The Urinary System
Chapter 17
Chapter 17 Objectives
To understand:
• Renal hormones that control blood volume
• Renal control of acid-base balance
• Mechanism of action of diuretics
• Kidney disease
• Role of the kidneys in heart failure
Kidney Function
• Regulates plasma and interstitial fluid by formation of
urine
• In process of urine formation, kidneys regulate:
– Volume of blood plasma, which contributes to BP
– Waste products in plasma
– Concentration of electrolytes
• Including Na+, K+, HCO3-, and others
– Plasma pH
Structure of Urinary System
• Kidneys – by vertebral
column below diaphragm
– About size of fist
– Filtration and urine
production
• Urine flows into ureters
– empty into bladder
• Bladder – temporary
storage for urine
• Urethra – drains urine to
the external environment
Structure of Kidney
• Cortex – outer region
– contains many
capillaries
• Medulla – consists of
renal pyramids
– separated by renal
columns
– Pyramids contain
minor calyces, unite
to form a major
calyx
Structure of Kidney
• Major calyces join to
form the renal pelvis
– Collects urine
– Conducts urine to
ureters which
empty into bladder
Micturition Reflex (Urination)
• Bladder – temporary storage for urine
– Detrussor muscle smooth muscular wall
– Stretching can cause spontaneous action potentials and
contraction
– Also innervated and controlled by parasympathetic ANS
• Drugs for overactive bladders target muscarinic ACh receptors
Micturition Reflex (Urination)
• Internal and external urethral sphincters – regulated by
reflex center in sacral part of spinal cord
• Filling of bladder – activates stretch receptors that send
impulses to the micturition reflex center
– Activates parasympathetic neurons with contraction of the
detrusor muscle
– Relaxes internal urethral sphincter creating sense of urgency
– There is voluntary control over external urethral sphincter
• Urination consciously initiated – descending motor tracts
stimulus to micturition center
– Inhibit somatic motor fibers of external urethral sphincter and
urine is expelled
Nephron
• Functional unit of
kidney
– responsible for
forming urine
– >1 million
nephrons/kidney
• Consists of small tubes
or tubules
– and associated
capillaries
• Filtrate – fluid formed
by capillary filtration
– Enters tubules, is
modified, and leaves as
urine
Renal Blood Vessels
• Blood enters kidney through renal artery
– divides into interlobar arteries into arcuate arteries into
interlobular arteries
Renal Blood Vessels
• Interlobular arteries give rise to afferent arterioles
which supply glomeruli
• Glomeruli – mass of capillaries inside glomerular
capsule
– Gives rise to filtrate that enters nephron tubule
• Efferent arteriole drains glomerulus
– Delivers that blood to peritubular capillaries and vasa recta
• Blood from peritubular capillaries enters interlobular
veins
Nephron Tubules and Associated Blood Vessels
The Tubules
• Fluid formed by capillary filtration enters the tubules to
be modified by transport processes
– Resulting in fluid that leaves as urine
• Reabsorption – transport of molecules out of the tubular
filtrate (from the tubules) back to the blood
• Secretion – transport of secreted molecules and ions
– Move out of the peritubular capillaries into interstitial fluid, then
– Transported across basolateral membrane of tubular epithelial
cells, and into the
– Lumen of the nephron tubule
• Excretion – transport of urine out of the body
Nephron Tubules
• Begins with glomerular
capsule:
– Transitions into proximal
convoluted tubule (PCT)
then to
– Descending and ascending
limbs of Loop of Henle (LH)
and finally to
– Distal convoluted tubule
(DCT)
• Tubule ends where it empties
into collecting duct (CD)
Renal Corpuscle
• Glomerular (Bowman’s) capsule and glomerulus
– Where glomerular filtration occurs
– Filtrate passes into proximal convoluted tubule
Proximal Convoluted Tubule
• Walls – single layer of epithelial cuboidal cells with
millions of microvilli
– Increase surface area for reabsorption
• Reabsorption – salt, water, and other molecules needed
by the body
– transported from the lumen through the tubular cells and into
surrounding peritubular capillaries
Type of Nephrons
• Cortical nephrons originate in outer 2/3 of cortex
• Juxtamedullary nephrons originate in inner 1/3 cortex
– Long LHs
– Important in producing concentrated urine
Glomerular Filtration
• Glomerular capillaries and Bowman's capsule form a
filter for blood
– Fenestrated capillaries contain large pores between its
endothelial cells
• Big enough to allow any plasma molecule to pass
• 100-400 times more permeable than other capillaries
Glomerular Filtration
• To enter the tubule filtrate
must pass through narrow
slit diaphragms
– formed between pedicels
of podocytes
• Filtered molecules pass out
of the fenestrae and
through filtration slits
– Enter the capsular cavity
– Plasma proteins are excluded
from the filtrate by the
glomerular basement
membrane and slit diaphragm
SEM of Glomerular Capillaries and Capsule
• Pedicels interdigitate around the glomerular capillaries
– Spaces between adjacent pedicels form ‘filtration slits’
Glomerular Filtration
• Plasma proteins – mostly excluded from the filtrate
because of large size and negative charge
– Slit diaphragms lined with negative charges repel negatively-
charged proteins
– Some protein (especially albumin) normally enters the filtrate
but most is reabsorbed, or transported across the PCT
– Filtered albumin reabsorptionis performed by receptor-
mediated endocytosis
• Previously basement membrane was considered as the
primary filter but recent research found
– Genetic defects in proteins that compose the slit diaphragm
results in massive leakage of protein in the filtrate (proteinuria)
Filtration Barrier
• Separates the capillary
lumen
– from cavity of the
glomerular capsule
EM of filtration barrier between the capillary lumen
and glomerular capsule
Formation of Glomerular Ultrafiltrate
• Only a fraction of plasma proteins (green) are filtered
• Smaller plasma solutes (purple) easily enter glomerular ultrafiltrate
– But most are reabsorbed
Glomerular Filtration Rate (GFR)
• Volume of filtrate produced by both kidneys/minute
– ~115 ml/minute in women
– ~125 ml/minute in men
– Totals about 180L/day (45 gallons)
• Total blood volume average ~5.5 L
– Most filtered water must be reabsorbed or death would ensue
from water lost through urination
Regulation of GFR
• Diameter of afferent arterioles – vasoconstriction or
dilation affects rate of blood flow to glomeruli and thus
GFR
– Controlled by extrinsic and intrinsic mechanisms
• Extrinsic regulatory mechanisms – produced by
sympathetic innervation
• Intrinsic mechanisms – renal autoregulation within the
kidney
Sympathetic Effects
• Sympathetic activity
constricts afferent
arteriole
– Helps maintain BP
– Shunts blood to
heart and muscles
Renal Autoregulation
• Defined as ability of kidneys to maintain relatively
constant GFR in the face of fluctuating blood pressure
• 2 mechanisms responsible:
– Myogenic constriction of afferent arteriole
• due to smooth muscle responding to an increase in arterial
pressure
– Tubuloglomerular feedback
• via effects of locally produced chemicals on afferent
arterioles
Renal Autoregulation
• Tubuloglomerular feedback – negative feedback between afferent
arteriole and volume of filtrate
– Increased flow of filtrate sensed by macula densa (juxtaglomerular
apparatus) in thick ascending LH signals afferent arteriole to constrict
Reabsorption of Salt and H2O
• PCT – returns most molecules and H2O from filtrate back
to peritubular capillaries
– About 180 L/day of ultrafiltrate produced but only 1–2 L of
urine excreted/24 hours
• Urine volume varies according to needs of body
• Obligatory water loss – minimum of 400 ml/day urine needed to
excrete metabolic waste produced by the body
Reabsorption of Salt and H2O
• Reabsorption – transport of molecules out of the tubular filtrated
back into the blood
• Water is never transported – other molecules transported and
water follows by osmosis
Reabsorption in PCT
• Coupled transport of glucose
and Na+ into the cytoplasm
• Primary active transport of
Na+ across basolateral
membrane by Na+/K+ pump
• Glucose is then transported
out of the cell by facilitated
diffusion
– And reabsorbed into the
blood
PCT – Salt and Water Reabsorption
• Na+ actively transported out of filtrate and Cl- follows passively by
electrical attraction
:
Significance of PCT Reabsorption
• PCT – about 65% Na+, Cl-, and H2O reabsorbed and
returned into bloodstream
• Additional 20% reabsorbed in descending loop of Henle
• Thus 85% of filtered H2O and salt are reabsorbed early in
tubule
– Constant and independent of hydration levels
– Energy cost 6% of calories consumed at rest
– Remaining 15% reabsorbed variably depending on level of
hydration
Concentration Gradient in Kidney
• In order for H2O to be reabsorbed, interstitial fluid must
be hypertonic
• Osmolality of medulla interstitial fluid (1200-1400
mOsm) is 4X that of cortex and plasma (300 mOsm)
– Concentration gradient results largely from loop of Henle
• Allows interaction between descending and ascending limbs
The Countercurrent Multiplier System
• Extrusion of NaCl from
ascending limb makes
surrounding interstitial
fluid more concentrated
• Concentration multiplied
due to descending limb
– Passively permeable to H2O
– Fluid concentration increases
– As surrounding interstitial
fluid becomes more
concentration
• Deepest region of medulla
– 1,400mOsm
Ascending Limb Loop of Henle
• Thin segment in depths
of medulla and thick
segment toward cortex
• Impermeable to H2O;
permeable to salt
– Thick segment Actively
Transports NaCl out of
filtrate
• Active Transport of salt
– filtrate becomes dilute
(100 mOsm) by end of
Loop of Henle
Transport of Ions in Ascending Limb
• In thick segment – Na+ and K+ together with 2 Cl- enter tubule cells
• Na+ then actively transported out into interstitial space, Cl- follows
passively
• K+ diffuses back into filtrate; some also enters interstitial space
Active Transport in Ascending Limb
• Na+ – actively transported across basolateral membrane by Na+/ K+
pump
• Cl- passively follows Na+ down electrical gradient
• K+ passively diffuses back into filtrate
Countercurrent Multiplier System
• Countercurrent flow and proximity allow descending and
ascending limbs of to interact
– This causes osmolality to build in medulla
• Salt pumping in thick ascending part raises osmolality
around descending limb, causes more H2O to diffuse out
of filtrate
– This raises osmolality of filtrate in descending limb causes more
concentrated filtrate to be delivered into ascending limb
– As concentrated filtrate is subjected to Active Transport of salts,
it causes even higher osmolality around descending limb
(positive feedback)
– Process repeats until equilibrium is reached when osmolality of
medulla is 1400
Vasa Recta
• For countercurrent multiplier system to be effective:
– Most of the salt extruded from ascending limbs must remain in
the interstitial fluid of the medulla
– Most of the water that leaves descending limbs must be
removed by the blood
• This is accomplished by the vasa recta
– Thin-walled capillaries parallel LH of juxtamedullary nephrons
– Walls permeable to water because of aquaporins channels,
NaCl, and urea but not plasma proteins
– Therefore colloid osmotic (oncotic) pressure in vasta recta is
higher than in surrounding tissue fluid
• results in movement of H2O from interstitial fluid into ascending vasa
recta that can be removed from the renal medulla
Countercurrent Exchange in Vasa Recta
• Important component of
countercurrent multiplier
• Permeable to salt, H2O (via
aquaporins), and urea
• Recirculates salt, trapping
some in medulla interstitial
fluid (maintains hypertonicity)
• Reabsorbs H2O coming out of
descending limb
• Descending section has urea
transporters
• Ascending section has
fenestrated capillaries
The Role of Urea in Urine Concentration
1. Urea diffuses out of
inner collecting duct (in
renal medulla) into
interstitial fluid
2. Urea then passes into
ascending limb
• Recirculates in interstitial
fluid of renal medulla
• Urea and NaCl in
interstitial fluid make it
very hypertonic, so
3. Water leaves the CD by
osmosis
Collecting Duct (CD)
• Plays important role in water conservation
• Is impermeable to salt in medulla
• Permeability to H2O depends on levels of ADH
Homeostasis of Plasma
Concentration
Maintained by ADH
• Secreted by post pituitary
in response to dehydration
• Stimulates insertion of
aquaporins PM of
collecting duct (CD)
• ADH high – H2O is drawn
out of CD by high
osmolality of interstitial
fluid
– And reabsorbed by vasa
recta
ADH Stimulation of
Aquaporins
a) ADH absent – aquaporins
located in membrane of IC
vesicles within CD
epithelial cells
b) ADH stimulates fusion of
vesicles and
c) Insertion of aquaporins
into PM
d) When ADH is withdrawn,
PM pinches inward forms
IC vesicle and removes
aquaporin channels
Osmolality of Different Regions of the Kidney
• Countercurrent multiplier
system in LH and
countercurrent exchange
in vasa recta
– Creates hypertonic renal
medulla
• Under influence of ADH
CD becomes more
permeable to H2O
– Thus more H2O is drawn
out by osmosis into
hypertonic renal medulla
and peritubular capillaries
Secretion is the Opposite of Reabsorption
• Secretion – active transport of substances from the peritubular
capillaries into the tubular fluid
• Secretion is opposite in direction to that which occurs in reabsorption
• Reabsorption decreases renal clearance; secretion increases renal
clearance
Renal Clearance
• Excretion rate = (filtration rate + secretion rate) - reabsorption rate
• If a substance in the plasma is filtered (enters filtrate in gomerular
capsule) but is neither reabsorbed nor secreted
• Its secretion rate must equal its filtration rate
• This fact is used to measure volume of blood plasma filtered/min by
the kidneys = glomerular filtration rate (GFR)
Tubular Secretion of Drugs
• Many drugs, toxins, and metabolites are secreted by
membrane transporters in the PCT
– Organic anion transporter (OAT) – major group of transporters
– Eliminate xenobiotics, therapeutic and abused drugs
– Located in basolateral membrane
– Larger xenobiotics eliminated by OATS in the liver that transport
xenobiotics into bile
• Organic cation transporters – eliminate particular
xenobiotics, such as nicotine
• These carriers considered polyspecific—overlapping
specificity (broad range of molecules)
Inulin Measurement of GFR
• Inulin – fructose polymer useful for measuring GFR
– because it is neither reabsorbed or secreted
• Rate at which a substance is filtered by the glomeruli can
be calculated:
– Quantity filtered = GFR x P
• P = inulin concentration in plasma)
• Quantity excreted (mg/min) = V x U
• V = rate of urine formation in ml/min
• U = inulin concentration in urine in mg/ml
• Amount filtered = amount excreted
GFR(ml/min) = V(ml/min) x U(mg/ml)
P(mg/ml)
Renal Clearance of Inulin
• a) Inulin present in blood
enters glomeruli , and b) some
of this blood together with
inulin is filtered
• All filtered inulin enters the
urine, most of filtered water is
reabsorbed (returned to
vascular system)
• Blood leaving the kidneys in
renal vein, therefore, contains
less inulin than the blood that
entered the kidneys in the
renal artery
– Because inulin is filtered but
neither reabsorbed nor
secreted, the inulin clearance
rate equals GFR
Renal Plasma Clearance (RPC)
• Volume of plasma from which a substance is completely
removed/min by excretion in urine
• If substance is filtered but not reabsorbed then all filtered will be
excreted RPC = GFR
• If substance is filtered and reabsorbed then RPC GFR (=120 ml/ min)
RPC = V x U V = urine volume/min
P U = concentration of substance in urine
P = concentration of substance in plasma
Clearance of Urea
• Urea is freely filtered into glomerular capsule
• Urea clearance calculations demonstrate how kidney handles a
substance: RPC = V X U/P
– V = 2ml/min; U = 7.5 mg/ml of urea; P = 0.2 mg/ml of urea
• RPC = (2ml/min)(7.5mg/ml)/(0.2mg/ml) = 75ml/min
– Urea clearance is 75 ml/min, compared to clearance of inulin (120 ml/min)
• Thus 40-60% of filtered urea is always reabsorbed
• Passive process – presence of carriers for facilitative diffusion of
urea
Measurement of Renal Blood Flow
• Not all blood delivered to glomerulus is filtered into
glomerular capsule
– 20% is filtered; rest passes into efferent arteriole and back into
circulation
– Substances that aren't filtered can still be cleared by active
transport (secretion) into tubules
Total Renal Blood Flow Using PAH
• Para-aminohihppuric acid (PAH) – clearance used to
measure total renal blood flow
– Normally averages 625 ml/min
– It is totally cleared by a single pass through a nephron
– So it must be both filtered and secreted
– Filtration and secretion clear only molecules dissolved in plasma
• To get total renal blood flow, amount of blood occupied by
erythrocytes must be taken into account
• 45% blood is RBCs; 55% is plasma
• total renal blood flow = PAH clearance
= 625/0.55 = 1.1L/min 0.55
Total Renal Blood Flow Using PAH
• a) Some PAH in glomerular blood b) is filtered into glomerular capsule; c)
PAH present in unfiltered blood is secreted from peritubular capillaries into
the nephron; d) so all of the blood leaving the kidneys is free of PAH
– The clearance of PAH therefore equals the total renal blood flow
Glucose and Amino Acid Reabsorption
• Filtered glucose and amino acids are normally 100%
reabsorbed from filtrate
– Occurs in PCT by carrier-mediated cotransport with Na+
• Transporter displays saturation if ligand concentration in
filtrate is too high
• Transport maximum (Tm) – level needed to saturate carriers
and achieve maximum transport rate
– Glucose and amino acid transporters do not saturate
under normal conditions
Glycosuria
• Presence of glucose in urine
• Occurs when glucose > 180-200mg/100ml plasma = renal
plasma threshold
– Glucose is normally absent because plasma levels stay below
this value
– Hyperglycemia: exceeds renal plasma threshold
– Diabetes mellitus: occurs when hyperglycemia results in
glycosuria
Electrolyte Balance
• Kidneys regulate levels of Na+, K+, H+, HCO3-, Cl-, and PO4-3
by matching excretion to ingestion
• Control of plasma Na+ is important in regulation of blood
volume and pressure
• Control of plasma of K+ is important in proper function of
cardiac and skeletal muscles
Role of Aldosterone in Na+/K+ Balance
• 90% filtered Na+ and K+ reabsorbed before DCT
– Remaining variably reabsorbed in DCT and cortical collecting
duct according to bodily needs
• Regulated by aldosterone (controls K+ secretion and Na+
reabsorption)
• In the absence of aldosterone, 80% of remaining Na+ is
reabsorbed in DCT and cortical collecting duct
• When aldosterone is high all remaining Na+ is reabsorbed
K+ is Reabsorbed and Secretion
• K+ almost completely
reabsorbed in PCT
• Under aldosterone
stimulation – K+
secreted into cortical
collecting ducts
• All K+ in urine is from
secretion
Juxtaglomerular Apparatus (JGA)
• Specialized region in each nephron where afferent arteriole comes
in contact with thick ascending limb LH
Renin-Angiotensin-Aldosterone System
• Activated by release of renin from granular cells within
afferent arteriole
– Renin converts angiotensinogen to angiotensin I
• ACE in lungs converts angiotensin I to angiotensin II
• Angio II stimulates release of aldosterone
Regulation of Renin Secretion
• Inadequate intake of NaCl always causes decreased blood
volume
– Because lower osmolality inhibits ADH, causing less H2O
reabsorption
– Low blood volume and renal blood flow stimulate renin release
• Via direct effects of BP on granular cells and
• By sympathetic activity initiated by arterial baroreceptor reflex
Macula Densa
• Located where tubule cells make contact with granular cells
• Act as sensor for tubuloglomerular feedback – needed for
autoregulation of GFR
– Signals afferent arteriole to constrict
– Signals granular cells to decrease secretion of renin when blood Na+ increased
Atrial Natriuretic Peptide (ANP)
• Produced by atria due to stretching of atrial walls
• An aldosterone antagonist
• Stimulates salt and H2O excretion
• Acts as an endogenous diuretic
Reabsorption of Na+ and Secretion of K+
• In DCT, K+ and H+ secreted in response to potential difference
produced by reabsorption of Na+
– High concentration of H+ may therefore decrease K+ secretion, and vice versa
Renal Acid-Base Regulation
• Kidneys help regulate blood pH by excreting H+ and/or
reabsorbing HCO3-
• Most H+ secretion occurs across walls of PCT in exchange
for Na+ (Na+/H+ antiporter)
• Normal urine is slightly acidic (pH 5 – 7) because kidneys
reabsorb almost all HCO3- and excrete H+
Reabsorption of HCO3- in PCT
• Indirect because apical membranes of PCT cells are
impermeable to HCO3-
• When urine is acidic, bicarbonate combines with H+ to
form carbonic acid
• Carbonic acid in filtrate is converted to carbon dioxide and
water in a reaction catalyzed by carbonic anhydrase (CA)
– located in apical cell membrane of PCT in contact with filtrate
Reabsorption of HCO3- in PCT
• When urine is acidic, HCO3- combines with H+ to form H2CO3
(catalyzed by CA on apical membrane of PCT cells)
• H2CO3 dissociates into CO2 + H2O
• CO2 diffuses into PCT cells and forms H2CO3 (catalyzed by CA)
• H2CO3 splits into HCO3- and H+ ; HCO3- diffuses into blood
Urinary Buffers
• Nephron cannot produce urine with pH < 4.5
• Excretes more H+ by buffering H+s with HPO4-2 or NH3
before excretion
• Phosphate enters tubule during filtration
• Ammonia produced in tubule by deaminating amino acids
• Buffering reactions
–HPO4-2 + H+ H2PO4-
–NH3 + H+ NH4+ (ammonium ion)
Diuretics
• Used to lower blood volume due to hypertension, congestive
heart failure, or edema
– Increase volume of urine by increasing proportion of glomerular
filtrate that is excreted
• Loop diuretics – most powerful
– inhibits active transport of salt in thick ascending limb of LH
• Thiazide diuretics – inhibit NaCl reabsorption in first part of DCT
• Carbonic anhydrase inhibitors – prevent H2O reabsorption in PCT
when HCOs- is reabsorbed
• Osmotic diuretics – increase osmotic pressure of filtrate
Sites of Action of Clinical Diuretics
Renal Function Tests and Kidney Disease
• Renal plasma clearance of PAH – measures total
blood flow to the kidneys
• Measurement of GFR by inulin clearance
• Plasma creatinine concentration provides index of
renal function
• Urinary albumin excretion rate – commonly
performed test
– Detect slightly higher than normal excretion rate of
albumin (microalbuminuria)
– First manifestation of renal damage caused by diabetes or
hypertension
Kidney Diseases
• Acute renal failure – impaired ability of kidneys to excrete
wastes and regulate blood volume, pH, and electrolytes
– Rise in blood creatinine and decrease in renal plasma clearance
of creatinine
– Can result from atherosclerosis, inflammation of tubules, kidney
ischemia, or overuse of NSAIDs
• Glomerulonephritis – inflammation of glomeruli
– Autoimmune attack against glomerular capillary basement
membranes
• Causes leakage of protein into urine resulting in decreased colloid
osmotic pressure and resulting edema
Kidney Diseases
• Renal insufficiency – nephrons have been destroyed as a
result of a disease (diabetes mellitus)
– Clinical manifestations include salt and H2O retention and
uremia (high plasma urea levels)
• Uremia accompanied by high plasma H+ and K+ which can cause
uremic coma
– Treatment includes hemodialysis
• Patient's blood passed through a dialysis machine – separates
molecules on basis of ability to diffuse through selectively
permeable membrane
• Urea and other wastes are removed
Kidney Diseases
• Diabetes insipidus – may be caused by:
– Drinking too much water (polydipsia)
– Inadequate secretion of ADH (central diabetes insipidus)
– Inadequate ADH action due to genetic defect in ADH
receptors or aquaporins (nephrogenic diabetes insipidus)
• Without adequate ADH (secretion or action) the
collecting ducts are not very permeable to H2O
– Why would this cause a problem?
The Kidneys and CHF
• Congestive Heart Failure – inability of the heart to
deliver an adequate blood flow (CO is low)
– Body becomes congested with fluid
– Due to heart disease or hypertension
– Associated with breathlessness, salt and water retention,
and edema
• How are the kidneys affected?
• What is the role of the kidneys in CHF?