Medical Physiology, 3rd Edition

Other Organic Solutes

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. 36-5A). 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. 36-5B). 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 image synthesis and gluconeogenesis (see pp. 829–831 and Fig. 39-5A).


FIGURE 36-5 Amino-acid handling by the kidney. In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. 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. For B, the alternate protein names for the SLC designations of the amino-acid transporters are in the second column of Table 36-1. AA, amino acid; PCT, proximal convoluted tubule; PST, proximal straight tubule.

TABLE 36-1

Amino-Acid Transporters*

A. Apical Uptake







(System image)




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


(System b0+)

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+)



(System B0+)

Neutral and cationic amino acids

Cotransports 2 Na+ and 1 Cl

Small intestine




(System Gly)





Cotransports with Na+ and Cl



(System B0)

Neutral amino acids (not Pro), including aromatic amino acids (Phe, Trp, Tyr)

Cotransports with Na+
(No Cl)




Kidney—Hartnup disease



Kidney, brain


(System IMINO)




Pro, imino acids

Cotransports 2 Na+ and 1 Cl

Kidney, small intestine, brain



Pro, Ala, Gly, GABA

Cotransports with H+

Small intestine, colon, kidney, brain



Pro, Gly, Ala, hydroxyproline

Cotransports with H+

Kidney, heart, lung

B. Basolateral Exit







(System GLY)

Gly (also N-methylglycine, i.e., sarcosine)

Cotransports Na+ and Cl

Small intestine




(System y+)

Cationic (i.e., basic) amino acids

None (facilitated diffusion)

Ubiquitous (not liver), basolateral in epithelia


(System y+L)




Cationic (i.e., basic) amino acids (Arg+, Lys+, ornithine+)

Exchanges for extracellular neutral amino acid plus Na+

Kidney, small intestine


(System y+L)




Cationic (i.e., basic) amino acids (Arg+, Lys+, ornithine+)

Exchanges for extracellular neutral amino acid plus Na+

Kidney, small intestine


(System L)

Neutral amino acids

Exchanges for neutral extracellular amino acid



TAT1 (MCT10)

Aromatic amino acids (Phe, Trp, Tyr)

None (facilitated diffusion)



(System A)

Gln, Ala, Asn, Cys, His, Ser

Cotransports Na+

Small intestine

SLC38A1, 2, 4

SNAT1, 2, 4

C. Basolateral Nutritional Uptake







(System N)





Gln, Asn, His

Cotransports Na+ inward, exchanges H+ outward


(System ASC)


Exchanges for extracellular neutral amino acids; Na+ dependent

Kidney, small intestine



Ala, Ser, Cys, Thr

D. Uptake by Other Tissues








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



Brain (astrocytes), heart, skeletal muscle



Brain (cerebellum)






GABA (also betaine, β-alanine, taurine)

Cotransports Na+ and Cl

Brain (GABAergic neurons)



Brain (GABAergic neurons), kidney



Kidney, brain



Brain (choroid plexus), retina, liver, kidney

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

GABA, gamma-aminobutyric acid.

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. 36-5B). Inside the cell, glutamate can be metabolized to α-KG in the synthesis of image 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).

TABLE 36-2

Patterns of Hyperaminoacidurias





A. Prerenal hyperaminoaciduria (“overflow”)



Elevated plasma concentration and thus elevated filtered load overwhelms Tm.

B. Competition

Side effect of hyperargininemia


High filtered load of one amino acid (e.g., Arg) inhibits the reabsorption of another, both carried by SLC7A9 (b0,+AT)/SLC3A1 (rBAT)

C. Renal aminoaciduria

Anionic aminoaciduria


Defective SLC1A1 (EAAT3); autosomal recessive disease

Hartnup disease (neutral aminoaciduria)

Neutral and ring-structure amino acids (e.g., phenylalanine)

Defective SLC6A19 (B0AT1); autosomal recessive disease

Cystinuria (cationic aminoaciduria)

Cystine (Cys-S-S-Cys) and cationic amino acids

Defective SLC7A9 (b0,+AT) or SLC3A1 (rBAT); autosomal recessive disease

Lysinuric protein intolerance (cationic aminoaciduria)


Defective SLC7A7 (y+LAT1) or SLC3A2 (4F2hc); autosomal recessive disease

D. Generalized proximal-tubule dysfunction

Fanconi syndrome

All amino acids

Metabolic, immune or toxic conditions (inherited or acquired) that impair function of proximal-tubule cell

Box 36-1


In general, an increase in the renal excretion of an amino acid (hyperaminoaciduria) may occur when the plasma concentration increases owing to any of several metabolic derangements or when the carrier-mediated reabsorption of the amino acid decreases abnormally.

Prerenal Hyperaminoacidurias (i.e., the Defect Is Before the Kidney)

Hyperargininemia (see Table 36-2, section A), an inherited condition in which a metabolic defect leads to an increase in plasma arginine (Arg) levels that, in turn, increases the filtered load of Arg. Although the reabsorption of Arg increases, the filtered load exceeds the Tm, and the renal excretion increases.


Because the same transporter (the heterodimeric SLC7A9/SLC3A1 in Table 36-1) that carries Arg across the apical membrane also transports lysine (Lys) and ornithine, competition from Arg decreases the reabsorption of the other two (see Table 36-2, section B). As a result, the urinary excretion of Lys and ornithine also increases. Because the metabolic production of Lys and ornithine does not change, plasma concentrations of these two amino acids, in contrast to that of Arg, usually fall.

Renal Aminoacidurias

The renal aminoacidurias result from an autosomal recessive defect in an amino-acid transporter (see Table 36-2, section C) and thus also affects absorption in the gastrointestinal tract (see Box 45-3). In Hartnup disease, the defective apical transporter (SLC6A19) normally handles neutral amino acids (e.g., alanine, serine), including those with rings (i.e., phenylalanine, tryptophan, tyrosine). In cystinuria, the affected apical transporter is the heterodimeric SLC7A9/SLC3A1 that carries cystine (Cys-S-S-Cys) and cationic amino acids (i.e., Arg, Lys, ornithine). An increased filtered load of one of these amino acids leads to increased excretion of all of them. Nephrolithiasis (i.e., kidney stones) may be a consequence of the increased excretion of the poorly soluble cystine.

Probably the most severe renal hyperaminoaciduria is lysinuric protein intolerance (LPI), resulting from the reduced reabsorption of Lys and Arg. The resulting low blood [Arg] impairs the urea cycle and detoxification of ammonium (hyperammonemia). Other features include alveolar proteinosis (the leading cause of death), hepatosplenomegaly, and—in severe cases—mental deterioration. The defective proximal-tubule basolateral transporter (the heterodimeric SLC7A7/SLC3A2) normally mediates the efflux of Arg and Lys into blood in exchange for the uptake of Na+ and neutral amino acids.

Generalized Proximal-Tubule Dysfunction

Fanconi syndrome (see Table 36-2, section D), which can be inherited or acquired, is characterized by a generalized loss of proximal-tubule function. As a result, several solutes—in addition to amino acids—inappropriately appear in the urine: low-molecular-weight filtered proteins, glucose, image, and phosphate.

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 (Tm). In contrast to the case of glucose, in which the Tm is relatively high, the Tm 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


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


FIGURE 36-6 Oligopeptide handling by the kidney. In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. 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.

Several peptidases are present at the outer surface of the brush-border membrane of proximal-tubule cells (see Fig. 36-6B), 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.


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. 36-7A). 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 β2-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.


FIGURE 36-7 Protein handling by the kidney. In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. 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.

Proximal-tubule cells use receptor-mediated endocytosis (see p. 42) to reabsorb proteins and polypeptides (see Fig. 36-7B). 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. 36-8A). 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 Tm in the proximal tubule.


FIGURE 36-8 Monocarboxylate, dicarboxylate, and tricarboxylate handling by the kidney. imageN36-18 In A, the yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. 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.


OAT1 and OAT3 in the Proximal Tubule

Contributed by Emile Boulpaep, Walter Boron

Note that the transporters labeled “OAT1 or OAT3” in Figures 36-8B and 36-9B are the same. Note that the “Organic anion” entering in Figure 36-8B could be PAH, and that the “Dicarboxylate” (DC2−) exiting in Figure 36-9B could be α-KG.


FIGURE 36-9 PAH handling by the kidney. imageN36-18 In A, the red box indicates the fraction of the filtered load secreted by the proximal tubule. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites when plasma [PAH] is low (<12 mg/dL). The values in the boxes are approximations. PCT, proximal convoluted tubule; PST, proximal straight tubule.

Two groups of Na+-dependent cotransporters carry carboxylates across the apical membranes (see Fig. 36-8B). 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. 36-9A). 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, imageN36-6 which is a dicarboxylate (see Fig. 36-9B). 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.


Role of OAT1 and OAT3 in the Renal Transport of Organic Anions

Contributed by Emile Boulpaep, Walter Boron

OAT1 and OAT3 transporters are members of the SLC22 family of organic ion transporters (see Table 5-4). The OAT1 and OAT3 proteins shown in Figure 36-8B are in fact the same transporters as shown in Figure 36-9B. The “Organic anion” entering the cell across the basolateral membrane in Figure 36-8B could be any of several monovalent organic anions (including the nonphysiological PAH), and the “Dicarboxylate” exiting the cell across the basolateral membrane in Figure 36-9B could be any of several dicarboxylates, including α-KG.


Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch. 2004;447:666–676.

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. 36-9B). At the apical membrane, the secreted anion appears to exchange for luminal Cl, urate, or OH.

TABLE 36-3

Organic Anions and Cations Secreted by the Late Proximal Tubule





cAMP and cGMP

Bile salts




Short-chain fatty acids

Prostaglandins (e.g., PGE2)


Creatinine (zwitterion)

Uremic organic anions*









Creatinine (zwitterion)






Penicillin G















Conjugated (endogenous and exogenous)

Glucuronate conjugates

Glutathione conjugates

Sulfate conjugates


*Hippurate-like aryl organic anions that interfere with PAH transport.

See page 950.

NMN, N-methylnicotinamide; PGE2, prostaglandin E2.

PAH secretion is an example of a Tm-limited mechanism

Just as glucose reabsorption saturates at its Tm as one increases plasma [glucose], PAH secretion (Fig. 36-10A, red curve) saturates at a sufficiently high plasma [PAH]. Starting from an initially low value, increasing plasma [PAH] causes excretion (green curve) to rise much faster than filtration (orange curve). Subtracting the amount filtered from the amount excreted, we see that the rate of PAH secretion at first rises rapidly with plasma [PAH]. However, as plasma [PAH] approaches ~20 mg/dL, the amount of secreted PAH reaches a plateau (Tm), typically 60 to 80 mg/min, indicating saturation of secretory mechanisms.


FIGURE 36-10 Effect of increasing plasma PAH concentrations on PAH excretion and clearance. In A, Tm is the transport maximum for reabsorption.

After plasma [PAH] has increased enough to reach the Tm, further increases in plasma [PAH] increase urinary excretion, but only as a consequence of the increase in the filtered load—not because of increased tubule secretion. At these high plasma PAH levels, the kidneys can no longer fully remove PAH from the blood in a single pass through the kidney, and therefore it is no longer appropriate to use PAH secretion to estimate renal plasma flow. At low plasma [PAH] values (<12 mg/dL), PAH extraction from plasma flowing through the kidney is nearly complete (~90%), which forms the basis for using PAH clearance as a measure of renal plasma flow.

Recall that as plasma [glucose] increases, glucose clearance rises to approach inulin clearance (see Fig. 36-4B). In contrast, PAH clearance (see Fig. 36-10B, red curve) decreases with increasing plasma [PAH] and falls to approach inulin clearance (orange curve). The reason is that, as plasma [PAH] increases, secreted PAH forms a progressively smaller fraction of the PAH appearing in the urine.

The proximal tubule both reabsorbs and secretes urate

Urate, a monovalent anion, is the end product of purine catabolism (Fig. 36-11A). Plasma [urate] is typically 3 to 7 mg/dL (0.2 to 0.4 mM) and is elevated in gout. The glomeruli filter urate, and then the proximal tubule both reabsorbs and secretes urate (see Fig. 36-11B). Reabsorption is the more important transport pathway in the human kidney, which excretes only ~10% of filtered urate under normal conditions.


FIGURE 36-11 Urate handling by the kidney. In B, the yellow arrows indicate reabsorption, whereas the red arrow indicates secretion. 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. In C, the upper portion of the cell illustrates transporters used in the reabsorption of urate, whereas the lower portion illustrates transporters used in the secretion of urate. DC2–, dicarboxylate; MC, monocarboxylate; PCT, proximal convoluted tubule; PST, proximal straight tubule.


The proximal tubule reabsorbs urate by both a paracellular route involving passive diffusion and a transcellular route involving active transport (see Fig. 36-11C, top portion). The contribution of the paracellular pathway can become apparent during extracellular volume depletion, which can lead to a compensatory enhancement of proximal-tubule fluid reabsorption. The resulting increase in luminal [urate] can then enhance paracellular urate reabsorption, thereby decreasing net urate excretion and raising plasma [urate].

The transcellular route involves an active apical uptake step, mediated by three different transporters. URAT1 (SLC22A12; see p. 125) exchanges luminal urate for intracellular monocarboxylates, whereas OAT4 (SLC22A11) and OAT10 (SLC22A13; see p. 125) both exchange luminal urate for intracellular dicarboxylates. imageN36-7 Once inside the cell, urate exits across the basolateral membrane by facilitated diffusion via the voltage-driven transporter URATv1 (SLC2A9).


Tertiary Active Transport of Urate

Contributed by Emile Boulpaep, Walter Boron

The apical uptake of urate in exchange for monocarboxylates (URAT1) or dicarboxylates (OAT4 or OAT10) in Figure 36-11C is an example of tertiary active transport.

In the case of monocarboxylates, an undefined Na/monocarboxylate cotransporter at the apical membrane mediates the uptake of monocarboxylates—an example of secondary active transport, energized by the inwardly directed Na+ gradient.

In the case of dicarboxylates, NaDC1 at the apical membrane mediates the Na+-driven uptake of dicarboxylates—another an example of secondary active transport, energized by the inwardly directed Na+gradient.

In both cases, the Na-K pump at the basolateral membrane (a primary active transporter) extrudes Na+ from the cell and thereby establishes the out-to-in Na+ gradient.

Uricosuric agents such as probenecid, salicylate, and other nonsteroidal anti-inflammatory drugs inhibit URAT1 and thereby increase urate excretion. Indeed, probenecid is useful in the treatment of gout.


Proximal-tubule cells are also capable of secreting urate. The basolateral step of urate secretion (see Fig. 36-11C, bottom portion) occurs by organic anion exchange via OAT1 and OAT3 (which also mediate basolateral PAH uptake; see Fig. 36-9B) in exchange for intracellular dicarboxylates such as α-KG. Once inside the cell, urate exits across the apical membrane via two SLCs, NPT1 (SLC17A1) and the voltage-driven NPT4 (SLC17A3), and via two ABC transporters (see Table 5-6), MRP4 (ABCC4) and BCRP (ABCG2; see Fig. 46-5D). Under certain conditions, renal urate excretion can exceed the quantity filtered, which indicates net secretion.

The late proximal tubule secretes several organic cations

The late proximal tubule (Fig. 36-12A) is also responsible for secreting a wide range of both endogenous and exogenous organic cations (see Table 36-3). Some of the most important secreted endogenous organic cations are the monoamine neurotransmitters (e.g., dopamine, epinephrine, norepinephrine, and histamine; see p. 315) and creatinine, the breakdown product of phosphocreatine. Despite this modest secretion, creatinine is a useful index of GFR (see p. 741). Exogenous secreted organic cations include morphine, quinine, and the diuretic amiloride (see pp. 758–759).


FIGURE 36-12 Organic cation handling by the kidney. In A, the red arrow indicates secretion. 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. OC, organic cation; PCT, proximal convoluted tubule.

At the basolateral membrane, the polyspecific organic cation transporter OCT2 (SLC22A2; see p. 115) mediates the uptake of these organic cations (see Fig. 36-12B) via facilitated diffusion. The driving force for this electrogenic process is the inside-negative membrane potential of the cell.

At the apical membrane, the organic cation–H exchangers MATE1 (SLC47A1) and MATE2-K (SLC47A2) as well as the ABC transporter MDR1 (ABCB1; see Table 5-6) move these cations from the cell to the lumen (see Fig. 36-12B). The energy for the extrusion of the organic cations via the MATEs is the H+ electrochemical gradient across the apical membrane from lumen to cell. Because the apical Na-H exchanger (a secondary active transporter) is largely responsible for establishing this H+ gradient, the cation-H exchange is an example of tertiary active transport.

Nonionic diffusion of neutral weak acids and bases across tubules explains why their excretion is pH dependent

Many cations or anions are, in fact, weak acids or bases in equilibrium with a neutral species (see pp. 628–629), which generally diffuses across a membrane much faster than the corresponding cation or anion. This rapid diffusion usually occurs because the neutral species is far more soluble in the lipid bilayer of cell membranes than is the charged species. imageN36-8


Mechanism of Nonionic Diffusion

Contributed by Walter Boron

Nonionic diffusion refers to the passive flux across a membrane of the uncharged (i.e., neutral or “not ionic”) form of a buffer pair. Thus, for the HA/A buffer pair (HA ⇌ H+ + A), HA is the nonionic component. For the BH+ or BH+/B buffer pair (BH+ ⇌ B + H+), B is the nonionic component. For buffer pairs in which both members are charged (e.g., image ⇌ H+ + image) then by definition neither of the members of the buffer pair can participate in nonionic diffusion.

In nonionic diffusion, the energy driving the net flux of HA or B across the membrane is the chemical or concentration gradient according to Fick's law (see p. 108):

image (NE 36-3)

Here, the flux JHA is positive when [HA]o > [HA]i (i.e., the extracellular concentration exceeds the intracellular concentration) and HA diffuses passively into the cell. PHA is the permeability of the cell membrane to HA. In the case of a neutral weak base, the flux would be

image (NE 36-4)

Notice that we have not said anything about the mechanism by which HA or B moves across the cell membrane. Traditionally, people had thought that neutral species (e.g., acetic or lactic acids, CO2, NH3) would simply dissolve in the lipid phase of a biological membrane according to the oil/water partition coefficient of the species in question. This simple mechanism may account for a part of the membrane permeability to these neutral substances, but certainly not all, and in some carefully studied cases, very little. Many small neutral species cross biological membranes via transporters or channels. Examples of transporters that can carry lactic acid across the plasma membrane are the MCT monocarboxylic acid transporters (SLC16 family; see Table 5-4). Other membrane proteins can serve as channels for dissolved gases. The first example of such a channel was aquaporin 1 (AQP1), which serves as a conduit for CO2 and also NH3. The rhesus (Rh) protein family also are channels for CO2 and NH3. Although the movement of the solute in question may occur via a transporter or a channel, the thermodynamic driving force is still the chemical gradient (i.e., the movement is still passive) and fits the description of nonionic diffusion.


Boron WF. Sharpey-Schafer lecture: Gas channels. Exp Physiol. 2010;95:1107–1130.

Changing the luminal pH can substantially affect the overall transport of a buffer pair. For example, acidifying the tubule lumen promotes the reabsorption of a neutral weak acid and the secretion of a neutral weak base. In the case of a neutral weak acid such as salicylic acid (Fig. 36-13A), the glomerular filtrate contains both the neutral weak acid (HA) and its conjugate weak base, which is an anion (A). The secretion of H+ into the lumen (see pp. 827–828) titrates the A to HA, thus raising luminal [HA] above intracellular [HA], so that HA rapidly diffuses across the apical membrane—by the process of nonionic diffusion—into the tubule cell and across the basolateral membrane into the blood. The more acidic the luminal fluid, the greater is the titration of A to HA, and the greater the nonionic diffusion of HA from lumen to blood.


FIGURE 36-13 Nonionic diffusion.

In the case of a weak base such as chloroquine (see Fig. 36-13B), the tubule filtrate contains both the neutral weak base (B) and the cationic species (BH+). The permeant neutral weak base B is subject to reabsorption down its concentration gradient by nonionic diffusion. The more alkaline the luminal fluid, the greater the titration of BH+ to B, the greater the nonionic diffusion of B from lumen to blood (i.e., reabsorption), which leaves less organic cation behind in the lumen for excretion. Thus, even though the proximal tubule may secrete the cation BH+, the final urinary excretion of the organic cation will be very dependent on urinary pH, with far less excretion at alkaline urinary pH and much more excretion at acidic urinary pH, as shown in Figure 36-13D.

A striking example of how luminal pH affects the clearance of a weak acid is the renal handling of salicylic acid and its anion species, salicylate. At a urinary pH of ~7.5, the amount of total salicylate (salicylic acid + salicylate anion) excreted is the same as the filtered load (see Fig. 36-13C); that is, the clearance of total salicylate (CSalicylate) equals GFR. Lower urinary pH values favor the titration of luminal salicylate anion to salicylic acid, which the tubule readily reabsorbs. Hence, lowering pH causes the fractional excretion of total salicylate (FESalicylate = CSalicylate/GFR; see p. 733) to fall to less than unity. At very low urinary pH values, the kidney reabsorbs virtually all salicylate, and FESalicylate approaches zero. However, at urinary pH values higher than ~7.5, FESalicylate increases markedly because the alkalinity keeps luminal levels of the salicylate anion high and levels of salicylic acid low, so that the neutral weak acid now diffuses from blood to lumen.

It is possible to treat overdoses of salicylate or acetylsalicylate (i.e., aspirin) by alkalinizing the urine with image or by increasing urine flow with diuretics. imageN36-9 The reason is that both high pH and high urine flow keep luminal levels of salicylic acid low, which maintains a sink for salicylic acid in the lumen. Both treatments enhance the urinary excretion of the drug and lower plasma concentrations.


Treatment of Salicylate Poisoning

Contributed by Erich Windhager, Gerhard Giebisch

As noted in the text on page 785, physicians can treat salicylate poisoning by using the principle of nonionic diffusion of a neutral weak acid, outlined in Figure 36-13A. Alkalinizing the tubule lumen increases the trapping of the salicylate anion in the urine. The most common cause of salicylate poisoning is the accidental or suicidal overdose of aspirin. Signs of the poisoning include a severe metabolic acidosis and a compensatory respiratory alkalosis. The twofold purpose of the treatment is to neutralize the metabolic acidosis and to eliminate the salicylate. The treatment is to administer NaHCO3 intravenously to alkalinize the urine above a pH of 7.5, while making sure that the plasma pH does not exceed 7.55.

The converse example of urinary pH dependence is seen in the excretion of a neutral weak base, such as chloroquine (see Fig. 36-13D). imageN36-10


Treatment of a PCP Overdose

Contributed by Erich Windhager, Gerhard Giebisch

Phencyclidine hydrochloride—whose formal name is phenylcyclohexyl piperidine HCl (PCP) and whose street names include “angel dust”—can be thought of as the salt BH+Cl. When dissolved in water, the BH+ will equilibrate with the neutral form of the drug (B) as follows: BH+ ⇌ B + H+.

It is possible to treat PCP intoxication by using the principle shown in Figure 36-13B; namely, by decreasing the urinary pH and thereby increasing the trapping of the phencyclidine cation (BH+) in the urine. Although PCP was originally developed as an intravenous anesthetic in the 1950s, its use was discontinued in 1965 because of its side effects, which include hallucinations and confusion. Today, the most common cause of PCP intoxication is recreational drug use. The therapy has two goals: to promote the rapid urinary excretion of the drug, and to treat the neurological symptoms with antidotes that target the neurotransmitter systems most activated in a particular patient. Regarding the urinary excretion, acidification of the urine can increase the rate of excretion 100-fold. Acidification of the urine can be promoted by administering vitamin C (ascorbic acid) or ammonium chloride. By the effect shown in Figure 36-13D, this maneuver increases the excretion of the drug. In the absence of urinary acidification, the slow clearance of PCP means that screening for substance abuse can produce a positive urine test result as long as 7 days after casual use and 30 days after habitual use.

The same approach can be used to increase the clearance of other weak bases, such as the psychotropic drug remoxipride.


Price WA, Giannini AJ. Management of PCP intoxication. Am Fam Physician. 1985;32:115–118.

Widerlov E, Termander B, Nilsson MI. Effect of urinary pH on the plasma and urinary kinetics of remoxipride in man. Eur J Clin Pharmacol. 1989;37:359–363.