Physiology - An Illustrated Review

17. Concentration and Dilution of Urine

17.1 Regulation of Water Balance

The regulation of body water depends on the dynamic balance between the rates of water movement into and out of the body. The two major mechanisms responsible for water balance are thirst and antidiuretic hormone (ADH) regulation of urinary water excretion.

– The circulating level of ADH regulates the amount of water reabsorption from distal tubules and collecting ducts into peritubular capillary blood. Therefore, the regulation of renal excretion of water is ultimately determined by factors that influence the rate of synthesis and release of ADH into the blood and its renal action. ADH is a peptide hormone synthesized in specialized hypothalamic neurons and transported within axons to the posterior pituitary, where it is stored until release. Because water gain or deficit significantly affects total solute concentration within body fluids, plasma osmolality is the most important regulator of ADH release (Figs. 16.6, p.169, and 17.1). The amount of ADH released increases with a rise in plasma osmolality via stimulation of hypothalamic osmoreceptors. A decrease in blood volume also stimulates ADH release, because the resulting decrease in atrial pressure relieves the inhibitory effect of atrial baroreceptors on ADH release. ADH binds to V₂ receptors on peritubular membranes of epithelial cells of the distal nephron and, via activation of the adenylate cyclase enzyme system, increases the permeability of luminal membranes of the epithelial cells to water.

Fig. 17.1  Regulation of water balance.

(1) Net water losses (hypovolemia) due, for example, to sweating make extracellular fluid (ECF) hypertonic. Osmolality rises of only 1 to 2% are sufficient to increase the secretion of antidiuretic hormone (ADH) from the posterior pituitary. ADH decreases urinary H₂O excretion. Fluid intake from outside the body is also required. The hypertonic cerebrospinal fluid (CSF) stimulates the secretion of (central) angiotensin II (AT II), which triggers hyperosmotic thirst. (2) In water excess, the osmolality of ECF is reduced. This signal inhibits the secretion of ADH, resulting in water diuresis and normalization of plasma osmolality within 1 hour.

– Water intake is regulated through a thirst center located in the hypothalamus. Thirst is also stimulated by both an increase in plasma osmolality and a decrease in extracellular fluid (ECF) volume, thus working in concert with the ADH mechanism to maintain water balance. Angiotensin also stimulates thirst.

17.2 Concentration and Dilution of Urine

The kidneys are able to produce urine that is either more concentrated or more diluted than plasma by altering the amount of water that is reabsorbed via the regulation of ADH (Fig. 17.2).

Production of Concentrated (Hyperosmotic) Urine

Hyperosmotic urine is produced when plasma ADH concentration is high and is facilitated by the corticomedullary osmotic gradient.

Fig. 17.2  Water reabsorption and excretion.

Approximately 65% of the glomerular filtrate is reabsorbed at the proximal tubule. The “driving force” is the reabsorption of NaCl. This slightly dilutes the urine in the tubule, but H₂O immedi ately follows this small osmotic gradient because the proximal tubule is “leaky.” The reabsorption of H₂O can occur through leaky tight junctions or through water channels (aquaporins) in cell membranes. The urine in the proximal tubule therefore remains isotonic. Oncotic pressure in the peritubular capillaries provides an additional driving force for water reabsorption. The more water filtered at the glomerulus, the higher this oncotic pressure. Thus, the reabsorption of water at the proximal tubule is, to a certain extent, adjusted in accordance with the glomerular filtration rate (GFR). Because the descending limb of the loop of Henle has aquaporins that make it permeable to water, the urine in it is largely in osmotic balance with the hypertonic interstitium, the content of which becomes increasingly hypertonic as it approaches the papillae. The urine therefore becomes increasingly concentrated as it flows in this direction. In the thin descending limb, which is only sparingly permeable to NaCl, this increases the concentration of Na⁺ and Cl⁻. Most water drawn into the interstitium is carried off by the vasa recta. Because the thin and thick ascending limbs of the loop of Henle are largely impermeable to water, Na⁺ and Cl⁻ passively diffuse (thin limb) and are actively transported (thick limb) out into the interstitium. Because water cannot escape, the urine leaving the loop of Henle is hypotonic. Final adjustment of the excreted urine volume occurs in the collecting duct. In the presence of antidiuretic hormone (ADH) via V₂ receptors, aquaporins in the luminal membranes are used to extract water from the urine passing through the increasingly hypertonic renal medulla. This results in maximum antidiuresis. The absence of ADH results in water diuresis. (FE_H2O, fraction excreted)

Corticomedullary Osmotic Gradient

The corticomedullary osmotic gradient is a gradient of osmolarity from the corticomedullary border (~300 m Osmol/kg H₂O) to the inner medulla. The maximum value reached in the papilla varies depending on hydration status, but it may reach 1200 mOsmol/kg H₂O in conditions of severe dehydration.

– The gradient is established by NaCl and urea and leads to the reabsorption of water (in the presence of ADH).

Role of NaCl in establishing the corticomedullary gradient. The corticomedullary osmotic gradient is established by the countercurrent multiplication system in the loop of Henle. This is dependent upon the close apposition of the descending and ascending limbs of the loop of Henle in the medulla and the transport characteristics of each limb.

– The descending limb of the loop of Henle is permeable to water but poorly permeable to solutes.

– The thick ascending limb of the loop of Henle actively reabsorbs NaCl but is impermeable to water.

These characteristics allow the ascending limb to dilute the tubular fluid and concentrate the medullary interstitium (“single effect”), creating a horizontal osmotic gradient between tubular fluid in the ascending limb and that in the descending limb. This horizontal osmotic gradient is then multiplied vertically along the length of the descending loop of Henle, generating an osmotic gradient within the tubular fluid. The medullary interstitium is equilibrated with the fluid in the descending limb because this nephron segment is highly permeable to water.

Role of urea in establishing the corticomedullary gradient. Urea is the other major solute within the medullary interstitium besides NaCl. Filtered urea undergoes passive net re-absorption into proximal tubule cells (Fig. 17.3). However, urea concentration at the end of the proximal tubule is approximately twice that of plasma due to water reabsorption. Urea is secreted into the tubular lumen in the deep regions of the loop of Henle. Due to the low permeability of the distal tubule and cortical collecting duct to urea, urea concentration in the tubular fluid remains high as the fluid flows through the medullary collecting duct, which is more permeable to urea. Urea diffuses out of the collecting duct, entering the interstitium and vasa recta, as well as reentering the loop of Henle. Therefore, there is a medullary recycling of urea.

– In the presence of ADH, urea constitutes ~40% of papillary osmolality because ADH increases the permeability of medullary collecting ducts to urea as well as to water.

– In the absence of ADH, < 10% of medullary interstitial osmolality is due to urea.

The medullary recycling of urea thus helps establish an osmotic gradient within the medulla with less energy expenditure (urea transport is passive) and enhances water conservation.

Role of the vasa recta in maintaining the corticomedullary osmotic gradient. The vasa recta are hairpin blood vessels in the renal medulla formed from efferent arterioles of juxtamedullary glomeruli in apposition to the loop of Henle and collecting ducts. Like other systemic capillaries, they are permeable to solutes and water. Because of their unique countercurrent arrangement, the vasa recta act as a passive countercurrent exchanger system (Fig. 17.4). As solutes are transported out of the ascending loop of Henle, they diffuse down their concentration gradients into the descending vasa recta. Thus, blood in the descending vasa recta becomes progressively more concentrated as it equilibrates with the corticomedullary osmotic gradient. In the ascending vasa recta, solutes diffuse back into the medullary interstitium and into the descending vasa recta. In this manner, solutes recirculate within the renal medulla, keeping the solute concentration high within the medullary interstitium. The passive equilibrium of blood within each limb of the vasa recta with the preexisting medullary osmotic gradient at each horizontal level helps maintain the medullary osmotic gradient necessary for the production of hyperosmotic urine.

Fig. 17.3  Urea in the kidney.

About 50% of the filtered urea leaves the proximal tubule by diffusion. Much of this reenters the tubule by secretion in the loop of Henle. Because the distal tubule and the cortical and outer medullary sections of the collecting duct are only sparingly permeable to urea, its concentration increases in these parts of the nephron. Antidiuretic hormone (ADH) can (via V₂ receptors) introduce urea carriers in the luminal membrane, thereby making the inner medullary collecting duct permeable to urea. Urea now diffuses back into the interstitium (where urea is responsible for half of the high osmolality there) and is then transported by carriers back into the descending limb of the loop of Henle, comprising the recirculation of urea. The nonreabsorbed fraction of urea is excreted (FE_urea).

Fig. 17.4  Countercurrent systems.

Countercurrent exchange of water in the vasa recta of the renal medulla occurs if the medulla becomes increasingly hypertonic toward the papillae and if the vasa recta become permeable to water. Part of the water diffuses by osmosis from the descending vasa recta to the ascending ones, thereby “bypassing” the inner medulla. Due to the extraction of water, the concentration of all other blood components increases as the blood approaches the papillae. The plasma osmolality in the vasa recta is therefore continuously adjusted to the osmolality of the surrounding interstitium, which rises toward the papillae. Conversely, substances entering the blood in the renal medulla diffuse from the ascending to the descending vasa recta, provided the walls of the vessels are permeable to them. The countercurrent exchange in the vasa recta permits the necessary supply of blood to the renal medulla without significantly altering the high osmolality of the renal medulla and hence impairing the urine concentration capacity of the kidney.

Note: If blood flow is rapid in the vasa recta, the osmotic gradient will decrease. This happens when a person takes on a large water load.

Production of Dilute (Hyposmotic) Urine

Hyposmotic urine is produced when plasma [ADH] is low.

– Isosmotic tubular fluid from the proximal tubule enters the descending limb of the loop of Henle. It becomes progressively more concentrated as it moves toward the bend because fluid in the descending limb equilibrates osmotically with fluid within the medullary interstitium. The concentrated fluid at the bend of the loop then becomes progressively more diluted as it flows through the ascending loop of Henle because NaCl is reabsorbed without water. When there is a very low level of ADH, the permeability of the collecting duct to water is very low. Consequently, no water will be reabsorbed in the distal nephron even though salts continue to be reabsorbed. Therefore, the diluted tubular fluid that emerges from the ascending loop of Henle will remain hyposmotic as it flows through the distal nephron and medullary collecting ducts, producing hyposmotic urine (~100 mOsmol/kg H₂O).

17.3 Measurement of Concentrating and Diluting Ability

Free Water Clearance

Free water (solute free water) is produced in the ascending loop of Henle and early distal tubule, where NaCl is reabsorbed without water.

Free water clearance (C_H2O) is defined as the amount of pure water that must be subtracted from or added to the urine (per unit of time) to make that urine isosmotic with plasma. It is used as a measure of the ability of the kidneys to concentrate or dilute urine.

– Urine is C_H2O positive when there is no ADH and free water is excreted (i.e., the urine has excess water).

– Urine is C_H2O negative when ADH is secreted and water is reabsorbed by the late distal nephron and the collecting ducts. The negative C_H2O represents the amount of water that would have to be added back to make the urine isosmotic.

Free water clearance is calculated from the following equation:

where  is free water clearance (in mL/min), V is urine flow rate (in mL/min), and C_osm is osmolar clearance, which equals V × (urine_osm/plasma_osm) (in mL/min).

Example: A patient with a plasma osmolality of 300 mOsmol/kg H₂O produces urine at a rate of 1.2 mL/min. The urine osmolality is 450 mOsmol/kg H₂O.

C_osm = 1.2 mL/min × [(450 mOsmol/kg H₂O)/(300 mOsmol/kg H₂O)] = 1.8 mL/min

Note: The negative value indicates that water would have to be added to make the urine isosmotic.

Table 17.1 summarizes the hormones that act on the kidney.

Nephrogenic diabetes insipidus

In nephrogenic diabetes insipidus, the kidney is unresponsive to ADH, and thiazide diuretics cause a paradoxical reduction in the excessive urination (i.e., they decrease polyuria). The mechanism for this effect is uncertain, but it is usually attributed to changes in Na⁺ excretion. Thiazides inhibit NaCl reabsorption in the early segments of the distal tubule but have little effect in the thick ascending limb, which is involved in concentrating the urine. Although all thiazides share this effect, chlorothiazide is most commonly used to treat this condition.