Association of Continuous-Equivalent Urea Clearances with Death Risk in Intermittent Hemodialysis

Research Article Association of Continuous-Equivalent Urea Clearances with Death Risk in Intermittent Hemodialysis Aarne Vartia,1Heini Huhtala,2and Jukka Mustonen3,4 1Savonlinna Central Hospital, 57120 Savonlinna, Finland 2School of Health Sciences, University of Tampere, 33014 Tampere, Finland 3School of Medicine, University of Tampere, 33014 Tampere, Finland 4Tampere University Hospital, 33521 Tampere, Finland Correspondence should be addressed to Aarne Vartia; [email protected] Received 19 January 2016; Accepted 30 March 2016 Academic Editor: Deepak Malhotra Copyright © 2016 Aarne Vartia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Several reports describe favorable results from frequent hemodialysis, but due to the lack of unequivocal dose measures it is not clear whether the benefits are due to more efficient toxin removal or other factors. Methods.Theassociationswithdeath risk of six continuous-equivalent urea clearance measures were compared in 57 conventional in-center hemodialysis treatment periods of 51 patients, together 114 patient years. The double pool dose measures were calculated with the Solute-Solver program and separately scaled to urea distribution volume or normalized with body surface area. Results. Mortality associated significantly with equivalent renal urea clearance (EKR) scaled to urea distribution volume (𝑉)(𝑝 = 0.033)andwithEKRnormalizedwith body surface area (BSA) (𝑝 = 0.044)butnotwith𝑉-scaled (𝑝 = 0.059) nor BSA-normalized (𝑝 = 0.183) standard clearance (stdK). Women had significantly higher normalized protein catabolic rate (nPCR), EKR/𝑉,andstdK/𝑉 than men but slightly lower BSA-normalized dose measures and lower mortality. Protein catabolic rate and dialysis dose correlated positively with each other and with survival. Conclusions. The prognostically most valid continuous-equivalent clearance in the present material was EKR/𝑉, calculated from double pool urea generation rate, distribution volume, and time-averaged concentration. 1. Introduction Survival correlates with urea-based hemodialysis session dose in many large registry studies (Lowrie et al. [1]: 43,334 patients, Port et al. [2]: 84,936 patients, and Miller et al. [3]: 88,153 patients) in conventional thrice-weekly schedule, but intherandomizedcontrolledHEMOtrialmeanequilibrated K𝑡/𝑉 (eK𝑡/𝑉) 1.53 did not result in a significantly better outcome than 1.16 [4]. Intermittent hemodialysis treatments can be compared to each other by the session dose measures URR, K𝑡,K𝑡/𝑉, and eK𝑡/𝑉 only if the treatment frequency is equal. Several observational studies, referred to in [5, 6], and the randomized controlled FHN trial [7] describe positive results from frequent (“daily”) hemodialysis. However, the role of solute removal efficiency remains obscure. Urea distribution volume (𝑉)isanessentialvariable in kinetic modeling and can be used as a representative of patient size, a scaling factor. However, it may have also an independent effect on outcome [1, 8], which weakens the value of K𝑡/𝑉 as a prognostic factor. BSA has recently been recommended for scaling of dialysis dose similarly as in expressing the glomerular filtration rate [9]. 𝑉-scaled dosing may result in suboptimal outcome in women and children. Equivalent renal urea clearance (EKR, Casino and Lopez) [10] and standard clearance (stdK, Gotch) [11, 12] take treatment frequency and residual renal function (RRF) into account and they were intended for use in comparing dialysis doses in different schedules and for continuous dialysis and renal function [13, 14]. RRFmaycontributesignificantlytothetotalweekly solute removal [14] but only minimally (usually <1%) to the delivered K𝑡/𝑉or URR measured from blood samples. Renal clearance (Kr) can be added mathematically to session K𝑡/𝑉 [15–17]. Continuous-equivalent clearance based on UKM Hindawi Publishing Corporation Advances in Nephrology Volume 2016, Article ID 9342853, 8 pages http://dx.doi.org/10.1155/2016/9342853 2Advances in Nephrology Table 1: Association of patient characteristics and dialysis dose measures with death risk in 57 hemodialysis treatment periods of 51 patients. Mean SD Min Max Univariate 𝑝OR 95% CI Age Years 61.6 15.5 16.7 91.6 0.103 1.038 0.993–1.085 Weight kg 75.1 18.2 44.2 123.6 0.525 0.989 0.957–1.023 BMI kg/m226.1 5.5 16.3 43.7 0.198 0.924 0.819–1.042 BSA m21.84 0.25 1.31 2.34 0.872 0.823 0.078–8.727 𝑉L 31.8 6.7 20.5 50.3 0.637 1.021 0.936–1.113 nPCR g/kg/day 1.15 0.24 0.73 1.74 0.058 0.065 0.004–1.095 nKrmL/min/1.73 m21.7 1.4 0.0 6.0 0.861 0.963 0.631–1.469 nEKR mL/min/1.73 m212.5 1.3 8.4 16.4 0.044 0.611 0.379–0.988 nstdK mL/min/1.73 m28.5 1.0 6.2 12.2 0.183 0.638 0.330–1.235 nEKRant mL/min/1.73 m215.1 2.3 8.3 20.3 0.113 0.806 0.617–1.053 nstdKant mL/min/1.73 m210.2 1.6 6.1 14.3 0.232 0.785 0.527–1.168 EKR/𝑉/week 4.35 0.64 2.36 5.82 0.033 0.326 0.117–0.912 stdK/𝑉/week 2.93 0.39 1.73 3.88 0.059 0.205 0.040–1.060 fr /week 2.9 0.3 2.0 3.7 0.413 0.503 0.097–2.606 𝑡dh/week 13.5 2.3 7.7 18.4 0.077 0.786 0.602–1.027 Table 2: Hemodialysis treatment period durations and reasons for discontinuation. 𝑁%Duration (years) Mean SD Min Max Continuing 19 33.3 2.5 1.7 0.4 5.8 Death 16 28.1 2.3 1.6 0.6 6.9 Transplantation 8 14.0 1.4 1.3 0.6 4.6 Transfer to another unit 8 14.0 1.3 1.2 0.3 3.8 Transfer to peritoneal dialysis 3 5.3 2.1 1.4 0.7 3.5 Decision 3 5.3 0.8 0.3 0.6 1.1 The numbers include hemodialysis treatment periods ongoing on January 1, 1998 (from that date on), and incident periods during the nine-year observation time until December 31, 2006 (unless terminated earlier). includes Krautomatically. Renal function is “qualitatively” better than dialysis with equal urea clearance [18]. In theory, the continuous-equivalent average clearance basedondoublepoolUKMandincludingRRFisfine,but the best measure is the one most closely associated with outcome. Only few earlier reports correlate mortality directly with ECC [7, 19–22]. The aim of the present preliminary study was to compare the prognostic value of different continuousequivalent urea clearances as dialysis dose measures. 2. Subjects and Methods The study is a retrospective registry analysis from a hospital providing adult hemodialysis services in a district with a catchment area of some 50,000 inhabitants in Eastern Finland. The observation time was nine years, from January 1, 1998, to December 31, 2006. The material comprises 57 conventional in-center hemodialysis treatment periods of 51 patients, in total 114 patient years. Periods lasting under 90 days are not included. Patient characteristics are described in Table 1. Table 2 presents the characteristics of the dialysis treatment periods. “Decision” refers to a unanimous decision by patient and physician to discontinue renal replacement therapy. Dosing of dialysis, including treatment frequency, was prescribed by the first author on multiple criteria (weight, hydration status, predialysis plasma urea concentration, and other laboratory values, eK𝑡/𝑉 targets, and patient’s preferences). Renal diagnosis, comorbidity, functional status, waiting for transplantation, age, anticipated survival time, andproteincatabolicrate(PCR)werenotusedasdosing criteria. The patients were encouraged by a dietician to use a diet containing protein 1.2 g/kg/day, but the actual dietary protein intake was not controlled. Urea kinetic modeling with interdialysis urine collection was performed monthly. Krwas interpolated from previous and next measurements if urine collection occasionally failed. RRF was detected in 68% of UKM sessions. In 15% of them, Krwas interpolated. The numbers describing the patient characteristics and dialysis dose measures are means of each treatment period. Double pool UKM calculations were conducted with the Solute-Solver program version 1.97 (July 2, 2010, with source code) [23], accessed November 12, 2015: http://www.ureakinetics.org/. Dialyzer mass area coefficient (K0𝐴)reportedbythe dialyzer manufacturer is used in Solute-Solver in calculating dialyzer clearance (Kd)from𝑄band 𝑄dwith Michaels’ equation [24]. Six double pool continuous-equivalent urea clearance measures were compared: EKR/𝑉 (/week). nEKR (mL/min/1.73 m2). nEKRant (mL/min/1.73 m2). stdK/𝑉 (/week). nstdK (mL/min/1.73 m2). nstdKant (mL/min/1.73 m2). Advances in Nephrology 3 Table 3: Dialysis treatment periods divided into two groups with approximately equal mean nPCR. EKR/𝑉𝑝value Low High Mean SD Mean SD Age Years 60.8 13.2 62.5 17.7 0.668 Weight kg 77.1 21.2 72.9 14.7 0.393 BMI kg/m226.5 6.5 25.7 4.4 0.595 BSA m21.86 0.27 1.81 0.22 0.441 𝑉L 33.7 7.5 29.8 5.1 0.024 nPCR g/kg/day 1.19 0.28 1.12 0.19 0.283 nKrmL/min/1.73 m22.0 1.4 1.4 1.4 0.102 nEKR mL/min/1.73 m212.1 1.5 13.0 1.0 0.005 nstdK mL/min/1.73 m28.3 1.1 8.7 0.9 0.240 nEKRant mL/min/1.73 m214.2 2.4 16.2 1.7 0.001 nstdKant mL/min/1.73 m29.8 1.7 10.7 1.3 0.023 EKR/𝑉/week 3.99 0.59 4.72 0.45 <0.001 stdK/𝑉/week 2.75 0.38 3.12 0.30 <0.001 Treatment frequency /week 2.8 0.4 3.1 0.2 0.006 Treatment time h/week 12.6 2.5 14.4 1.7 0.003 Treatment periods 𝑛29 28 Women % 31.0 46.4 0.233 Diabetics % 37.9 46.4 0.516 E n di ng w it h d e at h % 3 7.9 1 7. 9 0 . 0 92 Patient years 𝑛49.8 64.5 Deaths 𝑛11 5 Mortality /1000 py 221 78 0.049 Their definitions are described in the Appendix. EKR is based on time-averaged urea concentration; stdK is based on average peak concentration. All include diffusion, convection, and renal clearance. 2.1. Statistical Methods. Continuous variables are expressed as means with standard deviations (SD) and minimum and maximum values. Categorical variables are expressed as percentages. Univariate and multivariable binary logistic regression analyses were performed to identify variables associated with death. Variables with a univariate 𝑝value <0.10 were entered into the multivariable models. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Linear regression analysis was used to evaluate the interaction of dialysis dose and nPCR (Figure 1) and the material was split into two groups on the basis of EKR/𝑉 and nPCR (Table 3). SPSS 22.0 and STATA 13.1 were used in statistical calculations. The graph was drawn with Excel 2007. 3. Results The overall mortality was 140 per 1,000 patient years. The main results are shown in Table 1. Mortality was significantly associated only with EKR/𝑉 and nEKR. In multivariable analysis, EKR/𝑉 was the only variable having an association with death risk (OR = 0.326, CI = 0.117–0.912, and 𝑝 = 0.033). Figure 1 illustrates the linear regression between nPCR and EKR/𝑉. To eliminate the confounding effect of nPCR on the dose-mortality relationship, the material was split into two groups with approximately equal mean nPCR but different mean EKR/𝑉.Thelineseparatingthegroupsis depicted in Figure 1. Table 3 shows that the difference in mortality between the low and high dose groups is still significant. Men had lower nPCR, EKR/𝑉,andstdK/𝑉 and higher mortality than women (Table 4). Diabetics had higher weight, BMI, and BSA but did not differ significantly from nondiabetics in mortality (Table 5). Correlations between some patient characteristics and continuous-equivalent clearances are shown in Table 6. All clearances correlate with each other. 4. Discussion The association of six continuous-equivalent urea clearance measures with death risk was evaluated by statistical analysis. The most significant predictor in univariate analysis and the only significant one in multivariable analysis was EKR/𝑉, calculated from TAC (𝑝 = 0.033). The 𝑝value of stdK/𝑉 (from PAC) was 0.059. In the old NCDS, TAC had a closer correlation with outcome than PAC [25]. The stdK concept is compliant with the peak concentration hypothesis [26], not supported by the present results. Normalizing with BSA was tested by the variables nEKR and nstdK, with mL/min/1.73 m2(or L/week/1.73 m2)astheir unit. nEKR was significantly associated with death risk, but nstdK was not. In the present study, Kdwas derived from 𝑄b,𝑄d,andK 0𝐴reported by the dialyzer manufacturer. 4Advances in Nephrology Table4:Dialysistreatmentperiodsbygender. Women Men 𝑝value Mean SD Mean SD Age Years 63.3 14.5 60.6 16.1 0.529 Weight kg 65.2 15.3 81.2 17.4 0.001 BMI kg/m225.7 5.9 26.3 5.3 0.694 BSA m21.66 0.17 1.95 0.22 <0.001 𝑉L 26.1 3.6 35.3 5.7 <0.001 nPCR g/kg/day 1.23 0.23 1.10 0.24 0.043 nKrmL/min/1.73 m21.9 1.4 1.6 1.4 0.467 nEKR mL/min/1.73 m212.4 1.1 12.7 1.5 0.401 nstdK mL/min/1.73 m28.2 0.7 8.7 1.1 0.066 nEKRant mL/min/1.73 m214.8 1.9 15.4 2.6 0.349 nstdKant mL/min/1.73 m29.8 1.2 10.5 1.7 0.082 EKR/𝑉/week 4.64 0.57 4.17 0.62 0.005 stdK/𝑉/week 3.07 0.36 2.85 0.39 0.036 Treatment periods 𝑛22 35 Ending with death % 13.6 37.1 0.055 Patient years 𝑛50.6 63.7 Deaths 𝑛313 Mortality /1000 py 59 204 0.040 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 0.40 0.80 1.20 1.60 2.00 EKR/V (/week) nPCR (g/kg/day) Division line Regression line y = 1.50x + 2.66 y = 1.40x + 2.73 R2= 0.29 Figure 1: Linear regression between nPCR and dialysis dose (EKR/𝑉) and the line separating the groups of Table 3. Calculated with Michaels’ equation [24], a 50% error in K0𝐴 causes an error of some 10% in Kdwith usual 𝑄band 𝑄d. Errors in Kdcause in UKM proportional errors in 𝑉and 𝐺. In EKR/𝑉 and stdK/𝑉, the errors cancel each other out, but not in nEKR and nstdK. Two other BSA-normalized continuous-equivalent clearances nEKRant and nstdKant were calculated applying the method of Daugirdas et al. described in the Appendix [9, 27]. The anthropometric total body water is usually larger compared to the kinetic 𝑉. Thus, nEKRant and nstdKant are higher than the simple BSA-normalized values. They are UKM-based continuous-equivalent hemodialysis dose measures, where the possible errors in Kdare eliminated, normalized with two anthropometric measures of body size and with mL/min/1.73 m2as unit. However, normalizing with BSA with either method did not improve the predictive value of EKR/𝑉 and stdK/𝑉. IntheHEMOtrial,theage-adjustedmortalitydidnot differ significantly between genders, but women did benefit from higher dose [28]. In the present study, women had lower mortality and got higher EKR/𝑉 and stdK/𝑉 but slightly lower BSA-normalized doses (Table 4). Comorbidity other than diabetes was not analyzed. The rather wide range of dialysis doses in the present studyisprobablyduetotheopportunisticaspect:moremay be better, but with large patients it is not easy to achieve a high dose (Table 6). In Table 3, the distribution volume and the proportion of men were higher in the low dose group. Men had higher mortality and volume and lower 𝑉-scaled dialysis dose (Table 4). The patient characteristics and dialysis dose measures have multiple correlations or dependencies (Table 6). Figure 1 shows the linear regression between nPCR and EKR/𝑉. PCR is a function of EKR/𝑉 or stdK/𝑉 ((B.3) and (B.4) in Appendix). Thus, mathematical coupling is inevitable. It is also possible that nPCR depends on the dialysis dose Advances in Nephrology 5 Table5:Dialysistreatmentperiodsbydiabeticstatus. Diabetes 𝑝value Yes No Mean SD Mean SD Age Years 61.2 14.9 62.0 16.1 0.842 Weight kg 81.7 18.5 70.2 16.7 0.018 BMI kg/m228.1 6.3 24.6 4.4 0.016 BSA m21.92 0.22 1.78 0.25 0.037 𝑉L 32.9 6.3 30.9 6.9 0.260 nPCR g/kg/day 1.16 0.23 1.14 0.26 0.739 nKrmL/min/1.73 m21.5 1.0 1.9 1.6 0.243 nEKR mL/min/1.73 m212.7 0.9 12.4 1.6 0.356 nstdK mL/min/1.73 m28.6 0.8 8.4 1.1 0.350 nEKRant mL/min/1.73 m215.8 1.9 14.6 2.5 0.055 nstdKant mL/min/1.73 m210.7 1.3 9.9 1.7 0.047 EKR/𝑉/week 4.43 0.47 4.29 0.74 0.427 stdK/𝑉/week 2.99 0.27 2.89 0.46 0.360 Treatment periods 𝑛24 33 Ending with death % 25.0 30.3 0.660 Patient years 𝑛54.3 60.0 Deaths 𝑛610 Mortality /1000 py 110 167 0.439 Table 6: Spearman’s correlations, significant at the 0.01 level (2-tailed). Weight BMI BSA 𝑉nPCR nEKR nstdK nEKRant nstdKant EKR/𝑉stdK/𝑉 Weight 1 0.854 0.950 0.748 0.352 0.453 0.530 BMI 0.854 1 0.658 0.455 0.393 0.427 BSA 0.950 0.658 1 0.817 0.364 0.430 0.521 𝑉0.748 0.455 0.817 1 0.436 −0.475 −0.354 nPCR 1 0.493 0.519 0.535 0.609 nEKR 1 0.929 0.694 0.711 0.566 0.631 nstdK 0.352 0.364 0.436 0.929 1 0.569 0.686 0.351 0.509 nEKRant 0.453 0.393 0.430 0.493 0.694 0.569 1 0.962 0.821 0.850 nstdKant 0.530 0.427 0.521 0.519 0.711 0.686 0.962 1 0.706 0.809 EKR/𝑉−0.475 0.535 0.566 0.351 0.821 0.706 1 0.961 stdK/𝑉−0.354 0.609 0.631 0.509 0.850 0.809 0.961 1 (causality)orthatdosingofdialysisisguidedbyurea concentrations or adjusted for protein catabolic rate [29] as recommended by Gotch et al. [12, 30, 31] (reverse causality). All these factors may have a role in the present study, but their separate contribution could not be specified. In the HEMO trial, the effect of dose on nPCR and the role of mathematical couplingwereestimatedtobesmall[32]. PCR reflects dietary protein intake, which correlates with nutritional status and outcome [33]. In a recent large registry material mortality decreased with increasing nPCR until 1.3 g/kg/day [34]. Table 3 shows that in the present study EKR/𝑉had a significant association with mortality, although nPCR was slightly higher in the low EKR/𝑉 group. nPCR is associated with mortality directly and with the dialysis dose through the “fear of high urea concentrations” effect— an example of the mechanisms possibly underlying the dosetargeting bias [35]. nPCR and dialysis dose may have a synergistic effect on survival. A limitation of the present study is the small number of patients, which prevents robust conclusions. On the other hand, different dosing definitions were compared in the same material—a response to the challenge presented by Debowska et al. [36]. In summary, EKR/𝑉and nEKR were significantly associated with mortality but stdK/𝑉and nstdK were not. Normalizing with BSA [9, 37] did not improve the significance of the ECC measures. Appendix A. Continuous-Equivalent Clearance (ECC) EKR (ECCTA )andstdK(ECC PA ) are based on the definition of clearance (K): K=𝐸 𝐶.(A.1) 6Advances in Nephrology In steady state, the removal rate (𝐸) equals the generation rate (𝐺), and thus K=𝐺 𝐶.(A.2) In EKR, 𝐶is the time-average concentration (TAC) and, in stdK, it is the average predialysis concentration (peak average concentration, PAC): EKR =𝐺 TAC ,(A.3) stdK =𝐺 PAC .(A.4) The unit is, for example, mL/min or L/week. Both may be scaled to body size by dividing by urea distribution volume 𝑉and expressed as EKR/𝑉 and stdK/𝑉: EKR/𝑉 = EKR 𝑉,(A.5) stdK/𝑉 = stdK 𝑉.(A.6) 𝐺,𝑉, TAC, and PAC are determined by kinetic modeling, in the present study with Solute-Solver. TAC and PAC are whole-body water concentrations and 𝑉is the postdialysis total volume 𝑉𝑡. The most practical unit of EKR/𝑉 and stdK/𝑉 is /week. nEKR and nstdK are ECC values (ECCTA and ECCPA ) normalized with body surface area analogically to glomerular filtration rate or renal clearance, with mL/min/1.73 m2as the unit: nEKR =EKR BSA ∗1.73, nstdK =stdK BSA ∗1.73. (A.7) Daugirdas et al. have developed a method to get a BSAnormalized stdK𝑡/𝑉 [9, 27]: SAn-stdK𝑡/𝑉 = stdK𝑡/𝑉 ∗ Vant BSA ∗20,(A.8) where Vant is anthropometric TBW in liters, BSA is in m2, andtheconstant20isthemeanof𝑉/BSA (L/m2)intheir material. Similarly, nEKRant and nstdKant can be calculated by using a combined anthropometric scaling factor Vant/BSA (=TBW/BSA): nEKRant =EKR/𝑉 ∗ Vant BSA ∗1.73, (A.9) nstdKant =stdK/𝑉 ∗ Vant BSA ∗1.73, (A.10) with appropriate unit conversion factors. Vant/BSA takes gender into account. In the present material, its average value was 18.7 (18.3–20.3) L/m2for women and 21.9 (20.2– 24.5) L/m2for men. B. nPCR By definition (see (A.4) and (A.6)), 𝐺=stdK/𝑉 ∗PAC ∗𝑉. (B.1) In hemodialysis, nPCR is generally calculated by the Borah equation [38] with Sargent’s modification [39]: nPCR =(9.35 ∗ 𝐺 + 0.294 ∗ 𝑉) (𝑉/0.58),(B.2) where nPCR is expressed in g/kg/day, 𝐺is expressed in milligrams of urea-N/min, and 𝑉is expressed in L. By substituting 𝐺from (B.1) and using appropriate unit conversion factors we get nPCR = 0.0151 ∗ stdK/𝑉 ∗ PAC +0.171, (B.3) where nPCR is in g/kg/day, stdK/𝑉is in /week, and PAC is in mmol/L. 𝑉will be eliminated. nPCR is high if concentration (PAC) is high despite high or normal clearance (stdK/𝑉). stdK/𝑉 andPACcanbesubstitutedwithEKR/𝑉 and TAC: nPCR = 0.0151∗ EKR/𝑉∗ TAC + 0.171. (B.4) nPCR is inevitably correlated with stdK/𝑉 and EKR/𝑉.The body surface area-normalized ECC measures are not so closely associated with nPCR. Abbreviations BMI: Body mass index = weight/height2 BSA: Body surface area 𝐶: Concentration ECC: Continuous-equivalent clearance EKR: Equivalent renal clearance = 𝐺/TAC EKR/𝑉:EKRscaledto𝑉 eK𝑡/𝑉:EquilibratedK𝑡/𝑉 fr: Dialysis session frequency 𝐺: Generation rate Kd: Dialyzer clearance Kr:Renalclearance K0𝐴:Dialyzermassareacoefficient K𝑡: Clearance ∗session time K𝑡/𝑉:K𝑡scaled to distribution volume = Kd∗𝑡 d/𝑉𝑡 nEKR: EKR normalized with BSA (mL/min/1.73 m2) nEKRant: EKR normalized with BSA and Vant (mL/min/1.73 m2) nKr:K rnormalized with BSA (mL/min/1.73 m2) nstdK: stdK normalized with BSA (mL/min/1.73 m2) nstdKant: stdK normalized with BSA and Vant (mL/min/1.73 m2) nPCR: PCR scaled to normal body weight = PCR/(𝑉/0.58) (g/kg/day) Advances in Nephrology 7 PAC: Average predialysis concentration, peak average concentration PCR: Protein catabolic rate (g/day) py: Patient years 𝑄b: Dialyzer blood flow 𝑄d: Dialysate flow RRF: Residual renal function spK𝑡/𝑉:SinglepoolK𝑡/𝑉 stdK: Standard clearance = 𝐺/PAC stdK/𝑉:stdKscaledto𝑉 TAC: Time-averaged concentration TBW: Total body water (Watson) = Vant 𝑡d: Dialysis session duration UF: Ultrafiltration volume (positive, if fluid is removed) UKM: Urea kinetic model 𝑉:Distributionvolume Vant: Anthropometric 𝑉=TBW 𝑉𝑡:Postdialysis𝑉. Ethical Approval Thestudywasbasedonananalysisofregisterdatacollected andutilizedduringtheroutinecareofpatientsandconducted with the permission of the medical director of the hospital. There was no control group or randomization. The study was not presented to an ethics committee because there were no interventions and, according to Finnish law, registry reports are not subject to evaluation by ethics committees. The patient data were anonymized and deidentified prior to analysis. Competing Interests The authors declare that they have no competing interests. Acknowledgments The authors thank the team of the Dialysis Unit of Savonlinna CentralHospitalforcarefulbloodandurinesampling. References [1] E.G.Lowrie,Z.Li,N.Ofsthun,andJ.M.Lazarus,“Bodysize, dialysis dose and death risk relationships among hemodialysis patients,” Kidney International,vol.62,no.5,pp.1891–1897, 2002. [2] F. K. Port, R. A. Wolfe, T. E. Hulbert-Shearon, K. P. 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