Continuous-equivalent clearance (ECC)

2.5.1 Aiming at a universal dose measure

Dialyzer urea clearance may be several times greater than that of healthy kidneys, but conventionally it is in effect only during less than ten percent of the time. The fluid shifts and concentration fluctuations restrict the usefulness of intermittent hemodialysis.

Kt/V and other measures of a single dialysis session can be used in comparing dialysis dosing only if the treatment frequency is equal [Depner 2001a]. Clearance K (Kd) and duration t (td) have equal weight in Kt and Kt/V: four hours with K = 200 mL/min is equal to two hours with K = 400 mL/min, but Kd and td may not have the same impact on solute removal, due at least in part to the compartment effects [Basile et al. 2011, David et al. 1998, Eloot et al. 2008]. Prescribed weekly Kt/V is equal whether the patient is dialyzed six hours two times per week or two hours six times with equal dialyzer clearance, but solute concentrations and treatment outcomes are not equal.

The promising outcomes achieved recently with frequent HD accentuate the need of a universal dose measure in investigating the relationship between dose and outcome. It is not clear whether these are due to higher clearance or lesser fluctuation in volumes and concentrations or other factors. In most investigations the weekly dose has been higher in the frequent group or it has not been appropriately reported.

2.5.2 Definitions based on UKM

EKR (ECCTA) and stdK (ECCPA) are based on the definition of clearance:

K = E / C (1b on page 19) In steady state the removal rate E equals the generation rate G, thus

K = G / C (2b on page 19)

Urea concentrations fluctuate in intermittent dialysis. If C is the time-averaged concentration (TAC) during the dialysis cycle, then the equation can be said to describe the average clearance (dialysis + RRF), if G is constant [Depner 1991a]

and equal to removal rate E. Casino and Lopez named this expression equivalent renal clearance (EKR, time-average clearance) [Casino 1999, Casino and Lopez 1996]:

EKR = G / TAC (16)

In conventional intermittent hemodialysis EKR is typically 12-15 mL/min or 120-150 L/week, significantly higher than in CAPD or the renal clearance in ESRD patients without dialysis. The inferior efficiency of hemodialysis may be due to the intermittency, including compartment disequilibrium or differences in the solute transport profile of kidneys, peritoneum, and dialyzer membrane or other factors. Gotch tried to resolve the discrepancy by implementing the stdK concept [Gotch 1998, Gotch 1999, Gotch et al. 2000], based on the “peak concentration hypothesis”, which assumes that high concentration peaks are especially harmful [Clark and Ronco 2001, Keshaviah et al. 1989]. With comparable outcomes the weekly average peak concentration (PAC) in conventional hemodialysis and the constant concentration in CAPD are about equal.

stdK = G / PAC (17)

The unit of EKR and stdK is e.g. mL/min or L/week. Both may be scaled to body size by dividing by urea distribution volume V and expressed as EKR/V and stdK/V:

EKR/V = EKR / V (18)

stdK/V = stdK / V. (19)

The most practical unit of EKR/V and stdK/V is /week. G, V, TAC and PAC can be determined by kinetic modeling. Because Kr is an input variable in computing G by UKM, these variables are not pure dialysis measures but also include RRF.

EKR/V and stdK/V are equivalent continuous clearances scaled by distribution volume V. Unfortunately expressions with operators are used as variable names,

such as Kt/V, EKR/V and stdK/V. This may cause confusion in equations like 18, 19 and 29. In Studies I-IV of the present thesis EKR/V is called stdEKR.

stdKt/V is a dimensionless misnomer, not an ECC. In Studies II-V stdK/V is used instead of stdKt/V. With equal treatment stdK < EKR.

For full conformity with the peak concentration hypothesis, the predialysis concentration after the longest interval should be substituted for C in Equation 2b on page 19. EBPG 2007 recommend this approach and call the variable SRI [Keshaviah 1995, Tattersall et al. 2007], but it is poorly documented and has not been used in outcome studies. Of course, the actual peak concentration is simpler to determine than PAC or TAC.

The peak concentration hypothesis has not been confirmed empirically. In the old NCDS trial TAC correlated more closely with outcome than PAC [Laird et al.

1983]. The stdK/V concept may be an artificial attempt to render continuous and intermittent therapies commensurable. According to Daugirdas, stdK/V is not a true continuous urea clearance, but a clearance “compressed” by about 1/3 and is extremely sensitive to dialysis frequency. It may also reflect the impact of sequestered small molecular weight solutes [Daugirdas 2014]. There are no studies demonstrating which is more closely associated with outcome, EKR/V or stdK/V.

EKR/V is more sensitive to schedule asymmetry than stdK/V [Daugirdas and Tattersall 2010]. Schedule asymmetry is not addressed in the present thesis.

Comprehensive analyses concerning the relationships between EKR, stdK and SRI have been presented by [Waniewski et al. 2006, 2010] and [Debowska et al. 2011].

2.5.3 Simple equations

Ideally G, V, TAC, and PAC in the above equations should be from double-pool UKM for greater accuracy, especially in simulations. Gotch and Leypoldt have developed equations for estimating stdK/V without UKM [Gotch 2004, Leypoldt 2004, Leypoldt et al. 2004]. They do not take RRF and convection into consideration, but are pure diffusive dialysis measures [Diaz-Buxo and Loredo 2006a, Diaz-Buxo and Loredo 2006b]. [Daugirdas et al. 2010a] have proposed a complex calculation method involving fluid removal and residual kidney clearance.

Weekly URR is an approximation of stdK/V. FSR, SRI and URR are “kinetically”

additive, Kt/V is not [Waniewski and Lindholm 2004].

2.5.4 Guidelines

The KDOQI guidelines for hemodialysis adequacy have recently been updated to take RRF and UF into consideration in stdK/V and recommend 2.3/week as the target for schedules other than thrice weekly [National Kidney Foundation 2015].

The EBPG 2002 guidelines recommended 13 - 15 mL/min as the minimum adequate EKR if the patient has significant RRF [Kessler et al. 2002], but the 2007 version includes no recommendations for EKR [Tattersall et al. 2007]. Instead, a solute removal index SRI of 2.0/week is recommended as a minimum for patients with RRF or with other than a 3 x/week schedule.