1. Dialysis dose in thrice weekly dialysis schedules

We recommend eKt/V as the most clinically valid small solute measure of dialysis dose, and recommend monitoring of dialysis dose on a monthly basis for the majority of centre based dialysis patients. [1B]

We recommend targeting dialysis dose to achieve consistently a minimum eKt/V over 1.2 for thrice weekly patients, in the absence of a measured contribution from residual function. [1B]

We recommend a minimum of 12 hours per week for the majority of thrice weekly patients with minimal residual function. This may lead to higher than minimum eKt/V in smaller adult patients, which is appropriate. [1B]

Rationale

Dialysis adequacy encompasses concepts including the clinical assessment of general wellbeing, fluid status, and control of laboratory parameters, along with quantification of the dose of dialysis provided.

The purpose of dialysis is to provide enough removal of uraemic solutes and fluid that accumulate in kidney failure to maintain health and quality of life: more specific goals include control of uraemic symptoms, maintenance of safe electrolyte levels, prevention of nutritional decline, and optimum long term mortality. Whilst the earlier items in this list are readily assessed over a short time scale, concepts of dialysis dose are required to define the amount of dialysis likely to achieve longer term goals of treatment.

Due to the simplicity and low cost of measurement of urea in blood, measurement of dialysis adequacy has historically focused on clearance of small solutes, represented by urea. Concentration of a range of uraemic toxins of larger size (e.g., β 2 microglobulin) is likely to be important, but their measurement is not commonly performed.

Use of thrice weekly haemodialysis schedules emerged from the realisation during the early era of haemodialysis treatment that once or twice weekly haemodialysis schedules in patients with minimal residual function were insufficient to control the symptoms and complications of severe uraemia.

Most research on dialysis dose is therefore based on urea clearance, in patients on a thrice weekly schedule.

Urea clearance may be calculated by three methods in common use: Urea Reduction Ratio, and the ‘single pool’ and ‘equilibrated’ formulas for Kt/V. Kt/V is less commonly calculated by Urea Kinetic Modelling these methods are summarised mathematically in Appendix A. The diversity of methods can lead to duplication of effort, confusion over the meaning of targets, and impedes comparison between centres, so a single widely used method would be desirable. As the most adjusted method, and the one which has been most commonly validated in outcome literature, eKt/V appears to be optimum, and we have therefore given dose targets in terms of eKt/V. Equivalent targets using other methods may be derived for individual patients depending on their dialysis duration and fluid removal.

The literature on clinical outcome at different doses of dialysis is dominated by two randomised studies. The National Cooperative Dialysis Study (NCDS) was the landmark study which led to the concept of a threshold dialysis dose above which treatment was adequate, as well as the establishment of Kt/V as the accepted index of dialysis dose. Reporting in 1981, the study randomised 151 patients in a 2×2 design to high vs low time averaged urea, and short vs long dialysis duration the key finding was a lower rate of treatment failure (death or hospital admission) in the low urea (high dialysis dose) group [1]. When reanalysing the group with the newly proposed Kt/V measure, a clear threshold effect appeared, with Kt/V defining the watershed between ‘adequate’ and inadequate dialysis (Kt/V over vs under 1.0) [2].

A large number of observational studies subsequently reported an association between higher dialysis doses (beyond merely achieving the NCDS threshold) and improved survival [3 6], and this was tested in the HEMO study. Reporting in 2002, the HEMO study randomised 1846 patients in another 2×2 design to high vs standard dialysis dose (eKt/V 1.45 vs 1.05) and high vs low flux [7]. Over 2.8 years follow up with groups well separated in terms of achieved eKt/V (1.53 vs 1.16), higher dose provided no benefit in terms of survival or a number of secondary endpoints.

The basic concepts of these studies have not been superseded, hence the recommendation for dialysis dose (eKt/V > 1.2) is based largely on the eKt/V achieved in the standard dose group of the HEMO study. Alternative measures such as URR or spKt/V may be more familiar to some clinicians and equally useful for the majority of patients. Equivalent thresholds using these parameters are approximate since they vary between patients, but the differences are small: Appendix A summarises the mathematics behind these concepts.

Whether ‘adequate’ dialysis is the same for all patients or whether dose should be individualised is unclear, but the latter view is supported by several studies suggesting that gender and body size may affect the optimum dialysis dose [8 10]. Observational studies suggest that dialysis dose is more strongly related to survival in women than men, and when the HEMO study analysis is restricted to women, the high dose group show significantly improved survival. The reason for this interaction between gender and optimum eKt/V is unknown, but may be due to the scaling parameter ‘V’, which is lower in women and in less muscular patients, and is an independent predictor of survival. Alternative scaling factors such as body surface area, have been suggested [11 14], but none is in widespread use, and the collinearity between different body size parameters makes analyses difficult to interpret, but it seems likely that the optimum Kt/V may be higher than 1.2 in women and smaller patients, without a clear definition of ‘small’ [15].

Dialysis time

The optimum treatment duration for thrice weekly haemodialysis is slightly less clear, since it is difficult to separate the effect of treatment time from dialysis dose [16].

The evolution of dialysis technology has made dialysis dose targets achievable over short dialysis sessions. However, there are uraemic solutes other than urea, such as phosphate and β2 microglobulin, which are also important predictors of outcome, and which are inefficiently removed by dialysis [17,18]. Extending dialysis duration increases the removal of these highly sequestered and larger molecules, independent of any change in small solute clearance [19,20]. In the other part of its 2×2 design, the NCDS study also compared session duration (4.5 5.0 vs 2.5 3.0 hours) and although standard significance ‘level’ was not achieved (p=0.06), showed reduced treatment failure in the longer session group [1].

Most observational studies also report improved outcomes with longer treatment times. Low mortality rates were reported from Tassin with 8 hour overnight dialysis, attributed to improved blood pressure control and slower ultrafiltration [21,22], and lower mortality is associated with longer treatment times in national registry studies (over vs under 3.5 hours in US patients [23], and over vs under 4.5 hours in Australia [24]). The international DOPPS study examined the effect of treatment time whilst controlling for confounders using standard regression and instrumental variable approaches, concluding that patients with the longest treatment time (at least 4 hours) had the lowest risk for all cause and cardiovascular mortality [25]. Other clinical markers such as blood pressure, anaemia and phosphate control were also improved.

Whilst recognising the limitations of observational studies, a minimum duration for optimum dialysis clearly exists, and is most likely close to 4 hours, at least for patients with minimal residual kidney function. A duration threshold may lead to higher than minimum eKt/V in smaller adult patients, which is appropriate since optimal Kt/V may be higher in this group.

Summary

Optimal outcomes in patients on thrice weekly dialysis are achieved with sessions of at least 4 hours, providing eKt/V at least 1.2. Regular monitoring is strongly recommended, and this occurs monthly in the majority of units.

Under achievement may be addressed by attention to vascular access [26], session duration [27], blood or dialysate flow [28 30], dialyser efficiency [31] or anticoagulation [32], and in some patients under achievement may suggest the need for an augmented schedule. Achievement of these targets does not guarantee optimal outcome, with eKt/V being unaffected by missed sessions, for example.

These dose targets apply to thrice weekly patients, with minimal residual function, for whom survival duration is a primary treatment goal. There are specific clinical scenarios and different patient values for which it may be appropriate to adjust or disregard numeric targets for dialysis dose.

References

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