Tubular secretion and renal handling of potassium Stephen P. DiBartola, DVM Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus OH 43210

Terminology Transepithelial versus transmembrane potential difference Luminal versus basolateral membranes Transcellular versus paracellular transport

Luminal surface Basolateral surface Epithelial tight junctions Just think of it as a six-pack

Substances secreted by the renal tubules Weak acids (organic anions) or weak bases (organic cations)Weak acids (organic anions) or weak bases (organic cations) Foreign substances (e.g. drugs, PAH, PSP)Foreign substances (e.g. drugs, PAH, PSP) Substances that are not metabolized and excreted unchanged in the urine (e.g., PAH, PSP)Substances that are not metabolized and excreted unchanged in the urine (e.g., PAH, PSP) Substances that are slowly metabolized (e.g. thiamine)Substances that are slowly metabolized (e.g. thiamine)

Evidence for tubular secretion: PSP 70% of a dose of PSP is excreted after a single circulation through the kidneys70% of a dose of PSP is excreted after a single circulation through the kidneys 75% of PSP is bound to plasma proteins (25% is free and available for filtration)75% of PSP is bound to plasma proteins (25% is free and available for filtration) If FF = 20%, only 5% of dose can be filtered in one circulation through the kidneys (20% of 25%)If FF = 20%, only 5% of dose can be filtered in one circulation through the kidneys (20% of 25%) 65% of dose must have gotten into the urine by secretion (70% - 5%)65% of dose must have gotten into the urine by secretion (70% - 5%)

Normal plasma constituents that undergo secretion at specific sites in the renal tubule Hydrogen ionsHydrogen ions AmmoniumAmmonium PotassiumPotassium UrateUrate

Renal handling of potassium Kidneys are the primary regulator of potassium balanceKidneys are the primary regulator of potassium balance Potassium is the only plasma electrolyte that is both reabsorbed and secreted by the tubulesPotassium is the only plasma electrolyte that is both reabsorbed and secreted by the tubules

Renal handling of potassium Independent of state of balanceIndependent of state of balance 60% reabsorbed passively in proximal tubule60% reabsorbed passively in proximal tubule 20% reabsorbed in thick ascending limb of Henle’s loop via Na + -K + -2Cl - carrier20% reabsorbed in thick ascending limb of Henle’s loop via Na + -K + -2Cl - carrier Dependent on state of balanceDependent on state of balance Secretion by principal cells in cortical collecting duct and outer medullary collecting ductSecretion by principal cells in cortical collecting duct and outer medullary collecting duct Reabsorption by H + -K + ATPase in Type A (  ) intercalated cells in inner medullary collecting ductReabsorption by H + -K + ATPase in Type A (  ) intercalated cells in inner medullary collecting duct

Renal potassium handling: Proximal tubule Early proximal tubuleEarly proximal tubule TEPD lumen negativeTEPD lumen negative K + reabsorbed with water by solvent dragK + reabsorbed with water by solvent drag Late proximal tubuleLate proximal tubule TEPD lumen positiveTEPD lumen positive Paracellular route importantParacellular route important

Renal potassium handling: thick ascending limb of Henle’s loop TEPD lumen positive Paracellular route important Basolateral exit via K + channels and K + -Cl - cotransporter

Renal potassium handling: Late distal tubule and collecting duct Principal cells responsible for K + secretionPrincipal cells responsible for K + secretion TEPD lumen negativeTEPD lumen negative

Renal potassium handling: Late distal tubule and collecting duct Type A (  ) intercalated cells reabsorb K + and secrete H + K + enters at luminal membrane by H + -K + ATPase K + exits at basolateral membrane by K + channel

Major factors affecting K + movement across cortical collecting duct epithelium Chemical concentration gradient for K + across luminal membraneChemical concentration gradient for K + across luminal membrane Distal tubular flow rateDistal tubular flow rate Transmembrane PD across luminal membraneTransmembrane PD across luminal membrane Think of it like a river

Factors influencing renal excretion of potassium Sodium intakeSodium intake Potassium intakePotassium intake Mineralocorticoids (i.e. aldosterone)Mineralocorticoids (i.e. aldosterone) Hydrogen ion balanceHydrogen ion balance DiureticsDiuretics

Increased sodium intake More Na + reaches distal tubules and enters cells across luminal membranes stimulating Na + -K + ATPase in basolateral membranes and increasing intracellular K + concentrationMore Na + reaches distal tubules and enters cells across luminal membranes stimulating Na + -K + ATPase in basolateral membranes and increasing intracellular K + concentration Increased distal delivery of Na + increases tubular flow rate and moves secreted potassium downstreamIncreased distal delivery of Na + increases tubular flow rate and moves secreted potassium downstream

Increased potassium intake Increased numbers and activity of Na + -K + ATPase and amplification of basolateral membranes secondary to aldosterone secretionIncreased numbers and activity of Na + -K + ATPase and amplification of basolateral membranes secondary to aldosterone secretion Increased Na + -K + ATPase activity increases intracellular K + concentration favoring secretionIncreased Na + -K + ATPase activity increases intracellular K + concentration favoring secretion

Aldosterone Stimuli for release Volume depletion RAS activation Angiotensin II stimulates zona glomerulosa of adrenal gland to release aldosteroneVolume depletion RAS activation Angiotensin II stimulates zona glomerulosa of adrenal gland to release aldosterone Hyperkalemia also stimulates zona glomerulosaHyperkalemia also stimulates zona glomerulosa Other (minor) stimuliOther (minor) stimuli ACTHACTH HyponatremiaHyponatremia Decreased extracellular pH (acidosis)Decreased extracellular pH (acidosis)

Aldosterone Effects Main effect is to increase the number of open Na + channels in luminal membranes of principal cellsMain effect is to increase the number of open Na + channels in luminal membranes of principal cells Also stimulates H + ATPase in luminal membranes of Type A (  ) intercalated cellsAlso stimulates H + ATPase in luminal membranes of Type A (  ) intercalated cells

Aldosterone Inhibition of release Dopamine (released in response to increased ECF volume)Dopamine (released in response to increased ECF volume) Atrial natriuretic peptide (released in response to increased ECF volume)Atrial natriuretic peptide (released in response to increased ECF volume)

Nephron segments affected by aldosterone Connecting segment (late distal tubule)Connecting segment (late distal tubule) Cortical collecting ductCortical collecting duct Outer medullary collecting ductOuter medullary collecting duct

Glomerulus… Proximal tubule… Thin descending LH… Thin ascending LH… Thick ascending LH… Distal convoluted tubule… Connecting segment… Cortical collecting duct… Outer medullary collecting duct… Inner medullary collecting duct… Could you remind me again … what are the parts of the nephron? … What a bozo …

Hydrogen ion balance Alkalosis increases urinary excretion of potassiumAlkalosis increases urinary excretion of potassium ACUTE MINERAL METABOLIC acidosis decreases urinary excretion of potassiumACUTE MINERAL METABOLIC acidosis decreases urinary excretion of potassium ORGANIC METABOLIC acidosis does notORGANIC METABOLIC acidosis does not CHRONIC METABOLIC acidosis may increase urinary excretion of potassiumCHRONIC METABOLIC acidosis may increase urinary excretion of potassium

Effects of acid base balance on translocation of potassium H+H+H+H+ K+K+K+K+ H+H+H+H+ K+K+K+K+ ACIDOSISALKALOSIS An oversimplification in acidosis

pH effects on translocation of potassium H+H+H+H+ Cl - Org - H+H+H+H+ K+K+K+K+

DiureticsDiuretics Many diuretics increase urinary excretion of potassium (e.g. furosemide, thiazides, mannitol)Many diuretics increase urinary excretion of potassium (e.g. furosemide, thiazides, mannitol) They do so by increasing distal delivery of sodium and distal tubular flow rateThey do so by increasing distal delivery of sodium and distal tubular flow rate

Renal handling of urate In veterinary medicine, primarily important in Dalmatian dogsIn veterinary medicine, primarily important in Dalmatian dogs Urate is both reabsorbed and secreted in the renal tubuleUrate is both reabsorbed and secreted in the renal tubule Secretion resembles that of PAHSecretion resembles that of PAH Co-transported into cell with Na + at basolateral membraneCo-transported into cell with Na + at basolateral membrane Exits cell at luminal membrane by facilitated diffusion down its concentration gradientExits cell at luminal membrane by facilitated diffusion down its concentration gradient