Renal Handling of Solutes 2

MBBS
Glucose
 Renal Handling of Glucose
• Glomerular Filtration: Freely filtered
– Plasma glucose: Filtrate glucose=1:1
– 100mg/min (80mg/dl in plasma X 125ml/min)

• Almost all of the filtered glucose is reabsorbed

 Renal Handling of Glucose
Reabsorption
• Glucose reabsorption occurs in proximal tubule
• No other part of nephron is involved

• (Reabsorption of amino acids are similar)

 Renal Handling of Glucose
Reabsorption
1. From Lumen  Brush border epithelium
• Luminal surface of PT epithelium has SGLT
– (Sodium dependent Glucose Transporters)
– SGLT-2 in early PT (90%) and SGLT-1 in late PT (10%)
– Secondary active Na+/Glucose co-transporters
– Utilizes high tubular fluid:intracellular fluid Na+ conc. gradient to co-transport Glucose
• High gradient is created by Na/K ATPase pump functioning at basolateral surface of tubular
epithelium
– Is electrogenic: creates a –ve intra-luminal potential
 Renal Handling of Glucose
Reabsorption
2. From Tubular epithelium  Renal interstitium
 Blood
• Basolateral surface of PT epithelium has GLUT
– (Glucose Transporters)
– GLUT2 in early PT and GLUT1 in late PT
– Facilitated diffusion
– From interstitium, enters capillaries and into
circulation
 Renal Handling of Glucose
• Follows saturation kinetics
– Transport maximum (Tm)
• The rate of activity by transporters
• In kidneys for glucose
– 375mg/min (male), 300mg/min(female)
– Renal Threshold
• Minimum plasma level of a solute, beyond which it starts to
appear in urine.
• For glucose:
– Should have been 375/125 (GFR) = 300mg/dL
– Actual : 180-200mg/dL
– Because not all nephrons have the same Tm, some have lower Tm.
– This deviation from ideal Tm and its curve is creates splay
 Fanconi Syndrome
• Autosomal recessive
• Mutation in GLUT2
• Increased urinary excretion of
– HCO3
– Amino acids, glucose, phosphate, proteins
Sodium
 Na+ Handling
• PT: 65%
– Early: Na dependent sym and anti-porters
– Late:
• Na/Cl symporter (transcellular)
• Paracellular route: due to positive luminal potential
• LoH TAL: 25%
– NKCC channels: transcellular
– Paracellular route: due to positive luminal potential
• DCT and CD: 9%
– Early DCT: Na/Cl symporter
– Late DCT: Principal cells: ENaCs
 Regulation of Na+ handling
• Angiotensin II
– Stimulates Na+ reabsorption through all parts of nephron
• Aldosterone
– Stimulates Na reabsorption by
• increasing activity of Na/K ATPase pump
• Increasing ENaC in principal cells
– Also increases K+ excretion
– Acts on TAL, Aldosterone sensitive distal nephron (ASDN)
• ANP and BNP (Atrial and Brain Natriuretic Peptide)
– Primarily increase GFR by increasing renal blood flow
– Inhibit Na+ reabsorption
• Flow: all the reabsorption by luminal channels in nephron are flow dependent
– High flow rate of tubular fluid reduces reabsorption rate
 Gitelman Syndrome
• Autosomal recessive
• Mutation in Na/Cl symporter protein of Early DCT
• Characterized by
– Metabolic alkalosis
– Hypokalemia
– Hypocalciuria
 Liddle Syndrome
• Hyperactivating mutation in ENaC
• Characterized by
– Increased ECF volume
– Hypertension
Potassium
 Filtration
• Freely filtered
• @ 180 L/day X 4.2mEq/L = 756 mEq/day
 Renal Handling of K+
Reabsorption
• Constant amount
– PCT reabsorbs 65%
– LoH- TAL reabsorbs 25-30%
• Regulated/Variable rates
– DCT and CD varies as per
need of excretion
 K+ Handling
PCT
– 65% reabsorbed
• Mechanism: Paracellular reabsorption
– Early PT: Solvent drag
– Late PT: Positive transepithelial potential
 K+ Handling
TAL
• Reabsorbs 27%
• Transcellular pathway
– Via NKCC channel
• Paracellular pathway
– Due to positive transepithelial potential
 K+ Handling
Late DCT and CD:
• Net secretion or reabsorption rate is regulated by aldosterone
• Principal cells: secrete K+
– ROMK and BK apical K+ channels

• pH regulates intercalated cells

• Type A intercalated cells reabsorbs K+:
– Stimulated by acidosis, inhibited by alkalosis
– H/K ATPase pump for transcellular pathway
– Paracellular pathway (minimal, due to positive luminal potential)
• Type B intercalated cells secrete K+
– via apical K+ channels
– Stimulated by alkalosis, inhibited by acidosis
Late DCT and Cortical CD
• Intercalated cells
– Type A
– Type B
 K+ Regulation
• Plasma K+ levels: Direct effects
– High K+ stimulates Na/K ATPase pump
– Decreases K+ leak to interstitium
– Increases apical K+ channels
• Aldosterone level:
– Secretion stimulated by High plasma K+ levels and Angiotensin II
– Stimulates Na/K ATPase pump and increases number of apical K+ channels
– Causes Na+ reabsorption and K+ secretion
• Rate of flow of tubular fluid in distal nephron
– High flow rate maintains high concentration gradient of K+ across apical membrane allowing continuous
diffusion into lumen
– BK channels are flow sensitive, activated by high flow rate
• pH
– Acute acidosis decreases K+ secretion (by inhibiting Na/K ATPase pump)
– Chronic acidosis increases K+ secretion
 Bartter Syndrome
• Autosomal recessive
• Mutation in NKCC
• Characterized by
– Hypokalemia
– Metabolic alkalosis
– Hyperaldosteronism
H+/HCO3-
 Renal Handling of H+ and HCO3-
• Both Freely filtered
• HCO3: @ 180 L/day X 24 mEq/L
= 4320 mEq/day
• Kidney helps maintain pH by
– Secretion of H
– Reabsorption of HCO3
– Producing new HCO3
 H+ and HCO3 Handling
• Proximal Tubule
– Secrete H+ by NHE (Na/H exchanger)
– Carbonic anhydrase helps form H+ and HCO3
– HCO3 released into interstitium
• Na/HCO3 cotransport in early PT
• Cl/HCO3 exchanger in late PT
– For every 1 H+ secreted, 1 HCO3 is reabsorbed
(newly formed)
– No net secretion of H+
– Filtered HCO3 is reabsorbed by luminal
Na/HCO3 exchanger in early PT
 H+ and HCO3 Handling
• LoH (TAL) and early DCT
– Similar to late PT
 H+ and HCO3 Handling
Late DCT and CD
• Type A intercalated cells: secrete H+
– CA produces H+ and HCO3
– H+ is secreted by 1o active pumps
• H+ ATPase pump
• H/K ATPase pump
• Responsible for acidity of urine (max 4.5)
– HCO3 is reabsorbed in axchange for Cl-.
• Type B intercalated cells show opposite activity
due to location of channels
Phosphate and Ammonia
 Renal Handling of PO43- and NH3
• (Phosphate and ammonia buffer system)
• pK of a buffer system
– HCO3 system: 6.1
• Important due to high concentration
– Phosphate system: 6.8
• Important in renal system as urine is acidic
• But most of phosphate is reabsorbed (regulated by PTH)
– Ammonia system: 9.2
• Important due to high concentration
• Accounts for 50% of acid excretion in normal condition
 Phosphate handling
• Renal threshold for phosphate: 0.8mM/L
• PT reabsorbs 75-80%
– Na/PO4 co-transporter at luminal side
– Anion exchanger in basolateral side
• TAL and DCT: 10%
• Regulation:
– Parathyroid hormone (PTH) increases plasma PO4 and reduces
renal threshold  increases PO4 excretion
 Renal Handling of PO43- and NH3
• Both buffer systems neutralize excess H+ in lumen, and
• Generate new HCO3-
 NH3 regulation
• Formed in tubular epithelium from glutamine (all
parts of nephron)
– 1 glutamine forms 2 HCO3 and 2 NH4+
– Stimulated by acidosis
– NH4+ is antiported against Na+
– New HCO3 is reabsorbed
• Non-ionic diffusion and ionic trapping
– NH3 can freely diffuse through cell membrane, but
NH4+ cannot
– When urine is acidic, NH3 gets trapped inside lumen in
form of NH4+.
Calcium
 Ca Handling
• Only ionic form of plasma Ca++ (60%) is filtered
• 65% reabsorbed in PT
– Mostly paracellular (solvent drag and electric potential)
– Some transcellular: Ca channel (luminal side) and Ca ATPase and Na/Ca exchanger in
basolateral side
• 25-30% reabsorbed in LoH (TAL)
– Paracellular: due to positive lumen potential
– Transcellular route regulated by activity PTH
• Mechanism: PTH increases Ca++ channels, functions similar to PT
• 4-9% reabsorbed in DCT and CD
– Similar to TAL, regulated by PTH