1 - Tubular Secretion

Question 1

Objectives: Understand the principles of renal tubular secretion

Question 2

Objectives: Explain major examples of substances secreted

PAH

Clinical measurement?

What does secretion exhibit?

By what equation can it be used to measure the above?

Answer 2

• Organic Anion
• Used to measre effective renal plasma flow (ERPF)
• Secretion exhibits competition, T_M limitation
• Undergoes no significant tubular reabsorption–e.g. Amount entering = amount excreted
• Equation:
  
  • Excreted Load = Filtered Load + Secreted Load
  • (U_PAH x V) = (P_PAH x C_IN) + T_PAH
  • mg/min = mg/min + mg/min (units)

Question 3

Objective: When given the Effective Renal Plasma Flow (ERPF), how can the true RPF be obtained?

Answer 3

• By dividing ERPF by Extraction Ration (E) for PAH
  
  • E = fraction of substance which is removed from the plasma by kidneys
  • E = (A-V) / A
    
    • A = [Concentration] in Renal Arterial Plasma
    • V= [Concentration] in Renal Venous Plasma
• RPF = ERPF / E_PAH = C_PAH / E_PAH

Question 4

Objectives: Explain renal handling of weak organic acids and bases

Answer 4

• In nonionized form (HA, B) can undergo passive reabsorption or passive secretion
• Tubular transports is thus pH dependent
  
  • ​Acidic Tubular Fluid: Weak acids are uncharged and move by diffusion
    
    • Acidosis: Urine = acidic, excretion of organic anions decreases because they are reabsorbed
    • Alkalosis: Urine = alkaline, excretion of organic anions increases because they become “trapped” and are unable to be reabsorbed
  • Alkaline Tubular Fluid: Weak bases are uncharged and move by diffusion
    
    • Urine is normally acidic, thus weak bases are charged, and excreted

Question 5

Explain tubular secretion for organic anions and organic cations

Answer 5

• Organic Anions:
  
  • Low Sensitivity
  • Maximum transport rate
  • Mechanisms:
    
    • Enter: OAT; a-KG Antiporter mechanism
      
      • ​NaDC (Na in) maintains gradient
    • Exit: MRP2, OAT4
  • Exampls: cAMP, cGMP, Postaglandins, Vitamin C, antibiotics, diuretics
• Organic Cations:
  
  • Low Sensitivity
  • Maximum transport rate
  • Mechanisms:
    
    • Enter: Passive Diffusion or OCT-uniporter
      
      • ​OCTs more against gradient, driven by cell-negative potential difference
    • Exit: OC-H Antiporters (OCTN), MDR1
  • Examples: Creatinine, dopamine, epinephrine, norepinephrine,

Question 6

Explain renal handling of urate (uric acid)

What is it an example of?

How is this related to gout?

Answer 6

• >90% filtered urate is reabsorbed in early proximal tubule
• Active tubular secretion in late proximal tubule
  
  • This portion is homeostatically regulated
• Example of bi-directional transport
• Hyperuricemia = Gout
  
  • Decreased Filtration Rate + Maintained Tubular Reabsorption
  • Increased Reabsorption
  • Decreased Secretion
  • Increased Production

Question 7

Explain renal handling of potassium

What is it an example of?

Answer 7

• Kidneys primary regulator of K⁺ balance; net reabsorption of filtered K+; bi-directional transport
• Proximal Tubule - 67% Reabsorbed
• Thick Ascending Limb of LoH - 20% Reabsorbed
• Will continue to reabsorb at Distal Tubule and beyond; increasing with high K diet
• Mainly regulated via Secretion via Aldosterone homeostatic regulation (principal cells)

Question 8

Explain the mechanisms for K⁺ transport

Proximal Tubule

Distal Tubule

How is K+ secretion determined?

How do diuretics affect this?

How does low K+ intake affect this?

Answer 8

• Proximal Tubule - Both active and passive
  
  • Active - Pumps on luminal/basolateral cell membranes
  • Passive - most K+ reabsorption in Prox. Tubule
• Distal Tubule - K+ reabsorption and secretion are both passive and active and cell specific
  
  • Determinants:
    
    • [K⁺] gradient between principal cell and tubule fluid
      
      • K+ secretion will increase when ICF [K+] is high and/or TF [K+] is low
    • Flow Rate of Tubular Fluid (Increase = Increase Secretion)
      
      • Increased TF Flow = Low TF [K+] = Increased [K+] gradient = Increased Secretion into TF
      • Diuretics decrease Na+ reabsorption in Ascending Thick Limb of the LoH, and causes increased TF flow in Late Distal Tubule, which increases K+ secretion
      • Low K Intake ICF [K] is low, and luminal permeability to potassium will be low–increased flow will have no effect on K secretion

Question 9

How is K+ secretion determined?

How do diuretics affect this?

How does low K+ intake affect this?

Answer 9

• [K+] gradient between principal cell and tubule fluid
  
  • K+ secretion will increase when ICF [K+] is high and/or TF [K+] is low
• Flow Rate of Tubular Fluid (Increase = Increase Secretion)
  
  • Increased TF Flow = Low TF [K+] = Increased [K+] gradient = Increased Secretion into TF
  • Diuretics decrease Na+ reabsorption in Ascending Thick Limb of the LoH, and causes increased TF flow in Late Distal Tubule, which increases K+ secretion
  • Low K Intake = ICF [K] is low, and luminal permeability to potassium will be low–increased flow will have no effect on K secretion
• Electrical gradient across luminal embrane of K+ secreting cells
  
  • Na+ reabsorption causes lumen to become more negative, enhancing secretion of K+
  • Poorly rebsorbed anions (Bicarb) in the TF will maintain lumen negative potention and promote K+ secretion
• Aldosterone
  
  • ​Stimulates secretion of K+/H+ and reabsorption of Na+
  • Increases Na / K channels, and Na-K-ATPase Activity

Question 10

What are the primary causes for hypermineralcorticoidism?

Answer 10

• Hypertension (Increased Na+ Reabsorption)
• Hypokalemia (Increased K+ Secretion)
• Metabolic Alkalosis (Increased H+ Secretion)

Question 11

What does alkalosis result in?

Answer 11

Increase [K+] in prinicpal cells

Leads to increased [K+] secretion and potassium depletion

Question 12

What is the result of Acute vs Chronic Acidosis on K+ renal handling?

Answer 12

• Acute Acidosis:
  
  • Decrease [K+] in principal cells
  • Decrease [K+] secretion
  • = Acute potassium retention
• Chronic Acidosis:
  
  • Depression of H₂O and NaCl reabsorption in Proximal Tubule
  • Increase Distal TF Flow
  • Increased K+ secretion into TF
  • = Chronic potassium depletion

Question 13

Explain a clinical solution to Aspirin Poisoning

Answer 13

Alkalinizing the urine

Acetylsalicylate ion formed and “trapped” in nephron, thus increasing excretion of aspirin

Question 14

Explain the concept of forced diuresis

Answer 14

• Forced Diuresis is intentional change of pH of urine
• Forces excretion of acidic or alkaline drugs, will excrete OPPOSITE of blood/urine pH
• Forced Alkaline Diuresis: Furosemide (diuretic) + Sodium Bicarbonate
  
  • Excrete Acidic Drugs: Salicylates, Barbiturates, Lithium
• Forced Acidic Diuresis: Furosemide (diuretic) + Vitamin C
  
  • Excrete Basic Drugs: Cocaine, Amphetamine, Quinine, Strychnine
  • *Forced acidic rarely used, only enhances renal clearance a bit