2291Cell Biology and Physiology of the Kidney CHAPTER 309

+ –

Ca, Mg

3Na

Loop diuretics

THICK ASCENDING LIMB

C

Ca

H2O H2O

H2O

H2O

H2O

H2O

K

2K

Cl

Na

2Cl

+

+

+

+ +

+

Amiloride

CORTICAL COLLECTING DUCT

Principal cell

Type A

intercalated cell

D

Lumen Interstitium

Spironolactone

Eplerenone

Na

H

H

K

3Na

2K

K Aldosterone

Vasopressin

carbonic

anhydrase

HCO3 Cl

3Na

2K

Lumen Interstitium

3Na

Thiazides

DISTAL CONVOLUTED TUBULE

Ca

2K

Cl

Na

Cl

Ca

3Na

E

+ +

Lumen Interstitium

ANP

3Na

INNER MEDULLARY COLLECTING DUCT

K 2K

Urea

Na

Vasopressin

F

K

FIGURE 309-3 (Continued)

transporters such as Na+-glucose and Na+-phosphate cotransporters

present in apical membranes. In addition to the paracellular route,

water reabsorption also occurs through the cellular pathway enabled

by constitutively active water channels (aquaporin-1) present on both

apical and basolateral membranes.

Proximal tubular cells reclaim nearly all filtered bicarbonate by a

mechanism dependent on carbonic anhydrases. Filtered bicarbonate

is first titrated by protons delivered to the lumen mainly by Na+/H+

exchange. The resulting carbonic acid (H2

CO3

) is metabolized by brush

border carbonic anhydrase to water and carbon dioxide. Dissolved

carbon dioxide then diffuses into the cell, where it is enzymatically

hydrated by cytoplasmic carbonic anhydrase to re-form carbonic acid.

Finally, intracellular carbonic acid dissociates into free protons and

bicarbonate anions, and bicarbonate exits the cell through a basolateral

Na+/HCO3

− cotransporter. This process is saturable, which can result in

renal bicarbonate excretion when plasma levels exceed the physiologically normal range (24–26 meq/L). Carbonic anhydrase inhibitors such

as acetazolamide, a class of weak diuretic agents, block proximal tubule

bicarbonate reabsorption and are useful for alkalinizing the urine.

The proximal tubule contributes to acid secretion by two mechanisms involving the titration of the urinary buffers ammonia (NH3

)

and phosphate. Renal NH3

 is produced by glutamine metabolism in the

proximal tubule. Subsequent diffusion of NH3

 out of the proximal tubular cell enables trapping of H+, which is secreted by Na+/H+ exchange,

in the lumen as ammonium ion (NH4

+). Cellular K+ levels inversely

modulate proximal tubular ammoniagenesis, and in the setting of high

serum K+ from hypoaldosteronism, reduced ammoniagenesis promotes type IV renal tubular acidosis. Filtered hydrogen phosphate ion

(HPO4

2−) is also titrated in the proximal tubule by secreted H+ to form

H2

PO4

−, and this reaction constitutes a major component of the urinary

buffer referred to as titratable acid. Most filtered phosphate ion is reabsorbed by the proximal tubule through a sodium-coupled cotransport

process that is regulated by parathyroid hormone (PTH).

Chloride is poorly reabsorbed throughout the first segment of

the proximal tubule, and a rise in Cl− concentration counterbalances

the removal of bicarbonate anion from tubular fluid. In later proximal tubular segments, cellular Cl− reabsorption is initiated by apical

exchange of cellular formate for higher luminal concentrations of Cl−.

2292 PART 9 Disorders of the Kidney and Urinary Tract

TABLE 309-1 Inherited Disorders Affecting Renal Tubular Ion and Solute Transport

DISEASE OR SYNDROME GENE OMIMa

Disorders Involving the Proximal Tubule

Proximal renal tubular acidosis Sodium bicarbonate cotransporter (SLC4A4, 4q21) 604278

Fanconi-Bickel syndrome Glucose transporter, GLUT2 (SLC2A2, 3q26.2) 227810

Isolated renal glycosuria Sodium glucose cotransporter (SLC5A2, 16p11.2) 233100

Cystinuria

Type I Cystine, dibasic and neutral amino acid transporter (SLC3A1, 2p16.3) 220100

Non-type I Amino acid transporter, light subunit (SLC7A9, 19q13.1) 600918

Lysinuric protein intolerance Amino acid transporter (SLC7A7, 4q11.2) 222700

Hartnup disorder Neutral amino acid transporter (SLC6A19, 5p15.33) 34500

Hereditary hypophosphatemic rickets with

hypercalcemia

Sodium phosphate cotransporter (SLC34A3, 9q34) 241530

Renal hypouricemia

Type 1 Urate-anion exchanger (SLC22A12, 11q13) 220150

Type 2 Urate transporter, GLUT9 (SLC2A9, 4p16.1) 612076

Dent’s disease Chloride channel, ClC-5 (CLCN5, Xp11.22) 300009

X-linked recessive nephrolithiasis with renal failure Chloride channel, ClC-5 (CLCN5, Xp11.22) 310468

X-linked recessive hypophosphatemic rickets Chloride channel, ClC-5 (CLCN5, Xp11.22) 307800

Disorders Involving the Loop of Henle

Bartter’s syndrome

Type 1 Sodium, potassium chloride cotransporter (SLC12A1, 15q21.1) 241200

Type 2 Potassium channel, ROMK (KCNJ1, 11q24) 601678

Type 3 Chloride channel, ClC-Kb (CLCNKB, 1p36) 602023

with sensorineural deafness Chloride channel accessory subunit, Barttin (BSND, 1p31) 602522

Autosomal dominant hypocalcemia with Bartter-like

syndrome

Calcium-sensing receptor (CASR, 3q13.33) 601199

Familial hypocalciuric hypercalcemia Calcium-sensing receptor (CASR, 3q13.33) 145980

Primary hypomagnesemia Claudin-16 or paracellin-1 (CLDN16 or PCLN1, 3q27) 248250

Isolated renal magnesium loss Sodium potassium ATPase, γ1

-subunit (ATP1G1, 11q23) 154020

Disorders Involving the Distal Tubule and Collecting Duct

Gitelman syndrome Sodium chloride cotransporter (SLC12A3, 16q13) 263800

Primary hypomagnesemia with secondary hypocalcemia Melastatin-related transient receptor potential cation channel 6 (TRPM6, 9q22) 602014

Pseudoaldosteronism (Liddle’s syndrome) Epithelial sodium channel β and γ subunits (SCNN1B, SCNN1G, 16p12.1) 177200

Recessive pseudohypoaldosteronism type 1 Epithelial sodium channel, α, β, and γ subunits (SCNN1A, 12p13; SCNN1B,

SCNN1G, 16pp12.1)

264350

Pseudohypoaldosteronism type 2 (Gordon’s hyperkalemiahypertension syndrome)

Kinases WNK-1, WNK-4 (WNK1, 12p13; WNK4, 17q21.31) 145260

X-linked nephrogenic diabetes insipidus Vasopressin V2 receptor (AVPR2, Xq28) 304800

Nephrogenic diabetes insipidus (autosomal) Water channel, aquaporin-2 (AQP2, 12q13) 125800

Distal renal tubular acidosis

autosomal dominant Anion exchanger-1 (SLC4A1, 17q21.31) 179800

autosomal recessive Anion exchanger-1 (SLC4A1, 17q21.31) 602722

with neural deafness Proton ATPase, β1 subunit (ATP6V1B1, 2p13.3) 192132

with normal hearing Proton ATPase, 116-kD subunit (ATP6V0A4, 7q34) 602722

a

Online Mendelian Inheritance in Man database (https://www.ncbi.nlm.nih.gov/omim).

Once in the lumen, formate anions are titrated by H+ (provided by

Na+/H+ exchange) to generate neutral formic acid, which can diffuse

passively across the apical membrane back into the cell where it dissociates a proton and is recycled. Basolateral Cl− exit is mediated by a K+/

Cl− cotransporter.

Reabsorption of glucose is nearly complete by the end of the

proximal tubule. Cellular transport of glucose is mediated by apical

Na+-glucose cotransport coupled with basolateral, facilitated diffusion

by a glucose transporter. This process is also saturable, leading to glycosuria when plasma levels exceed 180–200 mg/dL, as seen in untreated

diabetes mellitus. Inhibitors of the Na+-glucose cotransporter SLGT2

in proximal tubules block glucose reabsorption and lower blood glucose, which has therapeutic benefits in diabetes mellitus and chronic

diabetic kidney disease.

The proximal tubule possesses specific transporters capable of secreting a variety of organic acids (carboxylate anions) and bases (mostly

primary amine cations). Organic anions transported by these systems

include several protein-bound drugs not filtered at the glomerulus

(penicillins, cephalosporins, and salicylates). Probenecid inhibits renal

organic anion secretion and was historically used to elevate plasma

concentrations of certain drugs such as penicillin and oseltamivir.

Organic cations secreted by the proximal tubule include various biogenic amine neurotransmitters (dopamine, acetylcholine, epinephrine,

norepinephrine, and histamine) and creatinine. The ATP-dependent

transporter P-glycoprotein is expressed in brush border membranes

and secretes several medically important drugs, including cyclosporine, digoxin, tacrolimus, and various cancer chemotherapeutic

agents. Certain drugs like cimetidine and trimethoprim compete with

2293Cell Biology and Physiology of the Kidney CHAPTER 309

endogenous compounds for transport by the organic cation pathways.

Although these drugs elevate serum creatinine levels, there is no actual

change in GFR in this setting.

Calcium and phosphorus homeostasis depends on normal functioning of the proximal tubule. Approximately 60–70% of filtered calcium

and ~85% of filtered phosphorus (in the form of inorganic phosphate)

are reabsorbed by the proximal tubule. Whereas calcium reabsorption

is mostly by passive diffusion through the paracellular route, phosphate reabsorption is mediated by sodium-coupled cotransport. In

addition to direct reabsorption, the proximal tubule contributes to

systemic mineral balance by participating in specific endocrine pathways. Circulating 25-hydroxy vitamin D (calcidiol) is bioactivated by

proximal tubular 1α-hydroxylase to produce 1,25-di-hydroxy vitamin

D (calcitriol), the most active form of the hormone, which acts on the

small intestine to promote calcium absorption. Phosphate balance

is affected by circulating fibroblast growth hormone 23 (FGF23), a

bone-derived hormone that interacts with its receptor (FGFR1) and

co-receptor (Klotho) on proximal tubular cells to suppress sodiumphosphate cotransport and promote renal phosphate excretion. PTH

stimulates proximal tubular 1α-hydroxylation of vitamin D, whereas

it suppresses sodium-phosphate cotransport. Derangements in PTH

and FGF23 account for abnormal calcium and phosphate balance in

chronic kidney disease.

The proximal tubule, through distinct classes of Na+-dependent and

Na+-independent transport systems, reabsorbs amino acids efficiently.

These transporters are specific for different groups of amino acids. For

example, cystine, lysine, arginine, and ornithine are transported by a

system comprising two proteins encoded by the SLC3A1 and SLC7A9

genes. Mutations in either SLC3A1 or SLC7A9 impair reabsorption

of these amino acids and cause the disease cystinuria. Peptide hormones, such as insulin and growth hormone, β2

-microglobulin, and

other small proteins, are taken up by the proximal tubule through

a process of absorptive endocytosis and are degraded in acidified

endocytic lysosomes. Acidification of these vesicles depends on a vacuolar H+-ATPase and Cl− channel. Impaired acidification of endocytic

vesicles because of mutations in a Cl− channel gene (CLCN5) causes

low-molecular-weight proteinuria in Dent’s disease.

LOOP OF HENLE

The loop of Henle consists of three major segments: descending thin

limb, ascending thin limb, and ascending thick limb. Approximately

15–25% of filtered NaCl is reabsorbed in the loop of Henle, mainly by

the thick ascending limb. The loop of Henle has an important role in

urinary concentration by contributing to the generation of a hypertonic medullary interstitium in a process called countercurrent multiplication. The loop of Henle is the site of action for the most potent class

of diuretic agents (loop diuretics) and also contributes to reabsorption

of calcium and magnesium ions.

The descending thin limb is highly water permeable owing to

dense expression of constitutively active aquaporin-1 water channels.

By contrast, water permeability is negligible in the ascending limb.

In the thick ascending limb, there is a high level of secondary active

NaCl transport enabled by the Na+/K+/2Cl− cotransporter on the

apical membrane in series with basolateral Cl− channels and Na+/K+-

ATPase (Fig. 309-3C). The Na+/K+/2Cl− cotransporter is the primary

target for loop diuretics. Tubular fluid K+ is the limiting substrate for

this cotransporter (tubular concentration of K+ is similar to plasma,

~4 meq/L), but transporter activity is maintained by K+ recycling

through an apical potassium channel. The cotransporter also enables

reabsorption of NH4

+ in lieu of K+, and this leads to accumulation of

both NH4

+ and NH3

 in the medullary interstitium. An inherited disorder of the thick ascending limb, Bartter’s syndrome, is a salt-wasting

renal disease associated with hypokalemia and metabolic alkalosis.

Loss-of-function mutations in one of five distinct genes encoding

components of the Na+/K+/2Cl− cotransporter (NKCC2), apical K+

channel (KCNJ1), basolateral Cl− channel (CLCNKB, BSND), or calciumsensing receptor (CASR) can cause Bartter’s syndrome.

Potassium recycling also contributes to a positive electrostatic

charge in the lumen relative to the interstitium that promotes divalent

cation (Mg2+ and Ca2+) reabsorption through a paracellular pathway.

A Ca2+-sensing, G protein–coupled receptor (CaSR) on basolateral

membranes regulates NaCl reabsorption in the thick ascending limb

through dual signaling mechanisms using either cyclic AMP or

eicosanoids. This receptor enables a steep relationship between plasma

Ca2+ levels and renal Ca2+ excretion. Loss-of-function mutations in

CaSR cause familial hypercalcemic hypocalciuria because of a blunted

response of the thick ascending limb to extracellular Ca2+. Mutations

in CLDN16 encoding paracellin-1, a transmembrane protein located

within the tight junction complex, leads to familial hypomagnesemia

with hypercalciuria and nephrocalcinosis, suggesting that the ion

conductance of the paracellular pathway in the thick limb is regulated.

The loop of Henle contributes to urine-concentrating ability by

establishing a hypertonic medullary interstitium that promotes water

reabsorption by the downstream inner medullary collecting duct.

Countercurrent multiplication produces a hypertonic medullary interstitium using two countercurrent systems: the loop of Henle (opposing

descending and ascending limbs) and the vasa recta (medullary peritubular capillaries enveloping the loop). The countercurrent flow in these

two systems helps maintain the hypertonic environment of the inner

medulla, but NaCl reabsorption by the thick ascending limb is the

primary initiating event. Reabsorption of NaCl without water dilutes

the tubular fluid and adds new osmoles to medullary interstitial fluid.

Because the descending thin limb is highly water permeable, osmotic

equilibrium occurs between the descending limb tubular fluid and the

interstitial space, leading to progressive solute trapping in the inner

medulla. Maximum medullary interstitial osmolality also requires partial recycling of urea from the collecting duct.

DISTAL CONVOLUTED TUBULE

The distal convoluted tubule reabsorbs ~5% of the filtered NaCl. This

segment is composed of a tight epithelium with little water permeability. The major NaCl-transporting pathway uses an apical membrane,

electroneutral thiazide-sensitive Na+/Cl− cotransporter in tandem with

basolateral Na+/K+-ATPase and Cl− channels (Fig. 309-3D). Apical

Ca2+-selective channels (TRPV5) and basolateral Na+/Ca2+ exchange

mediate calcium reabsorption in the distal convoluted tubule. Ca2+

reabsorption is inversely related to Na+ reabsorption and is stimulated

by PTH. Blocking apical Na+/Cl− cotransport will reduce intracellular

Na+, favoring increased basolateral Na+/Ca2+ exchange and passive apical Ca2+ entry. Loss-of-function mutations of SLC12A3 encoding the

apical Na+/Cl− cotransporter cause Gitelman syndrome, a salt-wasting

disorder associated with hypokalemic alkalosis and hypocalciuria.

Mutations in TRPM6 encoding Mg2+ permeable ion channels also

cause familial hypomagnesemia with hypocalcemia. A molecular complex of TRPM6 and TRPM7 proteins is critical for Mg2+ reabsorption

in the distal convoluted tubule.

COLLECTING DUCT

The collecting duct modulates the final composition of urine. The

two major divisions, the cortical collecting duct and inner medullary

collecting duct, contribute to reabsorbing ~4–5% of filtered Na+ and

are important for hormonal regulation of salt and water balance. Cells

in both segments of the collecting duct express vasopressin-regulated

water channels (aquaporin-2 on the apical membrane, aquaporin-3

and -4 on the basolateral membrane). The antidiuretic hormone vasopressin binds to the V2 receptor on the basolateral membrane and

triggers an intracellular signaling cascade through G protein–mediated

activation of adenylyl cyclase, which raises intracellular levels of cyclic

AMP. This signaling cascade stimulates the insertion of water channels

into the apical membrane of collecting duct cells to promote water permeability, water reabsorption, and production of concentrated urine.

In the absence of vasopressin, collecting duct cells are water impermeable, and urine remains dilute.

The cortical collecting duct contains high-resistance epithelia with

two cell types. Principal cells are the main water-reabsorbing, Na+-

reabsorbing, and K+-secreting cells, and the site of action of aldosterone, K+-sparing diuretics, and mineralocorticoid receptor antagonists

such as spironolactone and eplerenone. The other cells are type A and

2294 PART 9 Disorders of the Kidney and Urinary Tract

B intercalated cells. Type A intercalated cells mediate acid secretion

and bicarbonate reabsorption also under the influence of aldosterone. Type B intercalated cells mediate bicarbonate secretion and acid

reabsorption.

Virtually all transport is mediated through the cellular pathway for

both principal cells and intercalated cells. In principal cells, passive

apical Na+ entry occurs through an amiloride-sensitive, epithelial Na+

channel (ENaC) with basolateral exit mediated by the Na+/K+-ATPase

(Fig. 309-3E). This Na+ reabsorptive process is tightly regulated by

aldosterone and is physiologically activated by a variety of proteolytic

enzymes that cleave extracellular domains of ENaC; plasmin in the

tubular fluid of nephrotic patients, for example, activates ENaC, leading to sodium retention. Aldosterone enters the cell across the basolateral membrane, binds to a cytoplasmic mineralocorticoid receptor, and

then translocates into the nucleus, where it modulates gene transcription, which potentiates Na+ reabsorption and K+ secretion. Activating

mutations in ENaC increase Na+ reclamation and produce hypokalemia, hypertension, and metabolic alkalosis (Liddle’s syndrome). The

potassium-sparing diuretics amiloride and triamterene block ENaC,

resulting in lower Na+ reabsorption.

Principal cells secrete K+ through an apical membrane potassium

channel. Several forces govern the secretion of K+. Most importantly,

the high intracellular K+ concentration generated by Na+/K+-ATPase

creates a favorable concentration gradient for K+ secretion into tubular

fluid. With reabsorption of Na+ without an accompanying anion, the

tubular lumen becomes negative relative to the cell interior, creating

a favorable electrical gradient for secretion of potassium. When Na+

reabsorption is blocked, the electrical component of the driving force

for K+ secretion is blunted, and this explains lack of excess urinary

K+ loss during treatment with potassium-sparing diuretics or mineralocorticoid receptor antagonists. K+ secretion is also promoted

by aldosterone actions that potentiate regional Na+ transport, which

favor more lumen electronegativity, and by increasing the number

and activity of potassium channels. Fast tubular fluid flow rates that

occur during volume expansion or diuretics acting “upstream” of the

cortical collecting duct also promote K+ secretion, as does the presence of relatively nonreabsorbable anions (including bicarbonate and

semisynthetic penicillins) that contribute to the lumen-negative potential. Off-target effects of certain antibiotics, such as trimethoprim and

pentamidine, block ENaCs and predispose to hyperkalemia, especially

when renal K+ handling is impaired for other reasons. Principal cells,

as described below, also participate in water reabsorption in response

to vasopressin.

Intercalated cells do not participate in Na+ reabsorption but instead

mediate acid-base balance. These cells perform two types of transport:

active H+ transport mediated by H+-ATPase (proton pump) and Cl−/

HCO3

− exchange. Intercalated cells arrange the two transport mechanisms on opposite membranes to enable either acid or base secretion.

Type A intercalated cells have an apical proton pump that mediates

acid secretion and a basolateral Cl−/HCO3

− anion exchanger for bicarbonate reabsorption (Fig. 309-3E). Aldosterone increases the number

of H+-ATPase pumps, sometimes contributing to the development of

metabolic alkalosis. Secreted H+ is buffered by NH3

 that has diffused

into the collecting duct lumen from the surrounding interstitium. By

contrast, type B intercalated cells have the Cl−/HCO3

− exchanger on the

apical membrane to mediate bicarbonate secretion while the proton

pump resides on the basolateral membrane to enable H+ reabsorption.

Under conditions of acidemia, the kidney preferentially uses type A

intercalated cells to secrete the excess H+ and generate more HCO3

−.

The opposite is true in states of bicarbonate excess with alkalemia

where the type B intercalated cells predominate. An extracellular protein called hensin mediates this adaptation.

Inner medullary collecting duct cells share many similarities with

principal cells of the cortical collecting duct. They have apical Na+

and K+ channels that mediate Na+ reabsorption and K+ secretion,

respectively (Fig. 309-3F). Sodium reabsorption by inner medullary

collecting duct cells is also inhibited by the natriuretic peptides called

atrial natriuretic peptide or renal natriuretic peptide (urodilatin); the

same gene encodes both peptides but uses different posttranslational

processing of a common preprohormone to generate different proteins.

Atrial natriuretic peptides are secreted by atrial myocytes in response

to volume expansion, whereas urodilatin is secreted by renal tubular

epithelia. Natriuretic peptides interact with either apical (urodilatin)

or basolateral (atrial natriuretic peptides) receptors on inner medullary collecting duct cells to stimulate guanylyl cyclase and raise levels

of cytoplasmic cGMP. This effect in turn reduces the activity of the

apical Na+ channel in these cells and attenuates net Na+ reabsorption,

producing natriuresis.

The inner medullary collecting duct transports urea out of the

lumen, returning urea to the interstitium, where it contributes to the

hypertonicity of the medullary interstitium. Urea is recycled by diffusing from the interstitium into the descending and ascending limbs of

the loop of Henle.

HORMONAL REGULATION OF SODIUM

AND WATER BALANCE

The balance of solute and water in the body is determined by the

amounts ingested, distributed to various fluid compartments, and

excreted by skin, bowel, and kidneys. Tonicity, the osmolar state determining the volume behavior of cells in a solution, is regulated by water

balance (Fig. 309-4A), and extracellular blood volume is regulated by

Na+ balance (Fig. 309-4B). The kidney is a critical modulator of both

physiologic processes.

■ WATER BALANCE

Tonicity depends on the variable concentration of effective osmoles

inside and outside the cell causing water to move in either direction

across its membrane. Classic effective osmoles, like Na+, K+, and

their anions, are solutes trapped on either side of a cell membrane,

where they collectively partition and obligate water to move and

find equilibrium in proportion to retained solute. Normal tonicity

(~280 mosmol/L) is rigorously defended by osmoregulatory mechanisms that control water balance to protect tissues from inadvertent

dehydration (cell shrinkage) or water intoxication (cell swelling), both

of which impair cell function (Fig. 309-4A).

The mechanisms that control osmoregulation are distinct from

those governing extracellular volume, although there is some shared

physiology in both processes. While cellular concentrations of K+ have

a determinant role in any level of tonicity, the routine surrogate marker

for assessing clinical tonicity is the concentration of serum Na+. Any

reduction in total body water, which raises the Na+ concentration,

triggers a brisk sense of thirst and conservation of water by decreasing renal water excretion mediated by release of vasopressin from

the posterior pituitary. Conversely, a lower plasma Na+ concentration

triggers more renal water excretion by suppressing the secretion of

vasopressin. Whereas all cells expressing mechanosensitive TRPV1, 2,

or 4 channels, among potentially other sensors, respond to changes in

tonicity by altering their volume and Ca2+ concentration, only TRPV+

neuronal cells connected to the organum vasculosum of the lamina

terminalis are osmoreceptive. Only these cells, because of their neural

connectivity and adjacency to a minimal blood-brain barrier, modulate the downstream release of vasopressin by the posterior lobe of the

pituitary gland. Secretion is stimulated primarily by changing tonicity

and secondarily by other nonosmotic signals such as variable blood

volume, stress, pain, nausea, and some drugs. The release of vasopressin by the posterior pituitary increases linearly as plasma tonicity

rises above normal, although this varies, depending on the perception

of extracellular volume (one form of cross-talk between mechanisms

that regulate blood volume and osmolality). Changing the intake or

excretion of water provides a means for adjusting plasma tonicity; thus,

osmoregulation governs water balance.

The kidneys contribute to maintaining water balance through the

regulation of renal water excretion. The ability to concentrate urine

to an osmolality exceeding that of plasma enables water conservation,

whereas the ability to produce urine more dilute than plasma promotes

excretion of excess water. For water to enter or exit a cell, the cell membrane must express aquaporins. In the kidney, aquaporin-1 is constitutively active in all water-permeable segments (e.g., proximal tubule,

2295Cell Biology and Physiology of the Kidney CHAPTER 309

descending thin limb of the loop of Henle), whereas aquaporin-2, -3,

and -4 in the collecting duct promote vasopressin-regulated water permeability. Net water reabsorption is ultimately driven by the osmotic

gradient between dilute tubular fluid and a hypertonic medullary

interstitium.

■ SODIUM BALANCE

The perception of extracellular blood volume is determined, in part,

by the integration of arterial tone, cardiac stroke volume, heart rate, and

the water and solute content of extracellular fluid. Na+ and accompanying anions are the most abundant extracellular effective osmoles and

together support a blood volume around which pressure is generated.

Under normal conditions, this volume is regulated by sodium balance

(Fig. 309-4B), and the balance between daily Na+ intake and excretion

is under the influence of baroreceptors in regional blood vessels and

vascular hormone sensors modulated by atrial natriuretic peptides,

the renin-angiotensin-aldosterone system, Ca2+ signaling, adenosine,

vasopressin, and the neural adrenergic axis. If Na+ intake exceeds Na+

excretion (positive Na+ balance), then a rising blood volume will trigger a proportional increase in urinary Na+ excretion. Conversely, when

Na+ intake is less than urinary excretion (negative Na+ balance), blood

volume will fall and trigger enhanced renal Na+ reabsorption, leading

to decreased urinary Na+ excretion.

The renin-angiotensin-aldosterone system is the best-understood

hormonal system modulating renal Na+ excretion. Renin is synthesized

and secreted by granular cells in the wall of the afferent arteriole. Its

secretion is controlled by several factors, including β1

-adrenergic stimulation to the afferent arteriole, input from the macula densa, and prostaglandins. Renin and ACE activity eventually produce angiotensin II

that directly and indirectly promotes renal Na+ and water reabsorption.

Stimulation of proximal tubular Na+/H+ exchange by angiotensin II

directly increases Na+ reabsorption. Angiotensin II also promotes

Na+ reabsorption along the collecting duct by stimulating aldosterone

secretion by the adrenal cortex. Constriction of the efferent glomerular

arteriole by angiotensin II indirectly boosts the filtration fraction and

raises peritubular capillary oncotic pressure to promote tubular Na+

reabsorption. Finally, angiotensin II inhibits renin secretion through

a negative feedback loop. Alternative metabolism of angiotensin by

ACE2 generates the vasodilatory peptide angiotensin 1-7 that acts

through Mas receptors to counterbalance several actions of angiotensin

II on blood pressure and renal function (Fig. 309-2C).

Aldosterone is synthesized and secreted by granulosa cells in the

adrenal cortex. It binds to cytoplasmic mineralocorticoid receptors

in the collecting duct principal cells and boosts the activity of ENaC,

apical membrane K+ channel, and basolateral Na+/K+-ATPase. These

effects are mediated in part by aldosterone-stimulated transcription

of the gene encoding serum/glucocorticoid-induced kinase 1 (SGK1).

The activity of ENaC is increased by SGK1-mediated phosphorylation

of Nedd4-2, a protein that promotes recycling of the Na+ channel from

the plasma membrane. Phosphorylated Nedd4-2 has impaired interactions with ENaC, leading to higher channel density at the plasma membrane and greater capacity for Na+ reabsorption by the collecting duct.

Cell volume

pNa+ = Tonicity = = Effective osmoles

TB H2O

TB Na+ + TB K+

TB H2O

Net water balance

+ TB H2O

– TB H2O

Thirst

Osmoreception

Custom/habit

ADH levels

V2-receptor/AP2 water flow

Medullary gradient

Water intake Determinants

Renal regulation

Free water clearance

Hyponatremia

Hypotonicity

Water intoxication

Hypernatremia

Hypertonicity

Dehydration

Cell

membrane

Clinical result

A

 Extracellular blood volume and pressure

(TB Na+ + TB H2O + Vascular tone + Heart rate + Stroke volume) Net Na+ balance

+ TB Na+

– TB Na+

Taste

Baroreception

Custom/habit

Na+ reabsorption

Tubuloglomerular feedback

Macula densa

Atrial natriuretic peptides

Na Determinants + intake

Renal regulation

Fractional Na+ excretion

Edema

Volume depletion

Clinical result

B

FIGURE 309-4 Determinants of sodium and water balance. A. Plasma Na+

 concentration is a surrogate marker for plasma tonicity. Tonicity is determined by the number of

effective osmoles in the body divided by the total body H2

O (TB H2

O), which translates simply into the total body Na (TB Na+

) and anions outside the cell separated from the

total body K (TB K+

) inside the cell by the cell membrane. Net water balance is determined by the integrated functions of thirst, osmoreception, Na reabsorption, vasopressin

release, and the strength of the medullary gradient in the kidney, keeping tonicity within a narrow range of osmolality (~280 mosmol/L). When water metabolism is disturbed

and total body water increases, hyponatremia, hypotonicity, and water intoxication occur; when total body water decreases, hypernatremia, hypertonicity, and dehydration

occur. B. Extracellular blood volume and pressure are an integrated function of total body Na+

 (TB Na+

), total body H2

O (TB H2

O), vascular tone, heart rate, and stroke

volume that modulates volume and pressure in the vascular tree of the body. This extracellular blood volume is determined by net Na balance under the control of taste,

baroreception, habit, Na+

 reabsorption, macula densa/tubuloglomerular feedback, and natriuretic peptides. When Na+

 metabolism is disturbed and total body Na+

 increases,

edema occurs; when total body Na+

 is decreased, volume depletion occurs. ADH, antidiuretic hormone; AQP2, aquaporin-2.

2296 PART 9 Disorders of the Kidney and Urinary Tract

Chronic exposure to aldosterone is associated with lower urinary

Na+ excretion lasting only a few days, after which Na+ excretion returns

to previous levels. This phenomenon, called aldosterone escape, is

explained by lower proximal tubular Na+ reabsorption following blood

volume expansion. Excess Na+ that is not reabsorbed by the proximal

tubule overwhelms the reabsorptive capacity of more distal nephron

segments. This escape may be facilitated by atrial natriuretic peptides

that lose their effectiveness in the clinical settings of heart failure,

nephrotic syndrome, and cirrhosis, leading to severe Na+ retention and

volume overload.

■ FURTHER READING

Cherney DZ et al: Sodium glucose cotransporter-2 inhibition and

cardiorenal protection. J Am Coll Cardiol 74:2511, 2019.

Palmer BF, Clegg DJ: Physiology and pathophysiology of potassium

homeostasis. Am J Kid Dis 74:682, 2019.

Romero CA, Carretero OA: Tubule-vascular feedback in renal

autoregulation. Am J Physiol Renal Physiol 316:F1218, 2019.

Su W et al: Aquaporins in the kidney: Physiology and pathophysiology.

Am J Physiol Renal Physiol 318:F193, 2020.

van der Wiljst J et al: Learning physiology from inherited kidney

disorders. Physiol Rev 99:1575, 2019.

Acute kidney injury (AKI) is defined by the impairment of kidney

filtration and excretory function over days to weeks (generally known

or expected to have occurred within 7 days), resulting in the retention of nitrogenous and other waste products normally cleared by

the kidneys. AKI is not a single disease but rather a designation for

a heterogeneous group of conditions that share common diagnostic

features: specifically, an increase in serum creatinine (SCr) concentration often associated with a reduction in urine volume. It is important

to recognize that AKI is a clinical diagnosis and not a structural one.

A patient may have AKI with or without injury to the kidney parenchyma. AKI can range in severity from asymptomatic and transient

changes in laboratory parameters of glomerular filtration rate (GFR),

to overwhelming and rapidly fatal derangements in the ability of the

kidney to maintain effective circulating volume regulation, excrete

nitrogenous wastes and metabolic toxins, and maintain electrolyte and

acid-base composition of the plasma.

EPIDEMIOLOGY

AKI complicates 5–7% of acute-care hospital admissions and up to 30%

of admissions to the intensive care unit (ICU). AKI severity is staged

based on the magnitude of the rise in SCr and severity and duration

of oliguria (Table 310-1). The incidence of AKI has grown by more

than fourfold in the United States since 1988 and is estimated to have a

yearly incidence of 500 per 100,000 population, higher than the yearly

incidence of stroke. Large studies have shown that increases in SCr as

low as 0.3 mg/dL in hospitalized patients are independently associated

with an approximately fourfold increase in hospital mortality, with

higher changes in creatine, and longer duration of elevation associated

with greater increased risk of morbidity and mortality. Morbidity of

AKI in those admitted to the ICU exceeds 50% in many studies. AKI

also has longer term implications even if the patient survives the hospitalization. AKI increases the risk for the development or worsening of

chronic kidney disease (CKD) and development of dialysis-requiring

end-stage kidney disease (ESKD). AKI may also occur in the community. Common causes of community-acquired AKI include volume

depletion, heart failure, adverse effects of medications, obstruction of

310 Acute Kidney Injury

Sushrut S. Waikar, Joseph V. Bonventre

TABLE 310-1 Staging of Acute Kidney Injury Severity

STAGE SERUM CREATININE URINE OUTPUT

1 1.5–1.9 times baseline

OR

≥0.3 mg/dL (≥26.5 μmol/L) increase

<0.5 mL/kg per h for 6–12 h

2 2.0–2.9 times baseline <0.5 mL/kg per h for ≥12 h

3 3.0 times baseline

OR

increase in serum creatinine to

≥4.0 mg/dL (≥353.6 μmol/L)

OR

initiation of renal replacement

therapy OR, in patients <18 years of

age, decrease in eGFR to <35 mL/min

per 1.73 m2

<0.3 mL/kg per h for ≥24 h OR

Anuria for ≥12 h

the urinary tract, or malignancy. The most common clinical settings

for hospital-acquired AKI are sepsis, major surgical procedures, critical illness involving heart or liver failure, and nephrotoxic medication

administration.

■ AKI IN THE DEVELOPING WORLD

AKI is also a major medical complication in the developing world,

where the epidemiology differs from that in developed countries

due to differences in demographics, economics, environmental factors, and comorbid disease burden. While certain features of AKI

are common in developed and developing countries—particularly

because urban centers of some developing countries increasingly

resemble those in the developed world—many etiologies for AKI are

region-specific, such as envenomations from snakes, spiders, caterpillars, and bees; infectious causes such as malaria and leptospirosis;

and crush injuries and resultant rhabdomyolysis from earthquakes.

In developing countries, resources to diagnose and manage AKI are

often limited.

ETIOLOGY AND PATHOPHYSIOLOGY

The causes of AKI have traditionally been divided into three broad

categories: prerenal azotemia, intrinsic renal parenchymal disease, and

postrenal obstruction (Fig. 310-1).

■ PRERENAL AZOTEMIA

Prerenal azotemia (from “azo,” meaning nitrogen, and “-emia,” meaning in the blood) is the most common form of AKI. It is the designation

for a rise in SCr or BUN concentration due to inadequate renal plasma

flow and intraglomerular hydrostatic pressure to support normal glomerular filtration. The most common clinical conditions associated

with prerenal azotemia are hypovolemia, decreased cardiac output, and

medications that interfere with renal autoregulatory vascular responses

such as nonsteroidal anti-inflammatory drugs (NSAIDs) and inhibitors

of angiotensin II (Fig. 310-2). By definition, prerenal azotemia involves

no parenchymal damage to the kidney and is rapidly reversible once

parenchymal blood flow and intraglomerular hemodynamics are

restored. In many cases, however, prerenal azotemia may coexist with

other forms of intrinsic AKI associated with processes acting directly

on the renal parenchyma. Prolonged periods of prerenal azotemia may

lead to ischemic injury to the tubular cells with necrosis, hence termed

acute tubular necrosis (ATN).

Normal GFR is maintained in part by renal blood flow and the relative resistances of the afferent and efferent renal arterioles, which determine the glomerular plasma flow rate and the transcapillary hydraulic

pressure gradient that drive glomerular ultrafiltration. Mild degrees

of hypovolemia and reductions in cardiac output elicit compensatory

renal physiologic changes. Because renal blood flow accounts for 20%

of the cardiac output, renal vasoconstriction and salt and water reabsorption occur as homeostatic responses to decreased effective circulating volume or cardiac output in order to maintain blood pressure

and increase intravascular volume to sustain perfusion to the cerebral