BIO2305
Renal Physiology
Kidney Function
Regulation of body fluid osmolality & volume:
Excretion of water and Na+ is regulated in conjunction with cardiovascular, endocrine, & central
nervous systems
Regulation of electrolyte balance:
Daily intake of inorganic ions
Na+, K+, Cl-, HCO3-, H+, Ca2+, Mg+, & PO43Should be matched by daily excretion through kidneys
Regulation of acid-base balance:
Kidneys work in concert with lungs to regulate the pH in a narrow limits of buffers within body
fluids
Excretion of metabolic products & foreign substances:
Urea from amino acid metabolism
Uric acid from nucleic acids
Creatinine from muscles
Hemoglobin catabolism end products
Hormone metabolites
Foreign substances
e.g., drugs, pesticides, & other chemicals ingested in the food
Production and secretion of hormones:
Renin – activates the Renin-Angiotensin-Aldosterone System (RAAS), thus regulating blood
pressure & Na+, K+ balance
Prostaglandins & Kinins – vasoactive, leading to modulation of renal blood flow & along with
angiotensin II affect the systemic blood flow
Example: Bradykinin is a vasodilator that lowers blood pressure and takes part in
inflammation
Erythropoietin (EPO) – stimulates erythropoiesis (red blood cell formation) by bone marrow
Renal Anatomy
Nephron – the functional unit of the kidney
Renal Corpuscle:
Bowman’s capsule
Glomerulous (Glomerular
capillaries)
Promixal Convoluted Tubule (PCT)
Loop of Henle (“hen/lee”)
Distal Convoluted Tubule (DCT)
Collecting duct
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Functional Unit – Nephron
Production of filtrate
Reabsorption of organic nutrients
Reabsorption of water and ions
Secretion of waste products into tubular fluid
Two Types of Nephrons
Cortical nephrons
~85% of all nephrons
Located in the cortex
Juxtamedullary nephrons
Closer to renal medulla
Loops of Henle extend deep into renal
pyramids
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Cortical and Juxtamedullary Nephrons
Blood Supply to the Kidneys
Blood travels from afferent arteriole to capillaries within the Bowman’s capsule called the Glomerulus
Blood leaves the renal corpuscle via the efferent arteriole
Blood travels from efferent arteriole to peritubular capillaries and vasa recta, which eventually exit via
the renal vein
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Anatomical Review - Renal Corpuscle
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Glomerular Filtration
Glomerular filtrate is produced from blood plasma
Filtration of molecules restricted on the basis of size and
electrical charge
Three Filtration Barriers that filtrate must pass through:
Endothelial cell fenestrations of the glomerular
capillary
Basement membrane, the acellular gelatinous
membrane made of collagen and glycoprotein
(“lamina propria”)
Filtration slits formed by interlocking podocyte foot
processes
Filtrate is similar to plasma in terms of concentrations of
salts and of organic molecules (e.g., glucose, amino acids)
except it is essentially protein-free
Filtrate Composition
Solute Characteristics:
Neutral solutes
Solutes without a charge
Size:
Radius smaller than 180 nm are freely
filtered
Radius between 180 and 360 nm are
filtered to varying degrees
Radius greater than 360 nm are not
filtered
Example: Serum albumin
~7 g/day filtered (out of ~70,000 g/day passing
through glomeruli)
a small plasma protein
anionic
355 nm radius
Glomerular Filtration
Filtration is driven by Starling forces across the glomerular capillaries, and changes in these forces
and in renal plasma flow alter the glomerular filtration rate (GFR)
The glomerulus is more efficient than other capillary beds because:
Its filtration membrane is significantly more permeable
Glomerular blood pressure is higher resulting in a higher net filtration pressure
Plasma proteins are not filtered and are used to maintain oncotic (colloid osmotic) pressure of the
blood
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Glomerular Filtration Rate (GFR)
The Starling equation – equation that illustrates the role of hydrostatic and oncotic forces (Starling
forces) in the movement of fluid across capillary membranes
GFR - The total amount of filtrate formed per minute by the kidneys
Filtration rate factors:
Filtration Coefficient (Kf) - total surface area available for filtration and membrane permeability
Net filtration pressure (NFP) – the resulting glomerular pressure that is responsible for filtrate
formation
GFR = Kf x NFP
GFR is directly proportional to the NFP
Changes in GFR normally result from changes in glomerular capillary blood pressure
Forces Involved in Glomerular Filtration
Net Filtration Pressure (NFP) - pressure responsible for filtrate formation
NFP equals the glomerular hydrostatic pressure (HPg) minus the oncotic pressure of glomerular blood
(OPg) plus capsular hydrostatic pressure (HPc)
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Control of Kf (Filtration Coefficient)
Filtration Coefficient (Kf)
total filtration surface area and membrane permeability
It is normally 12.5 mL/min/mm Hg (a constant)
Kf is determined by 2 factors:
The permeability of the capillary bed
The surface area of the capillary bed
Kf = permeability of glomerulus x filtration surface area
Control of Kf (Filtration Coefficient)
Mesangial cells
Specialized smooth muscle cells wedged between glomerular capillaries
Have contractile properties; influence capillary filtration by closing some of the capillaries
Directly affect the filtration surface area
Podocytes change size of filtration slits
Kidney’s Receive 20-25% of CO
Distribution of CO to Kidneys: ~ 22% of CO reaches the kidneys
Filtration fraction: ~ 20% of the plasma that enters the glomerulus is filtered into the capsular space
and enters the PCT (@ NFP of 10 mm HG)
Male GFR: 125 mL/min
Produce 180 L of filtrate/day
Female GFR: 115 mL/min
Produce 160 L of filtrate/day
Required for adjustments and purification, not to supply kidney tissue
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Calculate GFR
Given:
HR = 70
SV = 71
% of CO that goes to Kidneys = 22%
% Hct = 45%
Filtration Fraction = 20%
Calculate GFR:
Regulation of Glomerular Filtration
If the GFR is too high, needed substances cannot be reabsorbed quickly enough and are lost in the
urine
If the GFR is too low - everything is reabsorbed, including lipid-soluble wastes that are normally
disposed of
GFR normally controlled by adjustment of glomerular BP
Three mechanisms control the GFR:
Renal autoregulation (intrinsic system)
Neural controls (sympathetic nervous system)
Hormonal mechanism (the renin-angiotensin system, ADH)
Autoregulation of GFR (local)
Under normal conditions (MAP = 80 –180 mm Hg) renal autoregulation maintains a nearly constant
glomerular filtration rate
Two mechanisms are in operation for autoregulation:
Myogenic mechanism:
Arterial pressure rises, afferent arteriole stretches
Vascular smooth muscles contract
Arteriole resistance offsets pressure increase; RBF (& hence GFR) remain constant.
Tubuloglomerular feedback mechanism:
Feedback loop consists of a flow rate (increased NaCl) sensing mechanism in macula
densa of juxtaglomerular apparatus (JGA)
Increased GFR (& RBF) triggers release of vasoactive signals
Constricts afferent arteriole leading to a decreased GFR (& RBF)
Decreased GFR (& RBF) triggers release of vasoactive signals
Dilates afferent arteriole leading to a increaced GFR (& RBF)
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Juxtaglomerular Apparatus
Arteriole walls have juxtaglomerular (JG) cells - enlarged, smooth muscle cells, have secretory
granules containing renin; act as mechanoreceptors
Macula densa - tall, closely packed distal tubule cells, lie adjacent to JG cells; function as
chemoreceptors or osmoreceptors
Extrinsic Controls
Neural Control:
When the sympathetic nervous system is at rest:
Renal blood vessels are maximally dilated
Autoregulation mechanisms prevail
Under stress:
Norepinephrine is released by the sympathetic nervous system
Epinephrine is released by the adrenal medulla
Afferent arterioles constrict and filtration is inhibited
The sympathetic nervous system also stimulates the renin-angiotensin mechanism
Hormonal Control:
A drop in filtration pressure stimulates the Juxtaglomerular apparatus (JGA) to release Renin
(RAAS) and Erythropoietin
Atria of the heart release Atrial Natriuretic Peptide (ANP)
ADH from the neurohypophysis inhibit diuresis
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Renin-Angiotensin-Aldosterone System (RAAS)
Atrial Natriuretic Peptide (ANP)
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Vasopressin (ADH) Mechanism
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Other Factors Affecting Glomerular Filtration
Prostaglandins (PGE2 and PGI2)
Vasodilators produced in response to sympathetic stimulation and angiotensin II
Are thought to prevent renal damage when peripheral resistance is increased
Nitric oxide – vasodilator produced by the vascular endothelium
Adenosine – vasoconstrictor of renal vasculature
Endothelin – a powerful vasoconstrictor secreted by tubule cells
Overview of Urine Formation
1) Glomerular Filtration
Filtration mainly by Starling forces
2) Tubular Reabsorption of valuable substances from the tubular fluid back into blood
Reabsorption by active or passive transport
3) Tubular Secretion of less desirable substances from the blood into the tubular fluid
Secretion mainly by active transport
Mass Balance:
Amount Filtered – Amount Reabsorbed + Amount Secreted = Amount Excreted in Urine
Reabsorption and Secretion
Accomplished via diffusion, osmosis, active and facilitated transport
Carrier proteins have a transport maximum (Tm) which determines renal threshold for reabsorption of
substances in tubular fluid
Transport Maximum (Tm):
Reflects the number of carriers in the renal tubules available
Exists for nearly every substance that is actively reabsorbed or secreted
When the carriers are saturated, excess of that substance is excreted
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Na+ Reabsorption
Sodium reabsorption is almost always by active transport via a Na+-K+ pump
Na+ reabsorption provides stored energy (Primary Active Transport) used in reabsorbing most
other organic nutrients (Secondary Active Transport)
Water reabsorption:
Na+ is reabsorbed, and H2O follows (osmosis)
Secondary Active Transport – Cotransport
Na+-linked Secondary Active Transport
(Cotransport System)
Occurs mostly in PCT
[Na+] gradient (stored energy) established by the
Na+/K+ pump is used to move other solutes
across membrane
Reabsorption of:
Glucose
Ions
Amino acids
Healthy fasting blood glucose level (BGL): 70
– 110 mg/dL
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Reabsorption: Transport Maximum (Tm)
Non-reabsorbed Substances
Substances are not reabsorbed if they:
Lack carriers
Are not lipid soluble
Are too large to pass through membrane pores
Creatinine and uric acid are the most important non-reabsorbed substances
Urea is lipid soluble (nonpolar), moves freely across membranes, and is reabsorbed from the
collecting duct to help increase osmolality in the countercurrent exchange mechanism
Tubular Secretion
Essentially reabsorption in reverse, where substances move from peritubular capillaries or tubule cells
into filtrate
Tubular secretion is important for:
Disposing of substances not already in the filtrate
Eliminating undesirable substances such as urea and uric acid
Ridding the body of excess potassium ions
Controlling blood pH
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Reabsorption and Secretion at the PCT
Glomerular filtration produces fluid similar to plasma without proteins
The PCT Reabsorbs 60-70% of the filtrate produced:
Sodium, all nutrients, cations, anions, (HCO3-), and water
Lipid-soluble solutes
Small proteins
H+ secretion occurs in the PCT
Transport Activities at the PCT
Reabsorption and Secretion at the DCT
DCT performs final adjustment of urine (last-minute tweaking of [solutes])
Active secretion or absorption
Absorption of Na+ and ClSecretion of K+ and H+ based on blood pH
Water is regulated by ADH (vasopressin)
Na+, K+ regulated by aldosterone
Na+ reabsorption
K+ secretion
Na+ and K+ generally move in opposite directions
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Tubular Secretion and Solute Reabsorption at the DCT
Control of Urine Volume & Concentration
Urine volume and osmotic concentration are regulated by controlling water and sodium reabsorption
Precise control allowed via facultative water reabsorption
Osmolality
The number of solute particles dissolved in 1 L of water
Reflects the solution’s ability to cause osmosis
Body fluids are measured in milliosmoles (mOsm)
The kidneys keep the solute load of body fluids constant at about 300 mOsm
This is accomplished by the Countercurrent Mechanism
Countercurrent Mechanism
Countercurrent Exchange System – the anatomical
arrangement of vessels so that flow in one vessel is in
the opposite direction from flow in the adjacent vessel
Two Components:
Filtrate in Loop of Henle that dip into the
Renal Medulla
Blood in Vasa Recta surrounding the
Loop of Henle
Solute concentrations in Loop of Henle and Vasa Recta
range from 300 to 1200 mOsm
Ions diffuse faster between fluids with a large difference
in gas concentration (a high concentration gradient)
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Countercurrent Multiplier
Vasa Recta maintains medullary (ISF) osmotic gradient by receiving and carrying away H2O from the
medulla
Maintains the osmotic gradient
Delivers blood to the cells in the area
Loop of Henle:
Descending Loop
highly permeable to water; impermeable to solutes,
Ascending Loop
permeable to solutes; impermeable to water
Collecting ducts in the deep medullary regions are permeable to urea, which helps maintain
medullary hypertonicity
Purpose of Countercurrent Exchange:
To produce hyperosmotic (high [ion]) ISF in the medulla
To produce a hyposmotic (dilute) filtrate in the absence of ADH
To produce a hyperosmotic (concentrated) filtrate in the presence of ADH
ADH (Vasopressin)
ADH is used when the body needs to retain water.
ADH inhibits diuresis and produces concentrated urine.
Decreases the amount of water lost at the kidneys
Elevates blood pressure
Cells of the collecting duct require aquaporins for water permeability and osmosis
ADH uses a G-protein/cAMP 2nd messenger system to stimulate the insertion
of aquaporins into the collecting duct cell membrane.
H2O then flow via osmosis toward the hyperosmotic medullary ISF and vasa recta
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Presence of ADH
In the presence of ADH, 99% of the water in filtrate is reabsorbed
H2O moves via osmosis out of the tubule, toward the highly concentrated medullary ISF
Urine osmolality can be as high as 1200 mOsm (4 x that of plasma)
Absence of ADH
In the absence of ADH, collecting ducts remain impermeable to water, and the filtrate within remains
diluted
Urine osmolality can be as low as 50 mOsm (1/6th that of plasma)
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ADH and Aquaporins
ADH uses a G-protein/cAMP 2nd messenger system to stimulate the insertion of aquaporins into the
collecting duct cell membrane
H2O then flows via osmosis toward the hypertonic medullary ISF and vasa recta
Water Balance Reflex: Regulators of Vasopressin Release
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Renal Clearance
The volume of plasma that is cleared of a particular substance in a given time:
RC = UV/P
RC = renal clearance rate
U = concentration (mg/ml) of the substance in urine
V = flow rate of urine formation (ml/min)
P = concentration of the same substance in plasma
Renal clearance tests are used to:
Determine the GFR
Detect glomerular damage
Follow the progress of diagnosed renal disease
Creatinine Clearance
Creatinine clearance is the amount of creatine in the urine, divided by the concentration in the blood
plasma, over time.
Glomerular filtration rate can be calculated by measuring any chemical that has a steady level in the
blood, and is filtered but neither actively reabsorbed or secreted by the kidneys.
Creatinine is used because it fulfills these requirements (though not perfectly), and it is produced
naturally by the body.
The result of this test is an important gauge used in assessing excretory function of the kidneys.
Inulin and PAH
Inulin is freely filtered at the glomerulus and is neither reabsorbed nor secreted. Therefore inulin
clearance is a measure of GFR
Substances which are filtered and reabsorbed will have lower clearances than inulin, Ux.
Substances that are filtered and secreted will have greater clearances than inulin, Ux.
Para-amino-hippuric acid (PAH) is freely filtered at the glomerulus and most of the remaining PAH is
actively secreted into the tubule so that >90% of plasma is cleared of its PAH in one pass through the
kidney.
PAH can be used to measure the plasma flow through the kidneys = renal plasma flow.
Excretion
All Filtration Products that are not reabsorbed
Excess ions, H2O, molecules, toxins, excess urea, "foreign molecules"
Kidney  Ureter  Bladder Urethra out of body
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Physical Characteristics of Urine
Color and transparency
Clear, pale to deep yellow (due to urochrome)
Concentrated urine has a deeper yellow color
Drugs, vitamin supplements, and diet can change the color of urine
Cloudy urine may indicate infection of the urinary tract
pH
Slightly acidic (pH 6) with a range of 4.5 to 8.0
Diet can alter pH
Specific gravity
Ranges from 1.001 to 1.035
Is dependent on solute concentration
Chemical Composition of Urine
Urine is 95% water and 5% solutes
Nitrogenous wastes include:
Urea
Uric acid
Creatinine
Other normal solutes include:
Na+, K+, PO43-(phosphate), SO4(sulfate)
Ca+2 (calcium), Mg+ (magnesium), HCO3- (bicarbonate)
Abnormally high concentrations of any urinary constituents may indicate pathology
Micturition
From the kidneys urine flows down the ureters to the bladder propelled by peristaltic contraction of
smooth muscle.
The bladder is a balloon-like bag of smooth muscle (detrussor muscle), contraction of which empties
bladder during micturition.
Pressure-Volume curve of the bladder has a characteristic shape
There is a long flat segment as the initial increments of urine enter the bladder and then a sudden
sharp rise as the micturition reflex is triggered.
Micturition (Voiding or Urination)
Bladder can hold 250 - 400mL
Greater volumes stretch bladder walls initiates micturition reflex:
Spinal reflex:
Parasympathetic stimulation causes bladder to contract
Internal sphincter opens
External sphincter relaxes due to inhibition
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Urination: Micturition reflex
Micturition (Voiding or Urination)
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