RENAL PHYSIOLOGY

By

DR KATONGOLE JOHN.
URINARY TRACT SYSTEM
..\LECTURE VIDEOS\Renal video\Medical Videos Urinary system The
nephron - YouTube.flv

Kidney

Ureter

Bladde
r
Urethra
CONTENTS
• Kidney functions
• Functional anatomy of the kidney
• Vascularization and blood flow to the kidney
• Urine formation
• Glomerular functions
• Tubular functions
• Medullary interstitial Osmolality Gradient: Counter-current mech.
• Auto-regulation of renal circulation
• Estimation of GFR and Renal Clearance
• Micturition
• Urinalysis
• References
KIDNEY FUNCTIONS

1. MAINTAINING OF HOMEOSTASIS

• maintains the blood volume and the normal composition of body

fluid compartments
• excretes waste products ( urea, creatinine, uric acid,
NH₃(ammonia), which are toxic for the organism
• regulates the blood concentration of electrolytes ( Na+, K +, Cl,
Ca++, sulphate, phosphate, bicarbonate)
• maintains the pH by secreting the H + : Acid-base balance
• maintains the osmolarity and water volume via the capacity to
adjust the water reabsorption
• regulates arterial blood pressure; RAAS mech.
• gluconeogenesis
2 Heamopoietic functions

• Secretes erythropoietin- RBC production

• Secretes thrombopoietin- thrombocytes production

KIDNEY FUNCTIONS

3. ENDOCRINE ROLE
• synthesis of erythropoetin - sensory cells at the proximal
convoluted tubules (PCT), which respond to changes in the
partial pressure of oxygen (pO2)
• 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
cholecalcipherol 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
KIDNEY FUNCTIONS

ENDOCRINE ROLE CONT’D

RENIN- ANGIOTENSIN- ALDOSTERON SYSTEM (RAAS)

• 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
RENIN ANGIOTENSIN SYSTEM (after R.Rhoades & G.Tanner, Medical
Physiology, 2003)
Schematic diagram of RAAS
KIDNEY FUNCTIONS

ENDOCRINE ROLE CONT’D

• 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
FUNCTIONAL ANATOMY OF THE URINARY SYSTEM
..\LECTURE VIDEOS\Renal video\A Journey Through the Nephron - YouTube.flv
The renal apparatus:
1) kidneys (produce urine)
2) urinary excretory pathways
• ureters
• urinary bladder (it accumulates and stores urine between 2
micturitions)
• urethra
STRUCTURE OF NEPHRON

DCT

PCT

BC
Gl
Efferent
Afferent

TDLH

TALH

CD

LH
FUNCTIONAL UNIT 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
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)
b) 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
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
STRUCTURE OF THE KIDNEY (after A.Despopoulos & S.Silbernagl , Color
Atlas of Physiology, 2003)
VASCULARIZATION OF THE KIDNEY

• By the renal artery (directly from the abdominal aorta)

-> interlobar arteries (terminal arteries, without
anastamosis; in case of an obstruction => necrosis of
that territory results) -> arcuate arteries -> interlobular
arteries -> afferent arterioles (enter the glomerolus) ->
capillary tuft (50) -> efferent arterioles-> peritubular
capillaries (loop around the tubules) -> interlobular
veins -> arcuate veins -> interlobar veins -> renal vein ->
inferior vena cava
• 2 networks of capillaries from the efferent arterioles
1) peritubular capillaries (collected by interlobular
veins)
2) vasa recta (around the tubules of the
juxtamedullary nephrons)
JUXTAGLOMERULAR APPARATUS

Juxtaglomerular apparatus is located in the hillum of every

glomerulus
• It is made up of juxtaglomerular cells and the macula densa
• Modified muscular layer in the structure of afferent and efferent
arterioles:
- increased number of smooth muscle cells of afferent
arterioles (Af. A) as long as the arteriole comes closer to the
glomerulus
- cells become thicker (with less actin/myosin filaments, but
with many granules containing RENIN)
- 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
JUXTAGLOMERULAR APPARATUS (after Vander et al., Human
Physiology: The mechanisms of body function, 2001)
RENAL BLOOD FLOW
• In an average 70-kilogram man, the combined
blood flow through both kidneys is about 1100
ml/min; 22% CO
• A large fraction of the oxygen consumed by the
kidneys is related to the high rate of active
sodium reabsorption by the renal tubules
• Renal blood flow is determined by the pressure
gradient across the renal vasculature divided
by the total renal vascular resistance:
 URINE FORMATION
- Urine formation begins with the filtration of plasma from
the glomerular capillaries into Bowman’s space; Glomerular
filtration
-flows sequentially through the successive parts of the
tubule-the proximal tubule, the loop of Henle, the distal
tubule, the collecting tubule, and the collecting duct-before
it is excreted as urine
-Along this course, some substances are selectively
reabsorbed from the tubules back into the blood, whereas
others are secreted from the blood into the tubular lumen.
-Basic renal processes;
•Amount excreted = Amount filtered + Amount secreted - Amount reabsorbed
•Urine excreted = Glomerular filtration + Tubular secretion – Tubular reabsorption
GLOMERULAR FUNCTIONS

• Glomerular filtration

• Glomerular membrane

• Factors influencing GR

• Regulation of GFR
 GLOMERULAR FILTRATION
Glomerular filtration is the process by which the blood
is filtered while passing through the glomerular
capillaries by filtration membrane.
•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 two kidneys receive 1.2-1.3 L/
min of blood (=22% 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
GLOMERULAR FILTRATION MEMBRANE

• 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
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 basement
membrane 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)
GLOMERULUS AND BOWMAN`S CAPSULE ( after A.Despopoulos & S.
Silbernagl, Color Atlas of Physiology, 2003)
FACTORS INFLUENCING GLOMERULAR FILTRATION (GF)

1) Permeability of the membrane

• Some substances have been used for studies of glomerular filtration
membrane permeability :
- anionic ferritin - 6.1 nm in diameter, negative electrical charge; it cannot pass
through the basement membrane
- cationic ferritin passes easier than anionic ferritin, but it is stopped by slit
membrane and podocytes
- colloidal gold
- dextrans (colloid substances used in perfusions to recover BV)
• 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)
• 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
FACTORS INFLUENCING GLOMERULAR FILTRATION

2) Surface area of filtration

• for the two kidneys is 1.2-1.5 m²
• active surface area depends on the number of working
nephrons (in humans all nephrons work all the time)
• decreased filtration surface/rate:
- when mesangial cells among the capillaries of the
glomerolus contract (by Angiotensin II and Thromboxan A₂)
- when podocytes are relaxed /flattened they cover more
of filtration surface
- in many renal diseases reduce the filtration surface
(nephrons are destroyed)
FACTORS INFLUENCING GLOMERULAR FILTRATION

3) Effective filtration pressure (Net Filtration Pressure)

The volume of filtered plasma depends on the difference between the hydrostatic
pressure and the colloid osmotic pressure of the blood and Bowman’s capsule
Pressure of filtration = hydrostatic pressure of the blood (HPB) – hydrostatic pressure of
Bowman’s capsule (HPBC) – colloidosmotic pressure of blood (CPB)
Filtration pressure = 45mmHg (HPB)- 10mmHg (HPBC)- 25mmHg (CPB) = 10mmHg
Hydrostatic pressure decreases with only 1-2 mmHg throught the length of capilllaries
but colloid osmotic pressure increases significantly
• Variations
- Glomerular filtration => variation if BP changes between 80-180mmHg
- Shock/collapse => glomerular filtration decreases (vasoconstriction at the
afferent and efferent arterioles). GF stops when BP < 40-50mmHg
- Vasoconstriction of the afferent arterioles => decreased glomerular filtration
CATECHOLAMINES etc.); at efferent arterioles => increased gomerular filtration
(by CATECHOLAMINES,
(by ANGIOTENSIN II,
II etc.)
- Increased hydrostatic pressure in Bowman’s capsule => impeded filtration
(stones, tumors, edema in the renal parenchyma)
- Colloidosmotic pressure
Decreased => increased filtration (hypoproteinemia)
Increased => decreased filtration (hyperproteinemia)
• GLOMERULAR FITRATION RATE
Glomerular filtration rate (GFR): is defined as the total quantity of filtrate formed
in all the nephrons of both the kidneys in the given unit of time.
Normal GFR is 125 mL/minute or about 180 L/day.
- It is the volume of fluid filtered from the glomeruli into Bowman’s space per
unit time.
Filtration fraction: is the fraction (portion) of the renal plasma, which
becomes the filtrate. It is the ratio between renal plasma flow and
glomerular filtration rate.
It is expressed in percentage.

Net filtration pressure: is the balance between pressure favoring filtration and
pressures opposing filtration. It is otherwise known as effective filtration
pressure or essential filtration pressure
Pressure of filtration = hydrostatic pressure of the blood (HPB) – hydrostatic pressure of
Bowman’s capsule (HPBC) – colloidosmotic pressure of blood (CPB)
Filtration pressure = 45mmHg (HPB)- 10mmHg (HPBC)- 25mmHg (CPB) = 10mmHg
REGULATION OF GFR and RBF

• 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
REGULATION OF GFR and RBF

2) Hormones
• Norepinephrine, Epinephrine constrict renal blood vessels
(afferent and efferent A.) and decrease GFR. 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
REGULATION OF GFR and RBF

3) Autacoids
• Endothelin - 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
Prostaglandins (PGE2 and PGI2) and Bradykinin => Increase
ncrease GFR
-Prostaglandins may help prevent excessive reductions in GFR and
renal blood flow under stressfull conditions: volume depletion or after
surgery
- the administration of nonsteroidal anti-inflammatory agents
(Aspirin), that inhibit prostaglandin synthesis => reduction in GFR
DIAGRAMMATIC REPRESENTATION OF TUBULAR EPITHELIUM

Tubular Basolater
Epithelia al
Tubular cell membran

yr a l l i p a C
r al ub utire P
Lumen e

Laminar
membrane

Tight junction

Interstitial fluid
TUBULAR FUNCTIONS

• Tubular reabsorption of;

• Glucose
• Amino acids and protein
• Urea and uric acid
• Sodium and its control
• Calcium
• Chlorine
• Bicarbonate
Tubular Secretion of;
Hydrogen
Ammonia
Potassium
TUBULAR FUNCTIONS

• 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
TUBULAR REABSORPTION OF GLUCOSE

• It takes place at the level of proximal tubules (PCT)

• 98% of filtered glucose is reabsorbed at PCT (cca.100g/day)
GFR: 125mL/min, normal glycemia: 80-120mg% => Glucose filtered/min: 125mg/min
(filtered load)
• The reabsorbed amount of glucose depends on the amount of filtered glucose and the
capacity to transport glucose
• Glucose transport capacity has a maximum = 375mg/min in males and 300mg/min in
females
• If maximum limit is exceeded => glucosuria (glucose excreted into the urine)
• Glucose threshold = glucose plasma concentration at which the maximum capacity of
reabsorption is exceeded and glucosuria occurs ; It is 180mg% for venous blood and
200mg% for arterial blood
Not all nephrons have the same filtration and reabsorption capacity
• Reabsorption - by symport with Na - at the apical membrane of tubular cells (secondary
active transport , mediated by SGLT 1). Glucose diffuses to the interstitial space (by GLT
2) and Na is pumped to the interstitial space (via Na-K-ATPase). Galactose and fructose
are competitors for the glucose-symport
• Renal diabetes - glucose reabsorption is reduced/ impeded ( normoglycemia with
glucosuria)
• Diabetes mellitus -with an overwhelmed glucose reabsorption capacity (hyperglycemia
with glucosuria)
REABSORPTION OF GLUCOSE AND OTHER ORGANIC SUBSTANCES (after A.
Despopoulos & S.Silbernagl, Color Atlas of Physiology, 2003)
TUBULAR REABSORPTION OF AMINO ACIDS AND PROTEINS

• 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 (free) albumin, 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
REABSORPTION OF OLIGOPEPTIDES AND PROTEINS
(after A.Despopoulos & S.Silbernagl, Color Atlas of Physiology, 2003)
TUBULAR REABSORPTION OF UREA AND URIC ACID

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
• if urinary flow > 2mL/min => 60-70% of urea is reabsorbed
• Urea reabsorption occurs also at the DCT and CD under ADH action
URIC ACID
• Plasma conc. = 3 –7 mg%
• 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
• pH measurement if there is a kidney stone suspicion
REABSORPTION OF UREA (after R.Rhoades & G.Tanner, Medical Physiology,
2003)
TUBULAR REABSORPTION OF SODIUM

• 1kg NaCl is filtered daily

• all the segments of the nephron participate in Na reabsorption (except
the descending limb of the loop of Henle)
• Na reabsorption by diffusion ( along an electrochemical gradient), by
symport with glucose and counter transport with H
• from cells Na is pumped into the interstitial space (via Na-K-ATPase)
• if Na-K-ATPase is blocked by Oubaine => Na reabsorption in the PCT is
reduced by 50%
• Na ions accumulate in the interstitial space => hyperosmotic environment
which attracts H2O to the interstitial space by osmosis (cells at the PCT
are permeable to H2O without hormonal intervention -ADH)
Cl anions follow Na movement
• 65% of filtered Na is reabsorbed at the PCT (along with diffusion of H₂O
from the interstitial space to the vessel)
• 25% of filtered Na is reabsorbed at the ascending limb of the loop of
Henle
• 8-10% of filtered Na is reabsorbed at the DCT and CD
CONTROL OF SODIUM REABSORPTION

• Na - the main cation of extracellular fluid

• It produces 90% of the osmotic pressure of the extracellular fluid
compartment
• Na concentration regulation => gives extracellular fluid volume
• Na intake is variable - 8-10g/day
• Renal excretion of Na is regulated by :
- ALDOSTERONE - mineralocorticoid hormone produced by the
suprarenal glands - increases Na reabsorption in exchange with K and H,
which are secreted
- CORTISOL increases Na reabsorption
- ATRIAL NATRIURETIC PEPTIDE (ANP) - secreted by atrial
myocytes; increases natriuresis (excretion of Na ) and GFR
• amount of Na reabsorbed varies proportionately with renal flow
• decreased Na or Cl concentrations at DCT stimulate macula densa cells
followed by a release of RENIN (by the juxtaglomerular apparatus), =>
stimulates the formation of ANGIOTENSIN II => stimulates the
ALDOSTERONE formation => increases the reabsorption of Na
TUBULAR REABSORPTION OF CALCIUM

• Ca is not completely filtered because a fraction of

plasma Ca is bound to proteins in blood (40%-
nonfiltrable)
• Daily are filtrated 10000mg
• 99.5% of filtered Ca is reabsorbed
• 65% reabs. in PCT, 25-30% in LH, 4-9% in DT and CT
• Parathyroid gland produces Parathormone (PTH)
• PTH increases Ca reabsorption in DCT and CD
• Acidosis (proteins bind less Ca) => increased amount
of Ca filtered => calciuria
TUBULAR REABSORBTION OF CHLORINE

• Cl is the main anion of the extracellular fluid

• Reabsorption depends to a great extend on Na
reabsorption ( Cl follows Na movement)
• At the thick ascending limb of the loop of
Henle - active Cl transport from the lumen to
the cytoplasm along with Na and K via a carrier
protein (Na-K-2Cl- transporter)
• Inhibition by diuretics e.g. FUROSEMID (inhibits
Na reabsorption)
TUBULAR REABSORPTION OF BICARBONATE
(Acid-base balance)

• Bicarbonate is completely filterable at the renal

corpuscles and undergoes tubular reabsorption in
various tubular segments (PCT, ascending loop of
Henle, and CD).
• Bicarbonate can also be secreted (in the collecting
ducts); less significant.
• Bicarbonate reabsorption is an active process,
• bicarbonate reabsorption is absolutely dependent
upon the tubular secretion of H ions,=> combine in the
lumen with filtered HCO3.
FORMATION OF NEW OF BICARBONATE

• When almost all the bicarbonate has been reabsorbed

• Extra secreted hydrogen ions combine in the lumen with a filtered
nonbicarbonate buffer, usually HPO4
• The hydrogen ion is then excreted in the urine as part of an
H2PO4
• net gain of bicarbonate by the plasma results (not merely
replacement for a filtered bicarbonate).
• Thus, when a secreted hydrogen ion combines in the lumen with
a buffer other than bicarbonate, the overall effect is not merely
one of bicarbonate conservation, but rather of addition to the
plasma of a new bicarbonate.
• This raises the bicarbonate concentration of the plasma and
alkalinizes it.
• There is other mechanism by which the tubules
contribute new bicarbonate to the plasma, one that
involves not hydrogen-ion secretion but rather the
renal production and secretion of ammonium (NH4)
• Tubular cells, mainly those of the PCT, take up
glutamine from both the glomerular filtrate and
peritubular plasma and, by a series of steps,
metabolize it.
• In the process, both NH4 and bicarbonate are formed
inside the cells. The NH4 is actively secreted (via Na/
NH4 countertransport) into the lumen and excreted,
while the bicarbonate moves into the peritubular
capillaries and constitutes new plasma bicarbonate.
TUBULAR SECRETION OF HYDROGEN
(Acid-base balance)

• Role - to maintain the normal blood pH

• Acids react first with a buffer system => neutralization
(mainly by NaHCO₃)
• E.g. by RBCs: acid + NaHCO₃ => sodium salt of acid +
H₂CO₃
• H₂CO₃ => CO₂ and H₂O
• CO₂is removed by respiration and sodium salt
removed through the urine
• With every mole of filtered urine also 1 mole of
NaHCO₃ is lost
• Kidneys secrete H ions until the urinary pH of 4.5 is
achieved
• Secretion of H in PCT, DCT and CD
TUBULAR SECRETION OF HYDROGEN

• PCT secretion via secondary active transport (antiport/

countertransport) with Na
• 1 H secreted and 1 Na + 1 HCO₃reabsorbed
At apical membrane of tubular cells
• DCT
• H secreted by active transport (without Na- H-ATPase)- H pumps
• H pumps stimulated by ALDOSTERONE (hormone produced by
the suprarenal glands; role in reabsorption of Na + H₂O and
secretion of H + K)
TUBULAR SECRETION OF HYDROGEN
• COLLECTING TUBULE
• Secretion via 2 types of cells (intercalated and principal cells):
1) Intercalated cells-
• o similar to the parietal cells of the stomach
• o rich in carbonic anhydrase (catalyses CO₂ + H₂O => H₂CO₃)
• o luminal membrane with ATPase for H secretion into urine
2) Principal
rincipal cells
production of H in the cells:
- by dissociation of H₂O
- using CO₂ as a source of H (CO₂ (by cell metabolism) -> blood-> tubular
cells where CO₂ + H₂O => H₂CO₃ => H + HCO₃(H secreted in the urine and HCO₃is
reabsorbed in the blood))
• H ions in urine react with buffer systems such as HCO₃, phosphates or NH₃to form
H₂CO₃, monobasic phosphates or NH₄
• Most H secreted in the PCT reacts with HCO₃ and flows as H₂CO₃ trough urine
H₂CO₃ => H₂O and CO₂ (which diffuses back to cells, reacts with H₂O => H₂CO₃
TUBULAR SECRETION OF HYDROGEN

• The secretion of H is 3.5 mmole/min (50 mole/day, mostly

secreted)
• Filtration of HCO₃ is 3.49 mmole/min
• 80-99% of reactions between H and HCO₃occur in the PCT
• The remaining unbuffered H combines with other buffer systems
especially with NaHPO₄ (monobasic sodium phosphate) or
Na₂HPO₄(dibasic sodium phosphate)
• If urine pH = 5, 90-96% of phosphates excreted via the urine are
present as monobasic phosphates
• Phosphate ions are the main component of the titratable acidity
of the urine
• At plasma pH = 7.4, this phosphate system is in the proportion -
1/5 basic (dibasic) and 4/5 acidic (monobasic) components
TUBULAR SECRETION OF AMMONIA
• 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)
• Acidosis => refers to any situation in which the hydrogen-ion
concentration of arterial plasma is elevated.
• Alkalosis => refers to any situation in which the hydrogen-ion
concentration of arterial plasma is reduced.
RENAL SYNTHESIS AND EXCRETION OF AMMONIA (after R.Rhoades &
G.Tanner, Medical Physiology, 2003)
TUBULAR SECRETION OF POTASSIUM
• Daily intake: 50-100 mmole
• Amount taken should be balanced with the amount excreted
• 90-95% excreted via urine, 5-10% excreted via GI tract
• Reabsorption especially at PCT (continued at the ascending limb of the loop of
Henle)
• Secretion at the DCT and CD
• Secretion takes place in 2 steps
1) Basolateral membrane
In the cells of the DCT and CD
Via a Na- K-ATPase every free K + 2 Na are reabsorbed
2) Apical membrane
• Passive mechanism due to an electrical gradient created by Na reabsorption which
favors K secretion (the more Na reabsorbed, the more K secreted)
- Secretion stimulated by ALDOSTERONE
- Competition between H and K for secretion
• Acidosis- increased H secretion
• Alkalosis- increased K secretion
• URINE CONCENTRATION FORMATION

Countercurrent multiplier system:

• Changes of urine osmotic pressure in loop of Henle.
• Osmotic gradient between cortex and medulla

Countercurrent mechanism in Vasa recta

(Medullary circulation)

Water reabsorption in the collecting duct

CHANGES OF URINE OSMOTIC PRESSURE IN THE LOOP OF HENLE

• Kidneys concentrate urine up to 1400mOsm/L

• Obligatory diuresis- 0,44 L of H₂O/day to eliminate waste products (600mOsm/day)
• Independent of fluid intake
• Desert animals can concentrate urine up to 6000mOsm/L
• Kidneys can excrete the same amount of solute either via 500ml/day at a concentration
of 1400mOsm/L or via 20L/day at concentration of 30mOsm/L
• At the PCT- H₂O is reabsorbed by osmosis (reabsorption of Na⁺ => hyperosmolarity of
interstitial space and causes H₂O to be reabsorbed => isoosmolarity (in the cortex)
• Change in osmotic pressure due to changes in the osmolarity of urine
Descending limb of the loop of Henle:
• - At the descending limb of the loop of 15% of the total H₂O reabsorbed is
reabsorbed here due to a high permeability (at the DCT- 5% reabsorbed , at the CD- 15%
reabsorbed )
• - Urine at the final portion of the descending limb is hypertonic (compared to the
interstitial space)
Ascending limb of the loop of Henle:
• - Impermeable to H₂O
• - Reabsorption of Na, K and Cl
• - Urine at the final portion of the ascending limb is hypotonic
• The opposing flows in the two limbs is termed a
countercurrent flow, as the entire loop functions as a
countercurrent multiplier system to create a hyperosmotic
medullary interstitial fluid.
• the fluid entering the descending limb of the loop from the
proximal tubule has the same osmolarity as plasma
• descending limb, does not reabsorb sodium chloride and is
highly permeable to water
• In entire length of the ascending limb, sodium and chloride
are reabsorbed into the medullary interstitial fluid.
• the ascending limb is relatively impermeable to water, so
that little water follows the salt.
• The net result is that the interstitial fluid of the medulla
becomes hyperosmotic compared to the fluid in the
ascending limb.
MECHANISMS WHICH MAINTAIN THE OSMOTIC GRADIENT BETWEEN
CORTEX AND MEDULLA

• Medulla: interstitial space is hyperosmotic (compared to the cortex which

is isoosmotic)
• Mechanism: counter-current-multiplier-mechanism at the loop of Henle
• - Primary urine is isoosmotic (altered by reabsorption and secretion later)
• - Descending limb of loop of Henle - increased permeability to H₂O, but
decreased permeability to solutes
• Hyperosmotic urine (more concentrated) + hypoosmotic interstitial
space(IS)
• Ascending limb of the loop of Henle - decreased permeability to H₂O,
increased permeability to solutes (active reabsorption of Na, Cl, K)
• Hypoosmotic urine (less concentrated) + hyperosmotic IS
• Na and Cl- reabsorbed in the same proportion as H₂O
• Na > H₂O reabsorbed => hyperosmotic IS and hypoosmotic urine
MECHANISMS WHICH MAINTAIN THE OSMOTIC GRADIENT BETWEEN
CORTEX AND MEDULLA

• Hyperosmolarity of the interstitial space maintained => most possible reabsorption of H₂O at
the CD
• Na from the ascending limb and Na from the hyperosmotic IS go to the descending limb
• The longer the loop f Henle, the greater the osmolarity in IS=> increased H₂O reabsorption at
the CD
• Depends on active transport of Na and Cl out of the ascending limb
• Gradient: established by continuous inflow of isotonic solution from the PCT
• Gradient against which Na and Cl are pumped out => increased osmolarity in the interstistial
space
• 50% of the hyperosmolarity is due to urea (suffers change because it diffuses from the
medullary part of the CD to the loop of Henle)
• Vasa recta:
• · Length (20mm) => increased resistance and decreased speed of blood flowing
• · Counter-current-exchange- bidirectional-passive (all walls permeable to H₂O+solutes)
• · To maintain hyperosmolarity in the interstitial space
• · Similar mechanism:
H₂O leaves the descending limb of the vasa recta (due to hyperosmolarity in the IS by the
loop of Henle)
H₂O taken up by the ascending limb (in exchange solvits leave the ascending limb)
• Passive process depending on the movement of H₂O and could not maintain the osmotic
gradient along the pyramids if the counter-current-multiplier-mechanism at loop of Henle was
to cease
Countercurrent mechanism in Vasa recta
(Medullary circulation)
• The blood vessels in the medulla is termed vasa recta—form
hairpin loops that run parallel to the loops of Henle and
medullary collecting ducts
• As the blood flows down the loop deeper and deeper into
the medulla, sodium and chloride do indeed diffuse into, and
water out of, the vessel.
• At the bend point, the blood then flows up the ascending
vessel loop, where the process is almost completely
reversed.
• vasa recta minimizes excessive loss of solute from the
interstitium by diffusion.
• both the salt and water being reabsorbed from the loops of
Henle and collecting ducts are carried away in equivalent
amounts by bulk-flow,
MECHANISM OF THE URINE CONCENTRATION (after R.Rhoades & G.Tanner,
Medical Physiology, 2003)
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
ACTION OF ADH IN THE COLLECTING DUCT (after R.Rhoades & G.
Tanner, Medical Physiology, 2003)
AUTO-REGULATION OF RENAL CIRCULATION

• Renal circulation has the capacity of autoregulation

• It is an intrinsic 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 of BP
• Autoregulation is explained by two major mechanisms:
1) tubuloglomerular feedback mechanism
2) myogenic mechanism
Other factor is high protein intake and glucose
 1) Tubuloglomerular feedback mechanism

• 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.
• Without renal autoregulation, increases in arterial blood pressure
=> increases in GFR and losses of NaCl and water from the ECF.
THE TUBULOGLOMERULAR FEEDBACK MECHANISM (after R.Rhoades & G.
Tanner, Medical Physiology, 2003)
2) Myogenic mechanism
• The increase in BP => stretches blood vessel
wall => opening stretch-activated cation
channels in smooth muscle cells => membrane
depolarization => opening voltage-dependent
Calcium channels => intracellular [Ca] rises =>
smooth muscle contraction => vessel lumen
diameter decreases => vascular resistance
increases
• Decreased BP induces the opposite changes
 Estimation of
glomerular filtration
rate
 Estimation of glomerular filtration rate:

This may be done using the clearance of a

substance present in plasma that is filtered
freely at the glomerulus, but is neither
reabsorbed nor secreted by the tubules.
Inulin, a polysaccharide of MW » 5000, satisfies
these criteria.

Renal Clearance:
The clearance of a substance is the volume of
plasma from which the substance was
completely cleared by the kidneys per unit time,
(units = vol. plasma/time),
CX = UX V
PX
 Inulin clearance
PA(inulin)x RPF PV(inulin)x RPF

No reabs; No
secretion.
Filtered = Pin X
GFR
Filtered = Excreted

Pin X GFR = Uin X V

Excreted = Uin
XV
Since inulin cannot be absorbed or secreted, all inulin
that is filtered at the glomerulus must
appear in the urine.
In the steady state, the rate of filtration (moles/min) of
inulin must be equal to its excretion in the urine
(moles/min).
Rate of inulin filtration (moles/min) = Pinulin (moles/ml) x
GFR (ml/min)
Rate of excretion of inulin (moles/min) = Uinulin (moles/ml)
x V (ml/min)
where Uinulin and Pinulin represent the concentrations of
inulin in urine and plasma, respectively, and V
represents the rate of urine flow.
2. inulin filtration rate = inulin excretion
rate

Pinulin x GFR = Uinulin x V

So that GFR = UinV/Pin

3. The right-hand-side of equation = the clearance of

inulin. (The clearance of any other substance is UV/P
for that substance.)

4. The GFR is equal to the clearance of inulin, or of any

other substance that is freely filtered, but neither
reabsorbed nor secreted.

5. The "normal" value of GFR for a 70 kg human is about

125 ml/min.
 Creatinine clearance:

In clinical practice creatinine clearance may

be used to estimate GFR for the following
reasons.
1. Inulin is not produced endogenously.
Therefore, it must be infused intravenously if it is to
be used in renal function tests.
It is much more convenient to use a substance that
is normally present in plasma that is freely filtered,
but neither secreted, nor reabsorbed.
2. Creatinine, a normal breakdown product of creatine,
is an endogenous compound that fulfils these
criteria.
Creatinine clearance - contd:

However, in humans, a small amount of

creatinine is secreted into the urine in the
proximal tubules.

Consequently, the rate of excretion of

creatinine exceeds its rate of filtration by 5
to 10%.

The clearance of creatinine thus exceeds the

true GFR by 5 to 10%.
Creatinine clearance - contd:

All that is required is a single plasma sample

and 24 hour urine collection.

In most renal diseases the GFR is

substantially reduced.

This is detected by a diminished creatinine

clearance or, more frequently, by elevated
Pcreatinine.
 PAcr x RPF PVcrx RPF

No reabs; No
secretion.
Filtered = PcrX
GFR
Filtered = Excreted
Small amount is
Pcr X GFR = Ucr X V secreted
Excreted = Ucr
XV
MICTURITION

• Urine formation is a continuous process: 1ml/min urine flows

from the kidney to the bladder (urinary flow)
• Urine flows from the kidney (formation)-> ureters (passage)->
bladder (storage)
• 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
• · Frequency- 3-6/minute
• · Speed - 3cm/sec
• · 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
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 thevurethra
• 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.
• 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)
INNERVATION OF THE URINARY BLADDER (after R.Rhoades & G.
Tanner, Medical Physiology, 2003)
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.
 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
MICTURITION REFLEX
• 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.
REFERENCES

• Despopoulos A, Silbernagl S, Color Atlas of Physiology, 5th

edition, Thieme, 2003
• Dorofteiu M, Mecanismele homeostazei sanguine, Editura Dacia,
Cluj-Napoca, 1989
• Ganong W.F, Review of Medical Physiology, 22nd edition, The
McGraw-Hill Companies, 2005
• Guyton A.C, Hall E.J, Textbook of Medical Physiology, 11th edition,
Elsevier Saunders, Philadelphia, 2006
• Rhoades R, Tanner G, Medical Physiology, 2nd edition, Lippincott
Williams & Wilkins, 2003
• Vander et al, Human Physiology: The Mechanism of Body
function, 8th edition, The McGraw Hill Companies, 2001