Composition of Body Fluids
Water is the most abundant constituent in the body, accounting for ∼50% of body weight in women and 60% in men. Total body water is distributed in two major compartments: 55–75% is intracellular [intracellular fluid (ICF)], and 25–45% is extracellular [extracellular fluid (ECF)]. ECF is subdivided into intravascular (plasma water) and extravascular (interstitial) spaces in a ratio of 1:3. Fluid movement between the intravascular and interstitial spaces occurs across the capillary wall and is determined by Starling forces, i.e., capillary hydraulic pressure and colloid osmotic pressure. The transcapillary hydraulic pressure gradient exceeds the corresponding oncotic pressure gradient, thus favoring the movement of plasma ultrafiltrate into the extravascular space. The return of fluid into the intravascular compartment occurs via lymphatic flow.
The solute or particle concentration of a fluid is known as its osmolality and is expressed as milliosmoles per kilogram of water (mosmol/kg). Water easily diffuses across most cell membranes to achieve osmotic equilibrium (ECF osmolality = ICF osmolality). Notably, the extracellular and intracellular solute compositions differ considerably owing to the activity of various transporters, channels, and ATP-driven membrane pumps. The major ECF particles are Na+ and its accompanying anions Cl− and HCO3−, whereas K+ and organic phosphate esters (ATP, creatine phosphate, and phospholipids) are the predominant ICF osmoles. Solutes that are restricted to the ECF or the ICF determine the tonicity or effective osmolality of that compartment. Certain solutes, particularly urea, do not contribute to water shifts across most membranes and are thus known as ineffective osmoles.
Vasopressin secretion, water ingestion, and renal water transport collaborate to maintain human body fluid osmolality between 280 and 295 mosmol/kg. Vasopressin (AVP) is synthesized in magnocellular neurons within the hypothalamus; the distal axons of those neurons project to the posterior pituitary or neurohypophysis, from which AVP is released into the circulation. A network of central osmoreceptor neurons that includes the AVP-expressing magnocellular neurons themselves sense circulating osmolality via nonselective, stretch-activated cation channels. These osmoreceptor neurons are activated or inhibited by modest increases and decreases in circulating osmolality, respectively; activation leads to AVP release and thirst.
AVP secretion is stimulated as systemic osmolality increases above a threshold level of ∼285 mosmol/kg, above which there is a linear relationship between osmolality and circulating AVP (Fig. 45-1). Thirst and thus water ingestion also are activated at ∼285 mosmol/kg, beyond which there is an equivalent linear increase in the perceived intensity of thirst as a function of circulating osmolality. Changes in blood volume and blood pressure are also direct stimuli for AVP release and thirst, albeit with a less sensitive response profile. Of perhaps greater clinical relevance to the pathophysiology of water homeostasis, ECF volume strongly modulates the relationship between circulating osmolality and AVP release so that hypovolemia reduces the osmotic threshold and increases the slope of the response curve to osmolality;hypervolemia has the opposite effect, increasing the osmotic threshold and reducing the slope of the response curve (Fig. 45-1). Notably, AVP has a half-life in the circulation of only 10–20 min; thus, changes in extracellular fluid volume and/or circulating osmolality can affect water homeostasis rapidly. In addition to volume status, a number of nonosmotic stimuli have potent activating effects on osmosensitive neurons and AVP release, including nausea, intracerebral angiotensin II, serotonin, and multiple drugs.
Circulating levels of vasopressin (AVP) in response to changes in osmolality. Plasma vasopressin becomes detectable in euvolemic, healthy individuals at a threshold of ∼285 mOsm/Kg, above which there is a linear relationship between osmolality and circulating AVP. The vasopressin response to osmolality is modulated strongly by volume status. The osmotic threshold is thus slightly lower in hypovolemia, with a steeper response curve; hypervolemia reduces the sensitivity of circulating AVP levels to osmolality.
The excretion or retention of electrolyte-free water by the kidney is modulated by circulating AVP. AVP acts on renal V2-type receptors in the thick ascending limb of Henle and principal cells of the collecting duct (CD), increasing cyclic adenosine monophosphate (AMP) and activating protein kinase A (PKA)–dependent phosphorylation of multiple transport proteins. The AVP- and PKA-dependent activation of Na+-Cl– and K+ transport by the thick ascending limb of the loop of Henle (TALH) is a key participant in the countercurrent mechanism (Fig. 45-2). The countercurrent mechanism ultimately increases the interstitial osmolality in the inner medulla of the kidney, driving water absorption across the renal collecting duct. However, water, salt, and solute transport by both proximal and distal nephron segments participates in the renal concentrating mechanism (Fig. 45-2). Water transport across apical and basolateral aquaporin-1 water channels in the descending thin limb of the loop of Henle is thus involved, as is passive absorption of Na+-Cl– by the thin ascending limb, via apical and basolateral CLC-K1 chloride channels and paracellular Na+ transport. Renal urea transport in turn plays important roles in the generation of the medullary osmotic gradient and the ability to excrete solute-free water under conditions of both high and low protein intake (Fig. 45-2).
The renal concentrating mechanism. Water, salt, and solute transport by both proximal and distal nephron segments participates in the renal concentrating mechanism (see text for details). Diagram showing the location of the major transport proteins involved; a loop of Henle is depicted on the left, a collecting duct on the right. UT, urea transporter; AQP, aquaporin; NKCC2, Na-K-2Cl cotransporter; ROMK, renal outer medullary K+ channel; CLC-K1, chloride channel. (From JM Sands: J Am Soc Nephrol 13:2795, 2002; with permission.)
AVP-induced, PKA-dependent phosphorylation of the aquaporin-2 water channel in principal cells ...