Homeostasis: Medical & Veterinary Sciences Triposes 1A

• Medical and Veterinary Sciences Triposes 1A Homeostasis are covered in ten lectures from February 13-25, 2025.
• Lectures 1-6 are by Dr. James Fraser ([email protected]) and lectures 7-10 are by Prof. Dino Giussani ([email protected]).

Course Aims

• Lectures and practicals aim to provide an understanding of kidney structure and function, focusing on the nephron.
• Lectures also aim to cover body fluid homeostasis, maintenance of constant composition and volume.
• They will also cover intrinsic and extrinsic control systems that regulate renal function.
• Some of the links between renal physiology and medical and veterinary practice are covered.

Introduction

• Kidneys produce urine and regulate body fluid composition and volume through integration with the cardiovascular system.
• Kidneys regulate rather than excrete.
• This regulation allows cells to operate in a normal internal environment despite changes in the external environment.
• The first three lectures cover kidney structure and basic mechanisms.
• Later lectures describe K+ concentration, pH, osmolality, Na+ content, and Ca2+, Mg2+, PO42- regulation.
• Kidneys also excrete waste, regulate erythropoiesis via erythropoietin, activate vitamin D3, and perform gluconeogenesis during fasting.

Resources

• The handout and lectures uses primarily "Medical Physiology,” Boron and Boulpaep (3nd Ed., Elsevier)
• Simple monographs by Koeppen & Stanton (4th Ed., 2007, Mosby) and Lote (4th Ed., 2006, Springer) are helpful.

Lecture 1: Introduction to Homeostatic Functions of the Kidneys

• The kidneys regulate osmolality, volume, and composition of body fluids.
• It does so by controlling excretion rates to match intakes; kidneys are sensors and integrators in regulation.

Principle of Balance

• Removal of a substance (excretion/metabolism) must match intake (ingestion/synthesis) to maintain constant body fluid composition.
• Kidneys mainly control excretion, allowing intake variations without disrupting homeostasis.
• Kidneys allow tolerance of fluid and electrolyte intake variations, while kidney adjusts the rate of change to abnormal intake.
• Kidneys work in conjunction with several other processes

Related Processes

• Regulating ingestion occurs via, thirst, hunger, and Na+ appetite.
• Major excretory routes include CO2 regulation, and excretion of bile and gastrointestinal secretions.
• Metabolic regulation includes, hepatic metabolism.
• Absorption control occurs via Ca2+, iron, and zinc uptake controls by the intestinal epithelium.

Body Fluid Compartments

• Body fluids are in intracellular and extracellular compartments, with extracellular fluid subdivided:
• Blood plasma is fluid in the vasculature.
• Interstitial fluid is fluid around cells and outside vasculature.
• Transcellular fluid includes fluid in synovial, digestive, and cerebrospinal fluid.
• Kidneys influence the composition and volume of plasma directly, and influences interstitial and intracellular fluid.

Plasma and Interstitium

• Blood plasma is a liquid component of whole blood with suspended blood cells.
• When whole blood is centrifuged, the composition is revealed as 55% plasma and 45% cellular components.

Plasma Contents

• 91% water
• 7% proteins (albumin, fibrinogen, globulins, etc.)
• 2% electrolytes, nutrients, hormones, etc.

Cellular Components

• Leukocytes (white blood cells)
• Platelets
• Erythrocytes (red blood cells)

Capillary Membranes

• Capillary membranes separate plasma from interstitial fluid and are permeable to water, electrolytes, and small molecules.
• Na+, K+, Cl- ions do not exert osmotic pressure across capillary membrane, despite high plasma concentration.
• Capillary membranes are impermeable to larger protein molecules.

Colloid Osmotic Pressure

• Plasma proteins exert osmotic pressure across capillary walls described as colloid osmotic pressure or oncotic pressure.
• Total plasma protein concentration is approximately 1.4 mM, mainly albumin.
• Osmotic pressure exerted by plasma protein is calculated using van't Hoff's equation: πV = nRT.
• π = osmotic pressure (mmHg), V = volume of solution (I), n = # of particles in solution (mol), R = gas constant, T = absolute temperature (K).
• Colloid osmotic pressure ≈ 27 mmHg.
• Negligible colloid concentration in interstitial fluid pulls water into capillaries.
• Hydrostatic pressure forces water out of capillaries; 1.4 mM protein may seem insignificant, but creates pressure

Starling's Equation

• Starling's equation describes the net fluid flux across a membrane through hydrostatic and colloid osmotic pressure.

Related Variables

• Jv is volume flow (ml min¯¹).
• Kf is the filtration coefficient (ml min¯¹ mmHg¯¹), a product of surface area and hydraulic conductivity.
• σis the protein reflection coefficient (dimensionless) membrane permeability is close to 1 in most capillary beds.

Simplified Starling's Equation

• Since Pif and πif are generally small and vary little, the Starling forces across most capillary membranes are: Jv = Kf (Pc - σπc)
• Pc (capillary hydrostatic pressure) and Pif (interstitial fluid hydrostatic pressure) drives fluid out of capillaries and πc and πif drives fluid into capillaries with Pc dropping along the capillary.
• Starling forces result in net filtration pressures shown below.

Autotransfusion

• Net movement of fluid along the length of a capillary: outward flux at the arteriolar end and a net inward flux at the venous end.
• Overall, small outward fluid flux which is mainly returned to the circulation through the lymphatic system.
• If outward flux increases, oedema results.
• If capillary pressures are low, Startling forces favor movement from the interstitium into the capillary, called autotransfusion

Clinical Significance

• Changes in Starling forces that increase fluid flow out of capillaries causes oedema and accumulation of interstitial fluid
• Cardiac failure occurs when capillary hydrostatic pressure increases, due to atrial pressure increases.
• Septicaemia: Capillaries become leaky to plasma proteins, reducing the colloid reflection coefficient.
• Oedema results if lymphatic blockage inhibits removal of excess fluid.
• Protein loss (Kwashiorkor) reduces oncotic pressure.

Fluid Movement

• Fluid movement between interstitial and intracellular spaces is influence by different variables than those between plasma and interstitium.
• Hydrostatic pressure difference between these two spaces are not considered, so only osmotic water movements are needed.
• Small ions (Na+, Cl, etc.) don't cross cell membranes freely.
• Osmolality of intracellular and interstitial fluid are equal.

Intracellular vs Interstitial Ions

• Intracellular: Na+ 15; K+ 120; Cl- 17; Proteins 4; HCO3- 5; Other 129; Total osmolality 290
• Interstitial: Na+ 142; K+ 4.2; Cl- 116; Proteins 0; HCO3- 25; Other 2.5; Total osmolality 290
• Steady-state, cells are permeable that imbalances drive transmembrane water from the lower to the higher osmolality.
• Na+ is the major extracellular cation, contributing to nearly half of the extracellular osmolality.
• Extracellular ion concentrations change by changing solute or solvent amounts, while changes in salt and water become homeostasis stresses.
• ECF osmolality regulation is important for cell volume stability.
• ECF osmolality is primarily controlled by regulating the water amount.

Clinical Scenarios

• Dehydration can cause cell volume and function shifts, while hyperhydration can cause brain swelling.
• Mannitol sugar can increase interstitial osmolality to draw water from cells.
• Water movement between capillaries/interstitial is determined by the Starling forces and that colloid osmotic pressure pulls fluid into capillaries.
• Fluid movement between interstitium/cells are determined by osmolality of extracellular and intracellular fluid.
• ECF osmolality control is through water regulation.

Extracellular Fluid Volume

• Plasma osmolality is tightly regulated to avoid fluid shifts.
• Kidneys regulate excretion of the solvent water.
• NaCl amount in the body determines extracellular fluid volume with control of body Na+ content discussed in lectures 8/9.

###Measuring Fluid Compartment Volume

• The volume of a fluid compartment can be measured straightforwardly.
• Add a known amount of a substance, A (in moles), to compartment with volume, V (in liters), and concentration, C (in mol l¹).
• Therefore C = A/V.
• Thus: V = A/C

Accurate Measurements

• A must be restricted to one compartment
• A must distribute evenly
• A must not change V itself
• A must not change over time (e.g. by metabolism or excretion)
• A must be non-toxic
• A must be easily measurable
• D2O or HTO water can be used for measuring the volume
• Single injection method is used for slowly excreted/metabolized substances

Single Injection Method

• Extrapolate back to time = 0 from a graph of log(concentration) / time, A/Co injection amount determines distribution volume.
• Albumin is used to measure plasma volume.
• Method requires repeated blood sampling over time.

Constant Infusion Method

• If excretion is fast by a single measurable route to work in infusion, infuse the substance at constant until plasma becomes constant.
• Use this method to measure total extracellular volume with inulin and calculate intracellular volume by ECF subtraction.

Defining Solutions

• The mole (mol): Avogadro's number (6.022 x 1023) of particles.
• Molar mass: the mass per mole of particles.
• Units of concentration (Molar or Molal)

Osmosis Pressure & Osmoles

• Osmosis: The tendency of solvent to move through a semi-permeable membrane from lower to higher.
• Osmotic pressure: the pressure to be applied in the concentrated solution.
• Osmole: 1 mol of osmotically active particles.
• Osmotic concentration (osmolal and osmolar): osmolarity is the # of osmoles per liter; osmolality is the # osmoles per kilogram of water.

Understanding Tonicity

• Isosmotic solutions have the same osmolality.
• Effective and Ineffective Osmoles: effective osmotes cannot cross, ineffective can.
• Tonicity relates to its effect on cell volume, a hypotonic causes it to swell, hypertonic, shrink, and isotonic, no change.
• Colloid osmotic pressure is exerted by colloidal molecules like proteins.

Renal Blood Supply

• Blood flow: blood enters kidneys at the renal hilum thru large renal arteries(25% of cardiac output, 2% of body weight)
• The artery divides into the interlobar arteries, and then, then feed arcuate arteries then interlobular arteries
• Efferent arterioles follow glomerular capillaries.
• Most blood flows through peritubular capillaries into which the majority of the filtrate is reabsorbed.
• Some blood (~1%) follows vasa recta ( descends to medulla before returning to the cortex).
• Medulla receives very little renal flow
• Blood returns via interlobular, arcuate, interlobar, and renal veins.
• Blood flow in the renal artery an vein is almost identical

Basic Renal Mechanisms

• Kidney work is blood filtering from glomerular, and the reabsorbing and secreting substances
• filtration occurs in the glomerulus. Finally, the greatly modified fluid is excreted as urine.
• Renal blood flow is about 25% of cardiac output (1.25 I min¯¹).
• The plasma glow is roughly 600 ml min¯¹
• 20% if the reneal plasm is filtered into Bowman's capsule

The Nephron

• Basic functional of the kidneys
• Proximal tubule absorbs majority (~70%) of all filtrate and amino acids
• Fluid absorbed in the proximal tubule is isotonic.
• Histologically, proximal tubule cells have a large surface area and many mitochondria.
• Loop of Henle separates the reabsorption of solutes and water.
• It renders fluid hyperosmotic to plasma and is central to the concentrating ability.
• Distal tubule controls plasma K+ and pH.
• Collection duct allows water reabsorption and makes hyperosmotic urine.
• The nephron has two populations, which are cortical or juxtamedullary
• Juxtamedullary nephrons have loops of Henle which extend to the inner Medulla

Ultrafiltration

• Ultrafiltration is movement of water and solution, is a 3 layer filter which consists of a "window" capillary membrane
• The function of the filtration barrier has 3 layers different roles

Filtration

1. fenestrated capillary layer
2. basement membrane
3. the podocytes

Glomerular Filtration Rate

• Determined with standing equation
• GFR is regulated by changing the glomerular capillary hydrostatic pressure
• Pc varies of by changing the resistance of to arterioles

Autoregulation

• Autoregulation exists in the range the GFR stays constantly relative

Potassium Importance

• K gradient is responsible for the membrane potential

Internal Potassium

• Potassium is lost by the kidneys

Potassium Intake

• On and average 100 Mmoles is eaten a day

Summary of Water Movements In The Kidney

• Ions are pumped out of the loop of henle, but water does not follow
• This makes the Madula hyperosmostic: the tube fluid leaving is Hypo-osmotic
• In the diluting kidney, low ADH, water is perm is bility in the DCT, CCT, and MCT, further ioni reabsorption giving Hypo-osmostic urine
• In the constrating kidney, HIgh ADH, water is drawn to hypo osmostic tube flow in Isosmostic
• Then, from New ISosmotic the fluid travels to high osmostic Medula creating hyperosmotic state