In medicine, a “dose” refers to the amount of a particular drug that is taken by a patient.  However, in dialysis the “dose” refers to the amount of a particular toxic marker that is removed from a patient’s blood.  By removing an adequate amount of this marker (ie, achieving an adequate dialysis dose), it is possible to improve solute and fluid homeostasis, reduced morbidity and mortality, control symptoms, and enhance quality of life.

Many methods have been proposed to measure the dose of dialysis; however, the most frequently used is the Kt/Vurea.  Urea is a small, water-soluble compound that is formed from the breakdown of amino acids and is dependent on protein intake.  Many early studies implicated urea as a major body toxin¹ and it was originally considered to be a good surrogate marker for other pathogenic solutes². Urea is currently used to quantify the dose of dialysis due to its abundance in renal failure, ease of measurement, wide volume of distribution, and good dialyzability^3-5.

The concept behind Kt/V urea arose from a reanalysis of the National Cooperative Dialysis Study (NCDS) by Gotch and Sargent in 1985⁶. The researchers showed that clinical outcomes could be better predicted when the dose of dialysis was expressed as the product of dialyzer urea clearance (K) and treatment time (t), divided by the urea distribution volume (V)^1,6-7.  The result was an expressionless number that described the volume of urea cleared during a dialysis session relative to the volume of urea distributed throughout the body² (see below).

Assuming no ultrafiltration or urea generation, the delivered Kt/V urea can be calculated from the urea concentration at the start and end of dialysis using the formula below³.  In the equation, ln stands for the natural logarithm, Co is the initial urea concentration, and Ct is the ending urea concentration.

Unfortunately, such a simple equation cannot account for other factors that may affect the delivered dose of dialysis^3,9.  The final concentration of urea not only depends on urea removal by the dialyzer, but also on urea generation (G) and the convective effects of ultrafiltration.  Similarly, the volume of distribution for urea (V) is not fixed and will vary according to intradialytic water removal.  As such, urea kinetic modeling (UKM) (sometimes called formal UKM) was developed as a more accurate method for determining Kt/V^1,3,8-11.  These models simulate the movement of urea during the dialysis session and derive values for V and G to calculate the dialysis dose^3,10,11 (see Table 1). Thus, these equations can account for the confounding effects of ultrafiltration as well as urea generation^9,11.

Table 1

Variables Estimated Using Urea Kinetic Modeling (UKM)
Variable	Explanation
V	Volume of distribution of urea, which equates closely to body water
G	Urea generation rate during dialysis
nPCR	Normalized protein catabolic rate, which is estimated fromG; in stable patients nPCR equals dietary protein
K	Dialyzer clearance extrapolated from the dialyzer mass transfer area coefficient (KoA)
Table adapted from O’Connor 200910.

UKM is currently the preferred method for determining Kt/V by the National Kidney Foundation KDOQI Guidelines⁴ and was used in the NCDS reanalysis discussed above⁶. Several different UKMs have been developed to quantify Kt/V, including the single pool Kt/V, equilibrated Kt/V, and weekly standard Kt/V.

Single-Pool Kt/V (spKt/V)

The most common model for calculating Kt/V is based on the assumption that urea is located in only one compartment (or pool) of the body^2,9,12. This idea of a single-pool Kt/V (spKt/V), predicts a linear decline in urea and an immediate equilibration between the blood and tissue compartments after dialysis. Thus, the spKt/V is calculated through measurement of the predialysis BUN concentration, followed by the postdialysis BUN concentration 10-15 seconds after the end of dialysis^4,7.  The lag-time is used to account for the confounding effects of blood recirculation within the fistula^7,11. The current KDOQI guidelines on hemodialysis adequacy recommend that the minimally adequate dose for conventional, thrice-weekly treatment be a spKt/V of 1.2, with a target dose of 1.4⁴.

The equation below is an example of a simplified, second generation logarithmic UKM formula used to calculatespKt/V, where ln is the natural logarithm, R is the postdialysis/predialysis serum urea ratio, t is the treatment time (hours), UF is ultrafiltration volume (liters), and W is the patient’s postdialysis body weight^2,13. However, it should be noted that this equation is only accurate when applied to dialysis given thrice-weekly for 2.5-5 hours⁴.

Equilibrated Kt/V (eKt/V)

Unlike spKt/V, the equilibrated Kt/V (eKt/V) recognizes that urea is not confined to one compartment of the body. Although the blood urea concentration is low at the end of a dialysis session, urea will eventually diffuse out of the cells and back into the extracellular space. In fact, the full equilibration of urea between the blood and tissue compartments is not complete until 30-60 minutes after the end of dialysis^2,7. The difference between the blood urea concentration at the end of dialysis and the concentration after full equilibration is referred to as “urea rebound.” Since spKt/V models do not account for this rebound effect, they are likely to overestimate the amount of dialysis received by the patient^7,9,11. Thus, the eKt/V (sometimes called double-pool Kt/V) was developed to account for the effects of urea rebound and more accurately reflect the delivered dose of dialysis.

Fortunately, patients do not need to remain in-center for an extra 30-60 minutes while the urea equilibrates.  Rebound can be predicted from a non-equilibrated postdialysis serum urea concentration and the spKt/V, as shown below^7,9.  Please note that the equation changes depending on whether the patient is dialyzing using an arterial-venous access (eg, AV fistula) or strictly venous access (eg, CV catheter).

Arterial Access:

Venous Access:  

Weekly Standard Kt/V (stdKt/V)

Interest in more frequent hemodialysis has prompted the creation of a weekly standard Kt/V (stdKt/V)¹⁴.  Unlike spKt/Vand eKt/V—which describe the effect of single session, intermittent treatment—the stdKt/V provides treatment information for a broad spectrum of dialytic therapies, including variable frequency hemodialysis (two to seven sessions per week), continuous and intermittent peritoneal dialysis, and continuous renal replacement therapies for acute renal failure.  As such, urea kinetic modeling with stdKt/V can be useful for comparing different treatment regimens and modalities^2,7,15.

Development of a stdKt/V was necessary since the single pool and equivalent Kt/V calculations, which are measured by taking the pre- and post-dialysis urea concentrations, do not accurately reflect the dose of more frequent HD regimens. These original models are inaccurate because the total urea mass removed per unit time decreases as the dialysis treatment time increases (ie, not as much urea is removed as the dose increases). Thus, a new model—the stdKt/V—was needed to accurately reflect the dialysis dose being provided. In determining stdKt/V, urea clearance, urea generation and blood urea concentration are calculated over a period of one week and normalized to body water (or rather, the total volume of distribution of urea). A minimum stdKt/V of 2.0 per week is recommended for all patients by the KDOQI guidelines and is roughly equivalent to a spKt/V of 1.2⁴.

Urea Reduction Ratio (URR)

Due to the complexity of UKM, the urea reduction ratio (URR) was proposed as a simpler alternative to measure dialysis dose.  The URR, which is expressed as a percentage, refers to the reduction in serum urea concentration during dialysis treatment and is mathematically related to spKt/V, as shown below ⁷. In the equations, Ct and Corepresent the postdialysis and predialysis serum urea concentrations, respectively.

The URR correlates well with dialysis outcomes, and is recognized by the KDOQI guidelines as an acceptable method to quantify the dialysis dose.  However, unlike UKM significant variability may occur because the URR does not take into account intradialytic urea generation or ultrafiltration^2,4. In order to provide adequate clearance, the KDOQI guidelines recommend that HEMODIALYSIS treatments less than 5 hours should have a minimum URR of 65% with a target dose of 70%⁴.

Impact of Residual Urea Clearance (K_R)

Previous studies have shown that a patient’s native residual urea clearance (K_R) can markedly decrease the need for dialysis and have an important influence on mortality¹⁶. Although the magnitude of this clearance is seemingly small, K_R is a continuous process that serves to attenuate the rise of toxins between dialysis treatments^4,9. Many practicing nephrologists do not compensate for residual function when calculating the hemodialysis dose due to the inconvenience and cost of measurements. More importantly, such practices may also have a negative psychological impact, as patients would continually see their dialysis dose increase as their disease progresses and native kidney function is lost⁹. However, several methods are available to incorporate K_R into the hemodialyzer clearance. These methods are discussed in detail in the most recent KDOQI guidelines, and are beyond the scope of this review⁴.

Other Markers of Dialysis Dose

Although urea is the most common marker used to quantify the dose of dialysis, urea is not closely correlated with the removal of larger water-soluble compounds, protein-bound solutes, or middle molecules^2,5.  As such, other molecules such as β2-microglobumin¹⁷, cystatin-C¹⁸, and phosphate¹⁹ have been investigated as markers of dialysis dose.

References

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2. Kuhlmann MK, Kotanko P, Levine NW. Chapter 90: Hemodialysis: Outcomes and Adequacy. In: Floege J, Johnson RJ, Feehally J, editors. Comprehensive Clinical Nephrology. St. Louis: Elsevier Saunders; 2010 p. 1060-1068.
3. Locatelli F, Buoncristiani U, Canaud B, Köhler H, Petitclerc T, Zucchelli P. Dialysis dose and frequency. Nephrol Dial Transplant 2005 Feb;20(2):285-96.
4. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 Updates: Hemodialysis Adequacy, Peritoneal Dialysis Adequacy and Vascular Access. American Journal of Kidney Diseases 2006;48:S1-S322.
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14. Diaz-Buxo J a, Loredo JP. Standard Kt/V: comparison of calculation methods. Artif Organs 2006 Mar;30(3):178-85.
15. Meyer TW, Sirich TL, Hostetter TH. Dialysis cannot be Dosed. Seminars in dialysis 2011 Sep;(4):[Epub ahead of print].
16. Termorshuizen F, Dekker F, van Manen J, Korevaar J, Boeschoten E, Krediet R, Group NS. Relative Contribution of Residual Renal Function and Different Measures of Adequacy to Survival in Hemodialysis Patients: An analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2. J Am Soc Nephrol 2004 Apr;15(4):1061-1070.
17. Baurmeister U, Vienken J, Ward R a. Should dialysis modalities be designed to remove specific uremic toxins? Semin Dial 2009;22(4):454-7.
18. Huang S-HS, Filler G, Yasin A, Lindsay RM. Cystatin C reduction ratio depends on normalized blood liters processed and fluid removal during hemodialysis. Clin J Am Soc Nephrol 2011 Feb;6(2):319-25.
19. Schmitt CP, Borzych D, Nau B, Wühl E, Zurowska A, Schaefer F. Dialytic phosphate removal: a modifiable measure of dialysis efficacy in automated peritoneal dialysis. Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis 2009;29(4):465-71.

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