Renal Physiology

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jknell
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206086
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Renal Physiology
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2013-03-10 00:45:59
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  1. Renal Embryology
    • 1. Intermediate mesoderm forms urogenital ridge
    • 2. Part of urogenital ridge forms nephrogenic cord
    • 3. Nephrogenic cord develops into:
    •      -pronephros
    •      -mesonephros
    •      -metanephros
  2. Pronephros
    • -develops at week 4
    • -most rostral portion
    • -degenerates, never functional
  3. Mesonephros
    • -functions as interim kidney for 1st trimester
    • -later contributes to male genital system (Wolffian Duct)
  4. Metanephros
    • -permanent
    • -first appears during 5th week of gestation
    • -nephrogenesis continues through 32-36 weeks
    • -most caudal portion

    • Ureteric Bud
    • -derived from the caudal end of the mesonephros
    • -gives rise to ureter, renal pelvis, calyces and collecting ducts
    • -fully canalyzed by 10th week

    • Metanephric Mesenchyme
    • -ureteric bud penetrates metanephric mesenchyme
    • -interaction induces differentiation and formation of glomerulus through distal convoluted tubule
    • *aberrant interaction can result in congenital malformations
  5. Kidney Anatomy
    • Ureter → major calyx → minor calyx → papilla → pyramid

    Renal artery → segmental artery → interlobar artery → arcuate artery → interlobular artery → afferent arteriole
  6. Glomerular Structure


    • Layers of Glomerular Filtration
    • 1. Vascular endothelium (fenestrated)
    • 2. Basement membrane (negative charge)
    • 3. Podocyte foot processes (visceral epithelial cells)

    • Mesangial cells:
    • -phagocytic properties
    • -contractile properties
    • -synthesize ECM

    • Juxtaglomerular cells:
    • -smooth muscle cells in btwn macula dense and efferent/afferent arterioles
    • -secrete renin (tubuloglomerular feedback)

    • Macula Densa:
    • -epithelium of thick ascending limb
    • -lies in close proximity to its parent glomerulus
    • -detect changes in tubular ionic composition
    • -send signals to JG cells to secrete renin
  7. Ureters: Course
    Ureters pass under uterine artery and under ductus deferens (retroperitoneal)

    "Water (ureters) under the bridge (uterine artery, vas deferens)"

  8. Fluid Compartments
    Total body water = 60% Total body weight (kgs)

    • TBW
    • 1/3 Extracellular Fluid
    • 2/3 Intracellular Fluid

    • Extracellular Fluid
    • 1/4 Plasma
    • 3/4 Interstitial Volume

    • 60-40-20 Rule (% of body weight)
    • -60% TBW
    • -40% ICF
    • -20% ECF

    "HIKIN': HIgh K INtracellular"

    Plasma volume can be measured by radiolabeled albumin

    ECF volume measured by inulin, osmolarity = 290 mOsm/L
  9. Glomerular Filtration Barrier
    -responsible for filtration of plasma according to size and net charge

    • Composed of:
    • 1. Fenestrated capillary endothelium (size barrier)
    • 2. Fused basement membrane with heparan sulfate (negative charge barrier)
    • 3. Epithelial layer (podocyte foot processes)

    *Charge barrier is lost in nephrotic syndrome → albuminuria, hypoproteinemia, generalized edema and hyperlipidemia
  10. Renal Clearance
    Cx = UxV/Px

    • where:
    • Cx is clearance (mL/min)
    • Ux is urine concentration of x
    • Px is plasma concentration of x
    • V is urine flow rate

    Volume of plasma from which the substance is completely cleared per unit time

    • Cx < GFR: net tubular reabsorption of X
    • Cx > GFR: net tubular secretion of X
    • Cx = GFR: no net secretion or reabsorption
  11. Glomerular Filtration Rate
    • Calculated by:
    • -inulin clearance
    • -inulin is freely filtered and neither reabsorbed nor secreted

    GFR = Cinulin (UV/P)

    • Also calculated by Starling's Law:
    • =Kf[(PGC-PBS) - (πGCBS)]
    • BS usually equals zero

    Normal GFR = 100 mL/min

    • Creatinine Clearance and GFR:
    • -an approximate measure of GFR
    • -slightly overestimates GFR b/c creatinine is moderately secreted by the renal tubules

    Incremental reductions in GFR define the stages of CKD
  12. Effective Renal Plasma flow
    • -can be estimated using PAH clearance
    • -PAH is both filtered and actively secreted in the PT (all PAH entering the kidney is excreted)

    ERPF = CPAH

    RBF = RPF/(1- Hct)

    ERPF underestimates true RPF by ~ 10%
  13. Filtration
    • Filtration Fraction (FF) = GFR/RPF
    • -Normal FF = 2-%

    Filtered Load = GFR x plasma concentration

    • Things that dilate afferent arteriole:
    • -PGs (inhibited by NSAIDs)
    • -↑RPF, ↑GFR → FF remains constant


    • Things that constrict efferent arteriole:
    • -AngII (inhibited by ACEIs)
    • -↓RPF, ↑GFR → FF increases
  14. Changes in Glomerular Dynamics
  15. Calculation of reabsorption and secretion rate
    -Filtered Load Equation
    -Excretion Rate Equation
    -Reabsorption Equation
    -Secretion Equation
    Filtered Load = GFR x Px

    Excretion Rate = V x Ux

    Reabsorption = filtered - excreted

    Secretion = excreted - filtered
  16. Glucose Clearance
    -normal plasma levels of glucose are completely reabsorbed in the proximal tubule by Na+/glucose cotransporter

    -plasma glucose ~ 160 mg/dL → glucosuria

    -Tm = all transporters are fully saturated, 350 mg/dL

    Glucosuria: important clinical clue to DM

    Normal pregnancy reduce reabsorption of glucose and amino acids in the PT → glucosuria and aminoaciduria
  17. Amino Acid Clearance
    -Sodium-dependent transporters in PT reabsorb AAs

    *Hartnup's Disease: deficiency of neutral AA (tryptophan) transporter → pellagra (4D's: diarrhea, dermatitis, dementia, death)
  18. Proximal Tubule Functions


    • -contains brush border
    • -isotonic reabsorption
    • -generates and secretes ammonia (acts as a buffer for secreted H+)

    • Reabsorbs all:
    • -glucose
    • -AAs

    • Reabsorbs Most:
    • -bicarb
    • -Na+
    • -Cl-
    • -phosphate
    • -water

    • Na+ Reabsorption
    • -Na+/solute cotransport (glucose, AAs)
    • -NHE
    • -65-80% of Na+ reabsorbed

    • Bicarbonate Reabsorption:
    • -bicarb combines with H+ (secreted by NHE) in tubular lumen → CO2 (needs CA)
    • -CO2 diffuses into tubular epithelial cells
    • -not direct reabsorption

    -85-90% of bicarb reabsorbed


    • Hormonal Regulation:
    • 1. PTH
    • -inhibits Na/Phosphate cotransport → phosphate excretion
    • 2. AngII
    • -stimulates NHE → increased Na, H2O and HCO3 absorption
    • -permits contraction alkalosis

    • Pharmacology:
    • -Carbonic Anhydrase Inhibitors
  19. Thin Descending Loop of Henle
    • Functions:
    • -passively reabsorbs water via medullary hypertonicity
    • -concentrating segment
    • -makes urine hypertonic

    • Physiology:
    • -permeable to water (AQP1)
    • -impermeable to NaCl
  20. Thick Ascending Loop of Henle


    • Functions:
    • -actively reabsorbs Na+(10-20%), K+ and Cl- (NKCC2 transporter)
    • -K+ backleak by ROMK channel (+ lumen)
    • -indirectly induces paracellular reabsorption of Mg2+ and Ca2+ through (+) lumen potential

    • Physiology:
    • -impermeable to water
    • -makes urine less concentrated

    • Pharmacology:
    • -Loop diuretics block NKCC2
  21. Distal Convoluted Tubule


    • Functions:
    • -early DCT actively absorbs Na+ (5-10%), Cl- (NCC Transporter)
    • -makes urine hypotonic

    • Hormonal Regulation:
    • 1. PTH: increases Na+/Ca2+ exchanger activity (sets up a gradient for Ca2+ reabsorption)

    • Pharmacology:
    • -Thiazide diuretics block NCC
  22. Collecting Duct


    • Functions:
    • 1. Principal Cells
    • -ENaC: Na+ reabsorption (3-5%)
    • -ROMK: passive secretion of K+
    • 2. Intercalated Cells
    •      -Type A: secrete H+
    •      -Type B: secrete HCO3- for Cl- (pendrin)

    • **Na+ reabsorption in exchange for secreting K+ and H+ (lumen potential) (regulated by aldosterone)
    • **water reabsorption regulated by ADH

    • Hormonal Regulation:
    • 1. Aldosterone: acts on mineralocorticoid receptor → insertion of ENac on luminal side

    2. ADH: acts at V2 receptor → insertion of aquaporin on luminal side

    • Pharmacology:
    • 1. K+ Sparing Diuretics (inhibit ENaC)
    • 2. Aldosterone Antagonists
  23. Relative Concentrations along Proximal Tubule


    • TF/P Ratio:
    • -tubular fluid to plasma ratio

    • TF/P > 1:
    • -solute reabsorbed less quickly than water
    • -Urea
    • -Cl-

    • TF/P = 1:
    • -solute and water reabsorbed at the same time
    • -Na+
    • -K+

    • TF/P < 1:
    • -solute is reabsorbed more quickly than water
    • -Phosphate
    • -HCO3-
    • -Amino Acids
    • -Glucose

    • Cl- Reabsorption:
    • -occurs at a slower rate than Na+ in the proximal 1/3 of the PT and then matches the rate of Na+ reabsorption more distally (thus its relative concentration increases before it plateaus)
  24. Renin-Angiotensin-Aldosterone System


    • Angiotensinogen:
    • -produced by liver

    • Renin:
    • -produced by JG cells
    • -converts angiotensinogen to angiotensin I
    • -release stimulated by: ↓BP, ↓Na+ delivery to MD cells, ↑ sympathetic tone (β1 receptors)

    • ACE:
    • -expressed on surface of renal and pulmonary epithelium
    • -converts Angiotensin I to Angiotensin II
    • *also breaks down bradykinin

  25. Angiotensin II
    • 1. Vasoconstriction (AT1 receptors on SM) → HTN
    • 2. Vasoconstriction of efferent > afferent arteriole (↑FF to preserve renal function in low volume states)
    • 3. Aldosterone secretion from adrenal gland (Na+ and H2O retention)
    • 4. ADH secretion from posterior pituitary (H2O reabsorption)
    • 5. ↑ PT Na+/H+ activity (Na+, HCO3-, H2O reabsorption → can permit contraction alkalosis)
    • 6. Stimulates hypothalamus → thirst

    • Affects baroreceptor function:
    • -limits reflex bradycardia, which normally accompanies pressor effects
    • -helps maintain blood volume and blood pressure
  26. ANP
    • -released from atria in response to increased volume
    • -may act as a check on RAAS
    • -relaxes vascular smooth muscle via cGMP
    • -causes ↑GFR, ↓renin
  27. ADH
    • -released from posterior pituitary
    • -primarily regulates osmolarity but also responds to low blood volume (protect volume over tonicity)

    • Functions:
    • -increases aquaporin insertion in principal cells of collecting duct → H2O reabsorption
  28. Aldosterone
    -released from adrenal gland in response to ATII

    • Functions:
    • -↑ENaC and Na+/K+ ATPase insertion in principal cells (Na+ and water reabsorption)
    • -upregulates principal cell ROMK channels and intercalated cell H+ channels (enhances K+ and H+ excretion)

    • -primarily regulates blood volume
    • -in low volume states both ADH and aldo protect blood volume
  29. Juxtaglomerular Apparatus
    • Consists of:
    • -JG cells (modified smooth muscle of afferent arteriole)
    • -Macula densa (NaCl sensor, part of DCT)

    • JG cells secrete renin in response to:
    • -↓ renal BP
    • -↓ NaCl delivery to distal tubule
    • -↑ sympathetic tone

    • β-Blockers:
    • -decrease BP by inhibiting renin release from JG cells
  30. Kidney Endocrine Functions
    • 1. Erythropoietin
    • -released by interstitial cells in the peritubular capillary bed in response to hypoxia

    • 2. 1,25-(OH)2 Vitamin D
    • -PT cells convert 25-OH vitamin D to active form
    • -PTH inhibits 1α-hydroxylase

    • 3. Renin
    • -secreted by JG cells in response to ↓ renal arterial pressure and ↑ renal sympathetic discharge (β1 effect)

    • 4. Prostaglandins
    • -paracrine secretion vasodilates the afferent arteriole to ↑GFR
    • **NSAIDs can cause acute renal failure by inhibiting PG synthesis, which keep the afferent arterioles vasodilated to maintain GFR
  31. Hormones acting on the Kidney
    • 1. ANP
    • -acts on PT
    • -secreted in response to increase atrial pressure
    • -causes increase in GFR and Na+ filtration with no compensatory Na+ reabsorption in distal nephron
    • -NET EFFECT: Na+ loss and volume loss

    • 2. PTH
    • -acts on PT, DCT
    • -secreted in response to: ↓ plasma Ca2+, ↑ plasma PO4 or ↓ plasma vitamin D

    -Causes: ↑ Ca2+ reabsorption (DCT), ↓ PO4 reabsorption (PT), ↑ vitD production, also ↑ Ca2+ and PO4 absorption from gut

    • 3. ATII
    • -secreted in response to: decreased BP
    • -Causes: efferent arteriole constriction leading to ↑GFR and ↑FF with compensatory Na+ reabsorption in proximal and distal nephron
    • -NET EFFECT: preservation of renal function in low volume state with simultaneous Na+ reabsorption to decrease additional volume loss

    • 4. Aldosterone
    • -acts at CD
    • -secreted in response to: decreased blood volume (by ATII) and increased plasma K+
    • -Causes: increased Na+ reabsorption, increased K+ secretion, increased H+ secretion

    • 5. ADH
    • -acts at CD
    • -secreted in response to: increased plasma osmolarity and decreased blood volume
    • -Causes: increased number of aquaporins and increases H2O reabsorption
  32. Shifts K+ OUT of cells (hyperkalemia)
    • "Patient with hyperkalemia? DO Insulin LAβ work"
    • Digitalis
    • HyperOsmolarity
    • Insulin deficiency
    • Lysis of cells
    • Acidosis
    • β-Antagonist
  33. Shifts K+ INTO cell (hypokalemia)
    "Insulin shifts K+ into cells"

    • Hypo-osmolarity
    • Insulin (↑ Na+/K+ ATPase)
    • Alkalosis
    • β-Agonist
  34. Electrolyte Disturbances: Na+
    • Low serum concentration
    • -nausea
    • -malaise
    • -stupor
    • -coma

    • High serum concentration:
    • -irritability
    • -stupor
    • -coma
  35. Electrolyte Disturbances: K+
    • Low serum concentration:
    • -U waves on EKG
    • -flattened T waves
    • -arrhythmias
    • -muscle weakness

    • High serum concentration:
    • -wide QRS
    • -peaked T waves
    • -arrhythmias
    • -muscle weakness
  36. Electrolyte Disturbances: Ca2+
    • Low serum concentration:
    • -tetany
    • -seizures

    • High serum concentration:
    • -stones (renal)
    • -bones (pain)
    • -groans (abdominal pain)
    • -psychiatric overtones (anxiety, altered mental status)
    • -not necessarily calciuria
  37. Electrolyte Distrubances: Mg2+
    • Low serum concentration:
    • -tetany
    • -arrhythmias

    • High serum concentration:
    • -decrease DTRs
    • -lethargy
    • -bradycardia
    • -hypotension
    • -cardiac arrest
    • -hypocalcemia
  38. Electrolyte Disturbances: PO4
    • Low serum concentration:
    • -bone loss
    • -osteomalacia

    • High serum concentration:
    • -renal stones
    • -metastatic calcifications
    • -hypocalcemia

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