Renal Function Regulation and GFR

Regulation of Renal Function

• Glomerular Filtration Rate (GFR) regulation, the countercurrent mechanism, and urine concentration regulation are key topics.
• Understanding intrinsic/extrinsic GFR regulation, the medullary osmotic gradient, and ADH's role in urine concentration are the main lecture outcomes.

Glomerular Filtration

• Blood pressure drives the filtration process.
• Net Filtration Pressure (NFP) is affected by glomerular hydrostatic pressure (BP), blood colloidal osmotic pressure, and capsular hydrostatic pressure.
• Net filtration pressure is about 10 mmHg.

Glomerular Filtration Rate (GFR)

• The GFR refers to the volume of filtrate formed each minute, typically 120-125 ml/min in adults and it is directly proportional to NFP.
• Renal autoregulation, neural activity, and hormone activity regulate GFR.
• Sympathetic stimulation reduces GFR by constricting renal arterioles, as does stress or emergency situations.
• In the renin-angiotensin mechanism, lowered pressure increases Angiotensin 2 production, which then constricts arterioles and reduces GFR.

Renal Autoregulation Mechanisms

• The myogenic mechanism constricts afferent arterioles when blood pressure rises.
• This reduces blood flow to the glomerulus and therefore maintains GFR.
• The tubuloglomerular feedback mechanism involves the macula densa responding to filtrate [NaCl].
• Increased GFR leads to insufficient NaCl reabsorption, increases NaCl levels in the distal nephron and the macula densa releases vasoconstrictors.
• This reduces NFP and GFR.
• These intrinsic mechanisms are ineffective with extremely low systemic BP.
• Autoregulation stops if the Mean Arterial Pressure (MAP) falls below 80 mmHg.

Tubuloglomerular Feedback

• Increased GFR leads to increased NaCl in tubular fluid.
• Increased NaCl uptake occurs across the macula densa membrane via a Na+-K+-2Cl- symporter.
• ATP and adenosine (ADO) levels increase.
• ATP binds P2X receptors and ADO binds A1 receptors, increasing intracellular calcium, which constricts the afferent arteriole.
• GFR is reduced by vasoconstriction.
• Also, renin release by granular cells decreases due to ATP and ADO.

Sympathetic Control

• SNS activity at rest dilates blood vessels, where renal autoregulation maintains a normal ECF volume.
• In stress or during emergencies, blood is redirected to vital organs when noradrenaline acts on α-adrenoceptors.
• This constricts afferent arterioles, inhibits filtrate formation, and stimulates renin release.

Urine Concentration and Volume Regulation

• Osmolality, measured in milliosmols (mOsm), defines the concentration of solute particles in 1L of water with body fluids maintained at ~300 mOsm.
• Kidneys regulate urine concentration and volume to maintain constant body fluids.

Nephron Types

• Juxtamedullary nephrons constitute 15% of all nephrons.
• They originate at the cortex-medulla junction.
• They are essential for producing concentrated urine since the Loops of Henle deeply invade the medulla.

Countercurrent System

• The system is used to regulate urine concentration and volume.
• Fluid moves in opposing directions through adjacent tube segments.
• An osmotic gradient is created from the cortex to the medulla and a countercurrent mechanism and juxtamedullary nephrons allow the kidneys to adjust urine concentration via ADH.

Countercurrent Multiplier

• The descending limb of Henle's loop is permeable to water but not solutes.
• The ascending limb is the opposite, impermeable to water but permeable to solutes.
• As tubular fluid moves down the loop of Henle, it becomes more concentrated.
• As it moves up through the limb, it becomes more dilute.
• Interstitial fluid osmolality increases down the descending limb.

Countercurrent Exchanger

• The vasa recta preserves the osmotic gradient supplying nutrients to medullary cells.
• As blood flows through the medulla, it loses water and gains NaCl.
• Then blood moves to the cortex, it gains water and loses NaCl.

Medullary Gradient Significance

• The body cannot concentrate urine above 300mOsm without the gradient.
• ADH regulates the gradient.
• ADH acts on the collecting ducts where it inserts aquaporins into the luminal membrane and water is reabsorbed.
• The number of aquaporins indicates how much water is reabsorbed.

Water Balance

• The body must have equal water intake and water output to stay hydrated.
• 60% of water intake comes from ingested fluids, 30% from solid food, and 10% from metabolic water.
• Water is lost through urine (60%), feces (4%), insensible losses (28%), and sweat (8%).
• Obligatory water losses include insensible losses, water with undigested food, and urine excretion.

Water Balance Regulation: ADH

• ADH/Vasopressin is secreted by the hypothalamus, increasing collecting ducts permeability and can be triggered by drugs, nicotine, alcohol and ANP and angiotensin II.
• It is released from the posterior pituitary when osmolality increases or blood volume/pressure decreases.
• ADH primarily increases water reabsorption and also urea, it stimulates NaCl reabsorption in the thick ascending limb of Henle's loop, the distal tubule, and the collecting duct.

ADH Osmotic Control

• Osmolality changes as little as 1% significantly affect ADH secretion.
• Hypothalamic osmoreceptors trigger ADH release when plasma osmolality rises.
• ADH is degraded rapidly, terminating secretion quickly.

ADH Hemodynamic Control

• Low blood volume/pressure stimulates ADH release.
• Various receptors, including those in the left atrium, pulmonary vessels, aortic arch, and carotid sinus, relay signals to the brainstem.
• Relaying signals to the supraoptic and paraventricular hypothalamic nuclei is less sensitive than osmoreceptors.
• 5-10% blood volume/pressure change is required.
• Changes in blood volume/pressure alter the response to osmolality, shifting the set point.

ADH on the Kidneys

• ADH binds to V2 receptors on the basolateral membrane.
• Associated G protein activates adenylyl cyclase (AC), increasing cAMP.
• CAMP activates protein kinase A, which inserts aquaporin-2 (AQP2) into the apical membrane.
• The protein is synthesized for AQP2 as well.
• AQP2 is internalized once ADH is suppressed.
• AQP 3 and AQP4 make the basolateral membrane permeable.