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
Na^+ \, reabsorbedWater \, reabsorbed
PCT65%65%
LoH20-30%15%
DCT\sim 5\%10-15%
CD1-4%5-9%

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