UREA

The Kidney Filters, Reabsorbs, and Secretes Urea

The liver generates urea from , the primary nitrogenous end product of amino acid catabolism (p. 997). The primary route for urea excretion is the urine, although some urea exits 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 per dl plasma"; normal values are 7 to 18 mg/dl. For a 70-kg human on a typical Western diet, and producing 1.5 to 2 liters/day of urine, the urinary excretion of urea is approximately 450 mmole/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 35-1A (i.e., average urine flow), the kidneys excrete approximately 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. In the very early proximal tubule (Fig. 35-1B), [urea] in the lumen is the same as in blood plasma. However, paracellular fluid reabsorption along the proximal tubule sweeps some urea along with it via solvent drag (p. 469). In addition, water leaves the lumen through the tubule cells, leaving behind urea, and generating a favorable transepithelial gradient for urea that drives its reabsorption by diffusion via the transcellular or paracellular pathway. The greater the fluid reabsorption along the proximal tubule, the greater is the reabsorption of urea via both solvent drag and diffusion.
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Figure 35-1 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 thin ascending limb (tALH) and the tip of the thin descending limb (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 after these segments are secreted. UT, urea transporter.
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Figure 35-2 Urea excretion versus urine flow. GFR, glomerular filtration rate. (Data from Austin JH, Stillman E [amp ] Van Slyke DD: Factors

governing the excretion rate of urea. J Biol Chem 46:91-112, 1921.)

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 (p. 835). Thus, the deepest portion of the tDLH, which has a urea transporter known as UT2, secretes urea via facilitated diffusion (Fig. 28-1C). 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 (Fig. 28-1D). 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 UT2 along their entire length, these cells secrete urea. Thus, both superficial and juxtamedullary nephrons contribute to urea secretion, raising urea delivery to approximately 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 that is unusual in that both the apical and basolateral steps occur via facilitated diffusion (Fig. 35-1E). The UT1 urea transporter moves urea across the apical membrane of the IMCD cell, whereas UT4 probably mediates urea movement across the basolateral membrane. Arginine vasopressin (AVP)-also known as antidiuretic hormone (ADH)-stimulates UT1 but not UT4. In Chapter 37, we discuss the role of urea transport in the urinary concentrating mechanism (p. 836). UT2, the prototypical member of the UT family, is a 43-kDa integral membrane protein with 10 putative membrane-spanning segments. UT2 is unusual among membrane proteins in that it is extremely hydrophobic; except for a large extracellular loop, almost the entire central portion of the protein may be embedded within the membrane. UT1, a splice variant of the same gene, is a 102-kDa protein with 20 membrane-spanning segments. UT1 is nearly a tandem repeat of UT2, with the two UT2-like domains linked by an intracellular loop. This loop has several putative phosphorylation sites for protein kinase A (PKA), which explains why AVP-which acts through cyclic adenosine monophosphate (cAMP) (p. 97)-stimulates only UT1. As is discussed in Chapter 37, UT3, which is closely related to UT2, is present in the descending limb of the vasa recta (p. 838).
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. 35-2). At low urine flow, when the tubule reabsorbs considerable water and, therefore, much urea, the kidneys excrete only approximately 15% of filtered urea (see Fig. 37-5). 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 the glomerular filtration rate (GFR) leads to a low urine flow and urea retention, and thus an increase in BUN. In clinical conditions such as volume depletion, in which the urine flow declines sharply (p. 864), urea excretion decreases out of proportion to the fall in GFR. The resulting high BUN can thus serve as laboratory confirmation of dehydration. The flow dependence of urea clearance contrasts with the behavior of creatinine clearance, which, like inulin clearance (p. 759), is largely independent of urine flow. Consequently, in patients with reduced effective circulating volume (p. 556), and thus a low urine flow, the plasma [BUN]/[creatinine] ratio increases from its normal value of approximately 10 (both concentrations in mg/dl).
Printed from STUDENT CONSULT: Medical Physiology (on 24 August 2006) 2006 Elsevier