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Renal Physiology
Dr Heddwen Brooks
Department of Physiology
[email protected]
Reading material
BME 511 Sherwood, Chapters 13-14
PSIO 603 Boron and Boulpaep, Chapters 32-39
Renal Structure
1
Position of Kidneys in Body Cavity
2
Structure of Kidney
Basic Functions of the Kidneys
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Eliminate METABOLIC WASTE PRODUCTS
Eliminate FOREIGN COMPOUNDS
Regulate BODY FLUID OSMOLALITY
Regulate plasma IONIC COMPOSITION
Regulate EXTRACELLULAR FLUID VOLUME
Help regulate ARTERIAL PRESSURE
Help maintain ACID-BASE BALANCE
Synthesize GLUCOSE
Metabolize/degrade POLYPEPTIDE HORMONES
Act as an ENDOCRINE organ:
– Erythropoietin
– 1,25-(OH)2vitamin D3
– Renin
3
Fundamental Processes
Involved in Urine Formation
Kidney: blood supply
Glomerulus
Afferent
arteriole
Efferent
arteriole
peritubular
capillary plexus
(cortex)
or
vasa recta
(medulla)
4
Blood in
Blood out
Capillaries
(vasa recta)
Filtrate made
ions, H20
reabsorbed
toxins, waste
secreted
20-25% of
plasma that
enters the
glomerulus is
filtered
To venous
system
Urine formation
Kidney: the nephron
Connecting
tubule
Collecting duct
Bowman’s capsule
(Renal corpuscle)
Proximal
convoluted
tubule
An ultrafiltrate of blood
plasma is forced through
into Bowman’s capsule
Distal convoluted tubule
As the ultrafiltrate travels along the nephron
most components are selectively reabsorbed
by the cells of the nephron
Loop of Henle
5
Quantitative Relationship between
Filtration, Reabsorption, Secretion &
Excretion
Filtered/min
/min –– Reabsorbed/min
/min ++ Secreted/min
/min == Excreted/min
/min
Filtered
Reabsorbed
Secreted
Excreted
Filtered/min
Reabsorbed/min
Secreted/min
Excreted/min
Strategy for Understanding
Renal Physiology
• Learn the basic mechanisms involved in filtration,
filtration
reabsorption and secretion,
and
understand
how
secretion
these processes can be regulated.
• Apply this information to describe the renal
handling of specific substances (Na+, H2O, K+, etc).
• Place these processes in the context of the role
of the kidneys in maintaining the optimum
internal environment.
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Filtration
• Glomerulus is made up of capillaries
• Fluid has to flow from capillaries (Starling
Forces) into Bowman’s capsule
• Fluid that enters the Bowmans capsule has the
same ionic composition as blood, but is almost
protein free…….in the normal kidney
• No Cells are filtered
• Filtration is size and charge selective
Ultrafiltration
The formation of a virtually proteinprotein-free filtrate of plasma
as blood passes through the glomerular capillaries
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Structural Components of the
Ultrafiltration Barrier
Kidney: renal corpuscle
Parietal layer
Visceral layer
Bowman's capsule
Capillary
wall
podocytes
8
Kidney: renal corpuscle
podocyte
Glomerular basement membrane
pedicel
endothelium
Capillary lumen
Kidney: renal corpuscle
1. Fenestrated endothelium allows passage of
most
elements of plasma, retains formed elements
2. GBM filters plasma (molecules the size of
albumin and larger are held back)
3. Podocytes secrete GBM, contribute to
Glomerular basement membrane barrier function, provide structural
reinforcement (pressures up to 40 mm
mercury)
endothelium
Capillary lumen
9
Kidney:
glomerular basement membrane
pedicels
Lamina rara interna
Lamina densa
Type IV collagen
Lamina rara externa
endothelium
Laminin, Fibronectin
Proteoglycans (polyanions)
• Most proteins cannot
pass through GBM
Capillary lumen
• Glucose, ions, water –
pass into ultrafiltrate
Glomerular basement membrane
is damaged in disease
Glomerular basement membrane
Glomerulonephritis
The GBM is susceptible to damage by
bound proteins, especially immunoglobulins
Damage to the GBM causes leakage of protein into urine (proteinuria)
10
Cross-sectional View of the
Glomerular Capillary Wall
Size and Charge barrier for macromolecular
passage
11
Which is more important:
Size/Shape or Charge?
• Estimates from Mathematical Models:
– 30% ↓ in charge density → 25-fold ↑ in albumin filtration
– 100% ↑ in “pore” radius → 5-fold ↑ in albumin filtration
• Loss of fixed negative charges probably results in a
physical rearrangement of proteins that contribute to the
size barrier.
– Glycoproteins contribute to the Basal Lamina structural
meshwork (a component of the size barrier) as well as
contributing fixed negative charges
• But does this really matter??
– Glomerular disease: Not really as both size- and chargeselective components of the filtration barrier are
compromised → protein in the ultrafiltrate
– If filtration of protein > protein reabsorption → proteinuria
– Proteinuria (or albuminuria) is the hallmark of
glomerular injury!
Strategy for Understanding
Renal Physiology
• Learn the basic mechanisms involved in filtration,
filtration
reabsorption and secretion,
and
understand
how
secretion
these processes can be regulated.
12
Absorption and Secretion
Absorption: removal of substances from the urine.
Movement of solutes or water from lumen to blood
™ Transcellular (across both cell membranes)
™ Paracellular (between cell membranes)
Secretion: addition of substances to the urine
Movement of solutes from blood to lumen
™ Toxins
™ Urea, Creatinine
Flexibility in how the kidney
can handle different substances
Filtered:
Reabsorbed:
Secreted:
Excreted:
inulin
glucose
sodium
penicillin
13
Transcellular v Paracellular
Water Movement
¾ All epithelial cells serve as selective permeability
barriers, separating fluids on each side that have
different chemical compositions.
¾ The epithelial cells lining the lumen transport selected
ions across the cell, from the lumen into the
extracellular fluid, where they diffuse into small
blood vessels
= Transcellular transport
Transcellular Transport
¾ Transcellular transport depends on two sets of
membrane-bound carrier proteins:
¾ One on apical surface of the epithelial cell (facing the
lumen) which moves selected molecules into the cell
from the lumen of the kidney
¾ One on the basolateral surface, which allows the
same molecules to leave the cell to enter the
extracellular fluid on the other side.
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Water follows the movement of solutes
down its concentration gradient
Transcellular Transport Important for Salt and H20
Na+
Channels
Exchangers
Na+
H20
H20
Aquaporins
Lumen
H20
H20
Aquaporins
Blood
(urine, chyme)
15
Fluid Compartments of the Body
Intracellular and Extracellular Space/Fluid
Intracellular space is the space within cell
membranes
Extracellular space is the space between cells
(interstitial fluid) and within blood vessels
(plasma)
Electrolyte composition (e.g. salt and water
content) of interstitial fluid and plasma is
identical
Compartmentalization of Body
Fluids
Total body water (TBW)= 60% of body weight
60% x 60kg = 36L
™ Intracellular water (ICF) = 2/3 of total body water
2/3 x 36L = 24 L
™ Extracellular water (ECF) = 1/3 of total body water 1/3 x 36L = 12 L
Extracellular Fluid
™ Plasma water = ¼ of extracellular water
1/4 x 12L = 3 L
™ Interstitial fluid = ¾ extracellular water
3/4 x 12L = 9 L
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Osmotic Composition of Major
Fluid Compartments
Osmolarity
Osmoles refers to the number of impermeable particles
dissolved in a solution, regardless of charge. This is
important for determining the diffusional movement
of water.
For substances that maintain their molecular structure
when they dissolve (e.g. glucose), the osmolarity and
the molarity are essentially the same.
For substances that dissociate when they dissolve, the
osmolarity is the number of free particles times the
molarity. Thus for a pure NaCl solution, a 1 Molar
solution would be 2 Osmolar (1 for Na, and 1 for Cl).
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¾ osmolarity (Osm) is defined as moles of dissolved
solute per volume of solution in liters
¾ In human plasma the concentration of dissolved
particles is about 290 X 10-3 M.
Osmotic gradient
• Osmotic gradient is required in order to achieve
net water movement between ECF and ICF
• Because water can move freely between
compartments, a change in the osmolarity of a
single compartment results in redistribution of
TBW between compartments (driven by the
osmotic gradient) until osmotic equilibrium is
restored.
18
Major Function of Kidney:
Homeostasis
Maintain optimal fluid environment in
the body
™
™
™
™
Regulates H20 - osmolarity
NaCl
Most ions
Maintains plasma volume = long term
regulation of blood pressure
Balance Concept
Net gain must equal net loss if substance remains in a
steady state
(e.g. water, salt)
Ingestion
+
(External gain)
™food
™air
Production
(Internal gain)
™metabolism
=
Excretion
+ Consumption
(External loss)
™urine
™stool
™expired air
™sweat
(Internal loss)
™metabolism
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Water balance
Electrolytes and Water
Salt is not produced or consumed by the
body so balance is maintained by regulating
the amounts excreted in body fluids (urine,
sweat, stool) such that they equal the
amounts ingested (ingestion = excretion)
Kidneys maintain water and salt balance in
the body by regulating output of both in the
urine
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