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. Urea differs from all the other organic solutes discussed in this chapter in several significant ways. (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.
Urea is derived from proteins, which form much of the functional and structural substance of body tissues. Proteins are also a source of metabolic fuel. Dietary protein is first digested into its constituent amino acids. These are then used as building blocks for tissue protein (eg, muscle), converted to fat or oxidized immediately. During fasting, the body breaks down proteins into amino acids that are used as fuel, in essence consuming itself. The metabolism of amino acids yields a nitrogen moiety (ammonium) and a carbohydrate moiety. The carbohydrate goes on to further metabolic processing, but the ammonium cannot be further oxidized and is a waste product. Ammonium per se is rather toxic to most tissues (except the medullary interstitium, see Chapter 9) and the liver immediately converts most ammonium to urea and a smaller, but crucial amount to glutamine. While normal levels of urea are not toxic, the large amounts produced on a daily basis, particularly on a high protein diet, represent a large osmotic load that must be excreted. Whether a person is well fed or fasting, urea production proceeds continuously and constitutes about half of the usual solute content of urine.
Urea constitutes about half the usual solute content of the urine.
The normal level of urea in the blood is quite variable (3–9 mmol/L),1 reflecting variations in both protein intake and renal handling of urea. Over days to weeks, renal urea excretion must match hepatic production; otherwise plasma levels would increase into the pathological range producing a condition called uremia. On a shorter-term basis (hours to days), urea excretion rate may not exactly match production rate because urea excretion is also regulated for purposes other than keeping a stable plasma level.
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 (Figure 5–4).
Urea handling by the kidney. The arrows indicate that urea is reabsorbed in the proximal tubule, secreted in the thin portions of the loop of Henle, and reabsorbed again in the inner medullary collecting ducts. The top halves of boxes indicate the percentage of the filtered load remaining in the tubule at a given location, and the bottom halves indicate tubular concentration relative to plasma. Note that, while the amount remaining in the collecting duct (and thus excreted) is half the amount filtered, the concentration is much higher than in plasma because most of the water has been reabsorbed. These numbers are highly variable, depending on several factors, particularly the hydration status.
As a molecule, urea is small (molecular weight, 60 Da), water-soluble, and freely filtered. Because of its highly polar nature, it does not permeate lipid bilayers, but a set of uniporters (UT family) transport urea in various places beyond the proximal tubule and in other sites within the body (particularly red blood cells). Because urea is freely filtered, the filtrate contains urea at a concentration identical to that in plasma. Let us assume a normal plasma level (5 mmol/L). As water is reabsorbed, the urea concentration rises well above 5 mmol/L, driving diffusion through the leaky tight junctions. Roughly, half the filtered load is reabsorbed in the proximal tubule 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. First, conditions in the medulla depend highly on the individual's state of hydration. Second, there is a difference between superficial nephrons with short loops of Henle that only penetrate the outer medulla and juxtamedullary nephrons, with long loops of Henle that reach all the way down to the papilla. For simplicity we consider all nephrons together.
The interstitium of the medulla has a considerably higher urea concentration than does plasma (for reasons explained later). 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 (as they were in the cortex), 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 (the loop of Henle has reversed what was accomplished in the proximal tubule). 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.
Some urea recycles between the tubule and medullary interstitium; about half the filtered load is excreted
During the transit through the cortical collecting ducts variable amounts of water are reabsorbed, significantly concentrating the urea. Just how much depends on factors discussed in the next chapter, but the luminal urea concentration is well above that of plasma. We indicated earlier 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, 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. This means that some of the urea recycles, that is, it is reabsorbed from inner medullary collecting ducts and secreted into thin limbs of the loop of Henle, from where it travels within the tubule to the collecting ducts again to repeat the process. The overall result of these events is that half the original amount of filtered urea passes into the final urine, an amount that, over the long term, must match hepatic production of urea if the body is to remain in balance for urea. The concentration of urea in the final urine can be more than 50× that in plasma, depending on how much water is reabsorbed. These processes are summarized in Figure 5–4.