Physio Renal 2006

8/13/2019 Physio Renal 2006

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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

Physio Renal 2006

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