HUMAN
RENAL SYSTEM PHYSIOLOGY
Lecture 5,6
BY: LECT. DR. ZAINAB AL - AMILY
Renal artery stenosis
• Glomerular capillary blood pressure is
determined in part by the aortic pressure and by
the preglomerular vascular resistance.
• The preglomerular vascular resistance is
predominantly at the afferent arteriole.
• A stenosis in the renal artery introduces a
preglomerular vascular resistance and decreases
glomerular capillary pressure.
• The decrease in glomerular capillary pressure
results in the fall in glomerular filtration rate
and the shift toward retention of sodium and
water.
• Retention of water and sodium causes an
increase in systemic arterial blood pressure;
and as soon as the blood pressure is
sufficiently high, glomerular capillary pressure
returns to normal.
• Renal artery constriction also limits blood flow to
the kidney and can result in a failure of the kidney
to grow and develop normally in children.
• Adults with significant renal artery stenosis often
exhibit an asymmetric or smaller than normal
kidney.
• Hypertension caused by renal artery stenosis is
often refractory to treatment.
• This is because the underlying defect persists and
any successful treatment of systemic hypertension
results in a lower renal perfusion (glomerular
capillary) pressure and shifts the renal fluid balance
into retention of sodium and water.
Glomerular Disorders
Glomerulo-nephritis:- Inflammation of the glomerulus
Immunologic abnormalities (most common)
Drugs or toxins
Vascular disorders
Systemic diseases
Viral causes
It is the most common cause of end-stage renal failure
Glomerulonephritis
Glomerular Disorders
• Glomerular diseases causes:1. Glomerular membrane surface area.
2. Glomerular capillary blood flow.
3.
Blood hydrostatic pressure.
5.
Negative ionic charge barrier.
4.
Glomerular capillary permeability.
So
Hematurea
+
Loss of Plasma Pr. In urine
hypoalbuminemia
Leakage of plasma fluid into the interstitial spaces
Edema
Glomerular diseases
Two categories
Nephritic syndrome
Nephrotic syndrome:group of diseases
Membr. glomerulonephritis
All the different types
Focal glomerulosclerosis
inflammation & injury
Minimal change disease
- Proteinuria – Oliguria
Loss of > 3.5 g/day of
- Hematuria - Hypertension
protein in urine
- Pyuria
- Azotemia.
Hypoalbuminemia, edema
- Edema
hyperlipidemia, & lipiduria
Pathophysiology of Nephrotic syndrome
Minimal change disease
Normal glumerular structure
Tubular Processing of the Glomerular
Filtrate:
A. Tubular Reabsorption:
• Unlike glomerular filtration, tubular reabsorption is more
selective:
i. Some substances such as glucose and AA are almost
completely reabsorbed from the tubules.
ii.Many ions in the plasma like Na+, Cl¯ and HCO3¯ are also
highly reabsorbed (variable reabsorption rate)
iii.Certain waste products such as urea and creatinine,
however, are poorly reabsorbed and excreted in relatively
large amounts.
–Therefore, the kidneys regulate the excretion of solutes
independently for the precise control of body fluid
composition.
• For a substance to be reabsorbed,
it must first be transported across
the tubular epithelial membranes
into the renal interstitial fluid (ISF),
and thence, the peritubular
capillaries.
• Reabsorption across the tubular
epithelium includes active or
passive transport mechanisms.
• Water or solutes can be
transported either through cell
membranes(transcellular
transport) or through junctional
spaces
between
the
cells
(paracellular transport),
• Then, to the peritubular capillary
by (ultrafiltration or bulk flow),
mediated by hydrostatic and colloid
osmotic forces.
Tubular Processing of the Glomerular
Filtrate:
A. 1. Active Transport:
• is the movement of solutes
against the electrochemical
gradient, which requires
energy that is derived from
metabolism.
i. Primary Active Transport:
•It is coupled directly to an
energy source such as the
hydrolysis of ATP by way of
membrane-bound
ATPase
pump.
• A good example is the (Na+–K+ ATPase) pump that
functions through most parts of the renal tubules.
Other examples include the (H+–K+ ATPase) pump.
• ii- Secondary Active Transport:
•Two or more substances interact with a specific
membrane protein (a carrier molecule) and are cotransported together across the membrane.
•An example is the secondary active transport of
glucose and AA in the proximal tubule.
• Glucose moves from tubular fluid into the cell on the
Na+-glucose cotransporter (called SGLT) in the luminal
membrane.
• Two Na ions and one glucose bind to the cotransport
protein, Na and glucose are released into the ICF.
• In this step, glucose is transported against an
electrochemical gradient; the energy for this uphill
transport of glucose comes from the downhill
movement of Na
• So secondary active transport of glucose occurs at the
luminal membrane, while passive (facilitated) diffusion
occurs at the basolateral membrane
• The proteins involved in facilitated diffusion of glucose
are Called GLUT 1 and GLUT 2 and passive uptake by
bulk flow at the peritubular capillaries.
Tubular Processing of the Glomerular
Filtrate (continues):
A. 1. Active Transport:
• Transport Maximum:
• For most substances that are actively
reabsorbed or secreted, there is a limit,
referred to as “transport maximum Tm”
• due to saturation of the specific
transport systems that are involved,
when the tubular load of that substance
exceeds the capacity of the carrier
protein or the specific enzymes involved.
• A good example is the glucose transport system. Under normal
conditions, glucose is transported at a rate of approximately (100
mg/ minute), called the filtered load of glucose
• What is filtered load?
• is the amount of substance that filters through the glomerular
membrane into tubules each minute.
Filtered load of glucose = GFR × Pglucose
• Where Pglucose=(80 mg/100mL), and hence, filtered load of
glucose = 100 mg/ minute.
• Essentially, all of the glucose is reabsorbed and not more than a
few mgs appear in urine/day.
• The amount reabsorbed is proportionate to the amount filtered
and, hence, to (Pglucose) × GFR) up to the transport maximum for
glucose (TmG); beyond which, the amount rises in urine
• The (TmG) is about (375 mg/ minute) in men and (300 mg/
minute) in women.
• What is renal threshold for a substance?
• Every substance that has a transport maximum also has
a specific (threshold) concentration in the plasma
below which none of it appears in the urine and above
which progressively larger quantities appear in urine.
• This concentration is called renal threshold,
e.g. renal threshold for glucose is 180 mg/100 ml.
• What are non-threshold substances?
• Substances which are excreted in urine at any
concentration in plasma are called non threshold
substances. They do not possess threshold level in
plasma, e.g. urea, uric acid, sodium (in proximal
tubules).
• A 63-year-old hospitalized woman becomes oliguric
and confused. A blood sample is drawn to measure
her glucose concentration, which is found to be 35
mg/dL.
• An IV access is obtained and an ampule of 50%
dextrose is given followed by a continuous infusion
of 10% dextrose. Most of the glucose that is filtered
through the glomerulus undergoes reabsorption in
which of the following areas of the nephron?
• a. Proximal tubule
• b. Descending limb of the loop of Henle
• c. Ascending limb of the loop of Henle
• d. Distal tubule
• e. Collecting duct
Tubular Processing of the Glomerular
Filtrate:
A. 2. Passive Transport (reabsorption):
• Substances that are passively reabsorbed do not
demonstrate a (Tm), because rate of transport is determined
by two main factors:
i. An electrochemical gradient for diffusion from the
tubular lumen towards the peritubular capillaries.
ii. Tubular cell membrane is permeable to this substance.
iii.Time that the fluid containing the substance remains
within the tubule. Transport of this type is referred to
(gradient-time transport), which in turn depends on the
tubular flow rate.
– An example of passively reabsorbed substances is the
passive reabsorption of urea, chloride and water:
• Movement of solutes out of the
tubule creates an osmotic gradient
that favors water movement in the
same direction. Only, if the
membrane is permeable to water.
• For chloride ions, the active
reabsorption of Na+ is closely
coupled to the passive reabsorption
of Cl- through the paracellular
pathways
by
way
of
an
electrochemical gradient.
• Finally, urea is also passively
reabsorbed from the tubules down a
concentration gradient caused by
water reabsorption from the lumen.
• Urea does not permeate the tubule
as water, and therefore, about half
the filtered urea passes into urine.
• B.Tubular Secretion: an active or passive process. ex. (PAH).
Tubular secretary processes involve the transport of
substances into the tubular lumen from the tubular cells
themselves, or through the tubular cells from the
peritubular capillaries.
The amount of a substance that is secreted in urine is
calculated as the amount excreted of that substance minus
the amount that is filtered. In case of active secretion,
there is also a limited capacity for the tubular secretion of
different substances caused by saturation of the transport
systems.
• The substances which are secreted by renal tubules.
• Potassium ions are secreted in the distal tubule and collecting
ducts. Potassium and hydrogen are both exchanged for
sodium which is reabsorbed. Potassium secretion is modified
by plasma level of aldosterone.
• Hydrogen ions are secreted throughout the renal tubule but
most significantly in the distal tubule.
• Certain foreign substances and drugs are secreted. Paraaminohippuric acid (PAHA-foreign substance) is secreted
actively by proximal tubular cells.
• penicillin is also similarly secreted.
• Tubular secretion of foreign substances is important in
clearing of the plasma of a substance in one passage through
the kidney.
• Tubular secretion of drugs plays important role in maintaining
the blood level of the drug and hence the therapeutic
efficiency.
Reabsorption of Na+ and Water Along Different Parts
of the Nephron :
• The amount of Na+ in the food is variable, but kidneys can
change their excretion rate in spite of the great variation of Na+
intake. Na+ is freely filtered at the glomerulus , around 99.4% of
the filtered Na+ is reabsorbed.
1) In the Proximal Convoluted Tubule:
• Na+ reabsorption is an active process, produced by the activity
of (Na+–K+ ATPase) pump in the basolateral membrane of the
tubular cells.
• In the first half of the proximal tubule, Na+ is reabsorbed by
co-transport along with glucose, aminoacids, organic acids and
other solutes.
• The second method by which (Na+) is reabsorbed by the renal
tubules is in exchange with the secreted (H+) ions.
• Depending on Pco2, CO2 in the tubular cells react with
H2O to form carbonic acid (H2CO3) under influence of
carbonic anhydrase enzyme, H2CO3 dissociates into (H+)
and (HCO3-) and (H+) is secreted in exchange with Na+
which is an example of a secondary active transport.
• The energy liberated from the downhill movement of
Na+ ions into the interior of the cell, enables the uphill
movement in the opposite direction of H+ ions outward
• There is a passive reabsorption of Cl¯ ions.
• The accumulation of these substances (Na+, Cl¯ and
HCO3¯) will increase the osmotic pressure in the ISF,
causing the passive reabsorption of water into it
• Na+, water and other substances are reabsorbed
from the ISF into the peritubular capillaries by
ultrafiltration (a passive process that is driven by
the hydrostatic and colloid osmotic pressure
gradient).
• At the end of the proximal convoluted tubules, 60 –
70% of the filtered solutes and water have been
removed.
• What is glomerulotubular balance in proximal
tubule?
• Under normal condition, almost a constant
percentage of sodium and fluid (about 65%) is
reabsorbed while the filtrate is passing through
proximal tubule regardless of the rate of glomerular
filtration.
• This is called glomerulotubular balance, e.g. when
GFR is 100 ml/min, tubular reabsorption is 65
ml/min. If GFR increases to 200 ml/min, tubular
reabsorption also increases to 130 ml/min, thus
maintaining proportional balance (65%).
• What is the importance of glomerulotubular
balance?
• Glomerulotubular balance prevents overloading of
more distal tubular segments when the GFR
increases.
• Glomerulotubular balance therefore acts as a
second line of defense to buffer the effects of
spontaneous increase in GFR on urine output.
• How much is the normal rate of reabsorption in
renal tubules?
• Normal rate of reabsorption in peritubular
capillaries is 124 ml/min. GFR, i.e. amount of filtrate
entering the tubule is 125 ml/min. Volume of urine
formed is therefore approximately 1 ml/min.
Reabsorption of Na+ and Water Along
Different Parts of the Nephron :
2) In the Loop of Henle:
• The descending limb and the thin segment of the ascending limb of
the loop of Henle are permeable to water;
• while, the thick ascending segment of Henle’s loop is impermeable to
water, but permits the co-transport of (Na+, K+ and Cl¯) out of the
tubular lumen.
• Therefore, the fluid in the descending limb becomes hypertonic to
plasma, as water moves to the hypertonic interstitium.
• On the other hand, it becomes hypotonic to plasma in the ascending
limb due to the movement of solutes out of the tubular lumen.
• Here, another 15% of the filtered water is reabsorbed.
Reabsorption of Na+ and Water Along Different
Parts of the Nephron :
2) In the Loop of Henle:
• The transport mechanism in the thick ascending limb depends on
a carrier that transports the three ions from the tubular lumen
into the tubular cells.
• (Na+- K+ ATPase pump) at the basolateral membrane of the
tubular cells has the important role, where it maintains a
favorable gradient for the movement of Na+ from the tubular
lumen into the cell.
• This portion of the renal tubule has a higher Na+- K+ ATPase
content than any other part.
• The K+ diffuses passively back into the tubular lumen.
• One Cl¯ ion diffuses passively into the ISF, and one is cotransported with K+ ion.
• A 65-year-old male with a past medical history of COPD,
hypertension, diabetes mellitus type II, and
hypercholesterolemia presents to the emergency department
with swelling of the legs and feet and shortness of breath.
After complete history, physical exam, and appropriate
diagnostic testing, it is determined that the patient is
experiencing volume overload as a result of an acute
exacerbation of congestive heart failure. The patient is started
on oxygen therapy, nebulizer treatments, and intravenous
furosemide, which inhibits sodium reabsorption in the thick
ascending limb of the loop of Henle via which of the following
mechanisms?
• a. Na+ Cl− cotransport
• b. Na+/H+ exchange
• c. Na+/K+ exchange
• d. Na+ − K+ − 2Cl− cotransport
• e. Na+/nutrient cotransport
Reabsorption of Na+ and Water Along Different Parts
of the Nephron :
3) In the Distal Convoluted Tubule and the Cortical Collecting
Duct:
• The first part is in effect an extension of the thick segment of the
ascending limb with the same reabsorptive characteristics.
• The second part of the distal tubule and the subsequent cortical
collecting duct have similar functional characteristics. They are
composed of two distinct cell types:
-The principal (P) cells.
- The intercalated (I) cells.
• P cells reabsorb Na+ and water from the tubular lumen, and secrete K+
into the lumen, depending again on the activity of the Na+- K+ ATPase
pump in each cell.
•Here, Na+ reabsorption and K+ secretion is under the
influence of aldosterone hormone, that is secreted
from the adrenal cortex.
•It increases the number of special active Na+
channels in the apical (luminal) membrane of the P
cells.
•It increases the Na+- K+ ATPase pump;
•thereby, Na+ and water reabsorption and K+
secretion are regulated according to the body
requirements.
Reabsorption of Na+ and Water Along Different
Parts of the Nephron :
3) In the Distal Convoluted Tubule and the Cortical Collecting Duct:
• The I cells avidly secrete H+ ions and reabsorb HCO3¯ and K+ ions.
Here, most H+ ions are secreted by an ATP- driven proton pump (H+ ATPase).
• Aldosterone hormone acts also on this pump to increase the distal H+
secretion. These I cells play a key role in acid – base regulation.
• Moreover, this segment is also under the control of antidiuretic
hormone (vasopressin, ADH), which increases the permeability of the
renal tubules to water.
• About 5% of the filtered water is removed in this segment.
Reabsorption of Na+ and Water Along Different Parts of
the Nephron :
4) In the Medullary Collecting Duct:
• In this portion of the collecting duct, water permeability is again
controlled by the levels of vasopressin hormone from the posterior
pituitary gland; which increases water permeability of the membranes
of the collecting ducts by causing rapid insertion of (aquaporin- 2) water
channels into the luminal membrane of the P cells.
• In the presence of enough vasopressin to produce maximal antidiuresis,
as much as 14.7% of the filtered water is removed from the collecting
ducts.
• This produces concentrated urine, with a total of 99.7% of the filtered
water being reabsorbed.
• On the other hand, in the absence of ADH, only about 2% of the filtered
water is reabsorbed along with the salt that is pumped out of the
collecting duct.
• A 57-year-old woman with chronic cardiac failure
presented at the University Medical Center to
participate in a clinical research study on the genetics
of heart failure. Genetic analysis showed an increase in
ADH gene expression and associated hypothalamic
biosynthesis of the hormone, in addition to increased
release of the hormone from the posterior pituitary. In
the presence of ADH, the filtrate will be isotonic to
plasma in which part of the kidney?
• a. Ascending limb of the loop of Henle
• b. Descending limb of the loop of Henle
• c. Cortical collecting tubule
• d. Medullary collecting tubule
• e. Renal pelvis
At which nephron site does
the amount of K+ in tubular
fluid exceed the amount of
filtered K+ in a person on a
high-K+ diet?
(A) Site A
(B) Site B
(C) Site C
(D) Site D
(E) Site E