Regulation of Renal Function

Regulation of Renal Function

• Dr. Catherine McDermott presents the regulation of renal function.
• The lecture introduces and discusses regulation of GFR, the Countercurrent Mechanism (including osmotic gradients in the kidney), and regulation of urine concentration.

Lecture Learning Outcomes

• Describe intrinsic and extrinsic mechanisms involved in regulating GFR.
• Explain the importance of the medullary osmotic gradient.
• Describe how the medullary osmotic gradient is created and maintained.
• Explain in detail how anti-diuretic hormone regulates urine concentration.

Glomerular Filtration

• Glomerular filtration is driven by blood pressure.
• Net Filtration Pressure (NFP) is influenced by glomerular hydrostatic pressure (BP), blood colloidal osmotic pressure, and capsular hydrostatic pressure.
• The net filtration pressure is 10 mmHg.

Glomerular Filtration Rate (GFR)

• GFR refers to the volume of filtrate formed each minute.
• GFR is directly proportional to NFP.
• Normal GFR in adults is 120-125 ml/min.

Regulation of Glomerular Filtration

• Renal autoregulation is an intrinsic control mechanism
• Neural control involves sympathetic activity decreasing GFR by constricting renal arterioles during stress/emergency situations and are an extrinsic control mechanism
• Hormonal control includes the renin-angiotensin mechanism where decreased pressure leads to the production of angiotensin II, resulting in constriction of arterioles, this is also an extrinsic control mechanism

Renal Autoregulation - Myogenic Mechanism

• Smooth muscle contracts when stretched.
• Increased BP causes afferent arterioles to constrict.
• This restricts blood flow to the glomerulus.
• The myogenic mechanism helps in maintaining GFR.

Renal Autoregulation - Tubuloglomerular Feedback Mechanism

• The macula densa, part of the juxtaglomerular apparatus, responds to the filtrate [NaCl].
• If GFR increases, there is insufficient time for tubular reabsorption, and NaCl remains high in the distal nephron.
• Macula densa releases vasoconstrictors.
• Decreases NFP and GFR.

Limits of Intrinsic Control

• Intrinsic mechanisms cannot handle extremely low systemic BP.
• Autoregulation ceases when MAP drops below 80 mmHg.

Tubuloglomerular Feedback

• Increased GFR leads to increased NaCl in tubular fluid.
• There is increased uptake of NaCl across the apical membrane of the macula densa via the Na+-K+-2Cl- symporter.
• This results in increased ATP and adenosine (ADO).
• ATP binds P2X receptors, and ADO binds A1 receptors in the membrane of smooth muscle surrounding the arteriole, increasing [Ca2+]i.
• Vasoconstriction of the afferent arteriole occurs.
• GFR is decreased.
• ATP and ADO also inhibit renin release by granular cells.

Sympathetic Control - Volume of ECF

• During normal ECF volume, SNS is at rest.
• Blood vessels are dilated.
• Renal autoregulation prevails.

Sympathetic Control - Stress/Emergency

• Blood shunts 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

• Osmolality is the number of solute particles dissolved in 1L of water.
• It reflects the solution’s ability to cause osmosis.
• Body fluids are measured in milliosmol (mOsm).
• Kidneys maintain body fluids at approximately 300mOsm by regulating urine concentration and volume.

The Nephron - Juxtamedullary Nephrons

• Juxtamedullary nephrons make up 15% of nephrons.
• These arise in the cortex-medullary junction.
• They are important in producing concentrated urine.
• Loops of Henle deeply invade the medulla.

Regulation of Urine Concentration and Volume - Countercurrent Mechanism

• Uses countercurrent mechanisms to acheive these aims
• Fluid flows in opposite directions through adjacent segments of the same tube.
• It establishes an osmotic gradient from the cortex to the medulla.
• Allows kidneys to vary urine concentration in collecting ducts (via ADH).
• It comprises the Loop of Henle of juxtamedullary nephrons (Countercurrent Multiplier) and Vasa Recta (Countercurrent Exchanger).

Countercurrent Multiplier

• The countercurrent multiplier involves the descending and ascending limbs of the Loop of Henle.
• The descending limb is freely permeable to water but impermeable to solutes.
• The ascending limb is impermeable to water but permeable to solutes.
• Tubular fluid becomes more concentrated as it moves down the Loop of Henle and then more dilute as it moves back up.
• Interstitial fluid osmolality increases as you move down the descending limb.

Countercurrent Exchanger - Vasa Recta

• The vasa recta maintains the osmotic gradient established.
• It supplies medullary cells with nutrients.
• Water is lost, and NaCl is gained as blood flows into medulla.
• As blood emerges from the medulla into the cortex, water is gained, and NaCl is lost.

Purpose of Medullary Gradient

• Without the medullary gradient, it would be impossible to raise the concentration of urine above 300mOsm.
• The gradient is controlled by ADH (antidiuretic hormone).
• ADH acts on collecting ducts.
• It inserts aquaporins into the luminal membrane.
• The amount of ADH determines the number of aquaporins inserted and the amount of water reabsorbed.

Water Balance

• To remain hydrated, water intake must equal water output; water intake and output are closely regulated.
• Water intake sources include ingested fluid (60%) and solid food (30%), as well as metabolic water (10%).
• Water output includes urine (60%) and feces (4%), insensible losses (28%), and sweat (8%).
• Obligatory water losses include insensible water losses from lungs and skin, water accompanying undigested food residues in feces, and urine solutes flushed out of the body in water.

Regulation of Water Balance: ADH (Antidiuretic Hormone / Vasopressin)

• ADH is produced by the hypothalamus and secreted from the posterior pituitary.
• Secretion is stimulated by increased osmolality of body fluids and decreased volume and pressure of the vascular system.
• Drugs, nicotine, alcohol, nausea, ANP, and angiotensin II can affect ADH secretion.
• ADH increases the permeability of collecting ducts to water (primary action) and urea.
• It stimulates reabsorption of NaCl by the thick ascending limb of Loop of Henle, DT, and collecting duct.

Osmotic Control of ADH Secretion

• The most important regulator of ADH secretion is osmolality.
• A ~1% change in osmolality can significantly alter ADH secretion.
• Osmoreceptors are located in the hypothalamus.
• Increased plasma osmolality triggers receptors to send a signal to ADH synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus.
• ADH is rapidly degraded in plasma, and circulating levels are rapidly reduced to zero once secretion is inhibited.

Hemodynamic Control of ADH Secretion

• Hemodynamic variables: Decreased blood volume or pressure stimulates secretion of ADH.
• Receptors involved: Left atrium and large pulmonary vessels, the aortic arch, and the carotid sinus.
• Signals are carried in afferent fibers of vagus and glossopharyngeal nerves to the brain stem and relayed to ADH-secreting cells of the supraoptic and paraventricular hypothalamic nuclei.
• Less sensitive than osmoreceptors; requires a 5-10% blood volume/pressure change to be activated.
• Changes in blood volume/pressure can affect the response to changes in osmolality.
• These cause a shift in set point.

Actions of ADH on the Kidneys

• ADH binds to the V2 receptor in the basolateral membrane.
• This activates an associated G protein on adenylyl cyclase (AC), increasing cAMP.
• cAMP activates protein kinase A.
• This results in the insertion of vesicles containing activated aquaporin-2 (AQP2) into the apical membrane of the cell, and synthesis of AQP2 is also increased.
• When ADH is removed, AQP2 is internalized.
• The basolateral membrane is permeable to water due to the presence of AQP 3 and AQP4.