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 anytime Time at the beginning of lectures to deal with questions Bring your questions to class

Transcript of Block1 pgy451-renal-awayda

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 Physiology

WHAT IS THE FUNCTION OF THE KIDNEY?

Awayda, 2014- PGY451

Renal Physiology

Main Function: fluid

Homeostasis

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

Awayda, 2014- PGY451

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.

Awayda, 2014- PGY451

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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Localization of Nephrons

From: http://www.biocourse.com/bcc/assets/

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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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

GFR

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

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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)

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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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Diagram of the Actions of ANP

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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

Awayda, 2014- PGY451

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:

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

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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Volume Contraction-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

Awayda, 2014- PGY451

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

Awayda, 2014- PGY451

Many Causes of Chronic Renal FailureGFR<30ml/min

Most common causes are:Diabetes and Hypertension

WHY?

From: Merck Manual of Diagnosis and Therapy