Renal Physiology 2019

Dr. Geeta Kurhade

Sr. lecturer, Physiology unit,FMS
[email protected]
 Objectives
6. List the specific functions of the kidney.
7. Define the term “Renal clearance” with the use of equations and state the renal
clearance of various substances e.g. albumin, glucose, inulin, penicillin, PAH.
8. Describe the regulation of renal blood flow.
9. Define renal plasma flow (RPF) and renal blood flow (RBF)and explain, with the use
of equations, the calculation of RPF and RBF.
10. Define glomerular filtration rate (GFR)
11. Describe the forces involved in glomerular filtration and the composition of
glomerular filtrate.
12. Define and quantify the normal filtration fraction.
13. Identify the main methods by which GFR is estimated and justify the use of
creatinine clearance over that of inulin in estimation of GFR.
Explain the relationship between filtration, reabsorption and secretion.
Major Functions of the Kidneys:
1. Excretion of
metabolic waste products
foreign substances (pesticides, chemicals, drugs etc.)
excess substance (water etc.)
metabolism and excretion of hormones
2. Regulation of:
a. Water and electrolyte balance,
b. Body fluid osmolality and electrolyte concentrations
c. Arterial pressure
d. Acid-base balance
3. Secretion of
Erythropoitin, 1,25-dihydroxy vitamin D3 (vitamin D activation)
renin, prostaglandin

4. Gluconeogenesis
1. Excretion of Metabolic Waste Products, Foreign Chemicals,
Drugs, and Hormone Metabolites.

• urea (from the metabolism of amino acids)

• creatinine (from muscle creatine)
• uric acid (from nucleic acids)
• end products of hemoglobin breakdown (such as bilirubin),
• metabolites of various hormones
• toxins and other foreign substances that are either produced by the
body or ingested, such as pesticides, drugs, and food additives.
 2.a &b. Regulation of Water and Electrolyte Balances
• Excretion of water and electrolytes must precisely match intake for
maintenance of homeostasis,
• If intake exceeds excretion, the amount of that substance in the body will
increase and vice-versa.
• E.g. Within 2 to 3 days after raising the sodium intake, renal excretion also
increases to about 300 mEq/day, so that a balance between intake and output
is re-established.
• During the 2 to 3 days of renal adaptation to the high sodium intake, there
is a modest accumulation of sodium that raises ECF volume slightly.
• Increased ECF volume triggers hormonal changes & other compensatory
responses that signal the kidneys to increase their sodium excretion.
 2.c. Regulation of Arterial Pressure :

• Kidneys play a dominant role in long-term regulation of arterial pressure by

excreting variable amounts of sodium & water.
• The kidneys also contribute to short-term arterial pressure regulation by
secreting vasoactive factors or substances, such as renin, that lead to the
formation of vasoactive products (e.g., angiotensin II).
2.d. Regulation of Acid-Base Balance :

• The kidneys excrete acids & regulate body fluid buffer stores along with the
lungs.
• The kidneys are the only means of eliminating certain types of acids, such
as sulfuric acid & phosphoric acid, generated by the metabolism of proteins
in the body.
3. Secretion of erythropoietin
• The kidneys secrete erythropoietin in response to hypoxia, which stimulates
the production of red blood cells.
• In people with severe kidney disease, severe anemia develops as a result of
decreased erythropoietin production.
• How does erythropoietin acts?

Regulation of 1,25–Dihydroxyvitamin D3 Production :

• The kidneys produce the active form of vitamin D, 1,25- dihydroxy-vitamin
D3 (calcitriol).
• Calcitriol is essential for calcium absorption by the gastrointestinal tract &
normal calcium deposition in bone. It regulates Ca &PO4 metabolism.
4. Gluconeogenesis :

• The kidneys synthesize glucose from amino acids & other precursors
during prolonged fasting- gluconeogenesis.(along with liver).

• With complete renal failure , potassium, acids, fluid, and other

substances accumulate in the body to cause death within a few days,
unless clinical interventions such as hemodialysis are initiated to
restore the body fluid & electrolyte balances.
• Nephron- Functional unit of kidney
 Nephron
• Each individual renal tubule & its
glomerulus is a unit (nephron).
• Each human kidney has approximately one
million nephrons.
• The glomerulus, which is about 200 μm in
diameter, is formed by the invagination of a
tuft of capillaries into the dilated, blind end
of the nephron (Bowman’s capsule).
• The capillaries are supplied by an afferent
arteriole and drained by the efferent
arteriole . The diameter of the afferent
arteriole is larger than the efferent arteriole.
• At the glomerulus that the filtrate is formed.
Nephron with uriniferous tubule
• More than a million of these tubules act together
to form the urine. Three main mechanisms
a.Glomerular filtration
b.Tubular reabsorption
c.Tubular secretion
• Two major parts
1.A urine-forming nephron
2.A collecting duct which concentrates urine by
removing water from it.
•Thousands of collecting ducts collect fluid form
several nephrons and convey it to the renal pelvis.
Two types of nephrons are present
 Cortical nephrons with short loop of Henle-85% (peritubular plexus)
 Juxtamedullary nephrons with long loops of Henle- help produce
concentrated urine. (vasa recta)
 Renal glomerular filtration membrane
• Two cellular layers separate the blood from the
glomerular filtrate in Bowman’s capsule: the
capillary endothelium & the specialized
epithelium of the capsule.
• The endothelium of the glomerular capillaries is
fenestrated, with pores that are 70–90 nm in
diameter.
• It is completely surrounded by the glomerular
basement membrane along with specialized cells
called podocytes.
• Podocytes have numerous pseudopodia that
interdigitate to form filtration slits along the
capillary wall. The slits are approximately 25 nm
wide, and each is closed by a thin membrane.
• The glomerular basement membrane, the basal
lamina, does not contain visible gaps or pores
• Stellate cells called mesangial cells are
located between the basal lamina and the
endothelium. They are similar to cells
called pericytes, which are found in the
walls of capillaries elsewhere in the body.
• Mesangial cells are especially common
between two neighboring capillaries, & in
these locations the basal membrane forms
a sheath shared by both capillaries.
• The mesangial cells are contractile and
play a role in the regulation of
glomerular filtration.
• Mesangial cells secrete the extracellular
matrix, take up immune complexes,
and are involved in the progression of
glomerular disease.
Renal glomerular filtration membrane contd…

• Functionally, the glomerular membrane permits the free passage of

neutral substances up to 4 nm in diameter & almost totally
excludes those with diameters greater than 8 nm.
• The charge on molecules as well as their diameters affects their
passage into Bowman’s capsule.
• The total area of glomerular capillary endothelium across which
filtration occurs in humans is about 0.8 m2.
Parts of Nephron 1. PCT: 15 mm long, 55 μm in diameter. Wall
made up of a single layer of cells united by
apical tight junctions with lateral intercellular
spaces. The luminal edges of the cells have a
striated brush border many microvilli.
2. loop of Henle: The descending portion of the
loop & the proximal portion of the ascending
limb are made up of thin, permeable cells. The
thick portion of the ascending limb is made up
of thick cells containing many mitochondria.
3. The cortical nephrons- have short loops of
Henle, and the juxtamedullary nephrons have
long loops extending down into the medullary
pyramids. In humans, only 15% of the nephrons
have long loops.
Juxtaglomerular apparatus:
• The thick end of the ascending limb of
the loop of Henle reaches the glomerulus
of the nephron from which the tubule
arose & nestles between its afferent &
efferent arterioles.
• Specialized cells at the end form the
macula densa, which is close to the
efferent & particularly the afferent
arteriole.
• The macula, the neighboring lacis cells,
& the renin-secreting granular cells in
the afferent arteriole form the
juxtaglomerular apparatus.
• DCT: starts at the macula densa, about 5 mm long. Its
epithelium is lower than that of the proximal tubule, a
few microvilli present, no brush border.
• Collecting ducts: The distal collecting tubules coalesce
to form collecting ducts, 20 mm long which pass
through the renal cortex & medulla to empty into the
pelvis of the kidney at the apexes of the medullary
pyramids.
• The epithelium of the collecting ducts is made up of
principal cells (P cells) & intercalated cells (I cells).
• The P cells: predominant, relatively tall & involved in
Na+ reabsorption & ADH stimulated water
reabsorption.
• The I cells: smaller in numbers & also found in the
distal tubules, have more microvilli, cytoplasmic
vesicles, & mitochondria. concerned with acid
secretion & HCO3– transport.
• The total length of the nephrons, including the
collecting ducts, ranges from 45 to 65 mm.
Prostaglandin (PGE2) & prostacyclin(PGI2) secretion by kidney

Prostaglandin (PGE2) is an important paracrine regulator of salt & water

homeostasis and is secreted by:
• the granular cells in the juxtaglomerular apparatus
• some of the specialized fibroblast-like cells in the interstitial tissue of the
medulla- called renal medullary interstitial cells (RMICs) .
• the macula densa, and
• cells in the collecting ducts.

Prostacyclin (PGI2) and other prostaglandins are secreted by the arterioles and
glomeruli.
Renal blood vessels
• The afferent arterioles are short,
straight branches of the interlobular
arteries. Each divides into multiple
capillary branches to form the tuft of
vessels in the glomerulus. The
capillaries coalesce to form the efferent
arteriole, which in turn breaks up into
capillaries that supply the tubules
(peritubular capillaries) before
draining into the interlobular veins.
• The arterial segments between glomeruli
& tubules are thus technically a portal
system, and the glomerular capillaries
are the only capillaries in the body that
drain into arteriole.
• Efferent arterioles have relatively little
smooth muscle.
• The capillaries draining the tubules of
the cortical nephrons form a peritubular
network.
• The efferent arterioles from the
juxtamedullary glomeruli drain not only
into a peritubular network, but also into
vessels that form hairpin loops (the
vasa recta).
• These loops dip into the medullary
pyramids alongside the loops of Henle.
• The descending vasa recta have a non-
fenestrated endothelium that contains a
facilitated transporter for urea.
• The ascending vasa recta have a
fenestrated endothelium, consistent with
their function in conserving solutes.
• Venous blood enters interlobular veins,
which in turn flow via arcuate veins to
the interlobar veins.
 Renal blood circulation, lymphatics contd...
• The efferent arteriole from each glomerulus breaks up into capillaries that supply
a number of different nephrons. Thus, the tubule of each nephron does not
necessarily receive blood solely from the efferent arteriole of the same nephron.
• In humans, the total surface of the renal capillaries is approximately equal to the
total surface area of the tubules, both being about 12 m2.
• The volume of blood in the renal capillaries at any given time is 30–40 mL.
• LYMPHATICS :The kidneys have an abundant lymphatic supply that drains via
the thoracic duct into the venous circulation in the thorax.
• RENAL CAPSULE: The renal capsule is thin but tough. If the kidney becomes
edematous, the capsule limits the swelling, and the tissue pressure (renal
interstitial pressure) rises. This decreases the glomerular filtration rate (GFR) &
can cause anuria in acute kidney injury.
Innervation of the renal vessels

• The sympathetic preganglionic innervation (lower thoracic & upper lumbar

segments of the spinal cord), & the post ganglionic fibers from superior
mesenteric ganglion are distributed primarily to the afferent and efferent
arterioles, the proximal and distal tubules, and the J-G apparatus.
• Nociceptive afferents that mediate pain in kidney disease parallel the
sympathetic efferents and enter the spinal cord in the thoracic and upper
lumbar dorsal roots.
• Other renal afferents presumably mediate a renorenal reflex by which an
increase in ureteral pressure in one kidney leads to a decrease in efferent
nerve activity to the contralateral kidney. This decrease permits an increase in
its excretion of Na+ and water.
•Renal blood flow
• In a resting adult, the kidneys receive 1.2–1.3 L of blood per minute (about
25% of the cardiac output).
• Renal blood flow -determined by applying the Fick principle to the kidney;
measure the amount of a given substance taken up per unit of time & divide
this value by the arteriovenous difference for the substance across the kidney.

• Because the kidney filters plasma, the renal plasma flow (RPF) equals the
amount of a substance excreted per unit of time divided by the renal
arteriovenous difference.
• Any excreted substance can be used –if its concentration in arterial and renal
venous plasma can be measured and if it is not metabolized, stored, or
produced by the kidney and does not itself affect blood flow.
 Measuring the renal plasma flow
• Measured by infusing p-aminohippuric acid (PAH) & determining its urine &
plasma concentrations.
• PAH is filtered by the glomeruli & secreted by the tubular cells, so that its
extraction ratio (arterial concentration minus renal venous concentration divided
by arterial concentration) is high.
• When PAH is infused at low doses, 90% of the PAH in arterial blood is removed in
a single circulation through the kidney.
• RPF = amount of PAH in the urine
the plasma PAH level (A-V) ( ignoring the level in renal venous blood)
• Peripheral venous plasma can be used because its PAH concentration is essentially
identical to that in the arterial plasma reaching the kidney.
• The value obtained should be called the effective renal plasma flow (ERPF) to
indicate that the level in renal venous plasma was not measured. In humans, ERPF
averages about 625 mL/min.
• Concentration of PAH in urine (UPAH): 14 mg/ml ; Urine flow (V):0.9 ml/min
and Concentration of PAH in plasma (PPAH):0.02 mg/ml
• EPRF=14x0.9/.02=630 ml/min.
• The ERPF determined in this way is the clearance of PAH.
• ERPF can be converted to actual renal plasma flow (RPF):
• Average PAH extraction ratio: 0.9
• Actual RPF = Effective Renal Plasma flow = 630 = 700 mL/min
Extraction ratio 0.9
• From the renal plasma flow, the renal blood flow can be calculated by dividing
it by 1 minus the hematocrit: Hematocrit (Hct): 45%
• Renal blood flow = RPF × 1 /1-Hct =700x1/.55 = 1273 mL/min
Pressure in renal vessels
• The mean systemic arterial pressure is 100 mm Hg,
• The glomerular capillary pressure is about 45 mm Hg.
• The pressure drop across the glomerulus is only 1–3 mm Hg, but a further
drop occurs in the efferent arterioles.
• The pressure in the peritubular capillaries is about 8 mm Hg.
• The pressure in the renal vein is about 4 mm Hg.
• Glomerular capillary pressure is about 40% of systemic arterial pressure.
 Regulation of renal blood flow
• Norepinephrine: constricts the renal vessel.
• Angiotensin II: constricts both the afferent and efferent arterioles.
• Acetylcholine: renal vasodilation.
• Dopamine: made in the kidney- renal vasodilation & natriuresis
• Prostaglandins: ↑ blood flow in the renal cortex & ↓ blood flow in the renal
medulla.
• A high-protein diet: ↑ glomerular capillary pressure and ↑ renal blood flow.
• Strong stimulation of the sympathetic noradrenergic nerves to the
kidneys: marked ↓ in renal blood flow (mediated by α1-adrenergic receptors),
↓ GFR & ↓ urinary sodium excretion.
• Fall in systemic blood pressure: the vasoconstrictor response produced by
decreased discharge in the baroreceptor nerves includes renal vasoconstriction.
• Exercise: ↓ Renal blood flow.
 Renal autoregulation -regulation of GFR
• There are changes in blood pressure over a large range.
• The kidney adjusts the dilation or constriction of the afferent arterioles,
which counteracts these changes and thus maintains GFR.
• Extrinsic mechanisms:
• Neural and hormonal control - these mechanisms can override renal
autoregulation & decrease the glomerular filtration rate when necessary.
• Hormonal control - when plasma volume increases, atrial natriuretic
peptide is a hormone produced in the heart and can increase the
glomerular filtration rate & urine output
Renal autoregulation
4th April 2019 Thursday 9-11 am.
 Intrinsic control mechanism of renal blood flow
• Myogenic mechanism: The vascular
smooth muscle— contracts when
stretched & relaxes when not stretched.
• Rising systemic blood pressure →
stretches vascular smooth muscle in the
arteriolar walls→ the afferent arterioles to
constrict → restricts blood flow into the
glomerulus & prevents glomerular blood
pressure from rising to damaging levels.
• Declining systemic blood pressure →
dilation of afferent arterioles → raises
glomerular hydrostatic pressure → both
responses help maintain normal NFP &
GFR.
 Tubulo-glomerular feedback mechanism
• By the macula densa cells of the JG complex,
located in the walls of the ascending limb of the
nephron loop.
• They respond to high levels of NaCl in filtrate
by releasing vasoconstrictor chemicals (ATP &
others) that cause intense constriction of the
afferent arteriole, reducing blood flow into the
glomerulus. This drop in blood flow decreases
the NFP & GFR, slowing the flow of filtrate &
allowing more time for filtrate processing
(NaCl reabsorption).

• The low NaCl concentration of slowly flowing

filtrate inhibits ATP release from macula densa
cells, causing vasodilation of the afferent
arterioles . This allows more blood to flow into
the glomerulus, thus increasing NFP & GFR.
 Hemodynamics of single nephron –Pressure changes
• The high-pressure filtering capillaries of
the glomerulus & the low- pressure
reabsorbing peritubular capillaries are
connected in series are
• The glomerular capillaries have a very
high hydrostatic pressure because the
efferent arterioles are very narrow &
thus have a very high resistance.
• Likewise, there is a large pressure drop
as blood flows past this high resistant
arteriole & the peritubular capillaries
have very low hydrostatic pressure.
 Nephron series Hemodynamics contd.. Flow changes
• The individual nephrons are connected in parallel. The blood flow through a
single nephron represents 2 arterioles & 2 capillary beds connected in series
where the flow must be equal at all points.
• If flow changes, it changes equally at all points in the system.
Flow (Q) = pressure gradient / resistance (R)
= (upstream pressure- downstream pressure) /resistance ( R )
Blood flows from high pressure to low pressure. Two factors decrease flow:
• ↓ the pressure gradient (↓ ing the upstream pressure or ↑ing the downstream
pressure)
• ↑ ing resistance at any point throughout the circuit
• Therefore, when considering blood flow through the nephron as a series circuit,
if resistance ↑es (vasoconstriction) at the afferent arteriole or efferent arteriole,
renal plasma flow decreases.
When an arteriole constricts, this ↑es the resistance at that arteriole and there are 2
changes to consider:
• Flow across the entire circuit ↓es
• Pressure builds up or ↑es before (upstream) the point of resistance &
pressure ↓es after (downstream) the point of resistance.

• Similarly when an arteriole vasodilates, this ↓es the resistance at that arteriole
& there are 2 changes to consider:
• Flow across the entire circuit ↑es
• Pressure ↓es before (upstream) the point of resistance and pressure ↑es after
(downstream) the point of resistance
• A patient with essential hypertension has increased renal artery pressure
leading to vasoconstriction of the afferent arterioles & vasodilation of the
efferent arterioles.
• High pressure at the juxtaglomerular apparatus leads to decreased renin
secretion → low angiotensin II → vasodilation of the efferent arterioles .

• A patient with renal artery stenosis has low renal artery pressures, leading to
low pressures at the afferent arterioles.
• The result will be vasodilation of the afferent arterioles and vasoconstriction of
the efferent arterioles (increased renin secretion leads to increased angiotensin
II)
Filtration and main forces affecting filtration
• Bowman’s space : As filtrate
accumulates in Bowman’s space,
pressure rises to force fluid into the
proximal tubule and all the way
through the whole length of the
nephron; the ONLY force from
filtration which moves the fluid along.
• This back pressure, which reflects the
work of forcing filtrate through the
nephron, bucks out the net filtration
pressure because it is outside the
capillary.
Systemic common capillaries
• Left hand panel of the figure.
Throughout the body, fluid leaves
capillaries into the tissues and then, as
one moves along the capillary length
P(OC) rises enough that filtration
gives place to reabsorption.
• This washes the space around
capillaries, so nutrients flow outward
to cells & their waste is swept up into
the capillaries & brought to the lungs,
kidneys & liver where either they are
excreted or change their chemical
natures.
 Filtration-Capillary Hydraulic Pressure
• Pressure inside the capillary, PGC, is about
55 mmHg. Losses along the capillary are so
small one can more or less draw them as
constant.
• The pressure inside is the result of the
pressure coming in from the afferent
arteriole & the back resistance from the
efferent arteriole. So the balance between
the two arterioles can actively control the
pressure inside the capillary.
• Because the pressure inside the Bowman’s
space, PBS, is about 15 mmHg, the net
pressure across the capillary for filtration
would be 55 – 15 or 40 mmHg.
Filtration- Capillary Osmotic Pressure
• The capillaries retain the blood
albumin & other large molecules.
These molecules exert a force on water
so that water will be drawn inward
from the filtrate – which is protein free
– back into the blood.
• That ‘oncotic’ or osmotic force from
large molecules counters the hydraulic
force.
• As filtration progresses, the
concentration of the large molecules
increases, so the capillary osmotic
pressure, (COP), rises (red line).
Net Filtration Pressure
• The pressure differential across the capillary and
podocytes drives filtration. This is the capillary
hydraulic pressure minus the sum of COP + PBS.
At the inflow it is about 55 – 38 or 17 mmHg. At
the end- it is about 55 – 44 or 11 mmHg.
• Flow will matter a lot. If flow goes down &
pressures remain the same, COP will rise more
rapidly because initial filtration is the same as at
higher flows but filtration is from a smaller
flowing volume. This can reduce the area between
PGC and PBS + COP even to the point that filtration
ceases before the end of the capillary.
• Contrariwise, if flows go up filtration will go up
for the same reasons – COP will rise more slowly.
 Net filtration pressure
• High hydrostatic pressure in the
glomerular capillaries (about 60 mm Hg)
causes rapid fluid filtration, whereas a
much lower hydrostatic pressure in the
peritubular capillaries (about 13 mm Hg)
permits rapid fluid reabsorption.

• By adjusting the resistance of the

afferent & efferent arterioles, the kidneys
can regulate the hydrostatic pressure in
both the glomerular & the peritubular
capillaries, thereby changing the rate of
glomerular filtration, tubular
reabsorption, or both in response to body
homeostatic demands.
Consequences of independent isolated constrictions or dilatations of
the afferent & efferent arterioles
Glomerular Cap Peritubular Cap Nephron plasma
pressure pressure flow

Dilate efferent ↓ ↑ ↑

Constrict efferent ↑ ↓ ↓

Dilate afferent ↑ ↑ ↑

Constrict afferent ↓ ↓ ↓
•Regulation of filtration
 Regulation of filtration
• The AA dilates when pressure falls
reducing tension in its walls. When
pressure rises it contracts.
• K/as ‘intrinsic autoregulation’- keeps
glomerular capillary flow & pressure
more or less constant over a range of
pressures & flows delivered to the
kidneys by the heart.
• Juxtaglomerular cells of the AA ––
produce & store renin in granules which
they release when they dilate.
• The renin, an enzyme that converts
angiotensin 1, to its active form,
angiotensin 2 (A2).
• The A2 travels to the efferent
arteriole that has receptors & can
respond to A2 by contracting. (but
does not affect the AA)
• Sympathetic nerve traffic &
catecholamines released as part of
stress reactions also cause renin
release but constrict the AA.
• The renin release helps maintain
filtration despite AA constriction.
• It Keeps Filtration Constant Under
Stress
Tubulo-glomerular feedback- • The thick ascending limb comes back to its
reminder glomerulus to form the JGA. When less sodium
chloride gets to that part of the nephron – the
macula densa cells stimulate renin release so that
EA constriction can raise filtration.
• The final result is a dual regulation. When
renal inflow falls, the AA dilates & via renin and
A2 constrict the EA. This latter keeps the
pressure up in the capillary and THUS filtration
remains reasonably constant over quite a range
of systemic BP & cardiac output.
• In stress reactions with sympathetic activity –
flight or fight – EA constriction makes
filtration constant even as AA constrict.
Secondly the tubulo-glomerular feedback from
the JGA senses fall in downstream sodium
chloride delivery and causes vasodilation of AA
thus increasing NFP & GFR.
 Regional blood flow & oxygen consumption
• The renal cortical blood flow:
• relatively great & little oxygen is extracted from the blood. Here large
volumes of blood is filtered through the glomeruli.
• Cortical blood flow is about 5 mL/g of kidney tissue/min (compared with 0.5
mL/g/min in the brain), & the arteriovenous oxygen difference for the whole
kidney is only 14 mL/L of blood.

• Medullary blood flow:

• The maintenance of the osmotic gradient in the medulla requires a relatively
low blood flow - about 2.5 mL/g/min in the outer medulla and 0.6 mL/g/min
in the inner medulla.
• However, metabolic work is being done, particularly to reabsorb Na+ in the
thick ascending limb of Henle, so relatively large amounts of O2 are
extracted from the blood in the medulla which is prone to hypoxia
• Glomerular filtration- measuring GFR- concept of clearance
• Glomerular filtration rate (GFR) is the volume of the fluid filtered through
the body's glomeruli per unit time (Measured in ml/min).
• The estimate of GFR is used clinically as an index of the renal function & to
assess the severity & the course of renal disease.
• A fall in GFR means the disease is progressing whereas an increase in GFR
suggests a recovery.
• Many times a fall in GFR may be the first & only clinical sign of renal
dysfunction.
 Normal GFR
• The GFR in a healthy adult of average size is approximately 125 mL/min.
• Its magnitude correlates fairly well with surface area, but values in women are
10% lower than those in men even after correction for surface area.
• A rate of 125 mL/min is 7.5 L/h, or 180 L/d, whereas the normal urine volume
is about 1 L/d.
• Thus, 99% or more of the filtrate is normally reabsorbed.
• At the rate of 125 mL/min, in 1 day the kidneys filter an amount of fluid equal
to four times the total body water, 15 times the ECF volume, and 60 times the
plasma volume.
Factors affecting the glomerular filtration rate
• Changes in renal blood flow
• Changes in glomerular capillary hydrostatic pressure
• Changes in systemic blood pressure
• Afferent or efferent arteriolar constriction
• Changes in hydrostatic pressure in Bowman’s capsule
• Ureteral obstruction
• Edema of kidney inside tight renal capsule
• Changes in concentration of plasma proteins, dehydration, hypoproteinimia
• Changes in glomerular capillary permeability
• Changes in effective filtration surface area
 Starling Forces govern the GFR
• The rate of glomerular filtration is essentially governed by Starling Forces.
• However, because the glomerular capillaries are surrounded by the fluid in
the Bowman's Capsule, the hydrostatic and oncotic pressure of Bowman's
Space is used instead of those of the 'Interstitial Fluid'.
• Importantly, because no plasma proteins can cross the glomerular barrier
during glomerular filtration, the oncotic pressure of fluid in Bowman's
Space is essentially zero and is thus removed from the starling equation.
• Formally: GFR = Kf [(Pc-Pb)-(Πc)]
GFR = Glomerular Filtration Rate (ml/min).
Kf = Permeability Constant of glomerular capillaries
Pc = Glomerular Capillary Hydrostatic Pressure
Pb = Bowman's Space Hydrostatic Pressure
Πc = Glomerular Capillary Oncotic Pressure
 Πc = Glomerular Capillary Oncotic Pressure
• The primary physiological
modulators of GFR are the afferent
& efferent arteriolar resistances (RA P
T
and RE).
u
• ↑ing the AA resistance (RA): drops p
in
the pressure within the glomerulus re
& thus ↓ GFR. b
flo
• The relationship between the
efferent arteriolar resistance (RE) &
GFR is more complicated.
a. Initially, ↑ ing RE boosts the
pressure within the glomerulus &
thus ↑ es GFR.
b. At higher values of RE the total
blood flow through the
glomerulus ↓es & thus GFR
drops.
 Modulation of GFR - GFR = Kf [(Pc-Pb)-(Πc)]
Effect of variation of systemic arterial pressure:
• ↑ ed or ↓ ed incoming systemic arterial blood pressures will ↑ or ↓ the hydrostatic
pressures within the glomerular capillaries. But due to autoregulatory mechanisms of
blood flow the incoming arterial pressure into the glomerulus are largely constant
over a wide range of systemic arterial pressure
Permeability Coefficient:
a. The permeability of filtration membrane can decline due to thickening of the
glomerular basement membrane e.g. diabetic nephropathy.
b. Total glomerular permeability can decline due to reductions in the total number of
functional glomeruli, thus reducing the total glomerular surface area as occurs in
hypertension.
Bowman's Space Hydrostatic Pressure
• In cases of urinary tract obstruction resulting in hydronephrosis, fluid backup into
Bowman's Space can increase its hydrostatic pressure and thus reduce GFR.
The concept of clearance:

• Metabolic waste products, ingested substances, and excess salt & water are
constantly being removed from the body (cleared) by a number of means-
urine, in the feces, biochemical transformation in the liver & exhalation.
• The rate of removal is expressed in either plasma half-life or clearance
the volume of plasma per unit time from which all of a specific substance is
removed.
• The general meaning of clearance is simply that a substance is removed from
the plasma by any of the mechanisms mentioned above- the metabolic
clearance rate.
• Renal clearance- means that the substance is removed from the plasma &
& excreted in the urine.
• The clearance of certain substances is a method to measure glomerular
filtration rate (GFR).
Unit of expressing clearance
• The units are volume per time (not amount of a substance per time).
• The volume is the volume of plasma that supplies the amount excreted
in a given time.
• For example, suppose each liter of plasma contains 10 mg of a
substance X, and 1 mg of substance X is excreted in 1 hour. Then 0.1
L of plasma supplies the 1 mg that is excreted, that is, the renal
clearance is 0.1 L/h.
• The red tube is a glomerulus
and the long cylinder at right
angles to the red glomerulus
is the whole nephron. The
urine leaving at the bottom
and filtrate coming in at the
top.
• The kidneys is shown as two
tubes in the picture.
• Blood flows in at Qi and
leaves at a lower flow Qo.
The difference (Qf) is
glomerular filtration rate
(GFR) – rate because we are
speaking about amounts per
unit time.
• The tubules as able to reabsorb
materials from the filtrate, or secrete
materials from blood into the
flowing filtrate.
• This is how the nephron transforms
filtrate into the final urine.
• If the substance is designated by the
letter X Creatinine (Cr), the GFR is
equal to the concentration of X in
urine (UX) times the urine flow per
unit of time (V) divided by the
arterial plasma level of X (PX).
• GFR= UX xV/ PX
• This value is called the clearance
of X (CX).
 Application of the concept of clearance to Estimation GFR :
Substances having the following
characteristics can be used to estimate
GFR.
• Stable plasma concentration that is
easily measured
• Freely filtered into Bowman’s space
• Not reabsorbed, secreted, synthesized,
or metabolized by the kidney
• Ideal substances include inulin, sucrose,
and mannitol.
• The clearance of inulin is considered
the gold standard for the measurement
of GFR, but it is not used clinically.
• Instead clinical estimates of GFR rely
on creatinine.
• Creatinine is released from skeletal muscle at a constant rate proportional to
muscle mass. Muscle mass decreases with age but GFR also normally
decreases with age. Creatinine is freely filtered & not reabsorbed by the
kidney, though a very small amount is secreted into the proximal tubule.
Creatinine production = creatinine excretion = filtered load of creatinine
= Pcr × GFR
• Thus, if creatinine production remains constant, a decrease in GFR increases
plasma creatinine concentration, while an increase in GFR decreases plasma
creatinine concentration.
• Thus the only practical numerical estimate is the calculated clearance of
creatinine. The following is all that is needed:
• Plasma creatinine concentration
• Timed collection of urine
• The urine concentration of creatinine
• Plasma creatinine, however, is not a
very sensitive measure of reduced
GFR. It only reveals large changes in
GFR.
• A significant reduction of GFR only
produces a modest elevation of plasma
or serum creatinine concentration.
• For e.g. in this graph the GFR reduced
to about 75 ml/min before a significant
increase in serum creatinine level was
detected.
• When using clearance of creatinine (C ) to determine GFR it should be
reminded that some creatinine is secreted by the tubules, thus the
clearance of creatinine will be slightly higher than inulin.
• However,the clearance of endogenous creatinine is a reasonable
estimate of GFR as the values agree quite well with the GFR values
measured with inulin. More common though is the use of PCr values
as an index of renal function (normal = 1 mg/dL).
Renal plasma clearance of other substances & GFR
True GFR – Inulin Clearance
• Inulin, a large carbohydrate polymer after filtration is neither reabsorbed nor
secreted in renal tubule. It passes as through a glass tube.
• The clearance of inulin is GFR.
A loading dose of inulin is administered intravenously, followed by a sustaining
infusion to keep the arterial plasma level constant.
After the inulin has equilibrated with body fluids, an accurately timed urine
specimen is collected & a plasma sample obtained halfway through the
collection.
Plasma & urinary inulin concentrations are determined and the clearance is
calculated:
 Clearance curves for some characteristic substances
• Inulin: The clearance of inulin is
independent of the plasma concentration,
thus plotting it on the graph produces a line
parallel to the X-axis.
• A rise in the plasma concentration produces
a corresponding rise in filtered load & thus a
corresponding rise in excretion rate (inulin
is neither secreted nor reabsorbed).
• Thus the numerator & denominator of the
clearance equation for inulin change in
proportion, leaving the quotient (clearance)
unchanged. (UV/P)
• It is always parallel to the x axis, and the
point of intersection with the y axis is
always GFR.
• If GFR increases, the line shifts upward;
• if GFR decreases, the line shifts down
 Clearance of Glucose
• At low plasma levels, the clearance of
glucose is zero because all of the filtered
load is reabsorbed.
• As the plasma levels rise, the filtered load
exceeds the tubular maximum TM in some
nephrons & as a result, glucose appears in
the urine and thus has a clearance.
• The plasma level at which glucose first
appears in the urine is called the plasma (or
renal) threshold.
• As the plasma level rises further, the
clearance increases and approaches that of
inulin. The clearance never equals inulin
because some glucose is always reabsorbed.
 Creatinine

• Because there is some secretion of creatinine,

the clearance is always greater than the
clearance of inulin.
• However, because only a small amount is
secreted, creatinine clearance parallels inulin
clearance and is independent of production
rate (excretion rises as plasma concentration
increases).
• Because it is endogenously produced, it is not
necessary to infuse it to get a clearance
measurement, as in case of inulin clearance.
• Therefore, the clearance of creatinine is the
preferred clinical method for determining
GFR.
• At low plasma concentrations, the clearance equals PAH
renal plasma flow.
• Plasma concentrations above TM reduce the
clearance of PAH resulting in some PAH appearing
in the renal venous plasma.
• As the plasma level rises further, the clearance
approaches but never equals GFR because some
PAH is always secreted.
• Remember, if a substance is in the renal vein, it is
not cleared. This could be because it was not filtered
(like albumin) or it was filtered and all reabsorbed
(like glucose).
• Summary of the highest clearance to the lowest
clearance:
• PAH > creatinine > inulin > urea > sodium >
glucose = albumin
 Free water clearance (CH2O)
• Free water clearance is the best measure of the balance between solute and
water excretion -whether the kidneys are responding appropriately to
maintain normal plasma osmolality.
• If urine osmolality is 300 mOsm/kg (isotonic urine), free water clearance is
zero.
• If plasma osmolality is too low, urine osmolality should be lower still
(positive free water clearance) in order to compensate.
• Positive-free water clearance tends to cause increased plasma osmolality;
negative free water clearance causes reduced plasma osmolality.
• CH2O (+) = hypotonic urine is formed (osmolality <300 mOsm/kg)
• CH2O (–) = hypertonic urine is formed (osmolality >300 mOsm/kg)
 Sample Calculation

• V=CH2O + Cosm
• Urine flow rate (V) = 3.0 mL/min
• Urine osmolarity (Uosm) = 800 mOsm/L
• Plasma osmolarity (Posm) = 400 mOsm/L
• Free water clearance (CH2O) = –3 mL/min
• Conclusion: This means the kidneys are conserving water; this is appropriate
compensation for the excessive plasma osmolarity in this patient.
Sodium clearance
• Sodium always appears in the urine, thus sodium always has a positive
clearance.
• The fractional excretion of Na+ (FE Na+;indicates the fraction (percentage)
of the filtered Na+ that is excreted. It is very useful in differentiating prerenal
from intrarenal acute renal failure.
• Since almost the entire filtered load of sodium is reabsorbed its clear- ance is
just above zero.
• Aldosterone, by increasing the reabsorption of sodium, decreases the FeNa+.
• Atrial natriuretic factor increases the FeNa+ by causing a sodium diuresis.
 Urea clearance
• Urea is freely filtered but partially reabsorbed. Some urea is always present in
the urine, a portion of the 120 mL/min filtered into Bowman’s space is always
clear ed.
• Since urea tends to follow the water and excretion is flow dependent, a
diuresis increases urea clearance and an antidiuresis decreases urea clearance.
• ADH increases reabsorption of urea in the medullary collecting duct →
increase in BUN → decrease in clearance.
• Thus if the plasma concentration is increasing in the renal venous plasma, less
is cleared from the plasma
• With a small volume of concentrated urine, the concentration of urea is
relatively high, but the excretion is less than in a diuresis that has a much
lower concentration of urea. It is the large volume in the diuresis that
increases the urea excretion and clearance.
Normal clearance values of different solutes
 Size of capillary bed
• Mesangial cells can contract causing reduction in the area available for
filtration. Contracted mesangial cells distort and encroach on the capillary
lumen. The glomerular ultrafiltration coefficient (Kf ) will be thus reduced.
• Angiotensin II is an important regulator of mesangial contraction, and there are
angiotensin II receptors in the glomeruli.
• Substances that cause contraction of mesangial cells: Endothelins ,
Angiotensin II, Vasopressin, Norepinephrine, Platelet activating factor, Platelet
derived growth factor, Histamine
• Substances that cause relaxation of mesangial cells: Atrial natriuretic
peptide (hormone secreted from the cardiac atria which increases renal sodium
excretion and reduction in extracellular fluid) , dopamine,PGE2,cAMP
• Okay