Liang et al. BMC Nephrology (2019) 20:82 https://doi.org/10.1186/s12882-019-1272-7 RESEARCHARTICLE Open Access Urea reduction ratio may be a simpler approach for measurement of adequacy of intermittent hemodialysis in acute kidney injury Kelly V. Liang1* , Jane H. Zhang2 and Paul M. Palevsky3 Abstract Background: Assessment of adequacy of intermittent hemodialysis (IHD) is conventionally based upon urea kinetic models for calculation of single pool Kt/Vurea (Kt/V), with 1.2 accepted as minimum adequate clearance for thrice weekly IHD. In the Acute Renal Failure Trial Network (ATN) Study, adequacy of IHD in patients with acute kidney injury (AKI) was assessed using Kt/V. However, equations for Kt/V require volume of distribution of urea, which is highly variable in AKI. Therefore, simpler methods are needed to assess adequacy of IHD in AKI. We assessed correlation of urea reduction ratio (URR) with Kt/V and determined URR thresholds corresponding to Kt/V values to determine if URR could be a simpler means to assess the delivered dose of IHD. Methods: Using patients who received IHD for 2.5–6 h and with pre-dialysis BUN ≥20 mg/dL, we plotted URR against Kt/V. We determined URR thresholds (0.60 to 0.75) corresponding to Kt/V ≥ 1.2, 1.3, and 1.4. We generated receiver operating characteristic (ROC) curves for increasing URR values for each level of Kt/V to identify the corresponding thresholds of URR. Results: There was strong correlation between URR and Kt/V. ROC curves comparing URR with Kt/V ≥ 1.2, 1.3, and 1.4 had area under the curves (AUC) of 0.99. Sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.2 were 0.769 (95% CI: 0.745 to 0.793) and 0.999 (95% CI: 0.997 to 1.000), respectively and the sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.4 were 0.998 (95% CI: 0.995 to 1.000) and 0.791 (95% CI: 0.771 to 0.811), respectively. Conclusions: Targeting a URR ≥0.67 provides a simplified means of assessing adequacy of IHD in patients with AKI. Use of URR will enhance ability to assess delivery of small solute clearance and improve adherence with clinical practice guidelines in AKI. Keywords: Acute kidney injury, Renal replacement therapy, Adequacy, Kt/V, Urea reduction ratio Background conventionally based upon urea kinetic models for Renal replacement therapy (RRT) is often required for calculation of single pool Kt/Vurea (Kt/V) [1–5]. The the management of acute kidney injury (AKI). Depend- Kidney Disease: Improving Global Outcomes (KDIGO) ing on hemodynamic status, RRT may be provided by Clinical Practice Guidelines for AKI recommend achiev- continuous dialysis (CRRT), hybrid forms of prolonged ing a threshold Kt/V of at least 1.3 3x/week or 3.9/week intermittent RRT (PIRRT) or intermittent dialysis (IHD). when delivering IHD in the setting of AKI [6]. These Assessment of adequacy of solute clearance in IHD is recommendations were substantially based upon data from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study, a multi- * Correspondence: [email protected] 1Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh center randomized trial comparing strategies of School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15213, USA more-intensive and less-intensive RRT in critically ill Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liang et al. BMC Nephrology (2019) 20:82 Page 2 of 7 patients with AKI which targeted a delivered Kt/V of except Sunday) when hemodynamically stable. Participants 1.2–1.4 in patients receiving IHD [7]. randomized to the less-intensive strategy (N = 561) received Rigorous quantification of dialysis dose using urea CVVHDF at an effluent flow rate of 20 mL/kg/h or SLED kinetic modeling is based on assumptions related to net on a 3-day-per-week schedule (every other day except nitrogen balance and the generation and volume of dis- Sunday) when hemodynamically unstable, or IHD on a tribution of urea that are not necessarily present in the 3-day-per-week schedule (every other day except Sunday) critically ill patient with AKI [8, 9]. Patients with AKI when hemodynamically stable. In each treatment arm, IHD are often hypercatabolic and in net negative nitrogen was prescribed with a targeted single-pool, variable-volume balance; may have rates of urea that are not constant (spvv) Kt/V of 1.2–1.4 per treatment. over time; have alterations in regional blood flow, par- ticularly in the setting of hemodynamic instability, that Calculation of Kt/V may produce disequilibrium in urea distribution between Kt/V was assessed at least three times per week during body compartments, invalidating standard single-pool the first two weeks of study therapy and at least weekly models; and may have a volume of distribution of urea thereafter using the second generation logarithmic (Vurea) that is variable and increased relative to patients (Daugirdas) equation: with end-stage renal disease [5, 10, 11]. Thus, the applic- = ¼ ‐ ðÞ‐ : ability of the formal urea kinetic models and standard Kt V ln R 0 008 x t þ ðÞÀ : : = logarithmic estimating equations for calculation of Kt/V 4 3 5xR x055 x UF Vurea that were developed in the end-stage renal disease where R is the ratio of post-dialysis BUN (BUN ) setting to estimate adequacy of small solute clearance in post divided by pre-dialysis BUN (BUN ), t is the dialysis patients with AKI receiving IHD is questionable. In pre session duration in hours, UF is the ultrafiltration particular, uncertainty regarding adjustments for Vurea volume in liters, and Vurea is the estimated volume of may introduce substantial error in the calculation of Kt/ distribution of urea [8, 9]. Blood samples for BUN were V using standard estimating equations. obtained immediately pre- and post-dialysis, with the In this post hoc analysis of data from the ATN study, post-dialysis BUN sample obtained using the slow-flow/ we sought to determine if use of the urea reduction ratio stop-pump technique [14] to prevent sample dilution (URR), based only on measurement of pre- and with recirculated blood and to minimize the variable ef- post-dialysis BUN and independent of estimates of V , urea fects of urea rebound. V was initially estimated as would provide a simpler but sufficiently reliable method urea 55% of pre-morbid body weight plus edema weight, for assessment of the delivered small solute clearance where edema weight was calculated as pre-morbid body during IHD for patients with AKI. In this analysis, we weight subtracted from current body weight and was assessed the correlation between URR and the systemat- recalculated each treatment. In patients with morbid ically calculated values of Kt/V in patients undergoing obesity, defined as actual weight > 130% of ideal body IHD in the ATN Study and determined URR thresholds weight (IBW), an adjusted pre-morbid body weight was that could be used as an alternative to Kt/V to assess calculated as IBW plus 25% of the difference between small solute clearance in critically ill patients with AKI ideal and actual pre-morbid weight with IBW calculated undergoing IHD. based on height, gender, and frame size with adjustment for limb amputation [15]. The rationale for this correc- Methods tion is based on the reduction in the percentage body ATN study design weight comprised by water (and hence V ) as the In the ATN Study, 1124 critically ill adults with severe urea percentage body fat increases. AKI attributable to acute tubular necrosis in the setting of sepsis or one or more failed non-renal organ systems Calculation of urea reduction ratio (URR) were randomized to strategies of either less-intensive or The urea reduction ratio was calculated as the quotient more-intensive RRT. Details of the design and primary of the difference between the BUN and the BUN results of the ATN study have been previously published pre post divided by the BUNpre: [7]. Written informed consent was obtained prior to ÀÁ enrollment and randomization of all participants. Partic- URR ¼ BUNpre À BUNpost =BUNpre ipants randomized to more-intensive RRT (N = 563) received continuous venovenous hemodiafiltration using the same BUN values used to calculate Kt/V. (CVVHDF) at an effluent flow rate of 35 mL/kg/h or sus- tained low-efficiency dialysis (SLED) on a 6-day-per-week Statistical methods schedule (every day except Sunday) when hemodynamically We compared paired Kt/V and URR measurements from unstable, or IHD on a 6-day-per-week schedule (every day all IHD treatments with measured pre- and post-dialysis Liang et al. BMC Nephrology (2019) 20:82 Page 3 of 7 BUNs, excluding treatments that were < 2.5 h or > 6 h in Table 1 Characteristics of patients receiving intermittent duration. In addition, we excluded data from IHD hemodialysis (IHD) included in analysis treatments with pre-dialysis BUN values < 20 mg/dL as Patients receiving the reliability of URR and Kt/V calculations is markedly IHD (N = 589) reduced when the pre-dialysis BUN is < 20 mg/dL.