Physiologic Principles of dialysis. part 1

1. Physiologic Principles
and Urea Kinetic
Modeling
By
Shazia Batool
Lecturer and Program Coordinator
DT(DEAHT)
University of Lahore

2. What is Dialysis
• Dialysis is a process whereby the solute composition of a solution A, is
altered by exposing solution A to a second solution B, through a
semipermeable membrane. Conceptually, one can view the
semipermeable membrane as a sheet perforated by holes or pores.
Water molecules and low-molecular-weight solutes in the two
solutions can pass through the membrane pores and intermingle, but
larger solutes (such as proteins) cannot pass through the
semipermeable barrier, the quantities of high-molecular-weight
solutes on either side of the membrane will remain unchanged.

4. MECHANISMS OF SOLUTE TRANSPORT.
• Solutes that can pass through the membrane pores are transported
by two different mechanisms:
• diffusion
• ultrafiltration (convection).

5. Diffusion
• The movement of solutes by diffusion is the result of random
molecular motion. The larger the molecular weight of a solute, the
slower will be its rate of transport across a semipermeable
membrane. Small molecules, moving about at high velocity, will
collide with the membrane often, and their rate of diffusive transport
through the membrane will be high. Large molecules, even those that
can fit easily through the membrane pores, will diffuse through the
membrane slowly because they will be moving about at low velocity
and colliding with the membrane infrequently

8. Ultrafiltration
The second mechanism of solute transport across semipermeable
membranes is ultrafiltration (convective transport). Water molecules are
extremely small and can pass through all semipermeable membranes.
Ultrafiltration occurs when water driven by either a hydrostatic or an
osmotic force is pushed through the membrane Those solutes that can pass
easily through the membrane pores are swept along with the water (a
process called “solvent drag”). The water being pushed through the
membrane is accompanied by such solutes at close to their original
concentrations. Analogous processes are wind sweeping along leaves and
dust as it blows and current in the ocean moving both small and large fish as
it flows. Larger solutes, especially those that are larger than the membrane
pores, are held back. For such large solutes, the membrane acts as a sieve.

11. Hydrostatic ultrafiltration
• Transmembrane pressure
• Ultrafiltration coefficient (KUF)

12. Transmembrane pressure
During hemodialysis, water (along with small solutes) moves from the
blood to dialysate in the dialyzer as a result of a hydrostatic pressure
gradient between the blood and dialysate compartments. The rate of
ultrafiltration will depend on the total pressure difference across the
membrane (calculated as the pressure in the blood compartment
minus the pressure in the dialysate compartment).

14. Ultrafiltration coefficient (KUF)
• The permeability of dialyzer membranes to water, though high, can
vary considerably and is a function of membrane thickness and pore
size. The permeability of a membrane to water is indicated by its
ultrafiltration coefficient, KUF. KUF is defined as the number of
milliliters of fluid per hour that will be transferred across the
membrane per mm Hg pressure gradient across the membrane.

15. Osmotic ultrafiltration.

16. Purpose of ultrafiltration.
Ultrafiltration during dialysis is performed for the purpose of removing
water accumulated either by ingestion of fluid or by metabolism of
food during the interdialytic period. Typically, a patient being dialyzed
thrice weekly will gain 1–4 kg of weight between treatments (most of it
water), which will need to be removed during a 3–4-hour period of
dialysis. Patients with acute fluid overload may need more rapid fluid
removal. Thus, the clinical need for ultrafiltration usually ranges from
0.5 to 1.2 L/hr.

17. Use of ultrafiltration to enhance solute
clearance
• Hemofiltration and hemodiafiltration.
Whereas diffusive removal of a solute depends on its size, all
ultrafiltered solutes below the membrane pore size are removed at
approximately the same rate. This principle has led to use of a technique
called hemofiltration, whereby a large amount of ultrafiltration (more than is
required to remove excessive fluid) is coupled with infusion of a replacement
fluid in order to remove solutes. Although hemodialysis and hemofiltration
often show comparable removal of small solutes such as urea (MW 60),
hemofiltration can effect much higher removal of larger, poorly diffusible
solutes, such as inulin (MW 5,200). Sometimes hemodialysis and
hemofiltration are combined. The procedure is then called hemodiafiltration.

18. Removal of protein-bound compounds
The normal kidney detoxifies protein-bound organic acids and bases.
Being protein bound, they are filtered to only a small extent and so
bypass the glomerulus. However, in the peritubular capillary network,
these substances are removed from albumin and are taken up by
proximal tubular cells. Then they are secreted into the tubular lumen,
to be excreted in the urine. Other protein-bound compounds (bound to
albumin and small proteins) are filtered in the glomerulus along with
their carrier proteins. In the proximal tubule, the filtered proteins are
catabolized along with their bound compounds.

19. The plasma concentration of such protein-bound substances is
markedly elevated in dialysis patients but the association between high
blood levels of these compounds and mortality is not completely clear.
Removal of protein-bound compounds by hemodialysis depends on the
percentage of the “free” fraction of the compound in plasma (the
fraction that is exposed to dialysis). Also, removal depends on how
quickly the free fraction is replenished by the protein-bound pool.
Substances that are tightly bound to proteins with a low free fraction in
the plasma will be removed to a small extent by conventional
hemodialysis.

20. SOLUTE REMOVAL FROM THE PERSPECTIVE
OF THE DIALYZER
In clinical use, the box containing two solutions in fig. becomes
the dialyzer, containing blood and dialysis solution. The latter consists
of highly purified water to which sodium, potassium, calcium,
magnesium, chloride, bicarbonate, and dextrose have been added. The
low-molecular-weight waste products that

21. accumulate in uremic blood are absent from the dialysis solution.
When uremic blood is exposed to dialysis solution, the flux rate of
these waste solutes from blood to dialysate is initially much greater
than the back-flux from dialysate to blood. Eventually, if the blood and
dialysate were left in static contact with each other via the membrane,
the concentration of permeable waste products in the dialysate would
become equal to that in the blood, and no further net removal of waste
products would occur. Transport back and forth across the membrane
would continue, but the rates of transport and back-transport would be
equal.

22. In practice, during dialysis, concentration equilibrium is prevented, and
the concentration gradient between blood and dialysate is maximized,
by continuously refilling the dialysate compartment with fresh dialysis
solution and by replacing dialyzed blood with undialyzed blood.
Normally, the direction of dialysis solution flow is opposite to the
direction of blood flow. The purpose of “countercurrent” flow is to
maximize the concentration difference of waste products between
blood and dialysate in all parts of the dialyzer.

23. A. Extraction ratio

24. Figure shows a schematic of a dialyzer and its effects on the serum urea
nitrogen (SUN) concentration of blood entering and leaving the
dialyzer. The extraction ratio is the percentage reduction of urea (or any
other solute) across the dialyzer. In the case shown, with blood flow
rate (QB) of 400 mL/min, the inlet SUN (blood urea nitrogen) is 100
mg/dL and the outlet concentration is 40 mg/dL; hence, the extraction
ratio is 60% (100 − 40)/100. The extraction ratio is not affected by the
inlet SUN level. Under the same conditions, if the inlet SUN were 200
mg/dL, the outlet SUN would be 80, and if the inlet SUN were 10, the
outlet SUN would be 4.

26. The extraction ratio is affected by the rate of blood flow through the dialyzer
(Fig. 3.4). If blood flow rate were reduced from 400 to 200 mL/min, the
outlet SUN would decrease from 40 to 12 mg/dL. If blood flow rate were
reduced to 1 mL/min, the outlet SUN would be very low, about 1 mg/dL, and
if a very high rate of blood flow were used, 20 L/min, the outlet SUN would
increase to about 97 mg/dL. The faster the blood flows through the dialyzer,
the less time it spends in the filter. The dialyzer blood compartment volume
is about 100 mL, so at a flow rate of 400 mL/min, the blood is spending
about 15 seconds in the dialyzer. On reducing the flow to 200 mL/min, the
transit time doubles, to 30 seconds, and because of this, the blood has more
time to be “cleaned,” and the SUN in the blood exiting the dialyzer is only 12
mg/dL. On reducing flow to 1 mL/min, the blood would spend a full 100
minutes in the dialyzer, and the outlet blood would have a very low
concentration of urea nitrogen.

27. On the other hand, at a very rapid flow rate, much higher than could be
achieved in practice, say 20,000 mL/min, the blood would spend only
0.3 seconds in the dialyzer. Still, the outlet SUN would be lower than
the inlet and might be about 97 mg/dL. In effect, the dialyzer is a
“washing machine,” and the less time the blood spends in the machine,
the lower the percentage of waste products removed from a given
volume of blood.

29. B. Concept of clearance

30. As shown in Figure 3.5, the blood exiting the dialyzer can be considered
in one of two ways. One can consider the entire volume and the
percentage reduction of solute in that volume, or one can separate out
the flow exiting the dialyzer into two streams—in the first stream, the
concentration of solute will be the same as the inlet concentration, and
in the second stream, all urea nitrogen will have been removed. One
can think of an extraction ratio or reduction in SUN of 60% for the
combined outlet stream, or one can consider that 60% of the fluid
flowing through the dialyzer has been completely cleared of urea. If we
mix the unchanged stream with the cleared stream, the concentration
of urea nitrogen in the mixed stream will be reduced by 60% relative to
that in the dialyzer

31. inlet. One can calculate what the relative flow rates of the unchanged
stream and the cleared stream would need to be to achieve mass
balance. In this case, the flow rate of the cleared stream is simply 60%
of the inlet flow rate. If the inlet flow rate is 400 mL/min, the flow rate
of the cleared stream would be 0.60 × 400 = 240 mL/min, and the flow
rate of the unchanged stream would be 160 mL/min. Thus, a dialyzer
extraction ratio of 60% translates into a dialyzer clearance of 0.6 ×
blood inflow rate (QB), or 240 mL/min. Clearance is usually abbreviated
as “K” or “KD.” Flow rate is abbreviated as “Q,” and blood flow rate is
abbreviated as “QB,” and dialysate flow rate as “QD.”

32. 1. Effect of dialyzer blood flow rate on
clearance

33. 1. Effect of dialyzer blood flow rate on
clearance
We now can look at the effects of blood flow (QB) on dialyzer clearance (KD).
From Table , we see that when blood flow is very low, 50 mL/min, the blood
in the dialyzer is cleaned very well, due to a long residence time in the
dialyzer, and the outlet SUN is only 1 mg/dL, with an extraction ratio of 99%.
However, the amount of blood cleared is limited by the flow rate of 50
mL/min; although 99% of the blood is cleared, 99% of 50 mL/min is a low
number. When the blood flow rate is increased, the blood is only partially
cleared of urea due to less time spent in the dialyzer, but even though the
extraction ratio falls as blood flow rate is increased, the volume of blood
cleared of urea nitrogen keeps increasing as the blood flow rate is increased.
Ultimately, when blood flow rate is very high, 20 L/min, the clearance in this
particular example is 600 mL/min, even though only 3% of the inlet SUN is
removed.

34. 2. The K0A, mass transfer area coefficient
If the extraction ratio remained constant at 60%, a doubling of the
blood flow rate would double the clearance. However, removal
efficiency falls at higher blood flow rates, and so the clearance does not
increase with QB in a 1:1 ratio. Ultimately, at very high blood flow rate,
the clearance will plateau. The theoretical maximum clearance of a
dialyzer ( for a given solute) at infinite blood and dialysate flow rates is
called the K0A and has units of mL/min. For the dialyzer in Table, the
K0A is close to 600 mL/min. The K0A also has a physical aspect. It is the
multiple of two quantities: K0, the permeability

35. coefficient of the dialyzer membrane for a given solute, and A, the total
effective surface area of the membrane in the dialyzer. Doubling the
surface area of the membrane in a dialyzer will roughly double the K0A.
Two dialyzers of the same surface area do not necessarily have the
same K0A, as the K0 values of the membranes used in those dialyzers
can be markedly different. The K0 can be increased by making the
membrane thinner, by adjusting its porosity, and by optimizing the fluid
path of dialysate in the dialyzer using spacer yarns and other features.

37. Figure shows the relationship between blood flow rate (QB) on the
horizontal axis and expected dialyzer clearance (KD) on the vertical axis.
Each isopleth (curved line) represents a different efficiency dialyzer,
where dialyzer efficiency is expressed as dialyzer K0A. The values of K0A
in Figure 3.6 range from 300 to 1,600 mL/min. Most dialyzers in
common use today for adults have K0A values of 800–1,600. This figure
shows that as the blood flow is increased, the clearance increases, but
the increase tends to level off. You can see that when QB is low (~200
mL/ min), dialyzers in the 800–1,600-mL/min K0A range have similar
clearances. This is because at this low blood flow rate, they are each
extracting almost all of the urea in the blood entering the dialyzer. The
benefits of a “high efficiency” (high K0A) dialyzer become apparent
primarily when the blood flow rate is high. Then the larger dialyzers
with thinner, more efficient membranes are able to keep the extraction
rate high, maximizing the increase in dialyzer clearance.

38. 3. Calculating the solute removal rate.
For a situation where a uniform solution is running through the
dialyzer, one can calculate the removal rate (in mg/min or mmol/min)
of a given solute. For example, if the inlet SUN is 1 mg/mL and we are
clearing 240 mL/min of blood of urea, then we are removing 240
mg/min of urea nitrogen from the patient.

39. 4. Effect of erythrocytes.
In the concept of clearance described earlier, the blood was treated as a
simple fluid. However, this is not the case. At a hematocrit of 30%, a blood
flow of 400 mL/min is really a plasma flow rate of 280 mL/min and an
erythrocyte flow rate of 120 mL/min. What is measured at the dialyzer inlet
and outlet are the plasma levels of a given waste product. For urea, the
presence of erythrocytes is not a major problem because urea diffuses into
and out of erythrocytes quickly. For example, if the outlet plasma urea
nitrogen level is 40 mg/dL, the urea concentration in erythrocytes will have
been reduced to about that level also. For creatinine and phosphorus and
many other solutes, the problem is more complex because these substances
do not equilibrate quickly between plasma and erythrocytes. In fact, very
little creatinine or phosphorus is removed from red blood cells during
passage through the dialyzer. When calculating the removal rate of
creatinine or phosphorus in mg/min or mmol/min, one needs to use the
plasma flow rate instead of the blood flow rate.

40. 5. Effect of blood water.
As noted, urea is dissolved in erythrocytes and plasma water and is
removed from both during passage through the dialyzer. Approximately
93% of plasma is water (depending on its protein concentration), and
about 72% of an erythrocyte is water. Some urea associates with the
nonwater portion of erythrocytes. On average, urea is dissolved in a
volume that is about 86% of the blood. The correction for blood water
becomes important when using the dialyzer clearance to compute how
much urea is being removed during a dialysis session. For solutes like
creatinine and phosphorus that are removed from the plasma
compartment only passage through the dialyzer, the volume of removal
is about 93% of

41. the plasma flow rate. Increasing the hematocrit (e.g., from
20% to 40%) causes only a trivial reduction of the blood water
urea clearance but will be associated with a noticeable
reduction in the clearance of creatinine or phosphorus, due
to the effect of hematocrit on the plasma flow rate.

42. 6. Effect of dialysis solution flow rate
. Dialyzer clearance of urea (and other solutes) depends on the dialysis
solution flow rate as well. A faster dialysis solution flow rate increases the
efficiency of diffusion of urea from blood to dialysate although the effect is
usually modest. The usual dialysis solution flow rate is 500 mL/min. A flow
rate of 800 mL/min will increase urea clearance by about 5%–8% when a
highefficiency dialyzer is used and when the blood flow rate is greater than
350 mL/min. On the other hand, in some daily, nocturnal, or intensive care
unit (ICU)–based applications, dialysate flow rate is markedly lower than 500
mL/min. Such a reduced dialysate flow rate can cause substantial reduction
in dialyzer clearance. The optimum dialysis solution flow rate is 1.5–2.0 times
the blood flow rate. Above that, the increase in efficiency is quite small,
especially with some of the newer dialyzers where the dialysis solution flow
path has been optimized.

43. 7. Effect of molecular weight on diffusive
clearance.
Because highmolecular-weight solutes move slowly through
solutions, they diffuse poorly through the membrane. As a result, the
extraction ratio for molecules larger than urea will be less than that of
urea; plus, to calculate clearance, this lower extraction ratio must be
multiplied by the plasma flow rate, and not the blood flow rate.

44. 8. Very large molecules
. Very large molecules, such as β2-microglobulin (MW 11,800), cannot
get through the pores of standard (low-flux) dialysis membranes at all.
Thus, dialyzer clearance of β2-microglobulin will be zero! “High-flux”
membranes have pores of sufficient size to pass this large molecule.
Also, some dialysis membranes remove β2-microglobulin by
adsorption.

45. 9. Dialyzer efficiency versus flux.
When we speak of dialyzer efficiency, we refer primarily to the ability of
a dialyzer to remove small solutes. The dialyzer efficiency is best
represented by the K0A for urea. The flux of a dialyzer refersto its ability
to remove very large molecules such as β2-microglobulin. There is no
single measure in common use to specify the flux of a dialyzer, though
water permeability(KUF) can be used. Usually high-flux dialyzers will
have a water permeability greater than 15–20 mL/hr per mmHg. One
can have a small, low-efficiency (K0A = 400 mL/min) dialyzer (e.g., for
use in children) that is high flux, or a high-efficiency dialyzer (K0A =
1,200 mL/min) that is low flux and that removes urea very well but that
removes no β2-microglobulin.