Regulation of Renal Hemodynamics

and GFR

L. Gabriel Navar, Ph.D.

Department of Physiology
Hypertension and
Renal Center of Excellence
Tulane University Medical School
New Orleans, LA

Performance Objectives
1. Define and calculate the renal fraction of the cardiac output and the factors that influence it.
2. Know the average values for renal blood flow (RBF) and glomerular filtration rate (GFR) in adult humans. Compare
blood flow and oxygen consumption in kidneys to that of skeletal muscle.
3. Define and calculate the filtration fraction.
4. Identify the extrinsic and intrinsic factors that regulate renal blood flow and renal vascular resistance. Predict changes
in RBF and GFR caused by increases in sympathetic nerve activity and increases in circulating epinephrine.
5. Identify the major sites of renal vascular resistance and describe the hydrostatic pressure profile along the renal
vasculature.
6. Describe the roles of hydrostatic and colloid osmotic pressures in regulating glomerular filtration rate. Describe the
filtration barriers in the glomerular membrane. How are proteins and macromolecules restricted from passing into the
tubular fluid?
7. Given the glomerular and Bowmans space hydrostatic and colloid osmotic pressures, be able to calculate the net
filtration force for glomerular filtration. Define the glomerular filtration coefficient and explain its role in determining GFR.
8. Define the phenomenon of renal autoregulation and describe the roles of tubuloglomerular feedback mechanism and
the myogenic mechanism.
9. Predict the changes in RBF and GFR caused by increased angiotensin II levels, increased prostaglandin E2 formation,
increases in nitric oxide formation and increases in renal sympathetic nerve activity.
10. Describe the changes in tubular reabsorption associated with changes in hydrostatic and colloid osmotic pressure in
the peritubular capillaries.
11. Review and be prepared to discuss questions on p. 46.

A National Surge in Kidney Disease

Kidney disease is
a national
epidemic, affecting
about 20 million
Americans, or one
out of every nine
adults. There is a
World Kidney Day
every year. This
year, it is on Mar. 8.
The Washington Post, August 23, 2005

Kidney Disease in the United States:

Living on the Kidney Belt

Kidney Disease in African Americans Goes

Undetected Until the Latest Stages
Good cholesterol, bad cholesterol and blood
sugar levels are familiar to most African
Americans at risk, but kidney disease is off the
radar screen, a new study reports.
The rate of kidney failure for African
Americans is four times higher than among
Caucasians and one reason for this is that
they are not aware when they have earlier
stages of kidney disease, at a time treatment
could prevent the damage from progressing to
the point when dialysis or kidney transplant is
necessary. The problem appears to be
specific for kidney disease, since most African
Americans who had diabetes, hypertension, or
high cholesterol knew so.

Outline of Presentation
1. Relationship of renal physiology and hemodynamics to
previous sections on cardiovascular function and body
fluid regulation
2. Issues of clinical relevance
3. Structural functional relationships and review anatomy
and histology and overall anatomy
4. Pressure profiles along the nephrovascular unit and
glomerular and peritubular capillary dynamics
5. Restriction of macromolecular permeability and role of
charge and size selectivity
6. Intrinsic versus extrinsic mechanisms
7. Effects of sympathetic stimulation

E. H. Starling

The kidney presents in the highest degree

the phenomenon of sensibility, the power of
reacting to various stimuli in a direction
which is appropriate for the survival of the
organism; a power of adaptation which
almost gives one the idea that its component
parts must be endowed with intelligence.

Homer Smith

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.

Salt and Water Homeostasis

Intake

Skin and
Respiratory
Losses

Fecal
Loss

Urinary
Excretion

Nervous
System

Net Balance of Salt and Water

EXTRACELLULAR FLUID VOLUME

Interstitial
Fluid Volume

Blood
Volume

Hormone
Systems

Cardiac
Output

Arterial
Pressure

Plasma
Compositional
Alterations

Renal
Excretion
of Salt
and Water

Nephrovascular Unit

From Boron and Boulpaep

Magic of the Kidney

Kidneys: Arteriolar Network

Renal Fraction

Cardiac Output = 6 liters/min

Picture from: http://www.tuberose.com/Kidneys.html

Renal Blood Flow = 1.2 liters/min

Renal Fraction
1.2 L/MIN

RBF
CO

= 0.2 or 20%

6 L/MIN

Renal Blood Flow

By: Kidney Weight
Total Renal Blood Flow = 1200 ML/MIN
Weight of Both Kidneys = 300 Grams (70 kg person)

RBF =

1200
300

= 4 ML/MIN-GM

Oxygen Consumption (Per 100 ML Blood)

20 ML O2

18.6 ML O2

A-V Difference = AO2 VO2

Total Oxygen Consumption

Total RBF

O2 Consumed
100 ML Blood

1200 ML/MIN X 1.4 ML = 16.8 ML/MIN

Total Oxygen Consumption

Arterial Venous Oxygen Shunt

Between Artery and Vein

AV
Oxygen
Shunt

I Mimura & M Nangaku. Nat Rev Nephrol 6:667-678, 2010

Arterial Venous
Oxygen Shunt

I Mimura & M Nangaku. Nat Rev Nephrol 6:667-678, 2010

Distribution of Glomerular & Postglomerular Blood Flow

Preglomerular Flow
% Total

Postglomerular Flow
% Total

Renal Vascular and Tubular Network

Renal Microvasculature

Glomerular Capillary

Endothelial Fenestrations

Glomerular Podocytes

Glomerulus Between Afferent and

Efferent Arterioles

Glomerular Charge and Size Selectivity

Preventing Leakage of Proteins into Tubules
Blood

Gel

BM Bowmans
Space

Jv

From: Ohlson et al
AJP: Renal 280:F396, 2001

Effects of Charge on Glomerular Permeability

Glomerular
Membrane

PGargandTRabelink.
ACKD18:233242,2011

Passage of Macromolecules Across

Glomerular Capillaries

Hydrostatic Pressure Profile Along the Kidney

mmHg
100

PRA

80

Filtration: PG > G
PG
Reabsorption: PC < C
if < C

60
40

PC

20
Arteries

Afferent
Arteriole

RA

Glomerular
Capillaries

Efferent Peritubular
Arteriole Capillaries Veins

RE
Navar, LG, 1998

Hydrostatic Pressures

60

20

Net Hydrostatic Pressure

= 40mmHg

Colloid Osmotic Pressures

25
-31

37
Net Pressure
= -31mmHg

Effective Filtration Pressure

Hydrostatic
Colloid
Osmotic Net

40
-31
9

Effective filtration pressure = HP COP = 40 31 = 9 mmHg

Hydrostatic Pressure Profile Along the Kidney

mmHg
100

Normal Human Values

(Both kidneys)

PRA

80

Filtration
PG

60
40

RBF = 1200 ml/min

RPF = 685 ml/min
GFR = 130 ml/min
FF = GFR/RPF = 0.19
Reabsorption
PC

20
Arteries

Afferent
Arteriole

Glomerular
Capillaries

Efferent Peritubular
Arteriole Capillaries Veins

RA = PRA PG/ RBF

RE = PG PC/ RBF - GFR

RA = (100 54)/1200

RE = (54 18)/(1200 130)

Navar, LG, 1998

Glomerular and Peritubular Capillary Dynamics

Possible Mechanisms Mediating Decreases in Filtered

Load or Enhancement of Peritubular Reabsorption
Preglomerular Constriction
glomerular pressure
blood flow and GFR
peritubular and renal interstitial pressure
Preglomerular and Efferent Constriction
No change or increases in glomerular pressure
glomerular colloid osmotic pressure
Less % change in GFR than in RBF
peritubular and renal interstitial pressure
Decreases in Filtration Coefficient
in GFR
No change or slight glomerular pressure
Less change in RBF than GFR

Afferent Arteriole and Renal Corpuscle

Smooth Muscle Cell

Ca2+

Ca2+
ROC

Ca2+

VOC

R
Gs

cAMP

PLC

Ad Cy

Phosphoinositides

Ca2+

Phosphorylated
MLCK
(inactive)

cAMP

DAG + IP3

PKA

Ca2+
SR
PKC

Ca2+-Cal

Active
MLCK

Phosphorylated
MLC

Calmodulin
Myosin Light
Chain Kinase
(MLCK)

Myosin
Light Chain
(MLC)

Actin

Tension
Development

Endothelial Influences on Vascular Smooth Muscle

Smooth Muscle Cell

TXA2

EDHF
NO

EDCF

ET
PGI2
PGF2

Ang II

Endothelial Cell
Shear
Stress

Platelet
Calcium
Activating
Ionophore
Factor
(A23187)

Substance P

ACE

Bradykinin Thrombin

Vasopressin

Serotonin

ATP/ADP
TGF1
Acetylcholine
Leukotrienes

Insulin

CGRP
Histamine

Ang I

Outline of Presentation
8. Renal autoregulation
a. Myogenic and tubuloglomerular
b. Feedback mechanisms

9. Other intrinsic regulations

a. Endothelial factors
b. Renin-angiotensin system
c.

Prostaglandins

10. Presentation of clearance concepts and filtered loads

11. Measurement of GFR
12. Measurements of renal plasma flow and use of PAH
clearance
13. Examples of clearance problems
14. Assignment of Clearance Problems

Inputs and Outputs of the Kidney

Arterial Pressure

Blood Composition

Intrarenal
Mechanisms

Venous
Effluent

Change in Volume
Change in Composition
Release of Hormones

Urine

Waste Products
Excess Electrolytes
Free Water Formation

Neural Inputs

Hormonal Signalling

Lymph

Return Proteins to
Circulation
Hormones

Glomerular and Peritubular Systems

Hydrostatic Pressure
Predominates Filtration

Colloid Osmotic Pressure

Predominates Reabsorption

The Tubular Transport Processes

Control of Renal Blood Flow & Renal Vascular Resistance

Arterial
Pressure

Renal
Nerves

Art. P

Renal
Blood
Flow

RVR

Renal
Vascular
Resistance

Hormones
Plasma
Composition

Intrinsic Control Mechanisms

(autoregulation, macula densa, paracrine factors)

Smooth Muscle Cell

Ca2+

Ca2+
ROC

Ca2+

VOC

R
Gs

cAMP

PLC

Ad Cy

Phosphoinositides

Ca2+

Phosphorylated
MLCK
(inactive)

cAMP

DAG + IP3

PKA

Ca2+
SR
PKC

Ca2+-Cal

Active
MLCK

Phosphorylated
MLC

Calmodulin
Myosin Light
Chain Kinase
(MLCK)

Myosin
Light Chain
(MLC)

Actin

Tension
Development

Endothelial Influences on Vascular Smooth Muscle

Smooth Muscle Cell

TXA2

EDHF
NO

EDCF

ET
PGI2
PGF2

Ang II

Endothelial Cell
Shear
Stress

Platelet
Calcium
Activating
Ionophore
Factor
(A23187)

Substance P

ACE

Bradykinin Thrombin

Vasopressin

Serotonin

ATP/ADP
TGF1
Acetylcholine
Leukotrienes

Insulin

CGRP
Histamine

Ang I

Hormones Affecting Renal Hemodynamics

1.Vasoconstricting Hormones:
A. Epinephrine
B. Angiotensin
2.Vasodilator Hormones:
A. Prostaglandins
B. Bradykinin
C. Atrial Natriuretic Peptide

Increased Nerve Activity

Segmented Vascular
Resistance
% Control

Glomerular
Filtration Rate

Plasma Flow
% Control

Effects of Renal Nerve Stimulation

Preglomerular
Efferent

Frequency of Renal Nerve Stimulation (Hz)

Hemorrhage
Induced Renal
Nerve Activation

ANP Responses

Renal Hemodynamics

INTRINSIC

EXTRINSIC

Control Mechanism:
Autoregulation
Tubuloglomerular Feedback
Paracrine Factors
Control Mechanism:
Sympathetic Nerves
Hormones
Other

RENAL BLOOD FLOW

ml/min.g

Renal Blood Flow Versus Pressure

Normal Range

4
3
2
1
0
0

50

100

150

200

RENAL ARTERIAL PRESSURE, mmHg

Circadian Rhythms in Blood Pressure in

Normal Subjects and Hypertensive Patients
Normotensive Patients
(N=6)
Blood Pressure
(mmHg)

Time of Day (h)

Hypertensive Patients
(N=20)
Blood Pressure
(mmHg)

Time of Day (h)

RA

20
15

RE

10
5

RENAL BLOOD FLOW

ml/min.g

VASCULAR RESISTANCE
mmHg.min.g/ml

Renal Autoregulatory Responses to

Changes in RAP

5
4
3
2
1
0

0
0

50

100

150

200

RENAL ARTERIAL PRESSURE, mmHg

50

100

150

200

RENAL ARTERIAL PRESSURE, mmHg

Myogenic Responses

Po

Pi

Tension
(T)

T = (Pi - Po) R
Gain =

Tension Decline Upon Constriction

Initial Tension Increase

P . (R - Rc)
=
(Pc - P) . Rc
Flow =

P R4

Ln8

Glomerular Filtration
Rate, ml/min/g

Renal Blood Flow

ml/min/g

Pressure
mmHg

Vascular Resistance
mmHg/min/g/ml

Renal Autoregulatory Responses to

Changes in RAP

Renal Arterial Pressure (mmHg)

Micropuncture and Microperfusion

Collection or
Pressure Pipette

Wax Blocking
Pipette

Distal
Tubule

Proximal
Tubule

Perfusion
Pipette

Macula Densa Vascular Pole

Components of the Tubuloglomerular

Feedback Mechanism
Arterial
Pressure

Proximal Tubule
and Loop of Henle
Reabsorption
Plasma Colloid
Osmotic Pressure

Glomerular
Pressure and
Plasma Flow

Preglomerular
Resistance

Glomerular
Filtration
Rate

Glomerulotubular
Balance
Proximal to
Distal Tubule
Flow

Afferent Arteriole

Early Distal Tubule:

Flow Related Changes
Osm and NaCl Conc.

Macula Densa:
a) Sensor Mechanism
b) Transmitter

Intact and Interrupted TGF

Tubuloglomerular Feedback Mechanism

Wax
Collection Blocking Perfusion
Pipette
Pipette
Pipette

Macula
Densa

Proximal
Tubule

Single Nephron
GFR

Distal
Tubule

Sensitivity: Ca++ Channel Blocker

Ang II Blockade
Cytochrome P450 Blockade
NO
PGI2

Normal
Sensitivity:
Ang II
NOS Blockade
Thromboxane
HETE

Distal Nephron Delivery

Autoregulation and TGF

Hemodynamic
Inputs

Tubular
Metabolic
Function

Renal Autoregulation
Physiological:

Capability to maintain hemodynamic function in

balance with metabolic capabilities of tubules.
maintain

RBF and GFR in face of extrinsic

perturbations
alter

RBF and GFR in response to body fluid

volume and functional demands

Reserve vasodilatory capability following

pathological insults.
glomerular pressure of all nephrons to
compensate for
Kf such as in acute renal failure
and glomerulonephritis

Pathological:

hyperfiltration

in remaining nephrons after loss of

functional nephrons

Renal Actions of Arachidonic Acid Metabolites

O
CH2-O-C-R
AA-CH

Receptor

PLA2

CH2-PO4-R'

COOH

Arachidonic Acid

Lipoxygenase

Cytochrome P450

Cyclooxygenase
Epoxygenase
HPETE
Hydroxylase

PGH2
Leukotrienes

12-HETE

Prostacyclin
Synthase

EETS
20-HETE

TXA2 Synthase
Isomerases

Renal
Vasoconstriction

Renal
Vasoconstriction

PGI2

PGE2

Renal
Vasodilation

Renal
TXA2

Renal
Vasoconstriction

Vasodilation

Renal
Vasoconstriction

Renal Hemodynamic Responses to NSAIDs in

Sodium Repleted and Depleted Conditions

GFR
ml/min

Na+ Replete

Renal Plasma Flow

ml/min

Na+ Deplete

Na+ Replete

Na+ Deplete

Control

NSAID

Renin Angiotensin System

Diuretics

Angiotensinogen
Renin

NaCl
Intake

Loop
Diuretics

Arterial
Pressure

ECFV
Volume

Stress
Trauma

Angiotensin I
ACE
Angiotensin
Inhibitors
Converting
Enzyme
Angiotensin II

Macula Densa
Baroreceptors
Sympathetic Nervous
System

Angiotensinases
PGE2

Juxtaglomerular Cells
Cytosolic

Ca++

Renin
Inhibitors

Receptor
Blockers

Renin
Release

cAMP

Metabolites Receptor Binding &

Biological Actions

Juxtaglomerular Apparatus

Effects of Angiotensin II

Renal Hemodynamic Control Mechanisms

Tubuloglomerular Feedback and Autoregulation:
alters filtered load to maintain balance with metabolically determined
tubular reabsorptive processes
maintains GFR and RBF during fluctuations in arterial pressure

Renin Angiotensin System:

alters levels of hemodynamic function in accord with status of sodium
balance
stimulates sodium reabsorption
increases sensitivity of TGF mechanism
reduces RBF and GFR

Prostaglandins:
complex system with capability to activate vasoconstrictor and
vasodilator systems
partially counteract actions of Ang II

Neural and Adrenergic Systems:

integration with overall need to maintain sodium balance
responds immediately to emergency conditions