3,4 - Formation of Urine

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Lecture 3 , 4

Formation of Urine
Each nephron is capable of forming urine by three processes
1) Glomerular filtration:
- Filtration from the glomerular capillaries into Bowman's capsule of a fluid that is nearly free of proteins.

2) Tubular reabsorption:
- It is the transfere of water and solutes from the filtrate back into the blood of the peri-tubular capillaries.

3) Tubular secretion:
- It is the transfer of solutes from the peri-tubular capillaries into the tubular lumen.

* The term excretion refers to what finally comes out in urine.


* The rate at which different substances are excreted in urine represents the sum of the
three processes.

Urinary excretion rate = Filtration rate - reabsorption rate + secretion rate.


Fig. (1), shows the basic mechanisms of nephron function.

Fig. (2-1)

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Glomerular Filtration

- 20 % Of the plasma flowing through the kidneys is filtered by the glomerular capillaries into Bowman’s
capsule. The filtered fluid is called Glomerular filtrate.

- Composition of the Glomerular filtrate:-


Fluid filtered by the glomerulus is protein-free ultra-filtrate of plasma i.e. plasma minus colloids.

- Glomerular membrane: -
The membrane that separates the blood in the glomerular capillaries from the Glomerular filtrate in
Bowman’s capsule is formed of three layers. (Figs.2 & 3).

Fig. (2) Fig. (3)

1. The capillary endothelium:-


It is perforated by small holes called fenestrae.

This layer does not act as a major barrier for plasma proteins as the fenestrations are relatively large
(70-90 nm in diameter).

2. Basement membrane:-
- It consists of a meshwork of collagen and proteoglycan fibrillae that have large spaces.

- The proteoglycan carry strong negative electrical charges, therefore, the basement membrane prevents
effectively filtration of plasma proteins, but filters large amounts of water and solutes.

3. Podocytes:-
These are epithelial cells that line the outer surface of the glomerulus. They have numerous pseudopodia that
interdigitate to form slit pores (25 nm wide) through which the glomerular filtrate moves.

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Mesangial cells:
These are stellate cells located between the basement membrane and the endothelium at bifurcation of the
capillaries (Fig. 4). These cells are contractile.

Function of the mesangial cells:


Play role in regulation of glomerular filtration rate as their contraction will reduce the surface area
available for filtration on the other hand their relaxation increases surface area.

Fig. (4) Relations of mesangial cells & podocytes to glomerular capillaries

• Surface area of the glomerular membrane:


The total surface area of the glomerular membrane across which filtration occurs in humans is about 0.8 m2.

 Permeability of the glomerular membrane:


The permeability of the glomerular capillaries is about 50 times that of the capillaries in skeletal muscle.

* Despite the great permeability of the glomerular membrane, it is highly selective in determining
which molecules will filter. This high selectivity is determined by:
1) Size of the solutes.

2) Electric change of the solute.

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1) Size of the solute:
- The permeability of the glomerular membrane to solutes decreases with increasing the molecular
diameter. ‫عكسى‬
- Neutral substances with effective molecular diameter of less than 4 nm are freely filtered and the filtration
of neutral substances with diameter of more than 8 nm approaches zero.

Between these values, filtration is inversely proportionate to diameter (Fig. 2-5).

2) Charge of the solutes:


- Negatively charged molecules are filtered less easily than positively charged molecules of equal molecular
diameter due to the negative charges in the basement membrane (Fig.5)

- This may explain why albumin with effective molecular diameter of approximately 7 nm, has a glomerular
concentration only 0.2% of its plasma concentration than the higher concentration that would be expected on
the basis of diameter alone (Circulating albumin is negatively charged).

- In certain kidney diseases, the negative charges on the basement membrane are lost leading to loss of
albumin in urine (Albuminurea) without an increase in the size of the pores in the membrane.

Fig. (5)

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Glomerular Filtration Rate (GFR)
* Definition:

Volume of the glomerular filtrate formed by the glomeruli of both kidneys per minute.

 Normal GFR:

- The GFR in an average - sized normal man is approximately 125 ml/min.

 Values in women are 10% less than those in men.

- It should be noted that 125 ml/min is 7.5 L/h or 180 L/day whereas normal urine volume is about
1 L /day.

 Therefore 99% or more of the filtrate is reabsorbed by the renal tubule.


- At the rate of 125 ml/min, the kidneys filter in one day an amount of fluid equal to 60 times the
plasma volume.

- Both BUN “blood uriy nitrogen “and plasma creatinine increase when GFR decreases.

- GFR decreases by 1ml/min/year after age 40 as part of aging process , although plasma creatinine
remains constant because of decreased muscle mass.

- GFR is considered the best test for kidney functions.

Measurement of GFR
By the use of:
1- Inulin Clearance 2- Creatinine Clearance

*Inulin is a polymer of fructose with a molecular weight of 5200 that is found in dahlia tubers.

 It possesses the following criteria: * ‫اسباب االختيار‬


1) Freely filtered through the glomeruli (not bound to plasma proteins).

So, the concentration of inulin in plasma = concentration of inulin in the filtrate.

2) Not reabsorbed or secreted by the renal tubules.

The amount filtered per minute = The amount excreted in urine per min.
3) Not metabolized.

4) Not stored in the kidneys.

5) Has not effect on filtration rate.

6) Easy to measure in plasma and urine.

 Steps:

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- A loading dose of inulin is injected intravenously followed by a sustained infusion to keep the
arterial plasma level constant. After inulin has equilibrated with body fluids, urine and plasma
samples are collected to determine concentration of inulin in each.

 Calculations:
- Quantity of inulin filtered per min = Quantity of inulin excreted in urine per min.

Cin X Pin = V X Uin Where:


Pin = concentration of inulin in plasma (same concentration as filtrate).

Uin = concentration of inulin in urine.

V = volume of urine / min.

Cin = volume of filtrate / min. i.e. GFR.

Cin is called the clearance of inulin which is the volume of plasma that is cleared from the quantity
of inulin excreted in urine / min.

Example:
Inulin is infused in a patient to achieve a steady-state plasma concentration of 2 mg/ml. A urine
sample collected during 2 hours has a volume of 120 ml and an inulin concentration of 240 mg/ml. What is
the patient's GFR?

Uinulin x V
GFR =
Pinulin
240 mg/ml x 1

2

 120 ml/min.

Creatinine Clearance = Ccr.

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Creatinine is an endogenous substance that is formed from creatine in muscle.

It possesses the following criteria: * ‫اسباب االختيار‬


1) Freely filtered.
2) Not reabsorbed.
3) Partially secreted by the renal tubule.

- GFR measured by creatinine clearance is slightly higher than GFR value measured with inulin because
creatinine is partially secreted .
- Endogenous creatinine clearance is easy to measure and is a worthwhile index of renal function.
- GFR can be estimated from the formula of “Cockcroft and Gault” which incorporates age,sex and weight
to estimate creatinine clearance from plasma creatinine level without any urinary measurement.

(140 - Age) X Weight (Kg)


________________________
eGFR =
P X 72
cr

For woman, the estimated GFR is multiplied by 0.85 because muscle mass is less.

Filtration fraction:
- Is the fraction of renal plasma flow filtered across the glomerular capillaries, i.e. the ratio of GFR to the
renal plasma flow.
Normal value 0.16 - 0.20.
- Thus, about 20% of the RPF is filtered. The remaining 80% leaves the glomerular capillaries by the
efferent arterioles and became the peri-tubular capillary circulation.

Control of GFR
- The factors govering filtration across the glomerular capillaries are the same as those govering filtration

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across all other capillaries.
These factors include:
1. Hydrostatic pressure gradient across capillary wall.
2. Osmotic pressure gradient across capillary wall.
3. Permeability of the glomerular capillaries.
4. Effective filtration surface area.
These factors are summarized by the Starling equation:

The GFR = KF (HPGc - HPBC) - (GC - BC)

= KF (HPGC - HPBC - GC + BC)

Where:
KF = The glomerular ultrafiltration co-efficient (ml/min/ mrnHg)
HPGC = The mean hydrostatic pressure in the glomerular capillaries (mmHg).
HPBC = The mean hydrostatic pressure in Bowman's capsule (mmHg). (Fig. 2-6)

GC = The osmotic pressure of plasma proteins in the glomerular capillaries (mmHg).

BC = The osmotic pressure of proteins in the filtrate (mmHg).

Forces favouring filtration (mmHg)


1- HPGC: approximately 60 mmHg.

2- BC : normally 0 mmHg because almost no protein is filtered across the glomerular capillaries. They are
repelled by the negative charges on the glomerular membrane.

Forces opposing filtration (mmHg)

1) HPBC= 18 mmHg. 2) GC = 32 mmHg

.These values are estimates for the normal humans.

- (Fig. 2-6) summarizes the forces causing filtration and those opposing by the glomerular capillaries. The
net filtering pressure = 60 - 18 – 32 = 10 mmHg

KF depends on:-
1. Permeability of the glomerular membrane.

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2. Surface area of the glomerular membrane.

KF ⇨ CAN’T be measured directly, but it is estimated by dividing GFR by the net filtration pressure since:

GFR = KF x net filtration pressure

KF = GFR / net filtration pressure = 125 ml / min /10 mmHg = 12.5 ml / min /1 mmHg

KF ⇨ is the glomerular filtration rate per one mmHg of filtration pressure.

* * Factors that affect GFR* *


From Starling equation, variations in the factors involved have predectable effect on GFR.

GFR = KF x (HPGC - HPBC) - (GC - BC)

1- Changes in ultrafiltration coefficient (Kf):


Kf: An increased Kf raises the GFR where a decrease in Kf reduces the GFR.

Kf is affected by:

1) Surface area of the glomerular capillaries: It's affected by:

a) Contraction of mesangial cells will reduce the surface area available for filtration; as contraction
at points where the capillary loops bifurcate shifts the blood flow from some capillary loops.

The following agents cause contraction of the mesangial cells and therefore decrease GFR

 Vasopressin ADH  Leucotrines A and D


 Norepinephrine  Endothelins
 ThromboxaneA2  PGF
 Histamine

b) Agents causing relaxation of mesangial cells with consequent increase of GFR.

 cAMP

 PGE2
 ANP
 Dopamin

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c) Some diseases lower KF by reducing the number of the functional glomerular capillaries, with
reduction of surface area for filtration e.g. chronic uncontrolled diabetes mellitus.

2) Permeability:
Increasing the thickness of the glomerular capillary membrane will reduce its permeability e.g. in
chronic uncontrolled diabetes mellitus and hypertension.

II. Changes in the glomerular capillary hydrostatic pressure:


- Increases in glomerular hydrostatic pressure raise GFR, whereas decreases in HPGC reduce GFR:
Glomerular hydrostatic pressure is determined by:

1. Diameter of the afferent arteriole:


a) Vasodilatation of the afferent arteriole  ++ HPGC ++ GFR

e.g. bradykinins, PGE2 and PGI2 .

b) Vaso-constriction of the afferent arteriole e.g. by noradrenaline during sympathetic stimulation


decrease HPGC decrease GFR..

- The increased sympathetic activity that occurs during exercise may reduce GFR to less than 50% of
normal.

2. Diameter of the efferent arteriole:


Moderate vasoconstriction of the efferent arteriole increases the resistance to the outflow from the
glomerular capillaries.

- This raises the HPGCslight increase of GFR. e.g. angiotensin II.

3. Arterial blood pressure:


- The renal blood flow and GFR are kept relatively constant despite marked changes in arterial blood
pressure (between 90-220 mmHg) by autoregulatory mechanisms.

Increased arterial pressure tends to raise HPGC and to increase GFR. However, this effect is buffered
by autoregulatory mechanisms. However, when the mean systemic pressure drops below 75 mmHg,
there is a sharp drop in GFR.

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Mechanisms of auto-regulation
a) Myogenic auto-regulation:
Will discuss later in regulation of renal blood flow.

This response is rapid and it is the first line of defense against rapid change in blood pressure. An
increase in ABP results in stretching of the afferent arteriolar wall  contraction of the smooth muscles
and returns the diameter towards normal to minimize change in glomerular capillary pressure. Conversely
a decrease in ABP results in relaxation of smooth muscle.

b) Tubulo-glomerular feed back:

Is responsible for auto-regulation of renal blood flow. L5


Will discuss later in regulation of renal blood flow

III. Changes in Bowman's Capsule Hydrostatic Pressure:


- Increasing HPBC reduces GFR.
- A stone in the ureter that obstructs the outflow of urine from the ureter will decrease GFR by raising
HPBC.

IV. Changes in the glomerular colloid osmotic pressure:


- Changes in the concentration of plasma proteins affect GFR as follows:

1. An increase in GC e.g. in dehydration will decrease GFR.


2. A decrease in GC e.g. in cases of hypoproteinemia will increase GFR.

V. Renal Vasodilators:
- PGE2, PGl2 and bradykinin produce renal vaso-dilatation, and increase in renal blood flow and GFR.
- Administration of anti-inflammatory drug like aspirin that block PG synthesis may cause marked
reduction in GFR.
- Prostaglandin synthesis in the kidneys in increased by sympathetic nervous system stimulation and
angiotensin II. This may protect the renal vessels from severe vasoconstriction during high
sympathetic activity and elevated angiotensin II in situation of severe cardiovascular stress like
haemorrhage.

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VI. Effect of protein intake:
- High protein intake increases renal blood flow and GFR.
- Mechanism:
- High protein intake rise of amino acids into the bloodfilter in Bowman's capsule.
- Increased amino acids reabsorption stimulate sodium reabsorption in the proximal tubules. This
decreases sodium delivery to the macula densa which in turn elicits tubule-glomerular feedback
afferent arteriole vasodilatation and efferent arteriole vasoconstriction that raises HPoc and GFR.
***********

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