In the renal medulla, NaCl and urea build up, resulting in the interstitial fluid at the tip of the inner medulla's papilla reaching a maximum osmolality of 1200 mOsm/kg H2O. About 600 mOsm/kg H2O is due to NaCl (300 mmol/L) and another 600 mOsm/kg H2O is due to urea (600 mmol/L). The establishment of the NaCl gradient is mostly complete at the transition between the outer and inner medulla.

The medullary gradient for NaCl is a result of the accumulation of NaCl that is reabsorbed by the nephron segments in the medulla during countercurrent multiplication. The ascending limb of the loop of Henle is the most significant segment in this process. On the other hand, the accumulation of urea within the medullary interstitium is more complex and occurs most effectively during antidiuresis when hyperosmotic urine is excreted. When dilute urine is produced, especially over extended periods, the osmolality of the medullary interstitium decreases. This decrease is primarily caused by a decrease in urea concentration. The decline in urea concentration is mainly due to washout by the vasa recta and diffusion of urea from the interstitium into the tubular fluid within the medullary part of the collecting duct. Even in the absence of AVP, the collecting duct in the cortical and outer medullary portions has low permeability to urea, while the inner medullary portion has relatively high permeability due to the presence of the urea transporters UT-A1 and UT-A3, whose expression is increased by AVP.

Reabsorbed urea is secreted into the thin descending limbs of Henle's loops via the urea transporter UT-A2 and enters the vasa recta through the UT-B transporter. The urea that is secreted into the descending thin limbs of Henle's loops gets trapped in the nephron until it reaches the medullary collecting duct again, where it can reenter the medullary interstitium. This recycling of urea facilitates the accumulation of urea in the medullary interstitium, reaching a concentration of 600 mmol/L at the tip of the papilla.

The hyperosmotic medulla is crucial for concentrating the tubular fluid within the collecting duct. Since water reabsorption from the collecting duct is driven by the osmotic gradient established in the medullary interstitium, the concentration of urine cannot be higher than that of the interstitial fluid in the papilla. Therefore, any condition that reduces the medullary interstitial osmolality impairs the kidneys' ability to maximize urine concentration. Urea in the medullary interstitium contributes to the total osmolality of urine. However, because the inner medullary collecting duct is highly permeable to urea, especially in the presence of AVP, urea cannot induce water reabsorption across this nephron segment. Instead, urea in the tubular fluid and medullary interstitium reach equilibrium, leading to the excretion of a small volume of urine with a high urea concentration.

It is the medullary interstitial NaCl concentration that reabsorbs water from the medullary collecting duct and thereby concentrates the nonurea solutes (such as NH4+ salts, K+ salts, creatinine) in the urine.
Fig. 35.8 , NaCl and urea accumulate in the renal medulla, and the interstitial fluid at the tip of the papilla of the inner medulla reaches a maximum osmolality of 1200 mOsm/kg H2O, with approximately 600 mOsm/kg H2O attributable to NaCl (300 mmol/L) and 600 mOsm/ kg H2O attributable to urea (600 mmol/L). Establishment of the NaCl gradient is essentially complete at the transition between the outer and inner medulla.
The medullary gradient for NaCl results from accumulation of NaCl reabsorbed by the nephron segments in the medulla during countercurrent multiplication. The most important segment in this regard is the ascending limb of the loop of Henle. Urea accumulation within the medullary interstitium is more complex and occurs most effectively when hyperosmotic urine is excreted (i.e., antidiuresis). When dilute urine is produced, especially over extended periods, the osmolality of the medullary interstitium declines (see
Fig. 37.7A ). This reduced osmolality is almost entirely caused by a decrease in the concentration of urea. This decrease reflects washout by the vasa recta (discussed later) and diffusion of urea from the interstitium into the tubular fluid within the medullary portion of the collecting duct, which is permeable to urea even in the absence of AVP. (NOTE: The cortical and outer medullary portions of the collecting duct have a low permeability to urea, whereas the inner medullary portion has a relatively high permeability because of the presence of the urea transporters UT-A1 and UT-A3, the expression of which is increased by AVP.) Some of this reabsorbed urea is secreted into the thin descending limbs of Henle’s loops via the urea transporter UT-A2, and some enters the vasa recta via the UT-B transporter. The urea that is secreted into the descending thin limbs of Henle’s loops is then trapped in the nephron until it again reaches the medullary collecting duct, where it can reenter the medullary interstitium. Thus urea recycles from the interstitium to the nephron and back into the interstitium. This process of urea recycling facilitates accumulation of urea in the medullary interstitium, where it can attain a concentration at the tip of the papilla of 600 mmol/L.
As described, the hyperosmotic medulla is essential for concentrating the tubular fluid within the collecting duct. Because water reabsorption from the collecting duct is driven by the osmotic gradient established in the medullary interstitium, urine can never be more concentrated than that of the interstitial fluid in the papilla. Thus any condition that reduces the medullary interstitial osmolality impairs the ability of the kidneys to maximally concentrate urine. Urea within the medullary interstitium contributes to the total osmolality of the urine. However, because the inner medullary collecting duct is highly permeable to urea, especially in the presence of AVP, urea cannot drive water reabsorption across this nephron segment. Instead, urea in the tubular fluid and medullary interstitium equilibrate, and a small volume of urine with a high concentration of urea is excreted.
It is the medullary interstitial NaCl concentration that is responsible for reabsorbing water from the medullary collecting duct and thereby concentrating the nonurea solutes (e.g., NH4 + salts, K+ salts, creatinine) in the urine.