Renal System

• Creatinine, a normal breakdown product of muscle protein creatine, is an endogenous compound that meets the criteria. However, in humans, a small amount of creatinine is secreted into the urine in the proximal tubules. How accurate is it to estimate GFR?

  overestimate to GFR slightly
• In order for a substance's GFR to be calculated it can only be filtered, not secreted or reabsorbed
• In order to estimate renal blood flow, a substance must be freely filtered and completely secreted through tubular secretion
• Traits of Para-Aminohippurate (PAH):

  • freely filtered
  • at low concentration pI, all PAH escaping filtration is secreted by the tubule
  • all secreting nephrons of plasma are cleared of PAH
  • C_PAH = renal plasma flow (blood into kidney)
• A person is infused with PAH. After equilibration, plasma PAH is 0.05 mg/mL, urine PAH is 25 mg/mL, and the urine flows 1.5 mL/min. What's the RPF (renal plasma flow) of the person?What's the renal blood flow is the hematocrit is 0.4?

  750 mL/min

  1250 mL/min
• Reabsorption:

  1. proximal tubule = water, organic nutrients, glucose, sodium, potassium, chlorine, amino acids, vitamins
  2. descending loop of henle = water
  3. ascending loop of henle = sodium, potassium, chlorine, calcium, bicarbonate
  4. distal tubule = selective absorption of sodium and water and active secretion of ions and acids
  5. collecting duct = sodium, chlorine, urea, water (if ADH)
• Reabsorption principles:

  1. sodium is reabsorbed by active transport
  2. electrochemical gradient drives anion reabsorption, partially through aquaporins
  3. concentration of other solutes increases as fluid volume in lumen decreases and permeable solutes are reabsorbed by diffusion
• Renal threshold is the plasma concentration at which a specific compound or ion will begin appearing in urine (saturation of mediated transport)
• The renal threshold is the x-axis value and the transport maximum (T_M) is the y-axis value that represents the highest rate it could work
• GFR=115 mL/min, T_M for glucose = 287.5 mg/min. Calculate the renal threshold for glucose.

  2.5 mg/mL
• What's the glucose renal threshold when GFR = 275 mL/min and T_M = 100 mg/min? When her plasma concentration is 15 mg/mL, what's the glucose clearance?

  0.36 mg/mL

  268 mL/min
• Glucose reabsorption occurs primarily in the proximal tubule
• Glucose reabsorption:

  1. glucose concentration inside cells is higher than outside because the SGLT uses energy from existing sodium concentration gradient to move glucose against its gradient
  2. glucose diffuses across the basolateral membrane into peritubular capillaries, facilitated by GLUT1/GLUT2
• Sodium reabsorption in the proximal tubule:

  basolateral side = active transport

  apical side = symport, antiport, and leak channels

  1. sodium enters cell through membrane proteins, moving down its gradient
  2. sodium is pumped out the basolateral side through the sodium-potassium ATPase
• Sodium-linked active reabsorption in the proximal tubule:

  • NaHCO3 and sodium solutes are primarily reabsorbed in the first half
  • co-transport with glucose, amino acids, and organic solutes
  • counter-transport with hydrogen ions
• Sodium-linked active reabsorption in the proximal tubule:

  1. sodium moving down its gradient using SGLT protein pulls glucose into the cell against its concentration gradient
  2. glucose diffuses out of the basolateral side of the cell using the GLUT protein
  3. sodium is pumped out by the sodium-potassium ATPase
• Urea passive resorption in proximal tubule:

  • no active transporters for urea in the proximal tubule
  • passive reabsorption due to urea concentration gradient
  • transcellular and paracellular pathways
• Protein transcytosis in the proximal tubule:

  • some small proteins and peptides can pass through the filtration barrier
  • most filtered proteins are removed from filtrate in the proximal tubule
  • urea diffuses, plasma proteins use receptor mediated endocytosis (leave through metabolism or exocytosis)
  • renal digestion of small filtered proteins terminates peptide signals
• Proximal tubule secretion:

  protons act as the apical Na/H exchanger (NHE)

  ammonium ions act as the Na/NH4-antiporter

  1. Na/H-antiporter secretes protons
  2. protons in filtrate combine with filtered bicarbonate to form carbon dioxide
  3. carbon dioxide diffuses into cell and combines with water to form proton and bicarbonate
  4. protons are secreted then excreted
  5. bicarbonate is reabsorbed
  6. glutamine is metabolized to ammonium ion and bicarbonate
  7. NH4 is secreted and excreted
  8. bicarbonate is reabsorbed
• Organic compounds are transported across the proximal tubule epithelium primarily by secondary and tertiary active transport with broad specificity

  • organic anions = bile salts, urate, vitamins, PAH, penicilin, toxic chemicals
  • organic cations = creatinine, dopamine, epinephrine, atropine, morphine, cimentiaine, isoproterenol, procainamide
• Organic acid secretion in proximal tubule:

  1. direct active transport = Na/K ATPase keeps intracellular sodium low
  2. secondary indirect active transport = Na/dicarboxylate-transporter (NaDC) moves dicarboxylate inside the cell using energy stored in the sodium concentration gradient
  3. tertiary indirect active transport = the basolateral organic anion transporter (OAT) concentrates organic anions (OA-) inside the cell using dicarboxylate gradient
  4. organic anions enter lumen by facilitated diffusion
• If a person takes both cimetidine (H2 antagonist to treat gastric ulcers) and procainamide (an antiarrhythimc medicine) then both their concentrations will be increased inside the body because they're competing to be excreted
• The clearance of penicilin is larger than GFR (F+S)
• Loop of Henle Reabsorption:

  • 30% of filtrate reaches here
  • reabsorbs 15% filtered water and 25% filtered salt, which are not reabsorbed proportionally because the thin and thick ascending have different absorption capacities
  • the 2 parallel loop of henle segments have different permeabilities
• Permeabilities of the parts of the loop of Henle:

  • thin descending = permeable to water and moderately permeable to urea and ions
  • thin ascending = impermeable to water and permeable to ions
  • thick ascending = impermeable to water and ions and actively pumps out sodium and chloride
• Distal tubule and collecting ducts reabsorb sodium, chloride (aldosterone sensitive), and water (ADH sensitive)
• Distal tubule and collecting duct secrete potassium (aldosterone sensitive), protons (PH dependent), NH4, organic ions, penicilin, and creatinine
• potassium exchanges for sodium and protons exchange for potassium in the distal tubule and collecting duct
• Acidosis:

  • type A intercalated discs
  • extra protons build up in the blood (low pH)
  • ATPase on the apical side pumps protons into the lumen to be secreted in the urine by bringing protons into the A cell as carbon dioxide (through combination with bicarbonate)
  • potassium filtered in the lumen is brought into the cell to be reabsorbed into the blood
• Alkalosis:

  • type B intercalated discs
  • low protons in the blood (high pH)
  • ATPase in the basolateral side brings in protons, which is made in the cell by taking apart carbon dioxide
  • chloride is reabsorbed from the lumen, while bicarbonate and potassium are excreted
• ADH sensitive water reabsorption (DT and CD):

  1. vasopression binds to membrane receptor
  2. receptor activates cAMP secondary messenger system
  3. cell inserts aquaporins into apical membrane
  4. water is absorbed by osmosis into the blood
• Vasopressin (ADH) causes the insertion of water pores called aquaporins into the apical membrane
• Vasopressin secretion is stimulated by:

  • osmolarity greater than 280 mOsm sensed by the hypothalamus
  • decrease in arterial strech due to decreased blood volume
  • decrease in blood pressure
• Excessive Hydration reaction:

  1. low blood osmolarity (less available solutes)
  2. decreased ADH secretion
  3. removal of water channels from collecting duct
  4. low water reabsorption by osmosis
  5. production of large urine volume
• Dehydration reaction:

  1. high blood osmolarity (less available solutes)
  2. increased ADH secretion
  3. insertion of water channels from collecting duct
  4. high water reabsorption by osmosis
  5. production of low urine volume
• Aldosterone sensitive sodium reabsorption in distal tubule and collecting duct:

  1. aldosterone combines with cytoplasmic receptor
  2. hormone-receptor complex initiates transcription in nucleus
  3. new protein channels and pumps form
  4. aldosterone-induced proteins modify existing proteins
  5. results in increased sodium reabsorption and potassium secretion
• Aldosterone is stimulated by:

  • decrease in blood pressure (through renin-angiotensin II)
  • increase in extracellular potassium concentration
• increase in potassium concentration stimulates aldosterone secretion to prevent hyperkalemia (leads to cardiac arrhythmias)
• increase in potassium plasma concentration causes an increase in aldosterone which causes an increase in potassium tubular secretion in exchange for sodium
• The medullary osmotic gradient is established and maintained by the juxtamedullary nephrons and vasa recta and the collecting duct exploits this gradient to form concentrated urine