Nephron

H2O
NaCl
K+
HCO3-

Nephron Physiology
Glucose
Amino Acids

Jason Ryan, MD, MPH

Transport Diffusion
Apical Membrane Basolateral Membrane
Lumen (Urine) Interstitium/Blood Lumen (Urine) Interstitium/Blood

Na
↑[Na]
↓[Na] ↑[Na]
↓[Na]
Na Na

Na
↓[Na] ↑[Na]
ATP

Na

Osmotic Diffusion Segments of Nephron

Proximal Tubule Distal Tubule
Lumen (Urine) Interstitium/Blood

Low Osmolarity High Osmolarity

(50mOsm) 1200mOsm Collecting Duct
H2O H2O

Descending
Limb

H2O
Ascending Limb

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 Proximal Tubule Proximal Tubule
Lumen (Urine) Interstitium/Blood
100%
Glucose Na+
Amino Acids
ATP
67% K
Water
Bicarb
NaCl
Potassium
Phosphate

Proximal Tubule Proximal Tubule

Lumen (Urine) Interstitium/Blood Lumen (Urine) Interstitium/Blood
Na+ Na

Na+ Na+
ATP ATP
K+ K+
Glucose Glucose
K+

Cl-
Cl
Anions
Hydroxide (OH-) Anions
Formate
Oxalate
Glucose Sulfate Glucose

Proximal Tubule Glucose Clearance

Lumen (Urine) Interstitium/Blood • Completely reabsorbed proximal tubule
Na
• Na/Glucose co-transport
Na
ATP • At glucose ~160mg/dl glucose appears in urine
Glucose K+ • Glucose ~350mg/dl all transporters saturated
K+ • Diabetes mellitus = “sweet” diabetes
Cl- • In pregnancy, ↓glucose reabsorption
Cl
Anions • Some glucosuria normal
Hydroxide (OH-) Anions
Formate
Oxalate
Sulfate Glucose
H2O

17
Amino Acid Clearance Proximal Tubule: Bicarb
Lumen (Urine) Na+ Interstitium/Blood
• Na/AA transporters in proximal tubule reabsorb all
amino acids Na

• Hartnup disease
HCO3- + H+ H+ + HCO3-
• No tryptophan transporter in proximal tubule
• Amino acids in urine
• Skin rash resembling pellagra (plaques, desquamation)
H2CO3
H2CO3
CA CA

CO2 + H2O CO2 + H2O

CA = Carbonic Anhydrase

Proximal Tubule Bicarb Fanconi’s Syndrome

Clinical Correlations

• Carbonic anhydrase inhibitors • Impaired ability of proximal tubule to resorb HCO3-,

• Weak diuretics glucose, amino acids, phosphate, and low molecular
• Result in bicarb loss in urine weight proteins
• Type II Renal Tubular Acidosis • Polyuria, polydipsia (diuresis from glucose)
• Ion defect • Non AG acidosis (loss of HCO3-)
• Inability to absorb bicarb • Hypokalemia (↑nephron flow)
• Metabolic acidosis
• Hypophosphatemia (loss of phosphate resorbtion)
• Growth failure, dehydration in children

Fanconi’s Syndrome Proximal Tubule

Key Points

• Inherited or acquired syndrome (rare) • Workhorse of the nephron

• Inherited form associated with cystinosis • Absorbs most water, Na, K, and other molecules
• Lysosomal storage disease • Loss of amino acids Hartnup disease
• Accumulation of cystine
• Glucose in urine diabetes
• Acquired causes: • Loss of bicarb in urine
• Lead poisoning
• Carbonic anhydrase inhibitors
• Tenofovir (HIV drug)
• Type II RTAs
• Tetracycline

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Proximal Tubule Thin Descending Loop Henle
Key Points

• Most common source renal cell carcinomas • Impermeable to NaCl

• Most common area damaged acute tubular necrosis • Concentrates urine
• Absorbs water
• Water leaves urine
• Drawn out by
hypertonicity in medulla H2O
H2O
H2O
H2O
H2O

Osmolarity of Nephron Osmolarity of Nephron

• Created by Na, Cl, and Urea
• Urea resorption by collecting duct essential to
300mOsm maintain these gradients for water resorption
Cortex

Outer Medulla 600mOsm

Inner Medulla 1200mOsm

Thin Descending Loop Henle Thick Ascending Loop Henle

Lumen (Urine) Interstitium/Blood
Na+

300
Cortex 300mOsm Na+ ATP
K+ K+
2Cl-
H2O
Outer Medulla H2O 600mOsm
K
H2O K
H2O Cl-
H2O
1200
Inner Medulla 1200mOsm Mg2+ Ca2+

19
 Thick Ascending Loop Henle Distal Tubule
Lumen (Urine) Interstitium/Blood
120
Na+
NaCl
300 NaCl
Cortex 300mOsm Na+ ATP
NaCl
NaCl K+
NaCl Cl-
Cl-
H2O
Outer Medulla H2O 600mOsm
H2O
H2O
H2O
1200
Inner Medulla
1200mOsm

Distal Tubule Collecting Duct

Lumen (Urine) Principal Cell Interstitium/Blood
Na+
Lumen (Urine) Interstitium/Blood
Na+
Na+ ATP
K+
K+
Na+ ATP
K+ H2O

Cl-
Cl-
Intercalated Cell
Ca2+ Na

Ca2+
ATP
H+

Key Points Collecting Duct Hormones

• Collecting duct functions • Amount of absorption/secretion heavily dependent on
• Resorb Na/H2O aldosterone and antidiuretic hormone (ADH)
• Secrete K+/H+
• Increased Na delivery to CD increased K excretion
• Contributes to hypokalemia with loops/thiazides

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Aldosterone Collecting Duct
Lumen (Urine) Principal Cell Interstitium/Blood
Na+
• Steroid (mineralocorticoid) hormone Na+
• Synthesized/released by zona glomerulosa cells of Aldosterone ATP
K+ Aldosterone
adrenal cortex K+
• Freely crosses cell membrane (steroid) H2O
• Binds to cytosolic protein receptor
• Activated receptor modifies gene expression
Intercalated Cell
• Increase Na/K-ATPase proteins and Na channels of
principal cells
• Also promotes K secretion principal cells
• Also promotes H secretion intercalated cells Aldosterone
Cl-
H+

Aldosterone Nephron Water Permeability

• Overall effect: Permeable Impermeable Variable
• ↑ sodium/water resorption (↑effective circulating volume)
• ↑K excretion
• ↑H+ excretion
• Release stimulated by:
• Angiotensin II
• High potassium
• ACTH (minor effect)

Antidiuretic Hormone (ADH) ADH Water Resorption

Vasopressin

• Promotes free water retention (inhibits secretion) • V2 receptors on principal cells collecting duct
• Two receptors: V1, V2 • G-protein, cAMP second messenger system
• V1: Vasoconstriction • Results is endosome insertion into cell membrane
• V2: Antidiuretic response • Endosomes contain aquaporin 2
• Secretion stimulated by hyperosmolarity • Water channel
• Volume loss: non-osmotic release • Result is ↑ permeability of cells to water
• Released by posterior pituitary

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 Collecting Duct Water Deprivation (High ADH)
Lumen (Urine) Principal Cell Interstitium/Blood

AQP-3 H2O

H2O 300
V2 ADH Cortex 300mOsm
AQP-2 Channel

AQP-4 H2O H2O

H2O
Outer Medulla 600mOsm
H2 O

Intercalated Cell H2O

1200
Inner Medulla
1200mOsm

High Water Intake (low ADH) How Diuretics Work

• Most diuretics block
resorption Na
300 • This sends more Na to
Cortex 300mOsm collecting duct
NaCl • ↑osmolarity collecting
NaCl duct
Outer Medulla
NaCl 600mOsm • ↑excretion of Na/H2O
NaCl

60
Inner Medulla
1200mOsm

ADH Urea Resorption Antidiuretic Hormone (ADH)

• Medullary interstitium very important for producing
maximally concentrated urine
• High osmolarity portion of kidney
• In setting of high ADH, large osmotic gradient exists to H2O
Permeable to H20
absorb water from urine NOT permeable to Urea
H2O
• As water leaves proximal collecting duct, urea
concentration rises
• This creates gradient for urea to leave urine in distal H2O
Permeable to H20
collecting duct (medullary portion) Urea AND permeable to Urea
• ADH also increases # of urea transporters

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Collecting Duct Sodium
5%
• Resorption Na/H2O
• Depends on ADH (H2O) and Aldosterone (Na)
67%
• Secretion of K+ and H+
• Depends on Aldosterone
• Urea resorption 3%

25%

1%

Water Concentration Changes

50/50 Solute 50/50
0%
Nephron Na/Cl
67% Water

50/50 <50/50
8-17%
Nephron Glucose
Bicarb
15%
50/50 >50/50

Nephron
Inulin
Cr
Variable

Concentration Changes
3.0
Inulin/Cr
PAH
2.0
Cl/Urea

Na/K
[Tubule]
1.0
[Plasma]

0.5

Glucose/
Amino Acids/
HCO3-
0
Distance Along Proximal Tubule

23