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Table 35-2. Composition of urine

ance Concentration

50-130 mEq/L

20-70 mEq/L

30-50 mEq/L

5-12 mEq/L

2-18 mEq/L

50-130 mEq/L

20-40 mEq/L

200-400 mM

nine 6-20 mM

5.0-7.0

ality 500-800 mOsm/kg H 2O

e* 0

acids* 0

n* 0

* 0

s* 0

cytes* 0

in* 0

*These values represent average ranges. Asterisks indicate that the presence of these substances in freshly voided urine ismeasured with dipstick reagent strips. These small strips of plastic contain reagents that change color in a semiquantitative manner in the presence of specific compounds. Water excretion ranges between 0.5 and 1.5 L/day.Modified from Valtin HV: Renal physiology, ed 2, Boston, 1983, Little, Brown.


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blood (see Chapter 37 ).

Endocytosis is another form of active transport. In endocytosis, a section of the plasma membraneinvaginates. The portions around this invagination then engulf the substance being transported. Oncethe substance is engulfed, the membrane completely pinches off and forms a vesicle in thecytoplasm. Endocytosis is an important mechanism for reabsorbing small proteins andmacromolecules by the proximal tubule and for the retrieval of water channels from the apicalmembrane of collecting duct cells. Because endocytosis requires ATP, it is a form of active transport.

GENERAL PRINCIPLES OF TRANSEPITHELIAL SOLUTE AND WATERTRANSPORT

Renal cells are held together by tight junctions (Fig. 35-1 ). The tight junctions separate the apicalmembranes from the basolateral membranes. Below the tight junctions, the cells are separated bylateral intercellular spaces. A useful way to visualize the renal epithelium is to consider a six-pack of soda: the soda cans are the cells and the plastic holder represents the tight junctions.
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Figure 35-1 Paracellular and transcellular transport pathways in the proximal tubule. See text for details. ATP, Adenosine

triphosphate.

In the nephron, a substance can be reabsorbed or secreted through cells (the transcellular pathway)or between cells (the paracellular pathway) ( Fig. 35-1 ). Na + reabsorption by the proximal tubule is agood example of transport by the transcellular pathway. Na + reabsorption in this nephron segmentdepends on the operation of Na +,K+-ATPase ( Fig. 35-1 ). Na +,K+-ATPase is located exclusively in thebasolateral membrane. This pump moves Na + out of the cell into the blood and moves K + into the cell.Thus, Na +,K+-ATPase lowers intracellular Na + concentration and increases intracellular K+ concentration. Because intracellular [Na +] is low (12 mEq/L) and the [Na +] in tubular fluid is high(145 mEq/L), Na + moves across the apical cell membrane down a chemical concentration gradientfrom the tubular lumen into the cell. Na +,K+-ATPase, sensing the addition of Na + to the cell, isstimulated to increase the rate of Na +extrusion into the blood. This action returns intracellular Na + to

normal levels. Transcellular Na+

reabsorption by the proximal tubule is thus a two-step process:1. Na + moves across the apical membrane into the cell down an electrochemical gradient
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established by Na +,K+-ATPase.

2. Na + moves across the basolateral membrane against an electrochemical gradient via Na +,K+-ATPase.

The reabsorption of Ca 2+ and K + across the proximal tubule is a good example of paracellular transport. Some of the water reabsorbed across the proximal tubule crosses the paracellular pathway. Some solutes dissolved in this water (in particular Ca 2+ and K +) are carried along with thereabsorbed fluid and are reabsorbed by the process of solvent drag.

SOLUTE AND WATER REABSORPTION ALONG THE NEPHRON

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In a quantitative sense, the reabsorption of NaCl and water represents the major function of thenephrons (approximately 25,000 mEq/day of Na + and 179 L/day of water are reabsorbed; Table 35-1 ).In addition, the transport of many other important solutes is linked either directly or indirectly toNa + reabsorption. In the following sections, we discuss the NaCl and water transport properties of each nephron segment and its regulation by hormones and other factors.

Proximal Tubule

The proximal tubule reabsorbs approximately 67% of the filtered water, Na +, Cl -, K+, and other solutes.In addition, the proximal tubule reabsorbs virtually all the glucose and amino acids filtered by theglomerulus. The key element in proximal tubule reabsorption is the Na +,K +-ATPase in the basolateral membrane. The reabsorption of every substance, including water, is linked in some way to theoperation of Na +,K+-ATPase.

Na + reabsorption.

Na + is reabsorbed by different mechanisms in the early (first half) and late (second half) segments of the proximal tubule. In the early segment, Na + is reabsorbed primarily with HCO 3- and a number of organic molecules (e.g., glucose, amino acids, P i, lactate). By contrast, in the second half of theproximal tubule, Na + is reabsorbed mainly with Cl -. This difference exists because of differences inNa + transport systems present in the early and late segments of the proximal tubule, and because of differences in the composition of tubular fluid at these sites.


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Figure 35-2 Na + transport processes in the first half of the proximal tubule. The transport mechanisms depicted in A and B arepresent in all cells in the first half of the proximal tubule. They are separated into different cells to simplify the

discussion. A, The operation of the Na +-H+ antiporter in the apical membrane and the Na +,K+-ATPase and the HCO 3- transporter in the basolateral membrane mediate NaHCO 3 reabsorption. CO 2 and H 2O combine inside the cells to form H + and HCO 3- in a

reaction facilitated by the enzyme carbonic anhydrase (CA). B, The operation of the Na +-glucose transporter in the apicalmembrane, in conjunction with the Na +,K+-ATPase and the glucose transporter in the basolateral membrane, mediate Na +-

glucose reabsorption. Na + reabsorption is also coupled with other solutes, including amino acids, P i, and lactate. Reabsorptionof these solutes is mediated by Na +-amino acid, Na +-P i, and Na +-lactate symporters located in the apical membrane and the

Na +,K+-ATPase and the amino acid, P i, and lactate transporters in the basolateral membrane.
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As illustrated in Fig. 35-2 , in the early segment of the proximal tubule, Na + uptake into the cell iscoupled with either H + or organic solutes. Na + entry into the cell across the apical membrane ismediated by specific symporter and antiporter proteins, and not by diffusion through channels. For example, Na +entry is coupled with the pumping of H + out of the cell by the Na +-H+ antiporter ( Fig. 35-2, A ). H + secretion results in NaHCO 3 reabsorption (see also Chapter 38 ). Na + also enters proximalcells by several symporter mechanisms, including Na +-glucose, Na +-amino acid, Na +-Pi, and Na +-lactate symporters ( Fig. 35-2, B ). The glucose (and other organic solutes) that enters the cell withNa + leaves the cell across the basolateral membrane by passive transporter mechanisms. AnyNa + that enters the cell across the apical membrane leaves the cell and enters the blood viathe Na +,K +-ATPase. In summary, in the early segment of the proximal tubule, the reabsorption of Na + is coupled to that of HCO 3- and a number of organic molecules. Reabsorption of many organicmolecules is so avid in this segment that they are almost completely removed from the tubular fluid(Fig. 35-3 ). The reabsorption of NaHCO 3 and Na +-organic solutes across the proximal tubuleestablishes a transtubular osmotic gradient that provides the driving force for the passive reabsorptionof water by osmosis. Because more water than Cl - is reabsorbed in the early segment of the proximaltubule, the Cl - concentration in tubular fluid rises along the length of the early proximal tubule ( Fig. 35-3).
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Figure 35-3 Concentration of solutes in tubular fluid as a function of length along the proximal tubule. [TF] is the concentrationof the substance in tubular fluid; [P] is the concentration of the substance in plasma. Values above 100 indicate that relativelyless of the solute than water was reabsorbed; values below 100 indicate that relatively more of the substance than water was

reabsorbed. (Modified from Vander AJ: Renal physiology, ed 4, New York, 1991, McGraw-Hill.)

In the second half of the proximal tubule, Na + is primarily reabsorbed with Cl - across both thetranscellular and paracellular pathways ( Fig. 35-4 ). Na + is reabsorbed with Cl - rather than with organicsolutes or HCO 3- as the accompanying anion. This occurs because the cells lining the late proximaltubule have different Na + transport mechanisms from those in the early proximal tubule. Furthermore,the tubular fluid that enters the late proximal tubule contains very little glucose and amino acids buthas a high concentration of Cl - (140 mEq/L) compared with that in the early proximal tubule (105mEq/L). The high Cl -concentration is due to the preferential reabsorption of Na + with HCO 3- andorganic solutes in the early proximal tubule (Fig. 35-2 ).

The mechanism of transcellular Na + reabsorption in the late proximal tubule is shown in Fig. 35-4 . Na + enters the cell across the luminal membrane by the parallel operation of Na +-H+ and one or moreCl- anion antiporters. Because the secreted H + and anion combine in the tubular fluid and reenter thecell, the operation of the Na +-H+ and Cl - anion antiporters is equivalent to NaCl uptake from tubular fluid into the cell. Na + leaves the cell by the action of Na +,K+-ATPase, and Cl - leaves the cell by theaction of a KCl symport protein in the basolateral membrane.

NaCl is also reabsorbed across the late proximal tubule by a paracellular route. Paracellular NaCl reabsorption occurs because the rise in [Cl - ] in the tubular fluid in the early proximal tubule creates aconcentration gradient of Cl -(140 mEq/L in the tubule lumen and 105 mEq/L in the interstitium). Thisconcentration gradient favors the diffusion of Cl - from the tubular lumen across the tight junctions into

the lateral intercellular space. Movement of the negatively charged Cl-

causes the tubular fluid tobecome positively charged relative to the blood. This positive transepithelial voltage causes thediffusion of positively charged Na + out of the tubular fluid across the tight junctions into the blood.Thus, in the late proximal tubule, some Na + and Cl - is reabsorbed across the tight junctions by passivediffusion. The reabsorption of NaCl establishes a transtubular osmotic gradient that provides thedriving force for the passive reabsorption of water by osmosis (as described below).

In summary, reabsorption of Na + and Cl - in the proximal tubule occurs across the paracellular pathwayand across the transcellular pathway. Approximately 17,000 mEq of the 25,200 mEq of NaCl filteredeach day is reabsorbed in the proximal tubule ( 67% of the filtered amount). Of this, two-thirds is

transported across the transcellular pathway, while the remaining one-third is transported across theparacellular pathway ( Tables 35-3 and 35-4 ).

Water reabsorption.

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ing duct Atrial natriuretic peptideUrodilatin

Table 35-4. Water transport along the nephron

ent Percentage of filteredreabsorbed

Mechanism of waterreabsorption

Hormones that regulatewater permeability

mal tubule 67% Passive None

f Henle 15% DTL only; passive None

tubule 0% No water reabsorption None

stal tubule and collecting 8%-17% Passive ADH, ANP*

*ANP inhibits the ADH-stimulated water permeability. ADH, Antidiuretic hormone; ANP, atrial natriuretic peptide.

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Figure 35-5 Routes of water and solute reabsorption across the proximal tubule. Transport of solutes, including Na +, Cl -, andorganic solutes, into the lateral intercellular space increases the osmolality of this compartment, which establishes the driving

force for osmotic water reabsorption across the proximal tubule. This occurs because some Na +,K+-ATPase and sometransporters of organic solute, HCO 3-, and Cl -, are located on the lateral cell membranes and deposit these solutes between

cells. Furthermore, some NaCl also enters the lateral intercellular space by diffusion across the tight junction (i.e., paracellular pathway). An important consequence of osmotic water flow across the transcellular and paracellular pathways in the proximaltubule is that some solutes, especially K + and Ca 2+ , are carried along in the reabsorbed fluid and are thereby reabsorbed by the

process of solvent drag.

The proximal tubule reabsorbs 67% of the filtered water ( Fig. 35-5 ). The driving force for water reabsorption is a transtubular osmotic gradient established by solute reabsorption (i.e., NaCl, Na +-glucose, and so forth). The reabsorption of Na + along with organic solutes HCO 3- and Cl - from thetubular fluid into the lateral intercellular spaces reduces the osmolality of the tubular fluid andincreases the osmolality of the lateral intercellular space. Because the proximal tubule is highlypermeable to water, water will flow by osmosis across both the tight junctions and the proximal tubular cells. Accumulation of fluid and solutes within the lateral intercellular space increases the hydrostaticpressure in this compartment. This increased hydrostatic pressure forces fluid and solutes to moveinto the capillaries. Thus, water reabsorption follows solute reabsorption in the proximal tubule. Thereabsorbed fluid is slightly hyperosmotic to plasma. An important consequence of osmotic water flowacross the proximal tubule is that some solutes, especially K + and Ca 2+, are carried along in thereabsorbed fluid and are thereby reabsorbed by the process of solvent drag ( Fig. 35-5 ). Thereabsorption of virtually all organic solutes, Cl -, other ions, and water is coupled to Na + reabsorption.Therefore, changes in Na + reabsorption influence the reabsorption of water and other solutes by theproximal tubule.

Fanconi's syndrome is a renal disease that is either hereditary or acquired. It results from animpaired ability of the proximal tubule to reabsorb amino acids, glucose, and low-molecular-weight

proteins. Because other segments of the nephron cannot reabsorb these solutes, Fanconi's syndromecauses an increase in the excretion of amino acids, glucose, P i, and low-molecular-weight proteins in
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the urine.

Protein reabsorption.

Proteins filtered by the glomerulus are also reabsorbed in the proximal tubule. As mentionedpreviously, peptide hormones, small proteins, and even small amounts of larger proteins, such asalbumin, are filtered by the glomerulus. The glomerulus filters only a small amount of proteins (theconcentration of proteins in the ultrafiltrate is only 40 mg/L). However, the amount of protein filteredper day is significant because the GFR is so high:

Protein reabsorption in the proximal tubule begins when the proteins are partially degraded byenzymes on the surface of the proximal tubule cells. These partially degraded proteins are taken intothe cell by endocytosis. Once they are inside the cell, enzymes digest the proteins and peptides intotheir constituent amino acids. Amino acids then exit the cell across the basolateral membrane andreturn to the blood. Normally, this mechanism reabsorbs virtually all of the protein filtered and hencethe urine is essentially protein free. However, because the mechanism is easily saturated, if theamount of protein filtered increases, protein will appear in the urine. Disruption of the glomerular filtration barrier to proteins will increase the filtration of proteins and result in proteinuria (theappearance of protein in the urine). Proteinuria is frequently seen with kidney disease.

During routine urinalysis, it is not abnormal to find traces of protein in the urine. Protein in the urinecan be derived from two sources: (1) filtration and incomplete reabsorption by the proximal tubule and(2) synthesis by the thick ascending limb of Henle's loop. Cells in the thick ascending limbproduce Tamm-Horsfall glycoprotein and secrete the protein into the tubular fluid. Because themechanism for protein reabsorption is upstream of the thick ascending limb (i.e., proximal tubule), thesecreted Tamm-Horsfall glycoprotein appears in the urine.

Organic anion and organic cation secretion.

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Table 35-5. Some organic anions secreted by the proximal tubule


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genous anions Drugs

adenosine monophosphate (cAMP) Acetazolamide

lts Chlorothiazide

ates Furosemide

e Penicillin

glandins Probenecid

Salicylate (aspirin)

Hydrochlorothiazide

Bumetanide

Adefovir

Cidovir

NSAID

Enalapril

NSAID, Nonsteroidal antiinflammatory drugs.

Table 35-6. Some organic cations secreted by the proximal tubule

genous cations Drugs

nine Atropine

mine Isoproterenol

hrine Cimetidine

nephrine Morphine


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Quinine

Amiloride

Procainamide

Verapamil

In addition to reabsorbing solutes and water, cells of the proximal tubule secrete organic cations andorganic anions ( Tables 35-5 and 35-6 present a partial listing). Many of these organic anions andcations are end products of metabolism that circulate in the plasma. The proximal tubule also secretesnumerous exogenous organic compounds, including p -aminohippuric acid (PAH), drugs such aspenicillin, some nonsteroidal antiinflammatory agents (e.g., ibuprofen, indomethacin, and naproxen),and the antiviral drug adefovir, which is effective in the treatment of human immunodeficiency virus(HIV)-infected patients. Many of these organic compounds can be bound to plasma proteins and arenot readily filtered. Therefore, excretion by filtration alone eliminates only a small portion of thesepotentially toxic substances from the body. Such substances are also secreted from the peritubular capillaries into the tubular fluid. These secretory mechanisms are very powerful and remove virtuallyall organic anions and cations from the plasma entering the kidneys. Hence, these substances areremoved from the plasma by both filtration and secretion.


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Figure 35-6 Organic anion secretion [e.g., p -aminohippuric acid (PAH)] across the proximal tubule. PAH enters the cell acrossthe basolateral membrane by a PAH--ketoglutarate ( KG)antiport mechanism. The uptake of KG into the cell, against itschemical gradient, is driven by the movement of Na + into the cell. The KG recycles across the basolateral membrane. PAHleaves the cell across the apical membrane down its chemical concentration gradient by a PAH-anion (A-) transporter and

possibly a voltage-driven transporter.

An example of organic anion secretion is PAH transport across the proximal tubule ( Fig. 35-6 ). Thissecretory pathway has a maximal transport rate, has a low specificity (i.e., it transports a variety of organic anions), and is responsible for the secretion of all organic anions listed in Table 35-5 . PAH istaken into the cell across the basolateral membrane, against its chemical gradient, in exchange for -ketoglutarate (KG) via a PAH-KG antiport mechanism. KG accumulates inside the cells via themetabolism of glutamate and by an Na +-KG symporter, also present in the basolateral membrane.Thus, PAH uptake into the cell against its electrochemical gradient is coupled to the exit of KG out of the cell down its chemical gradient; this activity is generated by the Na +-KG antiport mechanism andthe metabolism of glutamate. The resultant high intracellular concentration of PAH provides thedriving force for PAH exit across the luminal membrane into the tubular fluid via a PAH-anionantiporter and possibly a voltage-driven PAH transporter ( Fig. 35-6 ).

Because organic anions compete for the same transporters, elevated plasma levels of one anioninhibit the secretion of the others. For example, infusing PAH can produce a reduction of penicillinsecretion by the proximal tubule. Because the kidneys are responsible for eliminating penicillin, theinfusion of PAH into individuals receiving penicillin reduces urinary penicillin excretion, and therebyextends the biological half-life of the drug. In World War II, when penicillin was in short supply,hippurates were given with the penicillin to extend the drug's therapeutic effect.

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Figure 35-7 illustrates the mechanism of organic cation (OC +) transport across the proximal tubule.Organic cations are taken into the cell, across the basolateral membrane, by a mechanism thatinvolves facilitated diffusion. This uniport mechanism is driven by the magnitude of the voltagedifference (negative potential) across the basolateral membrane. Organic cation transport across theluminal membrane into the tubular fluid is mediated by an OC +-H+antiporter. Because the transportmechanisms for organic cation secretion are nonspecific, several cations compete for the transportpathway ( Table 35-6 ).

The histamine H2-antagonist cimetidine is used to treat gastric ulcers. Cimetidine is secreted by theorganic cation pathway in the proximal tubule. It reduces the urinary excretion of the antiarrhythmicdrug procainamide (also an organic cation), by competing with procainamide for the secretorypathway. It is important to recognize that coadministration of organic cations can increase the plasmaconcentration of both drugs to levels much higher than those seen when the drugs are given alone.This increase can lead to drug toxicity.

P-glycoprotein and multidrug resistance (MDR)-associated protein 2 (Mrp2) may also play an
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important role in the renal excretion of organic compounds. P-glycoprotein and Mrp2 possess ATPaseactivity, are located in the apical membrane of the proximal tubule, and transfer some organiccompounds from the cell interior into tubular fluid. These transporters are called MDR proteinsbecause they facilitate the removal of cytotoxic drugs from the cell interior. Other drug-transportingATPases, including Mrp1, are located in the basolateral membrane and move organic compoundsfrom the blood into the cells of the proximal tubule. P-glycoprotein transports hydrophobic cationiccompounds and some drugs including anticancer agents, digoxin, and immunosuppressive agentssuch as cyclosporin. Mrp2 transports conjugated anionic compounds such as glutathione-conjugatedleukotriene C4 and the glucuronide-conjugated of bilirubin.

Henle's Loop

Henle's loop reabsorbs approximately 25% of the filtered NaCl and K +. Ca 2+ and HCO 3- are also

reabsorbed in the loop of Henle (see Chapters 37 and 38 for more details). This reabsorption occursalmost exclusively in the thick ascending limb. By comparison, the ascending thin limb has a muchlower reabsorptive capacity, and the descending thin limb does not reabsorb significant amounts of solutes. The loop of Henle reabsorbs approximately 15% of the filtered water. Water reabsorptionoccurs exclusively in the descending thin limb. The ascending limb is impermeable to water.

The key element in solute reabsorption by the thick ascending limb is the Na +,K+-ATPase in thebasolateral membrane (Fig. 35-8 ). As with reabsorption in the proximal tubule, the reabsorption of every solute by the thick ascending limb is in some way linked to Na +,K+-ATPase. This pumpmaintains a low intracellular [Na +]. This low [Na +] provides a favorable chemical gradient for the

movement of Na+

from the tubular fluid into the cell. The movement of Na+

across the apicalmembrane into the cell is mediated by the 1Na +-1K+-2Cl - symporter, which couples the movement of 1Na + with 1K + and 2Cl -. Using the potential energy released by the downhill movement of Na + and Cl -,this symport drives the uphill movement of K + into the cell. An Na +-H+ antiporter in the apical cellmembrane also mediates Na + reabsorption as well as H + secretion (HCO 3- reabsorption) in the thickascending limb ( Chapter 38 contains details of HCO 3- reabsorption by the thick ascending limb).Na + leaves the cell across the basolateral membrane via the action of Na +,K+-ATPase, and K +, Cl -, andHCO 3- leave the cell across the basolateral membrane by separate pathways.
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Figure 35-7 Organic cation secretion (OC + ) across the proximal tubule. OC + enters the cell across the basolateral membrane byfacilitated diffusion. The uptake of OC + into the cell, against its chemical gradient, is driven by the cell-negative potential

difference. OC + leaves the cell across the apical membrane in exchange with H + by an OC +-H+ antiport mechanism.

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Figure 35-8 Transport mechanisms for NaCl reabsorption in the thick ascending limb of Henle's loop. The positive charge in thelumen plays a major role in driving passive paracellular reabsorption of cations. CA, Carbonic anhydrase.

The voltage across the thick ascending limb is important in the reabsorption of several cations. Thetubular fluid is positively charged relative to the blood because of the unique location of transportproteins in the apical and basolateral membranes. Two points are important here: (1) increased salt transport by the thick ascending limb increases the magnitude of the positive charge in the lumen,and (2) this voltage is an important driving force for the reabsorption of several cations, including Na +,K +, and Ca 2+ across the paracellular pathway (Fig. 35-8 ). Thus, salt reabsorption across the thickascending limb occurs by transcellular and paracellular pathways. Fifty percent of solute transport istranscellular and 50% is paracellular. Because the thick ascending limb is impermeable to water,reabsorption of NaCl and other solutes reduces the osmolality of tubular fluid to less than 150mOsm/kg H 2O.
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Bartter's syndrome is a set of autosomal-recessive genetic disorders characterized by hypokalemia,metabolic alkalosis, and hyperaldosteronism (see Table 35-7 ). Mutations in the genes coding for the1Na +-1K+-2Cl - cotransporter, the apical K + channel, or the basolateral Cl - channel in the thickascending limb ( Fig. 35-8 ) decrease NaCl and K + absorption by the thick ascending limb, which in turncauses hypokalemia and a decrease in the effective circulating volume (ECV), which stimulates thesecretion of aldosterone.

Inhibition of the 1Na +-1K+-2Cl - symporter in the thick ascending limb by loop diuretics, suchas furosemide, inhibits NaCl reabsorption by the thick ascending limb and thereby increases urinaryNaCl excretion. Furosemide also inhibits K + and Ca 2+ reabsorption by reducing the lumen-positivevoltage, which drives the paracellular reabsorption of these ions. Thus, furosemide also increasesurinary K + and Ca 2+ excretion. Furosemide also increases water excretion by reducing the osmolalityof the interstitial fluid in the medulla. Water reabsorption by the descending thin limb of Henle's loop ispassive and driven by the osmotic gradient between the tubular fluid in the descending thin limb(which is 290 mOsm/kg H 2O at the beginning of the limb) and the interstitial fluid (which is 1200mOsm/kg H 2O in the medulla). Thus, a reduction of the osmolality of the interstitial fluid will reduce

water reabsorption and thereby increase excretion.

Distal Tubule and Collecting Duct

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Figure 35-9 Transport mechanism for Na + and Cl - reabsorption in the early segment of the distal tubule. This segment isimpermeable to water. See text for details.

The distal tubule and the collecting duct reabsorb approximately 7% of the filtered NaCl, secretevariable amounts of K + and H +, and reabsorb a variable amount of water ( 8% to 17%). Water reabsorption depends on the plasma concentration of ADH. The initial segment of the distal tubule(early distal tubule) reabsorbs Na +, Cl -, and Ca 2+, and is impermeable to water ( Fig. 35-9 ). NaCl entryinto the cell across the apical membrane is mediated by a Na +-Cl -symporter ( Fig. 35-9 ). Na + leavesthe cell via the action of Na +,K+-ATPase, and Cl - leaves the cell by diffusion via channels. NaClreabsorption is reduced by thiazide diuretics, which inhibit the Na +-Cl - symporter. Thus, the dilution of the tubular fluid begins in the thick ascending limb and continues in the early distal tubule.

The last segments of the distal tubule (late distal tubule) and of the collecting duct are composed of two cell types, principal cells and intercalated cells. As shown in Fig. 35-10 , principal cells reabsorbNa + and water and secrete K +. Intercalated cells either secrete H + (reabsorb HCO 3- ) or secreteHCO 3- and thus are important in regulating acid-base balance (Chapter 38 contains details on H + andHCO 3- secretion by intercalated cells). Intercalated cells also reabsorb K +. Both Na + reabsorption andK+ secretion by principal cells depend on the activity of the Na +,K+-ATPase in the basolateralmembrane ( Fig. 35-10 ). By maintaining a low cell [Na +], this pump provides a favorable chemicalgradient for the movement of Na + from the tubular fluid into the cell. Because Na + enters the cell bydiffusion through Na +-selective channels in the apical membrane, * the negative charge inside the cellfacilitates Na + entry. Na + leaves the cell across the basolateral membrane and enters the blood via theaction of Na +,K+-ATPase. This sodium reabsorption generates a lumen-negative charge across the

late distal tubule and collecting duct. Cells in the collecting duct reabsorb significant amounts of Cl-

,probably across the paracellular pathway. Reabsorption of Cl - is driven by the voltage differencesacross the late distal tubule and collecting duct.

Liddle's syndrome is a rare genetic disorder characterized by an increase in the extracellular fluidvolume (ECFV), which causes an increase in blood pressure (i.e., hypertension). Liddle's syndrome iscaused by mutations in the genes that encode either the or subunit of ENaC. * These mutationscause Na + channels to become overactive. Inappropriately high rates of renal Na + absorption occur,which lead to an increase in the ECFV (see Chapter 36 ).Pseudohypoaldosteronism type I(PHA1) is an uncommon and inherited disorder characterized by an increase in Na + excretion, areduction in ECFV, and hypotension. PHA1 is due to mutations in the genes encoding the subunit of ENaC. These mutations inactivate the channel, resulting in inappropriately low rates of renalNa + absorption, which reduces the ECFV.

K+ is secreted from the blood into the tubular fluid by principal cells in two steps ( Fig. 35-10 ). First,K+ uptake across the basolateral membrane occurs via the action of Na +,K+-ATPase. In the secondstep, K + leaves the cells by passive diffusion. Because the [K +] inside the cells is high (150 mEq/L)and the [K +] in tubular fluid is low ( 10 mEq/L), K + diffuses down its concentration gradient across theapical cell membrane into the tubular fluid. Although the negative potential inside the cells tends toretain K + within the cell, the electrochemical gradient across the apical membrane favors K + secretionfrom the cell into the tubular fluid. Additional details of K + secretion and its regulation are consideredin Chapter 37 . The mechanism of K + reabsorption by intercalated cells is not completely understoodbut is thought to be mediated by an H +,K+-ATPase located in the apical cell membrane (see Chapters
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37 and 38 ).

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Figure 35-10 Transport pathways in principal cells and intercalated cells of the distal tubule and collecting duct. See text for details. CA, Carbonic anhydrase.

Amiloride is a diuretic that inhibits Na + reabsorption by the distal tubule and collecting duct by directly


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inhibiting Na + channels in the luminal cell membrane. Amiloride also inhibits Cl - reabsorption indirectly:inhibition of Na + reabsorption reduces the magnitude of the negative charge in the lumen, which is thedriving force for paracellular Cl - reabsorption. Because amiloride reduces the negative charge in thelumen, it also acts to inhibit K + secretion. By inhibiting K + secretion across the distal tubule andcollecting duct, amiloride reduces the amount of K + excreted in the urine. Consequently, amiloride isfrequently referred to as a K+-sparing diuretic. It is most often used in patients who excrete too muchK+ in their urine.

Genetic Diseases and Renal Transport Proteins

Many renal diseases have a genetic component. The disease-susceptibility genes for more than20 renal diseases have been identified, and many of these genes code for transport proteins. Thedisorders summarized in Table 35-7 are transmitted as single Mendelian traits and lead to

clinically relevant changes in renal function and fluid and electrolyte homeostasis. The rapiddevelopment of molecular genetics and the Human Genome Project, a cooperative effort toidentify the genome structure and sequence of human and animal models, will no doubt lead tothe identification of additional genes responsible for renal diseases, including those that contributeto complex polygenic diseases such as nephropathies associated with hypertension, diabetes,and lupus. Moreover, it is also becoming clear that disease progression in genetic disorders ismodulated by other molecular pathways such as the renin-angiotensin system and environmentalfactors. Detailed information on the molecular pathogenesis of renal disease will provide newopportunities for treatment and prevention. The challenges that lie ahead include a thoroughunderstanding of the molecular pathogenesis of renal genetic diseases and the development of novel treatments, including gene therapy and pharmacologic agents that target specific aspects of the molecular pathogenesis.

REGULATION OF NACL AND WATER REABSORPTION

Several hormones and factors regulate NaCl reabsorption. Table 35-8 summarizes, for eachhormone, the major stimulus for secretion, the nephron site of action, and the effect on transport.Angiotensin II, aldosterone, ANP, urodilatin, epinephrine, and norepinephrine released by sympatheticnerves are the most important hormones that regulate NaCl reabsorption and thereby urinary NaClexcretion. However, other hormones (including dopamine and glucocorticoids), Starling forces, andthe phenomenon of glomerulotubular balance also influence NaCl reabsorption. ADH is the only major hormone that directly regulates the amount of water excreted by the kidneys.

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Table 35-7. Monogenic renal diseases involving transport proteins


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ses Mode of inheritance

Gene Transport protein Nephronsegment

Phenotype

uria type I AR SLC3A1 Basic amino acid transporter (rBAT)

Proximal tubule Increased excretion of basic amino acidnephrolithiasis (kidney stone

Iand III IAR SLC7A9 b, +AT Proximal tubule

mal renaltubular acidosis AR SLC4A4 Na + -HCO 3- cotransporter Proximal tubule Hyperchloremic metabolic acidos

syndrome AR SLC12A1 (type I) Na +-K+-2Cl - transporter (furosemide sensitive)

TAL Hypokalemia, metabolic alkalosis, hyper dosteronis

KCNJ1 ( type II) Potassium channel

CLCNKB (type III) Chloride channel

ed nephrolithiasis

disease)

XLR CLC5 Chloride channel (C1C-5) Distal tubule Hypercalciuria, nephrolithiasis (kidney stone

magnesemia-calciuria syndrome

AR PCCLN-1 Paracellin-1 TAL Hypomagnesemia, hypercalciurinephrolithias

an syndrome AR SLC12A3 Thiazide-sensitivecotransporter

Distal tubule Hypomagnesemia, hypokalemic metabolalkalosis, hypocalciuria, hypotensi

ohypoaldo-steronism, AR SCNN1A, SCNN1B,and SCNN1G

, , and subunit of amiloride-sensitive Na + channel

Collecting duct Increased excretion ofNa +, hypotensi

syndrome AD SCNN1B, SCNN1G , , and subunit of amiloride-sensitive Na + channel

Col lecting duct Decreased excretionof Na +, hypertensi

ogenic diabetesus (NDI)

AR AQP2 Aquaporin 2 water channel Collecting duct Polyuria, polydipsia, plasma hyperosmolali

renal tubular acidosis ADAR

SLC4A1ATP6B1

Cl-/HCO 3- exchanger Subunit of H +-ATPase

Collecting duct Metabolic acidosis, hypokalemihypercalciuria, nephrolithiasis (kidney stone

AR ATP6N1A Accessory subunit of H +-ATPase

Modified from Guay-Woodford LM: Overview: the genetics of renal disease, Semin Nephrol 19(4):312, 1999 and Zelikovic I:Molecular pathophysiology of tubular transport disorders, Pediatr Nephrol 16:919, 2001.

AR, Autosomal recessive; IAR, incomplete autosomal recessive; XLR, X-linked recessive; b, + AT, light subunit of rBAT; TAL, thickascending limb of Henle's loop; AD, autosomal dominant.


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Table 35-8. Hormones that regulate NaCl and water absorption

one Major stimulus Nephron site of action Effect on transport

ensin II Renin PT NaCl and H 2O reabsorption

erone Angiotensin II, [K +]p TAL, DT/CD NaCl and H 2O reabsorption*

ECV CD H 2O and NaCl reabsorption

atin ECV CD H 2O and NaCl reabsorption

thetic nerves ECV PT, TAL, DT/CD NaCl and H 2O reabsorption*

mine ECV PT H 2O and NaCl reabsorption

P osm , ECV DT/CD H 2O reabsorption*

*All the hormones listed act within minutes, except aldosterone, which exerts its action on NaCl reabsorption with a delay of 1hour. PT, Proximal tubule; TAL, thick ascending limb; DT/CD, distal tubule and collecting duct; ECV, effective circulating volume;[K+] p, plasma [K +]; P osm , plasma osmolality. The asterisks indicate that the effect on H 2O reabsorption does not include the TAL.indicates a decrease and indicates an increase.

Angiotensin II.

The hormone angiotensin II has a potent stimulating effect on NaCl and water reabsorption in theproximal tubule. A decrease in the effective circulating volume (ECV) activates the renin-angiotensin-aldosterone system (discussed in Chapter 36 ), thereby increasing plasma angiotensin IIconcentration.

Aldosterone.

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Aldosterone is synthesized by the glomerulosa cells of the adrenal cortex. It stimulates NaClreabsorption by the thick ascending limb of Henle's loop and the distal tubule and collecting duct.Aldosterone also stimulates K + secretion by the distal tubule and collecting duct (see Chapter 36 ). The two most important stimuli for aldosterone secretion are an increase in angiotensin II


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Dopamine.

Dopamine, a catecholamine, is released from dopaminergic nerves in the kidneys and may also besynthesized by cells of the proximal tubule. The action of dopamine is opposite to that of norepinephrine and epinephrine. Dopamine secretion is stimulated by an increase in the effectivecirculating volume, and it directly inhibits NaCl and water reabsorption in the proximal tubule.

Antidiuretic hormone.

Antidiuretic hormone is the most important hormone that regulates water balance (see Chapters36 and 43 ). This hormone is secreted by the posterior pituitary in response to an increase in plasmaosmolality or a decrease in the effective circulating volume. ADH increases the permeability of thecollecting duct to water. Also, because an osmotic gradient exists across the wall of the collectingduct, ADH increases water reabsorption by the collecting duct (see Chapter 36 for details). ADH haslittle effect on urinary NaCl excretion.

Starling forces.

Starling forces (see also Chapters 20 and 34 ) regulate NaCl and water reabsorption across theproximal tubule ( Fig. 35-11 ). As described above, Na +, Cl -, HCO 3-, amino acids, glucose, and water are transported into the intercellular space of the proximal tubule. Starling forces between this spaceand the peritubular capillaries facilitate the movement of the reabsorbed substances into thecapillaries. Starling forces that favor this movement are the capillary oncotic pressure ( c) and thehydrostatic pressure in the intercellular space (P i). The opposing Starling forces are the interstitialoncotic pressure ( i) and the capillary hydrostatic pressure (P c). Normally, the sum of the Starlingforces favors movement of solute and water from the intercellular space into the capillary. However,some of the solutes and fluid that enter the lateral intercellular space leak back into the proximaltubular fluid. Starling forces do not affect transport by the loop of Henle, distal tubule, and collectingduct, because these segments are less permeable to water than is the proximal tubule.

A number of forces can alter the Starling forces across the peritubular capillaries surrounding theproximal tubule. For example, dilation of the efferent arteriole increases the hydrostatic pressure inthe peritubular capillaries (P c), whereas constriction of the efferent arteriole decreases P c. An increasein P cinhibits solute and water reabsorption by increasing the back leak of NaCl and water across thetight junction, whereas a decrease in P c stimulates reabsorption by decreasing back leak across thetight junction.

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Figure 35-11 Routes of solute and water transport across the proximal tubule and the Starling forces that modifyreabsorption. 1, Solute and water are reabsorbed across the apical membrane and then cross the lateral cell membrane. Some

solute and water reenter the tubule fluid (arrow labeled 3), and the remainder enters the interstitial space and then flows intothe capillary (arrow labeled 2 ). The width of the arrows is directly proportional to the amount of solute and water moving by the

pathways labeled 1 to 3. Starling forces across the capillary wall determine the amount of fluid flowing throughpathways 2 versus 3. Transport mechanisms in the apical cell membranes determine the amount of solute and water entering

the cell (pathway 1). c , Capillary oncotic pressure; P c , capillary hydrostatic pressure; i , interstitial fluid oncoticpressure; P i , interstitial hydrostatic pressure. Thin arrows across the capillary wall indicate the direction of water movement in

response to each force.

The oncotic pressure in the peritubular capillary is partly determined by the rate of formation of theglomerular ultrafiltrate. For example, if one assumes a constant plasma flow in the afferent arteriole,then as less ultrafiltrate is formed (i.e., as GFR decreases), the plasma proteins become lessconcentrated in the plasma that enters the efferent arteriole and peritubular capillary. Hence, theperitubular oncotic pressure decreases. The peritubular oncotic pressure is directly related to thefiltration fraction (FF = GFR/RPF). A fall in FF, because of a decrease in GFR at constant RPF,decreases the peritubular capillary oncotic pressure. This in turn increases the back flux of NaCl andwater from the lateral intercellular space into the tubular fluid, and thereby decreases net solute andwater reabsorption across the proximal tubule. An increase in FF has the opposite effect.

The importance of Starling forces in regulating solute and water reabsorption by the proximal tubule isunderscored by the phenomenon of glomerulotubular (G-T) balance. Spontaneous changes in GFRmarkedly alter the filtered load of sodium (filtered load = GFR [Na +]). Without rapid adjustments inNa + reabsorption to counter the changes, urinary Na + excretion would fluctuate widely and disturb the


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Na + balance of the whole body. However, spontaneous changes in GFR do not alter Na + balancebecause of the phenomenon of G-T balance. When body Na + balance is normal, G-T balance refersto the simultaneous increase in Na + and water reabsorption as a result of an increase in GFR and filtered load of Na +. Thus, a constant fraction of the filtered Na + and water is reabsorbed from the

proximal tubule despite variations in GFR. The net result of G-T balance is to reduce the impact of GFR changes on the amount of Na + and water excreted in the urine.

Two mechanisms are responsible for G-T balance. One is related to the oncotic and hydrostaticpressures between the peritubular capillaries and the lateral intercellular space (i.e., Starling forces).For example, an increase in GFR (at constant RPF) raises the protein concentration in the glomerular capillary plasma above normal. This protein-rich plasma leaves the glomerular capillaries, flowsthrough the efferent arteriole, and enters the peritubular capillaries. The increased oncotic pressure inthe peritubular capillaries augments the movement of solute and fluid from the lateral intercellular space into the peritubular capillaries. This action increases net solute and water reabsorption by theproximal tubule.

The second mechanism responsible for G-T balance is initiated by an increase in the filtered load of glucose and amino acids. As discussed earlier in this chapter, the reabsorption of Na + in the earlyproximal tubule is coupled to that of glucose and amino acids. The rate of Na + reabsorption thereforedepends in part on the filtered load of glucose and amino acids. As GFR and the filtered load of glucose and amino acids increase, Na + and water reabsorption also rise.

In addition to G-T balance, another mechanism minimizes changes in the filtered load of Na +. As

discussed earlier in this chapter, an increase in GFR (and thus in the amount of Na+

filtered by theglomerulus) activates the tubuloglomerular feedback mechanism. This action returns GFR and thefiltration of Na + to normal values. Thus, spontaneous changes in GFR (e.g., those caused bychanges in posture and blood pressure) increase the amount of Na + filtered for only a few minutes.Until GFR returns to normal values, the mechanisms that underlie G-T balance maintain urinaryNa + excretion constant and thereby maintain Na + homeostasis.

SUMMARY

1. The four major segments of the nephron (proximal tubule, Henle's loop, distal tubule, and collecting

duct) determine the composition and volume of the urine by the processes of selective reabsorption of solutes and water and selective secretion of solutes.

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2. Tubular reabsorption allows the kidneys to retain those substances that are essential and toregulate their levels in the plasma by altering the degree to which they are reabsorbed. Thereabsorption of Na +, Cl -, other anions, and organic solutes together with water constitutes the major function of the nephron. Approximately 25,200 mEq of Na + and 179 L of water are reabsorbed each


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day. The proximal tubule cells reabsorb 67% of the glomerular ultrafiltrate, and cells of the loop of Henle reabsorb about 25% of the filtered NaCl and about 15% of the filtered water. The distalsegments of the nephron (distal tubule and collecting duct system) have a more limited reabsorptivecapacity. However, the final adjustments in the composition and volume of the urine, and most of theregulation by hormones and other factors, occur in distal segments.

3. Secretion of substances into tubular fluid is a means for excreting various by-products of metabolism. It also eliminates exogenous organic anions and bases (e.g., drugs) and pollutants fromthe body. Many organic compounds are bound to plasma proteins and are therefore unavailable for ultrafiltration. Secretion is thus their major route of excretion in the urine.

4. Various hormones (including angiotensin II, aldosterone, ADH, ANP, and urodilatin), sympatheticnerves, dopamine, and Starling forces regulate NaCl reabsorption by the kidneys. ADH is the major hormone that regulates water reabsorption.

solute and water transport

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