The Concept of Renal Replacement Therapy Dose and Efficiency

Efficiency, Intensity, Efficacy: Kt/V

Efficiency of RRT is represented by the concept of clearance (K)—the volume of blood cleared of a given solute over a given time. K does not reflect the overall solute removal rate (mass transfer); rather, its value is normalized by the serum concentration. Even when K remains stable over time, the removal rate will vary if the blood levels of the reference molecule change. K depends on solute molecular size, transport modality (diffusion or convection), and circuit operational characteristics such as blood flow rate (Qb), dialysate flow rate (Qd), ultrafiltration rate (Qf), and hemodialyzer type and size. K can be used to compare the treatment dose during each dialysis session, but it cannot be employed as an absolute dose measure to compare treatments with different time schedules. For example, K is typically higher in IHD than in continuous RRT (CRRT) or sustained low-efficiency daily dialysis (SLEDD). This is not surprising, because K represents only the instantaneous efficiency of the system. However, mass removal may be greater during SLEDD or CRRT. For this reason, information about the time span during which K is delivered is fundamental to describe the effective dose of dialysis.

Intensity of RRT can be defined by the product “clearance × time” (Kt). Kt is more useful than K for comparing different RRTs. A further step in assessing dose must include the frequency of the Kt application over a particular period (e.g., 1 week). This additional dimension is given by the product of intensity × frequency (Kt × treatment days/week, or Kt × d/w). Kt × d/w is superior to Kt because it offers information beyond a single treatment, and patients with AKI typically require more than one treatment. This concept of Kt × d/w offers the possibility of comparing disparate treatment schedules (e.g., intermittent, alternate-day, daily, continuous). However, it does not take into account the size of the pool of solute that must be cleared. This requires the dimension of efficacy.

Efficacy of RRT represents the effective solute removal outcome resulting from the administration of a given treatment to a given patient. It can be described by the fractional clearance of a given solute (Kt/V), where V is the volume of distribution of the marker molecule in the body. Kt/V is an established marker of adequacy of dialysis for small solutes correlating with medium-term (several years) survival in patients undergoing chronic hemodialysis. Urea is used typically as a marker molecule in ESRD to guide treatment dose, and a Kt/V _UREA of at least 1.2 currently is recommended.

As an example, we can consider the case of a 70-kg patient who is treated for 20 hr/day with a postfilter hemofiltration of 2.8 L/hr at a zero balance. His K _UREA will be 47 mL/min (2.8 L/hr = 2800 mL/60 min), because we know that during postfilter hemofiltration the ultrafiltered plasma water will drag all urea across the membrane, making its clearance identical to the ultrafiltration flow. His treatment time (t) will be 1200 minutes (60 minutes for 20 hours). His urea volume of distribution will be approximately 42,000 mL (60% of 70 kg), roughly equal to total body water. Simplifying this patient's Kt/V _UREA , we will have 47 × 1200/42000 = 1.34.

However, Kt/V _UREA application in patients with AKI has not been validated rigorously. In fact, although the application of Kt/V to the assessment of dose in AKI is theoretically intriguing, many concerns have been raised because problems intrinsic to AKI can hinder the accuracy and meaning of such dose measurement. These problems include lack of a metabolic steady state, uncertainty about the volume of distribution of urea (V _UREA ), a high protein catabolic rate, labile fluid volumes, and possible residual renal function, which changes dynamically during the course of treatment. To evaluate V _UREA in patients with AKI, Himmelfarb et al. undertook a systematic study in a cohort of 28 patients with AKI. They determined V _UREA by various approaches to anthropometric measurements (Watson, 42.5 ± 7.0 L; Hume-Weyer, 43.6 ± 7.1 L; Chertow, 46.8 ± 8.1 L) and found that they yielded significantly lower measures than V _UREA determined by physiologic formulas or by bioimpedance (51.1 ± 11.6 L and 51.1 ± 13.3 L, respectively). Finally, all measures of V _UREA by blood-based kinetics exceeded measurements by any other method (7% to 50% difference). The investigators inevitably concluded that estimates of V _UREA cannot be used reliably in patients with AKI.

Furthermore, delivery of the prescribed dose in AKI can be limited by technical problems (e.g., access recirculation, poor blood flows with temporary venous catheters, membrane clotting, and machine malfunction) and by clinical issues (hypotension and vasopressor requirements that can be responsible for solute dysequilibrium within tissues and organs). These aspects are particularly evident during IHD, less so during SLEDD, and even less so during CRRT. This difference occurs because, after some days of CRRT, patients' urea levels approach a real steady state: Because the therapy is applied continuously, the effect of compartmentalization of solutes is minimized; from a theoretical point of view, purification of total body water can be considered uniform in all organs, and single-pool kinetics can be applied (spKt/V).

Despite all the uncertainty surrounding its meaning and the gross shortcomings related to its accuracy in patients with AKI, the idea that there may be an optimal dose of solute removal continues to have a powerful hold in the literature. This is likely due to evidence from ESRD, in which a minimum Kt/V of 1.2 thrice weekly is indicated as standard. However, the benefits of greater Kt/V accrue over years of therapy, whereas in AKI any difference in dose would apply for days to weeks. The view that it would still be sufficient to alter clinical outcomes remains somewhat optimistic.