Please review
Chapter 3 at this time. Many concepts developed in
Chapter 3 will be only briefly touched on here.
I. UREA AS A MARKER SOLUTE. Although uremic toxicity is due to both small- and large-molecular-weight solutes, small toxins appear to be of greater importance. For this reason (and there are practical, laboratory measurement issues as well), the amount of dialysis prescribed is based on removal of urea, which has a molecular weight of 60 Da. Urea is only slightly toxic per se, and so its plasma level is only reflecting concentrations of other, presumably more harmful, uremic toxins.
A. Urea removal versus serum level. Both removal and serum level should be monitored when checking dialysis adequacy. Monitoring of urea removal is more important. If removal is inadequate, then dialysis is inadequate, regardless of the serum level. On the other hand, a low serum urea level does not necessarily reflect adequate dialysis. Serum level depends not only on the rate of removal but also on the rate of urea generation. The generation rate is linked to the protein nitrogen appearance rate because most protein nitrogen is excreted as urea. A low serum urea level may be found in patients in whom removal is poor but in whom the generation rate is also low (e.g., due to poor protein intake).
B.
Measures of urea removal. These are the urea reduction ratio (
URR), the single-pool
Kt/V (
spKt/V), the equilibrated
Kt/V (
eKt/V), and the weekly standard
Kt/V (
stdKt/V) (see
Chapter 3).
C.
Dose of dialysis in terms of urea removal for thrice-weekly dialysis. In a secondary analysis of the randomized National Cooperative Dialysis Study, the rate of treatment failure increased dramatically in patients dialyzed three times per week when
spKt/V was <0.8, compared with when values were >1.0. In large observational studies, similar results were found. For this reason, the KDOQI Adequacy Workgroups have recommended a minimum
spKt/V for dialysis patients of 1.2, with a target value of at least 1.4. This translates to a
stdKt/V urea value of 2.1 when
stdKt/V is calculated using modeling or by a method that takes volume contraction into account. The European Best Practice Guidelines
recommend a slightly higher minimum amount of dialysis, defined as a minimum
eKt/V of 1.2. Values for
eKt/V values tend to be about 0.15 units lower than
spKt/V, the amount depending on the rate of dialysis. High-level evidence guideline recommendations depend on randomized studies, and in the field of dialysis adequacy, the only other larger randomized study that has been done is the HEMO study, where an
spKt/V of 1.7 was compared with an
spKt/V of 1.3 (the study doses were actually defined in terms of
eKt/V). Patients assigned to the higher dose of dialysis did not live longer, were not hospitalized less frequently, and were not found to manifest nutritional or other benefits. Apart from these two studies, there is little high-quality evidence regarding dialysis dose and outcomes, and almost all recommendations and guidelines in this area are primarily opinion-based.
1.
Effect of gender. In the randomized analysis of the HEMO trial, the women assigned to the higher dose of dialysis survived longer than the women assigned to the standard dose. Survival in the men assigned to the higher dialysis dose was slightly worse, so the overall effect of dose in the HEMO trial was negative, and it is not clear whether this dose-gender interaction was real or just a statistical fluke. If women need more dialysis, the reason is unclear. As detailed in
Chapter 3, an alternative method of scaling dialysis dose might be to scale to body surface area (BSA) instead of by urea distribution volume (
V). In healthy patients and in children, glomerular filtration rate (GFR) naturally scales to BSA, and an adult man and woman with similar values for BSA will have similar levels of GFR (Daugirdas, 2009). Because the ratio of
V:BSA is about 12%-15% different in men than in women, under current dosing guidelines, if a man and a woman have the same level of
V, they will get the same dose of dialysis; however, BSA in the woman will be 12%-15% higher, so theoretically one might argue that women need about 15% more dialysis than men. If one wishes to increase the dose of dialysis in terms of
stdKt/V, the increase in
spKt/V has to be increased by about twice as much. So this line of reasoning would suggest that the minimum
spKt/V in women should be about 25%-30% higher than that in men. However, the optimum method of scaling dialysis dose is not known, and there are no firm data other than the HEMO study and a few observational studies to suggest that BSA should be used to scale dialysis dose instead of
V.
2. Smaller patients. One can come up with four reasons why smaller patients should get relatively more dialysis when dose is measured as spKt/V:
a. Small patients (those with small values for V) would get a larger amount of dialysis if dose were scaled to BSA.
b. The KDOQI dose targets are in the form of spKt/V and not eKt/V; postdialysis urea rebound tends to be larger in smaller patients.
c. It is fairly easy to deliver a high Kt/V to small patients (and also women) in a short session length (e.g., 2.5 hours). Such short session lengths may not be sufficient to allow for removal of middle molecules, nor for adequate removal of excess fluid, and this may result in a chronically overhydrated patient.
d. Short session length treatments may give a seemingly adequate Kt/V level, but in patients who gain large amounts of fluid between treatments, short session lengths may require a relatively high ultrafiltration (UF) rate to remove this fluid and high UF rates are associated with a poor outcome.
3. Malnourished patients. When a patient’s weight is substantially below the weight of his or her peers, or when a patient has lost a large amount of weight, one opinion is to scale dialysis to the patient’s optimum “healthy” weight, and not the current reduced weight. The thinking is that the increased amount of dialysis will help return the patient to his or her healthier, premorbid condition.
4.
Residual renal urea clearance (Kru). Whether patients with substantial residual kidney function can be managed with lower doses of dialysis is an unanswered question. In one large study, when patient urine volume was >100 mL per day, the amount of dialysis delivered had little impact on survival (
Temorshuizen, 2004). Methods of adjusting dialysis dose for residual kidney function are entirely opinionbased. There are a variety of modeling-based adjustments that can be used. Readers can look to the European Best Practice recommendations (2002) and to the
NKF-KDOQI 2006 adequacy guidelines for some suggested guidance.
D.
Adequacy targets for schedules other than three times per week. There is no high-level evidence that can guide us in terms of dose titration when dialysis is given other than three times per week. One approach is to maintain a minimum
stdKt/V (calculated using modeling or the FHN equation) of 2.1 across all dialysis schedules (
Table 11.1). The value of 2.1 was chosen because it corresponds to a three-times-per-week schedule with an
spKt/V of 1.2 (
NKF-KDOQI, 2006).
1.
Four to six sessions per week. In one randomized trial that showed a benefit of more frequent dialysis, the FHN Daily Trial, the average delivered
stdKt/V averaged 3.7, considerably higher than the 2.1 minimum dose suggested by NKF-KDOQI. The average number of treatments delivered per week was 5, and the average delivered session length was 154 minutes (
FHN Trial Group, 2010).
2.
Twice-a-week dialysis. In the developing world, many patients are dialyzed only twice a week for economic reasons, and in the United States, this was not unusual in the recent past. Kinetic modeling using an
stdKt/V approach suggests that twice-a-week dialysis is not appropriate in patients without some modest degree of residual kidney function. On the other
hand, there are preliminary data suggesting that starting incident patients out on twice-a-week dialysis may result in longer preservation of residual kidney function (
Kalantar Zadeh, 2014). One observational study of twice-a-week dialysis done in the United States was unable to show an adverse association for this treatment strategy, and outcomes were actually a bit better than in patients dialyzed three times per week. Lack of harm may have been due to preferential selection of patients with some residual kidney function (
Hanson, 1999), but there was no definitive evidence that this was the case.
E. Adequacy targets based on metrics other than urea removal.
1.
Dialysis time. Urea removal is only one measure of dialysis adequacy. For solutes such as phosphorus and middle molecules, total weekly time is the major determinant of removal. Short weekly time also makes it difficult to remove excess salt and water from patients safely and effectively. The US KDOQI 2006 adequacy work group recommended a minimum session length of 3 hours for patients dialyzed three times per week with little residual renal function. The
European Best Practices Group (2002) recommends a minimum 4-hour treatment time. The benefits of dialysis sessions longer than 3.5 hours are not clear, and seem to be greatest in Japan and intermediate in Europe; benefits are difficult to demonstrate in the United States (
Tentori, 2012), perhaps because of the more intense dialysis given in that country. Also, dose-versus-outcomes data may be confounded by dose-targeting bias, a situation where survival is higher in patients who are meeting whatever dose target is being applied (
Daugirdas, 2013). In the United States, the average dialysis time is about 3.5 hours and is increasing toward 4 hours, similar to the practice in the rest of the world. A large randomized study (TiMe trial) is currently underway in the United States to determine whether setting a minimum dialysis time of 4.25 hours for all new (incident) patients, regardless of body size, will result in meaningful outcome benefits. A substantial number of patients in the United States dialyze in-center overnight
for about 6-9 hours per treatment. This strategy is described more completely in
Chapter 16.
Another argument against Kt/V is that a focus on urea removal tends to drive high-efficiency dialysis, with use of large dialyzers and rapid blood flows; the high efficiency of such treatments may result in solute disequilibrium and intradialytic side effects. Also, high blood flow rates delivered using the requisite larger needle sizes may engender more blood turbulence and platelet activation, as well as access dysfunction. A related question is whether one should make “optimum” use of the dialysis time by prescribing the highest blood flow that is consistently achievable, and using the most efficient (high K0A) dialyzer that one can afford. An alternative “slow and gentle” approach remains popular in Europe, according to which low blood flow rates and relatively small dialyzers are used. There are no randomized trials available to help choose between these two options. The best approach may be to set targets on the basis of both Kt/V (perhaps with higher minimum targets for women and smaller patients) and dialysis time. Changing the Kt/V target to a surface-area-adjusted value by itself solves the problem of short dialysis time given to smaller patients and women, as the amount of dialysis given to such patients based on surface area needs to be considerably larger, and this takes more time to deliver.
II. WRITING THE INITIAL PRESCRIPTION
A.
The dialysis dose: K ×
t. A dialysis prescription involves two main components: K, the dialyzer clearance, and t, the dialysis session length. K, in turn, depends on the dialyzer size used and the blood flow rate. The dialysate flow rate also plays a small role as discussed in
Chapter 3.
1. K usually ranges from 200 to 260 mL/min. For adult patients dialyzed using a blood flow rate of 400 mL/min, dialyzer clearance K will usually be about 230 ± 30 mL/min. One can use a urea kinetics calculator or a nomogram such as Figure 13.6, to get a reasonable estimate of dialyzer clearance from the blood flow rate and the efficiency of the dialyzer (K0A) being used. If we assume that K will be 250 mL/min for a dialysis session length of 4 hours, K × t will be 250 × 240 = 60,000 mL or 60 L. This represents the total volume of blood cleared of urea during the dialysis session.
2.
Targeting K ×
t on the basis of patient size and desired Kt/V. Assume that we have a clearance of 250 mL/min and a session length of 4 hours. How large a patient could we dialyze and still meet KDOQI guidelines? Remember that the guidelines suggest using a prescribed (
K ×
t)
/V of 1.4 to ensure that the delivered dose stays above 1.2. Over the 4-hour session we are delivering 60 L of
K ×
t, and if we want a prescribed
Kt/V of 1.4,
V must be 60/1.4 = 43 L, corresponding to a weight of about 78 kg. See
Tables 11.2 and
11.3 for some additional examples.
B.
How weight change during dialysis affects the dialysis prescription. In patients who have large weight gains, one will need a higher
Kt/V to get a given
URR than in patients with minimal weight gain (see
Figure 3.14 in
Chapter 3). For example, to get a
URR of 70%, one needs to prescribe a
Kt/V of only 1.3 if no fluid is removed, but one needs a
Kt/V of 1.5 if the weight loss during dialysis (
UF/W) is 6% of the body weight (see the 0.06
UF/W line in
Figure 3.14).
III.
CHECKING THE DELIVERED DOSE OF DIALYSIS. The dialysis dose is usually monitored on a monthly basis, according to KDOQI guidelines, by drawing a predialysis and postdialysis serum urea nitrogen (SUN). Alternatively and/or additionally, in vivo dialyzer clearance can be monitored during each treatment by checking the dialyzer sodium clearance, or delivered dialysis dose can be followed by tracking the UV absorbance of the spent dialysate, as described in
Chapter 3.
