Renal Electrolyte Regulation Notes

NOTES NOTES RENAL ELECTROLYTE REGULATION GLOMERULAR FILTRATION osms.it/glomerular-filtration ▪ Fluid passage through glomerular filtration barrier; approx. 125mL/min ▪ Glomerular filtrate: fluid that passes through all glomerular filtration barriers ▫ Blood minus red blood cells, plasma proteins ▪ Anything remaining in glomerulus carried away by efferent arteriole ▪ Starling forces → glomerular filtration ▫ Different pressures of fluids, proteins in glomerular capillaries, Bowman's space ▪ Most filtration occurs at beginning of glomerulus, nearer afferent arteriole ▪ ▪ ▪ ▪ peritubular capillaries Separates blood in capillaries from Bowman's space, Bowman's capsule Allows only water, some solutes to pass into Bowman’s space Three layers: endothelium, basement membrane, epithelium Juxtaglomerular apparatus: secretes renin Endothelium ▪ Comprised of glomerular capillary endothelial cells featuring pores (AKA fenestrations) ▪ Allows passage of solutes, proteins ▪ Blocks red blood cell passage Basement membrane ▪ Gel-like layer with tiny pores ▪ Blocks plasma protein passage ▫ Due to pore size, negative membrane charge Figure 61.1 An illustration depicting the glomerulus and its relationship to the rest of the nephron. Epithelium ▪ Comprised of podocytes (wrap around basement membrane) ▪ Also blocks plasma protein passage GLOMERULAR FILTRATION BARRIER ▪ Capillary walls of glomerulus ▫ Glomerulus: tuft of capillaries in nephron’s renal corpuscle ▫ Blood enters glomerulus through afferent arteriole → leaves through efferent arteriole → divides into Figure 61.2 The three layers of the glomerular filtration barrier. OSMOSIS.ORG 533

STARLING FORCES ▪ Determine fluid movement through capillary wall ▪ Includes hydrostatic/fluid pressures, oncotic/protein pressures ▪ Three Starling forces at play in glomerular filtration barrier ▫ Hydrostatic pressure of blood in capillary (Pgc) ▫ Hydrostatic pressure of filtrate in Bowman’s space (Pbs) ▫ Oncotic pressure of proteins in capillary (ℼgc) ▪ Determines net ultrafiltration pressure of glomerulus: Puf = Pgc - (Pbs + ℼgc) ▫ Net ultrafiltration pressure ↓ along each glomerular capillary—as fluid removed, proteins remain (↑ ℼgc) ▫ At filtration equilibrium, net ultrafiltration pressure equals 0 (no fluid filtered) Figure 61.3 Illustration depicting the three Starling forces at play in the glomerular filtration barrier. GLOMERULAR FILTRATION RATE (GFR) ▪ Filtrate volume produced by all of body’s glomeruli in one minute ▪ GFR = Puf × Kf where Kf is filtration coefficient ▫ Kf: indicates capillary’s fluid permeability ▫ Fenestrations, large surface area → high Kf for glomerular capillaries ▪ Depends on all three Starling forces 534 OSMOSIS.ORG Hydrostatic blood pressure in capillary ▪ Positive relationship ▪ Afferent arteriole vasoconstriction → ↓ renal blood flow ▫ ↓ hydrostatic blood pressure in capillary (↓ GFR) ▪ Afferent arteriole vasodilation → ↑ renal blood flow ▫ ↑ hydrostatic blood pressure in capillary (↑ GFR) ▪ Efferent arteriole vasoconstriction → ↑ fluid in glomerular capillary ▫ ↑ hydrostatic blood pressure in capillary (↑ GFR) ▪ Efferent arteriole vasodilation → ↓ fluid in glomerular capillary ▫ ↓ hydrostatic blood pressure in capillary (↓ GFR) Hydrostatic filtrate pressure in Bowman’s space ▪ Negative relationship ▪ Doesn’t normally occur ▪ Urine flow blockage → urine backup (e.g. stone lodged in ureter) ▫ ↑ hydrostatic filtrate pressure in Bowman’s space (↓ GFR) Oncotic protein pressure in capillary ▪ Negative relationship ▪ ↑ plasma protein concentration can ↑ oncotic protein pressure in capillary (↓ GFR) ▪ ↓ plasma protein concentration can ↓ oncotic protein pressure in capillary (↑ GFR) FILTRATION FRACTION (FF) ▪ Ratio of glomerular filtration rate to renal plasma flow ▫ FF = GFR / RPF ▪ Indicates how much fluid reaching kidneys is filtered into renal tubules

Chapter 61 Renal Physiology: Renal Electrolyte Regulation PROXIMAL CONVOLUTED TUBULE osms.it/proximal-convoluted-tubule First renal tubule segment Receives filtrate from renal corpuscle Passes filtrate to loop of Henle Lined by brush border cells ▫ Apical surface faces lumen; lined with microvilli ▫ Basolateral surface faces interstitium ▪ Surrounded by peritubular capillaries → reabsorption, secretion of solutes to/from blood via interstitium ▪ Reabsorbs Na+, K+, Ca2+, Cl-, Mg2+ into bloodstream ▪ ▪ ▪ ▪ Figure 61.4 The relationship between the proximal convoluted tubule's brush border cells and a peritubular capillary. NA+ MOVEMENT Natural concentration gradient from lumen into cells ▪ Cotransporters: use this energy to move other solutes (e.g. Na+-glucose cotransporter) ▪ Na+/K+ ATPase: pumps 3Na+ from cell into interstitium, 2K+ from interstitium into cell ▫ Movement against two concentration gradients → ATP required ▪ Na+/H+ exchanger: pumps Na+ from cell into cell, H+ from cell into lumen ▫ Assists HCO3- reabsorption by creating H2CO3 → H2O + CO2 Paracellular route ▪ Leaky tight junctions → some Na+ movement between cells ▫ ↓ claudin proteins → ↑ permeability ▪ Urea, water diffuse straight across cells → interstitium ▪ Glutamine breakdown inside cell → NH4+ (cell → lumen) + HCO3- (cell → interstitium) ▪ Organic acids, some medications diffuse directly from capillaries into lumen (e.g. penicillin) Figure 61.5 The Na+-glucose cotransporter uses the concentration gradient of Na+ to transport glucose against its concentration gradient. Figure 61.6 Na+/K+ ATPase and the paracellular route of Na+ movement. OSMOSIS.ORG 535

LOOP OF HENLE osms.it/loop-of-henle ▪ Receives filtrate from proximal convoluted tubule ▪ Passes filtrate to distal convoluted tubule ▪ Composed of descending, thin ascending, thick ascending limbs ▪ Establishes osmotic gradient; allows varying urine concentration ▪ Lined by epithelial cells ▫ Apical surface faces lumen ▫ Basolateral surface faces interstitium ▪ Surrounded by peritubular capillaries ▫ AKA vasa recta ▫ Reabsorption, secretion of solutes to/ from blood via interstitium Descending limb ▪ Filtrate that enters has osmolarity of ~300mOsm/L (interstitial osmolarity) ▪ Squamous epithelial cells have aquaporins on both surfaces ▫ Water moves across cells into interstitium ▪ Osmolarity ↑ to ~1200mOsm/L at bottom of loop Figure 61.7 Countercurrent multiplication is the process of creating the concentration gradient along the loop of Henle. It uses ATP. Thin ascending limb ▪ No aquaporins on thin ascending limb; Na+, Cl- channels instead ▫ Move from lumen into interstitium along concentration gradient ▪ Osmolarity ↓ to ~600mOsm/L at top of thin loop Thick ascending limb ▪ Cuboidal epithelium in thick ascending limb has Na-K-2Cl cotransporters ▫ Na+, K+, 2Cl- moved from lumen into cells using Na+ concentration gradient + ▪ Na /K+ ATPase works as previously ▪ K+, Cl- channels → move from cell into interstitium along concentration gradient ▪ Osmolarity ↓ to ~325mOsm/L at top of thick loop ▪ Countercurrent multiplication: process of creating concentration gradient along loop 536 OSMOSIS.ORG Figure 61.8 Aquaporins transport H2O out of the thin descending limb; channel proteins transport Na+ and Cl- out of the thin ascending limb; Na-K-2Cl cotransporters and channels transport Na+, K+, and Cl- out of the thick ascending limb.

Chapter 61 Renal Physiology: Renal Electrolyte Regulation DISTAL CONVOLUTED TUBULE osms.it/distal-convoluted-tubule Figure 61.9 Filtrate passes through the early and late portions of the distal convoluted tubule, then reaches the collecting duct. ▪ Receives filtrate from loop of Henle ▪ Passes filtrate to collecting ducts ▪ Composed of early, late distal convoluted tubules ▪ Lined by brush border cells ▫ Apical surface faces lumen; not lined with microvilli ▫ Basolateral surface faces interstitium ▪ Surrounded by peritubular capillaries → reabsorption, secretion of solutes to/from blood via interstitium Early distal convoluted tubule ▪ Impermeable to water ▪ Na+: natural concentration gradient from lumen → cells ▪ Cotransporters use this energy to move other solutes (e.g. Na+-Cl- cotransporter) ▪ Cl- moves from cells → interstitium through direct channels ▪ Ca2+ moves across cells → interstitium through direct channels ▫ On basolateral surface: Na+-Ca2+ channel pumps Na+ from interstitium → cell, Ca2+ from cell → interstitium ▪ Ca2+ reabsorption regulated by parathyroid hormone ▫ Creates more Na+-Ca2+ channels ▪ Na+/K+ ATPase works as previously Figure 61.10 Illustration of transporters present in the early distal convoluted tubule. Late distal convoluted tubule ▪ → collecting ducts ▪ Principal cells, α-intercalated cells dispersed among brush border cells ▪ Aldosterone upregulates pump synthesis ▪ Principal cells have ▫ K+ pumps (cell → lumen; uses ATP) ▫ Na+ pumps (“ENaC”; lumen → cell) ▫ Na+/K+ ATPases ▪ Aquaporin 2 in principal cells allows for water reabsorption in response to antidiuretic hormone ▪ α-intercalated cells have ▫ H+ ATPases, H+-K+ ATPases (movement against concentration gradients → ATP required) ▫ Na+/K+ ATPases Figure 61.11 Illustration of transporters present in the late distal convoluted tubule. OSMOSIS.ORG 537

TF/PX RATIO & TF/PINULIN osms.it/TF_Px-ratio-TF_Pinulin [TF/P]x RATIO ▪ Refers to concentration of substance (X) in tubular fluid (TF) and plasma (P) at given point in nephron Helps determine substance net secretion/ absorption ▪ [TF/P]x = 1 ▫ X: not reabsorbed/secreted (e.g. freely filtered) ▫ X: reabsorbed in proportion to water ▫ E.g. [TF/P]glucose = 1 when glucose, water reabsorbed equally in Bowman’s space ▪ [TF/P]x < 1 ▫ X: reabsorbed more than water ▫ E.g. [TF/P]glucose < 1 when glucose reabsorbed more than water along proximal tubule ▪ [TF/P]x > 1 ▫ X: reabsorbed less than water/X secreted into tubular fluid ▫ E.g. [TF/P]urea > 1 in presence of antidiuretic hormone (ADH) at collecting ducts (water reabsorbed, not urea) 538 OSMOSIS.ORG [TF/P]INULIN ▪ Inulin (inert substance—neither reabsorbed nor secreted) concentration throughout nephron helps determine how much is reabsorbed ▪ Inulin concentration will ↑ as water is reabsorbed ▪ Determined using this formula: Fraction of filtered water reabsorbed = 1− 1 [TF / P]inulin ▫ Fraction of filtered water reabsorbed = 1 - 1/2 = 0.5 (50%) ▫ [TF/P]inulin = 2 when 50% of water is reabsorbed (inulin concentration doubles) ▪ Double ratio formula determines fraction of filtered load of substance in nephron at any point [TF / P]x [TF / P]inulin ▪ If [TF/P]Na+ divided by [TF/P]inulin = 0.3, then 30% sodium remains in tubule, 70% reabsorbed

Chapter 61 Renal Physiology: Renal Electrolyte Regulation CALCIUM HOMEOSTASIS osms.it/calcium-homeostasis ▪ 1% Ca2+ found in intracellular fluid (ICF), extracellular fluid (ECF); 99% in bones, teeth ▪ Functions: cell membrane permeability, blood clotting, muscle contraction ▪ 40% plasma Ca2+ bound to protein ▫ Unbound is physiologically active ▫ Regulated by parathyroid hormone (PTH) Ca2+ HANDLING Filtration ▪ Only unbound Ca2+ (60%) is filtered ▪ Calculation of Ca2+ filtered load if total plasma Ca2+ = 5mEq/L and GFR = 180L/ day ▫ 180 X 5 X 0.6 = 540mEq/day Filtered load reabsorption ▪ Coupled with Na+ reabsorption in proximal tubule, loop of Henle (passively reabsorbed via electrochemical gradient created by Na+, water) ▫ 67% reabsorbed by proximal tubule ▫ 25% reabsorbed in thick ascending limb of loop of Henle (paracellular route); loop diuretics ↓ reabsorption/↑ secretion ▪ 8% reabsorbed in distal tubule ▫ Reabsorptive Ca2+ regulation site: only nephron segment not coupled with Na+ reabsorption; PTH, thiazide diuretics → ↑ Ca2+ reabsorption (hypocalciuric action) Excretion ▪ < 1% MAGNESIUM HOMEOSTASIS osms.it/magnesium-homeostasis ▪ < 1% Mg2+ found in ECF; 60% in bones, 20% in skeletal muscle, 19% in soft tissues, remainder found in ICF ▪ Functions: neuromuscular activity; enzymatic reactions within cells; ATP production; Na+, Ca2+ transport across cell membranes ▪ 20% plasma Mg2+ bound to protein ▫ Unbound is physiologically active Filtered load reabsorption ▪ 30% reabsorbed by proximal tubule ▪ 60% reabsorbed by thick ascending limb of loop of Henle ▫ Loop diuretics ↓ Mg2+ reabsorption (↑ excretion) ▪ 5% reabsorbed by distal tubule Excretion ▪ 5% Mg2+ HANDLING Filtration ▪ Only unbound Mg2+ (80%) is filtered OSMOSIS.ORG 539

PHOSPHATE HOMEOSTASIS osms.it/phosphate-homeostasis ▪ ICF phosphate (15%) used for DNA, ATP synthesis, other metabolic processes ▫ ECF phosphate (<0.5%) serves as buffer for H+ ▫ 85% in bones PHOSPHATE HANDLING Filtration ▪ Freely filtered across glomerular capillaries Filtered load reabsorption ▪ 70% reabsorbed by proximal tubule; 15% by proximal straight tubule via Na+-phosphate cotransporter in luminal membrane ▪ Excess phosphate excreted when Tm (transport maximum) is reached ▪ PTH inhibits Na+-phosphate cotransporter → ↓ phosphate Tm → phosphaturia Excretion ▪ 15% POTASSIUM HOMEOSTASIS osms.it/potassium-homeostasis ▪ Potassium (K+): primary intracellular cation ▫ Regulates intracellular osmolarity ▫ Concentration gradient across cell membrane establishes resting membrane potential, essential for excitable cell function (e.g. myocardium) INTERNAL K+ BALANCE ▪ Difference between intracellular K+ concentration (98% of total K+), extracellular K+ concentration (2% of total K+) maintained by Na+-K+ ATPase ▪ K+ shifts in/out of cells ▫ Potentially causes hypo-/hyperkalemia Outward K+ shifts ▪ ↓ insulin ▫ ↓ Na+-K+ ATPase activity → ↓ cellular K+ uptake ▪ Cell lysis ▫ K+ released from ICF + ▪ H -K+ exchange in acidosis ▫ ↑ blood H+ → H+ enters cell → K+ moves from ICF to ECF 540 OSMOSIS.ORG ▪ ↑ ECF osmolarity ▫ Osmotic gradient causes H2O movement out of cells → ↑ intracellular K+ → diffusion of K+ from ICF to ECF (H2O brings K+ with it) ▪ Exercise ▫ Cellular ATP stores depleted → K+ channels open in muscle cell membrane → K+ moves down concentration gradient to ECF ▪ 𝝰-adrenergic receptor activation ▫ Hepatic Ca2+-dependent-K+-channel activation → K+ moves from ICF to ECF Inward K+ shifts ▪ Insulin ▫ ↑ Na+-K+ ATPase activity → ↑ cellular K+ uptake ▪ H+-K+ exchange in alkalosis ▫ ↓ blood H+ → H+ leaves cell → K+ enters cell ▪ ↓ ECF osmolality ▫ Osmotic gradient causes H2O movement into cells → ↓ ICF K+ concentration → diffusion of K+ from

Chapter 61 Renal Physiology: Renal Electrolyte Regulation ECF to ICF ▪ β2-adrenergic receptor activation ▫ ↑ Na+-K+ ATPase activity → K+ enters cell EXTERNAL K+ BALANCE ▪ Dietary K+ intake = renal excretion of K+ via renal mechanisms K+ HANDLING Filtration ▪ Freely filtered across glomerular capillaries Filtered load reabsorption ▪ 67% reabsorbed by proximal tubule (isosmotic fluid reabsorption along with water, Na+) ▪ 20% reabsorbed by thick ascending limb ▫ K+ reabsorbed without water (impermeable to water) via Na+-K+-2Clcotransporter ▫ K+ diffuses through K+ channels across basolateral membrane (reabsorption)/K+ diffuses into lumen (no reabsorption) ▪ Fine-tuning of K+ balance at distal tubule, collecting duct depending on current physiological requirements ▪ Reabsorbed by 𝝰-intercalated cells/ secreted by principal cells ▫ Dietary K+: high K+ diet—K+ enters cells (via insulin) → ↑ intracellular K+ → ↑ K+ in principal cells → ↑ K+ secretion across luminal membrane → ↑ K+ excretion; low K+ diet—↓ K+ secretion by principal cell, ↑ K+ reabsorption by 𝝰-intercalated cells ▫ Aldosterone effects on principal cells: presence of aldosterone/ hyperaldosteronism (↑ K+ secretion); hypoaldosteronism (↓ K+ secretion) ▪ Acid-base imbalance effects on principal cells: alkalosis (↑ K+ secretion); acidosis (↓ K+ secretion) ▪ Diuretic effects on principal cells: loop, thiazide (↑ K+ secretion); K+ sparing (inhibit aldosterone effects → ↓ K+ secretion) ▪ Luminal anions (e.g. sulfate, HCO3-) in distal tubule, collecting duct (↑ lumen electronegativity by non-reabsorbable anions → ↑ K+ secretion) Excretion ▪ Varies from 1–110% of filtered load SODIUM HOMEOSTASIS osms.it/sodium-homeostasis ▪ Sodium (Na+): primary cation in ECF ▫ Determines ECF osmolarity Na+ BALANCE REGULATION ▪ Na+ balance (Na+ excretion = Na+ intake) determines ECF volume, blood volume, blood pressure (BP) ▫ Positive Na+ balance: ↑ Na+ retained → ↑ Na+ in ECF → ECF expansion → ↑ blood volume, ↑ blood pressure ▫ Negative Na+ balance: ↑ excreted, lost in urine → ↓ Na+ in ECF → ECF contraction → ↓ blood volume, ↓ blood pressure Effective arterial blood volume (EABV) ▪ ECF volume with arterial system perfuses tissue ▪ Normal ECF changes → parallel EABV changes (e.g. ↑ ECF = ↑ EABF) ▪ Edema: fluid filtered into interstitial space → ↑ ECF → ↓ EABV (↓ BP) → Na+ excretion altered by kidneys (attempts to restore normal EABF, BP) Na+ excretion regulation (↑/↓) mechanisms ▪ Sympathetic nervous system activity ▫ Baroreceptors detect ↓ BP → sympathetic nervous system activation → afferent arteriole vasoconstriction, ↑ OSMOSIS.ORG 541

Na+ reabsorption by proximal tubule ▪ Natriuretic hormones: respond to ↑ ECF volume → ↑ GFR, natriuresis (renal Na+, water excretion) → ↓ ECF ▫ Atrial natriuretic peptide (ANP): volume receptors detect atrial wall stretching → ANP secreted by cells in atria ▫ Brain natriuretic peptide (BNP): volume receptors in ventricles detect stretching → BNP secreted by cells in ventricles ▫ Urodilatin: synthesized in distal tubular cells → paracrine actions on kidney ▪ Peritubular Starling forces ▫ ↑ ECF volume → ECF dilution, ↓ ℼc (capillary oncotic pressure); ↓ proximal tubule Na+ reabsorption ▫ ↓ ECF volume → ↑ ECF concentration, ↑ ℼc; ↑ proximal tubule Na+ reabsorption ▪ Renin-angiotensin-aldosterone system (RAAS): ↓ arterial blood pressure (BP) → ↓ renal perfusion → juxtaglomerular apparatus secretes renin → angiotensinogen (plasma protein) converted to angiotensin I → angiotensin I converted to angiotensin II → adrenal cortex secretes aldosterone, vasoconstriction → ↑ Na+, Cl-, water reabsorption → ↑ ECF volume, ↑ BP Excess Na+ intake response ▪ → Na+ ECF distribution → ↑ ECF, ↑ EABV, ↓ ℼc → ↓ sympathetic activity, ↑ ANP (and other natriuretic hormones), ↓ RAAS → ↑ Na+ excretion Decreased Na+ intake response ▪ → ↓ ECF, ↓ EABV, ↑ ℼc → ↑ sympathetic activity, ↓ ANP (and other natriuretic hormones), ↑ RAAS → ↓ Na+ excretion 542 OSMOSIS.ORG Na+ HANDLING Filtration ▪ Freely filtered across glomerular capillaries Filtered load reabsorption ▪ 67% reabsorbed by proximal tubule ▫ Isosmotic reabsorption of water, Na+ ▫ Water reabsorption coupled with Na+ reabsorption ([TF/P]Na+ = 1) ▪ 25% reabsorbed by thick ascending limb ▫ Na+ reabsorbed without water (impermeable to water) via Na+-K+-2Clcotransporter ▫ Influenced by ADH, loop diuretics ▪ 5% reabsorbed by early distal convoluted tubule ▫ Na+ reabsorbed without water (impermeable to water) via Na+-2Clcotransporter ▫ Influenced by thiazide diuretics ▪ 3% reabsorbed by late distal convoluted tubule ▫ Influenced by aldosterone Excretion ▪ < 1% excreted (99% net Na+ reabsorption)