Regulation of Renal Function

Regulation of Renal Function

• Glomerular Filtration (GFR)
• Countercurrent Mechanism
• Regulation of Urine concentration are key discussion points

Lecture Outcomes

• Describe Intrinsic and Extrinsic GFR regulation
• Explain the medullary osmotic gradient
• Detail how Anti-Diuretic Hormone regulates urine concentration

Glomerular Filtration

• This is driven by blood pressure
• Net Filtration Pressure (NFP) is determined by:
  • Glomerular hydrostatic pressure (BP)
  • Blood colloidal osmotic pressure
  • Capsular hydrostatic pressure.
• Net filtration pressure is 10 mmHg

Glomerular Filtration Rate (GFR)

• The volume of filtrate formed per minute
• Directly proportional to NFP
• The rate is 120-125 ml/min in adults

Regulation of Glomerular Filtration

• Regulation occurs during renal autoregulation and neural and hormonal controls
• Sympathetic activity decreases GFR through constriction of renal arterioles during stress/emergency situations
• Renin-angiotensin mechanism: decreased pressure leads to angiotensin II production with constriction of arterioles

Renal Autoregulation

• Myogenic Mechanism: Smooth muscle contracts when stretched and increased BP causes afferent arterioles to constrict, restricting blood flow and maintaining GFR
• Tubuloglomerular Feedback Mechanism:
  • Macula densa responds to filtrate [NaCl]
  • High GFR means insufficient time for tubular reabsorption, so NaCl remains high in distal nephron
  • Macula densa releases vasoconstrictors which decreases NFP and GFR
• Intrinsic mechanisms have difficulties handling low systematic BP, autoregulation stops below 80 mmHg

Tubuloglomerular Feedback

• Increased GFR results in increased NaCl in tubular fluid
• Increased uptake of NaCl across apical membrane of macula densa occurs via Na+-K+-2Cl- symporter
• This increases ATP and adenosine (ADO)
• ATP binds P2X receptors and ADO binds A1 receptors in the membrane of smooth muscle surrounding the arteriole
• Increased Calcium increases causing vasoconstriction of the afferent arteriole
• GFR subsequently decreases
• ATP and ADO also inhibit renin release by granular cells.

Sympathetic Control

• When the volume of Extra Cellular Fluid is normal:
  • SNS is at rest
  • Blood vessels are dilated
  • Renal autoregulation prevails
• Stress/Emergency
  • Blood is shunted to vital organs
  • Noradrenaline acts on α-adrenoceptors
  • Afferent arterioles constrict
  • Filtrate formation is inhibited
  • Granular cells are also stimulated to release renin

Regulation of Urine Concentration and Volume

• Osmolality: Number of solute particles in 1L of water, reflects solution's osmosis ability
• Body fluids measured in milliosmol (mOsm)
• Kidneys keep body fluids at ~300mOsm by regulating urine concentration and volume

The Nephron

• Juxtamedullary nephrons contribute 15% of nephrons
  • Arise in cortex-medullary junction
  • Important for producing concentrated urine
  • Loops of Henle deeply invade the medulla

Regulation of Urine Concentration and Volume

• This achieved using countercurrent mechanism
• Fluid flows in opposite directions through adjacent sections of the same tubes
• Osmotic gradient established from cortex to medulla
• Kidneys adjust urine concentration in the collecting ducts via ADH
• It comprises Loop of Henle of juxtamedullary nephrons (countercurrent multiplier) and Vasa Recta (countercurrent exchanger)

Countercurrent Multiplier

• Descending limb permeable to free water but impermeable to solutes
• Ascending limb is impermeable to free water but permeable to solutes
• Tubular fluid becomes more concentrated as it goes down the Loop of Henle and becomes dilute as it moves back up
• Interstitial fluid osmolality increases as you descend the limb

Countercurrent Exchanger

• Vasa recta is used
• This maintains the osmotic gradient while supplying nutrients to medullary cells
• As blood flows into the medulla it gains NaCl and loses water
• Blood emerges to cortex gaining water and losing NaCl

Purpose of Medullary Gradient

• Elevating urine concentration above 300mOsm is impossible without this gradient
• It is controlled by ADH, by acting on collecting ducts and inserting aquaporins into the luminal membrane
• Amount of ADH dictates aquaporin number and water reabsorbed.

Water Balance

• Water intake must be equal to water output in order to maintain hydration
• Key water intake sources are fluids 60%, solid food 30% and metabolic water 10%
• Water output is made from urine 60%, solid food 4%, insensible losses 28% and sweat 8%
• Insensible losses in lungs and skin, water accompanying undigested food residues in feces and urine solutes being flushed are examples of water loss.

Regulation of Water Balance: ADH

• Antidiuretic Hormone (ADH), also known as Vasopressin, is critical for this purpose
• Secreted by the hypothalamus and released from the posterior pituitary
• Increased osmolality and decreased volume/pressure of vascular system causes release
• Stimulated by drugs, nicotine, alcohol, nausea, ANP and angiotensin II
• Increases permeability of collecting ducts and stimulates NaCl reabsorption by thick ascending loop of Henle and DT
• Water reabsorption and urea occur

Osmotic Control of ADH Secretion

• Major regulator of ADH secretion
• 1% change in osmolality has a big impact
• Osmoreceptors in the hypothalamus
• Increased plasma osmolality stimulates receptors to send signals to ADH synthesizing/secreting cells
• ADH is rapidly degraded where the circulating levels are reduced and secretion inhibited

Hemodynamic Control of ADH Secretion

• Lowering blood volume/pressure stimulates ADH secretion
• Receptors found in the left atrium, large pulmonary vessels, aorta, and carotid sinus
• Signals carried in afferent fibres of vagus and glossopharyngeal nerves to the brain stem
• Relayed to ADH-secreting cells of the supraoptic and paraventricular hypothalamic nuclei
• Changes in blood volume/pressure can affect the response to changes in osmolality by shifting regulation thresholds.

Actions of ADH on the Kidneys

• ADH binds to V2 receptors in basolateral membranes
• Results in activation of G protein with adenylyl cyclase (AC) and increased cAMP
• cAMP activates protein kinase A
• Water travels through aquaporin-2 created by ADH from vesicles, synthesized into the apical membrane cell
• When removing ADH it removes AQP2.
• Basolateral membrane is permeable to water due to AQP 3 and AQP4