Review of Renal Function and Regulation: 325 and 327

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Review of Renal Function and Regulation 3/25 and
3/27

• Review-Structure of glomerulus-
• Review-Type of transport in nephron-
• Review-Segmental differences along nephron-
• Definition of GFR test-
• GFR changes in disease-
• Renal autoregulation-
• Calculating GFR and RPF
• Reconsidering renal autoregualtion, the
  juxtaglomerular apparatus, and JG effects on GFR
  and RPF.

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WHY IS THE NEPHRON THE BUISNESS END OF KIDNEY?
WHAT DOES IT DO?

• Primary Function Control Fluid and Salt Balance
  in body
• Nephron is functional unit of kidney
• 1) Bowmans capsule
• 2) Glomerulussite of filtration
• 3) PCT (65 of reabsorption)
• 4) Loop of Henle (20 of reabsorption)
  cortical/medullary
• 5) DCT (10 of filtrate of reabsorption)
• 6) Collecting Ducts (5 of reabsorption)
• Your body filters an amazing 180 L/day-just try
  drinkign this much to keep up!
• Of this, if 90 is reabsorbed18 L urine/day
• if 99.5 is reabsorbed900ml
  Urine/day

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GLOMEROLAR (BOWMANS)CAPSULE AND THE GLOMERULUS
IS WHERE FILTRATION OCCURS.

• Arterial Supply Afferent and Efferent Arteriole
• Glomerular Capillaries under high pressure
• Capillaries rich in fenestrations (80nm wide)
• Basement Membrane (8 nm)-
• Podocytes and slits (30nm)
• Large proteins excluded, everything else can pass
  fenestrations, please dont forget that protein
  charge is very important!
• What happens to urine protein content if pores
  get too big?

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The key to the glomerulus is having fenestra that
are large enough to allow large amounts of fluid
to be filtered, yet small enough that cells and
proteins are unable to be filtered! It is also
important to have supporting structures on both
sides of the basement membrane to hold things in
place.
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GLOMERULAR FILTRATION RATE (GFR) TELLS HOW MUCH
FILTRATION IS OCCURING and ultimately if your
kidneys are working

• Kidney size, location and number
• How do we clinically measure renal function?
• Toxin solubility requires charge liver helps
  out.
• Filtrate lacks protein no oncotic pressure
• Filtration is a function of hydrostatic pressures
  across glomerulus and a function of oncotic
  pressures created by protein (look familiar?)
• Filtration Rate (60-18-28)(Kf)
• Typical GFR125 ml/minute

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Why do disease states often alter the GFR?

• Kf changes in disease albinuria and
  hematuriagtgtis the oncotic pressure of filtrate
  still zero?
• Autoregulation is phenomenal!!! (70 to 160 mmHg)
• What happens to GFR/reabsorption durign
  hypertension and hypotention?
• Removal of a kidney and GFR-
• Apheresis and chronic urinary tract infections
• Cranberry Juice and Renal Functiongt

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RENAL TRANSPORT PROCESSES CAN BE EITHER ACTIVE
(ATP USED) OR PASSIVE IN NATURE.

• 4 TYPES OF TRANSPORT Filtration- at
  glomerulus Reabsorption- Selectively along
  nephron Secretion- Removal of some
  toxins Excretion-Also called micturition
• 5 WAYS TO CROSS THE PLASMA MEMBRANE.
  Pinocytosis- Membrane Channels- Active
  Transport- Antiport- Fascilitated
  Diffusion-

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PROXIMAL CONVULUTED TUBULE IS FIRST PART OF
KIDNEY TO RECLAIM SALTS AND WATER.

• 65 of water reabsorption-
• Tubular Epithelium Luminal, Basolateral,
  Interstitial
• Tight Junctions-
• Na/K-ATPase pushes ions into interstium
• Secondary Active Tx Na-Glucose Co-transport
• Solvent Drag into peritubular capillary
• Filtrate not to different from what it was at
  start except volume is reduced 65.
• It is important to remember that uncharged
  molecules can be reabsorbed pretty easily! This
  is important in toxin removal!

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The key to reabsorption is that if you pump ions
out of the filtrate, water will follow via
solvent drag.
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LOOP OF HENLE IS AN AMAZING COUNTER CURRENT
MULTIPLIER FOR SALTS AND UREA.

• Reabsorbs 20 of water fine tuning of water
  reabsorption.
• Cortical vs. Medullary Loops degree of
  dehydration
• Poorly understood...
• Idea pull water out before it can get back into
  loop.
• Ascending Loop water impermeable/ NaCl-ATPase
• Descending Loop Very salt/water permeable
• Vasa Recta pulls up salts/water and carries it
  away.
• Volume further decreased
• UREA also appears to be critical!

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The Loop of Henle only works if the ascending
side is pumping NaCl out of the filtrate, this
drags water out of the descending side! Water is
then dragged into the vasa recta and quickly
carried away from the nephron.
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DISTAL CONVOLUTED TUBULE IS IMPORTANT FOR
REABSORBING 10 OF H2O.

• Impermeable to urea-
• Important for calcium and phosphate
  reabsorption (more in nutrition unit).
• Aldosterone causes it to actively transport
• Na/K-ATPase and therefore water
• Finer tuning of Na/K/H balance in body

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COLLECTING DUCTS PROVIDE THE LAST PLACE FOR THE
FINEST TUNING OF ONES VOLUME, SALT AND WATER
HOMEOSTASIS.

• Principal Cells Na resorption/K
  secretion Na/K-ATPase
• Intercalated Cells- H-ATPase dumps H into
  lumen CO2 and Carbonic anhydrase in
  cell/lumen Link HCO3 to Na and K transport
• Up to X1,000 gradient for H possible
• Vasopressin is ADH Presence brings aquaporin
  to plasma membrane Aquaporin at membraneH2O
  permeable Alcohol inhibits Post. Pit.
  Vasopressin release

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The longer the Loop of Henle, the greater the
osmotic gradient and the greater amount of water
you can remove from the descending loop AND the
collecting duct! Also note that urea is being
passively recirculated, but its importance still
isnt entirely known.
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TUBULAR SECRETION IS ONE WAY THE KIDNEY CAN
ACTIVELY REMOVE CAPILLARY CONTENTS

• Bicarbonate and chloride ions Active vs. Passive
• PCT reabsorbs some waste by accident-
• Pumps re-remove wastes
• Creatinine- metabolic dead-end waste product of
  phosphocreatine mostly from skeletal muscle.
• Charge keeps things away from epithelial cells-
• Liver is very important for drug detoxification
  and the formation of drug metabolites in the
  blood stream
• The Concentrating action (urine can be up to X100
  times more concentrate than blood) inside nephron
  may effect toxicity to kidney itself
• Consider a drug that is toxic at a blood plasma
  concentration100mM
• Plasma enter glomerulus and fluid reabsorbed in
  dehydrated state
• 180 L filtrate ? 180ml dark yellow urine
  180,000ml/180ml X1,000 concentrated!
• pH also important for removal of compounds-
• Consider applications to drug testing in the
  worksite

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STRICT AUTOREGULATION keeps the GFR at a constant
120 ml/minute and renal blood flow at an
amazingly constant 1,300 ml/min under a wide
range of conditions that include huge differences
in blood pressure and even the loss of a kidney.
HOW?
Flow ml/minute
GFR RPF RBF
120 700 1300
Arterial blood pressure too high
Arterial blood pressure too low
Range of healthy GFR Autoregulation
20 70 120
200 Mean Arterial Blood Pressure (mmHg)
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How do we experimentally evaluate renal function
Renal Plasma Flow and Glomerular Filtration Rate.

• Renal Clearance Amount of plasma from which
  waste is removed per unit time. FiltrationSecreti
  onReabsorptionRenal Clearance
• Basic Observed Effect
• (Urine Conc)(Urine formation rate)(Plasma
  Conc)(Fluid flow rate)
• Fluid can be plasma OR filtrate
• CUV/P

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Why bother measuring GFR and RPF in a clinical
setting in critically ill patients?

• GFR use a compound that is filtered, but not
  secreted or reabsorbed, we use Inulin to be
  precise, typically plasma and urine creatinine is
  used as a rough clinical GFR estimate.
• GFRUIV/PI
• GFR sample in book assumes each kidney was
  catheterized!!! Hence 60 ml/min X 2120 ml/min
• RPFuse a compound that is totally removed by
  filtration and secretion, but is not reabsorbed
• RPF-typically use PAH (paraminohipuric acid)
• RPFUPAHV/PPAH
• Clearance values for any compound partly
  reabsorbed/secreted can also be obtained!

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If you have no GFR or the GFR/Renal plasma Flow
ration is very bad you cannot clean nitrogenous
wastes, electrolytes and water from your blood
and will need dialysis within about two weeks or
massive accumulations of water (edema) and move
into a comma. Hemodialysis is used when your
kidneys FAIL.
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How do we grossly describe the qualities of urine
formation and glomerular filtrate clinically?

• How much Renal Filtrate in one healthy
  day?__________
• How much urine in one healthy day?_____________
• What percent of all filtrate volume is
  reabsorbed?_____________
• Color
• Oligouria-0.5l/day
• Anuria- no pee
• Polyuria/diuresis- 2l/day
• Pyuria-pus
• Odors and disease?
• Fresh(Pungent), Fruity(Diabetes), Mousy(PKU)
• Bacteria divide in bladder and create ammonia
• pH of urine-
• Osmolarity (mOsm) and Specific Gravity (g/ml)
• Why do bacteria generally not reside inside the
  kidney (pyelitis) except if you are unable to
  produce glomerular filtrate?

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Autoregulation of GFR at 125 ml/min only occurs
if 1) If you have 1, 2, OR 1 ½ fully functional
kidneys!2) If blood pressure is between 60mmHg
and 170 mmHg!Death is imminent if renal
autoregulation is lost!

• How is 60 mmHg maintained in the glomeruli with
  AA/AE constriction/dilation if
• BP120mmHg
• BP150mmHg
• BP70mmHg
• BP210mmHggt Protection vs damage
• BP50mmHggtProtection vs water loss
• What happens to regulation of nitrogenous
  waste at each pressure?
• When might glomeruli rupture and what would
  appear in the urine?
• When might anuria be observed and why does it
  occur with regards to the the Net Filtration
  Pressure?

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Your kidneys can regulate their own GFR based on
blood pressure and filtrate in the DCT!
AUTOREGULATION.

• Juxtaglomerular Apparatus site of
  autoregulation! Poorly Understood!
• The Distal Convoluted Tubules actually twist back
  over the Afferent and Efferent Arterioles
  creating a chance for the DCT to modify NFP/GFR!
• Juxtaglomerular Apparatus has 4 parts
• 1) Macula Densa Special DCT cells that detect
  high filtrate hypertonicity (are you dehydrated?)
• 2) Mesangial cells help MD and JG cells constrict
  arterioles
• 3) Sympathetic fibers innervate vessels smooth
  muscle and JG cells
• 4) Juxtraglomerular Cells around arteries release
  a hormone called renin that starts a cascade of
  events raising blood pressure!

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The JG Apparatus detects what?

• Juxtaglomerular Apparatus detects four different
  things
• 1) Hypertonic GFR detected via DCT AA and EA
  constrict!
• 2) Lack of stretch (pressure or volume) AA and
  EA constrict!
• 3) Excess stretch AA to constricts and EA to
  dilates! Protection!
• 4) Sympathetic nervous system input

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RENIN GIVES EACH KIDNEY LOCAL CONTROL OF DIVERSE
SYSTEMIC, NEURAL, AND RENAL ACTIONS, AND A GREAT
WAY TO RAISE BLOOD PRESURE AND COMPENSATE FOR
STRESS!

• Stimuli to JG Cells promotes renin secretion.
• Angiotensinogen from healthy liver
• VVV Renin VVV
• Angiotensin I goes to the lung
• VVV ACE VVV
• Angiotensin II is produced!
• Angiotensin II has 3 key actions
• 1) Thirst center of hypothalmus-in CNS fluids
• 2) Vasoconstirction in kidney and body
• 3) Adrenal Cortex secretes Aldosterone! And
  increased Na/H2O reabsorption
• How are ACE inhibitors used to treat hypertension?

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Given the importance of blood pressure
maintenance, it makes sense that angiotensin II
improves blood pressure in three totally
different way pathways (redundancy).