The Nephron: GFR

Question 1

Hydrostatic Pressue

Answer 1

Hydrostatic pressure is the force exerted at any given point by a fluid on/against a vessel wall.

HP favors fluid leaving the vessel (ultrafiltration)

Question 2

Oncotic Pressure

Answer 2

Oncotic pressure is the force exerted by proteins in a blood vessel’s plasma.

It favors fluid re-entering the vessel (reabsorption).

Question 3

Relationship of glomerulus to Bowman’s capsule

Answer 3

• The glomerulus, a bed of relatively impermeable glomerular capillaries, lies almost (≅5/6) completely surrounded by Bowman’s capsule
• Substances in plasma in these capillaries (except for protein and RBCs) are filtered into Bowman’s capsule to enter the glomerular filtrate
• How is this critical for the filtration process?
  
  • Urinary excretion rate = filtration rate - reabsorption rate + secretion rate
    
    • Filtration only substances
      
      • e.g., creatinine
      • urinary excretion rate = filtration rate
    • Partially reabsorbed substances
      
      • e.g., Na+, Cl-, HCO3- ions
      • urinary excretion rate = filtration rate - reabsorption rate
    • Completely reabsorbed substances
      
      • e.g., amino acids, glucose
      • urinary excretion rate = filtration rate - reabsorption rate = 0%
    • Completely secreted substances
      
      • e.g., organic acids and bases
      • urinary excretion rate = filtration rate + secretion rate = 100%
  • Each substance in the plasma has a different combination of these rates and that combination determines the rate at which it will be excreted in the urine.

Question 4

Determinants of Glomerular Filtration Rate (GFR)

Answer 4

• GFR = K_f x net filtration pressure
• Balance of hydrostatic and oncotic forces acting across the capillary membrane = net filtration pressure
  
  • ​hydrostatic P inside glomerular capillaries (P_G)→ promotes filtration
  • hydrostatic P inside Bowman’s capsule (P_B) → opposes filtration
  • oncotic P inside glomerular capillaries (ΠG) → opposes filtration
  • oncotic P inside Bowman’s capsule (ΠB) → promotes filtration (under normal conditions Π_B = 0)
• capillary filtration coefficient (K_f) = permeability x SA of capillaries
  
  • cannot be measured directly, use K_f = GFR/net filtration pressure to calculate
  • usually is not the 1° mechanism for normal day-to-day ∆s in GFR
  • Pathologically can ⇣GFR (HTN & DMII → thickening of capillary basement mb → ⇣K_f)
• Glomerular capillaries have a higher rate of filtration than other capillaries because thay have a:
  
  • higher hydrostatic pressure
  • large K_f
• Normal average adult GFR = 125 mL/min (or 180 L/day, which means that entire plasma volume of ≅3 L is filtered and processed ≅60 times a day!)

Question 5

Glomerular capillary membrane

Answer 5

• Is composed of three major layers (instead of usual two) from inner to outer:
  
  • Endothelium
    
    • perforated by thousands of fenestrae, which help ⇡ the filtration rate
    • endothelial cells have fixed ⊖ charges that prevent the passage of proteins
  • Basement membrane = meshwork of
    
    • Collagen
    • Proteoglycan fibrillae
      
      • have large spaces water and small solutes can pass through
      • proteoglycans have strong ⊖ electrical charges that prevent filtration of plasma proteins
  • Epithelium with epithelial cells called podocytes
    
    • ​Not continuous
    • Have long foot-like processes that encircle the outer surface of the capillaries
    • Slit pores between the feet are the areas through which the glomerular filtrate moves
    • Also have ⊖ charges to restrict protein filtration (plasma proteins like albumin are ⊖ and repelled away)

Question 6

Minimal change nephropathy

Answer 6

• No noticeable changes in kidney histoloy but,
• ⊖ charges on basement mb are lost, so some low-MW proteins, like albumin are filtered and excreted in the urine → proteinuria or albuminuria

Question 7

Increased Bowman’s Capsule Hydrostatic Pressure (P_B)

Answer 7

• Decreases GFR
• P_B ≅18 mmHg, under normal conditions
• ∆s in P_B do not serve as primary means of regulating GFR
• Pathologically, obstruction of the urinary tract →⇡⇡P_B → ⇣⇣GF
  
  • e.g., ureter stones from calcium or uric acid precipitation → obstruction
  • can eventually cause hydronephrosis (= distention and dilation of renal pelvis and calyces) and lead to kidney destruction

Question 8

Increased Glomerular Capillary Oncotic Pressure (Π_G)

Answer 8

• Decreases GFR
• Influenced by:
  
  • the arterial plasma oncotic pressure
    
    • increasing this raises Π_G and ⇣GFR
  • the fraction of plasma filtered by the glomerula capillaries [filtration fraction (FF)]
    
    • FF = GFR/renal plasma flow
    • increasing this also raises Π_G and ⇣GFR
    • This is how changes in renal blood flow can influence GFR independently of glomerular hydrostatic pressure. If P_Gis constant:
      
      • ⇡renal blood flow → ⇡GFR
      • ⇣ renal blood flow → ⇣GFR

Question 9

Increased Glomerular Capillary Hydrostatic Pressure (P_G)

Answer 9

• Increases GFR
• P_G ≅ 60 mmHg, in normal conditions
• Changes on P_G serve as the primary means of physiologic regulation GFR
  
  • ⇡P_G → ⇡GFR
  • ⇣P_G → ⇣GFR
• P_G is determined by 3 physiologically controlled variables:
  
  • arterial pressure
    
    • If ⇡, tends to ⇡P_G, ∴ ⇡GFR
  • afferent arteriolar resistance (R_A)
    
    • If ⇡R_A, ⇣P_G, and ∴ ⇣GFR
    • If ⇣R_A, ⇡ P_{<span>G</span>}, and ∴ ⇡GFR
  • efferent arteriolar resistance (R_E)
    
    • If ⇡R_E, ⇡ P_G, and ∴ ⇡GFR slightly
      
      • only if slight constriction, so that renal blood flow is not reduced
      • severe constriction reduces renal blood flow and tends to ⇣GFR
      • BIPHASIC effect
    • If ⇣R_E, ⇣P_G, and ∴ ⇣GFR

Question 10

Determinants of Renal Blood Flow

Answer 10

• Renal blood flow is determined by two things:
  
  • Pressure gradient across the renal vasculature
    
    • (Renal a. pressure - Renal v. pressure)
  • Total renal vascular resistance
• ∴ RBF = (RAP-RVP) / TRVR
• RAP ≅ systemic arterial pressure
• RVP ≅ 3 - 4 mmHg, under most conditions
• Most of TRVR lies in afferent arterioles, interlobular aa., and efferent arterioles. R here is controlled by:
  
  • sympathetic NS
  • various hormones
  • local internal renal control mechanisms
• RBF to renal medulla via vasa recta is low compared to RBF to renal cortex

Question 11

Control of GFR and RBF

Answer 11

• Strong Sympathetic NS activation → ⇣GFR
  
  • causes constriction of renal arterioles (via α₁-adrenergic receptors) → ⇣RBF and ⇣(or not ∆, due to efferent arteriole constriction) GFR
  • most important for reducing GFR in acute disturbances like brain ischemia or severe hemorrhage, so that blood preferentially shunts to the brain and heart.
  • To prevent excessive arteriolar constriction and renal ischemia, AngII and NE stimulate glomerular prostaglandin production.
• Hormones
  
  • E and NE released from adrenal medulla → renal arteriole constriction → ⇣GFR and RBF
    
    • Also have most influence in severe conditions
  • Angiotensin II (AngII)
    
    • low levels AngII → efferent arteriole constriction → ⇡GFR, but ⇣RBF
      
      • afferent arteriole not very sensitive to AngII because of the action of vasodilators released there (see below)
    • high levels Ang II → afferent and efferent arteriole constriction → ⇣RBF and GFR
• Autacoids
  
  • Endothelin = vasoconstrictor → ⇣GFR & RBF
    
    • physiologic role not understood other than in hemostasis
  • endothelium-derived Nitric Oxide (NO) → renal vasodilation → ⇣TRVR → ⇡GFR
  • Prostaglandins (PGE₂ and PGI₂)→ renal vasodilation → ⇣TRVR → ⇡RBF and GFR
  • Bradykinin → renal vasodilation → ⇣TRVR → ⇡RBF and GFR

Question 12

Autoregulation of RBF and GFR

Answer 12

= relative constancy of RBF and GFR despite ∆s in BP due to intrinsic feedback mechanisms of the kidney (even outside the body!)

• Purpose is to allow precise control of excretion
• Tubuloglomerular feedback
  
  • Consists of an afferent arteriole feedback mechanism and a (slightly different) efferent arteriole feedback mechanism
  • Macula densa senses changes in GFR by the concentration of NaCl present within its cells
    
    • ⇣[NaCl] means ⇣GFR → ⇡R_E (due to efferent arteriole constriction via ⇡renin and AngII) and ⇣R_A (due to afferent arteriole dilation via direct action from macula densa possibly with adenosine or nitric oxide release) → ⇡P_G → ⇡GFR
    • ⇡[NaCl] means ⇡GFR → ⇣ R_E and ⇡R_A → ⇣P_G → ⇣GFR
• Myogenic Autoregulation
  
  • Increased arterial pressure → Stretching of BVs → reflex contraction of arteriolar smooth muscle → ⇡R_A → ⇣RBF and GFR (balancing out the initial increase in RBF and GFR from the high BP)