Urea reduction ratio may be a simpler approach for measurement of adequacy of intermittent hemodialysis in acute kidney injury

Renal replacement therapy (RRT) is often required for the management of acute kidney injury (AKI). Depending on hemodynamic status, RRT may be provided by continuous dialysis (CRRT), hybrid forms of prolonged intermittent RRT (PIRRT) or intermittent dialysis (IHD). Assessment of adequacy of solute clearance in IHD is conventionally based upon urea kinetic models for calculation of single pool Kt/V_urea (Kt/V) [1‐5]. The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI recommend achieving a threshold Kt/V of at least 1.3 3x/week or 3.9/week when delivering IHD in the setting of AKI [6]. These recommendations were substantially based upon data from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study, a multicenter randomized trial comparing strategies of more-intensive and less-intensive RRT in critically ill patients with AKI which targeted a delivered Kt/V of 1.2–1.4 in patients receiving IHD [7].

Rigorous quantification of dialysis dose using urea kinetic modeling is based on assumptions related to net nitrogen balance and the generation and volume of distribution of urea that are not necessarily present in the critically ill patient with AKI [8, 9]. Patients with AKI are often hypercatabolic and in net negative nitrogen balance; may have rates of urea that are not constant over time; have alterations in regional blood flow, particularly in the setting of hemodynamic instability, that may produce disequilibrium in urea distribution between body compartments, invalidating standard single-pool models; and may have a volume of distribution of urea (V_urea) that is variable and increased relative to patients with end-stage renal disease [5, 10, 11]. Thus, the applicability of the formal urea kinetic models and standard logarithmic estimating equations for calculation of Kt/V that were developed in the end-stage renal disease setting to estimate adequacy of small solute clearance in patients with AKI receiving IHD is questionable. In particular, uncertainty regarding adjustments for V_urea may introduce substantial error in the calculation of Kt/V using standard estimating equations.

In this post hoc analysis of data from the ATN study, we sought to determine if use of the urea reduction ratio (URR), based only on measurement of pre- and post-dialysis BUN and independent of estimates of V_urea, would provide a simpler but sufficiently reliable method for assessment of the delivered small solute clearance during IHD for patients with AKI. In this analysis, we assessed the correlation between URR and the systematically calculated values of Kt/V in patients undergoing IHD in the ATN Study and determined URR thresholds that could be used as an alternative to Kt/V to assess small solute clearance in critically ill patients with AKI undergoing IHD.

Our data demonstrate that there is a tight correlation between paired URR and Kt/V values and that measurement of URR provides a simpler method with adequate reliability for assessment of the delivered small solute clearance during intermittent hemodialysis in critically ill patients with AKI. This relationship is not unexpected, as the estimating equation used for calculating Kt/V is a function of the ratio between post-dialysis and pre-dialysis BUN, which is equal to 1 – URR [7, 8].

ROC curves evaluating the performance of URR relative to Kt/V thresholds of 1.2, 1.3, and 1.4 had AUC of > 0.99. Based on our data, a URR of ≥0.67 corresponded to a Kt/V ≥ 1.2 with > 99% accuracy with URR values of 0.67–0.72 corresponding to Kt/V values of 1.2–1.4. The KDIGO Clinical Practice Guidelines for AKI recommend delivery of Kt/V of at least 3.9 per week, corresponding to a Kt/V of > 1.3 on a thrice weekly dialysis schedule [6]. This would correspond to delivery of hemodialysis with a URR > 0.69 three times per week.

Measurement of adequacy of small solute clearance during intermittent hemodialysis is most rigorously based on formal urea kinetic modeling. However, many of the assumptions underlying these models in the stable outpatient with end-stage renal disease do not apply to critically ill patients with AKI [3, 16]. In particular, urea kinetic models assume the existence of a relative steady state during the modeling period, with the patient remaining in neutral nitrogen balance and the pre-dialysis state remaining relatively stable over repeated cycles of hemodialysis. These assumptions are often not valid in critically ill patients with AKI, the majority of whom are hypercatabolic and are in negative nitrogen balance or have variable rates of urea generation [13]. Furthermore, alterations in regional blood flow, particularly in patients who are hemodynamically unstable, may produce disequilibrium in urea distribution between body fluid compartments, invalidating standard single pool models [13]. In addition, unlike patients with end-stage renal disease on chronic hemodialysis, the volume of distribution of urea (V_urea) in patients with AKI may exceed total body water [12] and may be highly variable due to variations in volume status over time. Thus, estimates of small solute kinetics in critically ill patients with AKI using formal urea kinetic models are inadequately validated as is the use of standard estimating equations [8, 9].

In the VA/NIH Acute Renal Failure Trial Network Study, Kt/V was estimated at least three times per week in patients receiving IHD during the first two weeks of study therapy and then at least weekly thereafter using a second generation logarithmic estimating equation. In order to adjust for variations in volume status, V_urea was re-estimated each treatment using an iterative process incorporating estimates of edema weight based on the difference between pre-morbid and post-dialysis body weight. The calculation of Kt/V used during the study was therefore cumbersome and not readily transferable to clinical practice. While the use of URR is less precise in estimating small solute clearance in intermittent renal replacement therapy, we have shown satisfactory correlation between paired values of URR and Kt/V in more than 3600 dialysis sessions. The use of URR is readily transferable to clinical practice and would facilitate assessment of the delivered dose of intermittent renal replacement therapy in the acute setting and the implementation of quality improvement processes to ensure appropriate delivery of therapy.

Limitations of our analysis must be noted. First and foremost, despite the fact that Kt/V calculation in the ATN study was rigorously protocolized, Kt/V was still calculated using a second generation logarithmic estimating equation rather than using formal urea kinetic modeling. Secondly, errors in estimation of Kt/V may have resulted from the protocolized methodology used in the ATN study to estimate V_urea. Third, all dialysis treatments utilized catheters and catheter recirculation can both reduce the delivered dose of dialysis and interfere with ascertainment of post-dialysis BUN. However, recirculation will not affect the relationship between the measured Kt/V and URR. Furthermore, post-dialysis sampling during the ATN study was rigorously protocolized using standard slow-flow (blood pump at < 100 mL/min) or stop-pump sampling techniques to minimize the effect of catheter recirculation on ascertainment of the post-dialysis BUN concentration. Finally, since we relied on repeated measurements in individual patients, this may have introduced a degree of covariance between URR and Kt/V measurements that was not accounted for in our analytic approach. However, our data represents the largest dataset of rigorously measured pre- and post-dialysis BUNs and of systematically calculated estimates of Kt/V with a wide variance in both URR and Kt/V values. In addition, given the technical aspects of URR and Kt/V measurement, biological factors within individual patients are unlikely to have significantly contributed to covariance.

In summary, we believe that the findings of our study validate the use of URR as a simpler means of assessing delivery of small solute clearance during intermittent hemodialysis in patients with AKI. Although this approach underestimates solute clearance associated with ultrafiltration, it should be recognized that multiple assumptions used in determination of Kt/V, such as the relationship of volume of distribution of urea to total body weight, do not hold in critically ill patients with AKI. The use of URR, which can be easily calculated, will enhance the ability to assess adequacy of acute dialysis treatments, improve adherence with the KDIGO clinical practice guidelines for delivered dose of intermittent renal replacement therapy in AKI, and facilitate implementation of quality assurance and performance improvement processes in the acute setting. Although the clearance of toxins is one of the key roles of dialysis in AKI, other important factors should also be considered when prescribing IHD in the critically ill population. Specifically, maintaining adequate fluid balance via fluid removal with dialysis, as well as considering the effect of more intensive hemodialysis on antibiotic clearance and efficacy of treatment of sepsis needs to be factored into decisions when prescribing IHD in AKI. Nevertheless, the need to achieve adequate small solute clearance remains a fundamental aspect in the prescription and monitoring of acute hemodialysis in critically ill patients with AKI. Our findings suggest that URR, which may be more simply calculated than Kt/V, is sufficient for assessment of delivery of small solute clearance. Our findings are of relevance to both clinical care and clinical research by simplifying the methods used to quantify small solute clearance during intermittent renal replacement therapy in critically ill patients with AKI.