physio renal 2006
TRANSCRIPT
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Renal Review
Ana Ivkovic and Rahul Dave
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Kidney functions
Primary: water regulation and electrolyte
balance--homeostasis
The renal system functions to maintain the
intravascular volume (of body fluids)
Other: Endocrine: renin, erythropoieten, calcitriol
Liver-like fxns: glucose synthesis
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Basic Concepts
Excretion = Filtration - Reabsorption +
Secretion
Filtration Bowmans capsuleReabsorption: Peritubular capillariesSecretion: Peritubular capillaries
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Measuring Fluid Compartments
Total Body Water: varies with fat
20-40-60 Rule
ICF high in K and Mg; ECF high in Na, Cl
Plasma high in protein; interstitial fluid low in protein--
Gibbs Donnan (neg. charged prots attract more pos. charge)
Smallest compartment (plasma) most important
(intravascular volume that is controlled by kidney)
Total Body Water = 60% total body weight
2/3 = ICF 1/3 = ECF
1/4 = Plasma 3/4 = Interstitial Fluid
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Osmolarity and Oncotic
Pressure Normal plasma osmolarity = 285-290 mOsm/L
Tightly controlled
Osmolarity vs. Osmolality Osmolarity = mmol solute/L solution Osmolality = mmol solute/kg h2O
Reflection coefficient: 0 = ineffective osmolyte (urea, ethanol--freely permeable)
1 = effective osmolyte (Na, K, glucose w/o insulin; drawwater)
Oncotic Pressure: the fraction of plasma osmolarity thatis due to plasma proteins
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Tonicity vs. Osmolarity
Osmolarity Describes the osmotic properties of a solution
Tonicity Refers to the osmotic effect on the volume of a cell
Ex: hypotonic soln--water moves in, cell swell
Isosmotic solns not necessarily isotonic (has to do
w/ concept of reflection coefficient--ex of ureasolution and RBC)
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Darrow-Yanet Diagrams--Think
Logically! All volume disturbances originate in the ECF
compartment
Changes in the ICF compartment are in responsetochanges in the ECF
hyposmotic contraction refers to the volume of
fluid that remains
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Volume contractions
Diarrhea, vomiting, loss of blood--isosmoticvolume contraction
Diaphoresis (sweating), dehydration--hyperosmotic contraction
Remember that sweat is hyposmotic
Addisons disease (lack of aldosterone)--hyposmotic volume contraction
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Volume expansions (rarer)
Isotonic volume expansion (isotonic saline IV):
ECF expands, ICF doesnt change
Hypertonic volume expansion: ECF osmolarityincreases, draws fluid from ICF
Hypotonic volume expansion: ECF osmolarity
decreases, adds fluid to ICF (examples:psychogenic polydipsia, SIADH)
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Renal vascularization
Renal artery --> interlobar
artery --> arcuate artery
--> interlobular artery-->
afferent arteriole* -->
glomerular capillaries-->
efferent arteriole* -->
peritubular capillaries
*serial arrangement of
arterioles--important!
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Juxtamedullary vs. Superficial
Nephron
JMN has long Loop of Henle Generates a concentrated urine
JMNs are what we lose with age
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Renal Clearance and Blood
Flow C.O. = 5.2 L/min
RBF = 1.2 L/min (20% of cardiac output)
RPF = .66 L/min (plasma = 55% of blood); also equal tothe clearance of PAH (filtered and secreted)
GFR = Clearance of inulin or creatinine
Inulin is filtered but not secreted or reabsorbed
Creatinine clearance a slight overestimate of GFRbecause it is partly secreted (GFR = 0.9 X Ccreatinine)
Filtration Fraction = GFR/RPF, normally 20%
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PAH
Used to measure RPF
Effective RPF = ([U]PAHx V) / [P]PAH= CPAH
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Clearance Ratio
CR = Cx/Cin
If CR = 1, substance x is only being filtered
If CR < 1, substance x is being reabsorbed
If CR > 1, substance x is being secreted
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GFR:
A. Is dependent on hydrostatic pressure inside glomerularcapillaries
B. Depends on the oncotic pressure inside glomerularcapillaries
C. Is equal to the clearance of inulin
D. Under normal conditions, is rarely dependent on theoncotic pressure inside Bowmans space
E. Creatinine is used to calculate it
F. Three of the above
G. All of the above
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Starlings Forces of capillary
exchange GFR = Kf(PGC- PBS- GC)
Hypoalbuminemia increases GFR
PBS: low unless obstruction present (kidney
stones increase GFR)
Basement membrane has fixed negative charge-->
neg. charged prots cant get across --> oncoticpressure in Bowmans space = 0
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AFFERENT AND EFFERENT ARTERIOLES ARE THE
MAJOR SITES OF REGULATED RESISTANCE IN THERENAL VASCULATURE:
Glomerular capillary is unique: 2 sites of vasoconstriction
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Autoregulation
Myogenic Mechanism (Bayless): intrinsic reflex
mechanism of smooth muscle; increased pressure causes
vasoconstriction
Tubuloglomerular feedback: macula densa senses
increased filtered load of NaCl--> sends signals to
afferent arteriole to vasoconstrict, thereby decreasing the
filtered load (by decreasing GFR back to normal) Both processes serve to keep RBF and GFR constant
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Sympathetic Innervation
There is no parasympathetic input to the kidneys
Sympathetic innervation of the afferent and efferent
arterioles is the major regulator of RBF and GFR Vasoactive compounds also act on afferent and efferent
arterioles: NE, Angiotensin II, Endothelin--> constrict;
Ach, NO, PGs, etc --> dilate
Low vs. severe sympathetic drive--examples of exerciseand hemorrhage
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Urine formation
Ultrafiltration of plasma
Reabsorption of H2O and solutes from tubular fluid
Active and passive processes Transcellular and paracellular (lateral space) transport;
latter occurs in proximal tubule due to leaky tight
junctions--> ions pass, followed by H2O
In collecting duct tight jxns are very tight and do notallow passage of water, proteins, or solutes
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Solute Regulation
in Nephron
Segments
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Reabsorption and Secretion
along Proximal Tubule Isosmotic fluid
reabsorption
Reabsorbs 2/3 of filteredload of Na and water
(Aquaporin 1)
Highly permeable to
H2O; solvent drag of Kand Ca
Understand TF/P graph
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Upper Segment of PT Na cotransported along with bicarb, glc, amino acids,
phosphate (luminal membrane)
H+ secreted as counter-transport with Na (luminalmembrane)
Sodium bicarbonate is reabsorbed (basolateralmembrane)
Under normal conditions, reabsorption will increase asplasma [gluc] increases
Once plasma [gluc] reaches a certain level, all glucosecarriers in the PT will be saturated, leaving some glucose
behind
Tm of SGLT-2 (sodium coupled) is 200g/dl, which isexceeded in diabetics; osmotic diuresis results
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Lower Segment of PT
NaCl reabsorbed transcellularly (1/3) and
paracellularly (2/3); due to transepithelial voltage
Amino Acids and Bicarbonate have beencompletely reabsorbed
Glucose SGLT-1 (2 Sodium coupled) transporters
move glucose against higher gradient
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Thick Ascending Limb
Reabsorbs 1/4 of filtered Na
Has the Na-K-2Cl cotransporter
Inhibited by Furosemide (loop diuretic) Impermeable to water; tubular osmolarity
decreases (diluting segment)--> separation ofmovement of water and solute
Lumen becomes positively charged, causingparacellular transport of Na, K, Ca, and Mg
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Early Distal Tubule/Collecting
Duct Also impermeable to water (like TAL)
Continues the dilution of urine; the cortical
diluting segment Reabsorption of Na/Cl (cotransporter)
Inhibited by Thiazide diuretics
Thiazide diuretics unique in that they increase Ca++reabsorption (Loop diuretics increase Ca++
excretion by diminishing NaK2Cl + lumen effect)
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Late Distal Tubule/Collecting
Duct: fine tuning Principal cells--reabsorb Na, H2O, andsecrete K+
Impermeable to water, except in presence of ADH (Vasopressin)
ADH causes water channels to relocate to apical cell membrane(AQUAPORIN 2)
Na (transcellularly) and Cl (paracellularly) are reabsorbed
Aldosterone causes an increase in Na absorption and increases K secretion
Spironolactone (K-sparing) blocks aldosterone; other K-sparing diuretics(Triamterene, Amiloride) act directly on the Na channel, independent ofaldosterone
Intercalated cells--secrete H+through primary active transport exchange H+ out of cell for K+ into cell; K+ reabsorption
possess carbonic anhydrase activity for bicarb reabsorption
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Miscellaneous Renal Stuff
Na+, Ca++ are never secreted;rather,fail to reabsorb
Prostaglandins released during hypovolemic shock toincrease RPF and prevent renal ischemia
Aldosterone: promotes Na reabsorption and K secretion(via action on principal cells); also promotes H+ secretion(via action on intercalated cells)-->a link between volumeand acid-base regulation
Posm = 2[Na] + 2[Glucose] + [BUN] ADH: OSMOREGULATION
ALDOSTERONE: Na+/VOLUME REGULATION
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Genetic Defects that Target
Tenal Transport Mechanisms Bartters Syndrome: defect in NaK2Cl
transporter
Gettelmans Syndrome: defect in Na/Clcotransporter
Liddels: defect in ENaC (turned on)
Pseudohypoaldosteronism: defect in ENaC
(turned off--> Na doesnt get reabsorbed-->volume contraction
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Graphs to be familiar with:
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WATER BALANCE
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Control Mechanisms of
Osmoregulation Osmoreceptors
Increase in plasma osm--> hypothalamus stimulatedto release ADH (hypothalamic set point 285
mOsm/L solution) Respond to < 2% change in plasma osmolarity
Most important control in osmoregulation
Baroreceptors Respond to changes in Blood Pressure
Require a 15-20% change in BP before activation
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Disorders of Osmoregulation
Psychogenic Polydipsia,
Hypothalamic/Central Diabetes Insipidus:
lowADH
Nephrogenic Diabetes Insipidus: ineffective
ADH (kidney unable to respond to ADH)
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Mechanisms to Concentrate Urine
Countercurrent Multiplication--creationof osmoticgradient Loop of Henle
Generates a urine that is concentrated as high as 600mosm/L
Urea recycling Medullary Collecting Duct
Needed to increase the osmolar gradient from 600 to1200 mosm/L
Kidneys use urea to do osmotic work when in state ofantidiuresis
Countercurrent exchange--vasa recta maintainsthemedullary insterstitial osmotic gradient set up by thecountercurrent multiplier
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Diuresis vs Antidiuresis
Understand the diagrams on p. 9
Water diuresis: most concentrated urine just
before ascending limb and TAL; most dilute atend of CD
Antidiuresis: most concentrated in lumen at level
of renal papillae (in medulla); most dilute at TAL
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SODIUM REGULATION
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Renin, Angiotensin, Aldosterone
Renin secretion stimulated by: Decrease in effective circulating volume (decreased
pressure at afferent arteriole)
Increase in sympathetic nerve activity
Tubuloglomerular feedback (decreased Na load sensed bymacula densa, causing renin release)
Angiotensin II: Arteriolar constriction--> increases TPR
Increases Aldosterone
Increases ADH and thirst
Aldosterone causes: Na reabsorption at principal cells
K secretion in CD
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Aldosterone secretion:
Increased by ACTH, Angiotensin II, high plasma
[K+], cases of volume contraction
Decreased by *ANP* and high plasma Na+(feedback inhibition) ANP: OPPOSES RAAS; increases Na+ excretion
during cases of volume expansion(cardiac
myocytes are stretched)
Note: Na+ alterations do not affect plasma osmolarity, rather
they affect the effective circulating volume; H2O homeostasis
and ADH determine plasma osmolarity
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Aldosterone escape
A protective mechanism during cases of abnormal
aldosterone elevation (example of adrenal tumor);
system becomes insensitive to aldosterone.
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Renal Physiology
Lectures 41 to 48
Rahul Dave ([email protected])
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I cant go through everything in detail.
Know the handout.
My goal is to make this make sense to you, and orient your
studying.
Pay attention to major vs minor factors.
Minor doesnt mean less important to study, but helps you keep changes
in perspective
You need to memorize the regulation, etc and understand the
logic. Its easy to talk yourself into something wrong.
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Potassium Balance
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K+ distribution and homeostasis Plasma K is low must be controlled well
Determines membrane potential
Metabolic alkalosis causes hypokalemia (andvice-versa)
Rules of thumb: understand mechanisms Na and K go opposite
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K+Transport
See diagrams in handout for cellular transport
pathways in different sections
K+ Transport
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MAJOR FACTORS
K+itself (K promotes its own secretion)
Aldosterone (Na+excr., K+reabs., H+excr.)
MINOR FACTORS
Tubular flow increases secretionADH no net effect
Alkalosis (acute) increases secretion
Tubular Na+ increases secretion
Insulin Increase reabsorption
Epinephrine Decreases secretion (fight/flight)
Regulation of K+
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See diagrams of cell transport pathways
Diuretics
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Control of Circulating Volume
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Small fraction of TBW cant detect it directly.
Also, since detection and changes are indirect, the
changes must occur slowly
Measured by BP (myogenic feedback) or [Na+]
(tubuloglomerular)
Controlled by changing Na+
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Baroreceptors detect pressure
Central (Left atrium; carotid sinus) ADH Na reabs; collecting duct permeability
Intrarenal volume sensors
Pressure: myogenic feedback Na (also K & Cl, maybe): tubuloglomerular
Low ECF volume makes you thirsty
Sympathetic overdrive (fight/flight)conserve
water & peripheral blood flow
Volume Sensors Effectors
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Cardiac atria secrete ANP lowers GFR
Aortic Arch Baroreceptor Sympathetic system
Macula Densa Renin-Ang-Ald System
Hydrostatic/Oncotic pressure balance
Adrenal Cortex hormones like aldosterone
All of these affect Na+balance!
Mechanisms Controlling ECF
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Calcium and
Phosphate Balance
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Hitchhiking only takes you so far. But try to
understand why & howthese are true.
In the PCT & TAL: Ca2+follows Na+paracellularly
In the DCT & CD: Ca2+is regulated by PTH
Rules of Thumb: Ca2+
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Try to understand why & howthese are true.
In the nephron it undergoes paracellular transport
Controlled by PTH in the proximal tubule
Rules of Thumb: PO43-
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Phosphate Trashing Hormone in urine Absorb (P) from gut & bone to incr. plasma (P)
Excrete it in the urine
But Ca2+and PO4cant be together
So if (P) is low, Ca2+is high, and vice-versa
PTH, not calcitonin, is a major controller ofCa2+.
PTH
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This is a stupid detail, but winds up being tested
sometimes (No promises about Hudson)
Vit D is synthesized in liver & KidneyD (liver)1-OH-D (kidney) 1,25-OH-D
You need Vitamin D to absorb Ca2+
Think: Vit-D fortified milk
Vitamin D Synthesis
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Acid-Base: Basics
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Buffers Blood seconds
Intracellular minutes
Lung hours compensated state
Kidneys days
Net acid excretion counts NH4, Titratable Acid, HCO3-
Titratable (weak) acids include lactic acid, ketone bodies, etc.
Strong acids are secreted as their Na salts (eg, Na2SO4)
Removing AcidorBase
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[HCO3-]= 24
pH = 6.1 + log = 7.4
0.03 x P-CO2= 40
Know this and make sure you can
calculate it!
Buffering Mechanisms
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CO2is an acid and gets blown out by respiration. So when you sprint, you develop lactic acidosis.
This is metabolic acidosis. To get rid of the acid,you hyperventilate and breathe faster.
Lung Mechanisms
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Mainly by HCO3-
H2O + CO2CAH2CO3HCO3-+ H+
Kidney Mechanisms
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Locations: look at cell diagrams
Regulation Proximal tubule: follows Na+
(understand why)
Na/H antiport. Whenever one H+exits, a tubular
HCO3-is used up to neutralize it. Also, to regenerate
that H+, a HCO3 is made, which is transported to the
blood.
Systemic Acidosis (in PCT, Henle, CD)
Kidney: HCO3-
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H+is usually tied to other ions
In the intercalated cell of collecting duct, there isa ATP-dependent H+pump that secretes H+
Upregulated by aldosterone
Kidney: H+
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The mechanisms are complicated
Know that H+acidifies & trapsNH3in the lumen (asNH4
+)
K+also regulates NH4+
production dont worry
(The mechanisms are important if you want to doreally well)
Nitrogen Removal(NH3orNH4+)
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Clinical Evaluation ofAcid-Base Disorders
the simple way
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Remember compensation is never 100%
pH < 7.4 . Acidosis
pH > 7.4 . Alkalosis
pH = 7.4 .. Youre fine (or mixed)
Q1. Acidosisor Alkalosis?
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If its acidosis(or alkalosis) look for the source of
acid(orbase)
HCO3< 24 CO2> 40
HCO3 > 24 CO2 < 40
metabolic respiratory
Metabolic or espiratory
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Check with the formulas
Fig 43.23 in Berne & Levy
Im not sure whether he gave you these formulas. If he didnt dont worry.
Check the nomogram It will tell you acute vs chronic.
Compensated orUncompensated?
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Note that HCO3-and CO2move in opposite
directions
If they move in the same direction you have a
mixed disorder.
Is it Mixed?
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Metabolic Acidosis: Diabetic ketoacidosis, diarrhea
Metabolic Alkalosis: antacid, vomiting (will loose
Cl too)
Respiratory Acidosis: Hypoventiliation, pulmonary
edema
Respiratory Alkalosis: Hyperventilation
Clinical Causes
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You can find these in Costanzo, Hudsons H/O or
Berne & Levy.
Best study tool: Draw these out yourself. Know them
cold.
Cell Diagrams
Stone Kidneys are cool
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Stone Kidneys are cool .
G d l k