Understanding Renal Hemodynamics

1
Understanding Renal Hemodynamics
L. Gabriel Navar, Ph.D. Department of
Physiology Hypertension and Renal Center of
Excellence Tulane University Medical School New
Orleans, LA
2
How Much Time Should be Spent on Renal
Hemodynamics when Teaching Renal Physiology Core?

• Highly relevant to clinical nephrology
• Relates to hypertension, renal failure and
  chronic kidney disease
• Clinicians expect students to understand
  clearance and be able to calculate glomerular
  filtration rate (GFR)

3
Renal Hemodynamics and Regulation of Glomerular
Filtration Rate
OBJECTIVES

• Know the definitions and average values for renal
  fraction, renal blood flow (RBF), glomerular
  filtration rate (GFR) and filtration fraction in
  adult humans.
• Identify the major sites of renal vascular
  resistance and describe the hydrostatic pressure
  profile along the renal vasculature.
• Identify extrinsic and intrinsic factors that
  regulate renal blood flow and renal vascular
  resistance. Predict changes in RBF and GFR
  caused by sympathetic activity and circulating
  epinephrine
• Describe the roles of hydrostatic and colloid
  osmotic pressures in regulating GFR.
• Describe the filtration barriers in the
  glomerular membrane and how proteins and
  macromolecules are restricted.

4
Renal Hemodynamics and Regulation of Glomerular
Filtration Rate
OBJECTIVES

• Given the glomerular and Bowmans space
  hydrostatic and colloid osmotic pressures and
  filtration coefficient, calculate the net
  filtration force and GFR.
• Define renal autoregulation and describe the
  roles of tubuloglomerular feedback mechanism and
  myogenic mechanism.
• Predict changes in RBF and GFR caused by
  increased Ang II, prostaglandin E2 and nitric
  oxide.
• Use clearance principle to determine clearances
  for substances such as creatinine, inulin and
  p-amino hippuric acid (PAH).
• Explain which clearances represent GFR and renal
  plasma flow and the criteria used to determine
  these associations. Calculate filtered load,
  tubular transport, excretion rate and clearance
  for any given substance.
• Determine if a substance undergoes net tubular
  reabsorption or net tubular secretion by
  comparing its clearance to GFR.

5
Outline of Presentation

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

6
Outline of Presentation

• Renal autoregulation
• Myogenic and tubuloglomerular
• Feedback mechanisms
• Other intrinsic regulations
• Endothelial factors
• Renin-angiotensin system
• Prostaglandins
• Presentation of clearance concepts and filtered
  loads
• Measurement of GFR
• Measurements of renal plasma flow and use of PAH
  clearance
• Examples of clearance problems
• Assignment of clearance problems

7
Salt and Water Homeostasis
Skin andRespiratoryLosses
FecalLoss
UrinaryExcretion
Intake
-
-
-

NervousSystem
Net Balance of Salt and Water
EXTRACELLULAR FLUID VOLUME
HormoneSystems
RenalExcretionof Saltand Water
InterstitialFluid Volume
BloodVolume
ArterialPressure
CardiacOutput
PlasmaCompositionalAlterations
From Navar, Adv. Physiol. Educ. 20 S221, 1998
8
Renal Fraction
1.2 L/MIN
RBF CO
0.2 or 20
6 L/MIN
For definitions, see Notes
9
A National Surge in Kidney Disease
Kidney disease is a national epidemic, affecting
about 20 million Americans, or one out of every
nine adults.
A Dubious Distinction The District Is at the
Front of a National Surge in Kidney Disease.
Experts Are Trying to Discover Why -- And Stem
the Deadly Problem - Ranit Mishori The
Washington Post, August 23, 2005
10
Kidney Disease in the United StatesLiving on
the Kidney Belt
11
Renal Mechanisms of HypertensionIntrarenal

• Chronic positive salt and water balance

• inability of kidneys to maintain appropriate salt
  excretion during excess salt intake
• diseases of kidney blood vessels leading to
  decreases in GFR
• intrinsic inability to excrete salt efficiently
  due to over-stimulation of reabsorptive
  mechanisms gene mutations of transporters
• chronic kidney disease

12
Outline of Presentation

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

13
Inputs and Outputs of the Kidney
Renal Nerves
Hormones
Cleansed Renal Vein Blood Flow
Dirty Renal Artery Blood Flow
KIDNEY
Renal Hormones
Lymph (tissue cleanser)
Urine Waste
14
Kidneys Arteriolar Network
15
Renal Vascular and Tubular Network
16
Renal Microvasculature
For definitions, see Notes
17
Glomerular Capillary
18
Glomerulus Between Afferent and Efferent
Arterioles
19
Outline of Presentation

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

20
Hydrostatic Pressure Profile Along the Kidney
Normal Human Values (Both kidneys) RBF 1200
ml/min RPF 685 ml/min GFR 130 ml/min FF
GFR/RPF 0.19
PRA
mmHg
100
80
Filtration
PG
60
40
Reabsorption
PC
20
Afferent Arteriole
Efferent Arteriole
Glomerular Capillaries
Peritubular Capillaries
Arteries
Veins
RE PG PC/ RBF - GFR
RA PRA PG/ RBF
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
RA (100 54)/1200
RE (54 18)/(1200 130)
For definitions, see Notes
21
Glomerular and Peritubular Capillary Dynamics
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
For definitions, see Notes
22
Glomerular Charge and Size Selectivity Preventing
Leakage of Proteins into Tubules
Bowmans Space
Blood
Gel
BM
Jv
From Ohlson et al. AJP Renal 280F396, 2001.
23
Passage of Macromolecules Across Glomerular
Capillaries
For definitions, see Notes
24
Outline of Presentation

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

25
Afferent Arteriole and Renal Corpuscle
For definitions, see Notes
26
(No Transcript)
27
Renal Hemodynamics
Control Mechanism Autoregulation Tubuloglomerular
Feedback
INTRINSIC
Control Mechanism Sympathetic Nerves Hormones Com
position of Blood
EXTRINSIC
28
Increased Nerve Activity
29
Outline of Presentation

• Renal autoregulation
• Myogenic mechanism
• Tubuloglomerular feedback mechanism
• Other intrinsic regulatory factors
• Endothelial factors
• Renin-angiotensin system
• Prostaglandins
• Presentation of clearance concept and filtered
  load
• Measurement of GFR
• Measurements of renal plasma flow and use of PAH
  clearance
• Examples of clearance problems
• Assignment of clearance problems

30
Renal Blood Flow Versus Pressure
5
Normal Range
4
RENAL BLOOD FLOW ml/min.g
3
2
1
0
RENAL ARTERIAL PRESSURE, mmHg
31
Circadian Rhythms in Blood Pressure in Normal
Subjects and Hypertensive Patients
Normotensive Patients (N6)
Hypertensive Patients (N20)
Blood Pressure (mmHg)
Blood Pressure (mmHg)
Time of Day (h)
Time of Day (h)
32
Renal Autoregulatory Responses to Changes in RAP
Pressure mmHg
Vascular Resistance mmHg/min/g/ml
Glomerular Filtration Rate, ml/min/g
Renal Blood Flow ml/min/g
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
For definitions, see Notes
Renal Arterial Pressure (mmHg)
33
Myogenic Responses
Po
Pi
Tension (T)
T (Pi - Po) . R
R
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
For definitions, see Notes
34
Macula Densa Vascular Pole
From Arendshorst and Navar, 2007
For citation, see Notes
35
Components of the Tubuloglomerular Feedback
Mechanism
Proximal Tubule and Loop of Henle Reabsorption
Arterial Pressure
Plasma Colloid Osmotic Pressure
Glomerulotubular Balance
Early Distal Tubule Flow Related Changes Osm
and NaCl Conc.
Proximal to Distal Tubule Flow
Glomerular Pressure and Plasma Flow
Macula Densa a) Sensor Mechanism b) Transmitter
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
36
Autoregulation and Tubuloglomerular Feedback
Tubular Metabolic Function
Hemodynamic Inputs
37
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

Pathological

• Reserve vasodilatory capability following
  pathological insults.
• ? glomerular pressure of all nephrons to
  compensate for Kf (filtration coefficient),
  such as in acute renal failure and
  glomerulonephritis
• hyperfiltration in remaining nephrons after loss
  of functional nephrons

?
38
Outline of Presentation

• Renal autoregulation
• Myogenic and tubuloglomerular
• Feedback mechanisms
• Other intrinsic regulations
• Endothelial factors
• Renin-angiotensin system
• Prostaglandins
• Presentation of clearance concepts and filtered
  loads
• Measurement of GFR
• Measurements of renal plasma flow and use of PAH
  clearance
• Examples of clearance problems
• Assignment of Clearance Problems

39
ENDOTHELIAL INFLUENCES ON VASCULAR SMOOTH MUSCLE
Smooth Muscle Cell
Vasodilation
Vasoconstriction
TXA2
EDHF
EDCF
NO
ET
PGI2
PGF2
Relaxing Factors
Ang II
Constricting Factors
ACE
Endothelial Cell
Platelet Activating Factor
Shear Stress
Calcium Ionophore (A23187)
Insulin
Thrombin
Bradykinin
Ang I
Vasopressin
Serotonin
ATP/ADP
CGRP
TGFb1
Histamine
Acetylcholine
Leukotrienes
Substance P
Adapted from Navar, Adv. Physiol. Educ. 20
S221, 1998.
For definitions, see Notes
40
Renal Actions of Arachidonic Acid Metabolites
O CH2-O-C-R
AA-CH
Receptor
PLA2
CH2-PO4-R'
Arachidonic Acid
Lipoxygenase
Cytochrome P450
Cyclooxygenase
Epoxygenase
HPETE
Hydroxylase
PGH2
EETS
Leukotrienes
ProstacyclinSynthase
12-HETE
20-HETE
TXA2 Synthase
Isomerases
PGI2
Renal Vasodilation
Renal Vasoconstriction
PGE2
Renal Vasoconstriction
Renal Vasoconstriction
TXA2
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
Renal Vasodilation
Renal Vasoconstriction
For definitions, see Notes
41
Renin Angiotensin System
Diuretics
Angiotensinogen
Renin
Renin
Inhibitors
NaCl
Arterial
ECFV
Stress
Intake
Pressure
Volume
Trauma
Angiotensin I
ACE
Angiotensin Converting Enzyme
Inhibitors
Loop
Macula Densa Baroreceptors Sympathetic Nervous
System
Diuretics
Angiotensin II
Receptor
Angiotensinases
Blockers
PGE2
Juxtaglomerular Cells
Renin Release
Cytosolic Ca
cAMP
Metabolites
Receptor Binding
Biological Actions
42
Effects of Angiotensin II
From Navar, Adv. Physiol. Educ. 20 S221, 1998.
For definitions, see Notes
43
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

44
Outline of Presentation

• Renal autoregulation
• Myogenic and tubuloglomerular
• Feedback mechanisms
• Other intrinsic regulations
• Endothelial factors
• Renin-angiotensin system
• Prostaglandins
• Presentation of clearance concepts and filtered
  loads
• Measurement of GFR
• Measurements of renal plasma flow and use of PAH
  clearance
• Examples of clearance problems
• Assignment of clearance problems

45
Measurement of Renal Plasma Flow
Renal Plasma Flow (RPF) Unknown
Constant infusion of indicator I into blood stream
Concentration of indicator in arterial plasma
(Pa(I))
Concentration of indicator in renal venous plasma
(PV(I))
Urine collection to determine Urine Flow (UF) and
indicator in urine (UI)
46
Renal Plasma Flow Calculation
I excreted I removed from plasma flowing
through kidney I excreted UF x UI I removed
from plasma I removed from each ml of plasma x
RPF I removed from each ml of plasma Pa(I) -
PV(I) ? RPF X (Pa(I) - PV(I)) UF x U(I)
UF x UI Pa(I) - PV(I)
RPF
47
Renal Plasma Flow Example
48
Renal Plasma Flow Clearance of PAH
When para-aminohippuric (PAH) acid is used
Since PV(PAH) is very small it can be neglected
so that
Effective renal plasma flow or PAH clearance
RPF ? 550ml/min (both kidneys)
49
Average Filtration and Reabsorption Values
Substance Amount Filtered Amount Excreted
Reabsorbed (avg./day) (avg./day)
Sodium 630 g 3.2
g 99.5 Water 180 L 1.8
L 99.0 Glucose 180 g 0
100.0 Urea 54 g 30.0
g 44.0
50
Clearance Concept

• Always relates to specific solute
• Always expressed as flow term
• Defines the volume of plasma that was cleared of
  that substance which was then excreted in urine

51
Using Clearance to Measure GFR
Special Conditions

• I is excreted only by filtration
• I is freely filtered without restriction
• I is not reabsorbed, secreted or metabolized

Therefore
IP
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Outline of Presentation

• Renal autoregulation
• Myogenic and tubuloglomerular
• Feedback mechanisms
• Other intrinsic regulations
• Endothelial factors
• Renin-angiotensin system
• Prostaglandins
• Presentation of clearance concepts and filtered
  loads
• Measurement of GFR
• Measurements of renal plasma flow and use of PAH
  clearance
• Examples of clearance problems
• Assignment of clearance problems

53
Practice Clearance Problems

• 2. Inulin is used to measure GFR because it is
  easily measured and only filtered. Also, PAH is
  used to estimate the plasma flow since it is
  extracted very efficiently by the kidney. Given
  the following data
• Urine flow 3 ml/min
• Plasma inulin concentration .22 mg/ml
• Urine inulin concentration 9.5 mg/ml
• PAH concentration in plasma .08 mg/ml
• PAH Concentration in urine 20 mg/ml
• C. Calculate the filtration fraction (FF).
• D. If the hematocrit (Hct) is 40, what is the
  total renal blood flow (RBF)?
• If the cardiac output (CO) is 6 liters/min, what
  is the renal fraction (RF)?

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Practice Clearance Problems

• 2. Inulin is used to measure GFR because it is
  easily measured and only filtered. Also, PAH is
  used to estimate the plasma flow since it is
  extracted very efficiently by the kidney. Given
  the following data
• Urine flow 3 ml/min
• Plasma inulin concentration .22 mg/ml
• Urine inulin concentration 9.5 mg/ml
• PAH concentration in plasma .08 mg/ml
• PAH Concentration in urine 20 mg/ml
• C. Calculate the filtration fraction (FF).
• D. If the hematocrit (Hct) is 40, what is the
  total renal blood flow (RBF)?
• If the cardiac output (CO) is 6 liters/min, what
  is the renal fraction (RF)?

55
Practice Clearance Problems

• 3. The following data were obtained from a
  patient at Charity Hospital over a 24-hour
  period
• V 1.44 Liters U (creatinine) 100
  mg/dl
• Plasma (creatinine) 1 mg
• U (urea) 220 mM/Liter
• Plasma (urea) 5 mM/Liter
• Determine
• A. GFR (ml/min).
• B. Filtered load of urea.
• Urea Excretion.
• Net urea reabsorption.

100 ml/min X .005 mM/ml .5 mM/min
1ml/min X .220 mM/ml .22 mM/min
.5 mM/min - .22 mM/min .28 mM/min