Urinary Concentration – The Medullary Osmotic Gradient

June 22, 2016 Anatomy, Critical Care, Hemodynamics, Histology, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , ,

The kidneys can produce a range of urine osmolalities depending on the levels of ADH. The production of hypo-osmotic urine is an understandable process: The tubules (particularly the thick ascending limb of Henle's loop) reabsorb relatively more solute than water, and the dilute fluid that remains in the lumen is excreted. The production of hyperosmotic urine is also straightfoward in that reabsorption of water from the lumen into a hyperosmotic interstitium concentrates that luminal fluid, leaving concentrated urine to be excreted.

The Mechanism to Generate Medullary Osmotic Gradient

There is a gradient of osmolality (hyperosmotic), increasing from a nearly iso-osmotic value at the corticomedullary border to a maximum of greater than 1000 mOsm/kg at the papilla. The peak osmolality is variable depending on dehydration or overhydration, where highest during periods of dehydration and lowest (approximately half of that during excess hydration) during excess hydration.

In the steady state there must be mass balance, that is, every substance that enters the medulla via tubule or blood vessel must leave the medulla via tubule or blood vessels. However, during development of the gradient there are transient accumulations of solute, and during washout of the gradient there are losses. To develop the osmotic gradient in the medullary interstitium, there must be deposition of solute in excess of water. It is reabsorption of sodium and chloride by the thick ascending limb in excess of water reabsorbed in the thin descending limbs that accomplishes this task. At the junction between the inner and outer medulla, the ascending limbs of all loops of Henle, whether long or short, turn into thick regions and remain thick all the way back until they reach the original Bowman's capsules. As they reabsorb solute without water and dilute the luminal fluid, they simultaneously add solute without water to the surrounding interstitium. This action of the thick ascending limb is absolutely essential and is the key to everything else that happens. If transport in the thick ascending limb is innhibited, the lumen is not diluted and the interstitium is not concentrated, and the urine becomes iso-osmotic.


  • For thick ascending limbs in the cortex, reabsorbed solute is taken up by abundant cortex blood flow so intersititum osmolality in the cortex approximately equal plasma
  • High concentratiion sodium level in outer medulla interstitium makes them diffuse into DVR and AVR
  • Hyperosmotic sodium in AVR can diffuse into nearby DVR – the countercurrent exchange

For those portions of the thick ascending limbs in the cortex, the reabsorbed solute simply mixes with material reabsorbed by the nearby proximal convoluted tubules. Because the cortex contains abundant peritubular capillaries and a hight blood flow, the reabsorbed material immediately moves into the vasculature and returns to the general circulation. However, in the medulla, the vascular anatomy is arranged differently and total blood flow is much lower. Solute that is reabsorbed and deposited in the outer medullary interstitium during the establishment of the osmotic gradient is not immediately removed, that is, it accumulates. The degree of accumulation before a steady state is reached is a function of the arrangement of the vasa recta, their permeability properties and the volume of blood flowing within them.

Imagine first a hypothetical situation of no blood flow. Sodium would accumulate in the outer medulla without limit, because there would be no way to remove it. But, of course the outer medulla is perfused with blood, as are all tissues. Blood enters and leaves the outer medulla through parallel bundles of descending and ascending vasa recta (DVR and AVR). These vessels are permeable to sodium. Therefore sodium enters the vasa recta driven by the rise in concentration in the surrounding interstitium. Sodium entering the ascending vessels returns to the general circulation, but sodium in the descending vessels is distributed deeper into the medulla, where it diffuses out across the endothelia of the vassa recta and the interbundle capillaries that they feed, thereby raising the sodim content throughout the medulla.

Later, the interbundle capillaries drain into ascending vasa recta that lie near descending vasa recta. The walls of the ascending vasa recta are fenestrated, allowing movment of water and small solutes between plasma and interstitium. As the sodium concentration of the medullary interstitium rises, blood in the ascending vessels also takes on an increasingly higher sodium concentration. However, blood entering the medulla always has a normal sodium concentration (approximtely 140 mEq/L). Accordingly, some of the sodium begins to re-circulate, diffusing out of ascending vessels and reentering nearbydescending vessels that contain less sodium (countercurrent exchange). So sodium is entering descending vasa recta from 2 sources – re-circulated sodium from the ascending vasa recta, and new sodium from the thick ascending limbs. Over time, everything reaches a steady state in which the amount of new sodium entering the interstitium from thick ascending limbs matches the amount of sodium leaving the interstitium in ascending vasa recta. At its peak, the concentration of sodium in the medulla may reach 300 mEq/L, more than double its value in the general circulation. Since sodium is accompanied by an anion, mostly chloride, the contribution of salt to the medullary osmolality is approximately 600 mOsm/kg.


  • While solute can accumulate without a major effect on renal volume, the amount of water in the medullary interstitium must remain nearly constant; otherwise the medulla would undergo significiant swelling or shrinking.
  • Because water is always being reabsorbed from the medullary tubules into the interstitium (from descending thin limbs and medullary colelcting ducts), that water movement must be matched by equal water movement from the interstitium to the vasculature.
  • Blood entering the medulla has passed through glomeruli, thereby concentrating the plasma proteins. While the overall osmotic content (osmolality) of this blood is essentially isosmotic with systemic plasma, its oncotic pressure is considerably higher.

The challenge for the kidneys is to prevent dilution of the hyperosmotic interstitium by water reabsorbed from the tubules and by water diffusing out of the iso-osmotic blood entering the medulla. The endotheial cells of descending vasa recta contain aquaporins. So water is drawn osmotically into the outer medullary interstitium by the high salt content in a manner similar to water being drawn out of tubular elements. At first glance it seems that this allows the undesired diluting effect to actually take place. But, of course, solute is also constantly being added from the nearby thick ascending limbs. The loss of water from descending vasa recta in the outer medulla serves the useful purpose of raising the osmolality of blood penetrating the inner medulla and decreasing its volume, thereby reducing the tendency to dilute the inner medullary interstitium. The ascending vasa recta have a fenestrated endothelium, allowing free movement of water and small solutes. Since the oncotic pressure is high, water entering the interstitium of the outer medulla from descending vasa recta is taken up by ascending vasa recta and removed from the medulla. In addition, water reabsorbed from tubular elements (descending thin limbs and collecting ducts) is also taken up by ascending vasa recta and removed, thereby preserving constancy of total medullary water content.

The magnitude of blood flow in the vasa recta is a crucial variable. The peak osmolality in the interstitium depends on the ratio of sodium pumping by the thick ascending limbs to blood flow in the vasa recta. If this ratio is high (meaning low blood flow), water from the isosmotic plasma entering the medulla in descending vasa recta does not dilute the hyperosmotic interstitium. In effect the "salt wins" and osmolality remains at a maximum. But in conditions of water excess, this ratio is very low (high blood flow) and the diluting effect of water diffusing out of descending vasa recta is considerable. In part the tendency to diulte is controlled by ADH (due to its vasoconstriction effect to limit the blood flow of DVR).


The peak osmolality in the renal papilla reaches over 1000 mOsm/kg. Approximately half of this is accounted for by sodium and chloride, and most of the rest is (500-600 mOsm/kg) accounted for by urea. Urea is a very special substance for the kidney. It is an end product of protein metabolism, waste to be excreted, and also an important component for the regulation of water excretion. For the handle of urea in the kidneys: 

1.There are no membrane transport mechanisms in the proximal tubule; instead, it easily permeates the tight junctions of the proximal tubule where it is reabsorbed paracellularly.

2.Tubular elements beyond the proximal tubule express urea transporters and handle urea in a complex, regulated manner.

The gist of the renal handling of urea is the following: it is freely filtered. About half is reabsorbed passively in the proximal tubule. Then an amount equal to that reabsorbed is secreted back into the loop of Henle. Finally, about half is reabsorbed a second time in the medullary collecting duct. The net result is that about half the filtered load is excreted.

Urea does not permeate lipid layer because of its highly polar nature, but a set of uniporters transport urea in various places beyond the proximal tubule and in other sites within the body. Because urea is freely filtered, the filtrate contains urea at a concentration identical to that in plasma. In the proximal tubule when water is reabsorbed, the urea concentation rises well above the plasma urea concentration, driving diffusion through the leaky tight junctions. Roughly, half the filtered load is reabsorbed in the proximal tubule by the by the paracellular route. As the tubular fluid enters the loop of Henle, about half the filtered urea remains, but the urea concentration has increased somewhat above its level in the filtrate because proportionally, more water than urea was reabsorbed. At this point, the process becomes fairly complicated.

The interstitium of the medulla has a considerably higher urea concentration than does plasma. The concentration increases from the outer to the inner medulla. Since the medullary interstitial urea concentration is greater than that in the tubular fluid entering the loop of Henle, there is a concentration gradient favoring secretion into the lumen. The tight junctions in the loop of Henle are no longer permeable, but the epithelial membranes of the thin regions of the Henle's loops express urea uniporters, members of the UT family. This permits secretion of urea into the tubule. In fact, the urea secreted from the medullary interstitium into the thin regions of the loop of Henle replaces the urea previously reabsorbed in the proximal tubule. Thus, when tubular fluid enters the thick ascending limb, the amount of urea in the lumen is at least as large as the filtered load. However, because about 80% of the filtered water has now been reabsorbed, the luminal urea concentration is now several times greater than in the plasma. Beginning with the thick ascending limb and continuing all the way to the inner medullary collecting ducts (through the distal tubule and cortical collecting ducts), the apical membrane urea permeability (and the tight junction permeability) is essentially zero. Therefore, an amount of urea roughly equal to the filtered load remains within the tubular lumen and flows from the cortical into the medullary collecting ducts.

During the transit through the cortical collecting ducts variable amounts of water are reabsorbed, significantly concentrating the urea.We indicated eariler that the urea concentration in the medullary interstitium is much greater than in plasma, but the luminal concentration in the medullary collecting ducts is even higher (up to 50 times its plasma value), so in the inner medulla the gradient now favors reabsorption and urea is reabsorbed a second time via another isoform of UT urea uniporter. It is this urea reabsorbed in the inner medulla that leads to the high medullary interstitial concentration, driving urea secretion into the thin regions of the loop of Henle.

Histology of Renal Tubules and Capillaries

October 8, 2015 Nephrology, Physiology and Pathophysiology No comments , , , , , ,

Renal Tubule

The renal tubule begins at and leads out of Bowman’s capsule on the side opposite the vascular pole (the tubule pole, compare the Arctic pole and Antarctic pole of Earth). The tubule has a number of segments divided into subdivisions. Throughout its length the tubule is made up of a single layer of epithelial cells resting on basement membrane and connected by tight junctions that physically link the cells together.

Renal tubule segments include proximal convoluted tubule, proximal straight tubule, descending thin limb of the loop of Henle, the ascending thin limb of the loop of Henle (only long loop nephrons), ascending thick limb of the loop of Henle, distal convoluted tubule, connecting tubule, and collecting duct.

The proximal tubule is the first segment. It drains Bowman’s capsule and consists of a coiled segment – the proximal convoluted tubule – followed by a shorter straight segment – the proximal straight tubule. The coiled segment is entirely within the cortex, whereas the straight segment descends a short way into the outer medulla. Most of the length and functions of the proximal tubule are in the cortex. The next segment is the descending thin limb of the loop of Henle. The descending thin limbs of all nephrons begin at the same level, at the point where they connect to straight portions of proximal tubules in the outer medullaThis marks the border between the outer and inner stripes of the outer medulla.

In contrast, the descending thin limbs of different nephrons penetrate down to varying depths in the medulla. At their ending they abruptly reverse at a hairpin turn and become an ascending portion of the loop of Henle parallel to the descending portion. In long loops, the ones that have penetrated deep into the inner medulla, the epithelium of the first portion of the ascending limb remains thin, although different functionally from that of the descending limb. This segment is called the ascending thin limb of Henle’s loop, or simple the ascending thin limb. Further up the ascending portion the epithelium thickens, and this next segment is called the thick ascending limb. In short loops, there is no ascending think portion, and the thick ascending portion begins right at the hairpin loop.

All thick ascending limbs begin at the same level, which marks the border between the inner and outer medulla. Therefore, the thick ascending limbs begin at a slight deeper level in the medulla than do thin descending limbs. Each thick ascending limb rises back into the cortex right back to the very same Bowman’s capsule from which the tubule originated. Here it passes directly between the afferent and efferent arterioles at the vascular pole of Bowman’s capsule. The cell in the thick ascending limb closest to Bowman’s capsule (between the afferent and efferent arterioles) are specialized cells known as the macula densa. The macula densa marks the end of the thick ascending limb and the beginning of the distal convoluted tubule. This is followed by the connecting tubule, which leads to the cortical collecting duct, the first portion of which is called the initial collecting tubule. Connecting tubules from several nephrons merge to form a given cortical collecting duct.

All the cortical collecting ducts then run downward to enter the medulla and become outer medullary collecting ducts, and continue to become inner medullary collecting ducts. These merge to form larger ducts, the last portions of which are called papillary collecting ducts, each of which empties into a calyx of the renal pelvis. Each renal calyx is continuous with the ureter. The tubular fluid, now properly called urine, is not altered after it enters a calyx. Up to the distal convoluted tubule, the epithelial cells forming the wall of a nephrons in any given segment are homogeneous and distinct for that segment. For example, the thick ascending limb contains only thick ascending limb cells. However, beginning in the second half of the distal convoluted tubule the epithelium contains 2 intermingled cell types. The first constitutes the majority of cells in a particular segment and are usually called principal cells. Thus, there a segment-specific principal cells in the distal convoluted tubule, connecting tubule, and collecting ducts. Interspersed among the segment-specific cells in these regions are cells of a second type, called intercalated cells, that is, they are intercalated between the principal cells. The last portion of the medullary collecting duct contains neither principal cells nor intercalated cells but is composed entirely of a distinct cell type called the inner medullary collecting-duct cells.

Renal VesselsScreen Shot 2015-10-04 at 4.06.11 PM

Blood enters each kidney at the hilum via a renal artery. After several divisions into smaller arteries blood reaches arcuate arteries that course across the tops of the pyramids between the medulla and cortex. From these, cortical radial arteries project upward toward the kidney surface and give off a series of afferent arterioles (AAs), each of which leads to a glomerulus within Bowman’s capsule. These arteries and glomeruli are found only in the cortex, never in the medulla. In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles, the efferent arterioles (EAs). The vast majority of the EAs soon subdivide into a second set of capillaries called peritubular capillaries. These capillaries are profusely distributed throughout the cortex intermingled with the tubular segments. The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney. EAs of glomeruli situated just above the corticomedullary border (juxtamedullary glomeruli) do not brach into peritubular capillaries the way most EAs do. Instead these arterioles descend downward into the outer medullar. Once in the medulla they divide many times to form buddies of parallel vessels called vasa recta. These bundles of vasa recta penetrate deep into the medulla.

Vasa recta on the outside of the vascular bundles “peel off” and give rise to interbundle networks of capillaries that surround Henle’s loops and the collecting ducts in the outer medullaOnly the center-most vasa recta supply capillaries in the inner medulla; thus, little blood flows into the papilla. The capillaries from the inner medulla re-form into ascending vasa recta that run in close association with the descending vasa recta within the vascular bundles. The structural and functional properties of the vasa recta are rather complex.