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Electrolyte and fluid balance.pdf

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Gordon Richardson

Human  kidney  physiology   Lecture  1  –  Fluid  compartments     Course  outline   1. Body  compartments   2. Glomerular  filtration   3. Tubular  function   4. Sodium  balance   5. Water  balance   6. Potassium  balance   7. Acid-­‐base  balance   8. Excreting  wastes/hormone  functions     What  does  the  kidney  do?   1. Maintains  normal  volume  and  composition  of  body  fluid  compartments   2. Excretes  waste  products  from  body   3. Helps  maintain  BP,  hemoglobin  level  and  calcium  levels  through  hormone  secretion   How  does  the  kidney  do  this?   1. Filters  a  large  volume  of  plasma  water  and  so lutes  (at  glomerulus)   2. Filtered  fluid  enters  tubules  which  add  or  remove  water  and  solutes  to  form  final  urine   –  which  is  excreted   3. Secretes  hormones  in  response  to  change  in  BP ,  hemoglobin  and  calcium     Objectives   -­‐ Know  body  fluid  compartments  and  what  determ ines  their  volume  and  composition   -­‐ Understand  factors  which  regulate  glomerular  filtration   -­‐ Understand  how  tubules  regulate  excretion  of  sodium,  potassium,  water  and  hydrogen  ion   -­‐ Understand  physiology  of  renin/angiotensin,  erythropoietin  and  vitamin  D     Case  of  the  day:  the  seizing  marathoner   -­‐ A  45  year  old  woman  runs  her  first  marathon  after  6  months  of  training   -­‐ Finished  in  5  hours   -­‐ Complained  of  headache   -­‐ Felt  nauseated,  vomited  then  had  grand  mal  seizure   –  taken  to  medical  area   -­‐ Serum  sodium  was  122  mmol/L  (140 )     Some  definitions   -­‐ Nephro  =  renal  =  kidney   o Nephrologist,  renal  artery,  kidney  failure   -­‐ Solutes  =  particles  dissolved  in  water  solution   o Sodium,  potassium,  glucose  etc   -­‐ Ions  (electrolytes)  =  charged  solutes  (cations  are  positive  +  and  anions  are  negative   -­‐)   -­‐ Osmolality  =  concentration  of  solutes  in  water  which  generates  an  osmotic  force     Osmosis   -­‐ The  movement  of  water  across  a  semi -­‐permeable  membrane  in  response  to  an  osmotic  gradient   -­‐ The  osmotic  gradient  =  a  difference  in  osmolality  in  compartments  separated  by  membrane   Osmosis -­‐ Water  moves  from  compartment  with  low  osmolality  to  that  of  high  osmolality     Body fluid volumes in a 70 kg male     Body  fluid  compartments   -­‐ Humans  are  50-­‐60%  water   A  simplified  view  of  the  body:   Body  water  in  two  large  compartments   -­‐ Intracellular  space   -­‐ Extracellular  space   -­‐ About  2/3  is  inside  cells  =  intracellular  fluid  (ICF)   -­‐ About  1/3  is  outside  cells  =  extracellular  fluid  (ECF)     Factors  that  determine  body  water  as  a  fraction  of  weight   -­‐ Ratio  of  fat/muscle   -­‐ Fat  has  very  little  water;  muscle  has  a  lot  of  water;  muscle  contains  most   water  in  body   -­‐ On  average,  there  is  more  fat/muscle  in:   o Women  compared  to  men  (50%  vs.  60%)   o Older  compared  to  younger   o Chronic  illness  compared  to  healthy   Ions in the ICF and Plasma (mEq/L)   Solutes  in  body  fluid   Charge ICF Plasma -­‐ Ions/electrolytes   o +  Sodium,  potassium,  calcium,  magnesium   Sodium + 10 140 o –  Chloride,  bicarbonate,  phosphate,  protein   Potassium + 150 4 -­‐ Fuels   o Glucose,  lactate,  amino  acids,  ketoacids   Calcium ++ .005 3 -­‐ Proteins   Chloride - 4 102 o Albumin,  globulins,  hormones   -­‐ Waste  products   Bicarbonate - 10 24 o Urea,  creatinine,  uric  acid  etc   Protein/ - n 130 14   phosphates ICF  vs  ECF   Osmolality  (particles  per  volume)   ICF=ECF  (because  water  will  cross  cell  membranes   through  water   channels  when  there  is  an  osmotic  gradient)     Charge  –  cells  have  a  negative  charge  compared  to  ECF    How are Differences Between ICF and DiffECF Generated?ween  ICF  and  ECF  generated     Na = 10   K = 140   2 K +   +   3 Na   1. Sodium-potassium -70mV   Na-K-ATPase ATPase   2. “Fixed” intracellular     polyanions - organic   phosphates and proteins   3. Multiple ion channels Why Is The Cell Negative?     Why  is  the  cell  negative?   -­‐ Cell  is  more  permeable   to  K  than  Na  Cell is more -­‐ Resting  membrane  e to K + than Na + potential  is  close▯ Resting membrane equilibrium  potential potential is close to   K equilibrium potential       Glucose-stimulated insulin secretion Importance  of  ionic  and  voltage  gradients  across  cell  membranes   -­‐ Nerve  conduction   -­‐ Muscle  conduction   -­‐ Pacemaker  activity  (heart)   -­‐ Transport  in  gut,  kidney,  salivary  glands,  eyes  etc  –  linked  to   sodium  transport  through  Na-­‐K-­‐ATPase   -­‐ Cell  signaling  (calcium)   o Insulin  secretion     Volume  of  ECF  vs  ICF  –  The  rules   -­‐ Sodium  is  restricted  to  ECF  and  is  the  main  ECF  osmole   -­‐ Water  crosses  cell  membranes  to  equalize  osmolality     -­‐ Body  fluid  osmolality  is  normally  kept  constant  by  regulating   water  intake  and  excretion     Example  1:  what  happens  to  ECF  to  ICF  volume  if  we  eat  salt -­‐NaCl-­‐ (alone)?   -­‐ Increase  in  ECF  sodium  content  and  concentration  (sodium  stays  in  ECF)   -­‐ Increase  in  ECF  osmolality   -­‐ Water  moves  from  ICF  to  ECF   -­‐ Decrease  in  ICF  volume  and  increase  in  ECF  volume;  cells  shrink   -­‐ Thirst  –  drink  water  until  ECF  osmolality  normal   -­‐ Unless  extra  sodium  is  excreted,  ECF  volume  remains  increased,  ICF  volume  is  normal     Example  2:  what  happens   to  ICF  and  ECF  volume  is  we  drink  water  (alone)   -­‐ Water  absorbed  from  gut  into  ECF,  lowers  ECF  sodium  concentration  and  osmolality   -­‐ Water  moves  from  ECF  to  ICF   -­‐ Both  ECF  and  ICF  volumes  increase   -­‐ Osmolality  is  brought  back  to  normal  by  excreting  water  through  k idnets   -­‐ Mechanism  –  inhibit  the  hormone  vasopressin  (antidiuretic  hormone   –  ADH)     Clinical  relevance  of  volume  rules   -­‐ ECF  volume  depends  on  sodium  content   o Increased  sodium  content  =  increased  ECFV   -­‐ ICF  volume  depends  on  ECF  sodium  concentration   -­‐ ↓ECF  sodium  concentration  (hyponatremia)  =  ↑  ICF  volume   -­‐ ↑  ECF  sodium  concentration  (hypernatremia)  =   ↓  ICF  volume   Capillaries   ECF  compartment  plasma  volume  vs  interstitial  volume   -­‐ Exchange  of  solutes  and  water  across  capillaries   (permeable  walls  of  smallest  blood  vessels)   -­‐ Water  flux  determined  by  Starling  forces:   o Hydrostatic  pressure  gradient   o Oncotic  pressure  gradient   -­‐ Oncotic  pressure  is  an  osmotic  force  due  to  charged   proteins  (mainly  albumin)     Albumin   -­‐ The  main  protein  in  plasma   -­‐ 40g/L  in  plasma  –  low  in  interstitium   -­‐ Mol.  Wt  60,000   -­‐ Capillaries  have  limited  permeability  to  albumin   -­‐ Provides  oncotic  pressure   –  plasma  >  ISF     Fluid  movement  across  capillaries   -­‐ Fluid  flux  =  permeability  x  (hydrostatic  pressure   gradient  –  oncotic  pressure  gradient)   -­‐ J v  =  f (ΔP-­‐Δπ)   -­‐ Hydrostatic  pressure  generated  within  capillaries  by   pumping  action  of  heart     Edema   Increased  ISF  volume  (edema)  with:   -­‐ Increased  capillary  hydrostatic  pressure  (heart  failure)   -­‐ Decreased  plasma  albumin  concentration  (liver  failure)   -­‐ Increased  capillary  permeability  (allergy,  tr auma)   -­‐ Lymphatic  obstruction     How  does  a  physician  determine  ECF  volume  in  a  patient?   -­‐ ECF  volume:  clinical  exam   o Plasma  volume:   § Jugular  venous  pressure   § Blood  pressure   Jugular Venous Pressure o Interstitial  volume   § Edema     How  does  a  physician  determine  ICF  volume  in  a  patient?   Serum  sodium  concentration  and  serum  osmolality   -­‐ Hyponatremia  and  hypoosmolality  =   ↑  ICFV   -­‐ Hypernatremia  =  ↓  ICFV     Case  of  the  Day:  seizing  marathon  runner   -­‐ Severe,  acute,  hyponatremia  (122  vs  140)   -­‐ Water  crosses  cell  membranes  from  ECF  to  ICF   External jugular vein Measuring jugular venous pressure -­‐ Brain  cells  swell,  intracranial  pressure  rises  –   causes  seizures,  coma,  death   -­‐ Due  to  excessive  water  intake  relative  to  losses  plus  stimulation  of  vasopressin   -­‐ Commonest  in  women  with  slow  pace   -­‐ Treatment:  rapid  intravenous  infusion  of  a  hypertonic  saline  solution  to  move  wate r  out  of  brain  cells     Summary   -­‐ TBW  =  50-­‐60%  body  weight   o 2/3  ICF,  1/3  ECF   -­‐ Volume  rules   o Sodium  stays  in  ECF   o Water  crosses  cell  membranes  to  =  osm   o Osmolality  kept  constant  through  adjusting  H O  balance   2 o Plasma  vs  interstitial  depends  on  balance  of  oncotic  and  hydrostatic  pressure     Lecture  2  –  Glomerular  function     Summary  of  lecture  1   -­‐ Sodium  is  restricted  to  ECF   –  main  ECF  osmole   -­‐ Water  crosses  cell  membranes  to  equalize  osmolality   -­‐ Normally  osmolality  is  kept  constant  by  regulating   water  intake  excretion   -­‐ Excess  sodium  =  increased  ECF  volume,  edema   -­‐ Sodium  depletion  =  reduced  ECF  volume,  low  blood  volume   -­‐ Water  excess  =  hyponatremia   -­‐  ↑  ICFV   -­‐ Water  deficit  =  hypernatremia   -­‐  ↓  ICFV     Case  of  the  day:  acute  kidney  failure  in  the  CCU   -­‐ A  75  year  old  man  has  major  myocardial  infraction  (heart  attack)  watching  Leafs  lose  a nother  one   -­‐ In  CCU  his  BP  is  low  (95/65)   -­‐ He  is  started  on  ACE  inhibitor  (reduces  angiotensin  II)  to  improve  heart  function   -­‐ Next  day  his  serum  creatinine  has  increased  to  200  from  100 µmol/L   -­‐ Why?     Solute  and  water  excretion   -­‐ Large  volume  of  filtered  plasma  water  through  glomerulus   -­‐ Fluid  and  solutes  enter  tubule  lumen     -­‐ Tubules  reabsorb  or  secrete  solute  and  water   -­‐ Final  urine  excretes  an  amount  of  water  and   solute  to  maintain  normal  body  fluid  compartment  volume  and   composition     The  Nephron   Arterioles and Capillaries About  1  million/kidney   Glomerulus The Nephron About 1 million/kidney Department of Medicine of Medicine   Scanning EM of exposed glomerulus   EM cross section of single capillary wall     capillary lumen, BS= Bowman’s space     EM cross section of single capillary wall EM cross section of glomerulus Glomerular  function   -­‐ Filtration  of  solutes  and  water  into  Bowman’s  space  and  proximal  tubule   -­‐ Very  high  blood  flow  to  kidney  (1000ml/min  –  20-­‐25%  of  cardiac  output)   -­‐ >90%  of  renal  blood  flow  goes  to  glomeruli  first  through  afferent  arterioles   -­‐ Blood  from  glomeruli  into  efferent  arterioles,  then  peritubular  capillaries   à  veins   -­‐ Glomerular  capillaries  are:   o Very  leaky  to  water  (high  uf)   o Bracketed  by  muscular  arterioles  before  (afferent)  and  after  (efferent)   o Contraction  or  dilatation  of  afferent  and  efferent  arterioles  help  regulated   GFR     What  regulates  GFR?   Afferent and Efferent Arterioles -­‐ Most  important  determinant  of  GFR  is  renal  blood  flow   -­‐ Determined  by  arterial   pressure  (BP)  and  renal  vascular  resistance     Efferent Afferent Autoregulation  of  renal  blood  flow  and  glomerular  filtration  rate   arteriole arteriole -­‐ Renal  blood  flow  is  constant  over  mean  arterial  pressures  70  to   PGC 150mmHg   -­‐ Main  factor:  myogenic  reflex  in  afferent  arteriole   o If  BP  falls,  afferent  arteriole  dilates   o If  BP  rises,  afferent  arteriole  constricts   Bowman’s space- -­‐ Other  factors  important  at  low  BP:   PT o Angiotensin  II  –  constricts  efferent  arteriole   o Prostaglandins  –  dilate  efferent  arteriole     Afferent Constriction Renal  vasoconstrictors  and  vasodilators   Constrictors:   -­‐ Angiotensin  II  –  efferent  arteriole  only   -­‐ Catecholamines  (noradrenaline)   Dilators:   -­‐ Prostaglandins   -­‐ Atrial  natriuretic  peptide   -­‐ Pregnancy   -­‐ High  protein  diets     Angiotensin  II  and  hypotension   -­‐ Low  BP  stimulates  angiotensin  II     Efferent Constriction -­‐ Angiotensin  II  causes  efferent  constriction     -­‐ Because  BP  is  low  and  renal  blood  flow  falls   –  this  could   reduce  GFR  markedly  (bad  thing)   -­‐ Angiotensin  II  increases  filtration  fraction,  thereby  limiting   drop  in  GFR     Effect of AII on GFR in Hypotension Afferent Efferent Normal PGC Efferent constriction increases filtration fraction (GFR/RBF): prevents drop in GFR with hypotensionnt RPF = 600 ml/min of Medicine GFR = 120 ml/min FF=0.20 Afferent Efferent Hypotension PGC BP = 90/60 Angiotensin II RPF = 400 Department GFR= 120 of Medicine FF= .30     Filtration  of  solutes   -­‐ Convection  (not  diffusion)   o Driven  by  hydrostatic  pressure   gradient  and  bulk  flow  of  water)   -­‐ Determined  by  molecular  weight:   o <15,000  freely  filtered  IE  [plasma]=[Bowman’s  space]   o 15,000-­‐60,000  progressive  restriction  to  filtration   o >60,000  (albumin)  –  negligible  filtration   -­‐ Freely  filtered   ▯ Would glucose be o Sodium,  potassium,  chloride,  glucose,  bicarbouseful?  urea,   creatinine  etc   ▯ No -­‐ Restricted     o Albumin,  globulins  (like  antibodies)   ▯ All filtered glucose   is reabsorbed by Measurement  of  glomerular  filtration  rate   -­‐ Most  important  and  most  used  measure  of  kidney  function   -­‐ Correlates  well  with  clinical  consequences  of  reduced  kidney   function;   most  kidney  disease  affect  glomerulus   -­‐ Measured  in  milliliters/min  (ml/min)   -­‐ Normal  is  >90  ml/min  (125L/day)   -­‐ We  want  solute  that  is  filtered,  neither  reabsorbed  nor  secreted  by  tubules   -­‐ Amount  filtered    =  amount  excreted   -­‐ “Clearance”  of  solute  from  circulation  then  =  GFR   -­‐ Would  glucose  be  useful?   –  No   -­‐ All  filtered  glucose  is  reabsorbed  by  tubules   ▯ Would urea be -­‐ Would  urea  be  useful?   –  No   useful? -­‐ About  50%  of  urea  is  reabsorbed  by  tubule   -­‐ Urea  clearance  is  only  50%  of  GFR   ▯ No -­‐ Inulin  is  perfect   -­‐ No  reabsorption  by  tubule   ▯ About 50% of urea -­‐ Its  clearance  =  GFR   is reabsorbed by -­‐ Only  problem:  inulin  has  to  be  given  intravenously   the tubule   Measurement  of  GFR   ▯ Urea clearance is -­‐ We  use  solute  like  inulin  that  is  freely  filtered  only 50% of GFR  secreted  nor   absorbed  by  tubules   -­‐ Then:  filtration  =  excretion  in  urine   -­‐ Filtration  =  GFR  x  plasma  concentration   -­‐ Excretion  =  urine  flow  rate  x  urine  concentration   -­‐ GFR  x  x  =  UV x x  U   ▯▯  ×  ▯▯ -­‐ GFR  =   ▯▯     Calculation  of  GFR  –  what  solute?   ▯ Inulin is perfect -­‐ Inulin  –  gold  standard  –  research  only   -­‐ Creatinine  –  endogenous  (muscle)  limited  secretion  (10%  orption by tubule normally)   -­‐ Collect  urine  for  24  hours,  measure  plasma  ▯reatIts clearance =  vo lume,   urine  concentration  of  creatinine  then   -­‐ GFR  =  UV  x creat /P creat   GFR   ▯ Only problem: GFR  by  creatinine  clearance   inulin has to be -­‐ Creatinine  production  from  muscle  constant  from  day  to  day   -­‐ Creatinine  clearance  a  reasonable  estimate  of  GFR  if  urine   intravenously collection  accurate  AND  steady  state  conditions  exist  (IE  creatinine   production  =  excretion  and  serum  creatinine  is  constant)   -­‐ If  urine  collection  incomplete,  measurement  of  GFR  is  wrong   -­‐ Collecting  a  24h  urine  in  a  pain  so…     Estimating  GFR  with  plasma   creatinine   -­‐ Since  GFR  =  creatinine  excretion/P creat,   -­‐ GFR  ∝  1/P creat   -­‐ Plasma  (or  serum)  creatinine  is  easy  to  measure   -­‐ Low  creatinine  =  high  GFR  and  vice  versa   -­‐ Plasma  creatinine  depends  not  only  on  GFR  but  on  muscle  mass   -­‐ So  plasma  creatinine  must  be  interpreted  in  context  of  patient’s  age,  weight  and  gender     Plasma  creatinine  as  measure  of  GFR   -­‐ GFR  is  inversely  proportional  to  P creat   -­‐ If  patient  has  baseline  creatinine  of  100 µM  and  GFR  of  100ml/min,  what  is  GFR  when  serum  creatinine  is:   -­‐ 200µmol/L     50ml/min   -­‐ 500µmol/L     20ml/min   -­‐ 1,000µmol/L     10ml/min   -­‐ Since  serum  creatinine  is  highly  dependent  on  muscle  mass,  formulae  exist  to  estimate  GFR  more  accurately  from   P   creatinine -­‐ Most  Canadian  laboratories  will  report  an  estimated  GFR  when  they  measure  seru m  creatinine  –  based  on  age,  gender,   race     Case  of  the  day:  acute  kidney  failure  in  CCU   -­‐ 75  year  old  man  with  low  BP  due  to  heart  attack   -­‐ Placed  on  an  inhibitor  of  angiotensin  II   -­‐ Serum  creatinine  doubled  therefore  GFR  decreased  by  50%     Why  did  GFR  fall?   1. Decrease  in  arterial  pressure   a. Normal  adaptation  is   i. Afferent  dilatation   ii. Efferent  constriction  through  angiotensin  II   2. ACE  inhibitors  reduce  AII   a. Cause  efferent  dilatation   b. Reduce  glomerular  capillary  pressure   c. Reduced  GFR   -­‐ Although  ACE  inhibitors  are  useful   drugs  they  are  associated  with  acute  kidney  failure     Summary   -­‐ Renal  blood  flow  is  20-­‐25%  of  cardiac  output   -­‐ GFR  normally  autoregulated  by  afferent  arteriolar  tone   o When  BP  low,  prostaglandins  and  angiotensin  II  are  important   o GFR  best  index  of  overall  kidney  h ealth   o Usually  use  serum  creatinine  to  estimate  GFR  in  humans     Lecture  3  –  tubular  function     Summary  of  GFR   -­‐ Renal  blood  flow  is  20-­‐25%  of  cardiac  output   -­‐ GFR  is  autoregulated  by  afferent  arteriolar  tone,  prostaglandins  and  angiotensin  II   -­‐ GFR  is  best  index  of  overall  kidney  health   -­‐ Usually  use  serum  creatinine,  adjusted  for  muscle  mass  to  estimate  GFR     Case  of  the  day:  sweet  pea   -­‐ A  15YO  M  has  routine  physical  by  his  family  doctor  including  a  urinalysis   -­‐ Blood  and  protein  are  negative  but  glucose  is  moderately  pos itive   -­‐ An  urgent  blood  glucose  is  normal   -­‐ Repeated  urinalyses  show  glucose  with  normal  blood  sugar   -­‐ Is  he  diabetic?     GFR  vs  tubular  function   -­‐ Normal  GFR  is  >90  ml/min  or  >125L/day   -­‐ Normal  urine  volume  =  0.5 -­‐2L/d  (depends  on  how  much  you  drink)   -­‐ Filter  >17,00  mmol  of  sodium  a  day  and  excrete  only  150mmol   -­‐ So  >99%  of  filtered  water  and  solutes  like  sodium  must  be  reabsorbed  by  tubules  every  day   Tubules  reabsorb  solute  and  water  and/or  secrete  solutes  so  that   -­‐ When  body  composition  and  volumes  are  normal,  intake  =   excretion  (steady  state)   -­‐ When  there  is  a  deficit  of  solute  or  water,  excretion  is  reduced   -­‐ When  there  is  excess  of  solute  or  water,  excretion  is  increased   -­‐ Kidney  tries  to  maintain  homeostasis   -­‐ Tubules  receive  signals  to  modify  reabsorption/excretion  designed  to  keep  body  fluid  composition/volume  normal   -­‐ Signals  may  be  hormones,  nerves,  pH,  electrolyte  concentration,  pressure     Hormonal  signals  to  kidney   Main Nephron Segments: -­‐ Vasopressin  (ADH  –  antidiuretic  hormone):  water  balance   -­‐ Aldosterone:  sodium  and  potassium  balance   -­‐ Angiotensin  II:  sodium  and  acid-­‐base  balance  ium 1. Proximal tubule -­‐ Parathyroid  hormone:  calcium,  phosphate   2. Loop of Henle   Main  nephron  segments:   1. Proximal  tubule   3. Distal tubule 2. Loop  of  Henle   Cross section 4. Collecting duct 3. Distal  tubule   4. Collecting  duct     Scanning EM of proximal tubule showing brush border microvilli on lumenal membrane which increases absorptive Cross section of a kidney tubule surface area Sites ofSite  of  reabsorption  and  secretion   Proximal Loop DCT+CD Tubule cell Water 70% 15% 15%* * Tubule Sodium 70% 20% 10%* Bicarbonate 75% 15% 10%* lumen Glucose 100%* 0 0 Capillary Potassium 70% 20% -100%*   Tight of Medicine * Site of regulation junctions   of Medicine   How  do  transporting  epithelial  cells  work?   -­‐ They  are  polarized   -­‐ Different  transport  proteins  on  lumenal  (apical)  and  basolateral  (blood)  membrane   -­‐ Na-­‐K-­‐ATPase  localized  to  basolateral  membrane     Model  of  tubular  reabsorption  and  secretion   -­‐ Driven  by  Na-­‐K-­‐ATPase  –  localized  to  basolateral  membrane  (next  to  peritubular  capillary)   -­‐ Makes  cell  sodium  concentration  low  and  IC  space  negatively  charged   -­‐ Lumenal  sodium  can  enter  cell  down  large  electrochemical  gradient   -­‐ Sodium  entering  cell  exits  basolateral  membrane  through  Na -­‐K-­‐ATPase   -­‐ Reabsorption  or  secretion  of  ot her  solutes  is  linked  to  sodium  through  lumenal  membrane  transporter  proteins   Model of Sodium Reabsorptionodium  cotransporters   o Sodium  antiporters     Lumen Capillary + Na = 140 mM + Na = 140 Na + Na = 10 mM Na + V = -70mV 3Na + X 2K + + Na Y Water   Renal  tubular  solute  transport   -­‐ Driven  by  Na-­‐K-­‐ATPase   -­‐ Absorption  into  cell  across  luminal  membrane  is   passive  (driven  by  electrochemical  gradient  of  sodium)   -­‐ Secretion  across  luminal  membrane  into  tubule  is   passive,  driven  by  sodium  movement  in  opposite  direction   -­‐ Transport  of  solutes  coupled  to  sodium  may  be   against  an  electrochemical  gradient   o Secondary  active  transport   -­‐ Water  moves  passively  down  osmotic  gradient   created  by  solute  transport     Solute  transport  across  tubules   -­‐ Sodium-­‐coupled  trans-­‐cellular  transport   o Sodium-­‐glucose,  sodium  phosphate,   sodium  chloride  etc   -­‐ Paracellular  transport  through  tight  junctions   driven  by  concentration  and/or  electrical  gradients   o Sodium,  chloride,  calcium,  magnesium  etc     Diuretic  drugs   -­‐ Among  most  commonly  prescribed  drugs  in  Canada   -­‐ They  block  lumenal  sodium  transporters  and  increase  sodium  excretion   -­‐ Each  type  of  diuretic  has  specific  target  sodium  transporter   -­‐ Most  common  target  loop  of  Henle,  distal  convoluted  tubule  or  collecting  duct   -­‐ Commonly  used  in  physiology  experiments     How  do  nephron  segments  differ?   -­‐ Specific  lumenal  transport  protei ns   -­‐ “Leakiness”  of  tubule  to  water  and  solute   o Nature  of  tight  junctions  connecting  cells   o Presence  of  channels  such  as  aquaporin   -­‐ Presence  of  hormone  receptors   –  aldosterone,  vasopressin  etc     Proximal  tubule   -­‐ Site  of  bulk  reabsorption  of  sodium,  chloride,   water,  potassium,  bicarbonate   -­‐ Most  important  lumenal  transport  protein  is  sodium -­‐hydrogen  exchanger  (NHE3)   o Mechanism  for  bicarbonate  reabsorption   -­‐ Site  of  glucose,  phosphate,  amino  acid,  cotransporter:  only  found  on  proximal  tubule   -­‐ Very  leaky  –  isotonic  reabsorption  of  sodium     Thick Ascending Thick  ascending  limb  of  loop  of  Henle   Limb -­‐ Reabsorbs  20-­‐30%  of  filtered  sodium   H 2 -­‐ Lumenal  transport  protein:  Na -­‐K-­‐2Cl  (NKCC2)   o Inhibited  by  diuretic  furosemide   -­‐ Very  impermeable  to  water   Na + -­‐ Fluid  leaving  thick  ascending  limb  always  less  concentrat ed  than   K + plasma  (hypotonic)     2Cl - -­‐ Salt  added  to  medullary  interstitium  without  water  concentrates   Na = 10 mM medulla  necessary  for  urine  concentration     Dilute lumen V = -70mV Distal  convoluted  tubule   fluid, concentrated -­‐ Reabsorbs  5-­‐10%  of  filtered  sodium,  water   interstitial fluid -­‐ Lumenal  sodium  transporter  is:   o Sodium  chloride  co-­‐transporter  (NCC)   o Inhibited  by  diuretic  group  thiazides   o Thiazides  are  less  potent  than  furosemide  because  this  segment  reabsorbs  less  sodium  than  loop   o Important  in  urinary  dilution     Cortical Collecting  duct   Collecting Duct -­‐ Reabsorbs  1-­‐3%  of  filtered  sodium   -­‐ Lumenal  sodium  transport  protein  is  epithelial  sodium   channel  (ENaC)   ENaC -­‐ Aldosterone  receptors  –  increases  number  and  open   + Na probability  of  sodium  channels  to  increase  sodium   reabsorption   Cl - -­‐ Vasopressin  (ADH)  receptors  –  increases  water   K + reabsorption  by  increasing  aquaporin  2   -­‐ Less  permeable  to  chloride  –  lumen  negative  PD  –   Na+ = 10 mM facilitates  potassium  secretion   V = -70mV -­‐ Low  capacity  but  capable  of  generating  large   P.D. - 60mV 0 concentration  gradients   Site  of  regulation  of  the  excretion  of:   -­‐ Sodium   -­‐ Potassium   -­‐ Water   -­‐ Ammonium  (acid-­‐base  regulation)     More  on  glucose   -­‐ One  of  the  most  studied  transport  processes   -­‐ Critical  to  avoid  losing  glucose  in  urine  (600  calories/day)   -­‐ Urine  is  normally  glucose  free   -­‐ Two  transporters:   Model of Sodium-Glucose SGLT 1 and SGLT 2 Cotransporter o One  more  proximal,  low  affinity,  high  capacity   o One  more  distal,  high  affinity,  low  capacity         Sodium-­‐glucose  transporters   -­‐ Early  proximal  tubule   o SGLT  II   o Na :  Glucose  =  1:1   o G /i o up  to  70/1   -­‐ Late  proximal  tubule   o SGLT  1   o Na :  glucose  =  2:1   o G /i o up  to  5,000/i   o Able  to  remove  all  glucose  from  lumen     Case  of  the  day:  sweet  pea   -­‐ This  young  man  has  renal   glycosuria   -­‐ Inherited  mutation  in  SGLT  2  gene   -­‐ Loss  of  function  of  SGLT  2   -­‐ Benign,  no  long  term  consequence   -­‐ Pharmacologic  inhibitors  of  SGLT  2  are  now  being  used  in  trials  to  treat  hyperglycemia  of  diabetes   o Lower  blood  glucose  and  reduce  weight     Summary  of  tubular  function   -­‐ Reabsorption  and  secretion  of  most  solutes  by  tubules  linked  to  sodium  and  Na -­‐K-­‐ATPase   -­‐ Sodium  crosses  lumenal  membrane  down  electrochemical  gradient   -­‐ Lumenal  sodium  transport  proteins  include   o Sodium  cotransporters   o Sodium  antiporters   o Sodium  channel   -­‐ Bulk  reabsorption  of  sodium,  water,  chloride,  bicarbonate   –  proximal  tubule  and  loop   -­‐ Regulation  of  sodium,  water,  chloride,  bicarbonate,  potassium   –  collecting  duct   -­‐ Proximal  tubule  –  leaky,  no  large  gradients   -­‐ Collecting  duct  –  tight-­‐  large  gradients  possible   -­‐ Organic  solute  transporters   –  all  proximal   -­‐ Diuretics  act  by  blocking  sodium  transport  across  lumenal  membrane  by  binding  to  lumenal  sodium  transport  protein   -­‐ Water  reabsorption  is  passive:   o Proximal  tubule  –  follows  sodium  isotonically   o Collecting  duct  –  depends  on  presence  of  ADH  and  aquaporin  2     Lecture  4  –  Sodium  balance     Agenda   -­‐ Regulation  of  sodium  excretion  by  kidney   -­‐ Renin/angiotensin/aldosterone  system   -­‐ Natriuretic  hormones   -­‐ Pathological  states:  sodium  retention  and  sodium  depletion     Case  of  the  day:  cholera  in  Haiti   -­‐ You  volunteer  in  medical  clinic  in  Haiti   -­‐ Denise  –  16YO  girl  brought  in  by  family   -­‐ 12hrs  ago  –  started  having  fever,  abdominal  cramps  and  profuse  watery  diarrhea  ~1L/h   -­‐ BP  90/50,  HR  130/min,  she  is  lethargic,  unable  to  drink,  sunken  eye s,  poor  skin  turgor   -­‐ What  are  you  doing  to  do  for  her?  (Knowing  diarrhea  fluid  is  high  in  sodium)     Overview   -­‐ Sodium  (salt)  critical  for  life   -­‐ Required  for  normal  blood  volume,  BP,  organ  perfusion   -­‐ Early  humans  probably  evolved  in  very  low  sodium  environment;  s alt  was  scarce   -­‐ Human  kidneys  are  designed  to  retain  sodium  to  maintain  blood  volume   -­‐ In  modern  times,  we  eat  too  much  salt,  leading  to  problems  like  high  BP   -­‐ Disorders  of  sodium  balance  are  very  common  in  humans   -­‐ We  may  lose  sodium  through  diarrhea,  sweating   o Result  in  low  ECF  volume,  low  BP,  shock   -­‐ We  may  retain  sodium  in  conditions  like  heart  failure   Hazard Ratio for All Cause Mortality by Normal and Recommended sodium intake o Results  in  edema,  weight  gain,  breathing  problems    ium Intake Is Sodium Bad for You? 1.8 mmol/day mg/day Tertiles of Salt Intake 1.7 1.6 Sodium intake Minimum required for life 10-20 200-450 mg/day 4000 5200 6600 1.5 1.4 Average in North America 150 3500 1.3 Relative risk of 1.2 Recommended maximum 100 2300 fatal stroke 1.00 1.60 2.33 1.1 1 Recommended 70 1600  um Intake and Risk of Death From Stroke in Japanese Men and Women Q1 Q2 Q3 Q4   Stroke 2004, 35:1543-1547 NHANES data for 12,000 people by quartile of dietary intake (Q1 lowest, Q4 highest) followed for 16 years (USA) Where  does  dietary  salt  come  from?   -­‐ Mainly  processed  foods  (75%)   -­‐ Bread,  cheese,  soup,  sauces,  meats,   restaurant  meals   -­‐ Very  little  from  salt  added  to  home  cooking  or  at  table   -­‐ “If  it  tastes  good,  its  probably  high  in  salt”  y Sodium Balance and the Kidney Sodium Balance and the Kidney Denise has cholera   Sodium in Diet Sodium in Diet Sodium in Diet sweating diarrhea diarrhea sweating Gut loss Skin loss Gut loss Skin loss 25% 75% 50% 25% Urine sodium Urine sodium decreases to 0 Normally, urine decreases if Sodium in urine with severe Sodium in urine sodium Sodium in urine 0 sodium losses excretion = there is loss from skin or 100% dietary sodium 50% from skin or gut intake gut       Sodium  excretion  by  kidneys   -­‐ Normally  dietary  sodium  =  urinary  sodium   o Can  use  24h  urine  collection  to  estimate  dietary  sodium   intake   -­‐ A  steady  state  condition  exists   -­‐ With  loss  of  sodium  from  gut  or  skin,  urine  sodium  excretion  decreases  to  maintain  normal  ECF  volume  and  steady   state   -­‐ The  kidney  can  excrete  urine  with  no  sodium  in  it   -­‐ How  accurately  does  kidney  maintain  ECF  volume  in  face  of  changing  intake  and  losses   -­‐ How  does  kidney  “know”  to  increase  or  decrease  excretion?     How  accurately  does  kidney  maintain  ECF  volume?   -­‐ An  experiment:  take  people  on  constant  sodium  intake  then  suddenly  increase  dietary  sodium   -­‐ When  sodium  intake  inc reases  (EG  50  à  300mmol/d)  it  takes  several  days  for  sodium  excretion  to  increase  to   300mmol/d)   -­‐ ECF  volume  increases  (+  sodium  balance)   -­‐ After  a  few  days,  sodium  intake  =  excretion,  a  new  steady  state  at  expanded  ECF  volume   -­‐ When  sodium  intake  decreases,  sod ium  excretion  does  not  decrease  immediately  so  ECF  volume  decreases   Change in Sodium Balance with Increase in Sodium Intake Clinical  relevance   -­‐ High  salt  diets  =  increased  ECF  volume   -­‐ Low  sodium  diets  =  low  ECF  volume   Dietary + Dietary Urine Na Na + -­‐ Dietary  sodium  is  a  risk  factor  for  high  BP   Urine -­‐ Reducing  sodium  intake  is  important  therapy  for:   mmol/day + o Edema  states  (CHF,  cirrhosis  with  ascites,  kidney   Na diseases)   o Hypertension     How  does  kidney  “know”  to  increase  or  decrease  sodium  excretion?   -­‐ Intravascular  volume  or  effective  circulating  volume  not   Weight/ECFV serum  sodium  concentration     What  is  effective  circulating   volume?   What Cardiovascular Receptors Assess Days Intravascular Volume? -­‐ How  well  cardiac  output  fills  arterial  system   -­‐ Effective  circulating  volume  is  low  when:   o Low  intravascular  volume  (diarrhea,  sweating,  hemorrhage  etc)   o Poor  heart  function  (congestive  heart  failure)   o Excessive  arterial  vasodilat▯tiJuxtaglomerular apparatus )   -­‐ Cardiovascular  receptors  see  these  three  states  the  same  way     What  cardiovascular  receptors  assess  intravascular  volume?  ors -­‐ Arterial  baroreceptors   -­‐ Juxtaglomerular  apparatus   -­‐taAtrial  stretch  receptors     Bowman’s capsule Efferent arteriole Ascending Glomerulus limb of loop of Henle Macula densa cells Proximal tubule Granular cells Afferent arteriole Endothelium (a) (b)     Renin-Angiotensin-Aldosterone System (1) Angiotensin II actions Angiotensinogen Figure 19-9 Renin Angiotensin I Angiotensin converting enzyme (ACE) Angiotensin II     Actions  of  angiotensin  II   -­‐ Peripheral  arteriolar  constrictor   o Increases  systemic  resistance  and  BP   -­‐ Stimulates  release  of  aldosterone  by  adrenal   o Aldosterone  increases  sodium  reabsorption   -­‐ Stimulates  proximal  tubule  sodium  reabsorption   o Through  sodium-­‐hydrogen  exchanger   -­‐ Stimulates  thirst  and  vasopressin   -­‐ Constricts  efferent  arteriole   o Helps  maintain  GFR     Regulation  of  renin  secretion   -­‐ Arterial  BP  (afferent  arteriolar  stretch,  macula  densa)   o Low  pressure  =  ↑  renin   -­‐ Sympathetic  nervous  system  (baroreceptors)   o ↑SNS  activity  =  ↑  renin   -­‐ Dietary  sodium   o Low  sodium  intake  =  ↑  renin     Renin  secretion  is  increased  with:   -­‐ Low  salt  diet  vs  high  salt  diet   -­‐ Diuretic  therapy   -­‐ Upright  posture  vs  recumbent   -­‐ Reduced  ECF  volume   o Diarrhea,  sweating,  blood  loss,  osmotic  diuresis   -­‐ Reduced  effective  circulating  volume   o Heart  failure     The  renin-­‐angiotensin-­‐aldosterone  system   -­‐ Multiple  effects  on  cardiovascular  system  and  kidney  to  raise  BP   -­‐ Increases  peripheral  arterial  resistance   Cortical Aldosterone -­‐ Reduced  sodium  excretion   Collecting Duct -­‐ Growth  factor  for  cardiac  myocytes,  arteries,  mesangium   +   ENaC Aldosterone   + MR Na -­‐ A  steroid  hormone  secreted  by  zona  glomerulosa  of  adrenal   - cortex   Cl + -­‐ Binds  to  mineralocorticoid  receptor  in  cortical  collecting  duct   K -­‐ Increases  activity  of  sodium  channel   o Increased  number  and  increased  open  probability   Na+ = 10 mM o Increases  sodium  absorption   V = -70mV P.D. - 60mV 0 o At  same  time  increases  excretion  of  potassium  and   hydrogen  ion     Atrial  natriuretic  peptide   -­‐ Discovered  in  Canada  ~1980  (de  Bold,  Sonnenberg)   -­‐ Secreted  by  atrial  myocytes  in  response  to  atrial  stretch   -­‐ Inhibits  collecting  duct  sodium  reabsorption   -­‐ Inhibits:  aldosterone,  SNS,  vasopressin,  increases  GFR     Factors  affecting  sodium  excretion   1. Reduced  GFR  =  reduced  filtered  sodium  (not  very  important)   2. Angiotensin  II  –  directly  stimulates  Na-­‐H  exchange  in  proximal  tubule   3. Aldosterone  –  stimulates  cortical  collecting  duct  sodium  reabsorption   4. Atrial  natriuretic  peptide  (from  atrial  stretch)  inhibits  sodium  reabsorption  from  MCD   However:  even  in  the  face  of  angiotensin  and  aldosterone  blockage,  humans  can  regulate  sodium  balance  so  system  is  far  more   complex  than  described  here     Extracellular  volume  depletion   +   -­‐ Excessive  sweating  (Na =  35mmol/L)   -­‐ Diarrhea  (Na =  100-­‐120mmol/L)   -­‐ Vomiting:  (Gastric  fluid  Na  =  10mM)   o Sodium  loss  in  urine  driven  by  bicarbonaturia   -­‐ Osmotic  diuresis  –  hyperglycemia   -­‐ Diuretics   -­‐ Blood  loss     Sodium  excess  states   -­‐ Congestive  heart  failure   o Low  cardiac  output  stimulates  sodium  retention   –  edema,  pulmonary  edema   -­‐ Cirrhosis  with  ascites   o Low  arterial  resistance  lowers  effective  circulating  volume,  stimulates  sodium  retention   -­‐ Kidney  disease   o Sodium  excretion  may  be  reduced     Renin-­‐angiotensin-­‐aldosterone  system  good  or  bad   -­‐ Evolutionary  adaptation  to  early  humans’  existent  in  hot  dry  environment  with  very  little  salt   -­‐ Very  effective  at  conserving  volume  and  BP   -­‐ But  in  high  salt  environment:   o Contributes  to  hypertension   o Aggravates  heart  failure  (fibrosis,  oxygen  demand,  reduces  peripheral  perfusion  etc)     Inhibition  of  renin-­‐angiotensin-­‐aldosterone  system   1. ACE  inhibitors  (Ramipril)   2. Angiotensin  receptor  blockers  (losartan)   3. Aldosterone  blocker  (spironolactone)   Useful  for:   -­‐ Congestive  heart  failure   -­‐ Hypertension   -­‐ Reducing  progression  of  chronic  kidney  disease   -­‐ Reducing  protein  loss  in  urine  in  CKD     Case  of  the  day:  cholera  in  Haiti   -­‐ Why  is  she  so  sick?   -­‐ Severe  depletion  of  sodium  because  of  high  stool   losses   -­‐ Very  low  ECF  volume   -­‐ Requires  immediate  intravenous  sodium  and   water  replacement   -­‐ Isotonic  saline  (150mmol/L)  –  will  likely  need  >10%  of  body  weight     What  if  she  was  able  to  drink?   –  What  would  you  give  her?     Oral  rehydration  fluid  
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