Layers of kidney Renal capsule Renal cortex Renal medulla (Renal pyramid) (renal column)
Block1 pgy451-renal-awayda
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Awayda, 2014- PGY451
Human Physiology 451/551
Renal Physiology- Dr. Awayda ([email protected], 242 Cary Hall)
Lecture Organization (participation encouraged)Ask questions anytimeTime at the beginning of lectures to deal with questionsBring your questions to class
Awayda, 2014- PGY451
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
Awayda, 2014- PGY451
Renal FunctionsTransport
• Regulation of water and inorganic ion balance•e.g., Na+, Cl-, etc...
• Removal of waste byproducts from the bloode.g., Urea, ammonia, creatinine, other non-nitrogenous waste
Ureaproteins→ amino acids →NH2 removed →ammonia, liver converts to urea Uric acidnucleic acid catabolismCreatininecreatine phosphate catabolism
Hormonal• Renin• 1,25-dihydroxyvitamin D3• Gluconeogenesis
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Renal Functions
Transport
• Regulation of water and inorganic ion balance•e.g., Na+, Cl-, etc...
FLUID HOMEOSTASIS
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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
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Body Fluid Compartments
Intracellular•ICF
Extracellular•ECF
•Plasma•Interstitial•Other Fluids
→→∆P
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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)
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Fluid Compartments
Human Anatomy and Physiology 6th edition, E. Marieb
VERY
STABLE
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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
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Electrolyte Composition
Modified from: Human Anatomy and Physiology 6th edition, E. Marieb
Reversed Na+ & K+ Concentrations
Very low intracellular Ca++
ISOTONIC
→ →→
→
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Organ Systems Affecting Body Fluid Composition
Respiratory
GI tract
Integument
Renal
Human Anatomy and Physiology 6th edition, E. Marieb
SKIN
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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.
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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
HCO3-(mEq) 4,320 2 4,318 >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
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Anatomy of the Kidney
Anatomical differences underlie physiological & functional differences
Cortical, Medullary, & Pyramidal regions
Basic unit “Nephron”
Varying depth of Nephrons
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Layout of Individual Nephrons
Modified from: Medical Physiology, Boron and Boulpaep
~ 106 Nephrons per Kidney
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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
Modified from: Medical Physiology, Boron and Boulpaep
Concentration * Flow = Amount
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GFR
Normal GFRMen 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
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Filtration Across the Renal Corpuscle
Glomerular Barrier (endothelial cells) Basal Lamina (acellular-mesangial origin) Bowman’s Capsule (epithelial cells)
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Podocytes and Fenestrated Endothelium
Modified from: Medical Physiology, Boron and Boulpaep
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Other Features at the Renal Corpuscle
Human Anatomy and Physiology 6th edition, E. Marieb
Note the Mesangial cells
Note the JGA
Note the MD Cells
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Selective Filtration
Modified From: Human Anatomy and Physiology 6th edition, E. Marieb
Size and Charge Fenestrated Endothelium
70-90 nm pores exclude blood cells
Basement membraneproteoglycan gel, -ve charge excludes molecules > 8nm (< 0.03% of plasma proteins enter, <10Kda)
Filtration slitspedicels on podocytes with negatively charged filtration slits, allow particles < 3nm to pass
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Charge and Size Exclusion
From: Koushanpour and Kriz, Renal Physiology
Neutral
Charged
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Forces Affecting Filtration- Pressure
HydrostaticGlomerularTubular
Osmotic/OncoticPlasmaTubular
∆P Leads to a GFR ≈ 180L/day (~ 1% is excreted)
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Forces Affecting Filtration
GFR = ∆P. (Kp . A)/X
Where ∆P 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
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OSMOLARITY
A discussion of osmolarity Jacobus van 't HoffNobel 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?
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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
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Osmotic Pressure
Develops due to water movement
~ 22.4 atm/Osm
170 mmHg/10 mOsm(max)
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Osmotic Regulation Between Fluid Compartments
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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
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Hydrostatic Pressures Across the Renal Vasculature
Factors influencing hydrostatic pressure
Resistance
Resistance
Resistance
Proportional to r4
Poiseuille’s Equation
(Conductance, 1/R)
g = (π.r4)
8n.l
from: Medical Physiology, Boron and Boulpaep
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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
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Hydrostatic Regulation of GFR
A) Autoregulation Myogenic
1)Stretch2)Nonlinear R
(24=16)B) Hormonal
1)TGF(Tubuloglomerular Feedback)
Mediated by JGA(Jugxtaglomerular Apparatus)
2)RASRenin-Angiotensin system & other hormones
C) Autonomic
Modified from: Medical Physiology, Boron and Boulpaep
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Mechanical Forces Affecting Filtration
Autoregulatory Changes
Modified from: Medical Physiology, Boron and Boulpaep
Increased C.O., Volume expansion 150 90 →70 15 →25
Decreased C.O., Volume contraction 65 40 → 50 25 → 15
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TGF/JGA
Distal Tubule
Mesangial
cells
Macula densaSensor cells for Na+/Cl- or flow. (Osmotic sensor), affect afferent arteriole resistance
Juxtaglomerular cellsRespond to decrease in AA pressure and to MD cells by vasoconstriction and by release of Renin
ReninProduced by JG cells leads to activation of the RASVery potent vasoconstrictor
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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
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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
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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
From: http://www.biocourse.com/bcc/assets/
Decreased Flow and pressure in the afferent arteriole
DecreasedNa, K, Cl in MD cells
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Other Hormones (ANP)
Atrial Natriuretic Peptide
Reduces blood pressure and blood volume by inhibiting: Events that promote vasoconstrictionNa+ 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
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Autonomic Regulation of GFR
ANS-Sympathetic Effects (anti-diuresis, decrease GFR):a) Arteriole vasoconstrictionb) JG cell stimulation- renin
ANS-Sympathetic Regulators: a) Exercise- moderate to strenuousb) Shock as in hemorrhagec) Baroreceptors. Report on blood volume/pressure
Under most conditions baseline conditions sympathetic influence is minimal- allows highest degree of control, why??
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Reabsorption & Secretion Along the Nephron
Balance of osmotic and hydrostatic forces (Starling) dictate filtration or re-absorption through out the nephron
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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:
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Renal Oxygen Consumption
Region orOrgan
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
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Mass Action
For any substance X which enters the nephron
Amount Filtered = GFR . Px
Amount excreted = UV. Ux
Difference of those two is: Secreted and reabsorbed
Law of mass balance:Amount excreted = Amount filtered - Amount reabsorbed +
Amount secreted
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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
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Calculating Clearance
U = concentration of X in urine
V = volume of urine (ml/min)
P = concentration of X in plasma
xP
V x
UCx
==xClearance
Example Na+
UNa= 300 mM
PNa= 150 mM
V = 5 ml/min
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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
ml/min 125 GFRP
U
Inulin
Inulin === VInulinC
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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
ml/min 600 RPFP
U
PAH
PAH === VPAHC
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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
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Free Water Clearance
Where COsm is Osmolar clearance and is:
OsmOH CC −= V2
)P
U1(
Osm
Osm2 −= VOHC
ml/min , P
U
Osm
Osm V=OsmC
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Examples of Renal Disease
Perfusion/Filtration related Diseases:
Volume Expansion
Volume Contraction
Renal Artery Stenosis
End Stage Renal Disease
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Volume Expansion
GFR may increase after a large increase of RFP- but in either case, this leads to a decrease of FF
⇓ Renin, and ANGII
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Stenosis
“Renal” baroreceptors – JG cells afferent arteriole detect ⇓ 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 ⇑ renin, ⇑ AngII
Renal angiogram
Magnetic resonance angiography
Modified from Harrison-Bernard, the APS
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Stages of Renal Dysfunction
<15End stage renal disease (uremia)5
15-29Severe renal failure (pre-end stage renal disease)
4
30-59Moderate renal failure (chronic renal failure)
3
60-89Early renal insufficiency- nearly invisible
2
>90Normal or increased GFR—people at increased risk or with early renal damage
1
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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 forcesDissipation of osmotic forcesMarked decrease of GFRToxic levels of plasma urea