1. Separation Technology in Dialysis
Allan P. Turner M.D.
February 17,2006
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2. Kidney Function
What we are trying to do is replicate the kidneys function. Kidney function is remarkable and only as we try to replace do we realize how much so. Blood contacts the glomerular membrane and an ultrafiltrate is generated. The ultrafiltratecontains everything smaller than albumin. This ultrafiltrate then passes through tubules and the tubules remove certain things from the ultrafiltrate and add certain things to the ultrafiltrate. They also regulate how much sodium and water is removed. The tubules use passive processes like diffusion and facilitated diffusion(where the solute to be removed must interact with a membrane carrier protein to be transported)and active processes where energy is required to transport substance to or from the ultrafiltrate. Ultimatly the ultrafiltrate becomes urine.
We will be talking about the ways we have to replace kidney function and how they fall short of the native kidney.This graft shows clearance of various sized particles in native kidneys and in several replacement methods. All the methods have to retain cells and albumin(although PD does allow albumin to escape.

3. Kidney Function
So when dialysis first came to be it worked well enough to keep paitient alive. Kidney failure was a death sentence and if life of a patient with kidney failure could be prolonged it was a success. And dialysis did prolong life even in its early stages. Now as the population with renal failure grows and grows it is not enough to prolong their life by months or years patient the government and others are asking what is the mortality on RRT and why is it less than that of a patient with normal renal function. As we try to answer this question we are learning more and more about how the separation techniques impact on mortality and we are trying to more and more closley mimick what the native kidney does. So the more we try to replicate the kidney the more in awe of its function we become.

4. Terms Used in Dialysis Diffusion Convection Ultrafiltration Clearance
Diffusion-net passive movement of solute across a membrane down a fovorable concentration(or electrical)gradient.
Convection-movement of solutes by bulk flow does not depend on concentration gradient. Solvent(water) (driven by hydostatic or osmotic force) is pushed through membrane and solute is carried with solvent as long as solute can go through the membrane pores.
Ultrafiltration-the movement of solvent(water in this case) across the membrane driven by a gradient. The gradient is pressure in hemodialysis. In PD the gradient is osmotic and the process could be called osmosis. Ultrafiltration is closly linked to convective clearance.
Clearance-the biological term used to describe removal of solute. If you have a black box with fluid coming into it at a rate of 100 ml/min and it has a concentration of X of 100mg/dl and at the exit from the black box Xs concentration is 50mg/dl then the clearance is 50ml/min, if the concentration is 20mg/dl the the clearance of X by the black box is 80ml/min, if the concentration is 0mg/dl then the clearance is 100ml/min
100 ml/min
100mg/dl
100 ml/min
50 mg/dl
Clearance=50 ml/min
100 ml/min
100mg/dl
100 ml/min
10 mg/dl
Clearance=90 ml/min

5. Options for RRT Hemodialysis CRRT(Hemodiafiltration)
3X a week for 3-4 hours
diffusive clearance with ultrafiltration of water
faster blood flow rates=less hemodynamic stability
CRRT(Hemodiafiltration)
a continuous process
used on critically ill patients in US
more convective clearance
lower blood flow rates and smaller filter=greater hemodynamic stability
Peritoneal Dialysis
peritoneal membrane used as semipermeable membrane
batch process
So if tomorrow you have the misfortune of needing to see me in clinic and we decide you kidneys are not functioning enough to keep you healthy we have options for how to replace your renal function. In reality our options in clinic would be transplant vs hemodialysis vs peritioneal dialysis. Transplant is essentially normal kidney function and the difficulty is in keeping you from rejecting the transplanted kidney so not included in this talk. Our talk is about separation technology and so we leave out transplant. CRRT would not really be an option for you coming into clinic its main advantage is in the hemodynamic stability it provides(ie in a critically ill patient in the ICU it allows us to do dialysis on patients whose blood pressure would not normally allow us to perform dialysis) It is included here because it represents a different technique of RRT and one which is growing in popularty as we learn more about its unique action. In 2 european countries you can do something very much akin to our CRRT as an outpatient on a chronic basis.

6. Description of Hemodialysis
A diffusion driven and size discriminatory process for the clearance of small solutes such as electrolytes and urea. UF is driven by the generation of negative hydraulic pressure on the dialysate side of the dialyzer. It was really designed to remove urea a small solute and electrolytes and enough fluid to keep patients from becoming volume overloaded
When hemodialysis was invented it was thought that urea(a small molecule was the toxin that caused people with renal failure to be ill and if we could remove urea and manage electrolytes such as potassium and bicarbonate and remove the fluid that a person would accumulate in a week(about 7-10 liters a week) then people could essentially have their renal function replaced. So that is what hemodialysis is designed to do. It is designed to do that to a person who is still working and therefore it was to minimally interfere in their life so only require about 12 hours a week. The person needed to be healthy otherwise so have a good heart and blood pressure.
3 components:1)membrane(filter / dialyzer), 2)delivery system consisting of a blood circuit and a dialysate circuit, 3)dialysate
Dialysate:solution containing Na,Cl,Hco3-,Ca,Mg,K, it lacks toxins
Kidneys work 24 hours a day 7 days a week and have a urea clearance of about 100ml/min so in a week 168 hours, minutes, clear about 1000 Liters of urea a week.
Dialysis has a urea clearance of about 260ml/min. Run 4hours 3 days a week so 12 hours a week so 720 minutes and clear about 187 liters a week of urea.
Have to keep the blood flow rates and dialysis rates up to get enough clearance.
Average blood volume of a normal adult is about 5000ml we have blood flow rates of hopefully 500 ml/min in conventional hemodialysis so in 10 minutes we would have pumper the equivalent of an adults entire blood volume through our filter. That requires a good heart and good blood pressure. That also requires that in a typical 3.5 hour treatment we will have a dialysate flow rate of 800ml/min and therefore use 168 liters of dialysate. This needs to not be sterile but needs to be of very high quality and that gets very expensive to make this quantity of ultrapure dialysate.
Primarily diffusion
Dialysate
looks like blood of healthy patient
3X week for 3-4 hours
Blood and dialysate flows are fast
QB=500 ml/min
QD=800 ml/min

7. Membrane(Dialyzer) Hollow Fiber Design Biologic vs synthetic Reuse
Terms
Biocompatibility
High efficiency
High flux
So lets look in more detail at the compents of hemodialysis. First looking at the semipermeable membrane what we would call the filter of the dialyzer.
Hollow fiber dialyzer
maximizes surface area for diffusion
can be biologic(Cellulose based) or synthetic based
In a push to save money we reuse filters. Some units insist on a new filter each treatment. After a treatment the filters for a specific patient arecleaned and used again until their quality is impaired. Reuse does affect the characteristic of the dialyzer.
Biocompatibility-some material activates complement- and this leads to problems
high efficiency-basically means large surface area so get maximal efficiency I terms of clearing urea and other small soultes
high flux-basically has larger holes in the filter allowing the removal of larger toxins and moleculer
trade off: synthetic membranes are more biocompatable, and have higher flux but cost more and cost is a huge issue.

8. Access Difficult Trade Offs rapidity of use chance of infection
patient comfort
need for addl procedures
So there was one small detail we did not mention when talking about hemodialysis and that is blood access. we said we will pump an adults entire blood volume through the dialyzer in 10 minutes and we will need to do that 3 times a week for 3.5 hours for the rest of their life.Minimizing any major complications such as infection, loss of limb or life. In ourunit of about 150 patients in the last 4 months we have had about 6 life threating infections, lost about 3 limbs and had 1 death due to access.
This really is not a part of the separtion technique but plays an important side role so I want to briefly address it.
With access we have trade offs.
-If it is ready to use quickly it probable won’t last long.
-If it is easy to use with mimimal discomfort to the patient it probably will easliy get infected.
-It may require numerous procedures to keep it functioning.

9. Access(PermCath) Use immediately No needle sticks High infection rate
High recirculation
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10. Access(AV Graft) Use in 2-3 weeks Some infection risk 2 needle sticks
low recirculation
numerous interventions to keep open
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11. Access(AV Fistula) 3-18 months to use Minimal infection risk
Can last a lifetime

12. Anticoagulation Blood clots Heparin Partial clotting
discovered in 1926
Partial clotting
limits diffusion
reduces surface area
Access must stop bleeding
Calcium
required for clotting
Blood clots and clotting is initiated by blood trauma. There is trauma to blood when it passes through the tubing and especially through the fibers of the hollow fiber dialyzer. This would lead to clotting and make dialysis impossible. Dialysis was attempted and originated well before 1926 but it was only with the discovery of heparin was it clinically possibly and only with the wider availablilty of heparin was is feasable on routine basis. Heparin usually comes from porcine intestines of bovine lung. It binds antithrombin III. ATIII serves to inhibit clottingfactors when heparin binds to it its inhibition increases and clotting is decreased. Heparin has a fast onset and a short half life.
If blood clots even partially it causes small clots which clog up some of the fibers and lead to reduced surface area. The thinner the blood the better diffusion will be. If you make a large hole in an AVF or AVG they will bleed and if blood is too thin they will bleed excessivly. Typically a large bolus is given at the start of dialysis after the needles are placed and then heparin is held for the last hour to allow the blood to thicken and pressure is held on the puncture sites for ideally 15 minutes until they stop bleeding.
The blood clotting system also needs calcium to lead to clotting so if calcium is removed from blood it will not clot. This will be useful later when we discuss anticoagulation in CRRT.

13. Dialysis Machine Blood Circuit Dialysate Circuit anticoagulate
deliver blood to membrane
safely return blood to patient
Dialysate Circuit
deliver dialysate at proper temperature, concentration, and pH
control ultrafiltration
So now we know something about hemodialysis, we know about accessing the blood that we will clean and we know how we will anticoagulate the blood. The dialysis machine really consists of 2 separate delivery systems. The blood circuit that anticoagulates the blood and deliveres it to the filter at the proper flow rate and pressure to run in a counter current manner against the dialysate and then after it passes through the dialyzer delieveres it back to patient in a safe manner.
The other part is the dialysate circuit. It serves to deliever dialysate to the membrane in the proper concentration, pH and temperature.

14. Dialysis Machine(Blood Circuit)
Roller pump
Heparin syringe pump
2 air traps
Air detector
Venous line clamp
needles are inserted into access.blood in tubing is pumped via roller pumps from the patient (called the arterial line) to the dialyzer. There is a syringe pump that infuses hepain into the blood before it hits the filter. There is a pressure monitor before the filter that records the arterial pressure and assures there is not too excessive suction on the art access.(In this schematic it is in the incorrect position it is actually before the pump. An air trap helps to eliminate any air that could be sucked into the blood line especially in this negative portion. The blood then goes through the filter There is a pressure gauge after the filter to monintor the "venous pressure) which serves to pick up any resistance to blood return to the paitien usually a problem with the access having a stenosis. There is an additional air trap and an air detector. If air is picked up here the pump shuts down and a clamp on the venous line prevents the blood from returning to the patient.

15. Dialysis Machine(Dialysate Circuit)
Warm, deaerate, mix concentrates, monitor conductivity and pH, pump
Detect blood leaks
Generate and monitor ultrafiltration
-Dialysis machines are all single pass-ie dialysate passes through machine once and then discarded.
-Handle a lot of dialysate daily.
-GOAL--warm it ,pump it, deaerate it, measure flow rate, measure and assure the composition, and watch for blood leaks
-deaereate it by exposing to subatmospheric pressures generated by vacuum pump. air cought in bubble trap
-The acetate concentrate contains most of the electrolytes(mg, potassium, calcium, and some acetate to keep it stable. It is a very stable solution due to the addition of the acetate and can be stored in large bacthes at a fixed concentration. It can also be mixed in smaller batches to adjust the potassium and the calcium(the only two which are usually adjusted.
-The bicarbonate concentrate contains sodium bicarbonate it comes in sealed containers(prevents contamination) and held on the front of the machine and changed when the cartridge is empty.
-the concentrates are kept apart to avoid precipitation of caco3 or magnesium carbonate.
The concentrate is proportioned via a fixed volume system or a servo controlled process where conductivity is monitored and proportioning is adjusted to maintain correct conductivity. In both cases conductivity is monitored and if out of range a bypass valve opens so the dialysate will not contact the membrane. When this occurs the blood continure to pump and enough ultrafiltration is maintianed to prevent any bacteria or toxins from crossing from the dialysate side to the blood side. The pH is also monitored to assure proper dialysate compensation.
-All dialysis machines now employ volumetric ultrafiltration control systems.
--Most use electromagnetic flowmeters to measure the flow in and out of the machine and using a processor use the pump and a flow valve to assure that the set ultrafiltration rate is maintained.
-some units use a balancing chamber(bellows pump) which serves to match dialysis flow in and out and then have a ultrafiltration pump which is set to remove the prescribed ultrafiltration rate set by the operator.

16. Dialysis Machine

17. Dialysis Machine

18. Dialysate
We have looked at how the dialysate is mixed in the dialysate circuit and now look briefly at how the concentrate and the water is generated.
-City water is used and an onsite water processing unit generates water of sufficient purity to be used for dialysis.
-Hot and cold water is mixed to get the temperature close, it goes throgh an initial filter and then through charcol adsorption tank which removes chlorine and chlorimines. Next it goes through a wate softerne to remove magnesium and calcium so it will not damage the RO membranes. Then through a series of RO units which serve to remove most impurities. After the ROs it goes to a storage tank which is sealed and continuosly stirred. After the storage tank is a UV light system and a series of filters designed to remove any bacterial endotoxins that would be left if bacteria get into the system and is killed by the UV light system. The system is regularly disenfected and water quality is monitored on a regular basis. (some newer systems use a heat based disinfection system. We currently use paraacetic acid in our disenfection system. There are set standards for which the water quality must be maintained. Trace elemtns such as aluminum can cause serious problems for patients and their levels are monitores in the system and in the patients for possible contamination.
The acid concentrate is mixed in large batches and stored and delivered to the dialysis machines. It contains 2k and 2 calcium. If a paitient needs a different concnetartion of k or ca it is mixed in smaller concentrates as seen on the front of the machines. The bicarb is never batched mixed as is too easy to become contaminated with bacteria. This other container is acetic acid used in disinfecting the machine.

19. Urea Clearance ?Urea = uremic toxin? Diffusion Urea: MW=60 (small) KoA
Clearance of urea of 250ml/min
Native kidneys provide urea clearance of about ml/min
Urea initially thought to be uremic toxin it could remove urea should be able to remove the toxins the kidneys ordinarily do. Now know not true.
-HD is really set up to remove urea, K, aobut 10l fluid a week, and give the patient hco3, and hemodialysis does this pretty well in a liminted time
-lets look at the clearance of urea
dialyzer mass transfer area coefficien(KoA)t for urea gives the theoritical maximum clearance of urea by a particular filter. It is essentially the clearance of urea at infinate dialysate and blood flows.
most filters are high efficency(ie large surface area and have a KoA urea of 700 or better. So you can see they get a urea clearance of at least 250ml/min not bad considering the native kidney get about ml/min. the problem is of course dialysis is 3.5 hrs 3 times a week and kidneys run 24/7

20. Urea Clearance
So now that we are using thes high efficiency dialyzers we need to maintain large blood flow rates to get the benefit from them and for that reason we need good acceses

21. Clearance of Other Solutes
Urea(MW 60), creatinine(MW 113), B12 (MW=1355), ß2 microglobulin (MW=11,800), albumin (MW=80,000)
Middle molecules
Diffusion not effective
-diffusive clearance of sloutes by hemodialysis decreases rapidly with increasing molecular weight
-high flux membranes help some byt no matter how large the pores in the filter diffusion is limited for larger molecules
-But look at this other graph and look at what we can do with ultrafiltraion; look how we can closly start to mimick the clearances seen in the kidney
-so ultrafiltration may be a way to help obtain clearance of larger molecules

22. Hemofiltration Convection to clear larger molecules
Replacement fluids without removed solute
Costly
-notice in hemodialysis the driving force is the concentration gradient but in ultrafiltration there is no concentration gradient
-a large quantity of fluid is ultrafiltered across the membrane and solute is dragged with it
-you must give replacement fluid that does not contain the solute you are trying to remove and look where that replacement fluid is going. It is being given intravenously so this fluid has the same very high and very expensive requirements as any other IVfluid would. Higher standards and more expensive than the water we use for dialysate.
-several european countries do this in their outpatient chronic units
-In the US medicare is footing the bill and they are not looking to spend any more money on dilaysis
-We all love to spend money in the hospital with the latest and greatest therapies
-acute renal failure in critically ill patients is an area where mortality is so very high that we are looking for any way to make it better-maybe hemofiltration will work here and someone will actually pay for it.
-a filter with large pores(high flux) is used sometimes called a hemofilter

23. Continuous Renal Replacement Therapy(CRRT)
Critically ill ICU patients
low BP
can’t tolerate large QB or large filter
often can’t be systemically anticoagulated
Continuous
low clearances but runs 24/7
Anticoagulation
regional anticoagulation instead of systemic
Combine hemodialysis and hemofiltration
hemodiafiltration
increases clearances even of middle molecules
continuous venovenous hemodiafiltration(CVVHDF)
CRRT gives us a place where we can use our hemofiltration techniques and hope to have a positive effect on paitient outcome.
-The typical ICU patient with renal failure is not well they usually have low blood pressure and would often not tolerate the blood flows needed for conventional hemodialysis,because their blood pressure would fall. also frequently they have bleeding complications and placing them on heparin for anticoagulation could cause major complications.
-If we run the process continuously we could decrease the blood rate and make it easier to tolerate from a hemodynamic standpoint.
-combining hemofiltration and hemodialysis can increae clearance especially of middle molecules.-instead of anticoagulation the whole patient just anticoagulate the blood in the blood circuit.
-The name quickly becomes a mouthful but is quite simple in reality CVVHDF.

24. CRRT vs Hemodialysis CRRT Hemodialysis QB 150ml/hr QB 500ml/hr
Dialysate
40ml/min(2500ml/hr)
CRRT
Replacement fluid
1000ml/hr QB
150ml/hr
Dialysate + Ultrafiltration +Replacement fluid
Dialysate
800ml/min(48,000ml/hr)
Hemodialysis
So mainly look at the differences in the flow rates of blood and of the addition of a replacement fluid in CRRT. Also note the size difference in the two filters.
-IN the ICU the fluids all come prepared. So the dialysate will not be generated with urified water and concentrates it comes in a premixed bag that is of IV quality so to even think about the cost of dialysate at 48 liters/hr is crazy. QB
500ml/hr
Dialysate + Ultrafiltration

25. CRRT Citrate Anticoagulation
Tri-Sodium Citrate
Blood
From C C C C C C
patient D
Liver
So in CRRT we use a differentt kind of anticoagulation. No heparin and anticoagulating the entire body. Here only the blood circuit is anticoagulated and tri sodium citrate is used to bind calcium. Without calcium blood cannot clot. The citrate binds the calcium. Some calcium is removed in the dialysis process. The citrate gets converted to bicarbonate and the calcium it has been binding is released. The patient has to be given calcium because of the calcium removed in the dialysis process.
Sometimes the trisodium citrate solution will be diluted so that it can be used as a replacement fluid. Like we see in this next protocol. I A
Citrate HCO3 L
Calcium Y C Z C C E R
Blood To C C C C C
patient C

26. CRRT Q Q Q Q = Q Q Q + + R Prefilter Fluid: 4L bag 0.67% Trisodium
Citrate 3- 23 mM /L Na +
140
mEq
Rate: mL
/hr 24
mmol
/h citrate
Gambro Prisma
Pre-Pump Pre-
Dilution Set
Dialysate :
4 L bag Na +
140
mEq /L Cl -
118.5
HCO 3 25 K
4.0 Mg
mEql
Rate: mL
/hr Q D Ca 2+
Gluconate 78
mEq
/L (20 g/L) in NS
Rate: 80 mL
/hr
PF iCa (
mmol
/L) V
Gambro Prisma
Gambro Prisma
with
with V
M60 AN69 Filter
M60 AN69 Filter
Patient Q B
iCa 2+ mL
/min
mmol /L
(actual Q
= Q
– Q ) B
B, machine R Q
= Q Q Q + + E R FR D

27. CRRT

28. Peritoneal Dialysis(PD)
Salmon dialysis
Peritoneal membrane
Capillaries
Diffusion, ultrafiltration( ie osmosis), convection, and absorption
-Salmon actualy have an opening into their peritoneal cavity. They can take in fluid let it sit for a while and then "void" it out like a pD patient. Don't know which came first.
-transport of solutes and water across a semipermeable membrane separating 2 fluid compartments
-membrane is the peritoneal membrane. It is made of mesothelial cells and conective tissue within this connective tissue are numerous capillaries.
-a cuffed catheter is placed into the peritoneal cavity. Dialysate (similar to that used in HD except for a large glucose concentration) is infused into the peritoneal cavity. The dialysate is allowed to dwell for a period of time(typiclly 4 hours). During that time diffusion occurs, uf occurs due to an osmotic gradient created by the large concentrtion of glucose(ie osmosis), convection occurs with the ultrafiltration but there is not that much uf and therefore not that much convection. Some of the infused fluid is absorbed into the abd wall and taken up by capillaries.
blood in the capillaries just below the peritoneal membrane is one compartment and dialysate infused into the peritoneal cavity is the other

29. PD Membrane Pd Membrane
surface area=BSA=1-2 m2
heteroporus, heterogeneous semipermeable membrane with complex physiology
Blood Flow
approx ml/min
3 pore model
large pores(macromolecules like proteins)
small pores(small solutes)
ultrapores(aquaporins)(water without solute)
The organs and walls of the peritoneal cavity are covered with a mesothelium and deep to that is connective tissue. embedded in the connective tissue are the peritoneal capillaries.
-The total surface are is about 1-2m2 about that of the BSA so if look at your skin that will be about your size of your peritoneal membrane. that is pretty close to the surface area of a hollow fiber membrane.
-The blood flow rate is not well established but felt to be about ml/hr so pretty low. Lower thatn CRRT
Have discovered that the walls of peritoneal capillaries offer the largest component of resistance and have devised the 3-pore model to describe the transport process.
1)large pores-let macromolecules through by convection mainly--appear to be clefts in the endothelium
2)small pores-let small solutes Cr, urea, K+ pass through via diffusion, appear to be inter-endothelian clefts
3)ultrapores -allow passage of solute free water.About 50 percent of UF comes through aquapores. This UF derived from aquaporins will not contribute to convective clearance

30. PD Ultrafiltration
Dextrose(3 concentrations) added to provide gradient for UF(osmosis)
Glucose diffuses into blood and diminishes gradient
Absorption of dialysate occurs limiting UF
Newer agents

31. PD Clearance High Transporters High Avg/Low AVG transporters
dialyze well
ultrafilter poorly
? Icodextran ?
best with freq. short dwells
High Avg/Low AVG transporters
Low Transporters
ultrafilter well
dialyze poorly
best with longer short dwells
Options
CAPD
CCPD

32. Future Which separation techniques improve mortality
Less expensive RRT as population grows
Improve patients quality of life
Biological systems