Transport of Urea, Glucose, Phosphate, Calcium, Magnesium, and Organic Solutes

The kidney filters, reabsorbs, and secretes urea

The liver generates urea from , 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 36-1 A (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.

In the very early proximal tubule (see Fig. 36-1 B ), [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). N36-1 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.

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. 36-1 C ) 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. 36-1 D ).

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. 36-1 E ). 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.

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).

The proximal tubule reabsorbs glucose via apical, electrogenic Na/glucose cotransport and basolateral facilitated diffusion

The fasting plasma glucose concentration is normally 4 to 5 mM (70 to 100 mg/dL; see p. 1038 ) and is regulated by insulin and other hormones. The kidneys freely filter glucose at the glomerulus and then reabsorb it, so that only trace amounts normally appear in the urine ( Fig. 36-3 A ). The proximal tubule reabsorbs nearly all the filtered load of glucose, mostly along the first third of this segment. More distal segments reabsorb almost all of the remainder. In the proximal tubule, luminal [glucose] is initially equal to plasma [glucose]. As the early proximal tubule reabsorbs glucose, luminal [glucose] drops sharply, falling to levels far lower than those in the interstitium. Accordingly, glucose reabsorption occurs against a concentration gradient and must, therefore, be active.

Glucose reabsorption is transcellular; glucose moves from the lumen to the proximal tubule cell via Na/glucose cotransport, and from cytoplasm to blood via facilitated diffusion (see Fig. 36-3 B, C ). At the apical membrane, Na/glucose cotransporters ( SGLT1, SGLT2; see pp. 121–122 ) couple the movements of the electrically neutral d -glucose (but not l -glucose) and Na ⁺ . Phloridzin, extracted from the root bark of certain fruit trees (e.g., cherry, apple), inhibits the SGLTs. The basolateral Na-K pump maintains intracellular Na ⁺ concentration ([Na ⁺ ] _i ) lower than that of the tubule fluid. Moreover, the electrically negative cell interior establishes a steep electrical gradient that favors the flux of Na ⁺ from lumen to cell. Thus, the electrochemical gradient of Na ⁺ drives the uphill transport of glucose into the cell (i.e., secondary active transport), thereby concentrating glucose in the cytoplasm. N36-2

In the early part of the proximal tubule (S1 segment), a high-capacity, low-affinity transporter called SGLT2 (SLC5A2) mediates apical glucose uptake (see Fig. 36-3 B ). This cotransporter has an Na ⁺ -to-glucose stoichiometry of 1 : 1 and is responsible for 90% of the glucose reabsorption. Indeed, SGLT2 inhibitors have recently become available to treat patients with hyperglycemia due to diabetes mellitus. N36-3 In the later part of the proximal tubule (S3 segment), a high-affinity, low-capacity cotransporter called SGLT1 (SLC5A1) is responsible for apical glucose uptake (see Fig. 36-3 C ). Because this cotransporter has an Na ⁺ -to-glucose stoichiometry of 2 : 1 (i.e., far more electrochemical energy per glucose molecule), it can generate a far larger glucose gradient across the apical membrane (see Equation 5-20 ). Paracellular glucose permeability progressively diminishes along the proximal tubule, which further contributes to the tubule's ability to maintain high transepithelial glucose gradients and to generate near-zero glucose concentrations in the fluid emerging from the proximal tubule.

Once inside the cell, glucose exits across the basolateral membrane via a member of the GLUT (SLC2) family of glucose transporters (see p. 114 ). These transporters—quite distinct from the SGLTs—are Na ⁺ - independent and move glucose by facilitated diffusion. Like the apical SGLTs, the basolateral GLUTs differ in early and late proximal-tubule segments, with GLUT2 in the early proximal tubule (see Fig. 36-3 B ) and GLUT1 in the late proximal tubule (see Fig. 36-3 C ). In contrast to the apical SGLTs, the basolateral GLUTs have a much lower sensitivity to phloridzin.

Glucose excretion in the urine occurs only when the plasma concentration exceeds a threshold

The relationship between plasma [glucose] and the rate of glucose reabsorption is the glucose titration curve. Figure 36-4 A shows how rates of glucose filtration (orange curve), excretion (green curve), and reabsorption (red curve) vary when plasma [glucose] is increased by infusing intravenous glucose. As plasma [glucose] rises—at constant GFR—from control levels to ~200 mg/dL, glucose excretion remains zero. It is only above a threshold of ~200 mg/dL (~11 mM) that glucose appears in the urine. Glucose excretion rises linearly as plasma [glucose] increases further. Because the threshold is considerably higher than the normal plasma [glucose] of ~100 mg/dL (~5.5 mM), and because the body effectively regulates plasma [glucose] (see p. 1038 ), healthy people do not excrete any glucose in the urine, even after a meal. Likewise, patients with diabetes mellitus, who have chronically elevated plasma glucose concentrations, do not experience glucosuria until the blood sugar level exceeds this threshold value.

The glucose titration curve shows a second property, saturation. The rate of glucose reabsorption reaches a plateau—the transport maximum (T _m ) —at ~400 mg/min. The reason for the T _m value is that the SGLTs now become fully saturated. Therefore, these transporters cannot respond to further increases in filtered glucose.

Figure 36-4 A also shows that the rate of glucose reabsorption reaches the T _m gradually, not abruptly. This splay in the titration curve probably reflects both anatomical and kinetic differences among nephrons. Therefore, a particular nephron's filtered load of glucose may be mismatched to its capacity to reabsorb glucose. For example, a nephron with a larger glomerulus has a larger load of glucose to reabsorb. Different nephrons may have different distributions and densities of SGLT2 and SGLT1 along the proximal tubule. Accordingly, saturation in different nephrons may occur at different plasma levels. N36-4

At low filtered glucose loads, when no glucose appears in the urine (see Fig. 36-4 A ), the clearance (see p. 731 ) of glucose is zero. As the filtered load increases beyond the thresh­old, and glucose excretion increases linearly with plasma [glucose], the clearance of glucose progressively increases. At extremely high glucose loads, when the amount of glucose reabsorbed becomes small compared with the filtered load, glucose behaves more like inulin (i.e., it remains in the tubule lumen). Thus, if we replot the glucose-excretion data in Figure 36-4 A as clearance (i.e., excretion divided by plasma [glucose]), we see that, as the filtered glucose load rises, glucose clearance N36-5 (see Fig. 36-4 B , red curve) approaches inulin clearance (orange curve).

N36-5

Glucose Clearance

As stated in the text, the glucose clearance is zero at plasma glucose values below the threshold and gradually rises as plasma glucose level rises. We can express the excretion of glucose quantitatively at plasma concentrations beyond the threshold, where the glucose reabsorption rate (T _m ) has reached its maximum:

All three terms in the above equation are plotted in Figure 36-4 A . The first term in the equation ( ) is represented by the green curve. The second term (GFR × P _G ) is the yellow curve. The term (T _G ) is the red curve. Dividing both sides of the equation by P _G yields the glucose clearance (C _G ):

Thus, as plasma [glucose] approaches infinity, the right-hand term reduces to GFR, and therefore glucose clearance approaches inulin clearance (see Fig. 36-4 B ). In patients with an extremely low threshold, N36-4 glucose clearance even more closely approximates GFR.

The four key characteristics of glucose transport—(1) threshold, (2) saturation (T _m ), (3) splay, and (4) clearance approaching GFR at infinite plasma concentrations—apply to several other solutes as well, including amino acids, organic-anion metabolites (e.g., lactate, citrate, and α-ketoglutarate [α-KG]), PAH, and phosphate.

The proximal tubule reabsorbs amino acids using a wide variety of apical and basolateral transporters

The total concentration of amino acids in the blood is ~2.4 mM. These l -amino acids are largely those absorbed by the gastrointestinal tract (see p. 923 ), although they also may be the products of protein catabolism or of the de novo synthesis of nonessential amino acids.

The glomeruli freely filter amino acids ( Fig. 36-5 A ). Because amino acids are important nutrients, it is advantageous to retrieve them from the filtrate. The proximal tubule reabsorbs >98% of these amino acids via a transcellular route, using a wide variety of amino-acid transporters, some of which have overlapping substrate specificity ( Table 36-1 ). At the apical membrane, amino acids enter the cell via Na ⁺ -driven or H ⁺ -driven transporters as well as amino-acid exchangers (see Fig. 36-5 B ). At the basolateral membrane, amino acids exit the cell via amino-acid exchangers—some of which are Na ⁺ dependent—and also by facilitated diffusion (see p. 114 ). Particularly in the late proximal tubule and “postproximal” nephron segments, where the availability of luminal amino acids is low, SLC38A3 mediates the Na ⁺ -dependent uptake of amino acids across the basolateral membrane. This process is important for cellular nutrition or for metabolism. For example, in proximal-tubule cells SLC38A3 takes up glutamine—the precursor for synthesis and gluconeogenesis (see pp. 829–831 and Fig. 39-5 A ).

TABLE 36-1

Amino-Acid Transporters *

A. Apical Uptake
GENE NAME	PROTEIN NAMES	LUMINAL SUBSTRATES	OTHER TRANSPORTED SPECIES	LOCATION
	(System )
SLC1A1	EAAT3, EAAC1	Anionic (or acidic) amino acids (Glu and Asp)	Cotransports 2 Na + and 1 H + inward, exchanges 1 K + outward (Electrogenic uptake of net + charge)	Kidney, small intestine, brain
Heterodimer: SLC7A9 SLC3A1	(System b 0+ ) b 0,+ AT rBAT	Cationic (i.e., basic) amino acids (Lys + or Arg + ) or Cys (Cys-S-S-Cys)	Exchanges for neutral amino acid (Electrogenic uptake of + charge when substrate is Lys + or Arg + )	Kidney—cystinuria
	(System B 0+ )	Neutral and cationic amino acids	Cotransports 2 Na + and 1 Cl –	Small intestine
SLC6A14	ATB 0+
	(System Gly)
SLC6A18	XT2	Gly	Cotransports with Na + and Cl –	Kidney
	(System B 0 )	Neutral amino acids (not Pro), including aromatic amino acids (Phe, Trp, Tyr)	Cotransports with Na + (No Cl – )
SLC6A19	B 0 AT1			Kidney—Hartnup disease
SLC6A15	B 0 AT2			Kidney, brain
	(System IMINO)
SLC6A20	SIT, XT3	Pro, imino acids	Cotransports 2 Na + and 1 Cl –	Kidney, small intestine, brain
SLC36A1	PAT1, LYAAT1	Pro, Ala, Gly, GABA	Cotransports with H +	Small intestine, colon, kidney, brain
SLC36A2	PAT2	Pro, Gly, Ala, hydroxyproline	Cotransports with H +	Kidney, heart, lung
B. Basolateral Exit
GENE NAME	PROTEIN NAMES	CYTOPLASMIC SUBSTRATES	OTHER TRANSPORTED SPECIES	LOCATION
	(System GLY)	Gly (also N -methylglycine, i.e., sarcosine)	Cotransports Na + and Cl –	Small intestine
SLC6A5 SLC6A9	GLYT2 GLYT1
SLC7A1	(System y + ) CAT-1	Cationic (i.e., basic) amino acids	None (facilitated diffusion)	Ubiquitous (not liver), basolateral in epithelia
Heterodimer:	(System y + L)
SLC7A6 SLC3A2	y + LAT2 4F2hc	Cationic (i.e., basic) amino acids (Arg + , Lys + , ornithine + )	Exchanges for extracellular neutral amino acid plus Na +	Kidney, small intestine
Heterodimer:	(System y + L)
SLC7A7 SLC3A2	y + LAT1 4F2hc	Cationic (i.e., basic) amino acids (Arg + , Lys + , ornithine + )	Exchanges for extracellular neutral amino acid plus Na +	Kidney, small intestine
Heterodimer: SLC7A8 SLC3A2	(System L) LAT2 4F2hc	Neutral amino acids	Exchanges for neutral extracellular amino acid	Kidney
SLC16A10	TAT1 (MCT10)	Aromatic amino acids (Phe, Trp, Tyr)	None (facilitated diffusion)	Kidney
	(System A)	Gln, Ala, Asn, Cys, His, Ser	Cotransports Na +	Small intestine
SLC38A1, 2, 4	SNAT1, 2, 4
C. Basolateral Nutritional Uptake
GENE NAME	PROTEIN NAMES	BASOLATERAL SUBSTRATES	OTHER TRANSPORTED SPECIES	LOCATION
	(System N)			Kidney
SLC38A3	SNAT3	Gln, Asn, His	Cotransports Na + inward, exchanges H + outward
	(System ASC)		Exchanges for extracellular neutral amino acids; Na + dependent	Kidney, small intestine
SLC1A4 SLC1A5	ASCT1 ASCT2	Ala, Ser, Cys, Thr
D. Uptake by Other Tissues
GENE NAME	PROTEIN NAMES	EXTRACELLULAR SUBSTRATES	OTHER TRANSPORTED SPECIES	LOCATION
SLC1A2	EAAT2, GLT-1	Anionic (or acidic) amino acids (Glu and Asp)	Cotransports 2 Na + and 1 H + inward, exchanges 1 K + outward (Electrogenic uptake of net + charge)	Brain (astrocytes), liver
SLC1A3	EAAT1, GLAST			Brain (astrocytes), heart, skeletal muscle
SLC1A6	EAAT4			Brain (cerebellum)
SLC1A7	EAAT5			Retina
SLC6A1	GAT1	GABA (also betaine, β-alanine, taurine)	Cotransports Na + and Cl –	Brain (GABAergic neurons)
SLC6A11	GAT3			Brain (GABAergic neurons), kidney
SLC6A12	BGT1			Kidney, brain
SLC6A13	GAT2			Brain (choroid plexus), retina, liver, kidney

GABA, gamma-aminobutyric acid.

* The “System” designation is a historical classification based on functional characteristics in intact epithelia, intact cells, or membrane vesicles.

For an amino acid to cross the proximal-tubule epithelium, it must move through both an apical and a basolateral transporter (see Table 36-1 ). For example, glutamate enters the cell across the apical membrane via SLC1A1. This transporter simultaneously takes up Na ⁺ and H ⁺ in exchange for K ⁺ (see Fig. 36-5 B ). Inside the cell, glutamate can be metabolized to α-KG in the synthesis of and gluconeogenesis, or it can exit across the basolateral membrane, perhaps by SLC1A4 or SLC1A5. The positively charged lysine and arginine cross the apical membrane in exchange for neutral amino acids, with their movement mediated by the heterodimeric transporter SLC7A9/SLC3A1. This process is driven by the cell-negative voltage and by relatively high intracellular concentrations of the neutral amino acids. Lysine and arginine exit across the basolateral membrane via the electroneutral, heterodimeric transporter SLC7A7/SLC3A2, which simultaneously takes up Na ⁺ and a neutral amino acid. Neutral amino acids other than proline can cross the apical membrane via SLC6A19, driven by Na ⁺ , and exit across the basolateral membrane via the heterodimeric SLC7A8/SLC3A2, which exchanges neutral amino acids. Neutral aromatic amino acids such as tyrosine can exit by facilitated diffusion, mediated by SLC16A10. Proline enters across the apical membrane together with H ⁺ via SLC36A1 and exits across the basolateral membrane via the neutral amino-acid exchanger SLC7A8/SLC3A2.

Because the same carrier can reabsorb structurally similar amino acids, competitive inhibition may occur in the presence of two related amino acids. This effect may explain why the tubules do not fully reabsorb some amino acids (e.g., glycine, histidine, and some nonproteogenic amino acids, such as l -methylhistidine and taurine), even though the transporter itself is normal. Competition can also occur in patients with hyperargininemia ( Table 36-2 and Box 36-1 ).

Apparent competition between transported solutes occurs when they compete for the same energy source. Because the apical uptake of many organic and some inorganic solutes (e.g., phosphate, sulfate) depends on the electrochemical Na ⁺ gradient, increasing the activity of one such transporter can slow others. For example, glucose uptake via electrogenic Na/glucose cotransport may compromise the reabsorption of some amino acids for two reasons: (1) raising [Na ⁺ ] diminishes the chemical Na ⁺ gradient for other Na ⁺ -driven transporters, and (2) carrying net positive charge into the cell depolarizes the apical membrane and thus decreases the electrical gradient.

With a few exceptions, the kinetics of amino-acid reabsorption resembles that of glucose: the titration curves show saturation and transport maxima (T _m ). In contrast to the case of glucose, in which the T _m is relatively high, the T _m values for amino acids are generally low. As a consequence, when plasma levels of amino acids increase, the kidneys excrete the amino acids in the urine, thus limiting the maximal plasma levels.

An H ⁺ -driven cotransporter takes up oligopeptides across the apical membrane, whereas endocytosis takes up proteins and other large organic molecules

Oligopeptides

The proximal tubules reabsorb ~99% of filtered oligopeptides ( Fig. 36-6 A ). Segments beyond the proximal tubule contribute little to peptide transport.

Several peptidases are present at the outer surface of the brush-border membrane of proximal-tubule cells (see Fig. 36-6 B ), just as they are in the small intestine (see p. 922 ). These brush-border enzymes (e.g., γ-glutamyltransferase, aminopeptidases, endopeptidases, and dipeptidases) hydrolyze many peptides, including angiotensin II (see p. 841 ), thereby releasing into the tubule lumen the free constituent amino acids and oligopeptides. Tubule cells reabsorb the resulting free amino acids as described in the previous section. The cell also absorbs the resulting oligopeptides (two to five residues)—as well as other peptides (e.g., carnosine) that are resistant to brush-border enzymes—using the apical H/oligopeptide cotransporters PepT1 (SLC15A1) and PepT2 (SLC15A2; see p. 123 ). PepT1 is a low-affinity, high-capacity system in the early proximal tubule, whereas PepT2 is a high-affinity, low-capacity transporter in the late proximal segments—analogous in their properties to SGLT2 and SGLT1 (see pp. 121–122 ).

Once inside the cell, the oligopeptides undergo hydrolysis by cytosolic peptidases; this pathway is involved in the degradation of neurotensin and bradykinin. The distinction between which oligopeptides the cells fully digest in the lumen and which they take up via a PepT is not clear-cut. Oligopeptides that are more resistant to hydrolysis by peptidases are probably more likely to enter via a PepT.

Proteins

Although the glomerular filtration barrier (see p. 726 ) generally prevents the filtration of large amounts of protein, this restriction is incomplete (see pp. 741–743 ). For example, the albumin concentration in the filtrate is very low (4 to 20 mg/L), only 0.01% to 0.05% of the plasma albumin concentration. Nevertheless, given a GFR of 180 L/day, the filtered albumin amounts to 0.7 to 3.6 g/day. In contrast, albumin excretion in the urine normally is only ~30 mg/day. Thus, the tubules reabsorb some 96% to 99% of filtered albumin ( Fig. 36-7 A ). In addition to albumin, the tubules extensively reabsorb low-molecular-weight proteins that are relatively freely filtered (e.g., lysozyme, light chains of immunoglobulins, and β ₂ -microglobulin), SH-containing peptides (e.g., insulin), and other polypeptide hormones (e.g., parathyroid hormone [PTH], atrial natriuretic peptide [ANP], and glucagon). It is therefore not surprising that tubule injury can give rise to proteinuria even in the absence of glomerular injury.

Proximal-tubule cells use receptor-mediated endocytosis (see p. 42 ) to reabsorb proteins and polypeptides (see Fig. 36-7 B ). The first step is binding to receptors at the apical membrane (the receptor complex composed of megalin, cubilin, and amnionless), followed by internalization into clathrin-coated endocytic vesicles. Factors that interfere with vesicle formation or internalization, such as metabolic inhibitors and cytochalasin B, inhibit this selective absorption. The vesicles fuse with endosomes; this fusion recycles the vesicle membrane to the apical surface and targets the vesicle content for delivery to lysosomes. At the lysosomes, acid-dependent proteases largely digest the contents over a period that is on the order of minutes for peptide hormones and many hours or even days for other proteins. The cells ultimately release the low-molecular-weight end products of digestion, largely amino acids, across the basolateral membrane into the peritubular circulation. Although the proximal tubule hardly reabsorbs any protein in an intact state, a small subset of proteins avoids the lysosomes and moves by transcytosis for release at the basolateral membrane.

In addition to the apical absorption and degradation pathway, the kidney has two other pathways for protein degradation. The first may be important for several bioactive proteins, particularly those for which receptors are present on the basolateral membrane (e.g., insulin, ANP, AVP, and PTH). After transcytosis, the proximal-tubule cell partially hydrolyzes peptide hormones at the basolateral cell membrane. The resulting peptide fragments re-enter the circulation, where they are available for glomerular filtration and ultimate handling by the apical absorption/degradation pathway. The second alternative pathway for protein degradation involves receptor-mediated endocytosis by endothelial cells of the renal vascular and glomerular structures. This pathway participates in the catabolism of small peptides, such as ANP.

In conclusion, the kidney plays a major role in the metabolism of small proteins and peptide hormones. Renal extraction rates may be large, and they account for as much as 80% of the total metabolic clearance. Thus, it is not surprising that end-stage renal disease can lead to elevated levels of glucagon, PTH, gastrin, and ANP. Under physiological conditions, glomerular filtration represents the rate-limiting step for the removal of low-molecular-weight proteins from the circulation—apical absorption by the tubules, intracellular hydrolysis, and peritubular hydrolysis do not saturate over a wide range of filtered loads.

Two separate apical Na ⁺ -driven cotransporters reabsorb monocarboxylates and dicarboxylates/tricarboxylates

The combined concentration of carboxylates in the blood plasma is 1 to 3 mM, of which lactate represents the largest fraction. The monocarboxylates pyruvate and lactate are products of anaerobic glucose metabolism (see pp. 1174–1176 ). The dicarboxylates and tricarboxylates include intermediates of the citric acid cycle (see p. 1185 ). Because these carboxylates are important for energy metabolism, their loss in the urine would be wasteful. Normally, the proximal tubule reabsorbs virtually all these substances ( Fig. 36-8 A ). Nevertheless, carboxylates may appear in the urine when their plasma levels are elevated. Urinary excretion may occur when the filtered load of acetoacetate and β-hydroxybutyrate—ketone bodies (see p. 1185 ) produced during starvation or during low-insulin states (diabetes mellitus)—exceeds the T _m in the proximal tubule.

N36-18

OAT1 and OAT3 in the Proximal Tubule

Note that the transporters labeled “OAT1 or OAT3” in Figures 36-8 B and 36-9 B are the same. Note that the “Organic anion” entering in Figure 36-8 B could be PAH, and that the “Dicarboxylate” (DC ²⁻ ) exiting in Figure 36-9 B could be α-KG.

Two groups of Na ⁺ -dependent cotransporters carry carboxylates across the apical membranes (see Fig. 36-8 B ). First, SLC5A8 and SLC5A12 transport monocarboxylates, including lactate, pyruvate, acetoacetate, and β-hydroxybutyrate. Second, NaDC1 (SLC13A2) carries dicarboxylates and tricarboxylates, such as α-KG, malate, succinate, and citrate.

Once inside the cell, the monocarboxylates exit across the basolateral membrane via the H ⁺ /monocarboxylate cotransporter MCT2 (SLC16A7). Because monocarboxylates enter across the apical membrane coupled to Na ⁺ and then exit across the basolateral membrane coupled to H ⁺ , monocarboxylate reabsorption leads to an accumulation of Na ⁺ by the cell and a rise in intracellular pH.

Dicarboxylates exit the cell across the basolateral membrane via multiple organic anion–carboxylate exchangers; for example, the renal organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8; see p. 125 ). These exchangers may overlap in substrate specificity, or even carry anions of different valence. Moreover, the molecular identities and stoichiometries of some of these transporters are unknown.

The proximal tubule secretes PAH and a variety of other organic anions

The kidneys handle PAH, as well as many other organic anions (e.g., many metabolites of endogenous compounds and administered drugs), by both filtration and secretion ( Fig. 36-9 A ). The synthetic monovalent anion PAH (see p. 749 ) is somewhat unusual in that ~20% of it binds to plasma proteins, largely albumin. Thus, only ~80% of PAH is available for filtration. Assuming a filtration fraction (see p. 746 ) of 20%, only 80% × 20%, or 16%, of the arterial load of PAH appears in Bowman's space. Nevertheless, at low plasma [PAH], the kidneys excrete into the urine nearly all (~90%) of the PAH entering the renal arteries, so that very little PAH remains in the renal veins. Because the kidneys almost completely clear it from the blood in a single passage, PAH is useful for measuring renal plasma flow (see pp. 749–750 ).

The nephron secretes PAH mainly in the late proximal tubule (S3 segment) via the transcellular route, against a sizeable electrochemical gradient. PAH uptake across the basolateral membrane occurs via the high-affinity OAT1 (SLC22A6) and the lower-affinity OAT3 (SLC22A8) transporters, driven by the outward gradient of α-KG, N36-6 which is a dicarboxylate (see Fig. 36-9 B ). This uptake of PAH is an example of tertiary active transport because the basolateral Na/dicarboxylate cotransporter NaDC3 (SLC13A3)—in a process of secondary active transport —elevates α-KG levels in the cell, creating the outward α-KG gradient. NaDC3 carries three Na ⁺ ions and one dicarboxylate into the cell. Finally, the basolateral Na-K pump—in a process of primary active transport —establishes the Na ⁺ gradient used to drive the accumulation of α-KG.

The apical step of PAH secretion probably occurs via exchange for luminal anions, electrogenic facilitated diffusion driven by the inside-negative membrane potential (e.g., via OATv1), or an ABC transporter (e.g., MRP4). Several anionic drugs (e.g., probenecid) that compete at the basolateral PAH-anion exchanger or the apical PAH-anion exchanger inhibit PAH secretion from blood to lumen.

The late proximal tubule secretes a wide variety of other organic anions in addition to PAH. These anions include the following ( Table 36-3 ): (1) endogenous anions, such as oxalate and bile salts; (2) exogenous anions such as the drugs penicillin and furosemide; and (3) uncharged molecules conjugated to anionic groups such as sulfate or glucuronate (see pp. 955–956 ). The proximal tubule secretes these anions into the lumen using basolateral and apical anion exchangers that are similar to those involved in PAH secretion (see Fig. 36-9 B ). At the apical membrane, the secreted anion appears to exchange for luminal Cl ⁻ , urate, or OH ^– .