Tubuloglomerular Feedback

• Feedback mechanism that aims to maintain constant GFR and rate of water and solute load delivery to the distal tubules, in the face of changing renal perfusion

Glomerulotubular Balance

• Mechanism that maintains constant fraction of fluid and solute reabsorption from the tubules, despite changes in GFR

Overview

• Water and electrolyte homeostasis
• glomerular filtration (125ml/min = 180L/day)
• tubular reabsorption (PCT reabsorbs 60% of water and Na+)
• tubular secretion
• Excretion of waste products
• urea (protein)
• creatinine (muscle)
• uric acid (nucleic acids)
• bilirubin (Hb)
• Hormone production
• Gluconeogenesis
• Acid-base balance
• Excretion of drugs and chemicals

Water Balance

Obligatory urine loss

• 700mmol waste products/day
• max urine osmolality 1400mosmoles/kg
• Hence minimum water loss 500ml/day

Free water

• non-osmotically obligated water
• the water in excess of that required to produce a solution of the same osmolality as plasma

Electrolyte Requirements

Na+	100-150mmol/day
K+	70-100mmol/day
Cl-	150mmol/day
Urea	400mmol/day

Endocrine Functions

• Production of hormones in the kidney
• 1,25 dihydrocholecalciferol
• Calcitriol, active form of Vit D
• Produced in PCT
• EPO
• Produced by endothelial cells of peritubular capillaries
• in response to renal hypoxia
• Prostaglandins
• Release of enzymes that initiate hormone production extrinsically
• Renin → Ang II → aldosterone
• Kallikrein → bradykinin
• Hormones that act on the kidney
• ADH
• aldosterone
• calcitiriol
• PTH
• ANP
• Produced in right atrium in response to ↑ stretch
• Relax glomerular mesangial cells → ↑ GFR
• v/d aff and v/c eff arterioles → ↑ GFR
• ↓ ADH release, ↓ aldosterone
• Inhibit Ang II
• v/c effect

Normal Values

• 1200ml/min
• 25% of CO (x10 its metabolic requirements)

Measurement

• p-aminohippuric acid (PAH) is filtered by glomerulus and secreted by tubules
• Has a high extraction ratio (ER) = 0.9
• Effective renal plasma flow (ERPF) = clearance of PAH (ignores the fact that ER not quite 1)

 

• ERPF = U_PAH.V/P_PAH
  
  • U_PAH - urinary concentration of PAH
  • V - volume of urine
  • P_PAH - plasma concentration of PAH
•   RBF = ERPF/ER . 1/(1 - hct)
  • hct - haematocrit

Control of RBF

1. Autoregulation
• myogenic mechanism (70-170mmHg)
• tubuloglomerular feedback
2. Sympathetic innervation
3. RAAS system
4. Atrial natriuretic peptide
5. Eicosanoids

 

• Noradrenaline → v/c internolar arteries and afferent arterioles
• Dopamine (made in kidney) → renal v/d and natriuresis
• Ang II → v/c efferent > afferent arterioles

 

Autoregulation

1. Myogenic mechanism (70-170mmHg)
2. Tubuloglomerular feedback

 

Tubuloglomerular Feedback

• Feedback mechanism that aims to maintain constant GFR and rate of water and solute load delivery to the distal tubules, in the face of changing renal perfusion
• Macula densa
• Sensor of fluid and NaCl flow rate in distal tubule
• Produces locally vasoactive agents in response to changes in flow
  • adenosine (v/c)
  • TXA2 (v/c)
  • NO (v/d)

Glomerulotubular Balance

• Mechanism that maintains constant fraction of fluid and solute reabsorption from the tubules, despite changes in GFR
• Don't get tubuloglomerular feedback and glomerulotubular balance mixed up!

Sympathetic Innervation

• Low thoracic to high lumbar sympathetic outflow
• Sympathetic stimulation results in ↓ RBF, but only a slight reduction in GFR

Renin

• Renin secreted by juxtaglomerular cells

Control of renin secretion

Increased

• ↑ sympathetic
• ↑ circulating catecholamines
• ↓ aff arteriole P
• ↓ flow past macula densa

Decreased

• Ang II
• ADH

Angiotensin

Production

Angiotensin II actions

• Adrenal cx → ↑ aldosterone secretion
• ↑ Facilitation of NA release from sympathetic nerves
• Contraction of mesangial cells → ↓ filtration coeff → ↓ GFR
• Thirst (OVLT, SFO)
• ↑ Secretion of ADH and ACTH (area postrema)

 

End results:

• Renal salt and water retention
• ↑ SVR
• ↑ CO
• ↑ Arterial pressure

Aldosterone

• Steroid hormone produced by zona glomerulosa of adrenal cortex
• Release stimulated by
• Ang II
• ↑ plasma [K+]
• ACTH
• Actions
• Stimulates Na+ reabsorption and K+ secretion by principal cells of the cortical collecting ducts
• Stimulates H+ secretion by type A intercalated cells

Anti-Diuretic Hormone

• Synthesised in hypothalamus
• Secreted by post pituitary
• ↑ water permeability of CD luminal membrane → ↑ water reabsorption
• Acts via cAMP → insert aquaporin 2 channel
• At high concs acts as vasoconstrictor
• ↓ RBF
• ↓ GFR
• Secretion stimulated by
• ↑ osmolality > 1% change (osmoreceptor in hypothalamus OVLT)
• hypovolaemia > 5-10% change (low P barorec)
• hypotension (high P barorec)
• Ang II
• Pain, stress, emotion
• nausea and vomiting
• carbamazepine
• (alcohol → ↓ secretion)

Atrial Natriuretic Peptide

• Produced in right atrium in response to ↑ stretch
• Relax glomerular mesangial cells → ↑ GFR
• v/d aff and v/c eff arterioles → ↑ GFR
• ↓ ADH release, ↓ aldosterone
• Inhibit Ang II
• v/c effect

Eicosanoids

• PGI2 and PGE2 are locally active vasodilators produced by kidney in clinical states associated with high concs of circulating vasoconstrictors
• Inhibition of COX in these states may ↓ RBF and impair renal function

Normal Values

• 125ml/hr
• 180L/day
• NB only 500ml-1L urine produced per day, meaning that > 99.4% of filtered water is normally reabsorbed by the kidneys
• This also means that if there is tubular dys function and impaired reabsorption of water, there is huge potential for excessive water loss (polyuric renal failure)

Balance of Starling's Forces

• Net fluid flux = k. [(PC - P_BC) - σ (π _C - π _BC)]
• k - filtration coefficient
• incorporates SA and hydraulic conductivity
• high in glomerulus due to many fenestrations
• σ - reflection coefficient (= 1)
• P_C - capillary hydrostatic pressure
• P_BC - Bowmans capsule hydrostatic pressure
• π _C - capillary oncotic pressure
• π _BC - Bowmans capsule oncotic pressure

 

Capillary	afferent  end	efferent end
PC	60	58
PBC	15	15
π C	21	33
π BC	0	0
net filtration P	24	10

 

Glomerular Capillary Hydrostatic Pressure

• Balance between relative resistances of afferent and efferent arterioles
• ↑ with ↑ sys P minimised by autoregulation (70-170mmg)

 

Glomerular Capillary Oncotic Pressure

• ↑ sympathetic → ↓ RBF → ↑ π _C due to filtration → ↓ net filtration P → ↓ GFR

 

Glomerular filtrate

• < 7,000 Da → freely filtered
• > 7,000 Da → ↓ ing filtration
• > 70,000 Da → no filtration
• Surface of glomerular filtration barrier has negative charge

 

Filtration Fraction

• GFR/RPF = 125/600 = 20%

Simplified Schematic

• This simple schematic shows how the main homeostatic mechanisms fit in together
• It should be fairly easy to remember in this format, but ideally in an exam answer it should be fleshed out with more detail (see Full Schematic)

Full Schematic

• This crazy busy schematic shows how all of the homeostatic mechanisms fit in together
• There's no way you would have time to reproduce this in full during the exam, but I think it is useful to try and get your head around how everything integrates together