Regulation of Renal Hemodynamics and GFR

L. Gabriel Navar, Ph.D.Department of Physiology

Hypertension and Renal Center of Excellence

Tulane University Medical SchoolNew Orleans, LA

Performance Objectives1. 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 Bowman’s 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.

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.

A National Surge in Kidney Disease

The Washington Post, August 23, 2005

Kidney Disease in the United States:Living on the Kidney Belt

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.

Kidney Disease in African Americans Goes Undetected Until the Latest Stages

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

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.

E. H. Starling

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

IntakeSkin and

RespiratoryLosses

FecalLoss

UrinaryExcretion

Net Balance of Salt and Water

EXTRACELLULAR FLUID VOLUME

InterstitialFluid Volume

BloodVolume

CardiacOutput

ArterialPressure

RenalExcretion

of Saltand Water

PlasmaCompositional

Alterations

NervousSystem

HormoneSystems

+ - - -

Nephrovascular Unit

From Boron and Boulpaep

Magic of the Kidney

Kidneys: Arteriolar Network

Renal Fraction

Cardiac Output = 6 liters/min

Renal Blood Flow = 1.2 liters/min

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

Renal Fraction

RBF

CO

1.2 L/MIN

6 L/MIN

= 0.2 or 20%

Renal Blood Flow

By: Kidney Weight

Total Renal Blood Flow = 1200 ML/MIN

Weight of Both Kidneys = 300 Grams (70 kg person)

RBF = = 4 ML/MIN-GM1200300

Oxygen Consumption (Per 100 ML Blood)

20 ML O2

18.6 ML O2

A-V Difference = AO2 – VO2

Total Oxygen Consumption

Total RBF O2 Consumed100 ML Blood

X

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

Total Oxygen Consumption

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

Arterial – Venous Oxygen Shunt Between Artery and Vein

AVOxygenShunt

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

Arterial – Venous Oxygen Shunt

Distribution of Glomerular & Postglomerular Blood Flow

Postglomerular Flow% Total

Preglomerular Flow% Total

Renal Vascular and Tubular Network

Renal Microvasculature

Glomerular Capillary

Endothelial Fenestrations

Glomerular Podocytes

Glomerulus Between Afferent and Efferent Arterioles

Blood Gel BM Bowman’sSpace

Jv

From: Ohlson et alAJP: Renal 280:F396, 2001

Glomerular Charge and Size Selectivity Preventing Leakage of Proteins into Tubules

Effects of Charge on Glomerular Permeability

Glomerular Membrane

P Garg and T Rabelink.  ACKD 18:233‐242, 2011

Passage of Macromolecules Across Glomerular Capillaries

Hydrostatic Pressure Profile Along the Kidney

mmHg

Filtration: PG > πG

Reabsorption: PC < πCπif < πC

PRA

PG

PC

Arteries AfferentArteriole

EfferentArteriole

GlomerularCapillaries

PeritubularCapillaries Veins

100

80

60

40

20

RA RE

Navar, LG, 1998

Hydrostatic Pressures

60 20

Net Hydrostatic Pressure= 40mmHg

Colloid Osmotic Pressures

-31

Net Pressure= -31mmHg

037

25

Effective Filtration Pressure

-31Hydrostatic Colloid

Osmotic Net

40

9

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

Hydrostatic Pressure Profile Along the Kidney

RE = PG – PC/ RBF - GFR

Normal Human Values(Both kidneys)

RBF = 1200 ml/minRPF = 685 ml/minGFR = 130 ml/min

FF = GFR/RPF = 0.19

mmHg PRA

PG

PC

Arteries AfferentArteriole

EfferentArteriole

GlomerularCapillaries

PeritubularCapillaries Veins

RA = (100 – 54)/1200 RE = (54 – 18)/(1200 – 130)

100

80

60

40

20

RA = PRA – PG/ RBF

Filtration

Reabsorption

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

Ca2+

Ca2+-Cal

Ca2+Phosphoinositides

cAMP

cAMP

PhosphorylatedMLCK

(inactive)

Calmodulin

Myosin LightChain Kinase

(MLCK)

MyosinLight Chain

(MLC)

Actin

DAG + IP3

PKC

VOC

PKA

S R

Ca2+

ROC

PLC Gs

Ad Cy

R+

-

Active MLCK

PhosphorylatedMLC

TensionDevelopment

Ca2+

Ca2+

Smooth Muscle Cell

Endothelial Influences on Vascular Smooth Muscle

NOEDHF

PGI2

TXA2EDCF

PGF2

ET

Smooth Muscle Cell

Endothelial Cell

Ang II

Ang I

ACE

CGRP

Insulin

Histamine

VasopressinThrombin

SerotoninBradykinin

Acetylcholine

ATP/ADPTGF1

Leukotrienes

ShearStress

CalciumIonophore(A23187)

PlateletActivating

Factor

Substance P

Outline of Presentation

8. Renal autoregulationa. Myogenic and tubuloglomerular b. Feedback mechanisms

9. Other intrinsic regulationsa. Endothelial factorsb. Renin-angiotensin system c. Prostaglandins

10. Presentation of clearance concepts and filtered loads11. Measurement of GFR12. Measurements of renal plasma flow and use of PAH

clearance13. Examples of clearance problems14. Assignment of Clearance Problems

Arterial Pressure

Blood Composition

Neural Inputs

Hormonal Signalling

IntrarenalMechanisms

VenousEffluent

Urine

Lymph

Change in VolumeChange in CompositionRelease of Hormones

Waste ProductsExcess ElectrolytesFree Water Formation

Return Proteins to Circulation

Hormones

“Inputs and Outputs” of the Kidney

Hydrostatic Pressure Predominates Filtration

Colloid Osmotic Pressure Predominates Reabsorption

Glomerular and Peritubular Systems

The Tubular Transport Processes

Control of Renal Blood Flow & Renal Vascular Resistance

Arterial Pressure

Renal Blood Flow

Renal Nerves

Hormones Plasma

Composition

Intrinsic Control Mechanisms (autoregulation, macula densa, paracrine factors)

Art. PRVR

Renal Vascular

Resistance

Ca2+

Ca2+-Cal

Ca2+Phosphoinositides

cAMP

cAMP

PhosphorylatedMLCK

(inactive)

Calmodulin

Myosin LightChain Kinase

(MLCK)

MyosinLight Chain

(MLC)

Actin

DAG + IP3

PKC

VOC

PKA

S R

Ca2+

ROC

PLC Gs

Ad Cy

R+

-

Active MLCK

PhosphorylatedMLC

TensionDevelopment

Ca2+

Ca2+

Smooth Muscle Cell

Endothelial Influences on Vascular Smooth Muscle

NOEDHF

PGI2

TXA2EDCF

PGF2

ET

Smooth Muscle Cell

Endothelial Cell

Ang II

Ang I

ACE

CGRP

Insulin

Histamine

VasopressinThrombin

SerotoninBradykinin

Acetylcholine

ATP/ADPTGF1

Leukotrienes

ShearStress

CalciumIonophore(A23187)

PlateletActivating

Factor

Substance P

Hormones Affecting Renal Hemodynamics

1.Vasoconstricting Hormones:A. EpinephrineB. Angiotensin

2.Vasodilator Hormones:A. ProstaglandinsB. BradykininC. Atrial Natriuretic Peptide

Increased Nerve Activity

Effects of Renal Nerve Stimulation

Segm

ente

d Va

scul

ar

Res

ista

nce

% C

ontr

ol

Glo

mer

ular

Fi

ltrat

ion

Rat

ePl

asm

a Fl

ow%

Con

trol

Preglomerular

Efferent

Frequency of Renal Nerve Stimulation (Hz)

Hemorrhage Induced Renal

Nerve Activation

ANP Responses

Renal Hemodynamics

INTRINSIC

EXTRINSIC

Control Mechanism:AutoregulationTubuloglomerular FeedbackParacrine Factors

Control Mechanism:Sympathetic NervesHormonesOther

Renal Blood Flow Versus Pressure

RENAL ARTERIAL PRESSURE, mmHg

RE

NA

L B

LOO

D F

LOW

ml/m

in. g

0 50 150100 200

5

4

3

2

1

0

Normal Range

Circadian Rhythms in Blood Pressure in Normal Subjects and Hypertensive Patients

Normotensive Patients(N=6)

Hypertensive Patients(N=20)

Blood Pressure(mmHg)

Blood Pressure(mmHg)

Time of Day (h) Time of Day (h)

Renal Autoregulatory Responses to Changes in RAP

RA

RENAL ARTERIAL PRESSURE, mmHg RENAL ARTERIAL PRESSURE, mmHgR

EN

AL

BLO

OD

FLO

Wm

l/min

. g

VAS

CU

LAR

RE

SIS

TAN

CE

mm

Hg.

min

. g/m

l

20

15

10

5

00 50 150100 200 0 50 150100 200

5

43

2

1

0

RE

Myogenic Responses

Po Pi

R

Tension(T)

T = (Pi - Po) R

Initial Tension IncreaseTension Decline Upon Constriction

Gain =

(Pc - P) . RcP . (R - Rc)

=

L n 8P R4

Flow =

Renal Autoregulatory Responses to Changes in RAP

Renal Arterial Pressure (mmHg)

Ren

al B

lood

Flo

wm

l/min

/gVa

scul

ar R

esis

tanc

em

mH

g/m

in/g

/ml

Glo

mer

ular

Filt

ratio

nR

ate,

ml/m

in/g

Pres

sure

mm

Hg

Proximal Tubule

Distal Tubule

Collection or Pressure Pipette

Wax Blocking Pipette

Perfusion Pipette

Micropuncture and Microperfusion

Macula Densa – Vascular Pole

Components of the Tubuloglomerular Feedback Mechanism

ArterialPressure Plasma Colloid

Osmotic Pressure

Proximal Tubuleand Loop of Henle

Reabsorption

Afferent ArteriolePreglomerularResistance

Macula Densa:a) Sensor Mechanismb) Transmitter

GlomerularPressure andPlasma Flow

GlomerularFiltration

Rate

Early Distal Tubule:Flow Related ChangesOsm and NaCl Conc.

GlomerulotubularBalance

Proximal toDistal Tubule

Flow

Intact and Interrupted TGF

Tubuloglomerular Feedback Mechanism

PerfusionPipette

CollectionPipette

WaxBlockingPipette

DistalTubule

MaculaDensa

ProximalTubule

Distal Nephron Delivery

Sing

le N

ephr

onG

FR

Ca++ Channel BlockerAng II BlockadeCytochrome P450 Blockade NO PGI2

Sensitivity:

Normal

Sensitivity: Ang IINOS Blockade Thromboxane HETE

Autoregulation and TGF

HemodynamicInputs

TubularMetabolicFunction

Renal Autoregulation

Physiological:

Pathological:

•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

hyperfiltration in remaining nephrons after loss of functional nephrons

Receptor PLA2

Arachidonic Acid

COOH

EETS20-HETE

Epoxygenase

Hydroxylase

PGE2

Leukotrienes 12-HETE

PGI2TXA2

TXA2 SynthaseIsomerases

ProstacyclinSynthase

PGH2

HPETE

O

CH2-O-C-R

AA-CH

CH2-PO4-R'

Lipoxygenase

Cyclooxygenase

Cytochrome P450

RenalVasodilation Renal

Vasoconstriction

RenalVasoconstriction

RenalVasodilation

RenalVasoconstriction

RenalVasoconstriction

Renal Actions of Arachidonic Acid Metabolites

Renal Hemodynamic Responses to NSAIDs in Sodium Repleted and Depleted Conditions

Na+ Replete

Na+ Deplete

Na+ Replete

Na+ Deplete

Control NSAID

Ren

al P

lasm

a Fl

owm

l/min

GFR

ml/m

in

Renin Angiotensin System

NaClIntake

ArterialPressure

ECFVVolume

StressTrauma

Macula Densa Baroreceptors

Sympathetic Nervous System

ReninRelease

Juxtaglomerular Cells

Cytosolic Ca++

cAMP

Diuretics

LoopDiuretics

Angiotensinogen

ReninInhibitors

Angiotensin IAngiotensinConverting

Enzyme

ACEInhibitors

ReceptorBlockersAngiotensinases

Receptor Binding &Biological Actions

Metabolites

Angiotensin II

Renin

PGE2

Juxtaglomerular Apparatus

Effects of Angiotensin II

●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

Renal Hemodynamic Control Mechanisms