Kidney

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• Renal-Chemistry
• Elizabeth Kim, MSN, ARNP, SRNA
• March 2006
• Anesthesiology Nursing Program
• Florida International University

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THE OUTLINE

• Brief Review of Nephrology AP
• Renal and Acid/Base Balance
• Review of Diuretics

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• Rapid Renal Blood Circulation
• Weight of Kidneys 0.5 body weight
• 20-25 of CO goes to Kidneys
• CO 6 L/min
• Renal blood flow 1.2-1.5 L/min
• O2 consumption 18 ml/min

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Urine Formation

• 1300 ml blood/min ? Renal Arteries
• 1298-1299 ml ? Renal Veins
• All that work for 1-2 ml ? Ureter

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Renal Blood Flow Afferent ArteriolegtGlomerulusgt
Efferent Arteriole gtPeritubular Capillariesgt
Renal Vein
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Phospholipid-Bilayer Membranes Not permeable to
polar molecules (interior lipid region/nonpolar)
Large hydrophilic molecules and ions do not
diffuse through the lipid bilayer and need
special channels to allow entrance and passage of
polar species.
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Definitions

• Polar molecules
• Have no net charge.
• Have a region with a cluster of positive charges
  and a region with a cluster of negative charges.
• Polar molecules are hydrophilic.
• Nonpolar molecules
• Have a positive and negative charges uniformly
  distributed throughout the molecule.
• Nonpolar are hydrophobic.

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Kidney Function

• Kidneys important in
• Regulation of ECF/ BP
• When extracellular fluid volume ?, BP ?
• If ? ? blood volume and pressuregt ? flow to
  brain and other organs
• Kidneys work with CV system to maintain pressure
  in acceptable range
• ADH and aldosterone cause active reabsorption of
  more sodium and water concentrate urine
• Regulation of ionic composition
• Electrolyte balance Na, K, Ca, Mg, Cl-
• Acid-base balance H and HCO3-

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ECF Intravascular Interstitial
compartments 20 of total body weight

• Na major cation () of ECF
• Cl- major anion (-) of ECF
• Regulators of fluid balance
• Hormonal regulation of Na balance
• Mediated by aldosterone
• Secreted when Na levels low
• ? reabsorption in distal tubules

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Basic Nephron ProcessesGlomerular
FiltrationTubular ReabsorptionTubular Secretion
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Renal Water Handling

• 3 Important Components
• Delivery of tubular fluid to diluting segments of
  the nephron.
• Separation of solutes and water in the diluting
  segment.
• Variable reabsorption of water in collecting
  ducts (CDs)

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Na Regulation

• Defend against Na overload
• Natriuretic peptides
• ANP (atria)
• BNP (brain)
• C-type natriuretic peptide

• Defends against Na depletion Hypovolemia
• RAAS axis
• Aldosterone ? Na excretion
• Baroreceptors (Ao Arch Carotid Body)
• Stretch receptors (Great veins, pulmonary
  vasculature atria)
• ?Stretch ?Sympathetic tone, ?Renal perfusiongt
  ?Renin.

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The Kidney Has an Osmotic Gradient From Cortex to
Medulla

• Cortex - Isotonic with the blood 300 mOsm/L
• Medulla - very Hypertonic 1200 mOsm /L

• Regulating osmolality Regulating Na
  concentration (sodium salts represent 90 of
  total osmolality of ECF).

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Loop of Henle (LOH)

• Descending LOH
• Water reabsorbed
• Solute retained
• Osmolarity 1,200 mOsm/kg

• Ascending LOH Distal Tubule (DT)
• Dilution of concentrated fluid
• Relatively impermeable to water
• Osmolarity leaving DT 50mOsm/kg

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Where Sodium goes, Water follows
Sodium Aldosterone
Water ADH
Sodium Out Dilution
Water Out Concentration
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• DT
• Aldosterone (adrenal cortex) Na Reabsorption
• CD
• Water Reabsorption
• Mediated by ADH (Vasopressin)
• Stimulate aquaporin 2 water channels in CD

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Segments of the Renal Tubule

• Proximal tubuleReabsorbs the bulk of filtered
  fluid
• Loop of Henle Establishes and maintains an
  osmotic gradient in the medulla of the kidney.
• Distal tubule and collecting duct Final
  adjustments on urine pH, osmolality and ionic
  composition.
• Reabsorption of water gt ADH
• Reabsorption of Na and secretion of K gt
  Aldosterone

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Homeostasis

• H ions are created and destroyed at all times.
• H is controlled through
• 1. Buffers
• 2. The Lungs
• 3. The Kidneys

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Acid-Base Balance3 Mechanisms for the regulation
of acid-base balance

• The Buffer system (secs)
• Respiratory system (mins)
• Renal system (hrs-day)
• Renal H excretion, which controls plasma HCO3-
• For each HCO3- reabsorbed or regenerated a H is
  secreted into the renal tubular fluid.
• Predominate buffers phosphate (HPO42) ammonia
  (NH3)

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Acid-Base Review

• Henderson-Hanselbalch Equation
• Relationship bt
• pH
• PaCO2
• NaHCO3-
• Defines the above relationship but substitutes H
  concentrations for pH

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Renal Acid-Base BalanceHCO3-/H2CO3 Buffering
SystemMajor extracellular buffering system

• To maintain normal pH, the kidneys must perform 2
  physiological functions
• 1st Reabsorb all the filtered HCO3 (85 at PT)
• 2nd Excrete the daily H load (CD)

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Hydrogen H2O CO2H2CO3H HCO3-

• Adding acid load to the body fluids results in
  consumption of HCO3- by H added and the
  formation of carbonic acid, forms H2O CO2
• Only the urinary system can eliminate excess
  hydrogen ions, permanently and restore the
  bicarbonate buffering ions to the blood.

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Hydrogen Ions

• Continuously produced as substrates are oxidized
  in the production of ATP
• Largest contribution of metabolic acids arises
  from the oxidation of carbohydrates, principally
  glucose.
• Net production of hydrogen ions 60 mEq/day.

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Hydrogen Ion Regulation

• Metabolic reactions in the body are highly
  sensitive to pH or H ion concentration.
• H ions change shapes of proteins, including
  enzymes (H changes can greatly effect the
  chemical reactions in your body.

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Hydrogen Gains Losses

• CO2 H20 ? H2CO3 ? HCO3- H
• Protein breakdown.
• Loss of HCO3- in GI tract. 
• Loss of HCO3- in kidney. 
• (3) and (4) result in a gain of plasma H because
  HCO3- is no longer available to bind H.

• Loss of H from stomach in vomiting.
• Loss of H in urine.
• Hypoventilation.

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Buffers

• Buffer Any substance that can reversibly bind
  H.
• HCO3- Important buffer. 
• Buffer- H ? Hbuffer
• When H increases, the reaction is forced to the
  right and more H is bound to buffer.
• CO2 H20 ? H2CO3 ? HCO3- H

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Homeostasis of H by the Kidneys

• HCO3- Excretion? Free H in plasma. 
• Alkalosis Kidney excretes HCO3- to free up H in
  the plasma.
• Acidosis Kidney tubules produce HCO3-

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Bicarbonate Filtration and Reabsorption

• HCO3-
• Easily filtered
• Undergoes marked tubular reabsorption in the
  proximal tubule and collecting ducts
• CO2 H20 ? H2CO3 (CA) ? HCO3- H
• HCO3- diffuses down its concentration gradient
  into the plasma.
• H secreted into the tubule. This combines with
  filtered HCO3- to form CO2 and H20.

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Bicarbonate filtration and reabsorption

• If plasma HCO3- is low, the H combines with
  other buffers.
• HCO3- is still produced in the renal tubules and
  diffuses into the plasma, raising plasma HCO3-.

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Kidney Response to Acidosis

• H is secreted to reabsorb all the filtered
  bicarbonate.
• More H is secreted to bind to other buffers in
  the urine.
• More HCO3- is created and diffuses into the
  plasma, to bind H and make the plasma more
  alkaline.
• Glutamine metabolism and ammonium (NH4)
  excretion increase. Ammonium grabs H and HCO3-
  goes into the plasma, making it more alkaline.

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Kidney responses to Alkalosis

• H secretion is down, so H cannot reabsorb all
  the bicarbonate. A significant amount of
  bicarbonate is excreted in the urine.
• Glutamine metabolism and ammonium excretion are
  down, so little bicarbonate goes into the plasma.

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Renal Mechanisms Acid-Base Balance
CO2 H2O
H2CO3
HCO3- H
Carbonic anhydrase

• Kidneys alter/replenish H by altering plasma
  HCO3-
• ? H plasma (alkalosis) ? kidneys excrete lots
  of HCO3-
• ? H plasma (acidosis) ? kidneys produce new
  HCO3-

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HCO3- Reabsorption H2O CO2 H2CO3HCO3- H
Lumen
Blood

• Na-H exchange
• Permits HCO3- reabsorption/acid excretion

Na
Na
K
HCO3- Na H
Na H
HCO3-
HCO3-
HCO3- reabsorption relies on tubular secretion
of H,
CA Accelerates the dissociation of H2CO3 into
H2O CO2
H2CO3 H20 CO2
H2CO3
CA
CA
CA combines CO2 and water to form HCO3- and H
CO2 H20

• Daily glomerular ultrafiltrate 180L (contains
  4300 mEq of HCO3- )
• H in the tubular lumen combines w/ filtered
  HCO3-
• Body produces excess acids during normal
  metabolism
• To maintain balance the kidneys excrete more H
  ions and the urine becomes more acidic.

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Carbonic Anhydrase H2O CO2 H2CO3HCO3- H
Lumen
Blood

• 1. Na-H exchange
• Permits HCO3- reabsorption/acid excretion

Na
Na
K
HCO3- Na H
Na H
HCO3-
HCO3-
Dehydration CA Accelerates the dissociation of
H2CO3 into H2O CO2
H2CO3 H20 CO2
H2CO3
Rehydration CA combines CO2 and water to form
HCO3- and H
CA
CA
CO2 H20
CA

• Brush border
• Keeps the luminal H low
• Lumen Filtered HCO3- is converted to CO2.
• Intracellular Converted back to HCO3- to be
  returned to the systemic circulation, thus
  reclaiming the filtered HCO3-.

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HPO42- H gt H2PO4-
Recombine H with another buffer e.g.
HPO42- Excreted as H2PO42- Net gain of HCO3- by
plasma

• In the normal kidney about 1 mg/kg of acid must
  be cleared each day.  This is done by reclaiming
  filtered bicarb and excreting hydrogen ions with
  phosphate buffers and ammonium. Bicarb then
  diffuses into the blood and hydrogen into the
  urine, buffered by ammonium and phosphates.

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NH3 H gtNH4
Lumen Blood

• Renal production and secretion of ammonium (NH4)
• Urinary H excretion renal addition of new
  HCO3- to plasma

Glutamine
Glutaminase
NH3 Glutamate
NH3
Glutamate
NH3 H H
Na Na K
K
ATPase
Na Na
NH4
NH3 produced in renal tubular cell by
glutaminase on amino acid glutamine. Unionized,
rapidly crosses into the renal tubule down its
concentration gradient.
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DiureticsWeak Organic Acids

• Most diuretics inhibit sodium transport
• Interfere with the normal regulatory activity of
  the kidney.
• Block the entry of Na from the urine into the
  cell.

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• The Glomerulus
• Glomerular filtration rate (GFR) can be changed
  by drugs affecting renal blood flow (RBF)
• Xanthine alkaloids (caffeine, theophylline,
  aminophylline)
• weak diuretic effect
• Increased cardiac output and vasodilation
  resulting in increased RBF, which increases GFR

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• The Proximal Convoluted Tubule
• Majority 2/3 of filtered Na is reabsorbed at
  proximal tubules.

CAI
Lumen
Blood
Na
Na
K
HCO3- Na
Na H
H
HCO3-
HCO3-
H2CO3 H20 CO2
H2CO3
Increase Urine pH
CA
CA
CO2 H20

• Carbonic anhydrase inhibitors
• Blocks NaHCO3 reabsorption in the luminal
  membranes of the proximal tubule cells
• Causes sodium bicarbonate to be excreted in urine
• -SO2NH2 (sulfonamide) group is essential for
  activity
• Will increase urine pH within 30 minutes.
  Maximal increase in 2 hours.

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Osmotic DiureticsProximal Convoluted TubuleThin
descending limb (Does not participate in salt
reabsorptionWater reabsorption only)

• 2 main mechanisms of action
• Increase osmolarity in renal filtrate Result
  less water reabsorbed and more water excreted.
• Increase in plasma osmolarity. Extracts water
  from intracellular compartment to the blood
  compartment. Decreases blood viscosity and
  increases renal blood flow.

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• Osmotic Diuretics
• Mannitol (Osmitrol)
• Monosaccharide not normally found in mammals
• Nonreabsorbable solute primarily undergoes
  glomerular filtration
• Reduces Na reabsorption due to ? urine flow
  rates
• Mannitols large size and its several hydroxyl
  groups give it a low membrane permeability
• No specialized transporters for this solute.

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Na-K-2Cl- CotransportTAL Actively reabsorbs
NaCl and KCl via the Na-K-2Cl-symport (35 salt
absorption). TAL not permeable to water
Blood
Urine
Na
2Cl- K Na
2Cl- K Na
K
K 2Cl-
K 2Cl-
K
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• Thick Ascending Limb
• Major site of salt absorption and action of an
  important group of diuretics
• 25 of filtered Na is reabsorbed by these
  cells.
• Loop diuretics
• Most effective diuretics available
• Inhibits Na/K/2Cl- transport system to reduce
  the reabsorption of NaCl in the thick ascending
  limb of the loop of Henle

LASIX

• Inhibition of this transporter system leads to
  accumulation of K in the cell because of Na/K
  ATPase bringing K into the cell also. This
  results in back diffusion of K into the tubular
  lumen which reduces the lumen positive potential
  and causes an increase in Mg and Ca excretion

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Early Distal Tubule Thiazides Inhibit Na-Cl-
symport

• Increase renal excretion of K, Mg
• Not effective at low GFR

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Late Distal Tubule Spironolactone Competitively
inhibits aldosterone Inhibits Na reabsorption in
the late distal tubule and collecting duct.
Decreases K secretion
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