The Netter Collection of Medical Illustrations VOLUME 5

Plate 3-11 Physiology

RENAL HANDLING OF CALCIUM, RENAL HANDLING OF CALCIUM AND PHOSPHATE
PHOSPHATE, AND MAGNESIUM
Calcium handling Phosphate handling

CALCIUM 50–60% 80%
(paracellular) (trans-
More than 98% of total body calcium is in bones, cellular)
whereas the remainder is located in intracellular and
extracellular fluid. Normal plasma concentrations, 10–15% 5%
which range from 8.8 to 10.3 mg/dL, are maintained (trans- (trans-
by the actions of PTH, 1,25-hydroxyvitamin D, and cellular) cellular)
calcitonin on bones, the gastrointestinal tract, and the
kidneys. 15% ? 15% excreted
(para-
About half of the extracellular calcium load is in an cellular)
active, ionized form, whereas the remainder complexes
with albumin and other anions. The ionized calcium is 1% excreted
freely filtered at the glomerulus, and normally almost
all of it is reabsorbed. Distal Tubule Proximal Tubule

In the proximal tubule, 50% to 60% of the filtered Lumen Blood Lumen Blood
load is reabsorbed along a paracellular route. A chemi- Ca2+
cal gradient is established as sodium and water are reab- Ca2+ PMCA 3Na+ 3Na+ ATP
sorbed, concentrating calcium in the tubular fluid. Ca2+ Pi 2K+
Meanwhile, an electrical gradient is established by the TRPV5
paracellular reabsorption of chloride, which leaves a
positive charge in the lumen. Specialized tight junction Pi
proteins, such as claudin-2, may form a cation-specific
paracellular pathway. NCX1

In the thick ascending limb, 15% of the filtered load 3Na+ A–
is reabsorbed along a paracellular route. An electrical
gradient, formed secondary to K+ recycling, drives this Modulation of Ca2+ reabsorption Modulation of Pi reabsorption
process. Claudin-16, another tight junction protein, is
an important component of this paracellular pathway, Factor Nephron Site Mechanism Effect Factor Nephron Site Mechanism Effect
and mutations are associated with familial hypomagne-
semia with hypocalciuria. DCT TRPV5 channels PTH Proximal tubule Na/Pi symporter
PTH NHE-3 transporters
In the distal convoluted and connecting tubules, 10% CaSR FGF-23 Proximal tubule Na/Pi symporter
to 15% of the filtered load is reabsorbed along a transcel- Proximal tubule
lular route. Calcium crosses the apical membrane through Pi intake Proximal tubule Na/Pi symporter
TRPV5 channels, binds to calbindin, then exits the baso- Plasma Thick ascending
lateral membrane on the NCX1 Na+/Ca2+ exchanger and, [Ca2+] limb
to a lesser degree, a Ca2+ ATPase (PMCA).
In the proximal tubule, 80% of the filtered load MAGNESIUM
The collecting duct makes an unknown, but likely
minor, contribution to calcium reabsorption. is reabsorbed along a transcellular route. Phosphate About half of total body magnesium is in bone, and
crosses the apical membrane on Na+/Pi symporters. nearly all of the remainder is in intracellular fluid. Only
Hypocalcemia triggers release of PTH, which has The pathway of basolateral exit is poorly understood 1% is in the extracellular space, with normal plasma
numerous effects on renal function. In the proximal concentrations ranging from 1.8 to 2.3 mg/dL. About
tubule, it inhibits the NHE-3 Na+/H+ exchanger, but may involve a phosphate/anion exchanger. 80% of the extracellular load is unbound to proteins
reducing the gradient for paracellular calcium reab- and freely filtered at the glomerulus. About 95% to
sorption. (This seemingly paradoxical effect allows In the distal convoluted tubule and connecting 98% of the filtered load is normally reabsorbed. 20%
PTH to increase phosphate excretion, as discussed is reabsorbed in the proximal tubule via an unknown,
later.) In the distal nephron, however, it up-regulates tubule, 5% of the filtered load is reabsorbed along a likely passive, mechanism. Another 60% to 70% is
the apical TRPV5 calcium channel, causing a net reabsorbed in the thick ascending limb through a para-
increase in calcium reabsorption. Meanwhile, hypercal- transcellular route that remains poorly understood. cellular route, driven by the electrical gradient resulting
cemia both suppresses PTH release and directly inhib- from K+ recycling. Claudin 16 is thought to form the
its calcium reabsorption. In the thick ascending limb, Hyperphosphatemia promotes release of PTH, pore for paracellular magnesium reabsorption. Finally,
for example, the increased load of reabsorbed calcium which down-regulates Na+/Pi symporters and basolat- 5% to 10% of the filtered load is reabsorbed in the
activates a basolateral calcium-sensing receptor (CaSR), eral Na+/K+ ATPases in the proximal tubule. As a distal nephron through an apical Mg2+ channel known
which then inhibits NKCC2 transporters and ROM-K as TRPM6. The pathway for basolateral exit is not
channels, reducing the electrical gradient for calcium result, phosphate reabsorption is suppressed. Addition- known.
reabsorption.
ally, hyperphosphatemia causes the release of FGF-23
Finally, acidosis inhibits the TRPV5 calcium channel,
whereas alkalosis has the opposite effect. from osteocytes and osteoblasts in bone, which
causes decreased Na+/Pi expression. Finally, increased
PHOSPHATE dietary phosphate intake appears to directly down-
regulate Na+/Pi transport through a PTH-independent
About 85% of total body phosphate is stored in mechanism. Hypophosphatemia, meanwhile, causes the
bones, 14% in soft tissues, and 1% in extracellular fluid.
Normal plasma concentrations, which range from 3 to opposite effects.
4.5 mg/dL, are maintained by the actions of PTH,
1,25-hydroxyvitamin D, and phosphatonins on the para-
thyroid glands, bones, gastrointestinal tract, and kidneys.

About 90% of plasma phosphate is unbound and
freely filtered at the glomerulus. About 85% of the
filtered load is normally reabsorbed.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 77

Plate 3-12 Urinary System: VOLUME 5

MODEL OF THE COUNTERCURRENT MULTIPLIER: PART I

285 285 285 185 285 185 285 285
385 185
385 185 185 185 285
385 185 385 385 485
385 185 385 185
385 185 185 485
385 685
1
385 185 385 185 885 685

185 485 285 1085 885
385
585 385 1285 1085
485 285 485
385 4
3
2

COUNTERCURRENT the loop of Henle. In this model, a tube of fluid is osmolality of filtrate as it enters the descending limb. A
MULTIPLICATION divided by a membrane in all but its most inferior transmembrane gradient is established as the transport-
aspect. The left side represents the entire descending ers pump solute across the membrane.
The countercurrent multiplier system is a sophisticated limb, whereas the right side represents the entire
apparatus that evolved in mammals and birds to con- ascending limb. Fluid enters at the top of the left-sided In Panel 2, fluid begins to move through the circuit.
serve water. It forms a longitudinal concentration gradi- column, travels beneath the membrane, and then Thus, at the hairpin turn, concentrated fluid from the
ent in the medullary interstitium that increases in exits at the top of the right-sided column. The descending limb mixes with less concentrated fluid
strength toward the papilla. This gradient is crucial for dividing membrane is impermeable to water but con- from the ascending limb. As a result, a fluid of average
water reabsorption from the renal tubules, which is a tains active transporters, which pump solute from concentration is formed. Because the active transport-
passive process that depends on osmotic pressure from the ascending limb to the descending limb. These ers can establish a 200 mOsm gradient, the last part of
the interstitium. transporters are powerful enough to establish a the descending limb becomes correspondingly more
transmembrane gradient of about 200 milliosmoles concentrated.
The creation and maintenance of this gradient is best (mOsm).
understood by first considering a simplified model of In Panel 3, the flow process continues, and as con-
In Panel 1, the entire tube is filled with fluid concen- centrated fluid continues to rise in the ascending limb,
trated at 285 mOsm, which is roughly equal to the reestablishment of the 200 mOsm transmembrane gra-
dient causes a corresponding rise in the concentration

78 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-13 Physiology

MODEL OF THE COUNTERCURRENT MULTIPLIER: PART II

285 100 Loop of Henle Collecting duct
Descending limb Ascending limb

285 100 285
300 NaϩClϪ
NaϩClϪ 525 H2O ADH
ADH
300 300 300 100 300 Urea 100 300 300
525 525 H2O
750Vasa Recta 750 H2O
975 Vasa Recta 975 525
1200 NaϩClϪ NaϩClϪ
1200
525 525 325 Urea 325 525
H2O

NaϩClϪ NaϩClϪ H2O ADH
750 750
750 750 550 750 Urea 550
H2O

NaϩClϪ NaϩClϪ ADH H2O
Urea 975
975 975 775 975 Urea 775 975
H2O 1000
NaϩClϪ Urea H2O ADH
1200 H2O Urea

1200 1000 1200 1200 1200

5 6 Urine

COUNTERCURRENT In Panel 5, which represents the actual loop of Henle, of ADH (see Plate 3-17), the collecting duct becomes
MULTIPLICATION (Continued) these same events occur but with important differences. permeable to water, which is reabsorbed from the col-
First, the limbs are separated by an interstitium, rather lecting duct lumen into the interstitium. This process
of fluid in the descending limb. At this stage, solute is than a single membrane. The ascending limb is imper- is entirely passive, depending on the osmotic pressure
still being retained within the system, and thus the meable to water but reabsorbs solutes into the intersti- of the interstitium. Thus the maximum concentration
outgoing fluid is less concentrated than the incoming tium. The descending limb, in contrast, is permeable to in the medullary interstitium determines the maximum
fluid. water but not to solutes. As a result, the concentration of concentration of the final urine.
fluid in the descending limb rapidly equilibrates with the
In Panel 4, steady state has been reached, meaning concentration in the interstitium. Another difference is The addition of the collecting duct also illustrates
that no additional solute is being added to the system. that the fluid leaving the loop of Henle is hypo-osmotic how urea contributes to formation of the interstitial
Thus the incoming and outgoing fluid are iso-osmotic. to the fluid coming in, reflecting the fact that a small concentration gradient, especially in the inner medulla.
The overall effect of this process has been to establish amount of solute is continuously lost from the intersti- In the presence of ADH, the inner medullary collecting
high longitudinal gradients, whereas the transmem- tium, preventing a steady state from being reached. duct becomes permeable to urea. As water is reabsorbed
brane gradient is comparatively small. from the cortical and outer medullary collecting ducts,
In Panel 6, the collecting duct is added to the model urea becomes highly concentrated within the tubular
and runs parallel to the loop of Henle. In the presence fluid. Once the inner medulla is reached, urea flows out

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 79

Plate 3-14 Urinary System: VOLUME 5

MODELS TO DEMONSTRATE PRINCIPLE OF COUNTERCURRENT EXCHANGE SYSTEM OF VASA RECTA IN MINIMIZING DISSIPATION OF MEDULLARY OSMOTIC GRADIENT

300 Solute 285 Solute 300 300 Solute 285 315
525 H2O 300 H2O H2O 300 Solute
750 525 525 H2O 300
975 Solute 750 525 Solute 750
1200 H2O 975 H2O 525
1200
Solute Solute 525 750 Solute Solute 525
H2O H2O H2O H2O

Solute Solute 750 975 Solute 750
H2O H2O H2O Solute 750
H2O
Solute
H2O Solute 975 975 Solute
H2O H2O 975

Solute 1200 1200 Solute 1200 1200
H2O H2O

7 8

COUNTERCURRENT proximal tubule and loop of Henle. By reentering the capillaries. This process is known as countercurrent
MULTIPLICATION (Continued) tubular fluid in this manner, urea is returned to the exchange.
inner medullary collecting duct to once again be reab-
of the collecting duct and accumulates in the intersti- sorbed. This process, known as urea recycling, tends to The blood leaving the medulla, however, does not
tium, contributing to the concentration gradient. Thus, minimize urea depletion from the inner medulla. completely reabsorb all of the effluxed plasma. Thus
as further described on Plate 3-17, ADH not only pro- outgoing blood is slightly hyperosmotic compared
motes water reabsorption from the collecting duct, but The final elements that need to be added to this with incoming blood. As a result, the anatomic configu-
it also activates mechanisms that strengthen the con- model are the capillaries of the vasa recta, which are ration of the vasa recta minimizes, but does not com-
centration gradient, thereby ensuring water reabsorp- permeable to water. If these vessels passed straight pletely prevent, solute loss from the medulla. These
tion is maximal. through the interstitium (Panel 7), osmotic pressure losses are also small, because the blood flow to the
would draw out plasma and dilute the concentration medulla is very low. Release of ADH further constricts
Once deposited in the interstitium, some urea drifts gradient. Instead, the capillaries turn back upon them- the vasa recta capillaries, ensuring maintenance of the
from the inner medulla and is secreted back into the selves (Panel 8), and thus water that effluxes from the high interstitial concentrations required for maximal
descending capillaries is reabsorbed in the ascending urine concentration.

80 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-15 Physiology

URINE CONCENTRATION IN LONG-LOOPED NEPHRON (ADH PRESENT)

285 285 Distal Na؉Cl؊ 285
Na؉Cl ؊ convoluted H2O

H2O tubule
285
Proximal Na ؉Cl ؊ 100
convoluted
tubule

Cortex 285

285 H2ONa؉Cl؊ 100 H2O 200
285 285 ADH

285 300 285 525 315 285
H2O Na؉Cl؊
Urea 285
Na؉Cl؊
URINE CONCENTRATION AND Proximal straight tubule Na؉Cl؊ H2O ADH
DILUTION AND OVERVIEW OF 300 H2O 300
WATER HANDLING Urea 100
Na؉Cl؊ H2O ADH
In normal kidneys more than 180 liters of fluid are
filtered into the nephrons each day, but nearly all of it Na؉Cl؊ Collecting
is reabsorbed into the peritubular circulation. duct
Urea Na؉Cl؊ Thick Na؉Cl؊
Tight junctions form a watertight seal between ascending H2O
tubular epithelial cells throughout most of the nephron. H2O Urea limb
Thus, water reabsorption occurs primarily through a Descending H2O 325 H2O
transcellular route, requiring specialized channels 525 thin limb 525
known as aquaporins (AQPs) in both the apical and Na؉Cl؊ Urea 525 525
basolateral compartments of the plasma membrane. Na؉Cl؊
525
Because aquaporins are channels, and not pumps, the
reabsorption of water is a passive process, dependent on Medulla Urea Na؉Cl؊ 975 750 Na؉Cl؊ ADH
osmotic pressure from solutes concentrated in the sur- H2O Urea 550 H2O 750
rounding interstitium. H2O H2O Urea
750 750 Urea
In each tubular segment, the reabsorption of water Na؉Cl؊ 750
can be greater than, less than, or equal to the reabsorp-
tion of solutes. As a result, urine becomes more con- 750 Urea ADH
centrated as it passes through some segments and more Na؉Cl؊
diluted as it passes through others. The final concentra- Urea Na؉Cl؊
tion of excreted urine is determined in the collecting
duct, which reflects not only the fact that this segment H2O Na؉Cl؊ H2O
is located at the end of the nephron, but also that it Urea
reabsorbs water at a variable rate based on hormonal
input. 975 975 Urea 775 H2O 975
H2O Urea 975
Proximal Tubule. The proximal tubule reabsorbs Urea Na؉Cl؊
two thirds of the filtered water. There is a large gradient Na؉Cl؊
for water reabsorption from this segment because of the Urea ADH
high rate of solute reabsorption. As solute begins H2O Ascending 1200
to accumulate in the interstitium, water crosses from thin limb
the tubular lumen to the interstitium through AQP-1 1200
channels in both the apical and basolateral plasma 1200 1000 1200 Na؉Cl؊
membranes. H2O
Urea 1200
Because water reabsorption from the proximal tubule
is directly dependent on the rate of solute reabsorption, Note: Figures given are
and because AQP-1 channels are always present, the exemplary rather than specific
filtrate remains iso-osmotic to plasma as it passes
through this segment. Water impermeable (aquaporins absent)
Water permeable (aquaporins present)
Descending Thin Limb. The descending thin limb
reabsorbs an additional fraction of the filtered water. (juxtamedullary) nephrons differ not only in length but Because water reabsorption exceeds solute reabsorp-
There is a large gradient for water reabsorption from also in cellular composition. In short-looped nephrons, tion in the descending thin limb, tubular fluid becomes
this segment even though it reabsorbs only a small the descending thin limb consists of type I cells, whereas more concentrated. This process, however, is not under
amount of solute. This gradient reflects the high rates in long-looped nephrons, it consists of type II cells in tight control. As a result, the descending thin limb does
of reabsorption from the thick ascending limb, which the outer medulla and type III cells in the inner medulla. not have a major role in determining the final concen-
is adjacent to the ascending thin limb and adds solute Type I and II cells are more permeable to water than tration of excreted urine.
to its surrounding interstitium. As in the proximal type III cells. Thus, in long-looped nephrons, water
tubule, water crosses the tubular epithelium through reabsorption from the descending thin limb decreases Ascending Thin Limb and Thick Ascending Limb.
AQP-1 channels. near the inner medulla. The ascending thin limb (found only in long-looped
nephrons) and thick ascending limb do not contain
As described on Plate 1-24, the descending thin
limbs of short-looped (cortical) and long-looped

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 81

Plate 3-16 Urinary System: VOLUME 5

URINE DILUTION IN LONG-LOOPED NEPHRON (ADH ABSENT)

280 280 Distal 280
Na؉Cl؊ convoluted
Proximal Na ؉Cl ؊ tubule
H2O convoluted
280 280 tubule 100 Na؉Cl؊

Cortex 100
280
280 H2ONa؉Cl؊ 100
URINE CONCENTRATION AND 280 280
DILUTION AND OVERVIEW OF
WATER HANDLING (Continued) 280

aquaporin channels and are therefore impermeable to 280 280 325 300 100
water. The extensive reabsorption of solutes from these 280
segments, however, dilutes tubular fluid and establishes 280 Proximal Na؉Cl؊
a concentration gradient for water reabsorption from straight Thick
adjacent segments, such as the descending thin limb and ascending
collecting duct. tubule Na؉Cl؊ Na؉Cl؊ limb HN2aO؉Cl؊
H2O H2O
Because the dilution process in the ascending limb is 100 Collecting
not under tight control, this segment does not have a Descending H2O Na؉Cl؊ duct Na؉Cl؊
major role in determining the final concentration of 300
excreted urine. 300 thin limb 300 125

Distal Convoluted Tubule. Like the thick ascending Medulla H2O 300 325 NH2aO؉Cl؊ 100 325
limb, the distal convoluted tubule reabsorbs solutes but Na؉Cl؊ Na؉Cl؊
is impermeable to water. Therefore, this segment
dilutes tubular fluid but, for the same reasons as the 325 325 H2O
thick ascending limb, does not have a major role in
determining the final concentration of excreted urine. H2O Na؉Cl؊ 375 350 75 350
H2O 150 HN2aO؉Cl؊
Connecting Tubule and Collecting Duct. The con- 350 350 Na؉Cl؊
necting tubule and collecting duct reabsorb a variable
volume of filtered water, which determines the final H2O 350 375 Na؉Cl؊
concentration of excreted urine.
375 375 Na؉Cl؊ 175 H2O 375
By reabsorbing more or less free water from the H2O Na؉Cl؊ 400
urine, these segments can dilute or concentrate plasma, Na؉Cl؊
helping to offset the changes in osmolality that result H2O Ascending Na؉Cl؊
from inconsistent intake of water and salt over the thin limb 50
course of each day. The hormone that controls water 400 400
reabsorption is known as antidiuretic hormone (ADH, 400
or vasopressin). Note: Figures given are
exemplary rather than specific
In response to increases in plasma osmolality, ADH
is released from the posterior pituitary. In the connect- Water impermeable (aquaporins absent)
ing tubule and collecting duct this hormone causes Water permeable (aquaporins present)
vesicles containing AQP-2 channels to fuse with the
apical plasma membrane of principal cells. Since AQP-4 and increases urea reabsorption from the inner medul- reabsorption of sodium from this segment, dilutes the
channels are always present in the basolateral plasma lary collecting duct. Some of the urea that drifts toward urine to a minimum osmolality of 50 mOsm/kg H2O.
membrane of these cells, the insertion of AQP-2 chan- the cortex is secreted back into more proximal segments
nels is sufficient to cause a dramatic increase in water of the renal tubules so that it can be deposited again in Over the course of several hours, variable input from
reabsorption. the inner medulla. the ADH system leads to accumulation of urine in
the bladder that has an osmolality between 50 and
Because of the countercurrent multiplier system, In response to decreases in plasma osmolality, ADH 1200 mOsm/kg H2O. In patients with abnormal serum
there is a strong gradient for water reabsorption from release is inhibited, and AQP-2 channels are conse- sodium concentrations, measurement of the urine
the collecting duct that increases in strength toward the quently endocytosed. The lack of water reabsorption osmolality can indicate whether the defect lies in the
papillae. Because water reabsorption is a passive process, from the collecting duct, coupled with the ongoing urine concentration process or elsewhere.
the maximum achievable urine concentration is equal
to the peak osmolality in the medullary interstitium,
about 1200 mOsm/kg H2O. Such concentrations are
only achievable in long-looped nephrons, however,
because short-looped nephrons do not reach the inner
medulla.

In addition to its direct effects on aquaporin chan-
nels, ADH has several actions that enhance the coun-
tercurrent system and thus increase the gradient for
water reabsorption. In particular, this hormone increases
solute reabsorption from the thick ascending limb, con-
stricts vasa recta capillaries to reduce solute washout,

82 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-17 Physiology

ANTIDIURETIC HORMONE MECHANISM OF ANTIDIURETIC HORMONE IN REGULATING URINE VOLUME AND CONCENTRATION

ADH, also known as vasopressin, plays a crucial role ADH is synthesized in the Numerous factors affect
in maintaining the normal osmolality of extracellular hypothalamus (supraoptic, plasma osmolality and volume
fluid, which depends primarily on the extracellular paraventricular nuclei)
sodium concentration. ADH exerts its effect by altering Exchange of
the osmolality of excreted urine, which can range from fluid and salts
50 to 1200 mOsm/kg H2O. with tissues

When plasma osmolality increases, ADH release Drinking
causes extensive water reabsorption in the distal water
nephron. As a result, the urine becomes highly concen-
trated, and the plasma consequently becomes more ADH is released from the Bleeding
dilute. In contrast, when plasma osmolality decreases, posterior pituitary in response
inhibition of ADH release prevents water reabsorption to increased plasma osmolality Sweating Effusions Vomiting
in the distal nephron, leading to dilution of urine and or decreased plasma volume or diarrhea
concentration of plasma. (see graphs below)
H2O
MECHANISMS OF RELEASE Pressor effect on vasa recta Na+

ADH is produced in the supraoptic and paraventricular Up-regulation of sodium and Na+Cl– H2O
nuclei of the hypothalamus. It is then conveyed along water retention from tubules Na+Cl– Na+
axons to the posterior pituitary for storage and release.
Systemic vasoconstriction H2O
ADH release occurs primarily in response to activa- Max Na+
tion of osmoreceptors in the anterior hypothalamus.
These receptors, located outside of the blood-brain Na+Cl– H2O
barrier, are extremely sensitive to changes in plasma Na+
osmolality. Their activation has been hypothesized to Urea
occur when there is a loss of intracellular fluid second-
ary to increased extracellular osmotic pressure. In H2O
support of this hypothesis, the osmoreceptors are not Na+
equally sensitive to all solutes. Sodium, for example, Urea
reliably activates osmoreceptors at high concentrations
because, as a predominantly extracellular ion, it estab- Max Concentrated
lishes a transmembrane osmotic gradient. In contrast, urine
urea and glucose generally do not activate osmorecep- Plasma [ADH]
tors even at high concentrations because they freely Plasma [ADH]
enter cells, thus failing to establish an osmotic gradient.
When patients experience extreme insulin depletion, 0 0
however, osmoreceptors may become sensitive to high
concentrations of glucose, presumably because of its 270 290 310 –30 –20 –10 0 10 20
increased restriction to the extracellular space. Plasma osmolality (mOsm/kg H2O) % Change in blood volume or pressure

ADH is also released in response to intravascular dysfunction of ADH-mediated aquaporin insertion outer medullary collecting duct, urea becomes
volume depletion. In this setting, the primary objective (see Plate 3-27). increasingly concentrated in the tubular lumen.
is to retain intravascular volume, rather than to adjust • ADH increases the reabsorption of sodium and Once urea reaches the IMCD, it is reabsorbed
plasma osmolarity. Such release is mediated by barore- urea, which increases the solute concentration in along its chemical gradient into the interstitium.
ceptors in the atria, aorta, and carotid sinus, which send the medullary interstitium. As a result, there is a • ADH exerts a pressor effect on vasa recta capillar-
afferent signals to the brain along the vagus and glos- larger gradient for water reabsorption. In the ies, which minimizes the drift of solute away from
sopharyngeal nerves. This sensing mechanism is not thick ascending limb, ADH up-regulates apical the medullary interstitium.
nearly as sensitive as the osmolality-sensing apparatus, NKCC2 Na+/K+/2Cl− cotransporters and • ADH increases peripheral vascular resistance via
however, and does not become active until 5% to 10% ROM-K channels. Over the long term, ADH also the V1a receptor, an important effect in volume
of plasma volume has been lost. increases transcription of NKCC2 cotransporters. depletion states. As a result, ADH is a useful pressor
In the collecting duct, ADH up-regulates apical hormone in vasodilatory states, such as septic shock.
Finally, ADH is also released in response to increased ENaC channels and inner medullary urea trans- In addition, ADH may be given during cardiac
levels of angiotensin II (AII), a hormone released during porters. As water is reabsorbed in the cortical and resuscitation.
renal hypoperfusion (see Plate 3-18).
83
EFFECTS

ADH exerts multiple effects on the kidneys and cardio-
vascular system, which include the following:

• In collecting ducts, ADH binds to V2 receptors on
the basolateral membrane of principal cells, initiating
a signaling cascade that leads to apical insertion of
aquaporin channels. The collecting duct becomes
permeable to water, which is reabsorbed because of
the high osmotic pressure generated by the solute
concentrated in the medullary interstitium. Over the
long term, ADH also increases transcription of aqua-
porin channels. Nephrogenic diabetes insipidus is a
well-characterized condition in which there is

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-18 Urinary System: VOLUME 5

TUBULOGLOMERULAR FEEDBACK AND MODULATION OF RENIN RELEASE

TUBULOGLOMERULAR
FEEDBACK/RENIN-ANGIOTENSIN-
ALDOSTERONE SYSTEM

TUBULAR-GLOMERULAR INTERACTION Granular cells
Release of renin-filled
Each tubule communicates with its parent glomerulus vesicles is modulated
as part of a feedback circuit that counteracts the varia- by signals from the
tions in the glomerular filtration rate (GFR) that result macula densa,
from changes in renal perfusion pressure. As a result, sympthatic nerves,
the GFR remains nearly constant under a wide range and local stretch
of hemodynamic conditions. receptors

Both the sensor and effector limbs of this feedback NaCl Efferent
circuit reside in the juxtaglomerular apparatus, located arteriole
where the distal tubule of a nephron contacts its NaCl NaCl
parent glomerulus. As described on Plate 1-20, the jux-
taglomerular apparatus contains the macula densa NaCl
(located in the thick ascending limb), terminal afferent
arteriole, initial efferent arteriole, and extraglomerular Afferent arteriole Sympathetic nerves Macula densa Extraglomerular
mesangium. Within this structure, the macula densa Activation of local Stimulate afferent Increased Naϩ/ClϪ mesangial cells
acts as the flow rate sensor. When tubular flow rates are stretch receptors promotes arteriolar constriction reabsorption stim- (polkissen, Lacis
decreased, as occurs when the GFR is decreased, the constriction. Input from and release of ulates afferent cells)
macula densa produces a signal that causes afferent macula densa and renin-filled vesicles arteriolar constriction Likely act as
arteriolar vasodilation, restoring the GFR to normal. In sympathetic nerves also from granular cells and suppresses renin signaling
contrast, when tubular flow rates are increased, as affect tone. release from granular intermediaries
occurs when the GFR is increased, the macula densa cells. Diminished between the
produces a signal that causes afferent arteriolar vaso- reabsorption macula densa
constriction, again restoring the GFR to normal. stimulates afferent and granular cells
arteriolar vasodilation
The interactions between the macula densa and and promotes renin
glomerulus also affect activation of the renin-angiotensin- release.
aldosterone system (RAAS). Whereas TGF is designed
to control for fluctuations in the single nephron GFR, Stimulus Effect
activation of the RAAS helps address the changes in Increased tubular flow
overall volume status that such fluctuations often imply. Decreased tubular flow Afferent arteriolar constriction
When tubular flow rates are reduced, for example, the Afferent arteriole stretching Suppression of renin release
macula densa triggers renin secretion from granular Sympathetic tone
cells, which are located in the walls of the terminal Afferent arteriolar dilation
afferent arteriole and initial efferent arteriole. Renin Activation of renin release
release has multiple effects, described later in detail,
that promote volume retention and systemic vasocon- Afferent arteriolar constriction
striction. When flow rates are increased, renin secretion Suppression of renin release
is suppressed.
Afferent arteriolar constriction
In addition to signals from the macula densa, several Activation of renin release
additional factors can also modulate both afferent arte-
riolar tone and renin release. A rise in renal perfusion constriction of the afferent arteriole and inhibition of increase in intracellular calcium levels. A wave of intra-
pressure, for example, causes stretching of the afferent renin release. In contrast, when tubular flow rates are cellular calcium is transmitted across gap junctions to
arteriole, which increases calcium influx into smooth low, decreased activation of NKCC2 transporters leads the smooth muscle and granular cells of the afferent and
muscle and granular cells. The result is afferent arterio- to dilation of the afferent arteriole and activation of efferent arterioles, causing constriction of the afferent
lar vasoconstriction, which preserves the local GFR, renin release. arteriole and inhibition of renin release. In contrast,
as well as suppression of renin release. Meanwhile, when there is low tubular flow and diminished reab-
increased sympathetic tone, as occurs during volume The exact signals that connect the NKCC2 trans- sorption by NKCC2 transporters, the adenosine signal
depletion, leads to afferent arteriolar vasoconstriction, porters of the macula densa to the afferent and efferent is eliminated, leading to dilation of the afferent arteriole
which redirects blood toward organs with high oxygen arterioles remain poorly understood; however, there is and stimulation of renin release.
extraction (brain, heart, skeletal muscle), as well as acti- increasing evidence that adenosine plays a key role. In
vation of renin release. one proposed model, increased reabsorption by In addition, there is some evidence that macula densa
NKCC2 transporters stimulates basolateral Na+/K+ cells contain COX-2 enzymes that are also stimulated
MECHANISMS OF TUBULOGLOMERULAR ATPases. The increased ATP consumption yields ADP when there is diminished reabsorption by NKCC2
and AMP, which local proteins convert into adenosine. transporters; these appear to synthesize prostaglandins
FEEDBACK Adenosine, in turn, activates receptors on the surface that stimulate dilation of the afferent arteriole and
of nearby extraglomerular mesangial cells, causing an promote renin release.
The available evidence suggests that the macula densa,
located at the end of the thick ascending limb, senses
tubular flow based on the concentrations of sodium and
chloride in the local filtrate. The sensing apparatus
appears to be apical Na+/K+/2Cl− (NKCC2) cotrans-
porters. When tubular flow rates are high, there is a
slight decrease in solute reabsorption before the macula
densa, and thus higher concentrations of sodium and
chloride are present at this area. Increased activation
of NKCC2 transporters ensues, which leads to

84 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-19 Physiology

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

TUBULOGLOMERULAR Liver Renin
FEEDBACK/RENIN- Angiotensinogen Renin hydrolyzes
ANGIOTENSIN-ALDOSTERONE valine–leucine bond
SYSTEM (Continued) of angiotensinogen Kidney
to yield angiotensin I
These mechanisms explain the likely role of TGF in Valine
several pathologic conditions. In acute tubular necrosis, Leucine
for example, there is damage to the proximal tubule,
which increases the electrolyte load delivered to the Histidines
macula densa. As a result, there is severe afferent arte-
riolar constriction, which is likely a major cause of the
decreased filtration function that accompanies this con-
dition. In the early stages of diabetic nephropathy (see
Plate 4-46), chronic glucosuria leads to increased
glucose-mediated proximal tubular reabsorption, which
decreases the electrolyte load delivered to the macula
densa. As a result, there is afferent arteriolar vasodila-
tion, leading to hyperfiltration.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM Kidney Lung

Once renin is released it cleaves angiotensinogen (pro- Angiotensin II Converting enzyme in lung, kidney, Angiotensin I
duced in the liver) to angiotensin I. Angiotensin con- (octapeptide) and other vascular beds removes two (decapeptide)
verting enzyme (ACE) then rapidly converts angiotensin amino acids (leucine, histidine) to
I to angiotensin II (AII). ACE is primarily located in produce angiotensin II
pulmonary capillaries but has also been identified else-
where, including on glomerular endothelial cells. AII, Systemic vasoconstriction Constriction of both Up-regulation of tubular
in turn, promotes the release of aldosterone. Adrenal gland afferent and efferent sodium and water retention
arterioles (effect greater
Because this hormonal network is activated in on efferent arterioles)
response to renal hypoperfusion, its effects raise sys-
temic blood pressure through expansion of extracellular Release of aldosterone and epinephrine
volume and systemic vasoconstriction.
ADH release
AII has multiple effects. First, it exerts a direct Thirst
pressor effect on the systemic vasculature. Second, it
constricts the efferent (and, to a far lesser extent, affer- Nervous system
ent) artery, which reduces renal plasma flow without
affecting the GFR (see Plate 3-3). These changes thus Moreover, it acts on the adrenal medulla to promote secretion through the mechanisms described in the
reduce the fraction of the cardiac output required for pages that follow.
normal renal function. They also promote increased catecholamine release.
reabsorption from the proximal tubule, since the In recent years, AII has been recognized to have
increase in filtration fraction yields greater osmotic Finally, AII also stimulates the release of aldosterone, many additional effects that are still in the process of
pressure and lower hydrostatic pressure in the peritu- being characterized. In the heart, for example,
bular capillaries. as mentioned above. The major renal effect of aldoste- AII appears to promote myocyte hypertrophy and
rone is to up-regulate apical ENaC and basolateral Na+/ fibroblast proliferation, which contribute to the
In addition to these hemodynamic effects, AII directly K+ ATPases in principal cells of the connecting tubule adverse cardiac remodeling that occurs in the setting of
promotes sodium and fluid reabsorption from the tubules systolic dysfunction. Likewise, in the kidney, AII
by up-regulating transporters such as apical NHE-3 Na+/ and collecting duct. The result is an increase in sodium appears to promote inflammation and extracellular
H+ exchangers and basolateral Na+/K+ ATPases in the matrix production, contributing to the progressive glo-
proximal tubule, as well as apical epithelial sodium chan- reabsorption, which increases the negative charge in the merulosclerosis seen in chronic kidney disease. Because
nels (ENaC) in principal cells of the collecting duct. of these effects, ACE inhibitors are becoming the stan-
tubular lumen that promotes secretion of potassium. In dard of care in all patients with heart failure or chronic
AII also stimulates the production of other hormones kidney disease.
and vasoactive substances. For example, just as prosta- addition, aldosterone increases synthesis and apical
glandins may play a role in stimulating renin release, insertion of the NCC Na+/Cl− cotransporter in the
AII appears to stimulate production of vasodilatory distal convoluted tubule, further promoting reabsorp-
prostaglandins, such as PGE-2, in the afferent arteriole.
This effect may enhance TGF-related vasodilation of tion of sodium and chloride. Finally, aldosterone also
the afferent arteriole, and it may partially explain AII’s up-regulates apical H+ ATPases in type A intercalated
selective vasoconstrictor effect on the efferent arteriole. cells of the collecting duct, which promotes acid
The interactions between prostaglandins and AII likely
explain the precipitous decline in the GFR that may
be seen in volume-depleted patients who receive ACE
inhibitors or nonsteroidal antiinflammatory drugs. In
such patients, blockade of AII or prostaglandin produc-
tion may interfere with the afferent arteriolar vasodila-
tion required for maintenance of an adequate GFR.

AII also acts at the subfornical organ in the brain,
located outside the blood-brain barrier, to promote the
release of ADH (see Plate 3-17) and to stimulate thirst.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 85

Plate 3-20 Urinary System: VOLUME 5

ROLES OF CHEMICAL BUFFERS, LUNGS, AND KIDNEYS IN ACID-BASE HANDLING

Metabolic production of acid and alkali CO2 Equilibrium Curves
(for normal arterial and venous blood)
Food Source Acid/Alkali Quantity 55 Mixed venous
(mEq/day)

Carbohydrate CO2 15 - 20,000 CO2 content (mL/dL blood)
Fat

Amino acids H2SO4 50
S-containing HCl Pulmonary
Cationic
Anionic HCO3– Arterial

Organic ions HCO3– 100 (acid) 45 Tissue
60 (alkali) Capillaries

Phosphate H2PO4– 30 (acid) 40

Total 70 (acid)

1 mEq/kg/day of nonvolatile acid production

30 40 50
PCO2 (mm Hg)

Carbon dioxide transport

ACID-BASE BALANCE Hb•NHCOO Hb•NH2

The average human diet contains a significant acid load, Hb•NH2 Hb•NHCOO– CO2
but blood pH nonetheless remains within a narrow
range (7.36 to 7.44) under normal conditions. Such CO2 H2O H2O Body
homeostasis is crucial for normal cellular function, and tissues
it reflects the coordinated actions of extracellular and Alveoli Carbonic H+ Carbonic
intracellular chemical buffers, the lungs, and the of lung anhydrase
kidneys. Dysfunction of these systems can lead to aci- anhydrase
dosis or alkalosis, either respiratory or metabolic. H+
HCO3–

Cl– Cl–
HCO3–
CHEMICAL BUFFERS AND THE LUNGS
CO2 in physical solution
The aerobic metabolism of carbohydrates and fats
yields a significant load of carbon dioxide. Although Role of lungs and kidneys in acid-base balance CO2
carbon dioxide is itself not an acid, it rapidly combines
with water to form carbonic acid, which dissociates into “Acid Load” Volatile acid (CO2 )
a proton and bicarbonate ion. This reaction is catalyzed
by carbonic anhydrase, a zinc metalloenzyme found H+ + HCO3– H2O + CO2 CO2
in both the intracellular and extracellular spaces, as
follows: H+
H+ H+
Carbonic HCO3− + H+ H+
anhydrase
CO2(dissolved) + H2O H2CO3

In this manner, the constant generation of carbon H+ H+ Nonvolatile acid (HA) CO2 NH3,
dioxide could lead to a significant acid load. Because H+ H+ + A– HA + Ta
carbon dioxide is a volatile gas, however, it can be (=titratable
excreted from the lung, which minimizes its impact. H+ H+ H+ NaHCO3 H2O acids)
From the peripheral tissues, CO2 can reach the lung in +
multiple different manners. First, it may simply be dis- Body tissues NaHCO3
solved in plasma. Second, it can enter erythrocytes NaA NH4A, TaHA
and become bound to hemoglobin. Finally, and most
importantly, it can enter erythrocytes and be converted Replenish
by carbonic anhydrase into a proton, which is buffered
within the cell by hemoglobin, and bicarbonate, which which is then excreted from the lungs. The ventilation The equilibrium constant, Ka, is equal to:
is secreted into the plasma in exchange for chloride. rate is centrally modulated in response to fluctuations
in arterial pH so that as more protons are added to the [ [ ]] [ ]Ka =
The metabolism of proteins, in contrast, generates blood, more carbon dioxide is eliminated from the HCO3− × H+
nonvolatile sulfur- and phosphate-based acids, which lungs. CO2(dissolved) × [H2O]
cannot be directly excreted from the lungs. To
neutralize such acids, the extracellular fluid contains The effect of this system can be demonstrated as If Ka′ is defined as Ka * [H2O], then additional
buffers that can bind or release protons as needed, so follows. Because carbonic acid is unstable, the above rearrangement gives:
as to minimize fluctuations in the overall proton con- equation can be simplified as follows:
centration. The most important extracellular buffer is [ ] [[ ] ]H+
bicarbonate (HCO3−), which can receive a free proton CO2(dissolved) + H2O U HCO3− + H+ = K a′ × CO2(dissolved)
and be converted back into water and carbon dioxide, HCO3−

86 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-21 Physiology

ACID-BASE HANDLING: RENAL BICARBONATE REABSORPTION

Lumen Blood

Na+ 3Na+

NHE-3 ATP

2K+
H+

H+ 3HCO3– NBC
+ 1
HCO3– ATP HCO3–
Na+
CA-IV
CA-II

H2O + CO2 CO2 + H2O

ACID-BASE BALANCE (Continued)

Reabsorbs 80% of filtered load

By taking the negative logarithm of the above

formula, and recognizing that by convention

−log [H+] = pH and −log [Ka′] = pKa,

[ [ ] ]pH = pKa − log
CO2(dissolved)
HCO3−

At normal body temperature, the concentration Na+ 3Na+
of dissolved carbon dioxide is equal to 3% of its
partial pressure. By substitution, and slight further NHE-3 ATP
rearrangement: H+ 2K+

pH = pK a + log [HCO3− ] H+ Lumen Type A Intercalated Cell
+ Blood
0.03 × pCO2 HCO3–

This formula, an expression of the general CA-IV HCO3– NBC K+ 3Na+
Henderson-Hasselbalch equation, demonstrates that as CA-II Na+ 3 ATP ATP
bicarbonate is depleted and carbon dioxide generated,
changes in pH are minimized if the partial pressure of H2O + CO2 CO2 + H2O 2K+
carbon dioxide is kept constant or even lowered. Thus, HCO3– H+
in normal circumstances, the respiratory rate is adjusted
so that PCO2 remains constant at about 40 mm Hg. H+ ATP HCO3–
+
For this system to remain sustainable, however, a new K+ HCO3– AE1
supply of free bicarbonate ions must be created to HCO3–
replenish the depleted extracellular buffers. Such CA-II Cl–
an event occurs in the renal tubules, where free bicar- Cl–
bonate ions are generated and their paired protons AE2 CA-IV
excreted.

KIDNEYS H2O + CO2 CO2 + H2O

The kidneys are responsible both for reabsorbing exist- Reabsorbs 15% of filtered load Reabsorbs 5% of filtered load
ing bicarbonate ions and for generating new bicarbon-
ate ions. The latter process is, by necessity, paired with apical surface on NHE-3 Na+/H+ exchangers and, to a About 15% of the filtered bicarbonate load is reab-
the excretion of protons, since otherwise the newly gen- lesser extent, H+ ATPases. Once the protons are in the sorbed in the thick ascending limb. The process in this
erated bicarbonate would simply be converted back into tubular fluid, membrane-bound carbonic anhydrase IV segment is comparable to that seen in the proximal
carbon dioxide. catalyzes their reaction with filtered bicarbonate ions to tubule; however, there does not appear to be a signifi-
produce carbon dioxide and water. The newly formed cant role for apical H+ pumps, the basolateral NBC
Bicarbonate Reabsorption. Bicarbonate is freely fil- carbon dioxide diffuses into proximal tubule cells, and transporter is of a different isoform, and the basolateral
tered at the glomerulus. About 80% of the filtered load the entire process begins again. Note that there is no membrane also features Cl−/HCO3− exchangers (AE2)
is reabsorbed in the proximal tubule. The process net proton secretion during this process because and K+/HCO3− symporters.
begins in the cytoplasm of the tubular epithelium, protons are recycled across the apical membrane to
where carbonic anhydrase II catalyzes the conversion of capture filtered bicarbonate. Nearly all of the remaining bicarbonate is reabsorbed
carbon dioxide and water into bicarbonate ions and in the collecting duct. Type A intercalated cells are
protons. The bicarbonate ions are reabsorbed into the
interstitium on basolateral NBC-1 Na+/HCO3− cotrans-
porters; the protons, meanwhile, are secreted across the

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 87

Plate 3-22 Urinary System: VOLUME 5
ACID-BASE HANDLING: RENAL BICARBONATE SYNTHESIS AND PROTON EXCRETION

Net Acid Excretion (NAE) = (UTA x V) + (UNH4 x V) + (UHCO3– x V)

Production and Excretion Normally 0
of Ammonium (no net excretion)

Lumen Blood

Glutamine

ACID-BASE BALANCE (Continued) NH3 2NH3 2CO2
+ NH3 2H2O
responsible for this process. Like the cells in earlier H+ + H+
segments, they possess cytoplasmic carbonic anhydrase CA-II
II, which converts carbon dioxide and water to bicar- NH4+ 2H+
bonate ions and protons. The protons, however, are
secreted in an Na-independent manner using H+ 2HCO3–
ATPases and H+/K+ ATPases, while the bicarbonate
is reabsorbed on Cl−/HCO3− exchangers (AE1, also NH4+ NH4+ 3HCO3–
known as band 3 protein). Na+ NHE
NBC
Fluctuations in acid-base status directly affect the 3 1
rate of bicarbonate reabsorption. In the presence of
an increased acid load, for example, proximal tubular NH4+ NH3 Na+
cells experience an increased intracellular proton con- NH4+ NH3 3Na+
centration, which stimulates NHE-3 cotransport via NH4+
direct pharmacokinetics and an allosteric effect. ATP
Likewise, increased CO2 concentration stimulates NH3
insertion of vesicles containing NHE-3 transporters 2K+
and H+ ATPases into the proximal tubular apical cell
membrane. Titration of
Urine Buffers
Several hormones also modulate the rate of bicar- (i.e., phosphate)
bonate reabsorption. Cortisol and endothelin-1, for
example, are released in response to acidosis and Lumen Blood NH3
increased bicarbonate reabsorption in the proximal
tubule. Angiotensin II, released in response to hypovo- K+
lemia, also increases bicarbonate reabsorption in the
proximal tubule, where it upregulates the apical NHE-3 ATP HCO3– NH3
exchanger.
Buffer H+ AE1 N+H3 ATP HCO3–
Although under normal circumstances bicarbonate + Cl– H+ H+ Cl–
reabsorption is complete, under certain conditions H+
there is active secretion of bicarbonate into the cortical CA-II
collecting duct. Type B intercalated cells are responsi- AE1
ble for this process; they possess pendrin, an HCO3−/
Cl− exchanger, on their apical surface and an H+ ATPase ATP
on their basolateral surface.
H+-buffer 3Na+ NH4+ ATP CA-II
Bicarbonate Synthesis / Proton Excretion. As men- CO2 K+
tioned above, synthesis of new bicarbonate ions must + H2O ATP CO2 3Na+
be coupled with net excretion of protons. The apical + H2O 2K+ ATP
proton pumps, however, can only tolerate a 1000:1 2K+
transepithelial proton gradient, which is equivalent
to a minimum urine pH of 4.4 (given a normal plasma NH4+
pH of 7.4). To circumvent this limitation, protons are
buffered in urine by titratable acids or excreted as Type A Intercalated Cell Type A Intercalated Cell
ammonium.
pKa of 6.8 is near physiologic pH. Using the Henderson- Most of the H2PO4− is protonated in the collecting
Titratable Acids. Urine contains several weak acids Hasselbalch equation, the ratio of protonated to unpro- duct. As described previously, type A intercalated cells
that serve as urinary buffers. These buffers are also tonated species can be expressed as follows: possess cytoplasmic carbonic anhydrase II, which con-
called “titratable acids” because their concentration can verts carbon dioxide and water to bicarbonate ions,
be determined based on how much NaOH is required pH = 6.8 + log [HPO42− ] which are reabsorbed, and protons, which are secreted.
to titrate collected urine to a pH of 7.4. [ H 2PO4 − ] Some of the secreted protons contribute to bicarbonate
reabsorption, as described previously, but most combine
Phosphate, which exists in plasma primarily as At a pH of 7.4, the ratio of HPO42− to H2PO4− is 4:1 with buffers such as HPO42−. The overall process leads
HPO42−, is the major titratable acid in urine because its based on the above equation. Thus, four fifths of the to net synthesis of bicarbonate ions and excretion of
filtered phosphate is available to buffer protons. protons.

88 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-23 Physiology
Kidney
Lung ACIDOSIS AND ALKALOSIS
Tissues

CO2 HCO؊3

Acid-base
balance

Respiratory

ACID-BASE BALANCE (Continued) Lung or HCO؊3
airway disease
Several factors can stimulate proton secretion in the CO2 HCO؊3 Metabolic
collecting duct. In the setting of acidosis, subapical Neuromuscular CO2
vesicles containing additional H+ ATPases fuse with the disease Adds acid
apical plasma membrane of type A intercalated cells. If (anion gap):
acidosis is chronic, type A intercalated cells become Sedation Diabetes
hypertrophic, further increasing their acid-secreting CNS disease or injury Uremia
capabilities. Increased delivery of sodium to the collect- Lactic
ing duct results in greater reabsorption through ENaC, Acidosis
resulting in a more negative intraluminal charge that acidosis
promotes the secretion of protons, just as it promotes CO2
the secretion of potassium. Aldosterone also stimulates Loses base
proton secretion through several mechanisms. First, it (non-anion gap):
stimulates sodium reabsorption through ENaC, which Diarrhea
results in a strong negative charge in the collecting duct Renal tubular
lumen that increases the gradient for proton secretion.
Second, it has a direct stimulatory effect on H+ ATPases. acidosis
Finally, hypokalemia also stimulates proton secretion
through up-regulation of H+/K+ ATPases, as well as Respiratory HCO3؊
through stimulating basolateral efflux of potassium in
exchange for protons, which increases the intracellular Alkalosis Pain or Metabolic
proton concentration and thus the gradient for proton anxiety
secretion. Adds base:
Drugs Alkali
Ammonium. In proximal tubular cells, the metabo- Fever
lism of glutamine offers another mechanism for synthe- Pregnancy ingestion
sizing new bicarbonate ions and excreting protons. The Liver failure
metabolism of each molecule of glutamine yields two Hypoxia Loses acid:
ammonia (NH3) ions, one during the conversion to CNS disease or injury Diuretics
glutamate (by glutaminase), and another during the Vomiting
conversion to α-ketoglutarate (by glutamate dehydro- CO2 Gastric
genase). α-Ketoglutarate yields two carbon dioxide
molecules as it passes through the citric acid cycle. HCO3؊ suction

The carbon dioxide molecules combine with water cotransporter), deprotonated, and released as NH3 into Acidosis directly up-regulates ammoniagenesis through
to form bicarbonate ions, which are reabsorbed, and the interstitium. Although this mechanism seems coun-
protons. The protons rapidly combine with the newly terproductive, it creates a high concentration of NH3 various mechanisms. Hypokalemia also up-regulates
synthesized NH3 to form ammonium (NH4+), a reaction in the medullary interstitium, which favors its diffusion
that can occur either in the cytoplasm or tubular lumen. back into the collecting duct. Such diffusion is enhanced ammoniagenesis, whereas hyperkalemia down-regulates
In the former case, NH4+ is secreted into the lumen of by the presence of NH3 transporters, such as Rhcg, on it, likely because of the effects of basolateral H+/K+
the NHE-3 exchanger. In the latter case, the protons the basolateral and apical surfaces of type A intercalated
are secreted into the lumen on the NHE-3 exchanger, cells. Once NH3 enters the collecting duct lumen, it is exchange on intracellular pH. Angiotensin II also up-
and the hydrophobic NH3 freely diffuses across the reprotonated and finally excreted.
apical plasma membrane. regulates ammoniagenesis by stimulating the NHE-3
exchanger, which increases NH4+ secretion. Meanwhile,
The NH4+ in the tubular lumen exists in dynamic several factors increase proton secretion in the collecting
equilibrium with NH3. As a result, NH3 can freely
diffuse back into the interstitium. If this NH3 were not duct, as described in the section on titratable acids.
reclaimed, the free protons left in the tubular lumen
would rapidly deplete titratable acid buffers. Therefore,
to ensure that any lost NH3 reenters the tubular lumen,
NH4+ is reabsorbed across the cells of the thick ascend-
ing limb (e.g., on the K+ position of the NKCC2

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 89

Plate 3-24 Urinary System: VOLUME 5
ROLE OF KIDNEYS IN ERYTHROPOIESIS

High oxygen tension

Oxygen

ADDITIONAL FUNCTIONS: HIF-1␣ HIF-1␤
ERYTHROPOIESIS AND VITAMIN D
PHDs
ERYTHROPOIESIS HIF-1␣ OH

Red blood cells must be plentiful enough to ensure VHL HIF-1␣ OH
adequate oxygenation of peripheral tissues, yet not so Ubiquitination and
numerous as to compromise the free flow of blood.
Therefore, erythropoiesis must be under tight control. degradation
The kidneys play an essential role in this process
because they sense hypoxia, the major sign of Low oxygen tension + CFU-E
inadequate erythrocyte mass, and respond by secreting
erythropoietin, the major promoter of erythrocyte HIF-1␣ HIF-1␤ Proerythroblast
production. Hypoxia-responsive Basophilic
element in nucleus erythroblast
The oxygen-sensitive production of erythropoietin
occurs in peritubular fibroblasts. These cells are respon- HIF-1␣ HIF-1␤ Polychromatic
sible for constitutive production of hypoxia-inducible p300 CBP erythroblast
factor 1 (HIF-1), a heterodimeric protein with α and β
subunits. Erythropoietin

In the setting of high oxygen tension, the α subunit
undergoes rapid hydroxylation by proline hydroxylases
(PHDs). The hydroxylated α subunit then combines
with the von Hippel-Lindau tumor suppressor, under-
goes ubiquitination, and is degraded in proteasomes.

In contrast, in the setting of hypoxia, the HIF-1 het-
erodimer persists and combines with various proteins,
such as p300 and CBP, to form a transcription factor.
This factor binds to the hypoxia-responsive element
located near the EPO gene and upregulates the synthe-
sis of many proteins, including erythropoietin. In the
bone marrow, erythropoietin enhances the survival and
maturation of colony-forming units-erythroid (CFU-
E), which then give rise to erythrocytes.

Erythropoietin deficiency occurs in advanced renal
failure, resulting in the emergence of a significant nor-
mocytic anemia. The increasing availability of recom-
binant erythropoietin agents, however, has all but
eliminated the need for transfusion in dialysis patients.
Nonetheless, there is a small but significant increased
risk of cardiovascular events and death associated with
this class of drugs.

VITAMIN D Orthochromatic
erythroblast
Vitamin D is a fat-soluble vitamin that can be acquired
either from diet or from sunlight-induced conversion Reticulocyte
of epidermal fats. In either case, vitamin D undergoes
numerous modifications in various organs, including reaches the kidneys, again on vitamin D–binding Erythrocyte
the kidneys, to become a bioactive hormone. (For an proteins. 25(OH)D enters proximal tubular epithelial
illustration, see Plate 4-67). cells via receptor-mediated endocytosis, where it is enzyme is upregulated in the presence of 1,25(OH)2D,
converted by 1-α-hydroxylase to 1,25-dihydroxyvitamin which therefore regulates its own synthesis.
Vitamin D synthesis begins when ultraviolet waves D [calcitriol, the bioactive vitamin, abbreviated as
in sunlight cause photoisomerization of 7- 1,25(OH)2D]. 1-α-hydroxylase is upregulated in Vitamin D’s major functions are to increase the intes-
dehydrocholesterol to vitamin D3 (cholecalciferol), or the presence of PTH, hypocalcemia, and hypophospha- tinal reabsorption of calcium and phosphate, to stimu-
when vitamin D2 (ergocalciferol) or D3 is ingested and temia. Another proximal tubular enzyme, known as late bone metabolism, and to suppress the release of
absorbed. Major dietary sources of vitamin D include 24-α-hydroxylase, can synthesize an inactive form of PTH. As a result, profound bone mineralization defects
fatty fish and fortified milk. Because vitamin D is fat vitamin D known as 24,25-dihydroxyvitamin D. This occur in states of deficiency. Such defects are a major
soluble, inadequate absorption occurs in fat malabsorp- component of the phenomenon known as renal osteo-
tion states, such as pancreatic insufficiency or cystic dystrophy, which occurs in end-stage renal disease (see
fibrosis. Plate 4-70).

Vitamins D2 and D3 are carried on plasma vitamin
D–binding proteins to the liver, where 25-hydroxylase
converts them to 25-hydroxyvitamin D [calcidiol, abbre-
viated as 25(OH)D]. From there, 25(OH)D eventually

90 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-25 Physiology

RENAL TUBULAR ACIDOSIS PROXIMAL RENAL TUBULAR ACIDOSIS

Normal urinary acidification Proximal renal tubular acidosis

Blood Proximal Naϩ HCO3Ϫ Kϩ HPO42Ϫ Blood Proximal Naϩ HCO3Ϫ Kϩ HPO42Ϫ
tubule tubule

The kidneys play a key role in maintaining systemic pH NBC HCO3Ϫ Hϩ NHE3 CO2 NBC HCO3Ϫ Hϩ NHE3
near 7.4. The renal tubular acidoses (RTAs) are a group CA-II CA-IV CA-II
of disorders in which systemic acidosis occurs because
the kidneys are unable either to excrete acid or to con- ATP H+2O ATP H+2O
serve bicarbonate. In either case, the result is a variable Kϩ CO2 Kϩ CO2
degree of normal anion gap metabolic acidosis accom-
panied by an abnormal serum potassium concentration. ATP ATP
The RTA subtypes are classified as proximal or distal
(pRTA, dRTA) based on which nephron segment is CO2 NH3 NH4+ CO2 NH3
malfunctioning.
CO2 NH3 NH4+ CO2 NH3
PROXIMAL RTA
Glutamine Glutamine
The proximal tubule reabsorbs 80% of the filtered
bicarbonate (see Plate 3-21). Proximal tubular cells also Collecting duct Hϩ Collecting duct
metabolize glutamine, a process that yields bicarbonate, NH3
which is reabsorbed, and NH4+, which is secreted into
the nascent urine. Type A intercalated cell Type A intercalated cell

Proximal RTA (pRTA), in which these processes fail, HCO3Ϫ Hϩ CA-IV HCO3Ϫ Hϩ CA-IV
usually occurs as a component of generalized proximal CO2 CO2
tubular dysfunction (renal Fanconi syndrome). Most AE1 CA-II ATP AE1 CA-II ATP NH4+
cases are acquired, reflecting exposure to substances Cl_ NH4+ Cl_
that interfere with proximal tubular function, such as
myeloma proteins or drugs (e.g., cytotoxic drugs or Naϩ H+2O ATP H2PO4Ϫ Naϩ H+2O ATP H2PO4Ϫ
sodium valproate). In rarer cases, generalized proximal ATP CO2 ATP CO2
dysfunction may result from inherited diseases, such as Kϩ Kϩ
cystinosis (see Plate 4-64). In even rarer cases, pRTA
may be an isolated phenomenon (i.e., otherwise normal Principal cell ENaC Principal cell ENaC
proximal function), as seen in individuals with reces-
sively inherited defects in the basolateral NBC Na+/ ATP ROM-K ATP ROM-K
HCO3− transporter. Kϩ maxi-K Kϩ maxi-K

Because the distal nephron can recapture some of the Final urine Final urine
bicarbonate that is not reabsorbed in the proximal
tubule, pRTA generally features a milder acidosis than Normally, bicarbonate is extensively reabsorbed Proximal RTA causes increased urinary excretion
dRTA. Indeed, once serum bicarbonate levels decline in the proximal tubule, and consequently the of bicarbonate and potassium. Once serum
to 15 mEq/L, reabsorption in the distal nephron can fractional excretion of bicarbonate is very low. bicarbonate concentrations are low enough,
fully compensate for the proximal dysfunction. At this however, the collecting duct can recapture all
point, bicarbonate wasting ceases, urine pH decreases of the bicarbonate wasted from the proximal tubule.
(often becoming acidic), and serum bicarbonate con-
centrations stabilize. If patients are given an intrave- In response to a load of bicarbonate salts, however,
nous infusion of sodium bicarbonate, however, the kidneys will resume wasting bicarbonate.
bicarbonate wasting resumes (with a fractional excre-
tion of ≥15%) and the urine pH increases. This With global proximal dysfunction, as shown above,
sequence of events is diagnostic of proximal RTA. there is also increased urinary excretion of sodium,
glucose, amino acids, phosphate, uric acid, albumin.
In addition to acidosis, pRTA features hypokalemia
because the nonreabsorbed bicarbonate produces a cia (depending on age) because of inefficient renal acti- worsening hypokalemia, and thus potassium supple-
negative charge in the collecting duct lumen, promot- vation of vitamin D. Meanwhile, patients ments are often required as well. If there is generalized
ing K+ secretion through ROM-K channels. If there is with isolated pRTA, like those with NBC transporter proximal tubular dysfunction, vitamin D and phosphate
generalized proximal tubule dysfunction, the increased mutations, often have aberrant calcification within the supplements are also helpful.
distal Na+ load that reaches the cortical collecting duct eyes (band keratopathy), cataracts, and mental
also produces a negative intraluminal charge as it is retardation. DISTAL RTA
reabsorbed. In addition, the increased urine flow
through the distal tubule, which results from proximal Proximal RTA is often difficult to treat because the The collecting duct contains principal cells and inter-
salt wasting, stimulates K+ secretion through flow- marked bicarbonaturia mandates that large quantities calated cells (ICs), with the latter responsible for acid-
sensitive maxi-K channels. of alkali be provided on a regular basis. Extensive base handling. Within the IC population, at least two
bicarbonate supplementation, however, often causes
Although acidosis and hypokalemia are the hallmarks
of pRTA, several additional abnormalities are often
seen. Patients with generalized proximal tubular dys-
function, for example, exhibit salt wasting, polyuria,
phosphaturia (and hypophosphatemia), glucosuria,
uricosuria (and hypouricemia), aminoaciduria, microal-
buminuria, and low molecular weight proteinuria
(e.g., retinol binding protein or β2-microglobulin).
Moreover, patients often develop rickets or osteomala-

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 91

Plate 3-26 Urinary System: VOLUME 5

CLASSIC DISTAL RENAL TUBULAR ACIDOSIS

Normal urinary acidification Distal renal tubular acidosis

Blood Proximal Naϩ HCO3Ϫ Kϩ HPO42Ϫ Blood Proximal Naϩ HCO3Ϫ Kϩ HPO42Ϫ
tubule tubule
RENAL TUBULAR ACIDOSIS
NBC HCO3Ϫ Hϩ NHE3 CO2 NBC HCO3Ϫ Hϩ NHE3 CO2
(Continued) CA-II CA-IV CA-II CA-IV

subtypes of cells have been described: type A and type ATP H+2O ATP H+2O
B. Type A cells secrete protons and reabsorb bicarbon- Kϩ CO2 Kϩ CO2
ate, whereas type B cells do the reverse. It is unclear if
type A and B cells are molecular mirror images or sepa- ATP ATP
rate cell types; however, the acid load in the average
human diet dictates that the great majority of ICs be CO2 NH3 NH4+ NH4+ CO2 NH3NH4+ NH4+
type A.
CO2 NH3 CO2 NH3 Hϩ
Classic distal RTA (i.e., hypokalemic dRTA) reflects NH3
type A cell dysfunction. Because there is inadequate Glutamine Glutamine
secretion of protons, the kidneys are unable to appro-
priately acidify urine in the setting of systemic meta- Collecting duct Hϩ Collecting duct
bolic acidosis or following an acid load (e.g., with NH3
ammonium chloride). The urine anion gap (urine
Na+ + K− − Cl−) is a useful tool for confirming this Type A intercalated cell Type A intercalated cell
defect; it will be positive in patients with metabolic
acidosis if there are low levels of urine NH4+, the major HCO3Ϫ Hϩ CA-IV HCO3Ϫ Hϩ
unmeasured cation, secondary to impaired urine CO2 AE1 CA -II
acidification. AE1 CA-II ATP ATP
Cl_ NH4+ ATP
In most cases classic dRTA is acquired. Major causes (mislocalized)
include immunologic diseases (e.g., Sjögren syndrome)
and drugs (e.g., lithium, amphotericin). Rarely, classic Naϩ H+2O ATP H2PO4Ϫ Naϩ H+2O
distal RTA can occur during pregnancy, although it ATP CO2
typically resolves after delivery. Genetic causes have ATP CO2 Kϩ
also been reported, such as autosomal dominant (and, Kϩ
rarely, autosomal recessive) mutations in the gene
encoding AE1, as well as autosomal recessive mutations Principal cell ENaC Principal cell ENaC
in subunits of the apical proton pump.
ATP ROM-K ATP ROM-K
No matter the cause, classic dRTA generally features Kϩ maxi-K Kϩ maxi-K
hypokalemia, at least in part because the lack of proton
secretion in the collecting duct increases the gradient Final urine Final urine
for potassium secretion. Nephrolithiasis and/or neph-
rocalcinosis are also common, since calcium precipita- Normally, acid is excreted as free protons, In distal RTA, the lack of proton secretion in the
tion is favored by urine alkalinity, which results from ammonia, and titratable acids. collecting duct prevents protonation of ammonium
failure of proton secretion, and hypocitraturia, which and titratable acids, as well as excretion of free
results from the increased citrate reabsorption that protons. As a result, urine is inappropriately akaline
occurs in response to acidosis. Metabolic bone disease despite systemic acidosis. In addition, there is
(osteomalacia or rickets) may occur because of the increased potassium excretion.
effects of acidosis on bone, even though calcium and
phosphate levels are usually normal. In patients with most often found in the context of renal insufficiency, developmental hiatus in distal nephron function, which
autosomal recessive dRTA, progressive and irreversible especially that caused by diabetes mellitus. normally continues to mature after birth. Nontransient
bilateral sensorineural hearing loss is common, reflect- RTA with both proximal and distal tubular dysfunction
ing the functional significance of the H+ pump in the Hyperkalemic dRTA is treated by withdrawing pre- does, however, accompany one form of autosomal
cochlea. cipitating drugs and providing sodium bicarbonate. recessive osteopetrosis (Guibaud-Vainsel syndrome or
Fludrocortisone and/or potassium-lowering drugs, marble brain disease). Investigators have identified loss
Classic dRTA is treated with alkali replacement. If such as oral resins, are also helpful, since reducing of carbonic anhydrase 2, an enzyme expressed both
treatment is not instituted early on, however, serum potassium concentrations increases renal ammo- throughout the nephron and in osteoclasts, as the bio-
chronic kidney disease may occur secondary to nephro- niagenesis and ammonia excretion. chemical defect. The disease presents in infancy, with
calcinosis or uncontrolled nephrolithiasis with conse- major signs including thickened but brittle bones, short
quent obstruction. Of note, alkali treatment does not MIXED RTA stature, mental retardation, dental malocclusion, and
improve deafness in patients with autosomal recessive visual impairment from optic nerve compression. Cal-
disease because orally administered alkali cannot access The entity of transient mixed proximal/distal RTA cification of the basal ganglia may occur.
the inner ear compartment. arising just after birth is thought to mark a

Hyperkalemic dRTA is chiefly a by-product of distal
nephron dysfunction secondary to aldosterone resis-
tance or deficiency. Acidosis reflects both the absence
of aldosterone-induced proton secretion and the inhibi-
tory effects of hyperkalemia on ammoniagenesis.

Most cases are related to drugs or to hyporeninemic
hypoaldosteronism. The most commonly implicated
drugs include trimethoprim, cyclosporine, and ACE
inhibitors. Trimethoprim acts as an antagonist of the
ENaC, whereas cyclosporine inhibits the basolateral
Na+/K+ ATPase. Hyporeninemic hypoaldosteronism is

92 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-27 Physiology

DIABETES INSIPIDUS

Central

Failure of osmoreceptors

NEPHROGENIC DIABETES Idiopathic destruction of In supraopItnhicysnupupocrplaehouypsstiiaclot-ract Blood
INSIPIDUS hormone-producing cells In neurohypophysis
Neurosurgery
In diabetes insipidus (DI), abnormalities in ADH sig- Trauma Failure to
naling prevent patients from appropriately concentrat- (skull fracture, hemorrhage, produce ADH
ing tubular fluid, leading to the continuous production concussion)
of large volumes of dilute urine. DI is termed “central” Infection Filtration
if there is diminished production of ADH, usually (meningitis, encephalitis, normal
because of abnormalities in the hypothalamus or poste- tuberculosis)
rior pituitary, or “nephrogenic” if there is diminished Tumors
renal response to ADH. Nephrogenic DI (NDI) can (craniopharyngioma,
occur because of inherited mutations or, more com- lymphoma, meningioma,
monly, acquired insults to the renal tubules. pituitary tumor, metastasis)
Infiltration
PATHOPHYSIOLOGY (Langerhans cell histiocytosis,
sarcoidosis)
A detailed description of ADH physiology is available
on Plate 3-17. In brief, elevations in serum osmolality Inherited defects in
trigger release of ADH from the posterior pituitary. In ADH production
the kidneys, ADH binds to V2 receptors on the
basolateral surface of principal cells, located in the col- Nephrogenic
lecting duct, which triggers translocation of aquaporin
2 (AQP-2) channels from endosomes to apical cell Post. Ant.
membranes. As a result, water is reabsorbed through a
transcellular route from the tubule lumen into the Pituitary
interstitium. In addition, ADH up-regulates apical gland
ENaC and urea transporters in the collecting duct, as Normal
well as Na+/K+/2Cl− cotransporters (NKCC2) in the central
thick ascending limb, to increase the concentration of production
solute in the interstitium and draw more water out of of ADH
the collecting duct.
ADH Block ‫؍‬Normal
Inherited NDI, which is the major cause of NDI in Block electrolyte
children, typically results from mutations in either the ADH reabsorption
V2 receptor or AQP-2 channel. V2 mutations account
for 90% of cases and are inherited in an X-linked reces- Renal tubules do not Failure
sive pattern. Females may exhibit a variable level respond to endogenous of water
of disease depending on their particular pattern of or exogenous ADH reabsorption
X-inactivation (lyonization). AQP-2 mutations account
for most of the remaining cases and can be inherited in Large volumes of dilute urine
an autosomal recessive or dominant pattern. Other
tubular disorders, such as Bartter syndrome, can also Other drugs that may cause diabetes insipidus include release of bilateral ureteral obstructions because of
feature increased urine production because of failure to demeclocycline, amphotericin B, and orlistat. The tubular injury; and amyloidosis, if there is extensive
establish an adequate concentration of solutes in the mechanisms are diverse and not completely under- tubular deposition.
medullary interstitium; thus, even though ADH is stood. V2 receptor antagonists, such as tolvaptan, may
present and functional, there is a diminished transcel- cause transient NDI. Finally, acquired NDI may also PRESENTATION AND DIAGNOSIS
lular gradient for water transport. occur in the setting of normal aging, which causes a
decreased density of collecting duct transporters; The major symptom of both central and nephrogenic
Acquired NDI, which is more common in adults, is hypercalcemia and hypokalemia because these states DI is polyuria, arbitrarily defined as greater than 3 L/
most frequently the result of long-term lithium usage, interfere with reabsorption in the thick ascending limb day of urine production in adults and 2 L/day in chil-
commonly employed to treat bipolar disorder. About and therefore decrease the medullary solute gradient; dren. Additional features often include constant thirst
40% to 50% of patients who take lithium will experi-
ence this complication to some degree; among them,
about half will experience significant polyuria, starting
as early as 8 weeks after therapy begins. Lithium is
freely filtered at the glomerulus and primarily reab-
sorbed in the proximal tubule. A small amount, however,
is reabsorbed through apical ENaC in principle cells of
the collecting duct. It accumulates within the cell,
where it appears to interfere with the second messenger
cascade that connects V2 activation to luminal insertion
of AQP-2 channels. For reasons that are poorly under-
stood, but which may involve a selective toxic effect
on principal cells, these effects can persist even after
lithium is discontinued.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 93

Plate 3-28 Urinary System: VOLUME 5

MAJOR CAUSES AND SYMPTOMS OF NEPHROGENIC DIABETES INSIPIDUS
Major causes
Inherited

Extracellular space

Water

ADH

V2 receptor Adenylyl
cyclase

NEPHROGENIC DIABETES ␥ ␣ ␣ Aquaporin 2
INSIPIDUS (Continued) ␤ channels
␣
(polydipsia) and fatigue. In children with inherited
NDI, failure to thrive and mental retardation may G protein
occur secondary to repeated episodes of severe dehy-
dration, if diagnosis and treatment have been delayed. cAMP ATP

Patients with polyuria should be questioned regard- Intracellular RR RR Insertion of
ing their water intake to assess for possible primary space CC aquaporin
polydipsia (i.e., compulsive water consumption, which Inactive PK-A CC channels
leads by necessity to polyuria). In addition, their medi- Active PK-A
cations should be carefully reviewed to determine if
they are taking diuretics or medications (such as lithium) 90% ~10%
known to cause DI. A prior history of trans-sphenoidal Loss of V2 receptor Loss of aquaporin 2 channels
neurologic surgery strongly suggests central DI. Finally, X-linked recessive inheritance Autosomal dominant or recessive inheritance
family history should be assessed for possible inherited
disease. Acquired ؉
؉
On serum chemistries, hypernatremia is suggestive of Lithium (major cause)
severe dehydration secondary to polyuria, whereas Demeclocycline ؉
hyponatremia indicates primary polydipsia. Hypokale- Amphotericin B ؉
mia and hypercalcemia may cause NDI, as previously Orlistat
stated, and should be noted if present. Fasting glucose
levels should be normal to exclude hyperglycemia as a Aging Release of Hypokalemia
cause of osmotic diuresis. Serum creatinine concentra- bilateral ureteral Hypercalcemia
tion may be slightly elevated in the setting of severe Amyloidosis obstructions
dehydration, with an elevated BUN:creatinine ratio and
bland urine sediment suggestive of a prerenal state (see Symptoms Possible presenting symptoms in infants with inherited disease:
Plate 4-1). In general:

In children and adults, a water deprivation test is the Mental Growth retardation
gold standard for diagnosis. This procedure tests the retardation
urine-concentrating capabilities of the kidneys in
response to dehydration. In normal individuals, there Polyuria Polydipsia
will be an appropriate increase in urine osmolality as • Adults: >3L/day of urine
the body attempts to conserve free water. In patients • Children: >2L/day of urine Usually male
with DI, in contrast, the urine osmolality remains (see above)
depressed, with the exact level depending on various
testing parameters and whether the DI is complete or Polyuria
partial. The distinction between central and nephro-
genic DI may be established by assessing the response Anorexia,
to exogenous vasopressin agonists, such as desmopres- vomiting
sin, which will lead to urine concentration in central DI
but have no effect in nephrogenic DI. Constipation

Of note, patients with primary polydipsia may have Polydipsia Failure to gain weight
findings that resemble those of partial NDI because
their urine-concentrating abilities are frequently
impaired (as a result of medullary wash-out) but the
addition of desmopressin has no effect (since they have
intact secretion of endogenous ADH). Thus a careful
history may be required to make the distinction.

TREATMENT It is important for all patients to maintain adequate reabsorption in the proximal tubule. Thiazide diuretics
hydration. If young children cannot obtain their own are preferred over loop diuretics because the latter
All potentially modifiable causes of NDI should be water, it must regularly be offered to them. A low-salt impair creation of the solute gradient in the medulla,
reversed. Lithium, for example, should be discontinued, diet should be instituted to promote solute and water which interferes with urine concentration. In addition,
and hypokalemia or hypercalcemia should be corrected. reabsorption in the proximal tubule. amiloride has been proposed as a potentially preventa-
These measures may lead to complete recovery of renal tive measure in patients taking lithium, because this
function, although lithium-associated NDI may be irre- In addition, a diuretic can be offered because it can agent appears to limit lithium influx into principal cells.
versible in some cases. paradoxically reduce urine output by causing a slight Its efficacy, however, remains unknown.
volume depletion, which up-regulates salt and water

94 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS