Formation of urine
Urinary vs Plasma Concentrations
Formation of urine
SECRETION
Glomerular filtration
• Filtration of plasma
• Through the glomerular capillaries
• Into the renal tubules
Tubular reabsorption
• Removal of water and solutes from the
tubular fluid
Tubular secretion
• Secretion of solutes into the tubular fluid
Glomerular Filtration
• Filtration : bulk transport of fluid along with
its dissolved small quantity of solutes across a
membrane.
• Glomerular Filtration :
Glomerular Filtration
Glomerular Filtration
• One tenth of renal blood flow gets filtered
• Same as plasma
– Osmolality, pH
– Electrical conductivity
– Concentration of electrolytes and small organic
molecules.
• Difference from plasma
NO proteins
NO cells
Ultrafiltrate
Glomerular filtration rate
• Glomerular filtration rate (GFR) is the volume
of fluid filtered from the renal (kidney)
glomerular capillaries into the Bowman's
capsule per unit time.
• “GFR refers to volume of all the glomerular
filtrate formed by all the nephrons in both the
kidneys per minute”.
: 125 ml per min
170-180 liters per day
Normal
Mechanism
• Same as filtration across all other body
capillaries
• Depends on
1. Hydrostatic pressure gradient across
the capillary wall.
2. Osmotic pressure gradient across
the capillary wall.
3. Permeability of the capillaries
4. Size of the capillary bed
Starling forces
In the movement of fluid across
capillary membranes:
• Hydrostatic pressure : drives fluid out
• Osmotic pressure: attracts fluid inwards
• For each Nephron effective filtration pressure(EFP):
EFP= (PCap – PBow) – (COPCap – COPBow)
PCap : is the mean hydrostatic pressure in the
glomerular capillaries = 45 mm Hg
PBow the mean hydrostatic pressure in the
Bowman's space = 10mmHg.
COPCap : the oncotic pressure of the plasma in
the glomerular capillaries = 25mm Hg.
COPBow : the oncotic pressure of the filtrate in
the Bowman's space= 0 mmHg.
GFR
• GFR = Kf x EFP
Kf : glomerular ultrafiltration
coefficient
It is the product of the
Normal Kf = 12.5
glomerular capillary wall ml/min/mmHg
hydraulic conductivity (ie, its
permeability) and the effective
filtration surface area
GFR
• GFR = Kf x (PCap – PBow) – (COPCap – COPBow)
GFR = 12.5 [(45-10) – (25-0)]
=12.5 X 10
= 125 ml/min
Factors effecting GFR
• Age
• Renal blood flow
• Hydrostatic pressure in the glomerular
capillaries
– Systemic BP
– Glomerular arterial constriction
• Hydrostatic pressure in the Bowman's space
– Ureteral obstruction
– Renal edema
Factors effecting GFR
• Changes in concentration of plasma proteins
– Hypoproteinemia
– Dehydration
• Size of capillary bed
Agents Causing Contraction or
Relaxation of Mesangial Cells
Factors effecting GFR
• Status of glomerular membrane
– The permeability of the glomerular
capillaries is about 50 times that of the
capillaries in skeletal muscle.
– Neutral substances
• Less than 4 nm are freely filtered
• More than 8 nm filtration approaches zero
• Sialoproteins in the glomerular capillary wall
are negatively charged
• Like charges repel
• Filtration of anionic substances 4 nm in
diameter is less than half that of neutral
substances of the same size
Albumin( -ve charged), with an effective
molecular diameter of approximately 7
nm, normally has a glomerular
concentration only 0.2% of its plasma
concentration.
Filtration fraction
• Fraction of the plasma passing through the
kidneys which is filtered at the glomerulus
• i.e. ratio of GFR to renal plasma flow
= 125 / 700
= 0.16 to 0.20
i.e. 16 to 20 % of renal plasma flow
Arterial resistance, GFR and RPF
Measuring GFR
• GFR can be measured in intact experimental animals
and humans by :
 Measuring the excretion and plasma level of a
substance that is freely filtered through the glomeruli
and neither secreted nor reabsorbed by the tubules.
 Clearance value of the substance X = CX
CX= UXV/PX
UX : Concentration of X in urine (mg/ml)
V : Urine flow per unit of time (ml/min)
PX : Arterial plasma level of X (mg/ml)
Inulin clearance
• A polymer of fructose
with a molecular weight
of 5200.
• Freely filtered
• Neither reabsorbed nor
secreted in the tubules
• Nontoxic
• Not metabolized by the
body
Creatinine clearance
• Some creatinine is secreted by the tubules and some
may be reabsorbed.
• Inaccurate at low creatinine levels because the method
for determining creatinine measures small amounts of
other plasma constituents.
• Creatinine is endogenous
• The values are close to GFR values measured with
inulin
• Endogenous creatinine clearance is easy to measure
But when precise measurements of GFR are
needed inulin is used
Reabsorption and secretion in
renal tubules
Reabsorption and secretion
• Filtered load :
Amount of solute transported across
the glomerular membranes per unit time
GFR X plasma concentration of the solute
mg / min
Reabsorption and secretion
• Excretion rate:
Amount of substance that
appears in the urine per unit time
= Urine flow rate X urine concentration of
the substance
= VUx mg/min
Reabsorption and secretion
• Net Secretion : if excretion rate > filtered load
• Net Reabsorption : if filtered load > excretion rate
Renal tubular transport maximum
• Maximal amount of a solute that can be
transported (Reabsorbed or secreted) per
minute by the renal tubules.
• It is denoted as Tm
• Maximum tubular reabsorptive capacity
• Maximum tubular secretory capacity
Maximum tubular reabsorptive
capacity
• Active carrier mediated process
Eg :
• Phosphate ion
• Sulfate
• Glucose
• Amino acids
• Uric acid
• Albumin
• Acetoacetate, beta- hydroxybutyrate
• Alfa keto glutarate.
Maximum tubular secretory capacity
•
•
•
•
•
Penicillin
Certain diuretics
Salicylate
PAH
Thiamine.
Mechanisms of Tubular Reabsorption
& Secretion
• Small proteins and some peptide hormones are
reabsorbed in the proximal tubules by endocytosis.
• Other substances are secreted or reabsorbed in the
tubules by
– Passive diffusion between cells
– Through cells by facilitated diffusion down chemical or
electrical gradients
– Active transport against such gradients.
Movement is by way of ion channels,
exchangers, cotransporters, and pumps.
Mechanisms of Tubular Reabsorption
& Secretion
• Transepithelial transport
1. Transcellular pathway :2/3 of Na transport
(active).
2. Paracellular pathway: 1/3 of NaCl transport.
Transport of individual substances
Transport of individual substances
• PCT reabsorbs: 70% to 85% of the filtered Na,
Cl, HCO3, amino acids and glucose
• Reabsorption of water is passive
• Movement controled by gradients created by
movement of solutes
Transport
of
individual
substances
Renal Handling of Various Plasma Constituents
Na+ Reabsorption
• The reabsorption of Na+ and Cl– plays a major role
in body electrolyte and water homeostasis.
Amino
acids
H+
Organic
acids
Na+
transport
Glucose
Phosphate
Other
electrolytes
Co-transport
60%
30%
7%
3%
( Aldosterone)
Na+ Reabsorption
Passive Transport
Active Transport
1. Facilitated diffusion : Sodium diffuses across
the apical membrane into the cell down an
electrochemical gradient established by the
sodium-potassium ATPase pump on the
basolateral side of the membrane.
2. Active transport : Sodium is
transported across the basolateral
membrane against an electrochemical
gradient by the sodium-potassium
ATPase pump.
3. Solvent drag :Sodium, water, and other
substances are reabsorbed from the interstitial
fluid into the peritubular capillaries by
ultrafiltration, a passive process driven by the
hydrostatic and colloid osmotic pressure gradients.
Regulation of Na+ Excretion
• Na+ in the body is a prime determinant of the
ECF volume.
• Depends on changes in GFR and changes in
tubular reabsorption, primarily in the 3% of
filtered Na+ that reaches the collecting ducts.
Regulation of Na+ Excretion
• The factors affecting include
– Tubuloglomerular feedback
– Circulating level of aldosterone and other
adrenocortical hormones
– The circulating level of ANP and other natriuretic
hormones
– The rate of tubular secretion of H+ and K+.
Effect of aldosterone
Glucose Reabsorption
• Glucose, amino acids, and bicarbonate are
reabsorbed along with Na+ in the early portion of
the proximal tubule
• Glucose is removed from the urine by secondary
active transport.
Filtered load = 100 mg/min (80
mg/dL of plasma x 125 mL/min).
• Essentially all of the glucose is reabsorbed, and
no more than a few milligrams appear in the
urine per 24 h.
Renal threshold for glucose
• Plasma glucose level at which the glucose first
appears in the urine in more than the normal
minute amounts.
• 200 mg% in arterial plasma
• 180 mg% in venous plasma
• TmG for glucose is 375mg/min in men and 300
mg/min in women
Renal splay
• Renal threshold = TmG / GFR
= 375mg/min /125 ml/min
= 300 mg%
• i.e predicted renal threshold = 300mg%
• However, the actual renal threshold is about 200
mg/dL of arterial plasma ?????
• Ideal curve is linear. It is seen if
1. TmG in all the tubules was identical
2. All the glucose were removed from each tubule
when the amount filtered was below the TmG
Renal splay
• In humans it does not
happen
• Hence the actual curve
is rounded and deviates
considerably from the
"ideal" curve.
• This deviation is called
splay.
Glucose Transport Mechanism
• Glucose and Na+ bind to the sodiumdependent glucose transporter (SGLT- 2) in
the apical membrane, and glucose is carried
into the cell as Na+ moves down its electrical
and chemical gradient.
• The Na+ is then pumped out of the cell into
the interstitium, and the glucose is
transported by glucose transporter (GLUT-2 )
into the interstitial fluid.
Secondary active transport.
Glucose Transport Mechanism
GLUT-2
SGLT- 2
Water Transport
• Normally, 180 L of fluid is filtered through the
glomeruli each day, while the average daily
urine volume is about 1 L.
Aquaporins
• Rapid diffusion of water across cell
membranes depends on the presence of
water channels, integral membrane proteins
called aquaporins.
• 13 aquaporins have been cloned
• 4 aquaporins (aquaporin-1, aquaporin-2,
aquaporin-3, and aquaporin-4) play a key role
in the kidney.
Water Transport
• PCT
– Aquaporin-1 is localized to both the basolateral and
apical membrane of the proximal tubules
– Water moves rapidly out of the tubule along the
osmotic gradients set up by active transport of
solutes
– Obligatory resorption of water
– 80% absorption
– Isotonicity maintained
Water Transport
Collecting duct
ADH
Facultative resorption
Collecting Ducts
• The collecting ducts have two portions: a
cortical portion and a medullary portion.
• The changes in osmolality and volume in the
collecting ducts depend on the amount of
vasopressin acting on the ducts.
• This antidiuretic hormone from the posterior
pituitary gland increases the permeability of
the collecting ducts to water.
Anti diuretic hormone (ADH)
• Vasopressin acts on the collecting ducts via
increasing number of aquaporin-2 on the
apical membrane.
VASSOPRESSIN
(ADH)
Aquaporin is stored in
vesicles in the cytoplasm of
principal cells.
Vasopressin V2 receptor
Cyclic adenosine 5monophosphate
Insertion of these vesicles into
the apical membrane of cells.
Protein kinase A.
Increased permeability of
collecting duct to water
ADH
OsmoreceptorADH feedback
mechanism
for regulating
extracellular fluid
osmolarity
Hormones That Regulate Tubular
Reabsorption