the absence of pituitary anti-diuretic hormone. In these experiments, in dogs undergoing a water diuresis, reducing the glomerular filtration rate (GFR) to one kidney resulted in the production of urine with an osmolality of close to 350 mosmol/kg H2O, while urine from the contralateral kidney had an osmolality of ~70 mosmol/kg H2O [13]. There are two factors that may reduce electrolyte-free water excretion sufficiently and lead to the development of hyponatremia even in the absence of vasopressin actions; the volume of filtrate that is delivered to the distal nephron and the volume of water that is reabsorbed in the inner medullary collecting duct through its residual water permeability (RWP) [14]. A brief case example is provided to illustrate the quantitative importance of these factors in the pathophysiology of hyponatremia. A 71-year-old woman was started on hydrochlorthiazide 25 mg daily for treatment of hypertension. She had ischemic renal disease with an estimated GFR of 28 mL/min (40 L/ day). She consumed a low-salt low-protein diet and drank eight cups of water each day to remain ‘hydrated’. She was not taking any other drugs that may be associated with hyponatremia. A month later, she presented to her family doctor feeling unwell. Her blood pressure was 130/80 mmHg, her heart rate was 80 beats/minute, there were no postural changes in her blood pressure or heart rate, and her jugular venous pressure was ~1 cm below the level of the sternal angle. Her plasma Na concentration (PNa) was 112 mmol/L and her