Kidney Anatomy and Function Notes

Kidney Structure

• Hilus: Entry for renal artery and nerves, exit for renal vein, lymphatics, and ureter.

• Renal Sinus: Space within the kidney where major and minor calyces are located.

• Medulla: Inner part of the kidney divided into renal pyramids.

• Cortex: Outer part of the kidney that extends between the renal pyramids.

• Interlobar Artery: Located in between the lobes.

• Arcuate Artery: Arches out and around the pyramids.

• Cortical Radiate Artery: Radiates out into the cortex.

• Cortical Nephrons: Make up 80% of nephrons in humans.

  • Efferent arterioles form a dense peritubular capillary network, draining into the cortical radiate vein.

• Juxtamedullary Nephrons: 20% of nephrons.

  • Efferent arterioles descend into renal papillae to form hairpin vessels called vasa recta, draining into the cortical radiate vein.

  • Tubules extend deep into the medulla.

Nephron Structure

• Nephrons: Functional units of the kidney, comprised of vascular (glomerulus) and epithelial (tubule) components.

• Glomerulus: Network of vascular capillaries where plasma filtrate originates.

• Bowman's Capsule: Surrounds the glomerulus.

• Bowman's Space: Space between the glomerulus and Bowman's capsule, leading to the proximal convoluted tubule.

• Each kidney contains approximately 1 million nephrons (2 million total).

• Renal Corpuscle: Glomerulus + Bowman's space + Bowman's capsule.

• Afferent Arteriole: Brings blood into the glomerulus at the vascular pole.

• Glomerular Capillaries: Plasma is filtered through fenestrations (gaps) in the endothelial cells lining the capillary walls.

  • Fenestrations retain blood cells and large proteins.

• Basement Membrane: After passing through endothelial cells, filtrate passes through three layers of the basement membrane.

• Podocytes: Cells that cover the basement membrane with foot processes forming filtration slits.

• Filtration Membrane (3 layers):

  • Allows passage of water, solutes, and small proteins.

  • Prevents filtration of blood cells and large proteins.

• Glycoproteins:

  • Located in the basement membrane.

  • Negatively charged proteins repel large anions, preventing them from being filtered.

• Slit Diaphragms:

  • Thin membranes extending across filtration slits to further repel macromolecules.

• Mesangial Cells:

  • Form extracellular matrix supporting glomerular capillaries and the juxtaglomerular apparatus (JGA).

  • Interconnected with gap junctions, allowing signal transmission.

  • May pass signals between macula densa and granular cells.

  • Engulf and degrade macromolecules.

  • Can contract to change the total surface area available for filtration, regulating filtrate volume.

Juxtaglomerular Apparatus (JGA)

• Regulation: Renal blood flow, filtration rate, Na+ balance, systemic blood pressure.

• Components:

  • Extraglomerular mesangial cells.

  • Macula Densa: Cells connecting the ascending limb of the loop of Henle and the efferent arteriole.

  • Juxtaglomerular Cells (Granular Cells): Located on the wall of the afferent arterioles; synthesize and release renin.

• Tubules (Flow of Filtrate): Significant number of nephrons drain into the collecting duct.

Kidney Functions

1. Maintain Homeostasis

   • Regulate Extracellular Fluid Volume (ECF):

     • Low ECF = Low BP = inadequate blood flow to brain and organs.

     • Kidneys work with the cardiovascular system to ensure adequate BP and tissue perfusion.

   • Regulate Osmolarity (Free Particles):

     • Ensure blood osmolarity remains constant (approximately 290 mOsM).

     • Remove excess water and salts from the bloodstream.

   • Maintain Ion Balance (Total Concentration):

     • Regulate concentrations of Na+, K+, Ca2+.

   • pH Regulation:

     • Acidic plasma = H+ removal and HCO3- conservation.

     • Alkaline plasma = Conserve if plasma too alkaline.
       *Osmolarity / ion balance underlies fluid homeostasis: concentration determines volume

2. Excretion

   • Waste removal

     • Metabolic Waste:

       • Creatinine from muscle metabolism.

       • Nitrogenous waste: urea/uric acid, from protein breakdown.

       • Hemoglobin metabolite: urobilinogen (converted to urobilin = yellow urine).

     • Foreign Waste:

       • Drugs/environmental toxins actively removed.
         *Phosphocreatine/ creatine, ADP/ATP Cycling

• Use creatine phosphate as a quick source to turn ATP to ADP

• Remove excess creatine in kidneys through urine due to creatine (water kidneys excrete)

  • If creatine isn't filtered properly there is an increase levels in blood - marker of kidney damage

*Oxidation of Amino Acids

• AAs deaminated:

  • Liver rids body of toxic ammonia

    • Toxic ammonia NH_3 -> urea (excreted via urine)
      *Drug metabolism: detection in Urine

• Drugs (prescription, vitamins, illageal) are metabolized in the body: primarily in the liver

  • Metabolises in the bloodstream filtered by kidneys -> urine excretion. Also faecal excretion (bile)

• Eg. Marijuana: Primary pharmacologically active component of marijuana: delta-9- tetrahydrocannabinol-short T1/2

  • Human studies indicate that 80%-90% of the total dose of delta-9-THC is excreted within 5 days - approximately 20% in urine and 65% in faeces
    *Urine test can be based on metabolite detection: may have greater T1/2

1. Endocrine

   • Erythropoietin (EPO):

     • Secreted by cortical and outer medulla cells in response to low local blood O_2 levels.

     • Hormone regulates red blood cells synthesis in bone marrow: acts on haematopoietic stem cells.
       *Stem cells in marrow that develop into blood cells

     • Peptide hormone acts through tyrosine kinase receptors: stimulates phosphorylation signaling cascade in stem cells = differentiation to blood cell
       *EPO is important
       *Oxygen supply is critical in athletic performance
       *Blood doping used to be used - abnormally high levels of red blood cells
       *Clone EPO gene and make synthetic EPO

   • Renin:

     • Secreted by the kidneys.

     • Enzyme regulates production of hormones that control Na+ balance and BP homeostasis.

     • The renin-Angiotensin-Aldosterone-ADH pathways

     • Decrease BP = liver release angiotensinogen, juxtaglomerular cells of kidneys releases renin
       *NOTE: Angiotensinogen is always in blood stream
       *Renin (enzyme) convert angiotensin -> angiotensin 1
       *Angiotensin-converting enzyme (ACE) released from lungs (and other tissues)
       *Converts angiotensin 1 -> angiotensin 2 (active hormone - has functions that will help increase BP)

Renin-Angiotensin-Aldosterone System

• ACE degrades bradykinin, required for nitric oxide (NO) synthesis (vasodilation), therefore vasoconstriction can occur.

• Vascular endothelial cells express angiotensin 2 receptors (AT-R).

  • AT-R activation = inhibition of NO synthesis.

• AT-R also expressed by smooth muscle cells surrounding vessels: angiotensin 2 binds = contraction.

• Overall, decrease bradykinin, decrease NO synthesis + AT-R activation on smooth muscle cells = vasoconstriction.

• AT-R activation leads to aldosterone secretion from adrenal cortex.

• Decrease BP and (presence of_ angiotensin 2 stimulate ADH secretion from posterior pituitary gland = water reabsorption from collecting ducts of kidneys

  *The renin-Angiotensin-Aldosterone-ADH pathways
  *Overall
  *Decrease NO synthesis + AT-R activation on smooth muscle cells = vasoconstriction (renin/ angiotensin) (increase total peripheral resistance)
  *Na+ (and H2O) reabsorption from filtrate in distal tubule, back in to plasma volume (aldosterone) (increase blood volume and cardiac output)
  *ADH = aquaporins = H2O reabsorption (increase cardiac output)
  *Increase blood volume, return blood pressure to homeostasis
  *Remember: MAP = Q x TPR where MAP = Mean Arterial Pressure, Q = Cardiac output, TPR = total peripheral resistance.

Urine Production

• Production of urine involves 3 steps:

  • Glomerular Filtration: Transfer of filtrate from blood to nephron.

  • Tubular Reabsorption: Selective transfer of essential components back into the bloodstream.

  • Tubular Secretion: Selective transfer from blood to nephron - fine tuning to make sure certain solutes are at the right concentration in the blood (we can control these).

Glomerular Filtration

• Non-selective: nearly all blood components can pass glomerulus into Bowman's capsule (from blood into filtrate).
  *Except cells (eg. WBC, RBC) and large proteins
  *Therefore, filtrate has almost identical composition to plasma volume (excluding cells and proteins)
  *Glomerulus forms ~ 180L filtrate daily!
  *Plasma volume (~3L)
  *Entire plasma volume is filtered ~60 times per day
  *Entire plasma volume is filtered every 24 minutes - ie. we need tubular reabsorption
  *Occurs in Renal Corpuscle = glomerulus + Bowman's space + Bowman's capsule

  *Endothelial cells -> layers of basement membrane (glycoproteins, push -ve anions back into bloodstream) -> podocytes form filtration slits, slit diaphragm
  If plasma has to pass through all the layers there needs to be a pressure that forces it out

Starling Forces

• Starling forces govern fluid flow across capillary walls in glomerulus for filtration.

• Three forces involved in glomerular filtration:

  1. Glomerular-Capillary Blood Pressure

     • Systemic blood pressure is the driving force for filtration.

     • Glomerular capillary blood pressure is fairly high (approximately 7.5 kPa, 55 mmHg).

     • Diameter of efferent arteriole < afferent.
       *Forces plasma to be pushed through capillary wall and into Bowman's space

  2. Plasma-Colloid Osmotic pressure

     • Osmotic pressure due to [protein] difference between blood and filtrate.

     • Draws fluid back inside capillary via osmosis.
       *Chemical electrical gradient that draws things back in
       *Force = ~4 kPA
       *Recall: Water is drawn out of ISF -> PV due to osmosis (proteins in PV)

  3. Bowman's Capsule Hydrostatic Pressure

     • Occurs as a result of volume of filtrate inside capsule.

     • Affects glomerular filtration by resisting filtration into the nephron (tubules).
       *Force = ~2 kPA
       Net force creating filtration across the membrane

Glomerular Filtration Rate (GFR)

• Rate at which the glomerulus filters plasma.

• Determined by

  1. Balance between the three Starling forces (filtration pressure):

     • Glomerular capillary blood pressure.

     • Plasma colloid osmotic pressure.

     • Bowman's capsule hydrostatic pressure.

  2. Total surface area for filtration.

  3. Permeability of glomerulus.
     *Note: 2&3 are referred to as the ‘filtration coefficient’ (Kf) = SA x permeability’
     Glomerular filtration rate = net filtration pressure x Kf
     GFR can be altered by:
     * Sympathetic innervation
     * Hormonal influences
     Filtration coefficient is hard to calculate so we use estimated GFR (eGFR)
     *Calculated based on plasma creatinine (creatine phosphate breakdown), age, gender, race
     *Expressed as ml/min/1.73m2
     *The 1.73 = standardised body source area (BSA) use to normalize for all variables for an average 70 kg male
     Metabolised and excreted by the kidney due to metabolism of creatine phosphate to creatinine

Autoregulation of Filtration

Systemic blood pressure is the driving force for filtration and largely determines glomerular-capillary blood pressure
Mean arterial pressure varies: 80-170 mmHg
Changes in BP would affect glomerular filtration rate (GFR):
Kidneys have remarkable ability to maintain renal blood flow (RBF) and glomerular filtration rate (GFR) between narrow limits
Occurs through autoregulation of renal blood flow
Autoregulation of renal blood flow -> autoregulation of glomerular filtration rate
However, autoregulation cannot compensate for MAP changes outside this range
Goals
*Stabilise filtered load of solutes that reach tubules despite a range of arterial pressures
*Protect fragile flomerular capillaries over range of arterial pressures
From exercise to sleep

*Autoregulation (is intrinsic) occurs in afferent arteriole (not much happens in efferent)
*Resistance to flow rises with increasing perfusion pressure
Little change in efferent arteriole resistance, capillary resistance and venous resistance
Bp goes up -> passed to afferent arteriole which will constrict and reduce blood flow and pressure
The opposite will happen if there is a decrease
Helps maintain pressure inside glomerular capilaries -> prevents large changes in GFR

Occurs through two basic mechanisms:

1. Myogenic Response (muscle response):
   *Afferent arterioles can contract / dilate
   *For contraction: Stretch activated cation channels in vascular smooth muscle = depolarize membrane -> Ca2+ influx = contraction smooth muscle

2. Tubuloglomerular feedback
   *Flow-dependent mechanism directed by the macula densa cells of the juxtaglomerular apparatus
   *Eg. if GFR increases, filtrate flow rate increases in the tubule
   *Filtrate NaCl concentration will be high because of insufficient time for reabsorption

Sympathetic Regulation of Filtration

The sympathetic nervous system can also exert extrinsic regulatory influence over arteriolar blood flow at the glomerulus
(extrinsic commands from the sympathetic chain/CNS vs. Autoregulation: Intrinsic commands from within the organ)
The kidneys lack parasympathetic innervation
Sympathetic innervation overrides autoregulation
Purpose of extrinsic sympathetic innervation is to regulate blood pressure in the body
By modifying plasma volume filtered
Sympathetic fibres follow arterial vessels into kidneys
Axon terminals release norepinephrine
Receptors located on:
*Vascular smooth muscle cells
*Renal artery, afferent arteriole
*Proximal tubules
Exert 3 main effects: renal blood flow, glomerular filtration and tubular reabsorption

1. Vasoconstriction

2. Increased NA+ reabsorption by proximal tubule cells

3. Dense population of sympathetic fibres near juxtaglomerular apparatus stimulates renin secretion
   (Vasoconstriction + ADH secretion: Na+ reabsorption)
   *
   *Decrease in systemic blood pressure
   *Looking to bring GFR back up
   *Vasodilation to increase GFR
   *Decrease in BP
   Decrease in smooth muscles
   *If drop in blood pressure is outside of our normal levels, the sympathetic nervous system will take over - take control as it is more important
   *Another pathway with opposing effect
   *Decrease GFR to increase plasma volume and systemic blood pressure

Tubular Reabsorption

• Purpose: to ensure filtrate is not passed as urine.

• Selected substances are reabsorbed into peritubular capillaries.

• Recall: >99% of filtrate is reabsorbed:
  *Of ~180 liters of plasma filtered out of bloodstream / 24 hours, only 1.5L passes to bladder
  Selective permeability of nephron tubule membranes:
  *Permeable to substances important to bodily function
  *Poorly permeable to substances that are not required
  Urine contraines decrease conc important substances, unless in excess of body requirements
  Typical reabsorption values:
  *99% filtered water
  *100% filtered glucose
  *99.5% filtered Na+ and Cl-
  Reabsorption of solutes occurs through cells lining tubules
  *But larger solutes cannot fit between intercellular spaces
  Five barriers through which solutes must pass

1. Tubular cell (luminal) membrane

2. Cytosol of tubule cell

3. Basolateral membrane of tubule cell

4. Interstitial fluid

5. Wall of peritubular capillary
   Note: 1-5 = transepithelial transport
   At number 3 - active transport at basolateral membrane: energy required to move substance up gradient
   Due to the action of active transport - we can build up concentration gradients which allows for Passive transport: no energy required to move substance down gradient (into cell and across cytosol)

Sodium helps set up all these gradients

Tubular Reabsorption: Sodium

Kidneys are highly metabolically active organs
80\% of total renal energy requirement consumed in transport of sodium
Active transepithelial transport
>99\% of filtered Na+ is reabsorbed
67\% from proximal tubule
25\% from loop of Henle
8\% from distal and collecting tubules
The process of active transepithelial transport of sodium:

• Na+ passes from nephron to tubular cells: Simple diffusion

• Na+ actively removed from cells: Na+/K+ -ATpase pump keeps [Na+] low in cell

• Na+ pumped against [gradient]
  *Na+ moves from interstitial fluid into peritubular capillaries
  Use energy that created this to allow a lot of work to be done - Due to electrical pull from sodium a lot of things will follow - pulling chloride and bicarbonate with it
  Physiological significance: Movement of Na+ can be coupled with Cl-, HCO3-, H2O, glucose, PO4-
  Anions are simultaneously reabsorbed - Maintains electrical neutrality of fluid compartments
  HCO3- and Cl- accompany Na+ via passive reabsorption
  75\% of reabsorbed Na+ is accompanied by Cl-
  25\% of reabsorbed Na+ is accompanied by HCO3-
  High [solute] generates osmotic gradient: Water is reabsorbed
  Na+ reabsorption, accompanied by Cl- and HCO3- createsprimary osmotic gradient for water reabsorption Due to solute movement, an osmotic gradient is created that drags water along with it
  *Obligatory reabsorption - Na+ ‘holds’ water
  Hormonal influence on sodium reabsorption
  Renin-angiotensin-aldosterone pathway (recall)
  Decrease plasma volume detected by juxtaglomerular apparatus = renin secretion
  Renin = angiotensinogen (liver) -> angiotensin 1
  ACE (angiotensin converting enzyme) (lungs) = angiotensin 1 -> angiotensin 2
  Angiotensin 2 = vasoconstriction + aldosterone secretion (adrenal cortex)
  Aldosterone = ADH secretion = water reabsorption (inserts aquaporins into collecting ducts)
  Aldosterone = Na+ reabsorption from filtrate in distal tubule
  Indirect increases Cl- and HCO3- reabsorption
  Osmotic gradient = water reabsorption from tubule
  Drag more water back in Aldosterone increases sodium reabsorption from the filtrate in the distal tubule - steroid hormone
  Steroid hormones - bind to receptors that bind to steroid response elements on DNA and cause transcription from protein downstream from that

One of the proteins that aldosterone results in the transcription of is sodium pumps and channels - results in increase in the ability to reabsorb sodium

Atrial Natriuretic Peptide (ANP)
Secreted from atria of heart
In response to atrial stretch, due to increased plasma volume
Eg. increase in BV - increase in cardiac return = atrial stretch
Vasodilation afferent arterioles = increase GFR
Increase power size in glomerulus = Increase GFR
Inhibits Na+ reabsorption from distal tubules and collecting ducts
Na+ excretion into urine (natriuresis)
Inhibits renin, aldosterone, ADH secretion: therefore, decreased Na+ reabsorption (or indirect Cl-), water stasys in filtrate
Net effect: increase the excretion of water and decrease plasma volume back to its normal levels

Tubular Reabsorption: Chloride

Chloride ions are negatively charged (Cl-)
Passive reabsorption:
Follow electrical gradient caused by Na+ transport
The amount of Cl- reabsorbed determined by rate of Na+ reabsorption
Chloride ion channels on basolateral membrane to transport Cl- out of tubule cell

Tubular reabsorption: Glucose

Kidneys freely filter glucose in glomerulus
The kidneys do not regulate blood glucose levels
Simply reabsorb all glucose from filtrate back to blood stream
Mostly occurs in the proximal convoluted tubule
Glucose reabsorption is transcellular
Glucose moves from lumen to proximal tubule cell via Na/glucose cotransporter (SGLT2 and SGLT1)
Couples Na+ transport with glucose transport
Na+ is drawn in to cell due to -ve cytosol environment and low [Na+]
Na+ moving pulls glucose in to cell
Glucose moves from cytosol through basolateral membrane via GLUT2 & GLUT1

Tubular Reabsorption: Phosphate

Kidneys directly regulate phosphate ions
Excretion in urine occurs at normal plasma [phosphate] (unlike glucose)
Increased plasma [phosphate] = increase phosphate excretion = homeostasis
PO4- reabsorption occurs mainly (80%) in proximal tubule
10% in distal tubule, remaining 10% excreted in urine
PO4- entry into tubule cells via Na+/PO4- co-transpoter
Exit unknown
Parathyroid hormone: inhibits phosphate reabsorption = increase phosphate excretion
Binds to PTH receptor on tubule cells
Inhibits production of the Na+/PO4- cotransporter

Tubular Reabsorption: Calcium

Calcium exits in different forms in body, eg.
Protein-bound: non-filterable (40%)
Filterable (60% of total plasma) = Ca2+ complexed to anions such as carbonate + free Ca2+
Ca2+ reabsorption occurs:
Mainly (65%) in proximal tubule
25% in ascending limb
Minor distal convoluted tubule and collecting duct
Kidneys directly regulate calcium ions
Excretion in urine occurs at normal plasma [calcium]
Increase plasma [calcium] = increase calcium excretion = homeostasis
Ca2+ entry into tubule cell via calcium channels Diffusion
Exit via Ca2+ pump
Parathyroid hormone: most important stimulator of renal Ca2+ reabsorption
Opens social Ca2+ channels
Hyperparathyroidism causes Ca2+ build-up in kidneys = kidney stones

Tubular Reabsorption: Water

In a normally hydrated person: Water is passively reabsorbed by osmosis
80% of water reabsorbed: 65% in proximal tubule . 15% in loop of Henle
Obligatory reabsorption: Water reabsorption follows solute reabsorption (water is obliged to follow solutes)
Occurs regardless of the overall water load of the body
Not subjected to regulation but is dictated by osmosis:
The hypertonicity of the interstitial fluid dictates obligatory reabsorption (water is pulled from filtrate into ISF if hypertonic)
Hypertonicity maintained by Na+ pumping into ISF in medulla
Obligatory reabsorption (water follows solute reabsorption) Water moves into ISF between nephron and peritubular capillary or vasa recta
Water ends up in capillaries Capillaries contain increase in plasma protein
Water drawn into capillaries via increased colloid osmotic pressure
Role of aldosterone:
Stimulates Na+ reabsorption
Water reabsorption linked to Na+ reabsorption
Aldosterone exerts powerful effect on obligatory water reabsorption
80% of water reabsorbed occurs: 65% in proximal tubule . 15% in loop of henle
Obligatory reabsorption: Water reabsorption follows solute reabsorption (water is obligated to follow solutes)
Remaining 20%
Controlled by antidiuretic hormone (ADH)
Inserts aquaporins into distal tubule and collecting ducts
Water reabsorbed from filtrate
Are impermeable to water in the absence of ADH
Maximal ADH secretion = 99.8% reabsorption of filtered water = 0.3 ml/min urine production. Urine can never = 0!
No ADH = maximal dilute urine production (diuresis)
Create concentration gradient in medulla
Conditions where not much ADH is being secretion = very few aquaporins in collecting duct - meaning collecting duct is not permeable to water Filtrate continues out unchanged = large volume in dilute urine
Aquaporins into collecting duct = water permeable -> water flows out to try and equilibrate the high concentration in medulla -> small volume of concentrated urine

Potassium

K+ high in ICF
ECF (plasma) [K+] tightly regulated between 3.5-5.0 mM
Plays vital role in normal cell functioning Particularly membrane potential Cardiac, smooth, skeletal muscle, nervous system
Don't want K+ in ECF - as it will stuff up membrane potentials -> nothing will work!

Even normal dietary intake excessive: 80-120 mmol.day but only need 70 mmol for entire ECF
Keeping plasma K+ in homeostasis requires excretion at same rate as intake
Renal excretion = 90-95%, colon excretion = 5-10%
Even normal dietary intake excessive:
Must remove from plasma rapidly to avoid dangerous hyperkalemia
Acute [K+] load in plasma = insulin, epinephrine and aldosterone release
Stimulates K+ uptake from plasma into cells
Activates Na+/K+- ATPase pumps
Cells normally have high [K+], plasma should not, therefore a happy system!
Short term response
Acute [K+] load in plasma = insulin, epinephrine and aldosterone release
Stimulates K+ uptake from plasma into cells
Mostly reabsorbed in proximal convoluted tubule Then secreted into distal convoluted tubule
Ie. kidneys regulate potassium levels
Aldosterone: Can increase K+ excretion -> Na uptake from filtrate = K+ outflow
Only 20% of plasma and potassium is filtered in glomerulus - therefore 36% of potassium can be exerted in urine -> due to tubular excretion

Tubular Secretion

2nd route for getting rid of things from the blood
Certain substances are secreted from the peritubular capillaries into the tubule
Tubular secretion provides a second route for blood filtration
Recall: only 20% plasma filtered through glomerulus (80% remains)
Electrolytes removed from plasma via tubular secretion:
H+ dependent on pH of blood
If pH decreases - H+ ions are secreted into filtrate in tubules if blood is acidotic
Secretion is reduced when blood is alkaline
Potassium
K+ secreted into tubules and collecting ducts (nephron)
Coupled to Na+ reabsorption (Na+ out of tubule (nephron), K+ into tubule (nephron) due to coupling via Na+/K+-ATPase pump