Medical Physiology, 3rd Edition

Urea

The kidney filters, reabsorbs, and secretes urea

The liver generates urea from image, the primary nitrogenous end product of amino-acid catabolism (see p. 965). The primary route for urea excretion is the urine, although some urea exits the body through the stool and sweat. The normal plasma concentration of urea is 2.5 to 6 mM. Clinical laboratories report plasma urea levels as blood urea nitrogen (BUN) in the units (mg of elemental nitrogen)/(dL plasma); normal values are 7 to 18 mg/dL. For a 70-kg human ingesting a typical Western diet and producing 1.5 to 2 L/day of urine, the urinary excretion of urea is ~450 mmol/day.

The kidney freely filters urea at the glomerulus, and then it both reabsorbs and secretes it. Because the tubules reabsorb more urea than they secrete, the amount of urea excreted in the urine is less than the quantity filtered. In the example shown in Figure 36-1A (i.e., average urine flow), the kidneys excrete ~40% of the filtered urea. The primary sites for urea reabsorption are the proximal tubule and the medullary collecting duct, whereas the primary sites for secretion are the thin limbs of the loop of Henle.

image

FIGURE 36-1 Urea handling by the kidney. In A, we assume a normal urine flow and thus a urea excretion of 40% of the filtered load. The numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The tALH and the tip of the tDLH in juxtamedullary nephrons secrete urea. In superficial nephrons, the entire tDLH may secrete urea. The red box indicates the fraction of the filtered load jointly secreted by both nephron types. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.

In the very early proximal tubule (see Fig. 36-1B), [urea] in the lumen is the same as in blood plasma. However, water reabsorption tends to increase [urea] in the lumen, thereby generating a favorable transepithelial gradient that drives urea reabsorption by diffusion via the transcellular or paracellular pathway. In addition, some urea may be reabsorbed by solvent drag (see p. 467) across the tight junctions. The greater the fluid reabsorption along the proximal tubule, the greater the reabsorption of urea via both diffusion and solvent drag.

In more distal urea-permeable nephron segments, urea moves via facilitated diffusion through the urea transporters (UTs).imageN36-1 The SLC14A2 gene encodes not only UT-A2 but also the splice variants UT-A1 and UT-A3. The prototypical member of the UT family, UT-A2, is a glycosylated 55-kDa integral membrane protein with 10 putative membrane-spanning segments (TMs). UT-A3 also has 10 TMs. The bacterial homolog has three monomers, each of which contains a urea pore, with the pores arranged as a triangle. UT-A1 is a 97-kDa protein with 20 TMs. UT-A1 is basically UT-A3 linked—via an intracellular loop—to UT-A2.

N36-1

Urea Transporters

Contributed by Walter Boron

The UTs belong to the SLC14 family of transporters. The family has two gene members, SLC14A1 and SLC14A2. Both mediate facilitated diffusion. That is, the movement of urea is not coupled to that of another solute, but nevertheless exhibits saturation and other hallmarks of carrier-mediated transport.

SLC14A1: This gene has at least two variants: UT-B1 (also known as UT3) and UT-B2 (also known as UT11). These are expressed in the descending vasa recta and red blood cells.

SLC14A2: This gene has at least eight variants: UT-A1 (UT1), UT-A1b, UT-A2 (UT2), UT-A2b, UT-A3 (UT4), UT-A3b, UT-A4, and UT-A5. These are expressed predominantly in the kidney but also in other organs.

The putative fundamental topology of a UT protein is 5 membrane-spanning segments (TMs), a large extracellular loop, and an additional 5 TMs (for a total of 10 TMs). Somewhat paradoxically, the UT-A1 variant of SLC14A2—the first UT discovered—is a concatamer or two such units, linked by a long intracellular loop; it therefore has a total of 20 putative TMs.

References

Bradford AD, Terris JM, Ecelbarger CA, et al. 97- and 117-kDa forms of collecting duct urea transporter UT-A1 are due to different states of glycosylation. Am J Physiol Renal Physiol. 2001;281:F133–F143.

Sands J. Mammalian urea transporters. Annu Rev Physiol. 2003;65:543–566.

Shayakul C, Hediger MA. The SLC14 gene family of urea transporters. Pflugers Arch. 2004;447:603–609.

In juxtamedullary nephrons, as the tubule fluid in the thin descending limb (tDLH) approaches the tip of the loop of Henle, [urea] is higher in the medullary interstitium than in the lumen (see pp. 811–813). Thus, the deepest portion of the tDLH secretes urea via facilitated diffusion (see Fig. 36-1C) mediated by the urea transporter UT-A2. As the fluid turns the corner to flow up the thin ascending limb (tALH), the tubule cells continue to secrete urea into the lumen, probably also by facilitated diffusion (see Fig. 36-1D).

The tDLH of superficial nephrons is located in the inner stripe of the outer medulla. Here, the interstitial [urea] is higher than the luminal [urea] because the vasa recta carry urea from the inner medulla. Because the tDLH cells of these superficial nephrons appear to have UT-A2 along their entire length, these cells secrete urea. Thus, both superficial and probably also juxtamedullary nephrons contribute to urea secretion, raising urea delivery to ~110% of the filtered load at the level of the cortical collecting ducts.

Finally, the inner medullary collecting duct (IMCD) reabsorbs urea via a transcellular route involving apical and basolateral steps of facilitated diffusion (see Fig. 36-1E). The UT-A1 urea transporter moves urea across the apical membrane of the IMCD cell, whereas UT-A3 probably mediates urea movement across the basolateral membrane. Arginine vasopressin (AVP)—which is also known as antidiuretic hormone (ADH) and acts through cAMP (see p. 57)—stimulates UT-A1 and UT-A3. We discuss the role of urea transport in the urinary concentrating mechanism beginning on page 811.

UT-B1 and UT-B2, each encoded by SLC14A1, are present in the descending limb of the vasa recta (see p. 814).

Urea excretion rises with increasing urinary flow

Because urea transport depends primarily on urea concentration differences across the tubule epithelium, changes in urine flow unavoidably affect renal urea handling (Fig. 36-2). At low urine flow, when the tubule reabsorbs considerable water and, therefore, much urea, the kidneys excrete only ~15% of filtered urea (see Fig. 38-5). However, the kidneys may excrete as much as 70% of filtered urea at high urine flow, when the tubules reabsorb relatively less water and urea. During the progression of renal disease, the decline of glomerular filtration rate (GFR) leads to a low urine flow and urea retention, and thus an increase in BUN.

image

FIGURE 36-2 Urea excretion versus urine flow. PUrea, plasma concentration of urea. (Data from Austin JH, Stillman E, Van Slyke DD: Factors governing the excretion rate of urea. J Biol Chem 46:91–112, 1921.)

In clinical conditions such as volume depletion, in which the urine flow declines sharply (see Box 40-1), urea excretion decreases out of proportion to the fall in GFR. The resulting high BUN can thus serve as laboratory confirmation of volume depletion. The flow dependence of urea clearance contrasts with the behavior of creatinine clearance, which, like inulin clearance (see p. 740), is largely independent of urine flow. Consequently, in patients with reduced effective circulating volume (see pp. 554–555), and hence low urine flow, the plasma [BUN]/[creatinine] ratio increases from its normal value of ~10 (both concentrations in mg/dL).