1

Recommended text:
Chapters 19 & 20 – Human Physiology, Silverthorn. Pearson (6th Ed).
Vander’s Renal Physiology, D.C.Eaton & J.P. Pooler (6th Ed). Lange
medical Books/McGraw-Hill, New York, USA. ISBN: 0-07-135728-9

Kidney structure
Renal cortex

Renal artery
Renal vein Renal medulla

Renal pelvis Renal pyramid

Ureter

Adapted from Fig 19-1; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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Kidney function
1. Maintenance of water balance in the body

2. Regulation of body fluid osmolarity and solutes

3. Maintenance of acid-base balance

4. Eliminate metabolic waste and bioactive substances

5. Endocrine gland

6. Conversion of vitamin D to its active form

7. Gluconeogenesis

4
Distal Connecting
The nephron Proximal
convoluted
convoluted
tubule
tubule Initial portion
of cortical
tubule collecting
Renal corpuscle duct

Glomerulus
+ Macula Cortical
densa Bowman’s collecting
Bowmans capsule Capsule duct
Afferent and
Glomerulus
efferent
arterioles

Two components: Straight Proximal

convoluted Ascending
tubule thick limb
i) Vascular of Henle’s
loop
Cortex ↑
ii) Tubular Medulla ↓
Descending thin
limb of Henle’s Ascending
loop thin limb Medullary
of Henle’s collecting
loop duct

Papillary
duct
Adapted from Fig 19-1; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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Cortical and juxtamedullary nephrons

1. Cortical nephron
 Two types
 ~80% of nephrons
medulla
 corpuscle originates in outer layer of cortex

2. Juxtamedullary nephron cortex

 originates deep in cortex and extends deep

into medulla
 both the ascending and descending tubules
have thick and thin components

Adapted from Fig 19-1; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

Basic nephron function

1. Glomerular filtration
afferent efferent
arteriole arteriole

80% of the plasma that

Renal enters the glomerulus is
glomerulus not filtered and leaves
corpuscle Bowmans GF through the efferent
capsule arteriole
20% of the plasma
that enters the TR
glomerulus is Peritubular
filtered TS capillary

Kidney tubule
(entire length,
uncoiled)
To venous system

Urine
excretion
Adapted from Fig 19-3; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 66h Ed. With permission

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Basic nephron function

2. Tubular Reabsorption
The selective movement of substances from the tubular lumen
back into the venous system via peritubular capillaries

2. Tubular Secretion
The selective movement of
substances in the opposite direction

NB: Substances filtered or secreted

but not reabsorbed are excreted

Adapted from Fig 19-1; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

8
Glomerular Filtration
Urine formation begins with glomerular filtration, which occurs
at the interface between the glomerulus and Bowman’s capsule

Glomerulus
Efferent
arteriole

20%
180 liters/day

60× total
plasma volume! Proximal Afferent
convoluted arteriole
tubule 900 liters of
Lumen of plasma/day
Bowman’s
capsule

Adapted from Fig s 19-6; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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Glomerular Filtration
Why is the filtrate extracellular?
Glomerular capillaries flow into Bowman’s capsule, forming a 3-
layer ‘filtration barrier’

i) a single layer of porous endothelial capillary cells

 >100 more permeable than “normal” capillaries

Pores allow most substances, except large proteins, platelets and blood
cells, to pass

ii) an acellular gelatinous glycoprotein/collagen layer termed the

glomerular basement membrane

 glycoproteins are negatively charged, thus repelling many small

plasma proteins (but not the much smaller negatively charged ions – i.e.
Cl- and HCO3-

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Glomerular Filtration
iii) a third layer of specialized endothelial tubule cells
(podocytes) that encircle the glomerular capillaries

End result: complete extracellular filtration of near protein-free

fluid that is isosmotic with the plasma

Adapted from Fig 19-5; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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Proximal
tubule
US = “urinary” (Bowman’s)
Lumen of Bowman’s space
capsule
E = epithelial foot process
End = capillary endothelium
M Pod
Cap = lumen of capillary
GBM = glomerular
basement membrane
Efferent
arteriole Pod = podocyte cell body
M = mesengial cells
Afferent
arteriole

US

GBM

End
Cap

Figure 4.1 Vander’s renal physiology

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Forces of Glomerular Filtration
Because filtration is a passive mechanical process, a force must be
present to drive the plasma through the glomerular membrane
Average
Force Effect Magnitude (mm Hg)

1. Glomerular capillary Favours filtration

blood pressure 55

2. Net plasma-colloid Opposes filtration

30
osmotic pressure

3. Bowman’s capsule Opposes filtration

hydrostatic pressure
15

Net filtration favours filtration

10
pressure

Adapted from Fig 19-6; Human Physiology, Ed Silverthorn, D.U. (2010) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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Regulation of Glomerular Filtration

The rate of filtration in any capillary is determined by:
surface area
hydraulic permeability Filtration rate = hydraulic permeability X surface area X NFP
net filtration pressure

Filtration rate = filtration coefficient (Kf) X NFP

GFR = Kf X NFP

NFP = (PGC – GC) – (PBC – BC)

GFR = Kf X (PGC – PBC – GC)

All things being equal a change in any one of these factors will
influence GFR

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Direct Major factors that tend to increase the magnitude Change

determinants of the direct determinant to GFR
of GFR

Kf ↑ Glomerular surface area (because of relaxation of

glomerular mesangial cells or podocytes)
↑

PGC 1. ↑ Renal arterial pressure

↑
2. ↓ Afferent arteriolar resistance (afferent
dilation)
3. ↑ Efferent-arteriolar resistance (efferent
constriction)

PBC ↑ Intratubular pressure (obstruction of tubule or

extrarenal urinary system)
↓
1. ↑ Systemic plasma oncotic pressure
GC ↓
2. ↓ Renal plasma flow (greater rise in GC along
length of capillary)

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 15
Estimate of forces involved in Glomerular Filtration
PGC
60

Pressure (mmHg) 50
NFP

40

30 GC

20

10
PBC

0
50% 100%
Capillary length

16

Regulation of Glomerular Filtration

Despite pronounced changes in mean arterial pressure, the
glomerular filtration rate (GFR) is generally maintained
within fairly narrow limits

250

GFR
(ml/min) 125

0
0 80 180
Mean arterial pressure

Adapted from Fig 19-6; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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A. Intrinsic Control (autoregulation)

i) the myogenic response
E.g. ’d afferent arteriole pressure induces dilation
 ’s flow and, hence, GFR

ii) tubuloglomerular feedback

 mediated by specialized
tubular (macula densa) cells in
the juxtaglomerular region of the
distal convoluted tubule (DCT)

Taken from Fig 19-7; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6h Ed. With permission

18

Efferent Endothelial
arteriole cells
Bowman’s
capsule
Smooth
muscle cells
Extra glomerular
mesengial cells Glomerular
capillaries

Podocytes and
mesengial cells
Granular cells
Distal
convoluted
Afferent
tubule
arteriole

Adapted from Fig 19-7; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

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Tubuloglomerular feedback
Efferent
Afferent
Distal Macula
Changes in GFR affect the flow rate, and hence tubule densa

[Na+] of fluids moving past the macula densa cells

E.g. ’d [Na+] stimulates the release of chemical messages

that constrict smooth muscle cells in the afferent arteriole

 ’s net filtration pressure and GFR

Net effect of autoregulation

250

GFR 125 mostly compensates

(ml/min) for changes in MAP
0
0 80 180
Mean arterial pressure (mmHg)
Adapted from Fig 19-6; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

20

Regulation of Glomerular Filtration

B. Extrinsic Control
Mediated by sympathetic nervous input to afferent arterioles
in response to changes in blood pressure

Sympathetic nerve fiber

Efferent

Afferent
Distal
tubule Macula
densa

E.g. baroreceptor reflex – ’d sympathetic activity

 afferent arteriole vasoconstriction
 overrides the autoregulatory response

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B. Extrinsic Control
In addition, sympathetic stimulation causes the podocyte
foot processes to contract
 ’s filtration slit size, ’s Kf
Glomerular capillary
Basement membrane
Podocytes

Sympathetic stimulation Filtration slits

Result:
’d GFR

Adapted from Fig 19-5; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

22

Measurement of renal function

There are key parameters that we use to determine renal
function
Urine Flow Rate – UFR is very straightforward and is based
on volume per unit time: ml.kg-1.h-1

Glomerular Filtration Rate – GFR is not so straightforward and

here we introduce the concept of renal clearance

Plasma Renal Clearance – “volume of plasma per unit time

from which all of a substance is removed”

Plasma [ ] = 1mg.dL-1
Substance is excreted into urine at a rate of 0.5mg.min-1
therefore clearance rate is 50ml.min-1

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Measurement of renal function

Calculation of GFR requires a substance that is neither
secreted or reabsorbed - INULIN (see fig 19-13)

GFR = UFR X Uin/Pin (ml.kg-1.h-1)

where Uin = urine [inulin] & Pin = plasma [inulin]

Now we have a very valuable resource in the U/Pin [ ] ratio, so

if the U/Pin [ ] ratio was 2 what would this mean?

Therefore we can calculate the % of the filtered volume of

water that is reabsorbed as:

1
1- x 100(%)
UPin

24

Measurement of renal function

We can also calculate the osmolar clearance of the urine, that
is the rate at which the osmotically active components are
cleared from the plasma
Cosm = (Uosm/Posm) X UFR (ml.kg-1.h-1)
If Uosm = Posm then Cosm = UFR
If Uosm < Posm then Cosm < UFR

Therefore additional water is required to make up urine volume –

Free water clearance

CH2O = UFR - Cosm (ml.kg-1.h-1)

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Measurement of renal function

Can a substance have a greater clearance than the maximum
GFR?
Yes – remember substances can also be secreted
Clearance of Para-amminohippuric acid (PAH) is used to
calculate renal plasma flow = 625ml.min-1 ~ 20% of cardiac
output

So we can calculate the filtration fraction

GFR (plasma inulin clearance)

filtration fraction =
Renal plasma flow (PAH clearance)

125ml.min-1
filtration fraction = = 20%
625ml.min-1

26

Measurement of renal function

– Creatinine as a practical method
While inulin measurement is the gold standard creatinine can
also be used

As an end product of skeletal muscle metabolism of creatine,

plasma [creatinine] is proportional to skeletal muscle mass

Not perfect but from a clinical perspective it is a very easy and

routine procedure for determination of GFR

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 27

Tubular Reabsorption
It is essential that most nutrients, electrolytes and fluid be
returned to the blood

Accomplished by a highly selective process which also

concentrates nitrogenous wastes and excess ions for excretion

The magnitude of tubular reabsorption is tremendous:

 >99% of the filtered H2O (178.5 liters/day)

 100% of the filtered sugar

 99.5% of the filtered salt

 50% of the filtered urea is reabsorbed on a daily basis

28

Movement of solutes across an epithelia

Lumen Tubular cell ISF Capillary

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A. Active reabsorption
With the exception of the thin descending/ascending tubules,
Na+ reabsorption is primarily accomplished via energy-
dependent Na+-K+ ATPase transport

Lumen Tubular cell ISF Capillary

Na+ Na+
Diffusion ADP ATP Active transport
K+

Na+ Na+
Diffusion

Na+ is actively pumped across the basolateral membrane into the ISF
(interstitial fluid), ’ing tubular cell [Na+] while ’ing ISF [Na+]

Adapted from Fig 19-8; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

30
A. Active reabsorption

80% of the total energy requirement of the kidneys is used

for Na+ reabsorption, indicating the importance of this process

Na+ reabsorbed to varying extents throughout the nephron:

 ~ 65% from the proximal convoluted tubule (PCT)
 ~ 25% from the ascending limb of the loop of Henle
 8 to 10% from the late DCT and cortical collecting ducts

Thus, up to 2% of the filtered Na+ can be excreted

15
 Filtered load 31

Filtered load = GFR X plasma concentration

Plasma concentration of sodium = 140mEq/L

≡ 3.206g in 1L
≡ 0.003g in 1ml

GFR = 125ml.min-1
Therefore filtered load for sodium = 125 X 0.003
= 0.4g.min-1

NB: we could excrete as much as 2% of this

≡ 0.008g.min-1
≡ 11.52g.day-1

32
Roles of Na+ reabsorption

1. In the loop of Henle, Na+/K+/2Cl- co-transport plays a critical role in the

kidney’s ability to produce urine of varying concentrations and volumes

2. Regulation of ECFV
 in the distal portion of the nephron, Na+ reabsorption is
variable and under hormonal control

i) atrial natriuretic peptide (ANP)

 secreted by atria when myocardial cells excessively
stretched (i.e. ’d plasma volume)

ii) aldosterone (released from adrenal gland)

 stimulates insertion of Na+ channels and Na+-K+ ATPase pumps in
principal cells of the late DCT and early (cortical) collecting duct

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 33

Renin-angiotensin-aldosterone control
Afferent arteriole granular cells secrete renin when:
Efferent Endothelial
arteriole cells
Bowman’s
capsule
Smooth
muscle cells
Extra glomerular
mesengial cells Glomerular
capillaries

Podocytes and
mesengial cells
Granular cells

Afferent arteriole
Taken from
Adapted from
Fig
Fig
19-9;
19-7;
Human
Human
Physiology,
Physiology,
EdEd
Silverthorn,
Silverthorn,
D.U.
D.U.
(2010)
(2013)
Pearson,
Pearson,
Benjamin
Benjamin
Cummings,
Cummings,
New
New
York, 5th6Ed.
York, th Ed.
With
With
permission
permission

34

Renin-angiotensin-aldosterone control
Afferent arteriole granular cells secrete renin when:
i) intrarenal blood pressure ’s (afferent arterial baroreceptors)
ii) [NaCl] of fluid passing by macula densa ’s
iii) sympathetic stimulation ’s (via non-renal baroreceptors)

Renin cleaves angiotensin I off the plasma protein

angiotensinogen

Angiotensin I then converted to its active form

(angiotensin II - ATII) by angiotensin-converting enzyme (ACE)

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 35

Renin-angiotensin-aldosterone control
 afferent pressure
 NaCl &  SNS

Renin

Angiotensin II
Neg
Feedback

 Vasopressin Aldosterone
 Thirst
 Arteriolar
Vasoconstriction Na+ reabsorb

 H2O reabsorption
 H2O conservation

36

Roles of Na+ reabsorption

1. In the loop of Henle, Na+/K+/2Cl- co-transport plays a
critical role in the kidney’s ability to produce urine of
varying concentrations and volumes
2. Regulation of ECFV
• Natriuretic peptides, aldosterone, angiotensin II
and vasopressin
3. Passive reabsorption or secondary active
reabsorption

18
 37

Changes in tubular fluid composition in the

proximal convoluted tubule
Cl-

1.2
Tubular fluid/plasma

Na+ and osmolarity

1.0

0.8

0.6

0.4 bicarbonate

0.2
Amino acids, glucose,
lactate, proteins

2 4 6
Distance from Bowman’s space (mm)

38
B. Passive reabsorption
i) glucose and aa’s
Co-transported from the tubular lumen with Na+ against their
[gradient] by secondary active transport
Lumen Tubular cell ISF Capillary

Na+ Na+
Diffusion ADP ATP
Active transport
K+

Diffusion
Na+ Na+

Taken from
Adapted Fig
from 19-13;
Fig 19-8;Human
HumanPhysiology,
Physiology,Ed
EdSilverthorn,
Silverthorn,D.U.
D.U.(2010)
(2013)Pearson,
Pearson,Benjamin
BenjaminCummings,
Cummings,New York,56ththEd.
NewYork, Ed.With
Withpermission
permission

19
 39

B. Passive reabsorption

i) glucose and aa’s

Co-transported from the tubular lumen with Na+ against their
[gradient] by secondary active transport, but……

Tubular cells possess a limited number of co-transport carriers

therefore transport of some solutes has a maximum limit –
tubular/transport maxima (Tm)

E.g. glucose: Tm = 375 mg/min

 125 mg/min typically filtered
} 3 ‘safety margin’
(100 mg glucose/100 ml plasma)

40

Transport maxima for glucose (TmG)

Glucose flux (mg/min)

600
Filtered load
400 Reabsorbed

200 TmG
Excreted

100 200 300 400 500

Plasma glucose (mg/dL)

E.g. glucose: Tm = 375 mg/min

 125 mg/min typically filtered
} 3 ‘safety margin’
(100 mg glucose/100 ml plasma)
Adapted from Fig 19-10; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

20
 41

42

Changes in tubular fluid composition in the

proximal convoluted tubule
Cl-

1.2
Tubular fluid/plasma

Na+ and osmolarity

1.0

0.8

0.6

0.4 bicarbonate

0.2
Amino acids, glucose,
lactate, proteins

2 4 6
Distance from Bowman’s space (mm)

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ii) Cl- reabsorption

Generally a paracellular route, following the electrical
gradient established by the active transport of Na +
Also a transcellular route via Cl-/base antiporters

Lumen Tubular cell ISF Capillary

Exception:
Thick ascending
Na+ Na+ Na+ limb (Na+/K+/2Cl-
Cl- cotransporter)

’d ‘d
[solute] [solute]
iii) H2O
Removal of solutes from the tubular lumen decreases and
increases lumen and ISFosmolarity respectively

Adapted from Fig 19-8; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

44

Changes in tubular fluid composition in the

proximal convoluted tubule
Cl-

1.2
Tubular fluid/plasma

Na+ and osmolarity

1.0

0.8

0.6

0.4 bicarbonate

0.2
Amino acids, glucose,
lactate, proteins

2 4 6
Distance from Bowman’s space (mm)

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 45

 diffusion of H2O from lumen to ISF primarily via osmosis

through H2O pores in the luminal and basolateral plasma
membranes called aquaporins
Lumen Tubular cell ISF Capillary

H2O H2O H2O

Na+ Na+ Na+ Na+

H2O ’d
‘leaky’ tight [Protein]
junctions

 in proximal tubule only, some H2O passes intercellularly

peritubular capillaries have an elevated oncotic
pressure, Which ‘pulls’ H2O out of the ISF

What happens if there is an abnormally high amount of solute

in the lumen of the proximal tubule?
Adapted from Fig 20-5; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

46

Passive reabsorption
At least 12 different aquaporin isoforms known
 6 types in kidney
In PCT and thin descending tubules, aquaporins always present
 ~ 75% of H2O is obligatorily reabsorbed via this route

Presence of a specific aquaporin (AQP2) in principal cells of late

DCT & collecting ducts regulated by vasopressin

Vasopressin binds to membrane receptors - activates the

cAMP secondary messenger system, inserts AQP2 pores into
the luminal membranes
  plasma [vasopressin] =  H2O reabsorption

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 47

Osmolarity of tubular fluid and percentage of

water remaining
25%
<1%
Osmolarity (mOsm.L-1)

1400

1200

900
Maximal
vasopressin
600
7%
300
35% 25% No vasopressin
20%

Proximal Henle’s Distal Cortical Medullary

tubule loop tubule collecting collecting
duct duct

48

Passive reabsorption
Two stimuli control vasopressin secretion from the
posterior pituitary:
a) ECF osmolarity
Osmoreceptors in the hypothalamus stimulate vasopressin
release if osmolarity rises above 280 mosm/L

b)  blood pressure and  blood volume

‘d firing of carotid and aortic baroreceptors and stretch-
sensitive receptors in the atria stimulate vasopressin release

Diabetes insipidus – failure to produce vasopressin or

inability of principal cells to respond to this hormone

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 49

Passive reabsorption
iv) urea
Solute and H2O reabsorption in the PCT create a concentration 110%
gradient for urea, 5.5
however, ‘leaky’ tight junctions in this region are only
moderately permeable to urea (~50% reabsorbed)
epithelial membrane urea transporters in the thin regions of
Henle’s loop secrete an equivalent amount back into lumen 100%
1
Tight junctions in the loop of Henle, DCT and cortical/outer
medullary collecting ducts are impermeable to urea 50%
1.2
Generally ~ ½ of this waste product is again reabsorbed by
transporters in the inner medullary collecting ducts
50%
’d [vasopressin] ’s the amount of urea reabsorbed, 25
creating a larger vertical osmotic gradient in medulla

50

Tubular Secretion
Similar process as reabsorption, but in opposite direction and
of much lower magnitude
Substances that are selectively secreted include:
i) K+ – important for normal nerve and muscle function (ECF=4mM)
 most of the filtered K+ is first reabsorbed in the PCT
(via ‘leaky’ tight junctions) and thick ascending limb
(via Na+/K+/2Cl- co-transport)

25
 51

Regulation of K+ Secretion
Only about 2% of the body’s K+ is in the ECF
 very important to regulate within a very narrow range

K+ secretion, via K+ channels in the luminal membrane of late

DCT & cortical collecting duct principal cells, is subject to
regulation
 ‘d plasma [K+] (hyperkalemia) stimulates aldosterone
release by adrenal cortical cells

Conversely, ’d [aldosterone] = ’d K+ secretion

 additional K+ may be reabsorbed (in exchange for H+) by
type A intercalated cells in the collecting duct during
hypokalemia, with little or no K+ excreted (however, pH ’s)

52

Tubular Secretion
Similar process as reabsorption, but in opposite direction and
of much lower magnitude
Substances that are selectively secreted include:
i) K+ – important for normal nerve and muscle function (ECF=4mM)
 most of the filtered K+ is first reabsorbed in the PCT
(via ‘leaky’ tight junctions) and thick ascending limb
(via Na+/K+/2Cl- co-transport)
ii) H+ ions – important for regulating acid-base balance
 ’d secretion when body fluids become too acidic
iii) waste products such as creatinine and urobilin (urochrome)
iv) foreign substances - penicillin
 ~80% secreted in 3 – 4 hrs

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 53

Regulation of H2O balance

The osmolality of body fluids is closely regulated near 300
mosm/L

 however, urine concentration can range from

80 to >1200 mosm/L
This ability depends on the presence of a vertical osmotic
gradient in the ISF of the renal medulla

2 main factors:
1) Selective permeabilities in the nephron
a) Specialised ion and water transport
b) Urea recycling

2) Vascular architecture

Adapted from Fig 20-5; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

54

Countercurrent Multiplier System

[urea] ~ 5 mosm
A 2nd countercurrent system
(vasa recta) prevents
dissolution of this gradient 50% 300
urea
This ~900 mosm/L vertical impermeable
osmotic gradient is the
result of two equally
contributing components: 1200
[urea]
50%
~ 500 msom
1) urea ‘trapping’ in the inner medulla 50%

2) operation of a countercurrent muliplier that progressively

’s lumen [solute] as tubules descend into medulla
 net result: more NaCl is reabsorbed from Henle’s
loop (~25% of total) than H2O (~10% of total)
Adapted from Fig 20-4; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

27
 Vasa recta architecture
55

Taken from Fig 19.1h; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

56

Establishment of the osmotic gradient

1. Prior to the vertical osmotic gradient being established,
[ISF] and [tubular lumen] = 300 mosm/L

2. Active transport of solutes from the thick ascending limb

lumen to ISF
 impermeable to H2O

3. Net diffusion of H2O from descending tubule into ISF

 no net movement of solutes

4. As this stepwise process continues, filtrate moving down the

descending limb becomes more concentrated, while that
moving up the ascending limb becomes more dilute

28
 57

Counter current heat exchange

Taken from Fig 20.7; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

58

Counter current exchange in the loop of Henle

1. Prior to the vertical osmotic
gradient being established,
[ISF] & [lumen] = 300 mosm/L

2. Movement of solutes out of the

ascending limb lumen creates
localized gradients H2O
cannot follow

3. Net diffusion of H2O occurs by

osmosis out of the descending
limb into the ISF until the
osmolarities of the 2 fluids
equilibrate
Na+ Active pump
K+
Cl- Impermeable
H2O to water

Taken from Fig 20.7; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

29
 59

Ascending limb of the loop of Henle

Taken from Fig 20.7; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

60

How is hyperosmotic (or hyposmotic)

urine produced?
1. Glomerulus
(almost) Protein-free filtrate exiting Bowman’s capsule is
isosmotic (300 mosm/L) with plasma

2. Proximal convoluted tubule

a) 2/3 of Na+ actively re-absorbed (Na+-K+ ATPase pump)

b) Cl-, K+ and H2O follow passively

c) low urea permeability (~ 50% reabsorbed)

Result: 2/3 of filtrate absorbed, but still ~ isosmotic with plasma

30
 61

3. Thin descending Loop of Henle (L of H)

a) no active transport of Na+
b) many AQP channels – H2O passively enters ISF
c) some urea secreted into tubular lumen

Result: filtrate becomes highly concentrated (>1200 mosm/L)

4. Thin ascending L of H
a) intercellular diffusion of Na+ and Cl- from lumen to ISF
b) H2O impermeable
c) some urea secreted into tubular lumen
Result: filtrate becomes more dilute as it ascends up tubule

62

5. Thick ascending L of H
a) Na+/K+/2Cl- cotransport from lumen to tubular cell
Lumen Tubular cell ISF
2 Cl- 2 Cl- Na+-K+ATPase
secondary Na+ Na+
Na+ Na+ K+ K+ pump
active
transport K+ K+ Cl- Cl-
K+ K+ diffusion
K+ K+ Cl- Cl-

diffusion Na+ Na+

b) paracelluar diffusion of Na+ to ISF (~50% of total)

c) impermeable to urea and H2O

Result: filtrate becomes hyposmotic (<100 mosm/L) to plasma

Taken from
Adapted from
Fig
Fig
20-10;
20-7;Human
HumanPhysiology,
Physiology,Ed
EdSilverthorn,
Silverthorn,D.U.
D.U.(2010)
(2013)Pearson,
Pearson,Benjamin
BenjaminCummings,
Cummings,New York,56ththEd.
NewYork, Ed.With
Withpermission
permission

31
 63

6. Distal convoluted tubule and collecting duct

a) Active reabsorption of Na+ (and K+ secretion) by

principal cells if aldosterone secreted
  [aldosterone] =  Na+ uptake +  K+ secretion

b) H2O reabsorption by principal cells is variable and

dependent upon vasopressin levels
  [vasopressin] =  H2O permeability =  urine volume
( [urine] )
c) impermeable to urea (becomes very [ ]’d)
 however, urea transport from inner medullary collecting
duct back into ISF helps maintain [medullary gradient]
 ‘urea cycling’

64

Summary
A) Vasopressin present
 late DCT and collecting duct permeable to H2O

300
mosm/L
cortex

medulla

small volume,
concentrated urine
Taken from
Adapted from
Fig
Fig
20-5;
20-5;
Human
Human
Physiology,
Physiology,
EdEd
Silverthorn,
Silverthorn,
D.U.
D.U.
(2010)
(2013)
Pearson,
Pearson,
Benjamin
Benjamin
Cummings,
Cummings,
New
New
York, 5th6Ed.
York, th Ed.
With
With
permission
permission

32
 65

B) Vasopressin absent
 late DCT and collecting duct impermeable to H2O

300
mosm/L
cortex

K medulla

large volume,
dilute urine

Taken from
Adapted from
Fig
Fig
20-5;
20-5;
Human
Human
Physiology,
Physiology,
EdEd
Silverthorn,
Silverthorn,
D.U.
D.U.
(2010)
(2013)
Pearson,
Pearson,
Benjamin
Benjamin
Cummings,
Cummings,
New
New
York, 5th6Ed.
York, th Ed.
With
With
permission
permission

66

Renal acid-base balance (pH homeostasis)

Metabolic reactions are highly sensitive to [H+], and thus
ECF pH is tightly regulated

i) pH < 7.35 - acidosis

ECF pH regulated by excreting H+ in the urine and by
‘reabsorbing’ HCO3- from the filtrate

ii) pH > 7.45 - alkalosis

ECF pH regulated by secreting less H+ into the filtrate
and excreting excess HCO3- in the urine

Disturbances to acid-base balance may be respiratory or

metabolic in origin

33
 67

Respiratory acidosis/alkalosis
Changes in PCO2, brought about by hypo- or hyperventilation,
cause the pH to shift
Law of mass action
’ing the [ ] of one substance involved in a reversible
reaction drives that reaction towards the opposite side
ca
CO2 + H2O  H2CO3  H+ + HCO3-

 CO2  pH
(hypoventilation)
Ca = carbonic anhydrase

If the underlying cause of the pH disturbance is of respiratory

origin, compensation can only be achieved via the kidneys

68

Metabolic acidosis/alkalosis
pH disturbances arising from acids and bases of non CO2-origin

Acidosis
 anaerobic metabolism – lactic acidosis
 diabetes mellitus – ketoacidosis
 diarrhea – HCO3- secreted into sm. intestine not reabsorbed

Alkalosis
 excessive vomiting of acidic stomach contents
 excessive ingestion of antacids (Tums, Rolaids, etc.)

If the underlying cause of the pH disturbance is of metabolic

origin, both respiratory and renal mechanisms can compensate

34
 69

Renal compensation
Under acidotic conditions, nearly all of the filtered HCO3-
(~80%) is indirectly ‘reabsorbed’ by PCT cells
Na+ HCO3-
ISF
permeable
to HCO3-
Na+ HCO -
3

H2CO3 ca H2O + CO2

Na+
H+
impermeable
to HCO3-
Na+
Tubular
HCO3- + H+ H2O + CO2
lumen
(filtered)
Adapted from Fig 20-17;
22-20; Human Physiology, Ed Silverthorn, D.U. (2013) 5th Ed. With permission
(2010) Pearson, Benjamin Cummings, New York, 6

70

Excretion of excess H+
During acidosis, both intracellular and ECF [H+] ,
with excess H+ entering the filtrate in two ways:
1. filtration through the glomeruli
  [H+] = ’d [H+] filtration = ’d excretion
2. active secretion into lumen by H+-ATPase and H+-K+ ATPase
transporters in type A intercalated cells of the collecting duct
Lumen Type A cell ISF Capillary

H2O + CO2
CO2 HCO3 + - H+ H+
ca
H+ H+ + HCO3- HCO3-
Cl- Cl-
H+ Cl--HCO3-
K+ K+ antiporter

Note: acidosis is therefore often accompanied by hyperkalemia

Adapted from Fig 20-17;
20-22a;Human
HumanPhysiology,
Physiology,Ed
EdSilverthorn,
Silverthorn,D.U.
D.U.(2013)
(2010)Pearson,
Pearson,Benjamin
BenjaminCummings,
Cummings,New York,65ththEd.
NewYork, Ed.With
Withpermission
permission

35
 71

Excretion of excess H+
However, the nephron cannot produce a urine with a pH < 4.5
 excess H+ must be buffered by other means prior to
excretion
Urinary buffers:
a) initially, excess H+ buffered by filtered phosphate
that was not reabsorbed
-
HPO42 + H+  H2PO4-

b) once phosphate buffers become saturated, tubular cells

deaminate glutamine, producing NH3 and HCO3-
NH3 + H+ = NH4+ (ammonium ion)  urine
HCO3-  blood

72

Excretion of excess HCO3 -

The transport proteins of collecting duct type B intercalated

cells have an opposite polarity to those of type A cells
 i.e. transport proteins found on the opposite side of the cell

Lumen Type B cell ISF Capillary

H2O + CO2
ca H+
Cl- Cl-  H+
HCO3- HCO3- + H+ H+
K+ K+

Hence, during alkalosis excess HCO3- is secreted while H+

is returned to the blood

Adapted from Fig 20-17; Human Physiology, Ed Silverthorn, D.U. (2013) Pearson, Benjamin Cummings, New York, 6th Ed. With permission

36
 73

Renal handling of phosphate

About 90-95% of plasma phosphate is freely filtered

75% of this is reabsorbed in the PCT with a Na symporter

which of course has an associated Tm

Therefore there is always a small amount of excess that ends

up in the primary urine

Systemic acidosis usually enhances resorption of bone

74

Renal handling of calcium

About 60% of plasma calcium is freely filtered

Most is reabsorbed in the PCT (~ 60%) and this is largely

passive and paracellular

Calcium is filtered and reabsorbed but not secreted

Therefore regulation targets GFR and reabsorption, or uptake

37