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Regulation of Urine Osmolarity

  • The regulation of urine osmolarity is a key aspect of total ECF Osmoregulation. When ECF osmolarity rises the kidneys produce an increasingly concentrated urine thus returning free water to the ECF, yielding ECF dilution. Conversely, when ECF osmolarity falls the kidneys produce an increasingly dilute urine, thus eliminating free water from the ECF, leading to ECF concentration. Regulated secretion of ADH is the fundamental mechanism which connects ECF osmolarity to the concentration of urine. Although water is resorbed in multiple locations of the tubule, its regulated resorption by ADH occurs only in the late distal tubule and collecting duct.
ECF Osmolarity, Urine Osmolarity, and ADH
  • The extracellular fluid has a normal osmolarity of 300mOsm/L. When the kidneys produce a urine more concentrated than 300mOsm/L they are excreting more solutes compared to water than exists in the ECF, which acts to dilute the ECF and thus lower its osmolarity. Conversely, when the kidneys produce a urine less concentrated than 300mOsm/L they are excreting fewer solutes compared to water than exists in the ECF, yielding concentration of the ECF and thus an increase in its osmolarity. This is the fundamental inverse relationship between the osmolarity of the ECF compared to that of the urine and represents the basic mechanism by which modulation of the urine osmolarity can impact the ECF osmolarity
  • The molecular mechanism which links the ECF osmolarity to the urine osmolarity is Antidiuretic Hormone (ADH), a peptide hormone released by the posterior pituitary in response to increasing ECF osmolarity that triggers renal processes which promote concentration of the urine. The pathway that leads to ADH release begins with osmoreceptor cells in the hypothalamus adjacent to the supraoptic nuclei. These cells are directly stimulated by excessive extracellular fluid osmolarity and activate an adjacent population of hypothalamic neurons within the supraoptic neclei whose axons traverse the hypophysial stalk and and end in the posterior pituitary. Upon stimulation by osmoreceptors, this supraoptic population of neurons release ADH from their posterior pituitary nerve endings.
  • ADH has two basic actions. The first is to stimulate a series of urine-concentrating processes in the kidneys which are discussed further below. ADH also acts as a potent vasoconstricting substance as discussed further on the ADH Physiology page.
Tubular Modulation of Urine Osmolarity
  • Overview
    • The initial glomerular filtrate has an osmolarity equivalent to that of the ECF, that is 300mOsm/L. Water is resorbed at multiple loci within the tubule. However, whether the tubular fluid is diluted or concentrated depends on the ratio of water resorbed to that of solutes. The major segments at which the tubular fluid osmolarity changes are in the thick Henle and early distal tubule, known as the "diluting segments" of the nephron as well as the late distal tubule and collecting duct. The late distal tubule and collecting ducts of the nephron are the major loci of urine osmolarity regulation and their impact on urine osmolarity is controlled by ADH.
  • Proximal Tubule and Thin Henle
    • The net osmolarity of the tubular fluid does not change significantly in the proximal tubule or the thin Henle. In the proximal tubule water resorption occurs paracellularly and osmotically follows that of the solutes resorbed in this segment. Consequently, an equal proportion of solutes and water are resorbed, leading to no net change in tubular osmolarity. Although the osmolarity of the tubular fluid increases in the descending Henle due to water resorption, a nearly equal amount of solutes are resorbed in the ascending thin Henle, ultimately yielding no net change in the tubular fluid osmolarity by the end of Henle's thin segment.
  • Thick Ascending Loop of Henle and Early Distal Tubule
    • The thick ascending Henle and early dital tubule are highly impermeable to water and thus no water resorption occurs in these segments. However, these segments are responsible for a large proportion of solute resorption; consequently, the tubular fluid becomes highly dilute in these segments. Indeed, by the end of the early distal tubule the fluid can reach an osmolarity of 100 mOsm/L, thus explaining why they are collectively known as the "Diluting Segments" of the nephron.
  • Late Distal Tubule and Collecting Ducts
    • The late distal tubule and collecting ducts represents the major segment where water resorption occurs in a regulated fashion. The water permeability of these segments is purely determined by the presence of ADH, a peptide hormone whose regulated release occurs in response to rising ECF osmolarity as described above.
    • When the water permeability of the late distal tubule and collecting duct is high, significant amounts of water resorption can occur in this segment. This water resorption is driven by an increasing gradient of osmolarity in the renal interstitium that runs from the renal cortex to its most concentrated point in the renal medulla. This "Corticopapillary Osmotic Gradient" is composed of a gradient of sodium and urea and its generation is described further on the Corticopapillary Osmotic Gradient page.
    • As tubular fluid runs down the late distal tubule and collecting duct it encounters surrounding interstitial fluid whose osmolarity progressively increases. If the tubular membrane is permeable to water, due to the presence of ADH, then water will be progressively osmotically resorbed as it descends through the tubule. The ultimate osmolarity of the tubular fluid will match that of the most concentrated endpoint of the corticopapillary osmotic gradient, found in the renal papillae. Notably, the presence of ADH also enhances the size of the corticopapillary gradient, increasing its end-point concentration, in this way further serving to concentrate urine.
    • The molecular mechanism by which ADH controls the tubular water permeability of these final nephronic segments was unknown for many years. However, it is now clear that the presence of ADH results in the placement of pre-formed water channels, known as aquaporins, into the luminal membranes of principal cells. Consequently, in the presence of ADH, water is resorbed transcellularly whereas in the absence of ADH the aquaporin channels are removed from the principal cell membrane and thus water resorption is eliminated.
    • In the absence of ADH the water permeability of this segment is extremely low and the highly dilute tubular fluid exiting the diluting segments is simply excreted in the urine.
Generation of a Dilute and Concentrated Urine
  • Dilute Urine Formation
    • As seen above, whether the kidneys excrete a concentrated or dilute urine depends on the presence of ADH, a peptide hormone that regulates the water permeability of the late distal tubule and collecting duct. In the absence of ADH, little water is resorbed from the late distal tubule and collecting ducts; consequently, the highly dilute fluid generated in the Diluting Segments is simply excreted in the urine. In fact, because some solute resorption occurs in the final sections of the nephron, the tubular fluid becomes slightly more dilute, reaching an osmolarity of 50mOsm/L before being excreted. In this way the kidneys can excrete a highly dilute urine and in doing so can eliminate enormous amounts of free water from the extracellular fluid.
  • Concentrated Urine Formation
    • As ADH levels progressively increase, the water permeability of the late distal tubule and collecting ducts also rise, allowing for increasing free water resorption and thus urine concentration. The ultimate concentration of the excreted urine will match the osmolarity of the tail end of the corticopapillary gradient.
    • As discussed under the Corticopapillary Osmotic Gradient page, the size of the gradient is dependent on ADH. Indeed, when ADH levels are high the gradient is enhanced and can reach an osmolarity of 1200mOsm/L at its medullary end. However, at low levels of ADH, the medullary osmolarity of the gradient can be as low as 600mOsm/L, providing a much lower osmotic endpoint for water resorption. In this way, the presence of ADH displays a double-barrel influence on water resorption, by enhancing the late distal tubule and collecting duct permeability to water as well as enhancing the size of the corticopapillary gradient.