Physiology
Renal System
Behrouz Mahmoudi
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KIDNEY FUNCTIONS
MAINTAINING OF HOMEOSTASIS
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maintain the blood volume and the normal composition of body fluid
compartments
excrete waste products ( urea, creatinine, uric acid, NH₃(ammonia), which
are toxic for the organism
regulate the blood concentration of ions ( Na+, K +, Cl, Ca++, sulphate,
phosphate, bicarbonate)
maintain the pH by secreting the H +
maintain the osmolarity and water volume via the capacity to adjust the
water reabsorption
regulate arterial blood pressure
gluconeogenesis
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KIDNEY FUNCTIONS
ENDOCRINE ROLE
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synthesis of erythropoetin - sensory cells at the proximal
convoluted tubules (PCT), which respond to changes in the partial
pressure of oxygen (pO2)
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role in metabolism of vitamin D and Calcium
- active vitamin D needed to reabsorb Ca²+ in small intestine
- to activate vitamin D: an additional hydroxyl group is added
=> 1.25 dihydroxycholecalciferol
- Vitamine D pathway:
1. 7-dehydrocholesterol under the action of UV rays becomes
colecalcipherol or vit. D3 ( in skin)
2. Vit. D3 in liver becomes 25 OH D3 and then in kidneys 1,25 (OH)2
D3 or calcitriol → increase Ca absorption in the intestin
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KIDNEY FUNCTIONS
ENDOCRINE ROLE
RENIN- ANGIOTENSIN- ALDOSTERON SYSTEM (RAAS)
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juxtaglomerular cells (in the wall of the afferent arteriole) synthesize the
enzyme RENIN, a glycoprotein with 42000 D , that catalyses the
transformation of angiotensinogen (from liver) into angiotensin I.
Angiotensin I is transformed into Angiotensin II ( reaction catalyses by
angiotensin converting enzyme – in the lungs)
Angiotensin II causes vasoconstriction (especially in the skin, abdominal
organs, kidney (acts on efferent arterioles); less in brain, muscles, heart
Angiotensin II stimulates ALDOSTERONE secretion (in adrenal gland)
Renin is released in case of: renal ischemia (decrease of blood supply to the
kidney), decreased blood volume ( due to bleeding, dehydration),
hypotension (low blood pressure (BP), cardiac failure
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KIDNEY FUNCTIONS
ENDOCRINE ROLE
• Release prostaglandins E₂(Pg E₂), Pg F2 alpha and Pg I
(Prostacyclin)- they act more in a paracrine manner
- Pg E₂in hypertensive people :
- decrease the blood pressure
- increase : - renal blood flow and diuresis (volume
of excreted urine/day)
- natriuresis (amount of Na excreted via
urine/day)
- Pg F2 alpha => vasoconstriction
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STRUCTURE OF THE URINARY SYSTEM
The renal apparatus:
1) kidneys (produce urine)
2) urinary excretory pathways
• ureters
• urinary bladder (it accumulates and stores
urine between 2 micturitions)
• urethra
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STRUCTURE OF THE KIDNEY
• NEPHRON is the morphological and functional
unit of the kidney
- there are 1-1.2 millions of nephrons per kidney
- it is made up of : 1) renal corpuscle and 2) tubule
1) Renal corpuscle or Malpighian corpuscle/body
• Diameter of 200 μm
• It is placed in the cortex of the kidney
• It consists of : a) Capillary tuft (aprox. 50 capillaries) or glomerulus
b) Bowman’s capsule
• Role - at its level the process of plasma filtration
(glomerular filtration) takes place => primary
urine
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2) Tubule - 45 - 65 mm
For reabsorption and secretion processes
• a) Proximal convoluted tubule (PCT)
o length: 14-12 mm; diameter: 55 μm
o one layer of columnar cells on a basal
membrane
o cells with brush border at the apical
pole (towards the lumen) with many
microvilli (for reabsorption- increased
surface)
o cells have invaginations at the
basolateral pole (with a striated aspect
and many mitochondria)
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b)
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Loop of Henle - like a hairpin
it has 2 limbs: ascending and descending, each with a thin and a
thick segment
15-20% of glomeruli have long loops of Henle going deep into
medulla - 26mm
Cells: cuboidal in the thick limb and squamous in the thin limb
Macula densa: at the final portion of ascending limb the
structure is modified (with bigger and fewer cells rich in
mitochondria)
- Cells with osmo- /chemoreceptors sensitive to Na and Cl
concentrations in the urine
Juxtaglomerular apparatus: macula densa and juxtamedullary
cells
When the conc. of Na or Cl in the macula densa decreases =>
takes place the release of renin from juxtaglomerular cells
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c) Distal convoluted tubule (DCT)
o length: 5-8 mm; diameter: 30-40 μm
o only a few microvilli, but without a brush border
o several distal tubule together become 1 collecting
duct (CD), which crosses the cortex and medulla, opens
into the renal pelvis and continues into the ureters
d) Collecting duct (CD)
o across the cortex and the medulla of the kidney
o concentrates urine
o reabsorption of H2O under the influence of ADH
o collection of urine from 3000-5000 nephrons/CD
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VASCULARIZATION OF THE KIDNEY
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2 networks of
capillaries
from the
efferent
arterioles
1) peritubular
capillaries
(collected by
interlobular
veins)
2) vasa recta
(around the
tubules of the
juxtamedullar
y nephrons)
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JUXTAGLOMERULAR APPARATUS
Juxtaglomerular apparatus is located in the hillum of every
glomerulus
• It is made up of juxtaglomerular cells and the macula densa • cells of the juxtaglomerular apparatus act as baroreceptors sensing
changes in BP (cells are stimulated by distension of the afferent
arteriole; if not distended - release of RENIN)
• Low BP (wall of Af. A. is not distended) => Renin secretion =>
Angiotensin II => increase reabsorption of Na and water =>
increase BP
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RENAL CIRCULATION AND ITS REGULATION
• Renal circulation has the capacity of
autoregulation
• It is an intrinsec property of the kidney => it is
observed even on isolated, denervated kidney
• It is necessary for maintaining a constant GFR
and excretion of water and waste products
• BP = 80 –180 mmHg => a constant GFR and
RBF ( renal blood flow) are maintained
• It prevents the high variation of water and
solutes excretion together with the increase
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AUTOREGULATION OF THE RENAL CIRCULATION
1) Tubuloglomerular feedback mechanism
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The increase in BP => increase in GFR => increased NaCl delivery to the
macula densa => increased NaCl reabsorption by macula densa cells =>
constriction of afferent arteriole results
Vasoconstriction can be mediated by : Nitric oxide (NO) , adenosine, ATP
=> Renal blood flow (RBF), GFR are lowered to a more normal value.
The tubuloglomerular feedback mechanism = a negative-feedback
system that stabilizes RBF and GFR.
Tubuloglomerular feedback mechanism controls the amount of Na
presented to distal nephron segments, because these segments have a
limited capacity to reabsorb Na.
Renal autoregulation minimizes the impact of changes in arterial
blood pressure on Na excretion.
Decreased macula densa sodium chloride causes dilation of afferent
arterioles and increased Renin release
Without renal autoregulation, increases in arterial blood pressure =>
increases in GFR and losses of NaCl and water from the ECF.
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THE TUBULOGLOMERULAR FEEDBACK MECHANISM
(after
R.Rhoades & G.Tanner, Medical Physiology, 2003)
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GLOMERULAR FILTRATION
• First step in urine formation (reabsorption and secretion
follow)
• 25% of the plasmatic renal flow are filtered in the
Bowman’s capsule (primary urine)
• in resting condition, the tow kidneys receive 1.2-1.3 L/min of
blood (=25% of the cardiac output); of this 25% is
filtered (only H2O, micromolecules, small proteins, no
blood cells or substances bound by plasma proteins)
• Primary urine: 180 L/day, with a similar composition as
plasma
• Final urine: 1.0 – 1.5 L/day, with a composition
modified by reabsorption and secretion
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GLOMERULAR FILTRATION MEMBRANE
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Anatomical support for glomerular filtration. Structure (3 layers):
a) Endothelial cells of capillaries - the glomerular capillaries are fenestrated, with
holes of 40-100nm in diameter. The endothelial cell surface and the holes are covered
with a glycoprotein coat (glycocalyx), about 12 nm thick and with a negative electrical
charge
b) Basement membrane has 3 layers;
1. Internal lamina rara
2. Lamina densa (more dense middle layer)
3. External lamina rara
It is made up of proteoglycans and collagen fibers, with large spaces through which
water and micromolecules can pass. Thickness: 310-340nm
c) The epithelial cells of Bowman’s capsule are named podocytes with many footlike
extensions. Podocytes are fixed on the external lamina rara by pedicels. Between the
pedicels there is a thin membrane of 4-6 nm in thickness, named slit membrane.
- Pores of the slit membrane: 20-30 nm
- The surface of the podocytes and slit membrane is covered with glycocalyx. Due to
the negative electrical charge, proteins are repelled and their passage into the urine is
prevented. This process can be disturbed in many renal diseases (albumin can pass into
the urine => albuminuria)
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GLOMERULUS AND BOWMAN`S CAPSULE ( after A.Despopoulos & S.Silbernagl,
Color Atlas of Physiology, 2003)
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Permeability of the membrane
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Molecules bigger than albumin (69000 D) are stopped by slit membrane
- Plasma albumin: 0.2% passes into urine
- Haemoglobin: 5% passes into urine (less negatively charged than albumin)
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The smaller and more positively charged the particles are, the easier they
can pass through the filtration membrane
Substances with MW < 10000 D can be filtered
Substances bound by plasma proteins ( Ca 2+, free fatty acids) are not filtered
Glomerulonephritis - proteins can pass due to altered permeability (modified
glycocalyx amount/structure) => albuminuria
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REGULATION OF GFR and RBF
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GFR is influenced by : 1) sympathetic nervous sytem
2) hormones
3) autacoids
1) Sympathetic nervous system (SNS)
Afferent and less efferent arterioles receive
sympathetic fibers
- Strong stimulation of SNS => constriction of
afferent A. => decreases RBF => decreases GFR
- Moderate stim. of SNS => little influence of GFR
- Its role is more important in : bleeding, shock,
ischemia and less in normal conditions
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REGULATION OF GFR and RBF
2) Hormones
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Norepinephrine, Epinephrine constrict renal blood vessels
(afferent and efferent A.) and decrease GFR; are released from
adrenal medulla. Normally they have little influence on renal blood
flow, except some acute conditions (bleeding)
Angiotensin II constricts afferent arteriole; its formation increases
in circumstances associated with decreased arterial pressure or
volume depletion, which tend to decrease GFR.
The increased level of angiotensin II => constriction of efferent
arterioles => increases GFR => maintains normal excretion of
metabolic waste products ( urea and creatinine) that depends on
GFR for their excretion
Angiotensin II, by stimulating the secretion of Aldosteron =>
increases tubular reabsorption of sodium and water => restores
blood volume and blood pressure
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REGULATION OF GFR and RBF
3) Autacoids
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Endotelin - produces vasoconstriction of renal blood vessels
- increases in toxemia of pregnancy, acute renal failure, and chronic
uremia => decreases GFR
Endothelial-Derived Nitric Oxide (NO)
- decreases renal vascular resistance and increases GFR
- it is important for maintaining vasodilation of the kidneys
- administration of drugs that inhibit this normal formation of NO =>
increases renal vascular resistance and decreases GFR and urinary
sodium excretion => high BP
Prostaglandins (PGE2 and PGI2) and Bradykinin => Increase GFR
-Prostaglandins may help prevent excessive reductions in GFR and
renal blood flow under stresfull conditions: volume depletion or after
surgery
- the administration of nonsteroidal anti-inflammatory agents
(Aspirin), that inhibit prostaglandin synthesis => reduction in GFR
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TUBULAR REABSORPTION
• During the passage of filtrate through the renal
tubule => its composition is changed
• Substances move from the tubule to the
peritubular capillaries = tubular reabsorption and
• from peritubular capillaries to the tubular lumen =
tubular secretion
• Tubular reabsorption by :
- passive transport
- active transport
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TUBULAR REABSORPTION OF AMINO ACIDS AND PROTEINS
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Amino acids (Aa) are reabsorbed at the level of PCT. Daily 70 g of Aa are filtered .
It is similar to glucose reabsorption (Na coupled secondary active transport)
Almost complete reabsorption (maximum 1-2% excreted into the urine)
There are described several transport systems/ carriers:
1. transport of neutral amino acids (diaminic Aa)
2. transport of proline and hydroxyproline
3. transport of β-amino acids
4. transport of diaminic Aa (arginin, lysine) and dicarboxylic Aa (aspartic acid, glutamic acid)
Defects in reabs. of some Aa => cystinuria (L-cystine, L-arginine and L-lysine are
hyperexcreted) => urinary calculus
Proteins- especially albumin, but also lyzozyme, alpha 1-microglobulin, beta 2-microglobulin
are filtered
- reabsorption - by receptor mediated endocytosis. Proteins are digested by lysosomes inside
the cells of the renal proximal tubule, split into aminoacids, which are reabsorpted
- this type of reabsorption is nearly saturated at normal filtered loads of proteins => an
elevated plasma protein conc. or increased protein sieving coefficient => proteinuria
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REABSORPTION OF OLIGOPEPTIDES AND PROTEINS
(after A.Despopoulos & S.Silbernagl, Color Atlas of Physiology, 2003)
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TUBULAR REABSORPTION OF UREA AND URIC ACID
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UREA - daily formed: 25-30g (waste product of protein metabolism)
30-90% reabsorbed (according to diuresis and density of urine)
At PCT: 60-65% of water reabsorbed (isoosmotic reabsorption) => urea
concentration gradient is obtained
daily filtered: 54g of urea => daily reabsorbed: 30g
Urea reabsorption occurs also at the DCT and CD under ADH action
URIC ACID
It is both reabs. and secreted in PCT
waste product of nucleoprotein catabolism
daily excreted - 10% of filtrated uric acid = 1g/day
alkaline pH => uric acid from urine found as salts (urate - Na urate, K urate)
acidic pH => uric acid found as acid (uric acid) => stones formed
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TUBULAR REABSORPTION OF BICARBONATE
• Not reabsorbed as HCO₃(bicarbonate),
because in the presence of H: HCO₃+ H =>
H2CO₃ and H₂CO₃ => H₂O + CO₂
• CO₂ diffuses from the blood into tubular cells
• Acidosis: entire filtered HCO₃is reabsorbed
(under acid-base-balance only 99%)
• Alkalosis: more HCO₃excreted, less reabsorbed
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TUBULAR REABSORPTION OF BICARBONATE (after
R.Rhoades & G.Tanner, Medical Physiology, 2003)
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TUBULAR SECRETION OF AMMONIA
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60% from plasmatic glutamine
In tubular cells - glutaminase catalyses glutamine => glutamic acid + NH₃
Glutamine dehydrogenase catalyses glutamic acid => α-acetoglutamic acid
α-acetoglutamic acid is transformed into NH₄(ammonium)
- 40% from other Amino acids (alanine, leucine, lysine, aspartic acid)
- NH₃is liposoluble (diffuses from tubular cells)
- NH₃ + H => NH₄ (in tubular cells)
NH₄ is hydrosoluble and can’t pass back (remains in urine)
NH₄ + Cl => NH₄Cl
Chronic acidosis: NH₃synthesis increases 10 times within 3-5 days (increases
glutaminase activity, even before urine pH changes)
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RENAL SYNTHESIS AND EXCRETION OF AMMONIA (after R.Rhoades &
G.Tanner, Medical Physiology, 2003)
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WATER REABSORPTION IN THE COLLECTING TUBULE
• H₂O reabsorption under action of ADH (activates
aquaporins)
• ADH produced by the hypothalamus
• Stored in the posterior pituitary gland
• Realeased under certain conditions (if increased
blood osmolarity, decrease blood volume)
• Absence of ADH: 12% of filtered H₂O is excreted
(>20L/day) e.g. in diabetes insipidus
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ACTION OF ADH IN THE COLLECTING DUCT (after R.Rhoades &
G.Tanner, Medical Physiology, 2003)
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WATERY AND OSMOTIC DIURESIS
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Watery diuresis
Low osmolarity urine
After ingestion of hypotonic solutions
Diabetes insipidus (with normoglycemia)
ADH secretion is reduced
Experiment: ADH administration and normal fluid intake to animals =>
intoxication with H₂O can occur (=>death)
Osmotic diuresis
If substances in urine cannot be reabsorbed and keep H₂O from being
reabsorbed => increased diuresis and osmolarity of urine
Manitol- a polysaccharide filtered but not reabsorbed => increases
the volume and the osmolarity of urine
Glucose (diabetes mellitus) >180mg% => increased volume and
osmolarity of urine
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Ureters
2 tubes with a smooth muscle layer
derived from the renal pelvis
open into the urinary bladder via the 2
posterior corners of the trigone
• oblique route/orientation into the
bladder wall impedes reflux of urine into the
ureters
• muscular layer in the wall of the ureters
has rhythmical contractions/ peristaltic waves
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· push urine into urinary bladder
Distension of ureters => increased frequency of contractions
Ureter continues its activity even if when it is taken off from the
organism. It has automatism (have pace maker cells, can work without
innervation). The pace maker is placed next to the pelvis
Even if they can work without innervation, ureters have a rich
sympathetic and parasympathetic innervation
Stimulation of sympathetic nerves => inhibition of contractions
Stimulation of parasympathetic nerves => stimulation of contractions
Stones inside of ureters can produce pain. Pain/Algic impulses induces a
uretero-renal reflex, followed by constriction of renal arterioles, decrease or
blocking of urine production, by which it is prevent the excessive accumulation
of urine in the blocked ureter
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URINARY BLADDER
It is a muscular, cavitary organ
2 parts: body and neck (continuous with the urethra)
Trigone- triangle at the posterior wall with the openings of the ureters at the
superior corners and more anterior opening of the urethra
Continuous with the urethra ; in female: 4 - 5cm (increased frequency of urinary
tract infections), in men: 20cm
At 2 cm under the neck of the bladder, the urethra passes through the urogenital
diaphragm, which forms the external urethral sphincter. It is made up of striated
muscle fibers.
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Bladder has autonomic and somatic innervation
1) Sympathetic innervation
- derive from the lateral horn of the L2 segment of the spinal cord
- pass trough paravertebral ganglia chain (mesenteric and celiac ganglia)
- form a plexus next to the bladder from where hypogastric nerves (right and left)
innervate the bladder (especially the body
2) Parasympathetic innervation
derives from S2-S4 segments of spinal cord
fibers enter the pelvic nerve to the bladder (body and neck)
3) Somatic innervation
for the external urethral sphincter (with striated fibers)
derived from the anterior horns of S2-S4 segments of the spinal cord
belong to the pudendal nerve
afferent signals- nociceptive/pain signals via sympathetic fibers (hypogastric nerve)
are transmitted to the spinal cord; touch and stretch signals via parasympathetic fibers
(pelvic nerve)
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INNERVATION OF THE URINARY BLADDER (after R.Rhoades &
G.Tanner, Medical Physiology, 2003)
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FILLING OF THE URINARY BLADDER
• within certain limits, the storage of urine in the bladder is not
associated with a significant increase of pressure inside the bladder
• the graph/plot of intravesical (inside of bladder) pressure related to
volume is named cystogram
• accumulation of urine up to 400ml with a slight increase in pressure until 10 cm H2O
• accumulation of urine in the bladder above 400ml with a high
pressure increase => strong urge to urinate
• at a volume of 150ml inside the bladder => first desire to urinate
• constant pressure between 100-400 ml is due to intrinsic muscle
properties of the bladder, based on Laplace`s law : P = 2T/R
• law of Laplace: (increased distension => increased pressure)
• filling of the bladder increases the radius of the cavity and at the
same time the wall tension, without changing the pressure.
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MICTURITION REFLEX
• Micturition- process by which urine is excreted (diuresis- volume of
urine excreted daily)
• Initiated by stimulation of mechanoreceptors (distension of bladder
wall)
• Stimulus (increased pressure) -> stimulates mechanoreceptors->
sensitive fibers (pelvic nerve, parasympathetic) -> center at the spinal
cord, segments S2-S4 -> efferent fibers (pelvic nerve, parasympathetic)
• Nervous impulses are also transmitted through the ascending pathways
to the brain stem, hypothalamus and cortex.
• If the neurons of the medullary center are not inhibited by superior
centers they cause contraction of the detrusor muscle => urine is
pushed into the posterior urethra
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MICTURITION REFLEX
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This stimulates receptors in the posterior urethra => transmission of inhibitory signals to the
anterior horns of the spinal cord (via the pelvic nerve) => inhibition of the pudendal nerve =>
relaxation of the external urethral sphincter => micturition
Also supported by contractions of abdominal muscles
After initiation of micturition the reflex is self-mantaining
Initial contraction of the bladder stimulates mechanoreceptors => generation of intense impulses =>
stronger contractions
Remaining urine can be a risk factor for infections (may be due to disfunctions, prostate
hypertrophy)
Also increased pressure can cause retrograde movement of urine => impedes filtration => (hydro-)
nephrosis (edema of kidney)
Via medullary centers for the micturition reflex (under control of the superior centers) one can stop
micturition voluntarily
Up to the 18th month: micturition is a medullary reflex only
After 2 years: cortical control of micturition (development of the pyramidal tract, which is
completely myelinated at 2 years)
Adults have the capacity to maintain the extearnal sphincter contracted until the environmental
conditions allow the urination. When the intravesical urinary volume is more than 700 mL, the
micturition becomes painful and imperious.
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