Endothelium: fenestrated, Leaky, - charge glycoproteins

Basement membrane: - protein matrix

podocyte and slit diaphragm: foot processes in basement membrane, gaps betwene feet are covered by a thin slit diaphragm.

Albumin 40%

other plasma proteins 10%

proteins from renal tubule and urogenetal tract 50%

high β-2 microglobulin

albumin

(small proteins)

where is renin released?

what influences it?

released at JGA from granular cells at afferent and efferent arterioles.

• more sympathetic nerve = more renin release
• pressure in afferent arteriole.  (baroreceptor).  low P = more renin.
• signals from macula densa

Which structures are innervated by the SNS?

• afferent, efferent arterioles (vasoconstriction)
• JGA: more renin release
• renal tubules, enhances Na reabsorption.

NE

smooth muscle

vasoconstricter at alpha adrenergic

• volumtary control
• alpha motor neurons
• skeletal muscle

Sacral Nerve: sensory afferents & parasympathetic efferents

Sympathetic innervation: contraction at bladder neck to conserve urine.

1. Bladder stretches, sacral afferents stimulated
2. parasympathetic efferents respond, detrusor muscle contracts, urine goes into external
3. urine in urethra sends signal to inhibit tonic motor neurons of external sphyncter
4. relaxation of external sphyncter

Urea reabsorbed from urine into blood

so kidney failure sinc ewaste products back into blood.

oncotic: 0 (no proteins)

Oncotic: high since protein retained

Hydrostatic: decline along capilaries

a high filtration fraction means

higher fraction of plasma that is filtered

clearance of X > GFR

clearance of X < GFR

if clearance > GFR = also secreted

if clearance < GFR = reabsorbed.

what would lab results look like for a

drug filtered and reabsorbed from the kidney

What would lab results look like for

a drug filtered and secreted by the kidney?

what would lab results look like

for a drug completely filtered from the kidney?

Effects of changing afferent arteriolar resistance,

↓ resistance: ↑ Pc GFR & RBF

↑ resistance: ↓ Pc and GFR & RBF

↓ resistance: ↓ Pc and GFR.  ↑RBF

↑ resistance: ↑ Pc and GFR.  ↓RBF

↓ ∏c: ↑ GFR

↑ ∏c: ↓ GFR

Sympathetic renal nerve stimulation

due to:

results in:

due to: fall in BP, fear, pain, exercise

result in: ↓ RBF and GFR

made in kidney and systemically

ANG2 binds to AT1 who's effect is conserve water.

vasodilator counteracts ANG2 and NE

prevents RBF from going too low

stimulated by: sheer stress, ACH, bradykinin, ATP, histamine.

afferent arteriolar dilation

resulting in ↑ capillary pressure so ↑ GFR.

decrease capillary hydrostatic pressure

decrease proteinurea

produce less cytokines

vasodilator at afferent.

stimulated by low ECF volume, ANG2, sympathetic nerves

inhibited by NSAID

vasoconstrictors trigger PG

Vasodilator by releasing NO and PG

raises GFR and RBF

Angiotensin Converting Enzyme (ACE) breaks down Bradykinin

some will be excreted in urine

transport max is reached.

Na-K ATP ase

Na-Glucose symport

all in, H out

Na-K-ATPase

Na-K-2Cl symport

Na-H antiport

no water

Na-K-ATPase

Na-Cl symport

no water

Na-K ATPase

ENac

water ADH dependent

K secretion

(+) FWC +CH2O  -tCH2O

dilute

- FWC - CH2O  +tCH2O

concentrated

ECF volume

Sensor

effector

affected

Sensor: arterial and cardiac baroreceptors

effector: ANGII/ALD/SNS/ANP

Affected: Urine Na excretion

Plasma Osmolality

Sensor

effector

affected

Sensor: Hypothalamic osmoreceptors

Effector: ADH

Affected: Urine osmolality and thirst

• released from posterior pituitery
• regulated by hypothalamic osmoreceptor or arterial baroreceptor
• ↑ water reabsorption at distal tubule & colecting ducts

1. At principle cells ADH binds to V₂ receptor

2. V₂ increases cAMP -> insertian of aquaporin in apical membrane

1. iso osmolar fluid enters thin descending limb

2. water is removed, fluid becomes hyperosmotic

3. At thin ascending limb NaCl moves out

4. At thick ascending limb Na-K-2Cl removes solutes, liquid is hypo-osmolar

5. distal tubule and cortical collecting duct reabsorb more NaCl

6. medullary colecting duct NaCl reabsorbed

1. iso-osmolar fluid enters descending limb

2. water is removed, fluid is hyperosmolar at the end of the loop

3. in thin ascending limb NaCl moves out

4. In thick ascending Na-K-2Cl symport removes solute, fluid is hypo-osmolar

5. when ADH present, water permiability ↑ at late distal tubule and colecting duct

the colecting duct is only permeable to urea at the inner medulla,

ADH Phosphorylates UT-A₁ to ↑ urea permiability

EP on alpha-adrenoceptors: release K from cells

EP on beta-2 adrenoceptors: K uptake

• uptake K into cells (hours)
• ↑ excretion of K by kidney

secreted: principal cell

reabsorbed: intercalated cell

how does PH effect K balance?

Acidosis?

Alkilosis?

Acidosis:

(Hours) ↓ K secretion by inhibiting Na/K ATPase & ↓ K permiability at apical. 

(Days) ↑ K secretion because of aldosterone. 

ALkalosis:

(Hours) ↑ K secretion by stimulating Na/K ATPase & ↑ K permiability at apical

(Days) Hypokalemia

Osmotic diuretics

where?

how?

example

Where: proximal tubule

How: unreabsorbable solutes decrease osmotic driving force for water reabsorbtion.  less Na reabsorption because of solvent drag.

Example: Manitol

Carbonic anhydrase inhibitor

where?

how?

Why is it bad?

example?

Where: Proximal tubule

How:Inhibitng CA inhibits H for the Na/H antiport.  so less Na reabsorption at proximal.

Bad: Harder for kidney to acidify urine and conserve Bicarb.

Example: acetazolamide

Loop diuretics

Where?

How?

Example

Where: Thick ascending limb

How:inhibit the Na-K-2Cl symport.  Inhibit's kidney's ability to maximally concentrate & dilute urine.

Example: Furosemide

Thiazides

Where?

How?

Where: Early distal

How: blocks Na/Cl symport

K⁺ sparing diuretics

Spironolactone

Where?

How?

Where: principle cells of the late distal & colecting ducts

How: Aldosterone receptor antagonist

K⁺ sparing diuretics

Amiloride

Where?

How?

Where: principle cells of the late distal & colecting ducts

How: ENaC channel blocker

• Na in plasma water is normal
• Na in total plasma fraction is low
• hyperlipidemia, hyperproteinemia

• extra substance pulling water from ICF to ECF
• Hyperglycemia, Mannitol,

Hypotonic

(true)

Hyponatremia

• Effective osmolality of plasma is low

common cause of hyponatremia

• euvolemic (no signs)
• plasma ADH too high,
• effect of tricyclic antidepresents & Morphine
• treated with water restriction
• Tolvaptan (ADH blocker)

Central diabetes insipidus

(CDI)

Nepherogenic diabetes insipidus

(NDI)

KIdney can't respond to ADH

• drug induced like lithium,

• increase renin release via beta-1 receptors
• increases Na reabsorption at proximal

Atrial Natriuretic peptide for water balance

(ANP)

• ↑ Na/H₂O secretion
• ↑ GFR,
• ↓ Na reabsorption at proximal & collecting ducts.

Normal

HCO3

PCO2

PH

HCO3: 25 ± 2 (22-26)

PCO2: 40 ± 5 (35-45)

PH: 7.4 ± 0.05 (7.35-7.45)

early proximal tubule (80%)

Thick ascending limb (20%)

1. H₂O + CO₂ -> HCO₃ + H in the renal tubular cells catalyzed by Carbonic Anhydrase (CA)

2. H transported to tubular lumen by Na-H exchanger antiport. 

3. Bicarb transfered out of proximal cell into interstitial fluid by 3 HCO₃: 1 Na contransporter

4. in the proximal tubular luman secreted H + filtered HCO₃-> H₂O + CO₂.

Generation of Bicarb

Glutamine metabolism & generation of NH4

1. In proximal tubular cell, Glutamine is metabolised into 2 NH₄⁺ and 2 HCO₃^-

2. NH₄⁺ is transorted into lumen of proximal tubule by Na/H exchange and excreted

3. HCO₃^- transported to interstitial by Na-3HCO₃ co-transporter

Generation of bicarb

non-bicarb buffers (Ha₂HPO₄)

1. In medullary colecting tubule,

H₂O + CO₂-> H⁺ + HCO₃^-  by CA. 

2. H⁺ transfered into lumen by H ion ATPase, and is buffered by non-bicarbonate buffers like Na₂HPO₄ to make NaH₂PO₄ which is excreted.

3. Bicarbonate generated released to interstitial by Cl-Bicarb symport. 

Note: net gain of 1 bicarb

Hemoglobin: 35% of buffering.  better buffer in venous blood.

Phosphate: 5% of buffering (low concentration)

Bicarbonate: 53% of buffering

Plasma proteins: 7% of buffering (low concentration)

Proteins & phosphates:  (high concentration)

Bicarbonate: (low concentration)

If high H in plasma: bone exchanges free proton for Ca, Na, K on surface.

Chronic metabolic acidosis: Osteoclasts release CaCO₃, Calcium phosphate

40% buffering in chroic acidosis

If ECF high H: H enters cell, K exits cell

If ECF low H: H exits cell, K eters cell.

process can also be triggered by K concentration.

metabolic acid base buffering

(big picture)

50% buffered extracellularly, mostly by HCO₃^- (minutes)

50% buffered by bone or cells (2-4 hours)

extracellular HCO₃^- not effective,

must use intracellular buffers or transcellular (recovery takes hours)

PH 4.4

PH < 4.4 renal tube low on buffers.

breath fast

breath slow

fast: lowers plasma CO₂

slow: raise plasma CO₂

5 ↓ in PCO₂(from 40-35) : plasma HCO₃ ↓ 1

10 ↑ PCO₂ (40-50) : plasma HCO₂ ↑ 1

Corection: cause of problem solved

compensation: counter problem

Albumin 40%

other plasma proteins 10%

proteins from renal tubule and urogenetal tract 50%

high β-2 microglobulin

albumin

(small proteins)

where is renin released?

what influences it?

released at JGA from granular cells at afferent and efferent arterioles.

• more sympathetic nerve = more renin release
• pressure in afferent arteriole.  (baroreceptor).  low P = more renin.
• signals from macula densa

Which structures are innervated by the SNS?

• afferent, efferent arterioles (vasoconstriction)
• JGA: more renin release
• renal tubules, enhances Na reabsorption.

NE

smooth muscle

vasoconstricter at alpha adrenergic

• voluntary control
• alpha motor neurons
• skeletal muscle

Sacral Nerve: sensory afferent & parasympathetic efferents

Sympathetic innervation: contraction at bladder neck to conserve urine.

1. Bladder stretches, sacral afferents stimulated
2. parasympathetic efferents respond, detrusor muscle contracts, urine goes into external
3. urine in urethra sends signal to inhibit tonic motor neurons of external sphyncter
4. relaxation of external sphyncter

Sympathetic renal nerve stimulation

due to:

results in:

due to: fall in BP, fear, pain, exercise

result in: ↓ RBF and GFR

made in kidney and systemically

ANG2 binds to AT1 who's effect is conserve water.

vasodilator counteracts ANG2 and NE

prevents RBF from going too low

stimulated by: sheer stress, ACH, bradykinin, ATP, histamine.

afferent arteriolar dilation

resulting in ↑ capillary pressure so ↑ GFR.

decrease capillary hydrostatic pressure

decrease proteinurea

produce less cytokines

vasodilator at afferent.

stimulated by low ECF volume, ANG2, sympathetic nerves

inhibited by NSAID

vasoconstrictors trigger PG

Vasodilator by releasing NO and PG

raises GFR and RBF

Angiotensin Converting Enzyme (ACE) breaks down Bradykinin

some will be excreted in urine

transport max is reached.

Na-K ATP ase

Na-Glucose symport

all in, H out

Na-K-ATPase

Na-K-2Cl symport

Na-H antiport

no water

Na-K-ATPase

Na-Cl symport

no water

Na-K ATPase

ENac

water ADH dependent

K secretion

ECF volume

Sensor

effector

affected

Sensor: arterial and cardiac baroreceptors

effector: ANGII/ALD/SNS/ANP

Affected: Urine Na excretion

Plasma Osmolality

Sensor

effector

affected

Sensor: Hypothalamic osmoreceptors

Effector: ADH

Affected: Urine osmolality and thirst

• released from posterior pituitery
• regulated by hypothalamic osmoreceptor or arterial baroreceptor
• ↑ water reabsorption at distal tubule & colecting ducts

1. At principle cells ADH binds to V₂ receptor

2. V₂ increases cAMP -> insertian of aquaporin in apical membrane

1. iso osmolar fluid enters thin descending limb

2. water is removed, fluid becomes hyperosmotic

3. At thin ascending limb NaCl moves out

4. At thick ascending limb Na-K-2Cl removes solutes, liquid is hypo-osmolar

5. distal tubule and cortical collecting duct reabsorb more NaCl

6. medullary collecting duct NaCl reabsorbed

1. ISO-osmolar fluid enters descending limb

2. water is removed, fluid is hyperosmolar at the end of the loop

3. in thin ascending limb NaCl moves out

4. In thick ascending Na-K-2Cl symport removes solute, fluid is hypo-osmolar

5. when ADH present, water permeability ↑ at late distal tubule and collecting duct

the collecting duct is only permeable to urea at the inner medulla,

ADH Phosphorylates UT-A₁ to ↑ urea permeability

EP on alpha-adrenoceptors: release K from cells

EP on beta-2 adrenoceptors: K uptake

• uptake K into cells (hours)
• ↑ excretion of K by kidney

secreted: principal cell

reabsorbed: intercalated cell

how does PH effect K balance?

Acidosis?

Alkilosis?

Acidosis:

(Hours) ↓ K secretion by inhibiting Na/K ATPase & ↓ K permeability at apical. 

(Days) ↑ K secretion because of aldosterone. 

ALkalosis:

(Hours) ↑ K secretion by stimulating Na/K ATPase & ↑ K permeability at apical

(Days) Hypokalemia

• increase renin release via beta-1 receptors
• increases Na reabsorption at proximal

Atrial Natriuretic peptide for water balance

(ANP)

• ↑ Na/H₂O secretion
• ↑ GFR,
• ↓ Na reabsorption at proximal & collecting ducts.

Normal

HCO3

PCO2

PH

HCO3: 25 ± 2 (22-26)

PCO2: 40 ± 5 (35-45)

PH: 7.4 ± 0.05 (7.35-7.45)

early proximal tubule (80%)

Thick ascending limb (20%)

If ECF high H: H enters cell, K exits cell

If ECF low H: H exits cell, K enters cell.

process can also be triggered by K concentration.

Effects of changing afferent arteriolar resistance,

↓ resistance: ↑ Pc GFR & RBF

↑ resistance: ↓ Pc and GFR & RBF

↓ resistance: ↓ Pc and GFR.  ↑RBF

↑ resistance: ↑ Pc and GFR.  ↓RBF

↓ ∏c: ↑ GFR

↑ ∏c: ↓ GFR

(+) FWC +CH2O  -tCH2O

dilute

- FWC - CH2O  +tCH2O

concentrated

Osmotic diuretics

where?

how?

example

Where: proximal tubule

How: unreabsorbable solutes decrease osmotic driving force for water reabsorbtion.  less Na reabsorption because of solvent drag.

Example: Manitol

Carbonic anhydrase inhibitor

where?

how?

Why is it bad?

example?

Where: Proximal tubule

How:Inhibiting CA inhibits H for the Na/H antiport.  so less Na reabsorption at proximal.

Bad: Harder for kidney to acidify urine and conserve Bicarb.

Example: acetazolamide

Loop diuretics

Where?

How?

Example

Where: Thick ascending limb

How:inhibit the Na-K-2Cl symport.  Inhibits kidney's ability to maximally concentrate & dilute urine.

Example: Furosemide

Thiazides

Where?

How?

Where: Early distal

How: blocks Na/Cl symport

K⁺ sparing diuretics

Spironolactone

Where?

How?

Where: principle cells of the late distal & collecting ducts

How: Aldosterone receptor antagonist

K⁺ sparing diuretics

Amiloride

Where?

How?

Where: principle cells of the late distal & collecting ducts

How: ENaC channel blocker

• Na in plasma water is normal
• Na in total plasma fraction is low
• hyperlipidemia, hyperproteinemia

• extra substance pulling water from ICF to ECF
• Hyperglycemia, Mannitol,

Hypotonic

(true)

Hyponatremia

• Effective osmolality of plasma is low

common cause of hyponatremia

• euvolemic (no signs)
• plasma ADH too high,
• effect of tricyclic antidepresents & Morphine
• treated with water restriction
• Tolvaptan (ADH blocker)

Central diabetes insipidus

(CDI)

Nepherogenic diabetes insipidus

(NDI)

Kidney can't respond to ADH

• drug induced like lithium,

1. H₂O + CO₂ -> HCO₃ + H in the renal tubular cells catalyzed by Carbonic Anhydrase (CA)

2. H transported to tubular lumen by Na-H exchanger antiport. 

3. Bicarb transfered out of proximal cell into interstitial fluid by 3 HCO₃: 1 Na contransporter

4. in the proximal tubular luman secreted H + filtered HCO₃-> H₂O + CO₂.

Generation of Bicarb

Glutamine metabolism & generation of NH4

1. In proximal tubular cell, Glutamine is metabolized into 2 NH₄⁺ and 2 HCO₃^-

2. NH₄⁺ is transported into lumen of proximal tubule by Na/H exchange and excreted

3. HCO₃^- transported to interstitial by Na-3HCO₃ co-transporter

Generation of bicarb

non-bicarb buffers (Ha₂HPO₄)

1. In medullary collecting tubule,

H₂O + CO₂-> H⁺ + HCO₃^-  by CA. 

2. H⁺ transferred into lumen by H ion ATPase, and is buffered by non-bicarbonate buffers like Na₂HPO₄ to make NaH₂PO₄ which is excreted.

3. Bicarbonate generated released to interstitial by Cl-Bicarb symport. 

Note: net gain of 1 bicarb

Hemoglobin: 35% of buffering.  better buffer in venous blood.

Phosphate: 5% of buffering (low concentration)

Bicarbonate: 53% of buffering

Plasma proteins: 7% of buffering (low concentration)

Proteins & phosphates:  (high concentration)

Bicarbonate: (low concentration)

If high H in plasma: bone exchanges free proton for Ca, Na, K on surface.

Chronic metabolic acidosis: Osteoclasts release CaCO₃, Calcium phosphate

40% buffering in chroic acidosis

breath fast

breath slow

fast: lowers plasma CO₂

slow: raise plasma CO₂

5 ↓ in PCO₂(from 40-35) : plasma HCO₃ ↓ 1

10 ↑ PCO₂ (40-50) : plasma HCO₂ ↑ 1