Renal Lectures 3 & 4 Flashcards

Renal Processes

• Renal processes involve the following steps:
  • Filtration: Water and small molecules enter the tubule from the blood.
  • Reabsorption: Water and valuable solutes are returned to the blood from the tubule.
  • Secretion: Specific substances are removed from the blood into the tubule.
  • Excretion: Urine exits the tubule.
• These processes occur between the blood in the capillaries and the tubule.

Glomerular Filtration Rate (GFR)

• Learning Objectives:
  • Identify the features of the renal corpuscle that maximize filtration.
  • Describe the three pressures that act across the glomerular filter.
  • Describe physiological mechanisms whereby GFR is regulated.
  • Identify pathological mechanisms that will reduce GFR.
  • Describe how GFR can be estimated.
• Average GFR:
  • Males: 125 \, \text{ml/min}
  • Females: 105 \, \text{ml/min}
• If GFR is too high: Too little reabsorption may occur.
• If GFR is too low: Too much reabsorption may occur.
• Volume of blood filtered per day: 150-180 \, \text{Litres/day}. Most of the filtrate (~99%) is reabsorbed in the renal tubules.
• 1-2 litres of urine are excreted per day.
• To produce a normal GFR requires:
  1. A large total surface area for filtration: \sim 1 million glomeruli per kidney, forming an extensive capillary network.
  2. A thin porous membrane: Filtration membrane = fenestrated endothelium & filtration slits.
  3. A positive glomerular filtration pressure.

Filtration and Pressures

• Filtration pressure depends on the balance of 3 pressures:
  • Glomerular Hydrostatic Pressure (GHP): Blood pressure in the glomerulus.
  • Capsular Hydrostatic Pressure (CsHP).
  • Blood Colloid Osmotic Pressure (BCOP): Osmotic pressure due to plasma proteins.
• Plasma has more dissolved substances than filtrate. Therefore, water can be pulled back into the plasma by the process of osmosis.
• Glomerular filtration pressure is calculated as:
  \text{Glomerular filtration pressure} = \text{GHP} - (\text{CsHP} + \text{BCOP})
• Example:
  \text{Glomerular filtration pressure} = 55 \, \text{mmHg} - (15 \, \text{mmHg} + 30 \, \text{mmHg}) = 10 \, \text{mmHg}
• Changes in any of the pressures can potentially affect GFR.
• Provided there is a positive glomerular filtration pressure, urine can form!

Afferent and Efferent Arterioles

• The diameter of the efferent arteriole is smaller than the afferent arteriole.
• More blood gets into the glomerulus than can leave, creating a positive filtration pressure.
• So, GHP is normally high.

Effect on GFR

• Dilation of afferent arteriole or constriction of efferent arteriole: ↑ GFR
• Constriction of afferent arteriole or dilation of efferent arteriole: ↓ GFR

Factors that can cause Glomerular Filtration Rate to Fall

• ↓ blood flow to the kidney or fall in BP inside the glomerulus
• ↑ in capsular hydrostatic pressure (e.g., due to tubular obstruction such as kidney stone blocking ureter)
• ↑ in concentration of protein in the plasma; would draw water back into plasma

Regulation of GFR

1. Autoregulation
2. Hormonal regulation
3. Neural regulation

Autoregulation of GFR

• Myogenic Autoregulation:
  • Effect produced by smooth muscle in arterioles.
  • Myo = muscle, genic = producing.
  • ↑ BP → Walls of afferent arterioles stretch → Smooth muscle cells in afferent arterioles contract → Constriction of afferent arteriole = ↓ GFR
  • ↓ BP → Walls of afferent arterioles no longer stretched → Smooth muscle cells in afferent arterioles relax → Dilation of afferent arteriole = ↑ GFR
• Tubuloglomerular feedback:
  • Part of the renal tubule (the macula densa) provides feedback to the glomerulus.
  • ↑ GFR – ↓ reabsorption.
  • Macula densa cells detect ↑ Na^+, Cl^- and water in filtrate.
  • Release of vasoconstrictor from juxtaglomerular apparatus.
  • ↓ Blood flow into glomerulus = ↓ GFR

The Juxtaglomerular Apparatus

• DCT (important for autoregulation and hormonal regulation of GFR)
  • ↑ solutes in DCT = ↓ reabsorption

Hormonal Regulation of GFR

• Angiotensin II: potent vasoconstrictor → ↓ renal blood flow → ↓ GFR
• Atrial natriuretic peptide (ANP): dilates afferent arteriole → ↑ glomerular blood flow → ↑ GFR

Neural Regulation of GFR

• Sympathetic nerve to smooth muscle in wall of afferent arteriole.
• With acute large blood loss or exercise:
  • Sympathetic vasoconstriction → ↓ blood flow → ↓ GFR → ↓ urine output.
  • Conserves blood volume and allows blood flow to other body tissues.

Estimating GFR

• To measure GFR: You need to measure a readily filtered substance that is neither reabsorbed nor secreted further down the renal tubule (i.e., excreted unchanged in urine).
• Creatinine is used clinically.
• Estimated GFR (eGFR) uses a formula to calculate GFR from plasma creatinine concentrations.
• It factors in the patient's age, sex, and weight.
• The formula includes an estimate of body surface area and assumes this relates to muscle mass.
• Uses:
  • Monitor renal function.
  • Staging of chronic kidney disease.
  • Work out drug dosing (kidneys are the main route of drug excretion – if kidney function is reduced, this may affect excretion of drugs).

Effects of Loss of Functioning Nephrons

• Gradual reduction in:
  • Glomerular filtration.
  • Tubular reabsorption capacity.
• GFR gives an idea of the number of functioning nephrons. Number of Functioning Nephrons ↓ GFR ↓

GFR Decline with Age

• Normal physiological decline of GFR with age.

Pathophysiology

• Gradual drop in GFR due to:
  • ‘Clogged up’ filter.
  • Destruction of nephrons.
• Leads to reduced surface area of filter.
• Rising blood creatinine level indicates declining GFR & extent of kidney failure.
• Number of Functioning Nephrons ↓ GFR ↓ Chronic Kidney Disease (CKD)
• What will happen to:
  • GFR: It decreases.
  • Urine volume: It decreases or stops.
  • Which substances will accumulate in blood? Creatinine, Urea.
• Acute Kidney Injury

Reabsorption and Urine Concentration

• Filtration: Water and small molecules enter the tubule from the blood.
• Reabsorption: Water and valuable solutes are returned to the blood from the tubule.
• Secretion: Specific substances are removed from the blood into the tubule.
• Excretion: Urine exits the body.

Function of Renal Tubules

• Learning Objectives:
  • Identify the differences in composition between plasma and urine and the work that the tubules does on the filtrate.
  • Explain the terms reabsorption and secretion giving examples of substances handled by the tubules in these ways.
  • Describe the structural features of the PCT and its role in bulk reabsorption.
  • Describe the carrier-mediated transport of glucose, Tmax and renal threshold.
  • Outline mechanisms of sodium reabsorption along the tubule and explain why these are important for the handling of other ions and water by the tubule.
  • Describe the role of anti-diuretic hormone in controlling water balance.

Normal Constituents of Urine

• 96% water (surplus to water balance).
• 2% urea (from protein breakdown).
• Remaining 2% consists of:
  • Uric acid (from RNA/DNA breakdown).
  • Creatinine (from muscle creatine).
  • Ammonia (from amino acids).
  • Sodium.
  • Potassium.
  • Calcium, phosphate, chloride etc.
• Urine contains nitrogenous waste and ions in surplus to electrolyte balance.

Comparison of Urine and Plasma Composition

• Transport processes in the renal tubule radically alter the composition and volume of the filtered plasma.

Reabsorption

• In the tubules, substances are re-absorbed from filtrate into blood capillaries.
• Substances that are reabsorbed include:
  • Water
  • Glucose
  • Amino acids
  • Ions (e.g., Na^+, Ca^+, HCO_3^-
• 99% filtered fluid is reabsorbed by active transport, diffusion, and osmosis.

Secretion

• In the tubules, substances are secreted from blood capillaries into filtrate.
  • Mainly occurs in the PCT and DCT by active transport or diffusion.
• Examples of substances that are secreted include:
  • Ions (H^+, K^+
  • Ammonia
  • Urea
  • Toxins and drugs

Tubular Reabsorption (PCT)

• Proximal convoluted tubule (PCT) - Designed for reclaiming useful material in bulk.
  • 65% of the filtered NaCl (involves active transport).
  • Water follows salt (by osmosis).
  • Glucose and amino acids (by specific carriers in the tubule lining).
• The two features of the epithelial cells of the PCT promote this bulk reabsorption:
  1. Microvilli increase the surface area.
  2. Lots of mitochondria provide energy (ATP) for active transport.

Tubular Reabsorption (LoH)

• Loop of Henle:
  • Reabsorbs filtered salt (20-35%) and water (15%).
  • Descending loop permeable to water but less so to salt.
  • Ascending loop permeable to salt but impermeable to water.

Tubular Reabsorption (DCT & CD)

• Distal convoluted tubule & collecting duct.
• “Fine-tuning” of salt and water reabsorption back into blood.
• Controlled by hormones:
  • Aldosterone (salt and water).
  • Parathyroid hormone (calcium).
  • Anti-diuretic hormone (water).

Carrier-mediated Transport in the PCT

• Characterized by:
  • Transport maximum (Tmax) - rate of reabsorption when all carriers for a substance are saturated.
  • Renal threshold - determined by Tmax; concentrations in filtrate above the renal threshold will exceed the reabsorptive capacity of the nephron.
• What will happen to substances that exceed the renal threshold?
  • Start to appear in urine.
• Renal thresholds vary by substance:
  • glucose > amino acids > water-soluble vitamins.

Reabsorption of Glucose

• Transporters or carriers in the PCT reabsorb filtered glucose by secondary active transport - limited number of glucose transporters.
• This happens when plasma [glucose] exceeds \sim 10 \, \text{mmol/L}. This concentration is the RENAL THRESHOLD for reabsorption of glucose.
• If the Tmax is exceeded, what happens? Glucose will spill into the urine (glucosuria).
• What condition can cause this? Diabetes mellitus.

Sodium Reabsorption

• Sodium (& chloride) ions are the main solutes in extracellular fluid (ECF) and therefore the main determinants of ECF osmolarity.
• Reabsorption of other solutes depends on sodium reabsorption, e.g., glucose, amino acids.
• Tubule cells have various types of membrane transporter located in different parts of the tubule.

Mechanisms of Sodium Reabsorption

• In the PCT, Na^+ moves from lumen across the tubule epithelium by:
  • Diffusion Passive down concentration gradient
  • Co-transport Symporters or co-transporters carry Na^+ and another solute in the same direction (e.g., glucose, amino acids)
  • Counter transport Transporter carries Na^+ and another solute in opposite directions
• Na/K ATPase pump extrudes the Na^+ into interstitial fluid. Why is this important? To keep the Na^+ concentration in the cell low favouring reabsorption of Na^+ from the lumen.

Knock on Effects of Sodium Reabsorption

• The transport of Na^+ then causes passive reabsorption of water.
• Diffusion of Cl^- makes the interstitial fluid more negatively charged than tubular fluid. What effect will this have on the diffusion of other ions?
• They will become more concentrated and diffuse from the tubule to the blood capillary.
• Positive ions like Na^+ and Ca^{2+} will diffuse out of the tubule to the blood capillary more rapidly.

Sodium and Water Reabsorption

• The PCT absorbs the bulk of the water and salt from the filtrate
• Reabsorption of Na^+ also takes place in the LoH, DCT and collecting duct

Water Reabsorption

• Fluid intake can be highly variable, but the body's fluid volume remains stable.
• The body can regulate water loss through the kidney.
• Water re-absorption is regulated by anti-diuretic hormone (ADH).
• Osmoreceptors in the hypothalamus detect a decrease of water in the blood of as little as 1% (increased osmolarity).
• Anti-diuretic hormone (ADH) released by posterior pituitary.
  • Stimulates thirst
  • Acts on the collecting ducts to increase water reabsorption
• Increase in blood water concentration

ADH Action on the Collecting Ducts

• ADH stimulates insertion of AQUAPORIN channels in the epithelial cells of the collecting duct.
• Increases water permeability.
• More water reabsorbed.
• ADH deficiency leads to diuresis (excretion of up to 20 litres of very dilute urine daily). Diabetes insipidus

Water Reabsorption in the Loop of Henle

• The descending limb:
  • Is highly permeable to WATER but less so to salt
  • Water flows across the wall of the tubule into the interstitial fluid of the medulla by osmosis
  • This causes the fluid in the tubule to become progressively more concentrated towards the tip of the loop.
• The ascending limb actively transports salt out of the tubule into the interstitial fluid but water cannot follow.
  • This lowers the concentration of the tubular fluid
• When aquaporin channels are formed in the walls of the collecting duct, water flows out of the collecting duct by osmosis

Regulation of Blood Water Concentration

• Osmoreceptors in the hypothalamus detect a decrease of water in the blood (increased osmolarity).
• Anti-diuretic hormone (ADH) released by posterior pituitary
  • Stimulates thirst
  • Acts on the collecting ducts to increase water reabsorption
• Increase in blood water concentration
• Decrease in urine volume
• Osmoreceptors in the hypothalamus detect decreased osmolarity (too much water).
• No anti-diuretic hormone (ADH) released
• Water reabsorption in the collecting ducts decreases
• Decrease in blood water concentration
• Increase in urine volume