1. Clinical case presentation

2. INTRODUCTION Assessment of adequacy of dialysis
A central issue in the HD patients.
Simply following the blood urea nitrogen (BUN) is insufficient because
a low BUN can reflect inadequate nutrition rather than sufficient dialytic urea removal.

3. INTRODUCTION Monitoring the patient's symptoms insufficient,
the combination of dialysis plus erythropoietin to correct anemia can eliminate most uremic symptoms although the patient may be underdialyzed.
Thus, in addition to symptoms, patient nutrition and survival appear to best reflect dialysis adequacy.

4. Ideal Marker for dialysis adequacy
Retained in renal failure
Eliminated by dialysis
Proven dose-related toxicity
Generation and elimination representative of other toxins
Easily measured and calculated
Flexible can be used for multiple modalities
Incorporates residual renal function
We have no ideal marker

5. Urea kinetics MW 60, only slightly toxic per se
It is a marker for small MW uremic toxins
We can measure the rate of generation of urea.
Urea generation is in proportion to protein break down (PCR).
In stable patients the PCR is proportional to dietary protein intake.

6. BACKGROUND
The National Cooperative Dialysis Study (NCDS) established that
the timed average urea concentration and
the protein catabolic rate (PCR) were important determinants of morbidity and mortality in hemodialysis patients.
In particular, well-nourished patients with a more intensive dialysis prescription and a lower timed average BUN had a better outcome.
Lowrie EG; Laird NM; Parker TF; Sargent JA
N Engl J Med 1981 Nov 12;305

7. BACKGROUND
In a patient with little or no urine output, the PCR (in g/day) is equal to the sum of the dialysis and stool losses of urea, protein, and amino acids.
These losses (the PCR) are roughly equal to protein intake when a patient is in a steady state with a relatively constant predialysis BUN.

8. BACKGROUND
Urea was chosen by the NCDS as the clearance marker for the Kt/V since it is a reflection both of
dietary protein intake and
of the efficiency of removal of small uremic toxins.

9. BACKGROUND
Individualizing the hemodialysis prescription to a particular patient's needs using Kt/V can be a useful tool in
providing a safe and cost-effective dialysis treatment.
This can be accomplished with urea kinetic modeling, which allows for variations in dialysis time, use of larger, high efficiency, high-flux dialyzers, and optimization of dietary protein need.

10. BACKGROUND
Urea kinetic modeling is a method for verifying that the amount of dialysis prescribed (the prescribed Kt/V) equals the amount of dialysis delivered (the effective Kt/V).
Kinetic modeling also quantifies the amount of urea generated, which is a marker of the protein catabolic rate and therefore of protein intake.

11. What is the Kt/V
Formal UKM. Developed by Gotch on the reanalysis of NCDS.
Estimate urea clearance
K : dialyzer clearance (ml/min)
obtained from the manufacturer
t : dialysis time
V : theoretical volume of distribution of urea

12. DEFINITION AND CALCULATION OF Kt/V
The correction of total urea removal (Kt) for volume of distribution is important because,
in a large patient, a given degree of urea loss represents a lower rate of removal of the total body burden of urea (and presumably of other small uremic toxins).

13. In addition to urea generation and dialysis-induced changes in body water, the Kt/V is affected by the equilibration of urea from skeletal muscle to plasma water.
urea-rich blood in the venous circulation is not actually measured with the postdialysis BUN sample.
Instead, this sample consists of arterial blood flowing into the extracorporeal circuit under conditions in which vascular access recirculation is minimized.
The Kt/V calculated from this sample is called the single pool, nonequilibrated Kt/V.

14. By comparison, a postdialysis urea sample that reflects the equilibration of muscle and blood urea is called an equilibrated sample, representing the blood and muscle cell pool of urea within the body (eg, the double pool of urea).
Given that the urea concentration measured with the equilibrated sample is higher than that observed in the nonequilibrated sample, the equilibrated, double pool Kt/V is lower than the nonequilibrated, single pool Kt/V.
This difference is approximately 0.21 for the usual range of delivered doses of hemodialysis, and decreases with longer hemodialysis treatment times (t).

15. URR 1991 Lowrie Never validated by a RCT
Validated as an outcome predictor
Does not take into account convective urea clearance, urea generation or residual renal function. (however, errors underestimate the clearance)
Cannot calculate index of protein intake
Cannot be applied across modalities

16. Urea reduction ratio — A simpler model uses the urea reduction ratio (URR):
URR   =   (1  -  [postdialysis BUN  ÷  predialysis BUN])
Thus, the URR is 0.6 if the postdialysis BUN is 40 percent that of the predialysis value. Other investigators have used the percent reduction in urea (PRU), which involves the same calculation as the URR except that the result is multiplied by 100 to be expressed as a percentage.
Several different equations have been proposed to estimate the Kt/V from the PRU.
Kt/V   =   (0.026  x  PRU)  -  0.460
Kt/V   =   (0.024  x  PRU)  -  0.276

18. Sequential changes in BUN measured at the end of and after hemodialysis. A is the immediate postdialysis sample; B is an immediate postdialysis sample taken from the limb opposite the vascular access to eliminate access recirculation; C is delayed for two minutes to eliminate the effect of cardiopulmonary recirculation; and D is delayed for one hour when urea equilibration should be complete. Data from Depner, TA, Kidney Int 1994; 45:1522.

19. Urea rebound

20. Postdialysis BUN
However, with two to four hours of high-flux dialysis, the more rapid reduction in BUN
overestimates the true rate of urea removal because there has not been time for sufficient intracellular urea to diffuse out of the cells and equilibrate with extracellular stores.
Thus, the calculated Kt/V in this setting may exceed the true value by approximately 0.2.

21. Measuring the BUN on a specimen obtained 30 minutes after dialysis is completed can partially correct for this problem, as the value will be higher than that obtained immediately after dialysis.
A similar problem can occur with standard dialysis in patients with delayed urea equilibration with tissue stores.
As a result, the equilibrated postdialysis BUN value (eg, the BUN concentration in a specimen obtained 30 minutes after dialysis) is the most accurate measurement.
Its use in kinetic modeling avoids an overestimation of the actual hemodialysis dose.

22. However, the equilibrated value is too difficult to perform in the clinical setting.
Based upon samples from 70 hemodialysis patients, an attempt was made to identify a formula that correlated the 30 minute postdialysis sample with the five minute postdialysis urea sample obtained using the stop dialysate flow method.
Traynor JP; Geddes CC; Ferguson C; Mactier RA
Am J Kidney Dis 2002 Feb;39(2):308-14

23. Practice is to slow the blood pump to 100 mL/min and then obtain the blood sample BUN 15 seconds later.(KDOKI guideline)
Compared to later sampling times, this earlier measurement is thought to be the most accurate method to support formal kinetic modeling.
To ensure consistent values, measurement of the postdialysis BUN should be performed exactly the same way each time it is assessed.

24. Overview — There is no universally accepted target value for the Kt/V.
OPTIMAL KT/V
Overview — There is no universally accepted target value for the Kt/V.
Using urea kinetic modeling, a Kt/V of 1.05 was initially thought to represent adequate dialysis.
It is likely, however, that 1.05 defines only the lower limit of a minimally acceptable dialysis prescription.

25. HEMO study To address the question of optimal dialysis dose
1846 patients were randomly assigned to
a standard or high dose of dialysis and
a low- or high-flux dialyzer

26. HEMO study The standard dose goal: The high dose goal:
was an equilibrated Kt/V of 1.05, which is equivalent to a urea reduction ratio of 65 percent or a single-pool Kt/V of 1.25.
The high dose goal:
was an equilibrated Kt/V of 1.45, which is the same as a urea reduction ratio of 75 percent or a single-pool Kt/V of 1.65.

27. HEMO study The primary outcome death from any cause,
secondary outcomes
the rate of all hospitalizations (but excluding those related to access), and
the composite outcomes of the first hospitalization for a cardiac problem or
the first hospitalization for an infectious cause or death, and
the first decline of greater than 15 percent of the serum albumin concentration from baseline value, or death.

28. HEMO study

31. HEMO study
A significant survival benefit for women receiving a high dialysis dose was observed upon subgroup analysis (19 percent lower risk of death than women in the standard dose group).
This benefit remained after adjustment for body volume, body mass index, weight, age, and race.

32. HEMO study
By comparison, men receiving a high dose dialysis had a 16 percent higher risk of death than those receiving standard dose dialysis.
The degree to which this reflects a true gender effect is not clear, although some additional observational evidence independently supports the existence of gender differences in survival benefit.

33. HEMO study
In summary, similar outcomes were observed in the HEMO study with
high and standard dialysis doses
as well as
dialysis using high and low flux membranes.

34. Residual renal function
Continued urine output facilitates the regulation of fluid and electrolyte balance, and may enhance survival.
Among peritoneal dialysis patients, the beneficial effect of continued urine output on survival is clear, as shown in multiple studies.
Emerging observational evidence suggests that a survival benefit due to preserved renal function may also occur
among hemodialysis patients, particularly among those receiving inadequate dialysis dosing:

35. Netherlands Cooperative Study on the Adequacy of Dialysis
Evaluated the relationship between residual renal function and survival among 740 hemodialysis patients.
At three months after dialysis initiation, the mean Kt/V of urea with residual renal function was 0.6 per week.
Termorshuizen F; Dekker FW; van Manen JG; Korevaar JC; Boeschoten EW; Krediet RT
J Am Soc Nephrol 2004 Apr;15(4):

36. Netherlands Cooperative Study on the Adequacy of Dialysis
Survival was directly related to preserved renal function, as each increase of 1/week in the Kt/V was significantly associated with a lower relative risk of death (0.44).
In addition, survival in association with dialysis clearance was dependent upon preserved renal function, with dialysis clearances of less than 2.9/week being associated with a higher mortality only among anuric patients.
This value is less than that currently recommended.

37. 2006 K/DOQI guidelines
Suggest that the minimally adequate dose of dialysis can be reduced among patients with minimal residual renal function (less than 2 mL/min per 1.73 m2)
The minimum single-pool Kt/V can be no lower than 60 percent of the minimum target for those without residual renal function.

38. FREQUENCY OF MEASUREMENT OF DIALYSIS DOSE
An assessment of the dialysis dose in stable hemodialysis patients is performed once per month by most clinicians.
However, the calculated Kt/V in a particular patient may vary quite widely,
possibly requiring more frequent measurements and/or
average Kt/V values to accurately assess or adjust the dialysis dose.

39. Assess the causes of a low Kt/V or URR
Fistula integrity.
Treatment duration.
late arriving patient,
the late initiation of dialysis by staff,
early termination because of patient request or clinical events,
blood leak,
needle difficulties, and
excessive triggering of machine alarms.

40. Assess the causes of a low Kt/V or URR
Methods of obtaining BUN samples.
Technical errors resulting in an incorrectly low predialysis BUN or a high postdialysis BUN may result in a decreased Kt/V.
Dialysis machine and patient specific variables
inadequate machine calibration,
low blood flow rates,
episodes of hypotension requiring changes in treatment,
overestimation of dialyzer clearance.
others.

41. A secondary assessment
Should be performed if the initial analysis does not lead to the quick identification of the cause.
Additional measures to improve effective hemodialysis treatment times,
correct errors in blood sampling, or
improve dialyzer clearance.

42. A secondary assessment
Attempts to improve clearance may include
an assessment of extracorporeal pressures,
kinetic modeling of other patients using the same dialyzer model and
Kt/V prescription,
measures to decrease dialyzer clotting and fistula recirculation, and
calibration of blood and dialysis flows.
The use of two dialyzers in series or parallel may be another method to significantly improve clearance.

43. A secondary assessment
If the primary problem is cardiopulmonary recirculation or delayed transfer of urea out of the cells,
then urea clearance of the blood delivered to the dialyzer is already at near maximal levels.
As a result, increasing dialyzer size, blood flow, or dialysate flow will produce only a marginal improvement.
The only way to compensate for the reduced efficiency of urea removal is to increase the time on dialysis.

44. The effect of increasing dialyzer blood flow (Qb) on urea clearance (Kd) in hemodialysis for a given KoA approximately Increasing flow raises Kd by delivering more blood with a high urea concentration, thereby maintaining a favorable concentration gradient for urea diffusion across the dialysis membrane. There is a relative plateau above 500 mL/min due to limitations of the dialysis membrane. A similar relationship is seen between dialysate flow and Kd; in this setting, the concentration gradient is maintained as dialysate flow rises by the supply of new dialysate containing no urea.

45. Prescribed versus delivered dialysis: Importance of dialysis time

46. Once Qb, Qd, ultrafiltration are maximized (often with Qb as the limiting factor),
the most important determinant affecting the dose of dialysis is its duration (Td).

47. Vascular access recirculation
Access recirculation is another factor that can impair urea elimination and reduce delivered dialysis dose below that prescribed.
Access recirculation occurs when dialyzed blood exiting the dialyzer reverses flow after it reenters the arteriovenous fistula and is taken up by the dialyzer inlet.
Thus, the dialyzer is "seeing" blood from the systemic circuit that has been "diluted" with blood that has just been dialyzed.

48. Schematic representation of standard hemodialysis in which flow through the access is in parallel with the systemic circulation. The degree to which urea is removed is dependent upon the rate of urea equilibration between intracellular stores (IC) and the extracellular fluid (EC). Slow equilibrators will have a lower BUN during dialysis but a slower rate of total urea removal

49. Schematic representation of the performance of hemodialysis in which the access is in series with the systemic circulation. In this setting, all of the blood would go through the dialyzer and urea removal would be maximized.

50. DIMINISHED UREA CLEARANCE DUE TO DIMINISHED EQUILIBRATION WITH INTRACELLULAR STORES
The maximally efficient dialysis requires the delivery of blood with a high BUN to the dialyzer.
As urea is removed from the extracellular fluid by dialysis, urea moves out of the cells to replete extracellular stores.

51. DIMINISHED UREA CLEARANCE DUE TO DIMINISHED EQUILIBRATION WITH INTRACELLULAR STORES
This process is not instantaneous but follows two-pool kinetics with an average urea mass transfer coefficient (MTCurea) of 800 mL/min.
An MTCurea below 400 mL/min puts the patient at risk for underdialysis, since less urea is delivered to the dialyzer to be removed.
This problem can occur if urea is trapped in compartments with reduced flow (due to vascular disease); there may also be a genetic variation in the rate at which the cell membranes permit urea to leave the cells.

52. Schematic representation of the changes in BUN occurring during four hours of hemodialysis and the hour after dialysis is discontinued. Patients with a low mass transfer coefficient for urea (MTCurea) have, when compared to those with a high MTCurea, a more rapid reduction in BUN due to delayed urea equilibration with intracellular stores. This defect is associated with a greater urea rebound when dialysis is stopped and less total urea removal.

53. DIMINISHED UREA CLEARANCE DUE TO DIMINISHED EQUILIBRATION WITH INTRACELLULAR STORES
There will be a low intra- and postdialysis BUN (a misleading indicator of adequate dialysis) that leads to a low overall rate of urea removal.
The higher the MTCurea, the more net urea removal will occur because there will be a higher intra- and postdialysis BUN (which might suggest inadequate dialysis).

54. Factors that reduce dialysis delivery
The effect of increasing dialyzer blood flow (Qb) on total body urea clearance (Ktb) during hemodialysis. The top curve (Kd) represents the ideal curve in which all of the dialysis prescription is delivered. The lower curves reflect the progressive decrease in Ktb induced by the sequential addition of a low cardiac output (Qco = 5 L/min); plus a high access blood flow (Qac = 50% Qco); plus 15 percent access recirculation; plus a low rate of urea equilibration from the tissues (low MTCurea).

55. The different tissue compartments represent areas of the body with variable degrees of perfusion from the heart and urea sequestration. Within the gastrointestinal tract and skeletal muscle, the ratio of blood flow to urea content is low. These organs therefore sequester up to 80 percent of the total body urea, leading to urea rebound and reduced dialysis efficiency.

56. Regional blood flow model
This assumes that urea sequestration during dialysis occurs, not within cells, but within those organs in which the ratio of blood flow to urea content is low .
These organs, particularly skeletal muscle, may receive only 15 to 20 percent of the cardiac outflow but may sequester up to 80 percent of the total body urea. This model predicts that postdialysis urea rebound is dependent upon cardiac output (cardiac index) and the amount of muscle mass in a particular individual; it has now been validated in a number of studies.

57. Regional blood flow model
Urea is generated by the liver and then distributed to various tissue compartments.
These various tissue compartments have different rates of blood perfusion and the amount of potential urea "trapping" is a function of both the perfusion and the size of the compartment.
Although most compartments with poor perfusion have the highest potential risk of urea sequestration, they are generally small.
In contrast, the skeletal compartment is so large it acts as the dominant tissue "holding" urea.

58. OTHER LIMITING FACTORS
Inaccurate manufacturer's specifications — In vivo clearances are often as much as 20 percent lower than manufacturer's in vitro clearances. For this reason, it is desirable to evaluate specific dialyzer clearances in vivo in the dialysis unit using the formula:
C(x)   =   Qb  x  ([Ax  -  Vx]/Ax)
where C(x) refers to the clearance of solute x (urea, creatinine, phosphate, and vitamin B12 are most often used) and Ax and Vx refer to the concentration of x in the arterial and venous lines, respectively.

59. Inaccurate and decreased blood flow rates
The rate of blood flow through the dialyzer may be overestimated if there is
a problem with the dialyzer pump or
the blood line, such as the use of 6 mm tubing with a high blood flow setting or
decreased compliance of the plastic tubing.
Both of these blood line problems prevent full refill of the tubing after compression by the roller pump, resulting in undetected shortfalls in delivered blood flow.

60. Inaccurate and decreased blood flow rates
In general, higher blood flow rates are observed with AV accesses versus that obtained with central venous catheters.
The blood flow rate will also be diminished with hemodialysis catheter dysfunction, including reversal of the access lines.

61. Reduced fiber bundle volume from clotting
Clotting within the dialyzer can reduce the surface area available for effective dialysis.
Standard dialyzer reuse criteria rejects dialyzers in which the fiber bundle volume falls below 80 percent.
It has been suggested that careful attention to maintaining an adequate heparin anticoagulation of the fibers can minimize the degree of clotting and significantly improve polysulfone dialyzer clearances.

62. Residual urea clearance
Some patients with residual renal function may have significant urea loss from the native kidneys.
This can be measured and included with the "extracorporeal" dialysis Kt/V to generate a composite Kt/V; however, assuming that the native clearance is zero may minimize underdialysis.

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