Regulation of Organic and Inorganic Substances

and Electrolyte Balance

Renal Handling of Organic Renal Handling of Inorganic
Substances Substances
Glucose Sodium: RAAS/other factors
Amino Acids Potassium
Proteins and Peptides Magnesium
Ascorbic Acids Hydrogen
Uric Acid/Urea Chloride
Creatine/Creatinine Bicarbonate
Phosphate

Review

• The direction of reabsorption is from the Lumen → Cell → Blood

• The direction of secretion is from the Blood → Cell → Lumen
• Epithelial Cells have 2 Membrane:
o Apical Membrane
→ Facing the lumen
o Basolateral Membrane
→ Facing the blood

There are 2 Reabsorption Pathways through the tubular cell barrier:

• Through the luminal and basolateral membranes

• Through the tight junctions

Absorption of different substances can happen in different sites.

• Diffusion
• Facilitated Diffusion
• Osmosis
• Solvent Drag
Limitation: Equilibrium → membrane should be permeable to the
substance

• Primary Active
• Secondary Active
o Cotransport
o Countertransport
• Endocytosis
Limitation: Saturation, Competitive Inhibition, Stereospecificity
• The Simple Cuboidal Cell of the PCT are called Brush Border
Cells because of their numerous microvilli, which project into Renal Handling of Organic Substances
the lumen of the tubule
• Major Reabsorptive Area • Freely Filtered in the Glomerulus
• Brush Border increases the surface area for reabsorption o Filtration Rate = 100 mg/min (Pc x GFR)
• Plenty of mitochondria • Completely Reabsorbed
• Highly invaginated Basolateral Membrane o Reabsorption Rate = 100 mg/min
o Site = Early Portion of the Proximal Tubule
• Not Secreted, Not Excreted
o Secretion and Excretion Rate = 0 mg/min
• Glucose is one of the substances that have Very High Tm
o Tm = 375 mg/min
• Glucose is present in the blood, present in the filtrate, but not
in the urine
• Ideal Renal Threshold = 300 mg/dL

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• Actual Renal Threshold: Amino Acids
o Arterial = 200 mg/dL • Not Freely Filtered
o Venous = 180 mg/dL o Small Amount
→ “Splay” • Completely Reabsorbed
o 100% Reabsorbed
o Site: Early Portion of the Proximal Tubule
• Not Secreted, Not Excreted
o Secretion and Excretion Rate = 0 mg/min
• Present in the blood, present in the filtrate, but not in the urine

• Glucose is reabsorbed in the Apical Membrane

• Co-transported with Na
o For every 2 Na, you reabsorb 1 Glucose → Na-Glucose
Transporter (SGLT2)
• Reabsorbed along the Basolateral Membrane through
Facilitated Diffusion using a carrier called GLUT2 • Amino Acids are also Co-Transported with Na
• Once it is absorbed across the Basolateral Membrane, it also
uses Facilitated Diffusion and Simple Diffusion
• Transport Maxima (Tm) for Glucose is 375 mg/min
• If GFR is 125 mL/min, Glucose should not appear in the urine Proteins
until plasma glucose concentration is >300 mg/dL (renal • Peptide Hormones, Small Proteins, and small amount of
threshold for glucose) Albumin
(125 mL/min) (3 mg/mL) = 375 mg/min • Not Freely Filtered
o Filtration Rate = 7.2 g/day (GFR x Protein in the Ultrafiltrate)
• Completely Reabsorbed
(Pc x GFR) o Reabsorption Rate = 7.2 g/day
o Site: Early Portion of the Proximal Tubule
• Not Secreted, Not Excreted
Tm = 375 mg/min o Secretion and Excretion Rate = 0 mg/min
Normal Blood Sugar = 80-110 mg/dL; Average: 100 mg/dL • Present in the blood, sometimes not present in the filtrate, not
Plasma Concentration (Pc) → FBS present in the urine
NOTE: 1 dL = 100 mL • Sometimes present in the filtrate but is 100% reabsorbed →
still not present in the urine
𝑭𝑩𝑺 𝒙 𝑮𝑭𝑹
100 𝑚𝑔/𝑑𝐿
𝐹𝐵𝑆 = 100 𝑚𝐿
= 1 𝑚𝑔/𝑚𝐿

𝐺𝐹𝑅 = 125 𝑚𝐿/𝑚𝑖𝑛

1 𝑚𝑔⁄𝑚𝐿 𝑋 125 𝑚𝐿⁄𝑚𝑖𝑛 = 125 𝑚𝑔/𝑚𝑖𝑛

REMEMBER:
125 mg/min = normal
126 above = diabetic

• It is called Ideal because in here, we are assuming that all the

nephrons have a threshold of 375 mg/min
• If your sample is Arterial → 200 mg/dL
• If your sample is Venous → 180 mg/dL
• Since proteins are quite big, they are reabsorbed through
Endocytosis
• Will go to the blood through Exocytosis

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• Mediated by Apical Membrane Proteins that specifically bind
with Luminal Proteins and Peptides Endogenous Anions Drugs
• They are Multiligand Endocytic Receptors: Acetazolamide
o Megalin cAMP, cGMP Chlorothiazide
o Cubilin Bile Salts Furosemide
Hippurates Penicillin
Oxalate Probenecid
• Freely Filtered Prostaglandins: PGE, PGF Salicylate (Aspirin)
o Filtration Rate = 870 mmol/day Urate Hydrochlorothiazide
• Some are Reabsorbed Vitamins: Ascorbate, Folate Nonsteroidal Anti-
o Reabsorption Rate = 460 mmol/day inflammatory Drugs (NSAIDs):
o Site: Mainly in the Medullary Collecting Duct Indomethacin
→ Facilitated by ADH
• Not Secreted
o Secretion Rate = 0 mmol/day
• Some are Excreted
o Excretion Rate = 410 mmol/day (53%)

• Freely Filtered
o Filtration Rate = 50 mmol/day
• Most are Reabsorbed
o Reabsorption Rate = 49 mmol/day (98%)
• Secreted
o Secretion Rate = 4 mmol/day
• Excreted
o Excretion Rate = 5 mmol/day • The secretion of these substances happens in the Proximal
Tubule, specifically, the Proximal Straight Tubule
o Uric Acid
• Freely Filtered o Ascorbic Acid
o Filtration Rate = 12 mmol/day o Folic Acid
• Not Reabsorbed o Oxalate
o Reabsorption Rate = 1 (0) mmol/day (98%) o Hippurates
• Not Secreted o Bile Salts
o Secretion Rate = 1 (0) mmol/day • Organic Ion will bind to a transporter (OAT 1,2,3)
• Excreted o OAT = Organic Anion Transporter
o Excretion Rate = 12 mmol/day • These substances will be transported to through the transporter
• Tm = 16 mg/min in exchange for Alpha-Ketoglutarate (α-KG)
• α-KG can now be secreted via the MRP2 or 4
• α-KG can also be secreted and reabsorbed via the OAT4
• Freely Filtered and Reabsorbed in the PCT
• Excretion Rate is Regulated by:
o Glomerular Filtration Endogenous Anions Drugs
o Tubular Reabsorption Creatine Atropine
→ Proximal Tubule Dopamine Isoproterenol
o Tubular Secretion Epinephrine Cimetidine
→ Distal Tubule – promoted by Adrenal Steroid and Norepinephrine Morphine
increased filtered load of Na) Quinine
• Tm = 2 mg/min Amiloride
Procainamide

• Can be transported through OCT2 (Organic Cation Transporter

2)
• Transported out in exchange for Hydrogen

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 Renal Handling of Inorganic Substances
• Mediates transcellular reabsorption of water across many
nephron segments
• Freely Filtered • 2 Groups
• Partially Reabsorbed o Permeable to Water (Aquaporins)
o Site: PCT (>1st Half), Thick Ascending Loop of Henle, DCT, → AQP0, AQP1 – expressed in apical and basolateral
Collecting Duct membranes in PCT and Thin DLOP)
• Not Secreted → AQP2 – principal cells in CD – mediated byADH
o Secretion Rate = 0 mEq/day
→ AQP4, AQP5, AQP6, AQP8 - PCT
• Excreted o Permeable to Water and Small Solutes (Aquaglyceroporins)
o Excretion Rate < Filtration Rate
→ AQP3, AQP5, AQP7 (PCT), AQP9, and AQP10
• AQP3 and AQP4 (BBB) – expressed in basolateral membrane of
Sodium is one of the major substances that affect the principal cells in collecting duct
Osmolarity and ECF Volume o Can be expressed in other organs:
→ Eyes
→ Lungs
→ Skin
→ Secretory Glands
→ Brain

Late Segment

Early Segment
• Early Segment • 1 Na, 2 Cl, 1 K → NKCC2 – blocked by loop diuretics
o In the Early Segment of PCT, Na is reabsorbed with Organic • Can also be reabsorbed in exchange for Hydrogen
Substances (Glucose, Amino Acids, Phosphate, Lactate,
Vitamins) – Co-Transport
o Can also be reabsorbed in exchange for Hydrogen
• Late Segment
o Na is reabsorbed with Chloride – Paracellular Transport
o Can also be reabsorbed in exchange for Hydrogen

• When Na is
reabsorbed, Water
follows – Iso-osmotic
Reabsorption
• When you reabsorb
Na → Osmolarity
Increases → H2O 67% Early Segment
Follows
• Reabsorption of
Water is via Osmosis Late Segment
• Early Distal
o Na is reabsorbed with Cl via NCC Transporter – blocked by
Thiazide Diuretics
• Late Distal and Collecting Duct
o Na is reabsorbed in exchange for K – affected by
Aldosterone

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 • Set of autosomal recessive genetic diseases characterized • ECF K+ Concentration: N = 3.5 – 5.5 mEq/L
by hypokalemia, metabolic alkalosis, hyperaldosteronism, • ICF: 98% | ECF: 2%
and decreased ECF volume • Excretion:
• Inactivating mutations in the gene coding for 1Na-1K-2Cl o Kidneys – 90-95%
Symporter (NKCC2 or SLC12A1) o Feces – 5-10%
• Decreased NaCl reabsorption and K+ Reabsorption by the
Thick Ascending LOH Potassium Excretion is highly dependent on Renal Function.
Hyperkalemia is one of the most common condition associated
with Renal Failure.
Inactivating mutations in the gene coding for the 1Na+/1K+/2Cl
− symporter (NKCC2), the apical K+ channel (ROMK), or the • Freely Filtered
basolateral Cl− channel (ClCNKB) decrease both NaCl o Filtration Rate = 756 mEq/day
reabsorption and K+ reabsorption by the ascending thick limb, • Reabsorbed
which in turn causes hypokalemia (i.e., low plasma [K+]) and a o Reabsorption Rate = 644 mEq/day (87%)
decrease in ECFV. o Site: PCT and Ascending Loop of Henle
The fall in ECFV stimulates aldosterone secretion, which in turn • Secreted
stimulates NaCl reabsorption and H+ secretion by the distal o Secretion Rate = 31 mEq/day
tubule and collecting duct. • Excreted
o Excretion Rate = 92 mEq/day

• Stimulates Na (Water) reabsorption in the PCT, Thick Ascending

LOH, DCT, and Collecting Duct

• Increases Na reabsorption and K secretion in the Late DCT and

Collecting Duct
• Increases Na reabsorption in the Thick Ascending LOH

• Inhibits NaCl reabsorption in the Medullary Collecting Duct

• Inhibits ADH secretion in the Posterior Pituitary Gland
• ANP is secreted in the Atria
• BNP is secreted in the Ventricle

• Stimulates NaCl reabsorption in the PCT, Thick Ascending, DCT,

and Collecting Duct

• Inhibits reabsorption of NaCl in the PCT

• Urodilatin is secreted in the Kidney

• Secreted by the DCT and CD (not present in systemic
circulation) – (+) by Hypertension (HPN) and increased ECF
volume
• Influences kidney function only
• Increases NaCl excretion – (-) NaCl and Water reabsorption
(more potent than ANP)

• Produced by other organs (including kidney) • Proximal Convoluted Tubule (majority, 67%)
• Causes marked diuresis and natriuresis (inc. GFR and RBF) o K+ is reabsorbed via Primary Active Transport
• Secretion (+) by CHF and HPN • Thick Ascending LOH (25%)
o K+ is reabsorbed with Na and Cl (NKCC2) – Co-Transport
• Produced by neuroendocrine cells in the intestines (oral • Distal Convoluted Tubule
ingestion of NaCl) o K+ is reabsorbed in exchange for Hydrogen
• Increases NaCl excretion – (-) NaCl and water reabsorption • Collecting Duct
o Na is reabsorbed, K is secreted – affected by Aldosterone
Stimulates NaCl Reabsorption Inhibit NaCl Reabsorption
Angiotensin II ANP
Aldosterone BNP
Catecholamines Dopamine
Urodilatin
Adrenomedullin
Uroguanylin
Guanylin

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 • Not Secreted
• Catecholamines o Secretion Rate = 0 mEq/day
• Insulin • Excreted
• Aldosterone o Excretion Rate = 10 mEq/day
• Glucocorticoid
• ADH – increases K+ secretion
• Primarily reabsorbed in the PCT (70%)
• Some are reabsorbed in the Thick Ascending LOH (20%)
Increased ECF K+ Concentration • Some in the DCT (9%)
Increased Aldosterone • Some in the CD (1%)
Increased Tubular Flow Rate • Reabsorption of Calcium is facilitated by Parathyroid Hormone
(PTH)

• Increases the reabsorption of Calcium primarily in the Thick

Ascending LOH and DCT

• Also increases Ca reabsorption in the DCT and CD

These hormones increase reabsorption by increasing the

TRPV5/6 Transporter

• Calcium Secretion is activated by PMCa ATPase (Plasma

Membrane-Calcium ATPase)

Increased Decreased
Calcitonin (Thick Phosphate Depletion
Ascending/DCT)
PTH (most effective) Phosphate Loading
• When Flow Rate is fast, Primary Cilium bends
Calcitriol Metabolic Acidosis
o Primary Cilium serves as a mechanosensor → This mediates
Na-Ca Signaling Pathway Phosphate Volume Expansion
• When Primary Cilium bends → Na and Ca enters → ROMK is
activated → favor K+ Secretion
• Excretion is controlled primarily by an Overflow Mechanism
• Tm = 0.1 mM/min (Renal Threshold: 0.8 mM/min)
o GFR > Tm → Excretion of Excess PO4
o GFR < Tm → Complete Reabsorption of PO4
• Component of DNA, RNA, ATP, and Intermediaries of Metabolic
Pathway
• Important Renal Buffer

• When K+ Concentration is high, like in Hyperkalemia, secretion

is increased
• When K+ Concentration is low, like in Hypokalemia, secretion is
decreased
• Mechanism:
o When ECF K+ is high, Aldosterone is also increased
o Increased Aldosterone → Na+ is reabsorbed in exchange for • Recall: Na can be reabsorbed with Glucose, Amino Acids,
K+ Phosphate
• For every 3 Na you reabsorb, you also reabsorb Phosphate
• Transporters:
• Freely Filtered o NPT1, NPT2, NPT3
o Filtration Rate = 540 mEq/day (50%) • Reabsorbed in the PCT (80%), DCT (10%)
• Majority are Reabsorbed
o Reabsorption Rate = 530 mEq/day (98/2%)
o Site: PCT

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 Reabsorption
Growth Hormone
Phosphate Depletion
Metabolic Alkalosis
Hypercalcemia (Acute)
Vitamin D (Acute)
Volume Concentration
Secretion
PTH (most important)
Phosphate Loading
Metabolic Acidosis
Hypercalcemia (Chronic)
Vitamin D (Chronic)
Volume Expansion
Glucocorticoid
FGF-23 and 24

• Involved in many biochemical processes, activation of enzymes

• ½ stored in the bones
• 99% ICF | 1% ECF
• 50% bound to proteins

• Primarily reabsorbed in the Thick Ascending LOH (65%)

• PCT (25%), DCT (<5%), CD (10-15%)
• NKCC2 → Once you reabsorb Na, K, and Cl, the lumen becomes
positive so it repels Mg and Ca → Reabsorption

• Renal disease that is either hereditary or acquired, results

from an impaired ability of the Renal PCT to reabsorb HCO3,
Pi, amino acids, glucose, and low molecular weight proteins
• Urinary excretion of HCO3, Pi, amino acids, glucose, and low
molecular weight proteins is increased

• Rare genetic renal disorder characterized by an increase in

Arterial Blood Pressure (hypertension) secondary to an
increase in ECF volume
• Due to mutations of the genes that encode Na channels in
the apical membrane of principal cells that increases Na
reabsorption (hypernatremia)

Summary
• Osmoregulation is achieved by changes in water balance,
volume regulation primarily by changes in sodium balance
• Regulation of plasma osmolality or osmoregulation is governed
by osmoreceptors influencing the release of ADH and thirst
• Changes in effective circulating volume is sensed by multiple
volume receptors which activate effectors such as aldosterone
• ADH increases water reabsorption and therefore decreases
urine osmolality but does not affect Na+ transport
• Aldosterone enhances Na+ reabsorption but not directly that of
water

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