Renal System IV HLTH1030 Lecture Notes PDF

Renal System IV H LT H 1 0 3 0 – A n a t o m y a n d P h y s i o l o g y o f B o d y Systems Melandri Vlok School of Health Sciences Sydney | University of Notre Dame Australia [email protected] ACKNOWLEDGEMENT OF COU...

Renal System IV H LT H 1 0 3 0 – A n a t o m y a n d P h y s i o l o g y o f B o d y Systems Melandri Vlok School of Health Sciences Sydney | University of Notre Dame Australia [email protected] ACKNOWLEDGEMENT OF COUNTRY The University of Notre Dame Australia is proud to acknowledge the traditional owners and custodians of this land upon which our University sits. The University acknowledges that the Fremantle Campus is located on Wadjuk Country, the Broome Campus on Yawuru Country and the Sydney Campus on Cadigal Country. Four Major Renal Processes 1. Glomerular filtration flow into Bowman’s capsule 2. Tubular reabsorption tubules to peritubular capillaries 3. Tubular secretion peritubular capillaries to tubules 4. Excretion elimination from tubules out of body (urine) Body Water Content Represents 99% of fluid outside cells (extracellular fluid = ECF) Is an essential ingredient of cytosol - fluid inside cells (intracellular fluid = ICF) Body must maintain normal volume & composition of extracellular fluid (ECF) & intracellular fluid (ICF). Percentage of total body weight which is water: 45% to 70% The water content of fat cells vs other tissues Obese vs lean individuals (a reason for differences). ICF = 2/3 Plasma ECF = Interstiti 1/3 al Factors Affecting Plasma Composition Kidneys exert control over the volume and composition of plasma by regulating solute and water content. Volume and composition of plasma depend on each other and must be maintained within a narrow range. Osmotic Equilibrium: Plasma = ECF = Intracellular = 300mOsm. – No ECF Intracellular Urine = Variable mOsm Plasma = 300 mOsm 300 mOsm 300 mOsm Exchanges Affecting Plasma Content *Coloured areas highlight importance of exchange between plasma and renal tubules. Changes to Osmotic Equilibrium 1. Excessive drinking of pure water. Increased volume, same solutes. 2. Consumption of salty chips! Increased solutes, same volume. Kidneys compensate to avoid this situation by changing the rate of water reabsorption. Concept of Balance Factors Affecting Water Balance 1. Normovolaemia: Normal blood volume 2. Hypervolaemia: Increased blood volume (Positive fluid balance) 3. Hypovolaemia: Decreased blood volume (Negative fluid balance) Water Reabsorption Kidneys compensate for changes in plasma volume and osmolality by adjusting rate of water excretion. PCT Water excretion unregulated. 70% filtered water reabsorbed. Distal Tubule/Collecting Ducts: Water excretion regulated by Antidiuretic Hormone (ADH). Allows kidneys to vary volume of water excreted. Water Reabsorption Water reabsorption is PASSIVE, through OSMOSIS. Coupled (secondary) to osmotic gradients generated by reabsorption of solutes. Mechanism in which solute gradient is established varies depending on the segment of the renal tubule. Water can only move if tubular membrane permeable to water. Proximal Tubular Reabsorption of Sodium Na+: major extracellular solute, responsible for producing solute gradient, driving water reabsorption at PCT. Actively transported across basolateral membrane by Na+/K+ pump, maintaining low intracellular concentration. Na+ moves across apical membrane, via: Na+ ion channels. Secondary active transport coupled to others (e.g. coupled to Glucose). Water Reabsorption in PCT 1. Solutes (Na+, X, Y) actively reabsorbed, increasing osmolarity of peritubular fluid and plasma. 2. Water reabsorbed by osmosis. 3. Permeating solute (urea) reabsorbed passively, following water movement. Regulation of Urine Osmolarity Normal osmolarity of plasma = 300mOsm. When needing to eliminate excess water, kidneys excrete large volumes of dilute urine (50 mOsm). When needing to conserve water, kidneys concentrate urine to about 4x the osmolarity of plasma (1400 mOsm). Kidneys regulate urine volume and osmolarity by varying water and Na+ reabsorption in distal nephron. Medullary Osmotic Gradient A Medullary Osmotic Gradient is present within renal medulla. Outer medulla (near cortex) has the lowest osmolarity (300mOsm) Inner medulla has highest osmolarity (1200-1400mOsm). Outer Medulla Gradient necessary for water reabsorption. Exists because of phenomenon: Inner Medulla “Countercurrent Multiplier” Countercurrent Multiplier “Countercurrent” : fluid flow in descending and ascending limbs move in opposite directions. Creates osmotic gradient between inner and outer medulla as solutes actively pumped whilst water unable to follow. Properties of different portions of the LOH (juxtamedullary nephrons) are critical to creating the countercurrent multiplier. Loop of Henle Descending LOH: Permeable to water. Na+, K+ or Cl- transport does NOT occur here. Passive Active THICK Ascending LOH: Movement Movement Impermeable to water. Na+, K+ or Cl- co- Passive transporters. Movement Medullary Osmotic Gradient Countercurrent Multiplier Establishes Medullary Osmotic Gradient (1) Countercurrent Multiplier Establishes Medullary Osmotic Gradient (2) Countercurrent Multiplier Establishes Medullary Osmotic Gradient (3) Medullary Osmotic Gradient Established Fluid in PCT iso-osmotic at 300mOsm. Osmolarity in Descending LOH increases until 1400mOsm. Osmolarity in ascending LOH always lower than descending LOH. Osmolarity decreases in ascending LOH until hypo-osmotic. Fluid entering distal tubule 100 mOsm. Water Reabsorption in Distal Tubule & Collecting Ducts Fluid in DT and collecting duct is hypo-osmotic. Tendency for water to move from lumen to interstitial fluid along an osmotic gradient. Reabsorption depends on: 1. Osmotic gradient established by countercurrent multiplier. 2. Water permeability of epithelium. Water Reabsorption in Distal Tubule & Collecting Ducts Tight junctions in late DT and collecting duct prevent water diffusing out of lumen – NKCC-cells. Water permeability depends on water channels in Principle Cells in late distal tubule and collecting duct - Aldosterone. Water ducts open (reabsorption) in the presence of ADH. Antidiuretic Hormone (ADH) Increases water permeability in distal tubule and collecting duct, promoting water reabsorption and concentration of urine Also known as ADH or Vasopressin. Produced in hypothalamus. ADH Secreted from Posterior Pituitary. Regulates water permeability in late distal tubules and collecting ducts. Released into blood following signals from: 1. Osmoreceptors 2. Baroreceptors Osmoreceptors Detect changes in ECF osmolarity. Located in hypothalamus and digestive tract. Strongest stimuli for ADH secretion: Increased ECF osmolarity stimulates ADH secretion. Decreased ECF osmolarity inhibits ADH secretion. Baroreceptors Baroreceptors send signals to brain via PNS. Baroreceptors detect changes in blood volume and pressure. Decreased blood pressure and plasma volume stimulates ADH. Water permeability increases, reabsorption increases. *Kidneys cannot bring plasma volume back to normal, but minimize further fluid loss. Production of Dilute Urine In absence of ADH, late distal nephron impermeable to water. Water remains within the tubules. Large volumes of dilute urine are produced. Principles of Human Physiology, Germann & Stanfield, 3rd International Edition©, 2009, Benjamin Cummings, Fig 19.9, p 544 Production of Concentrated Urine In presence of ADH, late distal nephron permeable to water. Water moves into peritubular fluid due to osmotic gradient. Small volumes of concentrated urine produced. Maximum urine osmolarity is 1400 mOsm. Factors Influencing ADH Secretion Stimulation Inhibition *Increased ECF osmolarity Decreased ECF osmolarity *Decreased blood volume Hypervolaemia *Decreased MAP Increased MAP “Stress” (pain, exercise). Alcohol Nausea & vomiting Nicotine Diabetes Mellitus (DM) Diabetes mellitus: pancreatic insufficiency of or resistance to insulin. Inadequate levels of insulin resulted in blood glucose levels that exceeded renal threshold. Increased glucose excreted in urine, along with increased amounts of water, causing polyuria (PU) To compensate for increased renal water loss, patients increase their fluid intake: therefore, have polydipsia (PD) Therefore, patients have polyuria and polydipsia PU/PD Diabetes Insipidus (DI) Diabetes Insipidus (DI) is another type of diabetes, associated with ADH (not insulin). Two main types of DI occur*: 1. Central DI: Failure of ADH secretion from the posterior pituitary (arginine vasopressin deficiency) 2. Nephrogenic DI: Failure of kidneys to respond to normal levels of ADH (arginine vasopressin resistance) In both, renal water reabsorption falls, and large volumes of dilute urine are passed. Also presents as PU/PD (i.e. same symptoms as DM, different clinical signs, and causes) *Note: there are actually four types (beyond the scope of this course) with the others being caused by psychiatric disorders, medication, and pregnancy. Obligatory Water Loss Obligatory Water Loss: Minimum volume of urine that must be excreted to eliminate solutes remaining in tubular fluid. Maximum urine osmolarity equivalent to that reached in renal medulla interstitium (1400 mOsm in people). Not all solutes in tubular fluid are reabsorbed. Approximately 440 ml/day in adults under normal conditions. normal Urine Specific Gravity Measuring USG gives a clinical indication of renal concentrating ability. Normal USG varies among species and hydration status (normal >1.025). Isosthenuria (USG: 1.008 – 1.012) Represents a USG equal to protein-free plasma. No ability to dilute/concentrate urine. Usually signifies renal failure. Hyposthenuria (USG < 1.008) Kidneys able to dilute urine but unable to concentrate Tubules not responding to ADH E.g., diabetes insipidus Lecture Objectives Recommended Reading Tortora G et al. (2022) Chapter 26 and 27 Compare the main fluid compartments of the body Explain the factors that determine plasma composition Describe how and what is reabsorbed in the PCT Describe how the medullary osmotic gradient is established, and why this is important in regulating urine concentration Describe how and what is reabsorbed in the DCT and the collecting duct Explain the role of ADH, its regulation, and how it influences water reabsorption  Renal System V H LT H 1 0 3 0 – A n a t o m y a n d P h y s i o l o g y o f B o d y Systems Melandri Vlok School of Health Sciences Sydney | University of Notre Dame Australia [email protected] Osmotic Gradient: Summary What components are necessary to establish and maintain osmotic gradient? Regional differences between ascending & descending loops in water and solute absorptive capacity Contribution of urea recycling provides approx. 50% of medullary concentration gradient Handling of Urea by the PCT Freely filtered at glomerulus. Active reabsorption of solutes increase peritubular fluid and plasma osmolarity. Water is reabsorbed by osmosis, following solutes. Water reabsorption creates urea concentration gradient. PASSIVE urea movement from tubule to peritubular capillaries completely Approximately 50% urea filtered by glomerulus is dependent upon water movement. reabsorbed at the PCT. Handling of Urea by Distal Nephron LOH, DCT, cortical and first part of medullary collecting duct are impermeable to urea. Water reabsorption increases urea concentration in tubular fluid. Urea permeability increases at inner medullary collecting ducts. Transport further enhanced by ADH. Urea Summary Urea contributes to hyperosmolarity of interstitial fluid in medulla, required for: Water reabsorption. Urine concentration. Recirculation of urea makes it possible to achieve high concentrations of urea in urine This enables the kidneys to excrete the necessary amounts of urea in a small volume of water *A continuous high rate of filtration is required to prevent excessive urea build up in the blood = Toxic! Sodium Balance Sodium must be regulated for normal osmolality to be maintained Kidneys play primary role in regulating Na+ within body Renal regulation of sodium balance occurs at the level of filtration or reabsorption (not secreted) Hypernatraemia: Plasma sodium > normal Hyponatraemia: Plasma sodium < normal Sodium Reabsorption About 99% of filtered Na+ is reabsorbed: JG 1. 65% unregulated in PT. Apparatus 2. 30% in thick ascending PT: 65% unregulated limb of LOH. Distal 3. Small amount in distal Nephron: Permeabilit nephron under hormonal y control. influenced by Aldosteron Ascending Distal tubule and collecting e LOH: 30% duct largely impermeable to Na+ Permeability influenced by Distal nephron Aldosterone and ANP reabsorption “fine-tunes” sodium balance PCT Reabsorption of Sodium Distal Nephron Reabsorption of Sodium Distal nephron determines final qualitative changes in urinary excretion of sodium. Reabsorption similar to PCT except that movement across apical membrane differs: 1. Co-transport with other solutes (e.g. Cl) 2. Sodium ion channels (facilitated diffusion). Reabsorption at distal nephron is regulated by: 1. Aldosterone 2. Atrial natriuretic peptide (ANP) Distal Nephron Reabsorption of Sodium *Sodium reabsorption coupled to potassium (K+) secretion at distal nephron Regulation of Renin Release RAAS is most important regulator controlling aldosterone release Reduced MAP is the primary stimulus for renin release via: 1. Decreased stretch at afferent arteriole 2. Baroreceptor reflex stimulating sympathetic nerves 3.  GFR, reducing delivery of fluid and NaCl Aldosterone Steroid hormone produced/released at adrenal cortex. Release stimulated by presence of Angiotensin II through RAAS. Facilitates Na+ reabsorption and K+ secretion at distal nephron. Indirectly leads to increased water reabsorption through increased ECF osmolarity. Aldosterone Binding stimulates: 1. Opens Na+ and K+ channels. 2. Synthesis of new channels on apical membrane. 3. Synthesis and insertion of Na+/K+ pumps on basolateral membrane. 4. Simultaneously increases Na+ reabsorption and K+ secretion (cannot affect one without the other). Binds to receptors in cytosol of principal cells of late DT and collecting ducts Atrial Natriuretic Peptide (ANP) Inhibits sodium (Na) reabsorption. Secreted from the atrial walls in response to distension associated with  plasma volume ANP increases excretion of sodium by dilating afferent and constricting efferent arterioles, increasing GFR = increased filtered load of Na+ ANP decreases renal reabsorption of Na+ by: 1. Limiting the number of open Na+ channels in apical membrane of principal cells. 2. Inhibition of RAAS: Decreases  renin secretion from kidney and aldosterone from adrenal cortex. Atrial Natriuretic Peptide (ANP) Comparison of ADH, Aldosterone, & ANP Aldosterone ADH ANP Major stimuli  MAP via  osmolarity of ECF  Blood Volume Angiotensin II  MAP (RAAS)  Blood Volume Site of production Adrenal cortex Produced: Hypothalamus Cells of cardiac atria and release Released: Posterior Pituitary Main effect  Na+ reabsorption  Water reabsorption  Renin secretion (kidney)  K+ Secretion  GFR leading to Na+ excretion Plasma Potassium Levels Potassium concentration of ECF and plasma is precisely regulated Ratio of extracellular : intracellular K+ is critical to function of excitable cells Small changes in [K+] result in significant effects around the body (e.g. Neurological signs) Hyperkalaemia: Plasma potassium > normal. Hypokalaemia: Plasma potassium < normal. Renal Handling of K+ Regulation of plasma K+ occurs through secretion in distal nephron K+ is freely filtered at glomerulus Unregulated reabsorption from PCT (60%) and ascending LOH (30%) Regulated secretion in late distal tubule and collecting duct (diet dependent) Reabsorption of K+ at PTC K+ moves from peritubular fluid into cell via Na+/K+ pump. K+ moves from tubular fluid across apical membrane Moves down gradient via channels in basolateral membrane to peritubular fluid. K+ also moves between cells to peritubular fluid. Secretion of K+ at Distal Nephron Secretion occurs at Principal cells of distal nephron K+ moves from peritubular fluid into cell via Na+/K+ pump on basolateral membrane Ion channels in apical membrane allow K+ to be secreted into renal tubule (DCT) Potassium diffuses down concentration gradient from epithelial cells to tubular fluid Aldosterone Regulation of K+ secretion Aldosterone increases: 1. Na+/K+ pumps on basolateral membrane. 2. K+ channels on apical membrane. Facilitates movement of K+ from peritubular fluid to renal tubule. Aldosterone regulated by RAAS. Calcium Regulation Critical to function of all cells, particularly important in heart, muscle and bones. Plasma concentration regulated through kidneys, digestive tract, bone and skin. Calcium added to plasma from bone and by absorption from digestive tract. Calcium removed from plasma by bone and kidneys. Hypercalcaemia: Increased plasma Ca. Hypocalcaemia: Decreased plasma Ca. Calcium Balance Reabsorption: 70% PCT, 20% ascending LOH, remainder in DT Regulated by hormones: 1. Parathyroid hormone (PTH). 2. Calcitriol or 1,25-(OH)2 D3. 3. Calcitonin (lesser extent). 1. Parathyroid Hormone (PTH) Released from parathyroid glands in response to  plasma Ca2+ PTH increases plasma Ca2+ by: 1. Stimulating calcium reabsorption in ascending LOH and distal tubules 2. Stimulating activation of calcitriol in kidneys (Ca2+ absorption at gut and reabsorption at kidney) 3. Stimulating resorption of bone (Ca2+ mobilisation into plasma) 2. 1,25-(OH2)D3 or Calcitriol Steroid hormone Also termed 1,25-dihydroxycholecalciferol or calcitriol. Synthesised from Vitamin D3 (protohormone) in several steps, the final one occurring in kidney. Increases plasma calcium by stimulating Ca2+ absorption from digestive tract and reabsorption in distal nephron of kidneys. 3. Calcitonin Hormone secreted from thyroid gland Secretion triggered by hypercalcaemia Increases Ca2+ uptake by bone, but also decreases renal Ca2+ reabsorption Net effect: Decrease plasma Ca2+ levels Calcitoni n Calcitonin has much less important role than either PTH or 1,25-(OH2)D3 in Ca2+ regulation  osteoclasts  osteoblasts Rickets and Osteomalacia Soft “bendy” bones Vlok et al. 2022. The role of dietary calcium in the etiology of childhood rickets in the past and the present. AJHB. Main causes: osteomalacia 1. Extreme Vitamin D deficiency 2. Extreme calcium deficiency 3. Vitamin D and Calcium deficiency 4. Genetic conditions disrupting PTH pathway (many forms because of many steps in pathway) 5. Kidney disease Disruption of homeostasis impacts mineralisation of bones and development at growth plates (bones and cartilage) rickets Lecture Objectives Recommended Reading Tortora G et al. (2022) Chapter 26 and 27 Describe renal handling of urea and why urea recycling is so important Describe in detail how the kidneys regulate sodium and potassium List the differences between Aldosterone, ADH and ANP in terms of where they are produced/secreted, where they act and what they do at the kidney Relate the renal regulation of solute and water balance to the maintenance of plasma volume and blood pressure Describe in detail how the kidneys regulate calcium balance and the three (3) hormones that regulate plasma calcium concentrations QUESTIONS