Block1 pgy451-renal-awayda

Awayda, 2014- PGY451
Human Physiology 451/551
 Renal Physiology-
Dr. Awayda (awayda@buffalo.edu, 242 Cary Hall)
Lecture Organization (participation encouraged)
Ask questions anytime
Time at the beginning of lectures to deal with questions
Bring your questions to class

Renal Physiology
WHAT IS THE FUNCTION OF THE KIDNEY?

Renal Physiology
Main Function:
fluid
Homeostasis

Renal Functions
Transport
• Regulation of water and inorganic ion balance
•e.g., Na+, K+, Cl-, Ca++, Mg++, H+, etc...
• Removal of waste byproducts from the blood
•e.g., urea, ammonia, creatinine, other non-nitrogenous waste
 Hormonal
•Renin
•1,25-dihydroxyvitamin D3
•Gluconeogenesis
•Erythropoietin

Renal Functions
Transport
•e.g., Na+, Cl-, etc...
• Removal of waste byproducts from the blood
e.g., Urea, ammonia, creatinine, other non-nitrogenous waste
Urea
proteins® amino acids ®NH2 removed ®ammonia, liver converts to
urea
Uric acid
nucleic acid catabolism
Creatinine
creatine phosphate catabolism
Hormonal
• Renin
• 1,25-dihydroxyvitamin D3
• Gluconeogenesis

Renal Functions
Transport
•e.g., Na+, Cl-, etc...
FLUID HOMEOSTASIS

Hypertension Treatment
Diuretics
ACE/AngII inhibitors
ARB
Adrenergic Blockers
Vasodilators
C.O.= S.V. x H.R. (FLUID HOMEOSTASIS)
Increase: UNa.V, and/or Uv

Body Fluid Compartments
Intracellular
•ICF
Extracellular
•ECF
•Plasma
•Interstitial
•Other Fluids
DP
®
®

Distribution of Body Water
In a typical 70 Kg (156 lbs) individual:
Approximately 60% (40L) of body weight is water!
1/3 of this is extracellular (ECF)
2/3 of this is intracellular (ICF)

Fluid Compartments
Human Anatomy and Physiology 6th edition, E. Marieb
VERY
STABLE

Specific Fluid Composition
Total Body Volumes
(mEq) Plasma Interstitial Intracellular
Na+ 135-145 135-145 10-30
Cl- 95-105 95-105 10-20
K+ 3-5 3-5 120-145
Ca++ 1-2 1-2 0.0001
Protein 10-20 <1 50
Osmolarity 295 295 295

Electrolyte Composition
Modified from: Human Anatomy and Physiology 6th edition, E. Marieb
 Reversed Na+
& K+
Concentrations
Very low
intracellular
Ca++
ISOTONIC
®
®
®
®

Organ Systems Affecting Body Fluid Composition
Respiratory
GI tract
Integument
Renal
SKIN

Reliance on Circulation and Driving Forces
All are Epithelia
All Limited by
Diffusion
Distance Diffusion Time Significance
100 Ang 0.0000001 S Cell membrane thickness
1 micron 0.001 sec Size of most bacteria or
mitochondria
10 microns 0.1 sec Diameter of small
eukaryotic cells
100 microns 10 sec Diameter of large eukaryotic
cells
250 microns 1 min Radius of giant squid axon
2 millimeters 1 hr
Thickness of frog sartorius
muscle,
half thickness of lens of eye
5 millimeters 7 hr Radius of mature ovarian
follicle
2 centimeters 5 days Thickness of ventricular
myocardium
10 Cent 120 days Diameter of sea urchins &
other small animals
1 meter 32 yrs Half height of human
Data from Robert Macey. Mathematical models of membrane transport
processes. In: Membrane Physiology, edited by Thomas Andreoli, Joseph
Hoffman & Darrell Fanestil. NY: Plenum, 1980, p. 125-146.

Renal Daily Filtration Excretion and Resorption
Substance Filtered Excreted Resorbed (% Resorbed)
Water(L) 180 1.5 178.5 99.2
Na+(mEq) 25,200 150 25,050 99.4
K+(mEq) 720 100 620 86.1
Ca++(mEq) 540 10 530 98.2
HCO-(mEq) 4,320 2 4,318 3
>99.9
Cl-(mEq) 18,000 150 17,850 99.2
Glucose(mM) 800 0 800 ~100
Urea(g) 56 28 28 50
Osmolarity <295 50-1000
Adapted from: Principals of Physiology, Berne and Levy

Anatomy of the Kidney
Anatomical
differences
underlie
physiological
& functional
differences
Cortical,
Medullary, &
Pyramidal
regions
Basic unit
“Nephron”
Varying
depth of
Nephrons

Localization of Nephrons
From: http://www.biocourse.com/bcc/assets/

Layout of Individual Nephrons
Modified from: Medical Physiology, Boron and Boulpaep
~ 106 Nephrons
per Kidney

Renal Flow
~ 1/4th of C.O
(1200 ml/min)
flows through
the kidneys.
Arterial flow
into, and venous
flow out of the
kidneys follow
similar paths
Concentration * Flow = Amount

GFR
Normal GFR
Men 125 ± 15 ml/min/1.73 m2
Women 110 ± 15 ml/min/1.73 m2
GFR decreases 1% per year above 40
Diurnal variance in GFR- afternoon, ¯ night
GFR ¯ with exercise
GFR affected by diet- with high protein diet
Renal Reserve- ~½ of normal GFR

GFR
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm

Filtration Across the Renal Corpuscle
Glomerular Barrier (endothelial cells)
 Basal Lamina (acellular-mesangial origin)
 Bowman’s Capsule (epithelial cells)

Podocytes and Fenestrated Endothelium

Other Features at the Renal Corpuscle
Note the Mesangial
cells
Note the JGA
Note the MD Cells

Size and Charge
Fenestrated Endothelium
70-90 nm pores exclude
blood cells
Basement membrane
proteoglycan gel, -ve
charge excludes
molecules > 8nm (<
0.03% of plasma
proteins enter, <10Kda)
Filtration slits
pedicels on podocytes
with negatively charged
filtration slits, allow
particles < 3nm to pass
Selective Filtration
Modified From: Human Anatomy and Physiology 6th edition, E. Marieb

Charge and Size Exclusion
From: Koushanpour and Kriz, Renal
Physiology
Neutral
Charged

Forces Affecting Filtration- Pressure
Hydrostatic
Glomerular
Tubular
Osmotic/Oncotic
Plasma
Tubular
DP Leads to a
GFR » 180L/day
(~ 1% is excreted)

Forces Affecting Filtration
GFR = DP. (Kp . A)/X
Where DP is the net of all hydrostatic and oncotic
pressures, Kp is filtration coefficient, A is area and
X is corpuscle thickness
•GFR is affected by changes in any of these
parameters and averages ~ 125 ml/min
•Filtration Fraction ~ 0.2

OSMOLARITY
A discussion of osmolarity Jacobus van 't Hoff
Nobel Prize for Chemistry (1901)
the concentration of an osmotic solution
especially when measured in osmoles or
milliosmoles per liter of solution-
Meriam-Webster dictionary online
Is it useful?

What is Osmolarity?
 Osmolarity is a colligative property of solution
depends on the number of particles in solution
e.g., glucose, NaCl, CaCl2
 Osmotic solutions separated by a semi-permeable
membrane (water) develop an osmotic pressure.
“Effective Osmolarity”, “Reflection Coefficient”, “Tonicity”
 Pressure difference depends on and is due to the movement
of water from high to low water chemical activity

Osmotic Pressure
Develops due to water
movement
~ 22.4 atm/Osm
170 mmHg/10 mOsm
(max)

Osmotic Regulation Between Fluid Compartments

Diseases Affecting GFR and Filtration
What are the symptoms of glomerular disease?
•proteinuria: large amounts of protein in the urine
•hematuria: blood in the urine
•reduced glomerular filtration rate: inefficient filtering of wastes from the blood
•hypoproteinemia: low blood protein
•edema: swelling in parts of the body

Hydrostatic Pressures Across the Renal Vasculature
Factors influencing
hydrostatic pressure
Resistance
Resistance
Resistance
Proportional to r4
Poiseuille’s Equation
(Conductance, 1/R)
g = (p.r4)
8n.l
from: Medical Physiology, Boron and Boulpaep

Control of GFR
Three mechanisms control the GFR:
A) Renal autoregulation (intrinsic system)
B) Hormonal/Paracrine mechanisms
(Renin, Angiotensin II, Prostaglandins, ANP)
C) Neural controls (autonomic)
Major effect of all is on Vessel Resistance, some
effect on permeability

Hydrostatic Regulation of GFR
A) Autoregulation
Myogenic
1)Stretch
2)Nonlinear R
(24=16)
B) Hormonal
1)TGF
(Tubuloglomerular Feedback)
Mediated by JGA
(Jugxtaglomerular Apparatus)
2)RAS
Renin-Angiotensin system &
other hormones
C) Autonomic

Mechanical Forces Affecting Filtration
Autoregulatory
Changes
Increased C.O., Volume expansion 150 90 →70 15 →25
Decreased C.O., Volume contraction 65 40 → 50 25 → 15

TGF/JGA
Mesangial
cells
Distal Tubule
Macula densa
Sensor cells for Na+/Cl- or
flow. (Osmotic sensor),
affect afferent arteriole
resistance
Juxtaglomerular cells
Respond to decrease in AA
pressure and to MD cells
by vasoconstriction and by
release of Renin
Renin
Produced by JG cells leads
to activation of the RAS
Very potent
vasoconstrictor

TGF/JGA- Autoregulation
TGF responds to
changes of Na+ and Cl-loads
by altering
Afferent arteriole
diameter.
Occurs through local
“paracrine” mediators
such as:
adenosine and NO
Increased [Na+] or [Cl-]
causes a decrease of
GFR
high protein
diet, volume
expansion
AngII

TGF/JGA- Autoregulation
NKCC2- senses Na, K,
Cl or osmolarity
Increased electrolytes or
decreased osmolarity
causes a decrease of
GFR
News Physiol Sci 18: 169-174, 2003

RAS- Hormonal Regulation
efferent arterioles
AngiotensinII
a) Vascular-
Vasoconstrictor
(afferent and
efferent), and
mesangial cells
b) Transport- Direct
Epithelial Indirect,
Aldosterone
c) Other- Increase
sympathetic activity,
& thirst. Enhance
TGF response,
decrease Kf
Decreased
Flow and
pressure in
the afferent
arteriole
Decreased
Na, K, Cl in
MD cells
From: http://www.biocourse.com/bcc/assets/

Other Hormones (ANP)
Atrial Natriuretic Peptide
 Reduces blood pressure and blood volume by inhibiting:
 Events that promote vasoconstriction
Na+ and water retention
 Is released in the heart atria as a response to stretch (elevated
blood pressure)
 Has potent diuretic and natriuretic effects
 Promotes excretion of sodium and water
 Inhibits angiotensin II production

Diagram of the Actions of ANP

Autonomic Regulation of GFR
ANS-Sympathetic Effects (anti-diuresis, decrease GFR):
a) Arteriole vasoconstriction
b) JG cell stimulation- renin
ANS-Sympathetic Regulators:
a) Exercise- moderate to strenuous
b) Shock as in hemorrhage
c) Baroreceptors. Report on blood volume/pressure
Under most conditions baseline conditions sympathetic
influence is minimal- allows highest degree of control, why??

Reabsorption & Secretion Along the Nephron
Balance of
osmotic and
hydrostatic
forces (Starling)
dictate filtration
or re-absorption
through out the
nephron

Only Small Amounts are Excreted
Most of the fluid
entering the kidney
is reabsorbed
~99% GFR
Amount excreted = Amount filtered
-Amount reabsorbed
+Amount secreted
Law of mass balance:

Renal Oxygen Consumption
Region or
Organ
O2 Delivery
ml/min/100 g
Blood Flow
Rate
ml/min/100 g
O2
Consumption
ml/min/100 g
O2
Consumption/
O2 Delivery
(%)
Hepatoportal 11.6 58 2.2 18
Kidney 84.0 420 6.8 8
Renal outer
medulla 7.6 190 6.9 79
Brain 10.8 54 3.7 34
Skin 2.6 13 0.38 15
Skeletal
muscle 0.5 2.7 0.18 34
Heart 16.8 87 11.0 65

Amount excreted = Amount filtered - Amount reabsorbed +
Mass Action
Law of mass balance:
Amount secreted
For any substance X which enters the nephron
Amount Filtered = GFR . Px
Amount excreted = UV. Ux
Difference of those two is: Secreted and reabsorbed

Clearance
1. Is the equivalent volume of plasma that is cleared of a
substance “X” in a given time (virtual volume)
2. Provides a quantitative means of evaluating renal function
with respect to a specific substance “X”. Thus clearance:
a) is always solute specific, e.g., clearance of urea
b) Is expressed in flow units, e.g., volume/time
c) When compared to a standard, provides an index of absorption
or secretion of “X”, e.g., when compared to creatinine or PAH

Calculating Clearance
U = concentration of X in urine
V = volume of urine (ml/min)
P = concentration of X in plasma
Ux V
Px
Cx

= = x Clearance
Example Na+
UNa= 300 mM
PNa= 150 mM
V = 5 ml/min

Measuring GFR Using Clearance
Inulin or Creatinine = filtered but not
reabsorbed or secreted
i.e., all of the plasma that is filtered is
cleared of inulin
= Inulin V = = 
GFR 125 ml/min
U
P
Inulin
Inulin C

Measuring RPF Using Clearance
PAH = Para-aminohippuric acid filtered
and secreted but not reabsorbed
i.e., all of the plasma entering the
kidney is cleared of PAH
= U
V 
PAH = = Awayda, 2014- PGY451
RPF 600 ml/min
P
PAH
PAH C

Free Water Clearance
Used to assess renal function
CH2O reflects the ability of the kidneys to excrete dilute or
concentrated urine
Is defined as “the amount of distilled water that must
be subtracted from or added to urine to make that
urine isosmotic to plasma (~ 295 mOsm)”
CH2O > 0 indicates hyposmotic urine
CH2O < 0 indicates hyperosmotic urine

Free Water Clearance
H O Osm C = V - C
2
Where COsm is Osmolar clearance and is:
, ml/min
)
Osm V
Osm
(1 U
Osm
P
Osm
U
P
= Osm C
2 = V -
H O C

Examples of Renal Disease
Perfusion/Filtration related Diseases:
Volume Expansion
Volume Contraction
Renal Artery Stenosis
End Stage Renal Disease

Volume Expansion
GFR may increase
after a large
increase of RFP-but
in either case,
this leads to a
decrease of FF
ß Renin, and ANGII

Volume Contraction-ANGII

Stenosis
“Renal” baroreceptors – JG cells
afferent arteriole detect ß BP
 Constriction or stenosis or
narrowing of renal artery due
to atherosclerosis
 Stenosis of preglomerular
arteries or arterioles by
fibrosis
 Produces renal hypertension
due to Ý renin, Ý AngII
Renal angiogram
Magnetic resonance
angiography
Modified from Harrison-Bernard, the APS

>90
Normal or increased GFR—
people at increased risk or with
early renal damage
Early renal insufficiency- nearly 60-89
invisible
Moderate renal failure (chronic 30-59
renal failure)
Severe renal failure (pre-end 15-29
stage renal disease)
1
2
3
4
Stages of Renal Dysfunction
5 End stage renal disease (uremia) <15

ESRD
End Stage Renal Disease STAGE 5 (Rise in Creatinine
as a Marker and decrease GFR to <15% of normal).
Many Causes of ESRD, (Renal, Pre-renal, and
Post-renal). Symptoms of later stages:
Dissipation of hydrostatic forces
Dissipation of osmotic forces
Marked decrease of GFR
Toxic levels of plasma urea

Many Causes of Chronic Renal Failure
GFR<30ml/min
Most common causes are:
Diabetes and Hypertension
WHY?
From: Merck Manual of Diagnosis and Therapy

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