Applied Renal Physiology

CHAPTER • 2
Applied Renal Physiology
Stephen P. DiBartola
“Superficially it might be said that the function of the kidneys is to make urine; but in a more considered view, one
can say that the kidneys make the stuff of philosophy itself.”
Homer W. Smith
Each day the glomeruli of the kidneys filter an enormous any substance may be calculated, but the clearance of
volume of plasma water, and the tubules must reabsorb certain substances (e.g., inulin, p-aminohippuric acid
most of this water along with vital solutes so that only a [PAH], and creatinine) provides important information
small volume of water and unneeded solutes are excreted about renal function (see later discussion of measurement
as urine. For example, a normal 10-kg dog may have a of glomerular filtration rate and measurement of renal
glomerular filtration rate (GFR) of 4 mL/min/kg. In blood flow and renal plasma flow).
the course of one day, this dog would filter 57.6 L of
plasma water in its kidneys. If 60% of body weight is
water, this volume represents almost 10 times the dog’s GLOMERULAR FILTRATION
total body water. The same dog may have a urine output
of 33 mL/kg/day. Thus, more than 99% of plasma water GLOMERULAR MORPHOLOGY
filtered by the glomeruli is reabsorbed by the tubules. The The glomerular capillary wall or filtration barrier consists
proximal tubules and loops of Henle reabsorb approxi- of three components: the capillary endothelium, base-
mately 85% of the filtered water and solutes, whereas ment membrane, and visceral epithelium (Fig. 2-2).
the collecting ducts adjust the final composition of urine The glomerulus is a unique vascular structure consisting
to compensate for fluctuations in intake and prevent of a capillary bed interposed between two arterioles: the
changes in the volume and composition of body fluids. afferent and efferent arterioles. The glomerular capillary
The major functions of the various segments of the neph- divides into several branches, each of which forms a lob-
ron are depicted in Figure 2-1. ule of the glomerulus. The capillary endothelium of the
glomerulus is fenestrated by openings 50 to 100 nm in
CONCEPT OF RENAL diameter. These openings exclude cells from the ultrafil-
trate, but macromolecules are not restricted based on
CLEARANCE size. The luminal surface of the endothelium is covered
An appreciation of the concept of clearance is crucial to by negatively charged sialoglycoproteins that contribute
understanding how renal function is evaluated clinically. to the charge selectivity of the filtration barrier.
The renal clearance of a substance is the volume of plasma The glomerular basement membrane is composed of
that contains the amount of the substance excreted in the the lamina rara interna on the endothelial side, the central
urine in 1 minute. It is the volume of plasma that must be lamina densa, and the lamina rara externa on the epithelial
filtered each minute to account for the amount of the side. The lamina rara interna and lamina rara externa con-
substance appearing in the urine each minute under tain polar noncollagenous proteins that contribute to the
steady-state conditions. If the concentration of the sub- negative charge of the filtration barrier. The lamina densa
stance in urine is Ux and the urine flow rate is V, the contains nonpolar collagenous proteins that contribute
amount of the substance excreted in the urine per minute primarily to the size selectivity of the filtration barrier.
is UxV. If the concentration of the substance in plasma is The filtration barrier is permeable to molecules with
Px, the volume of plasma that contains the same quantity effective molecular radii less than 2 nm and impermeable
of that substance or the volume of plasma that must be fil- to those with radii greater than 4 nm.
tered per minute to account for that amount in the urine is The visceral epithelial cells or podocytes constitute
UxV/Px, the standard clearance formula. The clearance of the outermost portion of the filtration barrier. They cover
26
Applied Renal Physiology 27
Connecting segment and Glomerulus Proximal tubule

cortical collecting duct Filtration Isosmotic reabsorption of 65-70%
of filtered water and NaCl
Aldosterone-mediated
potassium secretion by
Reabsorption of 90%
principal cells −
of filtered HCO3
H+ ion secretion by
Major site of NH3 production
α-intercalated cells
Potassium reabsorption Reabsorption of almost all

by α-intercalated cells filtered glucose and amino acids
Reabsorption of potassium,
ADH-mediated water
phosphate, calcium, magnesium,
reabsorption
urea, and urate
Secretion of organic anions

and cations
Loop of Henle
Medullary collecting duct Countercurrent multiplier
Potassium reabsorption Reabsorption of 15-25% of

or secretion filtered NaCl
Final NaCl reabsorption Active regulation of

magnesium excretion
ADH-mediated water
and urea reabsorption Distal tubule
Small amount of
+
H ion and NH3 NaCl reabsorbed
secretion
Active regulation of
calcium excretion
Figure 2-1 Major functions of each portion of the nephron. (Drawing by Tim Vojt.)
the glomerular basement membrane and glomerular molecular mass of 5200 daltons and radius of 1.4 nm,
capillaries on the urinary side of the barrier with their pri- permeates freely, whereas serum albumin, with a molecu-
mary and interdigitating secondary foot processes. Filtra- lar mass of 69,000 daltons and radius of 3.6 nm,
tion slits, 10 to 30 nm in width, are located between the permeates minimally.
secondary foot processes. The podocytes are phagocytic The charge selectivity of the glomerulus resides in the
and may engulf macromolecules trapped by the filtration negatively charged sialoglycoproteins (e.g., laminin and
slits. They are invested with a negatively charged sialogly- fibronectin) and peptidoglycans (e.g., heparan sulfate)
coprotein coat that contributes to the charge selectivity of of the capillary endothelium, lamina rara interna, lamina
the filtration barrier. It is believed that the visceral epithe- rara externa, and visceral epithelium. At any given effec-
lial cells synthesize the glomerular basement membrane. tive molecular radius, negatively charged macromolecules
The mesangium is not a part of the filtration barrier but a experience greater restriction to filtration than neutral
stabilizing core of tissue, forming an anchor for the glomer- ones. Positively charged macromolecules experience less
ulus at the vascular pole and along the axes of the capillary restriction to filtration than neutral ones of the same
lobules. The mesangial cells are in contact with the base- size (Fig. 2-3).
ment membrane in areas where there is no capillary endo-
thelium. The extraglomerular mesangium fills the space DETERMINANTS OF GLOMERULAR
between the macula densa and the glomerular arterioles FILTRATION
and constitutes part of the juxtaglomerular apparatus The term glomerular filtration rate refers to the total fil-
(JGA). The mesangial cells contain microfilaments and tration rate of both kidneys and represents the sum of the
can contract in response to specific hormones (e.g., angio- single-nephron glomerular filtration rates (SNGFRs)
tensin II), thus altering the surface area available for of all nephrons. The number of nephrons per kidney
filtration. They also synthesize prostaglandins that contrib- reflects the size of the animal. The feline kidney has
ute to renal vasodilatation. The mesangium also contains approximately 200,000 nephrons, the canine kidney
macrophages that can clear filtration residues from the approximately 400,000, and the human kidney approxi-
mesangial space by phagocytosis. mately 1,200,000 nephrons. SNGFR may differ among
The glomerular capillary wall is a size-selective and a some groups of nephrons under normal conditions,
charge-selective barrier to filtration. Its size selectivity and additional changes may occur in response to such
resides primarily in the lamina densa of the glomerular factors as water deprivation, increased water intake,
basement membrane. The glomerulus generally excludes increased salt intake, or increased protein intake. Superfi-
molecules with radii greater than 4 nm. Inulin, with a cial cortical nephrons have short loops of Henle with little
28 APPLIED PHYSIOLOGY
1.0
Albumin
(3.6 nm)
EA
0.8
Fractional clearance
(Cdextran/Cinulin)
N MD
0.6
G Cationic
0.4
Neutral
B
M 0.2
Anionic
BM 0
EN
1.8 2.2 2.6 3.0 3.4 3.8 4.2
F
Effective molecular radius (nm)
EP Figure 2-3 Effect of electrostatic charge on filtration of
macromolecules across the glomerular capillary wall. (Drawing by
BS Tim Vojt.)
PT
SNGFR ¼ Kf ½ðPGC PT Þ ðpGC pT Þ

Figure 2-2 Schematic representation of the glomerulus
demonstrating the afferent and efferent arterioles, juxtaglomerular where PGC is the hydrostatic pressure in the glomerular
apparatus, and glomerular capillary loops. At the vascular pole, an
capillary, which falls slightly along the length of the glo-
afferent arteriole (AA) enters and an efferent arteriole (EA) leaves
merular capillary, averaging 55 mm Hg; PT is the hydro-
the glomerulus. At the urinary pole, the Bowman space (BS)
becomes the tubular lumen of the proximal tubule (PT). The static pressure in the Bowman space, which is higher than
epithelial cells composing the Bowman capsule (B) enclose the systemic interstitial pressure, averaging 20 mm Hg; pGC is
Bowman space. Smooth muscle cells proper of the arterioles and all the oncotic pressure in the glomerular capillary, which
cells derived from smooth muscle are shown in black, including the increases along the length of the capillary because of loss
granular cells (G).The afferent arteriole is innervated by sympathetic of protein-free ultrafiltrate into the Bowman space, aver-
nerve terminals (N). The extraglomerular mesangial cells are aging 20 mm Hg; and pT is the oncotic pressure in the
located at the angle between AA and EA and continue into the Bowman space and is negligible because the ultrafiltrate
mesangial cells (M) of the glomerular tuft. The glomerular capillaries is nearly protein free. If pT is neglected, the formula for
are outlined by fenestrated endothelial cells (EN) and covered from SNGFR simplifies to:
the outside by the epithelial cells (EP) with foot processes (F). The
glomerular basement membrane (BM) is continuous throughout the
SNGFR ¼ Kf ðPGC PT pGC Þ
glomerulus. At the vascular pole, the thick ascending limb touches
the macula densa (MD), the extraglomerular mesangium.31
These relationships are depicted in Figure 2-4, in which
average pressure values are those reported for dogs36
or no penetration into the renal medulla. These nephrons and cats.7 If the average pressures just described are con-
tend to excrete relatively more solute and water. sidered alone, it can be seen that the net filtration pressure
Juxtamedullary nephrons have long loops of Henle that in the glomerulus is approximately 15 mm Hg, which is
penetrate the inner medulla, and these nephrons tend similar to values obtained for systemic capillaries. The fact
to conserve solute and water. All of the nephrons in the that GFR is so much higher than the movement of fluid
canine and feline kidneys are thought to have long loops across systemic capillaries is explained by different values
of Henle. for Kf.
The glomerular ultrafiltrate is a protein-free ultrafil- The ultrafiltration constant, Kf, is dependent on the
trate of plasma containing water and all of the crystalloids surface area available for filtration and the permeability
of plasma in concentrations similar to those in plasma. per unit area of capillary to crystalloids and water. The
The concentrations are not exactly the same because of morphology of the glomerulus is such that the surface
the Gibbs-Donnan effect. The same Starling forces that area available for filtration is much greater than that
govern the movement of fluid across other capillaries in found in the capillary beds of skeletal muscle, and the unit
the body determine SNGFR, but there are some impor- permeability of the glomerular endothelium is more than
tant differences in the glomerulus that account for the 100 times that of skeletal muscle capillaries. This much
relatively high rate of filtration: higher value for Kf in glomerular capillaries than in
60 60 Afferent Efferent
Control
50 Net ultrafiltration 50
pressure
Pressure (mm Hg)
40 40
Decreased
PGC
resistance = ↑RBF ↑GFR
πGC
30 30 in afferent
20 20
Increased
10 PT 10 resistance = ↓RBF ↓GFR
in afferent
0 Distance along glomerular capillary 100%

(Afferent end) (Efferent end)
Decreased
resistance ↑RBF ↓GFR
Mean values for dog and cat in efferent
PGC Hydrostatic pressure in glomerular capillary 52 58
πGC Plasma oncotic pressure in glomerular capillary 20 22
PT Hydrostatic pressure in Bowman’s space 20 18 Increased
πT Oncotic pressure in Bowman’s space 0 0 resistance = ↓RBF ↑GFR
Net ultrafiltration pressure 12 18 in efferent
Figure 2-4 Graphic representation of the generation of net
filtration pressure in the glomerulus as governed by Starling
forces. (Drawing by Tim Vojt.) Figure 2-5 Effects of alterations in afferent and efferent arteriolar
tone on renal blood flow and glomerular filtration rate. (Drawing by
Tim Vojt.)
systemic capillaries accounts for the much higher rate of
filtration. The ultrafiltration coefficient, Kf, is not con- afferent and efferent vasodilatation and increased RBF
stant and can change as a result of disease and in response with little change in GFR at low concentrations of dopa-
to hormones that cause mesangial cells to contract (e.g., mine. Norepinephrine, angiotensin II, and antidiuretic
angiotensin II). hormone (ADH, vasopressin) cause vasoconstriction, at
Changes in the resistance of the afferent the same time promoting the production of prosta-
(preglomerular) and efferent (postglomerular) arterioles glandins that cause vasodilatation. These prostaglandins
may have a marked effect on GFR. Alterations in resis- (PGE2 and PGI2) play an important role in maintaining
tance in the afferent arterioles lead to parallel changes RBF in hypovolemic states when angiotensin II and nor-
in GFR and renal blood flow (RBF), but changes in resis- epinephrine concentrations are increased. The effects of
tance in the efferent arterioles lead to divergent changes these prostaglandins are limited to the kidneys because
in GFR and RBF (Fig. 2-5). The interplay of the effects of they are rapidly metabolized in the pulmonary circula-
neural and hormonal factors on vascular tone in the tion. Nonsteroidal anti-inflammatory drugs that inhibit
kidneys is complex, but the main purpose of these effects generation of prostaglandins by the cyclooxygenase path-
is to minimize even slight changes in GFR, which could way may cause renal ischemia and acute renal insufficiency
have drastic adverse effects on the volume and composi- in hypovolemic patients.10,12 Locally produced kinins
tion of the extracellular fluid. also cause vasodilatation and favor redistribution of
The resistance of these arterioles is regulated by the RBF to inner cortical nephrons. Mediators produced
autonomic nervous system and by numerous vasoactive locally by the vascular endothelium also contribute to
mediators (Table 2-1). Stimulation of the sympathetic afferent and efferent vasoconstriction (e.g., endothelin
nervous system results in release of norepinephrine from and thromboxane) and vasodilatation (e.g., nitric oxide
nerves terminating on the afferent and efferent arterioles. and prostacyclin).
Norepinephrine can cause afferent and efferent vasocon-
striction, but efferent arteriolar constriction usually MEASUREMENT OF GLOMERULAR
predominates. As a result, RBF decreases with minimal FILTRATION RATE
changes in GFR (i.e., filtration fraction [FF] increases). Consider a substance that is filtered by the glomeruli but
Angiotensin II also causes efferent more than afferent neither reabsorbed nor secreted by the tubules. Under
vasoconstriction and has similar effects on RBF and steady-state conditions, the following mass balance
GFR. Stimulation of dopaminergic receptors causes equation may be written:
so its clearance can be used to estimate GFR in the steady

TABLE 2-1 Effects of Selected
state. The only requirements for determination of endog-
Vasoactive Mediators on enous creatinine clearance are an accurately timed urine
Glomerular sample (usually 24 hours), determination of the patient’s
Hemodynamics body weight, and measurement of serum and urine creat-
inine concentrations.
Afferent Efferent In the dog and cat, creatinine is filtered by the
Substance Arteriole Arteriole glomeruli and is neither reabsorbed nor secreted by the
Vasodilators tubules.18–20,22 In most clinical pathology laboratories,
Acetylcholine Relax Relax creatinine is measured by the alkaline picrate reaction.
Nitric oxide Relax Relax This reaction is not entirely specific for creatinine and
Dopamine Relax Relax measures another group of substances collectively known
Bradykinin Relax Relax as noncreatinine chromogens. These substances are
Prostacyclin Relax Relax found in plasma, where they may constitute up to 50%
Prostaglandin E2 Relax No effect of the measured creatinine at normal serum creatinine
Prostaglandin I2 Relax Relax concentrations, but only small amounts appear in
Vasoconstrictors urine.21,22 When the creatinine concentration is deter-
Norepinephrine Constrict Constrict mined using the alkaline picrate reaction, the presence
Angiotensin II Constrict Constrict of noncreatinine chromogens causes endogenous creati-
Endothelin Constrict Constrict nine clearance to underestimate GFR. This problem
Thromboxane Constrict Constrict
may be avoided by using more accurate methods (e.g.,
Vasopressin No effect Constrict
peroxidase-antiperoxidase) to measure the creatinine
From Valtin H, Schafer JA. Renal function. Boston: Little, Brown, 1995: concentration.22 Values for endogenous creatinine
107. clearance in the dog and cat are approximately 2 to 5
mL/min/kg.5,17,22
Amount filtered ¼ amount excreted To circumvent the problem of noncreatinine
Px GFR ¼ Ux V chromogens and to improve accuracy, some investigators
have advocated determination of exogenous creatinine
where Px is the plasma concentration of x (milligrams per clearance. In this test, which is somewhat more cumber-
milliliter), Ux is the urine concentration of x (milligrams some, creatinine is administered subcutaneously to the
per milliliter), V is the urine flow rate (milliliters per min- animal to increase the serum creatinine concentration
ute), and GFR is the glomerular filtration rate (milliliters and reduce the relative effect of the noncreatinine
per minute). Dividing both sides of the equation by Px: chromogens. For example, a normal dog may have a
serum creatinine concentration of 1.0 mg/dL, of which
GFR ¼ Ux V =Px 0.5 mg/dL represents noncreatinine chromogens. This
measurement represents a 50% error. If, however, the
Note that this equation is the same as the formula for dog’s serum creatinine concentration is increased to
clearance presented before. Thus, the renal clearance of 10 mg/dL by subcutaneous administration of creatinine,
a substance that is neither reabsorbed nor secreted is the noncreatinine chromogens still represent only
equal to GFR. Inulin is a polymer of fructose with a 0.5 mg/dL, and the error is reduced to 5%. Exogenous
molecular mass of 5200 da. It is not bound to plasma creatinine clearance exceeds endogenous creatinine clear-
proteins and is freely filtered by the glomeruli. It is neither ance and more closely approximates inulin clearance in
reabsorbed nor secreted by the tubules. It is not the dog.20
metabolized by the kidneys or any other organ. It is The amount of any substance excreted by the kidneys
uncharged and not subject to the Gibbs-Donnan effect. is the algebraic sum of the amount filtered and the
In summary, inulin is an ideal substance for the measure- amount handled by the tubules:
ment of GFR, and inulin clearance is the laboratory stan-
dard for GFR determination. Normal values for GFR as Ux V ¼ Px GFR þ Tx
measured by inulin clearance are 3 to 5 mL/min/kg in
the dog16,21 and 2.5 to 3.5 mL/min/kg in the cat.16,45 where Tx is the amount handled by tubules (milligrams
Inulin clearance is not used clinically because it per minute).
requires intravenous infusion of inulin and an assay that The term Tx is a positive number if the substance
is not routinely available in most clinical pathology experiences net secretion and a negative number if it
laboratories. Creatinine is produced endogenously in experiences net reabsorption. Dividing both sides of
the body and excreted primarily by glomerular filtration, the equation by Px yields the familiar clearance formula:
Cx ¼ GFR þ Tx =Px As pressure increases, flow can remain constant only if

resistance increases proportionately. The site of this resis-
Thus, the clearance of a substance experiencing net tance change in the kidneys is the afferent arteriole.
reabsorption is less than GFR (Tx is negative), and the Autoregulation is intrinsic to the kidneys and occurs in
clearance of a substance experiencing net secretion is the isolated, denervated kidney and in the adrenalecto-
greater than GFR (Tx is positive). The ratio of the clear- mized animal. However, it is impaired by anesthesia in
ance of a substance to inulin clearance gives an indication proportion to the depth of anesthesia. The afferent
of the net handling of that substance by the kidneys. If the arterioles are maximally dilated at mean arterial pressures
ratio is less than 1.0, the substance experiences net of 70 to 80 mm Hg, and at lower pressures, GFR declines
reabsorption; if it is greater than 1.0, it experiences net linearly with RBF (i.e., autoregulation is lost). It is likely
secretion. that autoregulation of RBF is a consequence of the need
to regulate GFR closely and thus maintain tight control
RENAL BLOOD FLOW AND over water and salt balance.Two physiologic mechanisms
contribute to autoregulation. The myogenic mechanism
RENAL PLASMA FLOW is based on the principle that smooth muscle tends to
The kidneys receive 25% or more of cardiac output. The contract when stretched and relax when shortened. As
major sites of resistance within the kidneys are the afferent the afferent arteriole is stretched by increased perfusion
and efferent arterioles, with an approximately 80% to 90% pressure, it constricts, thus limiting transmission of this
decrease in perfusion pressure across this region of the increased pressure to the glomerulus and minimizing
renal vasculature (Fig. 2-6). Blood flow is not uniform any change in glomerular capillary hydrostatic pressure
throughout the kidneys. In dogs, more than 90% of and SNGFR. The myogenic mechanism represents a
RBF is normally directed to the renal cortex, less than coarse control that operates with a delay of 1 to 2 seconds.
10% to the outer medulla, and only 2% to 3% to the inner Tubuloglomerular feedback represents a local
medulla.51 The actual rate of flow to the renal cortex is intrarenal negative feedback mechanism for individual
approximately 100 times that of resting muscle and is nephrons. The morphologic basis for this physiologic
required for glomerular filtration. Blood flow to the mechanism is the JGA. Increased sodium chloride con-
medulla is similar to that of resting muscle, and this centration or transport in the distal tubule is sensed by
reduced flow is necessary for normal function of the uri- the extraglomerular mesangial cells of the JGA as they
nary concentrating mechanism. monitor sodium chloride transport across the tubular
cells of the macula densa. Transport of NaCl by the tubu-
AUTOREGULATION lar cells of the macula densa requires functional NKCC2
Autoregulation refers to the intrinsic ability of an organ to (the Naþ, Kþ, 2Cl- cotransporter) and ROMK (a potas-
maintain blood flow at a nearly constant rate despite sium channel) in the luminal membranes and functional
changes in arterial perfusion pressure. In the kidneys, Naþ, Kþ-ATPase in the basolateral membranes.46
between perfusion pressures of 80 and 180 mm Hg, Transcellular transport of NaCl causes generation of
GFR and RBF vary less than 10% (Fig. 2-7). Flow (Q) adenosine, which together with angiotensin II causes
is equal to pressure (P) divided by resistance (R). afferent arteriolar constriction in the parent glomerulus.
Renal Afferent Efferent Peritubular Intrarenal Renal

artery arteriole Glomerulus arteriole capillary vein vein
100
80
Pressure (mm Hg)
60
40
20
0
Figure 2-6 Pattern of hydrostatic pressure and vascular resistance in the renal circulation. (Drawing by
Tim Vojt.)
Autoregulatory range 90% of it is removed in one pass through the kidneys. It is not
600 80 metabolized or excreted by any other organ. Thus, it
approximately meets the preceding assumptions and RPF
Glomerular filtration rate (ml/min)

70
500 ¼ UPAHV/PPAH. Now it can be seen that the clearance of
Renal blood flow (ml/min)
GFR 60 PAH is an estimate of RPF. When PAH is infused during

400 a clearance study, it is essential that PPAH be maintained at
RBF 50
a concentration much below the tubular transport maxi-
300 40 mum (Tmax) for PAH. If not, PVX cannot be neglected.
Some blood flows through regions of the kidneys that do
30
200 not remove PAH (e.g., renal capsule, perirenal fat, and renal
20 pelvis), and as a result, PVX is not really zero. Thus, the term
100
10
effective RPF is more appropriately used when speaking of
PAH clearance. Furthermore, only 90% of PAH is removed
from the blood during a single pass through the kidneys.
0 50 100 150 200 250
80 180 This also contributes to the fact that PVX for PAH is not
Renal arterial blood pressure (mm Hg) really zero. A closer approximation of RPF can be deter-
Figure 2-7 Autoregulation of renal blood flow and glomerular mined by sampling renal arterial and venous blood and
filtration rate. (Drawing by Tim Vojt.) measuring their respective PAH concentrations. The
extraction ratio for PAH is then determined:
The afferent arteriolar constriction causes SNGFR to EX ¼ ðPAX PVX Þ=PAX

decrease, thus decreasing filtration and minimizing
NaCl loss in that nephron. This effect occurs locally A more accurate calculation of RPF is then:
in the region of the juxtaglomerular interstitium.
Tubuloglomerular feedback represents a fine control that RPF ¼ CPAH =EPAH
operates with a 10- to 12-second delay.
RPF ¼ UPAH V=PPAH EPAH
MEASUREMENT OF RENAL BLOOD
FLOW AND RENAL PLASMA FLOW The extraction ratio for PAH is 0.9 because approxi-
Consider the following mass balance equation52: mately 90% of it is removed from the blood in a single pass
Amount entering the kidneys ¼ amount leaving the through the kidneys. Notice that if we substitute the
kidneys equation for EX into the preceding equation, we get
RPF ¼ UXV/(PAX PVX), which is the same equation
PAX RPFA ¼ PVX RPFV þ UX V as derived before for RPF.
Another way to determine RPF is by use of the Fick
PAX RPFA PVX RPFV ¼ UX V principle, which states that the amount of a substance
(V) removed by an organ is equal to the blood flow to
where PAX is the renal arterial plasma concentration of x, the organ (Q) times the arteriovenous concentration
RPFA is the arterial renal plasma flow (RPF), PVX is the renal difference of the substance in question (CA CV):
venous plasma concentration of x, RPFV is the venous RPF,
UX is the urine concentration of x, and V is the urine flow. V ¼ QðCA CV Þ
If we ignore the slight difference between renal arterial
and venous plasma flow (with probably less than 1% Q ¼ V=ðCA CV Þ
error), the equation is simplified to:
Using the kidneys as an example and equating the amount
ðPAX PVX ÞRPF ¼ UX V of the substance removed to the amount excreted (UXV):
RPF ¼ UX V=ðPAX PVX Þ RPF ¼ UX V=ðPAX PVX Þ
If we choose a substance that is completely removed from Note that this equation is identical to that derived before
the blood in one pass through the kidneys, PVX is zero using the mass balance principle.
and RPF ¼ UX V/PAX. If the substance x is not If the hematocrit is known, RBF can be calculated
metabolized and is not excreted by any organ other than from the RPF by using the following equation:
the kidneys, its concentration in any peripheral vessel
equals PAX. Thus, RPF ¼ UXV/PX. RPF
PAH is filtered by the glomeruli and secreted by the RBF ¼
ð1 hematocritÞ
peritubular capillaries into the tubules so that approximately
In the dog and cat, normal values for RPF are 7 to 20 Transepithelial potential difference
− +
mL/min/kg and 8 to 22 mL/min/kg, respectively.38,39,45
If all of the plasma were filtered in one pass of blood Transmembrane potential difference
through the glomeruli, an immovable mass of red blood + − − +
cells would be all that remained behind at the efferent

arteriole of the glomerular capillary. This does not occur −66 mV −70 mV
−4 mV Interstitial
because pGC increases along the length of the capillary Tubular fluid fluid Blood
and, in conjunction with PT, effectively opposes Lateral

further filtration. The filtration fraction is the fraction intercellular
space
Luminal membrane
of plasma flowing through the kidneys that is filtered Basolateral
membrane
into the Bowman space. It is determined by the
Tight junction
following equation:
FF ¼ GFR=RPF
Transcellular
In the dog and cat, values for FF are 0.32 to 0.36 and
0.33 to 0.41, respectively. These values are higher than
those observed in humans in whom FF is approximately
0.20. Paracellular
RENAL TUBULAR FUNCTION

The terms reabsorption and secretion refer to the direc-
Basement
tion of transport across an epithelium. In the kidneys, membrane Endothelium
reabsorption refers to movement of water and solutes Figure 2-8 Diagram demonstrating selected terminology as
from the tubular lumen to the peritubular interstitium. applied to the renal tubular epithelium: luminal versus basolateral
Secretion refers to movement of water and solutes from membranes, transmembrane versus transepithelial potential
the peritubular interstitium to the tubular lumen. Some difference, and transcellular versus paracellular
substances experience reabsorption in one part of the transport. (Drawing by Tim Vojt.)
nephron and secretion in another part (e.g., urate and
potassium). The term reabsorption often is used to
denote net reabsorption, which is the algebraic sum of negative. The transepithelial PD affects movement of
the fluxes in both directions across the renal tubular charged solutes across the renal tubular epithelium and
epithelium. contributes to the electrochemical gradient for such
The luminal membranes separate the cytoplasm of the solutes.The paracellular route refers to movement of
tubular cell from the tubular fluid. The basolateral solutes and water between cells (i.e., from the tubular
membranes separate the cytoplasm of the tubular cell lumen to the lateral intercellular space across tight
from the lateral intercellular spaces and the peritubular junctions connecting epithelial cells). The transcellular
interstitium. The transmembrane potential difference route refers to movement of solutes and water through
(PD) refers to the electrical PD between the outside the cytoplasm of the tubular cells. The junctions between
and inside of the cell. The transepithelial or renal epithelial cells at the luminal surface are classified as
transtubular PD is the electrical PD between the tubular leaky (proximal tubules) or tight (distal convoluted
lumen and the peritubular interstitium and is the alge- tubules, collecting ducts). Leaky epithelia do not gener-
braic sum of the transmembrane PD between the tubular ate large transepithelial concentration gradients, exhibit
lumen and cell cytoplasm, and the transmembrane PD a small transepithelial PD, and have high water perme-
between the peritubular interstitium and cell cytoplasm. ability, whereas tight epithelia can generate large
These relationships are depicted in Figure 2-8. Trans- transepithelial concentration gradients, exhibit a large
membrane PD usually is 60 to 70 mV (cell interior transepithelial PD, and have low basal water permeability.
negative), whereas transepithelial PD is only a few The paracellular route allows movement of ions (e.g.,
millivolts. In the early proximal tubule, the tubular lumen potassium, chloride) and large, nonpolar solutes by pas-
is a few millivolts negative relative to the peritubular sive diffusion and solvent drag. Electrochemical, hydro-
interstitium, whereas in the later proximal tubule, the static, and oncotic gradients are important driving
tubular lumen is a few millivolts positive relative to the forces for reabsorption by the paracellular route. The
peritubular interstitium. In the thick ascending limb of paracellular route accounts for only 1% of the surface area
Henle’s loop, the transepithelial PD is lumen positive, available for reabsorption and 5% to 10% of water trans-
but in the distal tubule, the transepithelial PD is lumen port, whereas the transcellular route accounts for 99% of
the available surface area and 90% to 95% of water trans- the lipid bilayer of the cell membrane, which occurs for
port. Both passive and active transport processes occur by substances with high lipid solubility. Simple diffusion
the transcellular route, and all active transport processes can also occur through hydrophilic protein channels
must occur by this route. embedded in the cell membrane. Simple diffusion
That renal tubular reabsorption occurs may be requires no expenditure of metabolic energy. The rate
recognized intuitively by considering the composition of transfer of solute is dependent on the permeability
of normal urine. Many low-molecular-weight solutes characteristics of the membrane, the electrochemical gra-
essential to normal physiologic function (e.g., glucose, dient (i.e., the combination of the electrical PD and
amino acids, bicarbonate) are freely filtered at the glomer- chemical concentration difference across the membrane),
ulus but do not normally appear in urine. Thus, they must and the hydrostatic pressure across the membrane. The
have been reabsorbed along the course of the renal rate of diffusion is linearly related to the concentration
tubule. In the proximal tubule, water follows solute reab- of the diffusing solute, and there is no maximal rate of
sorption osmotically, and solute reabsorption is said to transfer (Vmax). Passive diffusion is not a saturable process
occur isosmotically (i.e., the reabsorbed fluid has the because a carrier is not involved.
same osmolality as extracellular fluid). Approximately Facilitated diffusion is the movement of a substance
two thirds of all water and solute reabsorption occurs across a membrane down its electrochemical gradient
in the proximal tubules. Almost 99% of glucose and after binding with a specific carrier protein in the mem-
amino acids and 90% or more of bicarbonate are brane. The carrier protein binds the substance to be
reabsorbed in the early proximal tubules (Fig. 2-9). transported at one side of the cell membrane. The
The reabsorption of bicarbonate occurs as a consequence occupied carrier then undergoes a conformational change
of the tubular secretion of hydrogen ions and is crucial to that causes translocation of the substance across the cell
renal regulation of acid-base balance (see Chapter 9). membrane. The substance is then released from the car-
rier on the other side of the membrane. Unlike simple dif-
RENAL TRANSPORT PROCESSES fusion, facilitated diffusion is a saturable process
Four types of transport processes contribute to renal characterized by a maximal rate of transfer (Vmax) because
tubular reabsorption: passive diffusion, facilitated diffu- a carrier is involved. The carrier has structural specificity
sion, primary active transport, and secondary active and affinity for the substance transported, and the process
transport. is subject to competitive inhibition. Facilitated diffusion
Passive diffusion is the movement of a substance does not directly require metabolic energy, and transfer
across a membrane as a result of random molecular may occur in either direction across the membrane,
motion. Simple diffusion can take place directly through depending on the prevailing electrochemical gradient.
Examples of facilitated diffusion in the proximal tubule
include the transport of glucose and amino acids at the
1.4
basolateral membrane.
Primary active transport is the movement of a sub-
stance across a membrane in combination with a carrier
Ratio of tubular fluid concentration
1.2 Chloride
to plasma fluid concentration
protein but against an electrochemical gradient. Active

1.0 Sodium, osmolality transport requires metabolic energy, which is supplied
by the hydrolysis of adenosine triphosphate (ATP). It is
0.8 a saturable process characterized by a Vmax and is subject
Phosphate to metabolic (e.g., cellular oxidative poisons) and com-
0.6
petitive (e.g., competition for the carrier by a structurally
0.4
similar compound) inhibition. Examples of primary
active transporters include Naþ, Kþ-adenosinetri-
0.2 Bicarbonate phosphatase (Naþ, Kþ-ATPase) in basolateral
membranes of tubular cells throughout the nephron,
Hþ-ATPase in luminal membranes of tubular cells
Amino acids, glucose
0
0 100
throughout the nephron, and Hþ, Kþ-ATPase in luminal
Percentage of proximal tubular length
membranes of a-intercalated cells in the collecting ducts.
Secondary active transport is the movement of two
Lumen positive substances across a membrane after combination with a
0
Lumen negative single carrier protein. The process is called cotransport
Transepithelial potential difference if the transported substances are moving in the same
Figure 2-9 Changes in the solute composition and transepithelial direction across the membrane (e.g., glucose, amino
potential difference along the length of the proximal acids, or phosphate with sodium at the luminal mem-
nephron. (Drawing by Tim Vojt.) brane of the proximal tubular cell) and countertransport
if the transported substances are moving in opposite ultrastructurally the most complex and suited for the
directions across the membrane (e.g., sodium and hydro- mechanisms of solute transport described earlier.31 This
gen ions at the luminal membrane of the proximal tubular morphologic complexity decreases along the length of
cell). The “uphill” (i.e., against a concentration gradient) the proximal tubule. In the first segment of the proximal
transport of one substance (e.g., glucose) is linked to the tubule (S1), sodium, water, bicarbonate, amino acids,
“downhill” (i.e., down an electrochemical gradient) glucose, and phosphate are transported. In the second
transport of another substance (e.g., sodium). When segment (S2), sodium, water, and chloride are
the carrier is occupied by only one of the substances, it reabsorbed, and organic acids and bases may be
is not mobile in the cell membrane, whereas an unoccu- transported.43 Organic acids and bases may also be
pied carrier or one that is occupied by both of the secreted in the third segment (S3).31 The low-specificity
substances is mobile in the membrane. This process is sat- transport system for organic anions and cations in the
urable, demonstrates structural specificity and affinity of proximal tubule allows elimination of many drugs and
the carrier for the substances transported, and may be other foreign organic compounds from the body.
competitively inhibited. The uphill transport occurs with-
out direct input of metabolic energy, and the substance SODIUM TRANSPORT
transported uphill is said to experience secondary active Sodium may enter tubular cells at their luminal surface by
transport. The metabolic energy for secondary active several different mechanisms. In the proximal tubule,
transport at the luminal membranes comes from the pri- sodium may be cotransported across the luminal
mary active transport of sodium out of the tubular cell at membranes of the cell with glucose, amino acids, or phos-
the basolateral membrane by Naþ, Kþ-ATPase, a process phate or may experience countertransport with hydrogen
that maintains a low intracellular sodium concentration. ions secreted into the tubular lumen by the Naþ-Hþ
Pinocytosis refers to the uptake by cells of particles antiporter that facilitates bicarbonate reabsorption. In the
too large to diffuse through the cell membrane. Filtered loop of Henle, sodium enters via an Naþ-Kþ-2Cl carrier
proteins are reabsorbed in the proximal tubule by this that is competitively inhibited by furosemide,37 and
mechanism. in the distal convoluted tubule, sodium enters via an Naþ
Solvent drag refers to the process, whereby water (the Cl cotransporter that is inhibited by thiazide diuretics.
solvent) moving across an epithelium by osmosis can drag In the collecting duct, sodium enters via a luminal sodium
dissolved solutes along with it. channel that generates a lumen-negative PD favoring
chloride reabsorption.
MORPHOLOGY OF THE PROXIMAL Thus, in most segments of the nephron, sodium enters
TUBULE the tubular cell at the luminal membrane down an electro-
Several morphologic features of proximal tubular cells chemical gradient that favors sodium entry into the cell
suggest their primary role in the reabsorption of solutes (i.e., the interior of the cell has a low sodium concentration
and water. The brush border of the luminal surface of and is negative with respect to the exterior). Sodium then
the proximal tubular cells consists of microvilli, which experiences primary active transport out of the cell and into
increase surface area, and lateral cellular interdigitations, the lateral intercellular spaces and peritubular interstitium
which increase the surface area of the basolateral by the Naþ, Kþ-ATPase located in the basolateral cell
membranes (Fig. 2-10). Abundant mitochondria supply membranes. This enzyme hydrolyzes ATP and translocates
energy in the form of ATP required for active transport. two potassium ions into the cell and three sodium ions out
The proximal tubule exhibits intrasegmental axial of the cell.1 It is located only in the basolateral membranes
heterogeneity with the most proximal segments being and functions to maintain a favorable electrochemical
gradient for the passive entry of sodium into the tubular
cells across their luminal membranes. Thus, sodium is
reabsorbed in conjunction with glucose, amino acids,
phosphate, and bicarbonate in the proximal tubule and
with chloride in the loop of Henle and distal tubule.
The different mechanisms for sodium reabsorption in
the nephron and the regulation of sodium reabsorption
in the kidneys are discussed in Chapter 3.
GLUCOSE TRANSPORT
Sodium attaches to a carrier in the luminal membrane of
the proximal tubular cell, and this step is followed by
attachment of glucose to the carrier. Translocation of
Figure 2-10 Three-dimensional model of a proximal tubular cell the carrier occurs, and glucose is released to the interior
showing microvilli and lateral cellular interdigitations.31 of the cell while sodium enters down its electrochemical
gradient (the interior of the cell is negative and its sodium PHOSPHATE
concentration is low). As the intracellular glucose con- The uptake of phosphate into the proximal tubular cell is
centration increases, glucose leaves the cell by facilitated similar to that of glucose in that it is coupled to sodium
diffusion across the basolateral cell membranes. The entry at the luminal membrane. The phosphate
Naþ, Kþ-ATPase in the basolateral membranes continues transporters NaPi-IIa and NaPi-IIc are responsible for
to remove sodium from the cell, thus maintaining a favor- luminal entry of phosphate in the proximal tubule.3 An
able electrochemical gradient for sodium entry and important distinction from glucose transport, however,
expending the metabolic energy required for glucose is that the Tmax for phosphate is low and readily exceeded
transport. Luminal uptake of glucose is mediated by at as plasma phosphate concentration increases. Hormones
least two transporters, a high-capacity, low-affinity trans- also alter the Tmax for phosphate, notably parathyroid
porter (SGLT2) present in the first portion of the proxi- hormone (PTH). PTH decreases the Tmax for phosphate
mal tubule (S1 and S2) and a low-capacity, high-affinity and increases renal phosphate excretion. Thus, the
transporter (SGLT1) later in the proximal tubule (S3).53 kidneys, acting in concert with PTH, serve as regulators
Glucose transport meets the criteria for carrier- of the plasma phosphate concentration.
mediated transport in that it is a saturable process. Plot-
ting the amount filtered (Px GFR), the amount AMINO ACIDS
excreted (Ux V), and the amount handled by the
The proximal tubular reabsorption of amino acids is also
tubules (Tx) for a substance against the plasma concentra-
coupled to luminal sodium uptake. The Tmax values for
tion of that substance (Px) yields a renal titration curve
the different groups of amino acids are very high, and
and allows determination of the renal threshold (plasma
99% of the filtered load of amino acids is reabsorbed in
concentration at which the substance first appears in
the proximal tubule. Thus, the kidneys are not regulators
the urine) and tubular transport maximum (maximal
of plasma amino acid concentrations. There are several
amount of the substance that can be transported by the
transport systems for amino acids in the proximal tubule,
tubules, Tmax or TM). A renal titration curve for glucose
including systems for neutral amino acids, cationic amino
is depicted in Figure 2-11. The Tmax for glucose is con-
acids and cystine, anionic amino acids, imino glycine acids
stant and relatively high, so it is usually not exceeded in
(proline, hydroxyproline, glycine), and ß-amino acids
health. Consequently, the kidneys do not regulate plasma
(e.g., taurine).6,52
glucose concentration. In humans, the Tmax for glucose is
approximately 375 mg/min. In the dog, it is approxi-
PINOCYTOSIS
mately 100 mg/min,27,47 and in the cat, 50 mg/min.32
In the renal titration curve, the Tmax for glucose is Low-molecular-weight proteins (including several
approached somewhat gradually. This characteristic is hormones and immunoglobulin light chains) are filtered
called splay and is thought to result from nephron hetero- at the glomerulus and reabsorbed by the proximal tubular
geneity. Some nephrons excrete glucose before the aver- cells, where they are hydrolyzed to their constituent
age Tmax is reached, whereas others continue to reabsorb amino acids, and these are returned to the circulation. Fil-
glucose after the average Tmax has been reached (i.e., the tered proteins of small molecular mass may be hydrolyzed
Tmax for glucose differs slightly among nephrons). to amino acids by brush border enzymes at the luminal
surface of the proximal tubular cell and their amino acids
taken into the cell by cotransport with sodium. Alterna-
800 Filtered tively, filtered proteins of larger molecular mass may
attach to endocytic sites on the luminal cell membrane.
Glucose filtered, excreted,
or reabsorbed (mg/min)
600 These sites invaginate to form endosomes, which then

fuse with lysosomes to form endolysosomes, in which
digestion of the proteins occurs. The amino acids leave
400
Reabsorbed the endolysosomes and cross the basolateral membranes
TmGluc ≅ 375 mg/min
of the tubular cells by facilitated diffusion. This endocytic
200
Splay mechanism has a very high capacity, which is not normally
exceeded in health.
0 Threshold
UREA
0 200 400 600 800 Urea is passively reabsorbed in the proximal tubules,
Plasma glucose concentration (mg/dL) depending on tubular flow rate. Increased tubular flow,
Figure 2-11 Glucose titration curve showing filtration, as occurs during diuresis, is the result of decreased reab-
reabsorption, and urinary excretion of glucose at increasing plasma sorption of water from the tubular fluid. This decreases
glucose concentrations. TmGluc refers to the maximal amount of the tubular fluid urea concentration and decreases the
glucose that can be transported per minute. (Drawing by Tim Vojt.) concentration gradient of urea across the tubular
epithelium. Thus, less urea is reabsorbed at higher tubu- medullary interstitium via UT-A1 and UT-A3 under the
lar flow rates. With decreased tubular flow, as occurs dur- influence of ADH. Reabsorbed urea enters the ascending
ing dehydration, there is increased reabsorption of water (venous) vasa recta and then is transferred to the
from the tubular fluid. This increases the concentration descending (arterial) vasa recta, which express UT-B.
gradient of urea across the tubular epithelium and This recycling of urea prevents the osmotic diuresis that
increases passive urea reabsorption. In dehydrated would occur if this urea load were excreted in the urine.
patients, increased reabsorption of urea may lead to an Knockout mice lacking UT-A2 do not have a reduc-
increase in blood urea nitrogen (BUN) even before tion in medullary urea concentration or decreased urinary
GFR is decreased. This contributes to the observation concentrating ability when fed a normal protein
that the BUN/creatinine ratio tends to be higher in diet, whereas knockout mice lacking UT-B do have
patients with prerenal azotemia than in hydrated patients decreased medullary urea concentration, as well as
with primary renal azotemia. decreased urinary concentrating ability and higher
The renal handling of urea plays an important role in BUN concentrations.15 These results suggest that coun-
the urinary concentrating mechanism (see role of urea tercurrent exchange of urea between the ascending
in The Urinary Concentrating Mechanism section). (venous) vasa recta and descending (arterial) vasa recta
Discovery of facilitated urea transporters (UT-A and is more important for urea trapping in the inner medulla
UT-B) in the kidneys has enhanced understanding of urea than is transfer of urea to the thin descending limbs of
recycling and called into question the “passive model” of Henle’s loop.
urinary concentration.15,49,54 Vasopressin (ADH)-
responsive urea transporters UT-A1 and UT-A3 in the THE URINARY
inner medullary collecting duct facilitate urea reabsorp- CONCENTRATING
tion and concentration in the interstitium, where it theo-
retically serves as a stimulus for passive NaCl reabsorption
MECHANISM
from the thin ascending limb of Henle’s loop. According Urinary concentration is a function of the juxtamedullary
to the “passive model” of urinary concentration,30,48 nephrons with long loops of Henle that penetrate deep
knockout mice lacking UT-A1 and UT-A3 should have into the renal medulla. There are two main steps in this
impaired ability to concentrate NaCl in the inner process. First, transport of sodium chloride without water
medulla, but this does not appear to be true. Such mice from the ascending limb of Henle’s loop renders the
have lower urea but not lower NaCl concentrations in medullary interstitium hyperosmotic. Second, vasopres-
the inner medullary interstitium, a finding inconsistent sin (ADH) increases the water permeability of the
with the “passive model.15” collecting duct, and tubular fluid traversing this segment
Urea reabsorbed from the inner medullary collecting of the nephron equilibrates osmotically with the
duct via AT-A1 and AT-A3 can reenter the thin hyperosmotic interstitium.
descending limb of Henle’s loop via UT-A2 and be car- Strikingly different transport properties of various
ried back to the collecting duct. This urea is concentrated portions of the nephron form the basis for understanding
in the collecting ducts as water is reabsorbed, setting the the urinary concentrating mechanism (Table 2-2). The
stage for urea to be reabsorbed again back into the inner hairpin configuration of Henle’s loop is the anatomic
TABLE 2-2 Differential Permeability Characteristics of Nephron Segments

Portion of Nephron NaCl Urea Water (ADH) Water (No ADH)
Descending limb of Henle’s loop* Passive Passive{ Passive Passive
Thin ascending limb of Henle’s loop* Passive Passive{ 0 0
Thick ascending limb of Henle’s loop Active 0 0 0
Distal convoluted tubule Active 0 0 0
Cortical collecting duct Active{ 0 Passive 0
Outer medullary collecting duct 0 0 Passive 0
Inner medullary collecting duct Active Passive Passive} 0
Modified from Rose BD. Clinical physiology of acid-base and electrolyte disorders. New York: McGraw-Hill, 1994: 112, with permission of the McGraw-Hill
Companies.
*Permeability to NaCl exceeds permeability to urea in these segments.
{
Passive reabsorption in these segments is facilitated by presence of urea transporters (UT-A2) and constitutes urea recycling.
{
Responsive to aldosterone.
}
Permeable to urea in the basal state and permeability increased by ADH-responsive urea transporters (UT-A1, UT-A3, and possibly UT-A4).
basis for countercurrent multiplication and allows a single given level. This is the countercurrent multiplier concept
osmotic effect to be multiplied over the length of the of urinary concentration.
loop. The vessels accompanying the loops of Henle into
the medulla are called vasa recta. They prevent dissipation ROLES OF THE COLLECTING DUCTS
of the medullary osmotic gradient by a process called coun- AND ANTIDIURETIC HORMONE
tercurrent exchange (see Role of the Vasa Recta section). The collecting duct is divided into three segments: the
The countercurrent multiplier concept was first applied cortical collecting duct, outer medullary collecting duct,
to urine concentration by W. Kuhn, a physical chemist, and inner medullary collecting duct. These segments dif-
in 1942.2,25 As early as 1909, however, K. Peter had noted fer in their permeability to sodium and urea (see
a correlation between the length of Henle’s loop and Table 2-2). The main role of the cortical collecting duct
the ability of a given species to concentrate its urine. is delivery of fluid with a very high urea concentration to
the outer medullary collecting duct. This occurs because
ROLE OF THE ASCENDING LIMB OF sodium chloride and water are removed from this seg-
HENLE’S LOOP ment of the nephron, but urea is not. The main functions
The ascending limb of Henle’s loop is impermeable to of the inner medullary collecting duct are to add urea to
water. Sodium chloride is actively transported from the the inner medullary interstitium and to produce maxi-
thick portion of the ascending limb without mally concentrated urine by osmotic equilibration of
accompanying water so that an osmotic gradient of tubular fluid with the hyperosmotic interstitium under
approximately 200 mOsm/kg is generated. This active the influence of ADH.9,29 This segment of the nephron
transport of sodium chloride is the primary energy- is permeable to urea, and its urea permeability is increased
requiring step of the urinary concentrating mechanism. by ADH (see previous section on urea).
Active sodium transport is accomplished by the Naþ, As just described, fluid entering the distal tubule is
þ
K -ATPase located in the basolateral membranes of the hypoosmotic to plasma (approximately 100 mOsm/kg).
tubular cells. This enzyme maintains a low intracellular Without the collecting duct, the so-called countercurrent
concentration of sodium and promotes passive entry of multiplier would dilute tubular fluid. In the presence of
sodium at the luminal membrane down a concentration ADH, this hypoosmotic fluid equilibrates osmotically
gradient. The luminal Naþ, Kþ, 2Cl- carrier (NKCC2) with the cortical interstitium (osmolality, 300 mOsm/
binds one sodium ion, one potassium ion, and two chlo- kg) as the tubular fluid flows through the cortical
ride ions.37 Chloride delivery is the rate-limiting step in collecting duct. By this process, approximately two thirds
this transport process, and loop diuretics such as furose- of the tubular water is removed before delivery to the
mide impair distal sodium reabsorption by competing medullary collecting duct. For example, 100 mOsm of
with chloride for the luminal carrier.37 solute in 1 L of tubular fluid is reduced to 100 mOsm
Fluid reaching the distal convoluted tubule is of solute in 0.33 L of tubular fluid (300 mOsm/kg) with
hypoosmotic (100 mOsm/kg) compared with the fluid 0.67 L of water reabsorbed. Even more water can be
entering the descending limb of Henle’s loop (300 reabsorbed, depending on how much active sodium reab-
mOsm/kg). If fluid in the loops were stationary, the sorption occurs in the cortical collecting duct in response
active transport of sodium chloride out of the thick to aldosterone stimulation. These effects markedly reduce
ascending limb without water would increase the intersti- fluid delivery to the medullary collecting duct. Tubular
tial osmolality to 400 mOsm/kg and decrease the osmo- fluid entering the medullary collecting duct is thus isos-
lality of the fluid within the ascending limb to 200 motic with plasma but much reduced in volume. It is in
mOsm/kg. The descending limb of Henle’s loop is the medullary collecting duct that the final concentration
highly permeable to water, and water would be extracted of urine occurs.
from this site, increasing the osmolality of the tubular The water permeability of the epithelium of the
fluid in this segment of the nephron to 400 mOsm/kg. collecting duct is dependent on the action of ADH. In
However, the fluid within Henle’s loops is not the presence of ADH, water is removed from the
stationary. New tubular fluid with an osmolality of 300 collecting duct as the fluid osmotically equilibrates with
mOsm/kg is constantly entering the descending limb a progressively hyperosmotic medullary interstitium,
of Henle’s loop from the proximal tubule. As fluid and the final osmolality of the urine may approximate that
continues to move through the loops and an osmotic gra- of the papillary interstitium. In humans, this maximal
dient of 200 mOsm/kg is generated, this single osmotic urine osmolality is 900 to 1400 mOsm/kg.44 In dogs
effect is multiplied over the length of Henle’s loop and cats, however, urine osmolality can approach 2800
(Fig. 2-12). The magnitude of the gradient from the and 3000 mOsm/kg, respectively.24,45 Water reabsorp-
beginning of the loop to its hairpin turn is a function tion in the distal convoluted tubule and connecting
of the length of the loop itself. Thus, the vertical osmotic tubule is minimal because of their relative impermeability
gradient greatly exceeds the horizontal gradient at any to water, regardless of the presence or absence of ADH.
Descending
Interstitium
Ascending
thick limb
thin limb
300 300 300 400 400 200 300 300 200 350 350 150
300 300 300 400 400 200 300 300 200 350 350 150
300 300 300 400 400 200 300 300 200 350 350 150
300 300 300 400 400 200 300 300 300 350 350 150
300 300 300 400 400 200 400 400 400 500 500 300
300 300 300 400 400 200 400 400 400 500 500 300
300 300 300 400 400 200 400 400 400 500 500 300
300 300 300 400 400 200 400 400 400 500 500 300
1 2 3 4
300 300 150 325 325 125 300 300 125 312 312 112
300 300 150 325 325 125 325 325 225 375 375 175
350 350 300 425 425 225 325 325 225 375 375 175
350 350 300 425 425 225 425 425 225 425 425 225
350 350 300 425 425 225 425 425 225 425 425 225
350 350 300 425 425 225 425 425 400 513 513 313
550 500 500 600 600 400 425 425 400 513 513 313
500 500 500 600 600 400 600 600 600 700 700 500
5 6 7 8
Ascending
Descending
thick limb
Interstitium
thin limb
312 312 112 312 312

375 375 175 375 375
375 375 175 375 375
425 425 225 425 425
425 425 225 425 425
513 513 313 513 513
513 513 313 513 513
700 700 500 700 700
Collecting duct
Figure 2-12 Stepwise operation of the countercurrent multiplier mechanism of urinary concentration.
Numbers refer to osmolalities (mOsm per kg H2O) of tubular fluid and interstitium. (Reprinted with
permission from Valtin H. Renal function: mechanisms preserving fluid and solute balance in health, 2nd ed.
Boston: Little, Brown, 1983: 166.)
Thus, water reabsorption in the cortical collecting duct ROLE OF THE VASA RECTA
under the influence of ADH is important in reducing If the water removed from the medullary collecting duct
the fluid load delivered to the medullary collecting duct. in the presence of ADH were allowed to remain in the
In the absence of ADH, the collecting duct is imperme- medullary interstitium, the hyperosmotic gradient would
able to water. The fluid entering this portion of the neph- dissipate rapidly. However, this does not occur because of
ron has an osmolality of approximately 100 mOsm/kg. the countercurrent exchange function of the vasa recta.
Under these conditions, additional sodium chloride with- Plasma in the vasa recta entering the medulla from the
out water is removed from the tubular fluid during its cortex encounters an increasingly hyperosmotic medul-
course through the cortical collecting duct and inner med- lary interstitium. As a result, water is removed from the
ullary collecting duct so that the final urine osmolality can vessels and solutes (e.g., sodium chloride and urea) enter
be as low as 50 mOsm/kg. However, the outer medullary the vessels. After passing the hairpin turn of the loop, the
collecting duct is impermeable to sodium. vasa recta climb back toward the renal cortex. Now they
Even in the absence of ADH, urine osmolality may be encounter a medullary interstitium of progressively
greater than 50 mOsm/kg if the animal is dehydrated. decreasing osmolality so that water enters the vessels
The GFR is decreased by dehydration, and there is an and solutes are removed. In this way, water is removed
increase in the proximal tubular reabsorption of sodium from and solutes are recycled back into the medullary
chloride and water. Less tubular fluid reaches the distal interstitium, thus preventing dissipation of the osmotic
nephron, and urine osmolality can approach 400 gradient. This process is known as countercurrent
mOsm/kg.50 exchange. That the vasa recta can effectively remove water
and recycle solute may be appreciated by considering the Distal tubule

Rights were not granted to include this content in electronic media.
different flow rates in the vasa recta and medullary Please refer to the printed book.
Urea
collecting duct. Although only 5% of RPF goes to the
Cortex 2
renal medulla, this flow is much greater than the approxi- H2O
−
mately 3% of GFR that enters the medullary collecting 1
Cl
Na+ H2O 2
ducts. Consider, for example, a 10-kg dog with a GFR Outer NaCl
Urea
of 4 mL/min/kg and an RPF of 12 mL/min/kg. RPF medulla
Cl−
in the medulla would be 6 mL/min (5% of 120), and Urea
H2O Na+
tubular fluid flow in the renal medulla would be 1.2
5
mL/min (3% of 40), a fivefold difference. These factors 4 HO NaCl
2 3
contribute to the effective removal of water from the H2O
Urea
medullary interstitium and prevent dissipation of the Inner
5
osmotic gradient in this region of the kidneys. medulla NaCl NaCl NaCl Urea
Urea
ROLE OF UREA NaCl
Although there is evidence for active transport of sodium Loop of Henle
chloride from the thick ascending limb of Henle’s loop, Collecting
tubule
active transport has not been demonstrated in the thin
Figure 2-13 Role of urea in the urinary concentrating
descending and ascending limbs. A two-solute model
mechanism. (From Jamison RL, Maffy RH: The urinary
of the urinary concentrating mechanism was developed concentrating mechanism, N Engl J Med 295:1059–1067, 1976.)
simultaneously in 1972 by Stephenson and by Kokko
and Rector.26,30,48 This model requires an important
contribution by urea as the second solute. lacking UT-A1 and UT-A3 have raised questions about
The thin descending limb of Henle’s loop has a low the “passive model” of sodium chloride concentration in
passive permeability for sodium chloride and limited the inner medulla (see previous discussion).
permeability to urea (except in segments that express
UT-A2), but it is highly permeable to water. The perme-
ability of the inner medullary collecting duct to urea is ENDOCRINE FUNCTIONS OF
enhanced by ADH via UT-A1, UT-A3, and possibly THE KIDNEYS
UT-A4. The distal convoluted tubule, cortical collecting
The kidneys are responsible for endocrine functions that
duct, and outer medullary collecting duct are relatively
play essential roles in the regulation of red cell production
impermeable to urea, even in the presence of ADH.
by the bone marrow, defense of the extracellular fluid vol-
Thus, the urea concentration of tubular fluid increases
ume (ECFV), and maintenance of calcium homeostasis.
markedly in this portion of the nephron.
Gradual loss of these endocrine functions occurs during
During a state of water conservation (i.e., antidiuresis),
the progression of chronic renal disease and contributes
the plasma ADH concentration is high. More urea is
to specific manifestations of the uremic syndrome, such
removed from the inner medullary collecting duct and
as nonregenerative anemia, systemic hypertension, and
enters the medullary interstitium. In dogs, urea
renal secondary hyperparathyroidism.
constitutes more than 40% of the total medullary solute
concentration during antidiuresis (after 24 hours of water
deprivation) but less than 10% during water diuresis.8,33 ERYTHROPOIETIN PRODUCTION
Urea increases medullary interstitial osmolality with- Erythropoietin (EPO) is a glycoprotein hormone with a
out a change in the sodium concentration in this region. molecular mass of 35,000 Da that stimulates red blood cell
Thus, water is removed osmotically from the thin production by the bone marrow. In the fetus, EPO is pro-
descending limb of Henle’s loop by the high concentra- duced in the liver, but shortly after birth production
tion of urea in the medullary interstitium. The sodium switches to the kidneys, which become the major source
concentration of the tubular fluid in the descending of EPO in the adult animal. Decreased oxygen delivery to
limb of Henle’s loop eventually exceeds the medullary the kidneys is the major stimulus for EPO production. An
interstitial sodium concentration because the thin oxygen sensor (thought to be a heme protein) detects
descending limb of Henle’s loop has a low permeability decreased oxygen tension and activates transcriptional
for sodium. The sodium permeability of the thin ascend- factors that increase transcription of the EPO gene.
ing limb of Henle’s loop is high, and as the tubular Peritubular interstitial fibroblasts in the renal cortex and
fluid rounds the hairpin turn and enters this portion outer medulla are the primary site of EPO synthesis in the
of the nephron, sodium can be removed passively into kidneys.35 EPO binds to receptors on erythroid progenitor
the medullary interstitium down a concentration gradi- cells in the bone marrow preventing apoptosis, and allows
ent (Fig. 2-13). Recent findings in knockout mice them to proliferate and differentiate into reticulocytes.13,23
Absolute or relative deficiency of EPO is the primary chloride to the macula densa, which inhibits renin release.
cause of the anemia of chronic renal failure.28 Recombi- The release of renin is inhibited by a direct effect of angio-
nant human EPO has been used successfully to correct tensin II on the granular cells, which constitutes a nega-
the anemia of chronic renal failure in human patients.14 tive feedback loop.
Although initially effective in correcting the anemia of Renin converts the a2-globulin angiotensinogen
renal failure in dogs and cats, use of recombinant human (which is synthesized and released by the liver) to angio-
EPO is associated with antibody formation in up to 50% tensin I, and this is the rate-limiting step of the RAS cas-
of treated dogs and cats after 1 to 3 months of treat- cade. Angiotensin-converting enzyme is found in vascular
ment.11 The resulting anemia can be more severe than endothelium and cleaves the carboxyl-terminal (C-termi-
that present before treatment because the induced nal) two amino acids from the inactive decapeptide angio-
antibodies can cross-react with the animal’s native tensin I to yield the active octapeptide angiotensin II.
EPO. The canine EPO gene has been isolated,34 and This step in the RAS cascade is not rate limiting, and most
recombinant canine EPO has been used to stimulate of the angiotensin I is rapidly converted to angiotensin II.
erythropoiesis in normal dogs42 and in those with natu- The effects of angiotensin II restore ECFV. Angiotensin
rally occurring chronic renal failure.41 It is not as effective II causes arteriolar vasoconstriction in many organs (renal,
when used in dogs that have developed red cell aplasia splanchnic, and cutaneous vascular beds are most sensi-
from previous treatment with recombinant human tive), which increases systemic blood pressure. It enhances
EPO. Recombinant feline EPO also has been synthesized the sensitivity of vascular smooth muscle to and facilitates
and used effectively to treat cats with anemia of chronic the release of norepinephrine from the adrenal medulla
renal failure.40 Unexpectedly, some cats that initially and sympathetic nerve terminals, thus secondarily affecting
responded to recombinant feline EPO later developed systemic blood pressure. Angiotensin II causes increased
anemia that was refractory to additional treatment with proximal tubular reabsorption of sodium by stimulating
recombinant feline EPO. the Naþ-Hþ antiporter in luminal membranes of proximal
tubular cells. It causes increased secretion of aldosterone
RENIN-ANGIOTENSIN SYSTEM from the zona glomerulosa of the adrenal cortex, and
The main role of the renin-angiotensin system (RAS) is aldosterone in turn causes increased reabsorption of
defense of the ECFV via sodium homeostasis. The role sodium chloride in the cortical collecting duct. Lastly,
of the kidneys in maintenance of sodium balance is angiotensin II causes alterations in glomerular and
discussed further in Chapter 3. postglomerular hemodynamics that enhance sodium and
Renin is an enzyme synthesized and stored in the gran- water reabsorption. Angiotensin II causes constriction of
ular cells of the JGA (specialized smooth muscle cells in the efferent and afferent arterioles, an effect thought to
the afferent arterioles). The kidneys are the most impor- be mediated by thromboxane A2. The efferent arteriole
tant source of renin, but renin is also found in many other constricts more than the afferent so that the FF increases
tissues (e.g., vascular endothelium, adrenal gland, and (i.e., RPF decreases more than GFR). Renal hemodynamic
brain). Local production of angiotensin II in some tissues changes favoring salt and water reabsorption occur in the
may be important in the regulation of local processes postglomerular capillary beds secondary to these glomer-
without having a systemic effect. The RAS of the brain ular hemodynamic changes. These changes include
may be involved in control of systemic blood pressure, decreased peritubular capillary hydrostatic pressure and
secretion of ADH, catecholamine release, and thirst. increased peritubular capillary oncotic pressure. Angioten-
There are three major stimuli for renin release. sin II can cause glomerular mesangial cells to contract,
Decreased renal perfusion pressure caused by systemic potentially reducing the surface area for filtration and
hypotension (pressure below 80 to 90 mm Hg) or ECFV decreasing the ultrafiltration coefficient, Kf. Angiotensin
depletion is sensed in the afferent arterioles by the II stimulates release of vasodilator prostaglandins (e.g.,
granular cells, which increase their secretion of renin. PGE2 and PGI2) from glomeruli. By this mechanism,
Stimulation of cardiac and arterial baroreceptors by the potentially harmful vasoconstrictive effects of angio-
systemic hypotension leads to increased sympathetic tensin II on the kidneys are minimized.
neural activity and increased concentrations of circulating
catecholamines, which in turn stimulate renin release via ACTIVATION OF VITAMIN D
b1-adrenergic receptors on granular cells. Lastly, changes Vitamin D3 (cholecalciferol) is obtained in the diet or by
in distal tubular flow and delivery of chloride affect renin ultraviolet irradiation of the compound 7-dehydrocho-
release. Decreased ECFV or chronic NaCl depletion lesterol in the skin. The liver hydroxylates cholecalciferol
decreases distal tubular flow and delivery of chloride to to 25-hydroxycholecalciferol, which is the predominant
the macula densa (partly as a consequence of enhanced form of vitamin D3 in plasma. In the kidneys, 25-
proximal reabsorption of water and NaCl), which in turn hydroxycholecalciferol is converted to the active form of
stimulates renin release. Expansion of the ECFV or NaCl vitamin D3, 1,25-dihydroxycholecalciferol (calcitriol), by
loading increases distal tubular flow and delivery of the enzyme 25-hydroxycholecalciferol-1a-hydroxylase,
which is found in the mitochondria of the proximal tubular 12. Dunn MJ. Nonsteroidal antiinflammatory drugs and renal
cells. Calcitriol interacts with its high-affinity receptor (the function. Annu Rev Med 1984;35:411.
13. Ebert BL, Bunn HF. Regulation of the erythropoietin
vitamin D receptor [VDR]) in target tissues forming a
gene. Blood 1999;94:1864–77.
ligand-activated transcription factor that travels to the 14. Eschbach JW, Egrie J, Downing M, et al. Correction of ane-
nucleus of the cell and interacts with specific DNA mia of end-stage renal disease with recombinant human
sequences in vitamin D-responsive genes. erythropoietin. N Engl J Med 1987;316:73–8.
The activity of the 1a-hydroxylase system is closely 15. Fenton RA. Essential role of vasopressin-regulated urea
transport processes in the mammalian kidney. Pflugers Arch
regulated by PTH, calcium, phosphate, and calcitriol itself,
2009;458:169–77.
which exerts negative feedback inhibition on 1a-hydroxy- 16. Fettman MJ, Allen TA, Wilke WL, et al. Single-injection
lase. Hypocalcemia and PTH stimulate calcitriol synthesis. method for evaluation of renal function with 14C-inulin
There is an inverse relationship between calcium and 3H-tetraethylammonium bromide in dogs and cats.
concentrations and the activity of the 1a-hydroxylase Am J Vet Res 1985;46:482.
17. Finco DR. Simultaneous determination of phenolsul-
enzyme system that may arise directly or may be secondary
fonphthalein excretion and endogenous creatinine clearance
to changes in the secretion of PTH in response to alterations in the normal dog. J Am Vet Med Assoc 1971;159:336.
in serum calcium concentration. Some evidence exists to 18. Finco DR, Barsanti JA. Mechanism of urinary excretion of
support a direct suppressive effect of calcium on 1a-hydrox- creatinine by the cat. Am J Vet Res 1982;43:2207.
ylase activity in proximal tubular cells.4 The 1a-hydroxylase 19. Finco DR, Brown SA, Crowell WA, et al. Exogenous creat-
inine clearance as a measure of glomerular filtration rate in
enzyme system is stimulated by hypophosphatemia and
dogs with reduced renal mass. Am J Vet Res 1991;52:1029.
inhibited by hyperphosphatemia. 20. Finco DR, Coulter DB, Barsanti JA. Simple, accurate
The major effects of 1,25-dihydroxycholecalciferol method for clinical estimation of glomerular filtration rate
(calcitriol) are increased intestinal absorption of calcium in the dog. Am J Vet Res 1981;42:1874.
and phosphate, a permissive effect on PTH-mediated 21. Finco DR, Duncan JR. Evaluation of blood urea nitrogen
and serum creatinine concentrations as indicators of renal
bone resorption of calcium and phosphate, and negative
dysfunction: a study of 111 cases and a review of related lit-
feedback control on PTH synthesis and secretion by erature. J Am Vet Med Assoc 1976;168:593.
the parathyroid glands. The actions of vitamin D are 22. Finco DR, Tabaru H, Brown SA, et al. Endogenous creati-
discussed in more detail in Chapter 6. nine clearance measurement of glomerular filtration rate in
dogs. Am J Vet Res 1993;54:1575.
23. Fried W. Erythropoietin and erythropoiesis. Exp Hematol
2009;37:1007–15.
REFERENCES 24. Hardy RM, Osborne CA. Water deprivation test in the dog:
Maximal normal values. J Am Vet Med Assoc 1979;174:479.
1. Avison MJ, Gullans SR, Ogino T, et al. Measurement of 25. Jamison RJ. The renal concentrating mechanism. Kidney
Na-K coupling ratio of Na-K ATPase in rabbit proximal Int 1987;32(Suppl. 21):S43.
tubules. Am J Physiol 1987;253:C126. 26. Jamison RL, Maffly RH. The urinary concentrating mech-
2. Berliner RW. Mechanisms of urine concentration. Kidney anism. N Engl J Med 1976;295:1059.
Int 1982;22:202. 27. Keyes JL, Swanson RE. Dependence of glucose Tm on
3. Biber J, Hernando N, Forster I, et al. Regulation of phos- GFR and tubular volume. Am J Physiol 1971;221:1.
phate transport in proximal tubules. Pflugers Arch 28. King LG, Giger U, Diserens D, et al. Anemia of chronic
2009;458:39–52. renal failure in dogs. J Vet Intern Med 1992;6:264–70.
4. Bland R, Walker EA, Hughes SV, et al. Constitutive expres- 29. Kokko JP. The role of the collecting duct in urinary concen-
sion of 25-hydroxyvitamin D3-1 alpha-hydroxylase in a tration. Kidney Int 1987;31:606.
transformed human proximal tubule cell line: evidence 30. Kokko JP, Rector Jr FC. Countercurrent multiplication sys-
for direct regulation of vitamin D metabolism by calcium. tem without active transport in inner medulla. Kidney Int
Endocrinology 1999;140:2027–34. 1972;2:214.
5. Bovee KC, Joyce T. Clinical evaluation of glomerular func- 31. Koushanpour E, Kriz W. Renal physiology: principles,
tion: 24-hour creatinine clearance in dogs. J Am Vet Med structure, and function. New York: Springer-Verlag; 1986.
Assoc 1979;174:488. 32. Kruth SA, Cowgill LD. Renal glucose transport in the cat
6. Bröer S. Amino acid transport across mammalian intestinal (abstract). Proc Am Coll Vet Intern Med 1982;78:1982.
and renal epithelia. Physiol Rev 2008;88:249–86. 33. Levitin H, Goodman A, Pigeon G, et al. Composition of
7. Brown SA. Determinants of glomerular ultrafiltration in the renal medulla during water diuresis. J Clin Invest
cats. Am J Vet Res 1993;54:970. 1962;41:1145.
8. Bulger RE. Composition of renal medullary tissue. Kidney 34. MacLeod JN, Tetreault JW, Lorschy KAS, et al. Expression
Int 1987;31:557. and bioactivity of recombinant canine erythropoietin. Am J
9. Chandhoke PS, Saidel CM, Knepper MA. Role of inner Vet Res 1998;59:1144–8.
medullary collecting duct NaCl transport in urinary 35. Maxwell PH, Ferguson DJP, Nicholls LG, et al. Sites of
concentration. Am J Physiol 1985;249:F688. erythropoietin production. Kidney Int 1997;51:393.
10. Clive DM, Stoff JS. Renal syndromes associated with nonste- 36. Navar LG, Bell PD, Crowell WA, et al. Evaluation of the
roidal antiinflammatory drugs. N Engl J Med 1984;310:563. single nephron glomerular filtration coefficient in the
11. Cowgill LD, James KM, Levy JK, et al. Use of recombinant dog. Kidney Int 1977;12:137.
human erythropoietin for the management of anemia in 37. O’Grady SM, Palfrey HC, Field M. Characteristics and
dogs and cats with renal failure. J Am Vet Med Assoc function of Na-K-2Cl cotransport in epithelial tissues.
1998;212:521–8. Am J Physiol 1987;253:C177.
38. Osbaldiston GW, Fuhrman W. The clearance of creatinine, 46. Schnermann J, Briggs JP. Tubuloglomerular feedback:
inulin, para-aminohippurate and phenolsulfonphthalein in mechanistic insights from gene-manipulated mice. Kidney
the cat. Can J Comp Med 1970;34:138. Int 2008;74:418–26.
39. Powers TE, Powers JD, Garg RC. Study of the double iso- 47. Shannon J, Farber S, Troast L. The measurement of glucose
tope single-injection method for estimating renal function Tm in the normal dog. Am J Physiol 1941;133:752.
in purebred beagle dogs. Am J Vet Res 1977;38:1933. 48. Stephenson JL. Concentration of urine in a central core
40. Randolph JF, Scarlett JM, Stokol T, et al. Expression, bio- model of the renal counterflow system. Kidney Int
activity, and clinical assessment of recombinant feline eryth- 1972;2:85.
ropoietin. Am J Vet Res 2004;65:1355–66. 49. Tsukaguchi H, Shayakul C, Berger UV, et al. Urea
41. Randolph JF, Scarlett J, Stokol T, et al. Clinical efficacy and transporters in kidney: molecular analysis and contribution
safety of recombinant canine erythropoietin in dogs with to the urinary concentrating process. Am J Physiol
anemia of chronic renal failure and dogs with recombinant 1998;275:F319–F324.
human erythropoietin-induced red cell aplasia. J Vet Intern 50. Valtin H, Edwards BR. GFR and the concentration of urine
Med 2004;18:81–91. in the absence of vasopressin, Berliner-Davidson re-
42. Randolph JF, Stokol T, Scarlett JM, et al. Comparison of explored. Kidney Int 1987;31:634.
biological activity and safety of recombinant canine eryth- 51. Valtin H, Schafer JA. Renal function. Boston: Little, Brown
ropoietin with that of recombinant human erythropoietin and Company; 1995. p. 98.
in clinically normal dogs. Am J Vet Res 1999;60:636–42. 52. Verry F, Singer D, Ramadan T, et al. Kidney amino acid
43. Rose BD. Clinical physiology of acid-base and electrolyte transport. Pflugers Arch 2009;458:53–60.
disorders. New York: McGraw-Hill; 1994. p. 94. 53. Wright EM. Renal Naþ-glucose cotransporters. Am J
44. Rose BD. Clinical physiology of acid-base and electrolyte Physiol Renal Physiol 2001;280:F10–F18.
disorders. New York: McGraw-Hill; 1994. p. 115. 54. Yang B, Bankir L. Urea and urine concentrating ability: new
45. Ross LA, Finco DR. Relationship of selected clinical renal insights from studies in mice. Am J Physiol Renal Physiol
function tests to glomerular filtration rate and renal blood 2005;288:F881–F896.
flow in cats. Am J Vet Res 1981;42:1704.

Applied Renal Physiology

Uploaded by

Copyright:

Available Formats

Applied Renal Physiology

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Applied Renal Physiology

Uploaded by

Copyright:

Available Formats

CHAPTER • 2

Applied Renal Physiology

Connecting segment and Glomerulus Proximal tubule

Potassium reabsorption Reabsorption of almost all

Secretion of organic anions

Potassium reabsorption Reabsorption of 15-25% of

Final NaCl reabsorption Active regulation of

SNGFR ¼ Kf ½ðPGC PT Þ ðpGC pT Þ

0 Distance along glomerular capillary 100%

so its clearance can be used to estimate GFR in the steady

Cx ¼ GFR þ Tx =Px As pressure increases, flow can remain constant only if

Renal Afferent Efferent Peritubular Intrarenal Renal

Glomerular filtration rate (ml/min)

GFR 60 PAH is an estimate of RPF. When PAH is infused during

The afferent arteriolar constriction causes SNGFR to EX ¼ ðPAX PVX Þ=PAX

RPF ¼ UX V=ðPAX PVX Þ RPF ¼ UX V=ðPAX PVX Þ

cells would be all that remained behind at the efferent

and, in conjunction with PT, effectively opposes Lateral

RENAL TUBULAR FUNCTION

protein but against an electrochemical gradient. Active

600 These sites invaginate to form endosomes, which then

TABLE 2-2 Differential Permeability Characteristics of Nephron Segments

312 312 112 312 312

and recycle solute may be appreciated by considering the Distal tubule

You might also like