- Email: [email protected]
Vurea target for peritoneal dialysis patients does not provide an equal dialysis dose for all
clinical investigation
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A single weekly Kt/Vurea target for peritoneal dialysis patients does not provide an equal see commentary on page 1162 dialysis dose for all Sally El-Kateb1, Sivakumar Sridharan2, Ken Farrington2,3, Stanley Fan4 and Andrew Davenport1 1
UCL Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, United Kingdom; 2Renal Unit, Lister Hospital, Stevenage SG1 4AB, United Kingdom; 3University of Hertfordshire, Hatfield, United Kingdom; and 4Barts Health NHS Trust, London, United Kingdom
Dialysis adequacy is traditionally based on urea clearance, adjusted for total body volume (Kt/Vurea), and clinical guidelines recommend a Kt/Vurea target for peritoneal dialysis. We wished to determine whether adjusting dialysis dose by resting and total energy expenditure would alter the delivered dialysis dose. The resting and total energy expenditures were determined by equations based on doubly labeled isotopic water studies and adjusted Kturea for resting energy expenditure and total energy expenditure in 148 peritoneal dialysis patients (mean age, 60.6 years; 97 male [65.5%]; 54 diabetic [36.5%]). The mean resting energy expenditure was 1534 kcal/d, and the total energy expenditure was 1974 kcal/day. Using a weekly target Kt/V of 1.7, Kt was calculated using V measured by bioimpedance and the significantly associated (r [ 0.67) Watson equation for total body water. Adjusting Kt for resting energy expenditure showed a reduced delivered dialysis dose (ml/kcal per day) for women versus men (5.5 vs. 6.2), age under versus over 65 years (5.6 vs. 6.4), weight <65 versus >80 kg (5.8 vs. 6.1), low versus high comorbidity (5.9 vs. 6.2), all of which were significant. Adjusting for the total energy expenditure showed significantly reduced dosing for those employed versus not employed (4.3 vs. 4.8), a low versus high frailty score (4.5 vs. 5.0) and nondiabetic versus diabetic (4.6 vs. 4.9). Thus, the current paradigm for a single target Kt/Vurea for all peritoneal dialysis patients does not take into account energy expenditure and metabolic rate and may lead to lowered dialysis delivery for the younger, more active female patient. Kidney International (2016) 90, 1342–1347; http://dx.doi.org/10.1016/ j.kint.2016.07.027 KEYWORDS: body surface area; Kt/Vurea; peritoneal dialysis; resting energy expenditure; total body water; total energy expenditure Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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ore than 3 million patients with end-stage kidney disease are currently treated by dialysis worldwide, with w300,000 treated by peritoneal dialysis (PD). As with hemodialysis, there are clinical guidelines recommending that patients receive a minimal amount of dialysis based on urea clearance.1 These urea-based clearance targets are derived from observational studies.2 However, prospective studies comparing different peritoneal dialysis regimens designed to achieve different urea clearance targets consistently failed to demonstrate any advantage for greater urea clearance in terms of patient morbidity or mortality.3–5 Indeed, PD technique and patient survival have been linked to preservation of residual renal function6 rather than PD urea clearance.7 The amount of urea clearance (Kt/Vurea) for dialysis patients is currently based on the volume of distribution of urea, total body water (TBW) derived from anthropomorphic measurements.8 However, TBW varies with body composition, as some tissues such as muscle contain more water than fat,9 and also varies between racial groups10 and patients with diabetes and other comorbidities.11 As such, for the same Kt/Vurea, the delivered urea clearance has been suggested to differ among patients.12 Rather than dosing the amount of dialysis required on urea clearance based on volume of distribution, an alternative approach based on metabolic activity has been proposed.13 Urea is generated as a by-product of intracellular nitrogen metabolism. Total body metabolic activity is a composite of resting metabolic rate and that due to physical activity. Previous studies in PD patients have concentrated on measuring resting energy expenditure (REE).14,15 but this underestimates total energy expenditure (TEE), by excluding that due to activity energy expenditure. We recently validated an assessment of TEE and REE in dialysis patients using a patient self-reported questionnaire and doubly labeled isotopic water.16,17 To establish whether there is a difference in the amount of dialysis delivered for a fixed Kt/Vurea target, we calculated urea clearance adjusted for energy expenditure to determine whether some groups of patients would be at a disadvantage under current clinical guideline recommendations.
Correspondence: Andrew Davenport, UCL Centre for Nephrology, Royal Free Hospital, University College London Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom. E-mail: [email protected]
RESULTS
Received 29 April 2016; revised 11 July 2016; accepted 14 July 2016; published online 18 September 2016
We studied 148 adult PD patients with a mean calculated REE of 1534 241 kcal/d and TEE 1974 414 kcal/d (Table 1).
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Table 1 | Patient demographic characteristics, peritoneal dialysis prescription, results of peritoneal dialysis adequacy, and transport status in all patients and those with contemporaneous bioimpedance measurements Variable N Male, % Age, yr Weight, kg Body surface area, m2 White African/Afro-Caribbean South Asian East Asian Employed Dialysis vintage, mo Comorbidity score Heart disease, % Myocardial infarction, % Diabetes mellitus, % Frailty Hemoglobin, g/l Serum albumin, g/l C-reactive protein, mg/l Serum glucose, mmol/l IFCC, mmol/mg Serum cholesterol, mmol/l Serum urea, mmol/l Serum creatinine, mmol/l Peritoneal cycler, % Icodextrin use, % Icodextrin volume, l/d 22.7–23.0 glucose use, % 22.7–23.0 glucose, l/d Previous peritonitis episodes Total weekly Kt/Vurea Weekly urinary Kt/Vurea Weekly peritoneal Kt/Vurea Total creatinine cleared per week/1.73 m2 Urine creatinine cleared per week/1.73 m2, L Peritoneal creatinine cleared per week/1.73 m2, L Urine <100 ml/d, % Urine volume, ml/d 4-hr dialysate/plasma creatinine 24-hr ultrafiltrate, ml Protein nitrogen appearance, g/kg per day
Total Cohort
Bioimpedance Group
148 65.5 60.6 17.5 73.6 16.7 1.86 0.24 43.2 24.3 27.7 5.4 20.3 9.1 (3.5–25.2) 4.0 (0–6.0) 19.7 10.2 32.4 3.0 (3.0–4.0) 109.9 4.8 36.5 5.5 5.0 (2.0–16.8) 5.9 (4.9–8.5) 38.4 (33.3–51.4) 4.47 1.44 18.4 6.1 698 (523–871) 85.5 75.7 1.8 (0.5–2.0) 57.4 2.5 (0–5.0) 0 (0–1) 2.1 (1.7–2.6) 0.8 (0.3–1.3) 1.2 (0.9–1.6) 67.4 (55.8–84.7)
118 63.6 59.5 18.2 73.1 16.6 1.85 0.24 42.4 21.1 29.7 6.8 22.9 9.4 (3.8–25.5) 4.0 (0–6.0) 19.7 9.4 29.7 3.0 (3.0–4.0) 110.5 4.5 36.6 5.6 5.0 (2.0–15.0) 5.7 (4.9–5.1) 36.2 (32.7–47.5) 4.50 1.50 18.5 5.9 696 (525–909) 83.9 81.2 1.8 (1.0–2.0) 54.2 2.9 (0–6) 0 (0–1) 2.1 (1.7–2.60) 0.9 (0.3–1.4) 1.2 (0.8–1.6) 70.1 (55.8–86.7)
29.6 (13.4–58.4)
28.9 (12.7–59.4)
35.6 (23.2–45.2)
37.3 (23.5–49.3)
12.2 946 (450–1249) 0.71 0.11 566 (200–908) 0.89 0.26
15.3 940 (448–1408) 0.73 0.11 536 (192–899) 0.89 0.25
IFCC ¼ International Federation of Clinical Chemists. Values shown as number, mean SD, median (interquartile range), and percentage.
Twenty-five percent were classified as high comorbidity18 and 48% as frail.19 Male patients were heavier than female patients and had a greater REE and TEE (Table 2). Patients who were employed, those with greater weight, and greater protein nitrogen appearance (PNA) had a higher TEE (Table 2), whereas those with greater frailty and comorbidity, those who were diabetic, and those who were Asian tended to have a lower TEE. As previous studies have suggested that Kt be adjusted for body surface area (BSA), we compared Watson TBW with BSA. Although there was a strong association between TBW and BSA (r2 ¼ 0.99, P < 0.001 for women and r2 ¼ 0.83, Kidney International (2016) 90, 1342–1347
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Table 2 | Estimates of daily REE and TEE in patients according to age, comorbidity, frailty, and ethnicity groupings Variable Male Female Age <65 yr Age >65 yr Nondiabetic Diabetic Employed Unemployed Low comorbidity High comorbidity Low frailty score High frailty score Weight <64 kg Weight 64–80 kg Weight >80 kg PNA <60 g/d PNA >60 g/d Non-Asian Asian
REE, kcal/d 1597 1412 1646 1408 1522 1556 1577 1523 1532 1539 1533 1535 1305 1514 1775 1450 1622 1561 1522
217 2401 209 2111 233 254 237 242 245 231 227 256 151 1421 1591 214 2291 225 243
TEE, kcal/d 2029 1868 2173 1750 2021 1893 2305 1890 2012 1862 2049 1894 1706 1973 2233 1826 2133 2060 1866
423 3772 392 3141 435 3662 511 3401 441 300 453 3532 306 4141 3391 317 4381 462 3592
REE, energy expenditure; TEE, total energy expenditure; PNA, protein nitrogen appearance. Daily PNA g/d. Results expressed as mean SD. 1 P < 0.01 comparing groups, adjusted for multiple comparisons (Bonferroni method). 2 P < 0.05, adjusted for multiple comparisons (Bonferroni method).
P < 0.001 for men), BSA was relatively greater at lower TBW volumes and relatively lower at higher TBW volumes. TBW had also measured by bioimpedance at the time of adequacy testing in 118 of the patients (79.7%) (Table 1). There was no statistically significant difference in TBW: Watson equation, 40.3 6.1 versus bioimpedance, 40.6 3.4 L; mean difference on Bland-Altman analysis, 0.72 L (Figure 1). Although the mean difference for women was 1.43 L and that for men was 0.31 L, the 95% limits of agreement were broad; 9.20 to 10.16 L for women, and from 11.04 to 11.66 L for men. There were positive correlations between BSA and both REE and TEE (r ¼ 0.92, P < 0.001 and r ¼ 0.59, P < 0.001, respectively) and also between TBW and both REE and TEE (r ¼ 0.85, P < 0.001 and r ¼ 0.66, P < 0.001, respectively). Clinical guidelines have recommended a minimal weekly Kt/Vurea of 1.7. We then calculated Kt values for a weekly Kt/ Vurea of 1.7 using both Watson equation and bioimpedance estimates of TBW. These Kt values were then adjusted by BSA, REE, and TEE. There was a positive relationship between TBW and Kt/TEE (Figure 2). The results of the adjusted Kt dialysis dosing are shown in Table 3 and Figure 3 for different patient groups. For the same prescribed dialysis dose (Kturea), women, younger patients, patients who were employed, and patients weighing less (Figure 3) received less dialysis than men, older patients, unemployed patients, and heavier patients (Table 3). In addition, patients with fewer comorbidities and less frailty, nondiabetic patients, and patients of non-Asian races also tended to receive less dialysis than those with more comorbidities and those who were diabetic, frail, and of Asian ethnicity. 1343
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Figure 1 | Bland-Altman analysis of total body water (TBW) measured by bioimpedance or calculated by the Watson equation. Mean difference: 0.72 L (95% limits of agreement 9.2 to þ10.7 L).
Multivariable analysis showed that sex was a significant predictor of Kt/BSA (Table 4). Sex and age were significant predictors of Kt/REE. For Kt/TEE, sex, age, and employment were common predictive factors irrespective of whether Kt was derived using TBW calculated by the Watson equation or bioimpedance. Both high comorbidity and diabetes were additional predictive factors for TEE, adjusted using the Watson formula for TBW (Table 4). DISCUSSION
Traditionally, the target amount of dialysis for patients with end-stage kidney failure has been based on Kt/Vurea adjusted for TBW volume. However, multiple prospective trials have failed to show an association between greater PD urea clearance and survival.3,4,7 Cellular metabolism, in particular protein turnover, generates waste products that accumulate in patients with end-stage kidney failure. As these azotemic toxins are generated by cellular metabolism, it has been suggested that the amount of dialysis required for patients should be based on metabolic rate rather than urea clearance.2 Studies to date have concentrated on measuring resting metabolic rate,14,15 but this overlooks physical activity and, as such, potentially underestimates energy expenditure. We used equations based on patient
Figure 2 | Relationship between Watson total body water (TBW) for men and women and total urea clearance adjusted for total energy expenditure (TEE) ml/kcal per day. 1344
self-reported physical activity questionnaires, which have been validated using doubly labeled isotopic water,16 to estimate REE and TEE. As expected, energy expenditure was associated with body weight, male sex, and younger age group.20 Patients with higher REE and TEE had a higher PNA rate due to increased urinary and peritoneal urea losses. However, we also noted that although REE was similar, TEE was lower with increasing frailty and comorbidity, in particular in patients with diabetes and in unemployed patients, compared with those patients with less frailty and lower comorbidity scores who were not diabetic or those who were employed. We also found that patients of an Asian background had lower TEE compared with white and African/Afro-Caribbean patients. This is in keeping with previous observations of lower energy expenditure, particularly in South Asian patients, and this has been suggested to be due to differences in terms of body composition related to brown fat tissue stores.21 We then compared the delivered dialysis dose assuming that all patients received the minimum weekly KtVurea target as recommended by clinical practice guidelines,1 using Kt calculated by both the Watson formula8 and TBW as measured by bioimpedance.22 Although we found no significant difference between TBW by either method, the mean bias was greater for bioimpedance-measured TBW than that estimated using the Watson equation. However, the 95% limits of agreement were broad,9 suggesting that at the individual patient level, TBW should preferably be measured. Previous reports have shown major differences between TBW derived by the Watson formula and TBW derived by bioimpedance were observed with obese patients with a body mass index >35; in our study group, <2% had a body mass index of this level. We then adjusted the delivered dialysis dose by both BSA, which is relatively greater for patients with lower TBW and relatively lower for those with greater TBW and also for both REE and TEE. Adjusting Kt for BSA, which has been advocated for hemodialysis patients,23 we found that this resulted in a lower dose being delivered to women and those with a high PNA rate and lower body weight. Adjusting for REE, female sex, younger age, lower weight, lower PNA along with frailty and comorbidity scores, and ethnicities other than Asian, all received relatively less delivered dialysis. When Kt was adjusted for TEE, then women, younger patients, and those weighing less, those who were employed, and those with less frailty, in particular those without diabetes, all would receive lower delivered dialysis dosing compared with men, heavier patients, those unemployed, those more frail, comorbid patients, and those with diabetes. Previous studies targeting a dialysis dose defined by a weekly KtVurea for PD patients have not shown an advantage of 1 target compared with another.3,4 Our study shows that achieving the same urea clearance does not equate to the same delivered dose of dialysis and, as such, potentially explains why prospective studies have failed to show a significant benefit of 1 KtVurea target for all patients. Kidney International (2016) 90, 1342–1347
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Table 3 | Comparison of a fixed total weekly Kt/V of 1.7 (urea clearance l/m2 per day or ml/kcal per day) adjusted for BSA, REE, and TEE for peritoneal dialysis patients comparing sexes, age, diabetic/nondiabetic, employment status, comorbidity, weight, ethnicity, high and low frailty, comorbidity, PNA rate, employed, unemployed, and ethnicity (Asian vs. other races) Variable Male Female Age <65 yr Age >65 yr Diabetic Nondiabetic High frailty Low frailty High comorbidity Low comorbidity Unemployed Employed High PNA rate Low PNA rate Asian Other
Kt/BSA 5.13 4.42 4.83 4.95 4.96 4.84 4.91 4.86 4.99 4.85 4.89 4.89 4.79 4.95 4.87 4.87
0.36 0.401 0.46 0.42 0.45 0.46 0.47 0.43 0.43 0.45 0.43 0.54 0.40 0.482 0.46 0.42
Kt/REEW 6.15 5.50 5.58 6.38 6.03 5.90 6.06 5.85 6.19 5.87 5.99 5.82 5.91 5.98 5.97 5.90
9.61 0.411 0.55 0.491 0.58 0.66 0.66 0.602 0.63 0.621 0.61 0.71 0.62 0.68 0.65 0.60
Kt/TEEW 4.96 4.23 4.29 5.18 5.00 4.53 4.96 4.46 5.14 4.55 4.87 4.07 4.75 4.62 4.67 4.79
0.71 0.651 0.53 0.611 0.691 0.82 0.75 0.781 0.66 0.801 0.72 0.821 0.78 0.87 0.85 0.69
Kt/REEBIA 6.23 5.64 5.93 6.12 5.92 6.06 6.01 6.01 5.91 6.05 5.96 6.19 5.77 6.23 6.10 5.79
0.62 0.641 0.73 0.62 0.65 0.71 0.61 0.75 0.63 0.71 0.73 0.51 0.70 0.592 0.65 0.762
Kt/TEEBIA 4.93 4.27 4.52 4.93 4.93 4.57 4.90 4.54 4.90 4.62 4.81 4.31 4.56 4.81 4.71 4.64
0.70 0.711 0.81 0.651 0.692 0.78 0.71 0.781 0.63 0.81 0.75 0.721 0.70 0.81 0.76 0.80
BIA, bioimpedance; BSA, body surface area; DM, diabetic; REE, resting energy expenditure; TEE, total energy expenditure; W, Watson formula. Volume (V) was estimated by the Watson formula or measured by BIA. 1 P < 0.01 after Bonferroni post hoc correction for multiple testing. 2 P < 0.05 after Bonferroni post hoc correction for multiple testing.
There are a number of limitations that should be considered. We used solely a weekly target Kt/Vurea, whereas some guidelines additionally recommend liters of creatinine cleared as an additional target for PD patients, and there may be differences between these targets depending on use of PD cyclers, and the amount of residual renal function.1,24 We adjusted Kt using both the Watson equation and bioimpedance. There were some differences between these methods. The Watson equation was established using a healthy population, whereas PD patients have increased TBW.25 As such, bioimpedance measurements are preferable, but ideally should be measured with the peritoneal dialysate drained.26 In addition, we calculated PNA rates using equations developed in a previous era, when patients were predominantly treated by continuous ambulatory PD and glucose-only dialysates,27 and although these are often used
as a surrogate for dietary protein intake, these estimates may not be as reliable for patients with increasing comorbidity, and we did not formally estimate dietary protein intake. Although we accepted that using Kt/Vurea for dialysis dosing has some limitations,28 more recent observational studies have suggested an advantage for adjusting Kt for BSA.23 We found that adjusting for BSA detected a difference between men and women and in relation to body weight and PNA. However, adjusting for TEE additionally demonstrated that younger and more fit patients, employed patients, and patients with less comorbidity received a relatively lower delivered dialysis dose compared with older, more frail, comorbid, and diabetic patients. Although we chose to investigate the effect of a weekly target Kt/Vurea of 1.7, our findings would be equally applicable to any set Kt/V target applied to patients. Therefore, we suggest that a single Kt/Vurea target dose is not applicable to all patients, and the dose of dialysis should be increased for those who are more physically active with greater TEE. On the other hand, the results of our study should not be misinterpreted to imply that some patient groups require less dialysis treatment. Our results generate a hypothesis that requires formal testing to determine whether increasing the minimum target dose of dialysis in some groups of PD patients improves patient outcomes. Patients and methods
Figure 3 | Adjusted daily urea clearance according to body weight. Fixed weekly Kt of 1.7 urea adjusted for body surface area (BSA) and resting energy expenditure (REE) and total energy expenditure (TEE) using Watson (W) total body water or bioimpedance (BIA) measured total body water. *P < 0.05 and **P < 0.01 versus weight <64 kg after Bonferroni correction. Kidney International (2016) 90, 1342–1347
Adult patients with end-stage kidney disease established on PD were recruited from University College London partner hospitals when attending for outpatient assessments of PD adequacy. Corresponding spent dialysate effluent, 24-hour urine collections, and serum samples were analyzed by standard methods, and the weekly dialysis dose was calculated as Kt/Vurea. The PNA rate was estimated using the Bergström equation and normalized for body weight (g/kg per day).27 Patient demographic characteristics were obtained from 1345
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Table 4 | Multivariable step backward models for weekly Kt adjusted for BSA, REE, TEE using both total body water calculated by Watson equation and measured by BIA, unstandardized b, SE, standardized b, and 95% CL Variable Kturea/BSA Male Kturea/REEW Male Age, yr Kturea/REEBIA PNA rate Male Age, yr Kturea/TEEW Male Age, yr Unemployed High comorbidity Diabetic Kturea/TEEBIA Male Age, yr Unemployed
b SE b
Standardized
b
t
95% CL
13.5 0.6, 0.87
P Value <0.001
0.70 0.05
0.77
0.58 0.08 0.02 0.01
0.44 0.54
7.5 0.43, 0.74 9.3 0.2, 0.25
<0.001 <0.001
0.01 0.01 0.39 0.12 0.01 0.01
0.37 0.28 0.19
4.4 0.01, 0.02 3.2 0.15, 0.63 2.3 0.01, 0.01
<0.001 0.002 0.025
0.59 0.02 0.52 0.30 0.21
0.10 0.01 0.11 0.11 0.10
0.35 0.44 0.26 0.16 0.12
6.1 7.5 4.5 2.7 2.0
0.51 0.13 0.01 0.01 0.44 0.15
0.33 0.32 0.24
3.8 0.25, 0.77 7.5 0.01, 0.02 3.0 0.15, 0.74
0.40, 0.02, 0.29, 0.01, 0.01,
0.79 <0.001 0.013 <0.001 0.74 <0.001 0.52 0.009 0.41 0.045 <0.001 <0.001 0.004
BIA, bioimpedance; BSA, body surface area; CL, confidence limits; PNA, protein nitrogen accumulation; REE, resting energy expenditure; TEE, total energy expenditure; W, Watson equation. BSA model, r2 0.60 adjusted, 0.59; model adjusted for REEW, r20.60; adjusted 0.59; model adjusted for REEBIA r20.42; adjusted, 0.37. Model adjusted for TEEW r20.42, adjusted 0.3, and adjusted for TEEBIA r20.35, adjusted 0.33. Sex (female vs. male).
computerized hospital records, and comorbidity was determined using self-administered comorbidity grading18 based on medical conditions and complications including diabetes mellitus (as defined by WHO criteria), cardiac disease, respiratory disease, liver disease, arthritis, depression, malignancy, and a frailty score previously reported in patients with chronic kidney disease.19 We defined a high comorbidity score as $4.0 and a high frailty score $4.0, in keeping with previous studies.18,19 TBW was calculated using the Watson equation.8 In addition, in 118 of the patients, contemporaneous measurements of TBW made with bioimpedance (InBody 720, InBody, Seoul, South Korea; Body Composition Monitor, Fresenius, Bad Homberg, Germany), which had been performed in a standardized manner,28,29 were available for review. Bioimpedance measurements made by the Body Composition Monitor and InBody were standardized using previously derived equations.30 BSA was calculated using the Gehan and George equation, as recommended by the European Best Clinical Practice guidelines.24 Physical activity data were obtained using the Recent Physical Activity Questionnaire,16 which collects information about both activity and the time spent performing activities over the preceding 4 weeks, including activities performed at home and work and during leisure time. The Recent Physical Activity Questionnaire has been validated against a doubly labeled water technique in the general population and has been shown to be a reliable tool for estimation of energy
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expenditure in patients with chronic kidney disease.16 Physical activity data were determined by each reported activity being assigned a metabolic equivalent of task (MET) value according to the Compendium of Physical Activities.31 The equations for calculating REE and TEE are detailed in the Supplementary Appendix. UK clinical guidelines recommend a minimum weekly Kt/ Vurea of 1.7.1,32 Hence, in order to compare minimum dialysis targets using alternative scaling parameters, weekly Kt was calculated as Kt ¼ 1.7 multiplied by V. Corresponding target values of Kt/BSA, Kt/REE, and Kt/TEE were calculated by dividing daily Kt by the respective parameters. Ethical approval of the study was granted by the UK National Research Ethics Committee–Essex, and the study was registered in UK Clinical Research Network portfolio number 14018. All patients provided written informed consent in keeping with the Declaration of Helsinki. Statistical analysis
Statistical analysis was performed using the Student t test or Mann-Whitney U test, analysis of variance, the Kruskal-Wallis test with appropriate post hoc correction, the Pearson or Spearman test for univariate correlation (GraphPad Prism, version 6.0, San Diego, CA), and step backward linear regression of variables on univariate analysis of P < 0.1 and those considered to be clinically relevant, with log transformation of variables that were not normally distributed and removal of variables that were not statistically significant unless they improved model fit. Models were checked for collinearity using SPSS, version 22 (SPSS Inc., Chicago, IL) and the Bland-Altman comparison (Analyse-It Software, version 3.0, Leeds, UK). Data are presented as the mean SD, median (interquartile range), mean and 95% confidence limits (CL), or percentage. DISCLOSURE
All the authors declared no competing interests. ACKNOWLEDGMENTS
The study was funded by a grant from the British Renal Society. SE-K was awarded an International Society for Nephrology fellowship. SUPPLEMENTARY MATERIAL Supplementary Appendix. Resting energy expenditure (REE) was estimated from a newer novel predictive equation that was derived and validated in a cohort of hemodialysis patients.18 Supplementary material is linked to the online version of the paper at www.kidney-international.org. REFERENCES 1. Woodrow G, Davies SJ. Peritoneal Dialysis (PD) (Guidelines PD 3.1 – 3.3). Available at: http://www.renal.org/guidelines/modules/peritonealdialysis-in-ckd#sthash.Br67xjah.dpuf. Accessed July 25, 2016. 2. Jansen MA, Termorshuizen F, Korevaar JC, et al. Predictors of survival in anuric peritoneal dialysis patients. Kidney Int. 2005;68:1199–1205. 3. Paniagua R, Amato D, Vonesh E, et al.; Mexican Nephrology Collaborative Study Group. Effects of increased peritoneal clearances on mortality
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17. Vilar E, Machado A, Garrett A, et al. Disease-specific predictive formulas for energy expenditure in the dialysis population. J Ren Nutr. 2016;29:59–66. 18. Sridharan S, Berdeprado J, Vilar E, et al. A self-report comorbidity questionnaire for haemodialysis patients. BMC Nephrol. 2014;15:134. 19. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173:489–495. 20. Finkel T. The metabolic regulation of aging. Nat Med. 2015;21:1416–1423. 21. Boon MR, Bakker LE, van der Linden RA, et al. High prevalence of cardiovascular disease in South Asians: central role for brown adipose tissue? Crit Rev Clin Lab Sci. 2015;52:150–157. 22. Davies SJ, Davenport A. The role of bioimpedance and biomarkers in helping to aid clinical decision-making of volume assessments in dialysis patients. Kidney Int. 2014;86:489–496. 23. Ramirez SP, Kapke A, Port FK, et al. Dialysis dose scaled to body surface area and size-adjusted, sex-specific patient mortality. Clin J Am Soc Nephrol. 2012;7:1977–1987. 24. Dombros N, Dratwa M, Feriani M, et al.; EBPG Expert Group on Peritoneal Dialysis. European best practice guidelines for peritoneal dialysis. 7 Adequacy of peritoneal dialysis. Nephrol Dial Transplant. 2005;20(suppl 9):ix21–ix23. 25. Papakrivopoulou E, Booth J, Pinney J, Davenport A. Comparison of volume status in asymptomatic haemodialysis and peritoneal dialysis outpatients. Nephron Extra. 2012;2:48–54. 26. Fan S, Sayed RH, Davenport A. Extracellular volume expansion in peritoneal dialysis patients. Int J Artif Organs. 2012;35:338–345. 27. Bergström J, Heimbürger O, Lindholm B. Calculation of the protein equivalent of total nitrogen appearance from urea appearance. Which formulas should be used? Perit Dial Int. 1998;18:467–473. 28. Davenport A. Effect of intra-abdominal dialysate on bioimpedance-derived fluid volume status and body composition measurements in peritoneal dialysis patients. Perit Dial Int. 2013;33:578–579. 29. Fürstenberg A, Davenport A. Assessment of body composition in peritoneal dialysis patients using bioelectrical impedance and dualenergy x-ray absorptiometry. Am J Nephrol. 2011;33:150–156. 30. McCafferty K, Fan S, Davenport A. Extracellular volume expansion, measured by multi-frequency bioimpedance, does not help preserve residual renal function in peritoneal dialysis patients. Kidney Int. 2014;85: 151–1557. 31. Ainsworth BE, Haskell WL, Herrmann SD, et al. 2011 Compendium of Physical Activities: a second update of codes and MET values. Med Sci Sports Exerc. 2011;43:1575–1581. 32. Daugirdas JT. Kt/V (and especially its modifications) remains a useful measure of haemodialysis dose. Kidney Int. 2015;88:466–473.
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A single weekly Kt/Vurea target for peritoneal dialysis patients does not provide an equal see commentary on page 1162 dialysis dose for all Sally El-Kateb1, Sivakumar Sridharan2, Ken Farrington2,3, Stanley Fan4 and Andrew Davenport1 1
UCL Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, United Kingdom; 2Renal Unit, Lister Hospital, Stevenage SG1 4AB, United Kingdom; 3University of Hertfordshire, Hatfield, United Kingdom; and 4Barts Health NHS Trust, London, United Kingdom
Dialysis adequacy is traditionally based on urea clearance, adjusted for total body volume (Kt/Vurea), and clinical guidelines recommend a Kt/Vurea target for peritoneal dialysis. We wished to determine whether adjusting dialysis dose by resting and total energy expenditure would alter the delivered dialysis dose. The resting and total energy expenditures were determined by equations based on doubly labeled isotopic water studies and adjusted Kturea for resting energy expenditure and total energy expenditure in 148 peritoneal dialysis patients (mean age, 60.6 years; 97 male [65.5%]; 54 diabetic [36.5%]). The mean resting energy expenditure was 1534 kcal/d, and the total energy expenditure was 1974 kcal/day. Using a weekly target Kt/V of 1.7, Kt was calculated using V measured by bioimpedance and the significantly associated (r [ 0.67) Watson equation for total body water. Adjusting Kt for resting energy expenditure showed a reduced delivered dialysis dose (ml/kcal per day) for women versus men (5.5 vs. 6.2), age under versus over 65 years (5.6 vs. 6.4), weight <65 versus >80 kg (5.8 vs. 6.1), low versus high comorbidity (5.9 vs. 6.2), all of which were significant. Adjusting for the total energy expenditure showed significantly reduced dosing for those employed versus not employed (4.3 vs. 4.8), a low versus high frailty score (4.5 vs. 5.0) and nondiabetic versus diabetic (4.6 vs. 4.9). Thus, the current paradigm for a single target Kt/Vurea for all peritoneal dialysis patients does not take into account energy expenditure and metabolic rate and may lead to lowered dialysis delivery for the younger, more active female patient. Kidney International (2016) 90, 1342–1347; http://dx.doi.org/10.1016/ j.kint.2016.07.027 KEYWORDS: body surface area; Kt/Vurea; peritoneal dialysis; resting energy expenditure; total body water; total energy expenditure Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
M
ore than 3 million patients with end-stage kidney disease are currently treated by dialysis worldwide, with w300,000 treated by peritoneal dialysis (PD). As with hemodialysis, there are clinical guidelines recommending that patients receive a minimal amount of dialysis based on urea clearance.1 These urea-based clearance targets are derived from observational studies.2 However, prospective studies comparing different peritoneal dialysis regimens designed to achieve different urea clearance targets consistently failed to demonstrate any advantage for greater urea clearance in terms of patient morbidity or mortality.3–5 Indeed, PD technique and patient survival have been linked to preservation of residual renal function6 rather than PD urea clearance.7 The amount of urea clearance (Kt/Vurea) for dialysis patients is currently based on the volume of distribution of urea, total body water (TBW) derived from anthropomorphic measurements.8 However, TBW varies with body composition, as some tissues such as muscle contain more water than fat,9 and also varies between racial groups10 and patients with diabetes and other comorbidities.11 As such, for the same Kt/Vurea, the delivered urea clearance has been suggested to differ among patients.12 Rather than dosing the amount of dialysis required on urea clearance based on volume of distribution, an alternative approach based on metabolic activity has been proposed.13 Urea is generated as a by-product of intracellular nitrogen metabolism. Total body metabolic activity is a composite of resting metabolic rate and that due to physical activity. Previous studies in PD patients have concentrated on measuring resting energy expenditure (REE).14,15 but this underestimates total energy expenditure (TEE), by excluding that due to activity energy expenditure. We recently validated an assessment of TEE and REE in dialysis patients using a patient self-reported questionnaire and doubly labeled isotopic water.16,17 To establish whether there is a difference in the amount of dialysis delivered for a fixed Kt/Vurea target, we calculated urea clearance adjusted for energy expenditure to determine whether some groups of patients would be at a disadvantage under current clinical guideline recommendations.
Correspondence: Andrew Davenport, UCL Centre for Nephrology, Royal Free Hospital, University College London Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom. E-mail: [email protected]
RESULTS
Received 29 April 2016; revised 11 July 2016; accepted 14 July 2016; published online 18 September 2016
We studied 148 adult PD patients with a mean calculated REE of 1534 241 kcal/d and TEE 1974 414 kcal/d (Table 1).
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Table 1 | Patient demographic characteristics, peritoneal dialysis prescription, results of peritoneal dialysis adequacy, and transport status in all patients and those with contemporaneous bioimpedance measurements Variable N Male, % Age, yr Weight, kg Body surface area, m2 White African/Afro-Caribbean South Asian East Asian Employed Dialysis vintage, mo Comorbidity score Heart disease, % Myocardial infarction, % Diabetes mellitus, % Frailty Hemoglobin, g/l Serum albumin, g/l C-reactive protein, mg/l Serum glucose, mmol/l IFCC, mmol/mg Serum cholesterol, mmol/l Serum urea, mmol/l Serum creatinine, mmol/l Peritoneal cycler, % Icodextrin use, % Icodextrin volume, l/d 22.7–23.0 glucose use, % 22.7–23.0 glucose, l/d Previous peritonitis episodes Total weekly Kt/Vurea Weekly urinary Kt/Vurea Weekly peritoneal Kt/Vurea Total creatinine cleared per week/1.73 m2 Urine creatinine cleared per week/1.73 m2, L Peritoneal creatinine cleared per week/1.73 m2, L Urine <100 ml/d, % Urine volume, ml/d 4-hr dialysate/plasma creatinine 24-hr ultrafiltrate, ml Protein nitrogen appearance, g/kg per day
Total Cohort
Bioimpedance Group
148 65.5 60.6 17.5 73.6 16.7 1.86 0.24 43.2 24.3 27.7 5.4 20.3 9.1 (3.5–25.2) 4.0 (0–6.0) 19.7 10.2 32.4 3.0 (3.0–4.0) 109.9 4.8 36.5 5.5 5.0 (2.0–16.8) 5.9 (4.9–8.5) 38.4 (33.3–51.4) 4.47 1.44 18.4 6.1 698 (523–871) 85.5 75.7 1.8 (0.5–2.0) 57.4 2.5 (0–5.0) 0 (0–1) 2.1 (1.7–2.6) 0.8 (0.3–1.3) 1.2 (0.9–1.6) 67.4 (55.8–84.7)
118 63.6 59.5 18.2 73.1 16.6 1.85 0.24 42.4 21.1 29.7 6.8 22.9 9.4 (3.8–25.5) 4.0 (0–6.0) 19.7 9.4 29.7 3.0 (3.0–4.0) 110.5 4.5 36.6 5.6 5.0 (2.0–15.0) 5.7 (4.9–5.1) 36.2 (32.7–47.5) 4.50 1.50 18.5 5.9 696 (525–909) 83.9 81.2 1.8 (1.0–2.0) 54.2 2.9 (0–6) 0 (0–1) 2.1 (1.7–2.60) 0.9 (0.3–1.4) 1.2 (0.8–1.6) 70.1 (55.8–86.7)
29.6 (13.4–58.4)
28.9 (12.7–59.4)
35.6 (23.2–45.2)
37.3 (23.5–49.3)
12.2 946 (450–1249) 0.71 0.11 566 (200–908) 0.89 0.26
15.3 940 (448–1408) 0.73 0.11 536 (192–899) 0.89 0.25
IFCC ¼ International Federation of Clinical Chemists. Values shown as number, mean SD, median (interquartile range), and percentage.
Twenty-five percent were classified as high comorbidity18 and 48% as frail.19 Male patients were heavier than female patients and had a greater REE and TEE (Table 2). Patients who were employed, those with greater weight, and greater protein nitrogen appearance (PNA) had a higher TEE (Table 2), whereas those with greater frailty and comorbidity, those who were diabetic, and those who were Asian tended to have a lower TEE. As previous studies have suggested that Kt be adjusted for body surface area (BSA), we compared Watson TBW with BSA. Although there was a strong association between TBW and BSA (r2 ¼ 0.99, P < 0.001 for women and r2 ¼ 0.83, Kidney International (2016) 90, 1342–1347
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Table 2 | Estimates of daily REE and TEE in patients according to age, comorbidity, frailty, and ethnicity groupings Variable Male Female Age <65 yr Age >65 yr Nondiabetic Diabetic Employed Unemployed Low comorbidity High comorbidity Low frailty score High frailty score Weight <64 kg Weight 64–80 kg Weight >80 kg PNA <60 g/d PNA >60 g/d Non-Asian Asian
REE, kcal/d 1597 1412 1646 1408 1522 1556 1577 1523 1532 1539 1533 1535 1305 1514 1775 1450 1622 1561 1522
217 2401 209 2111 233 254 237 242 245 231 227 256 151 1421 1591 214 2291 225 243
TEE, kcal/d 2029 1868 2173 1750 2021 1893 2305 1890 2012 1862 2049 1894 1706 1973 2233 1826 2133 2060 1866
423 3772 392 3141 435 3662 511 3401 441 300 453 3532 306 4141 3391 317 4381 462 3592
REE, energy expenditure; TEE, total energy expenditure; PNA, protein nitrogen appearance. Daily PNA g/d. Results expressed as mean SD. 1 P < 0.01 comparing groups, adjusted for multiple comparisons (Bonferroni method). 2 P < 0.05, adjusted for multiple comparisons (Bonferroni method).
P < 0.001 for men), BSA was relatively greater at lower TBW volumes and relatively lower at higher TBW volumes. TBW had also measured by bioimpedance at the time of adequacy testing in 118 of the patients (79.7%) (Table 1). There was no statistically significant difference in TBW: Watson equation, 40.3 6.1 versus bioimpedance, 40.6 3.4 L; mean difference on Bland-Altman analysis, 0.72 L (Figure 1). Although the mean difference for women was 1.43 L and that for men was 0.31 L, the 95% limits of agreement were broad; 9.20 to 10.16 L for women, and from 11.04 to 11.66 L for men. There were positive correlations between BSA and both REE and TEE (r ¼ 0.92, P < 0.001 and r ¼ 0.59, P < 0.001, respectively) and also between TBW and both REE and TEE (r ¼ 0.85, P < 0.001 and r ¼ 0.66, P < 0.001, respectively). Clinical guidelines have recommended a minimal weekly Kt/Vurea of 1.7. We then calculated Kt values for a weekly Kt/ Vurea of 1.7 using both Watson equation and bioimpedance estimates of TBW. These Kt values were then adjusted by BSA, REE, and TEE. There was a positive relationship between TBW and Kt/TEE (Figure 2). The results of the adjusted Kt dialysis dosing are shown in Table 3 and Figure 3 for different patient groups. For the same prescribed dialysis dose (Kturea), women, younger patients, patients who were employed, and patients weighing less (Figure 3) received less dialysis than men, older patients, unemployed patients, and heavier patients (Table 3). In addition, patients with fewer comorbidities and less frailty, nondiabetic patients, and patients of non-Asian races also tended to receive less dialysis than those with more comorbidities and those who were diabetic, frail, and of Asian ethnicity. 1343
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Figure 1 | Bland-Altman analysis of total body water (TBW) measured by bioimpedance or calculated by the Watson equation. Mean difference: 0.72 L (95% limits of agreement 9.2 to þ10.7 L).
Multivariable analysis showed that sex was a significant predictor of Kt/BSA (Table 4). Sex and age were significant predictors of Kt/REE. For Kt/TEE, sex, age, and employment were common predictive factors irrespective of whether Kt was derived using TBW calculated by the Watson equation or bioimpedance. Both high comorbidity and diabetes were additional predictive factors for TEE, adjusted using the Watson formula for TBW (Table 4). DISCUSSION
Traditionally, the target amount of dialysis for patients with end-stage kidney failure has been based on Kt/Vurea adjusted for TBW volume. However, multiple prospective trials have failed to show an association between greater PD urea clearance and survival.3,4,7 Cellular metabolism, in particular protein turnover, generates waste products that accumulate in patients with end-stage kidney failure. As these azotemic toxins are generated by cellular metabolism, it has been suggested that the amount of dialysis required for patients should be based on metabolic rate rather than urea clearance.2 Studies to date have concentrated on measuring resting metabolic rate,14,15 but this overlooks physical activity and, as such, potentially underestimates energy expenditure. We used equations based on patient
Figure 2 | Relationship between Watson total body water (TBW) for men and women and total urea clearance adjusted for total energy expenditure (TEE) ml/kcal per day. 1344
self-reported physical activity questionnaires, which have been validated using doubly labeled isotopic water,16 to estimate REE and TEE. As expected, energy expenditure was associated with body weight, male sex, and younger age group.20 Patients with higher REE and TEE had a higher PNA rate due to increased urinary and peritoneal urea losses. However, we also noted that although REE was similar, TEE was lower with increasing frailty and comorbidity, in particular in patients with diabetes and in unemployed patients, compared with those patients with less frailty and lower comorbidity scores who were not diabetic or those who were employed. We also found that patients of an Asian background had lower TEE compared with white and African/Afro-Caribbean patients. This is in keeping with previous observations of lower energy expenditure, particularly in South Asian patients, and this has been suggested to be due to differences in terms of body composition related to brown fat tissue stores.21 We then compared the delivered dialysis dose assuming that all patients received the minimum weekly KtVurea target as recommended by clinical practice guidelines,1 using Kt calculated by both the Watson formula8 and TBW as measured by bioimpedance.22 Although we found no significant difference between TBW by either method, the mean bias was greater for bioimpedance-measured TBW than that estimated using the Watson equation. However, the 95% limits of agreement were broad,9 suggesting that at the individual patient level, TBW should preferably be measured. Previous reports have shown major differences between TBW derived by the Watson formula and TBW derived by bioimpedance were observed with obese patients with a body mass index >35; in our study group, <2% had a body mass index of this level. We then adjusted the delivered dialysis dose by both BSA, which is relatively greater for patients with lower TBW and relatively lower for those with greater TBW and also for both REE and TEE. Adjusting Kt for BSA, which has been advocated for hemodialysis patients,23 we found that this resulted in a lower dose being delivered to women and those with a high PNA rate and lower body weight. Adjusting for REE, female sex, younger age, lower weight, lower PNA along with frailty and comorbidity scores, and ethnicities other than Asian, all received relatively less delivered dialysis. When Kt was adjusted for TEE, then women, younger patients, and those weighing less, those who were employed, and those with less frailty, in particular those without diabetes, all would receive lower delivered dialysis dosing compared with men, heavier patients, those unemployed, those more frail, comorbid patients, and those with diabetes. Previous studies targeting a dialysis dose defined by a weekly KtVurea for PD patients have not shown an advantage of 1 target compared with another.3,4 Our study shows that achieving the same urea clearance does not equate to the same delivered dose of dialysis and, as such, potentially explains why prospective studies have failed to show a significant benefit of 1 KtVurea target for all patients. Kidney International (2016) 90, 1342–1347
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Table 3 | Comparison of a fixed total weekly Kt/V of 1.7 (urea clearance l/m2 per day or ml/kcal per day) adjusted for BSA, REE, and TEE for peritoneal dialysis patients comparing sexes, age, diabetic/nondiabetic, employment status, comorbidity, weight, ethnicity, high and low frailty, comorbidity, PNA rate, employed, unemployed, and ethnicity (Asian vs. other races) Variable Male Female Age <65 yr Age >65 yr Diabetic Nondiabetic High frailty Low frailty High comorbidity Low comorbidity Unemployed Employed High PNA rate Low PNA rate Asian Other
Kt/BSA 5.13 4.42 4.83 4.95 4.96 4.84 4.91 4.86 4.99 4.85 4.89 4.89 4.79 4.95 4.87 4.87
0.36 0.401 0.46 0.42 0.45 0.46 0.47 0.43 0.43 0.45 0.43 0.54 0.40 0.482 0.46 0.42
Kt/REEW 6.15 5.50 5.58 6.38 6.03 5.90 6.06 5.85 6.19 5.87 5.99 5.82 5.91 5.98 5.97 5.90
9.61 0.411 0.55 0.491 0.58 0.66 0.66 0.602 0.63 0.621 0.61 0.71 0.62 0.68 0.65 0.60
Kt/TEEW 4.96 4.23 4.29 5.18 5.00 4.53 4.96 4.46 5.14 4.55 4.87 4.07 4.75 4.62 4.67 4.79
0.71 0.651 0.53 0.611 0.691 0.82 0.75 0.781 0.66 0.801 0.72 0.821 0.78 0.87 0.85 0.69
Kt/REEBIA 6.23 5.64 5.93 6.12 5.92 6.06 6.01 6.01 5.91 6.05 5.96 6.19 5.77 6.23 6.10 5.79
0.62 0.641 0.73 0.62 0.65 0.71 0.61 0.75 0.63 0.71 0.73 0.51 0.70 0.592 0.65 0.762
Kt/TEEBIA 4.93 4.27 4.52 4.93 4.93 4.57 4.90 4.54 4.90 4.62 4.81 4.31 4.56 4.81 4.71 4.64
0.70 0.711 0.81 0.651 0.692 0.78 0.71 0.781 0.63 0.81 0.75 0.721 0.70 0.81 0.76 0.80
BIA, bioimpedance; BSA, body surface area; DM, diabetic; REE, resting energy expenditure; TEE, total energy expenditure; W, Watson formula. Volume (V) was estimated by the Watson formula or measured by BIA. 1 P < 0.01 after Bonferroni post hoc correction for multiple testing. 2 P < 0.05 after Bonferroni post hoc correction for multiple testing.
There are a number of limitations that should be considered. We used solely a weekly target Kt/Vurea, whereas some guidelines additionally recommend liters of creatinine cleared as an additional target for PD patients, and there may be differences between these targets depending on use of PD cyclers, and the amount of residual renal function.1,24 We adjusted Kt using both the Watson equation and bioimpedance. There were some differences between these methods. The Watson equation was established using a healthy population, whereas PD patients have increased TBW.25 As such, bioimpedance measurements are preferable, but ideally should be measured with the peritoneal dialysate drained.26 In addition, we calculated PNA rates using equations developed in a previous era, when patients were predominantly treated by continuous ambulatory PD and glucose-only dialysates,27 and although these are often used
as a surrogate for dietary protein intake, these estimates may not be as reliable for patients with increasing comorbidity, and we did not formally estimate dietary protein intake. Although we accepted that using Kt/Vurea for dialysis dosing has some limitations,28 more recent observational studies have suggested an advantage for adjusting Kt for BSA.23 We found that adjusting for BSA detected a difference between men and women and in relation to body weight and PNA. However, adjusting for TEE additionally demonstrated that younger and more fit patients, employed patients, and patients with less comorbidity received a relatively lower delivered dialysis dose compared with older, more frail, comorbid, and diabetic patients. Although we chose to investigate the effect of a weekly target Kt/Vurea of 1.7, our findings would be equally applicable to any set Kt/V target applied to patients. Therefore, we suggest that a single Kt/Vurea target dose is not applicable to all patients, and the dose of dialysis should be increased for those who are more physically active with greater TEE. On the other hand, the results of our study should not be misinterpreted to imply that some patient groups require less dialysis treatment. Our results generate a hypothesis that requires formal testing to determine whether increasing the minimum target dose of dialysis in some groups of PD patients improves patient outcomes. Patients and methods
Figure 3 | Adjusted daily urea clearance according to body weight. Fixed weekly Kt of 1.7 urea adjusted for body surface area (BSA) and resting energy expenditure (REE) and total energy expenditure (TEE) using Watson (W) total body water or bioimpedance (BIA) measured total body water. *P < 0.05 and **P < 0.01 versus weight <64 kg after Bonferroni correction. Kidney International (2016) 90, 1342–1347
Adult patients with end-stage kidney disease established on PD were recruited from University College London partner hospitals when attending for outpatient assessments of PD adequacy. Corresponding spent dialysate effluent, 24-hour urine collections, and serum samples were analyzed by standard methods, and the weekly dialysis dose was calculated as Kt/Vurea. The PNA rate was estimated using the Bergström equation and normalized for body weight (g/kg per day).27 Patient demographic characteristics were obtained from 1345
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Table 4 | Multivariable step backward models for weekly Kt adjusted for BSA, REE, TEE using both total body water calculated by Watson equation and measured by BIA, unstandardized b, SE, standardized b, and 95% CL Variable Kturea/BSA Male Kturea/REEW Male Age, yr Kturea/REEBIA PNA rate Male Age, yr Kturea/TEEW Male Age, yr Unemployed High comorbidity Diabetic Kturea/TEEBIA Male Age, yr Unemployed
b SE b
Standardized
b
t
95% CL
13.5 0.6, 0.87
P Value <0.001
0.70 0.05
0.77
0.58 0.08 0.02 0.01
0.44 0.54
7.5 0.43, 0.74 9.3 0.2, 0.25
<0.001 <0.001
0.01 0.01 0.39 0.12 0.01 0.01
0.37 0.28 0.19
4.4 0.01, 0.02 3.2 0.15, 0.63 2.3 0.01, 0.01
<0.001 0.002 0.025
0.59 0.02 0.52 0.30 0.21
0.10 0.01 0.11 0.11 0.10
0.35 0.44 0.26 0.16 0.12
6.1 7.5 4.5 2.7 2.0
0.51 0.13 0.01 0.01 0.44 0.15
0.33 0.32 0.24
3.8 0.25, 0.77 7.5 0.01, 0.02 3.0 0.15, 0.74
0.40, 0.02, 0.29, 0.01, 0.01,
0.79 <0.001 0.013 <0.001 0.74 <0.001 0.52 0.009 0.41 0.045 <0.001 <0.001 0.004
BIA, bioimpedance; BSA, body surface area; CL, confidence limits; PNA, protein nitrogen accumulation; REE, resting energy expenditure; TEE, total energy expenditure; W, Watson equation. BSA model, r2 0.60 adjusted, 0.59; model adjusted for REEW, r20.60; adjusted 0.59; model adjusted for REEBIA r20.42; adjusted, 0.37. Model adjusted for TEEW r20.42, adjusted 0.3, and adjusted for TEEBIA r20.35, adjusted 0.33. Sex (female vs. male).
computerized hospital records, and comorbidity was determined using self-administered comorbidity grading18 based on medical conditions and complications including diabetes mellitus (as defined by WHO criteria), cardiac disease, respiratory disease, liver disease, arthritis, depression, malignancy, and a frailty score previously reported in patients with chronic kidney disease.19 We defined a high comorbidity score as $4.0 and a high frailty score $4.0, in keeping with previous studies.18,19 TBW was calculated using the Watson equation.8 In addition, in 118 of the patients, contemporaneous measurements of TBW made with bioimpedance (InBody 720, InBody, Seoul, South Korea; Body Composition Monitor, Fresenius, Bad Homberg, Germany), which had been performed in a standardized manner,28,29 were available for review. Bioimpedance measurements made by the Body Composition Monitor and InBody were standardized using previously derived equations.30 BSA was calculated using the Gehan and George equation, as recommended by the European Best Clinical Practice guidelines.24 Physical activity data were obtained using the Recent Physical Activity Questionnaire,16 which collects information about both activity and the time spent performing activities over the preceding 4 weeks, including activities performed at home and work and during leisure time. The Recent Physical Activity Questionnaire has been validated against a doubly labeled water technique in the general population and has been shown to be a reliable tool for estimation of energy
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expenditure in patients with chronic kidney disease.16 Physical activity data were determined by each reported activity being assigned a metabolic equivalent of task (MET) value according to the Compendium of Physical Activities.31 The equations for calculating REE and TEE are detailed in the Supplementary Appendix. UK clinical guidelines recommend a minimum weekly Kt/ Vurea of 1.7.1,32 Hence, in order to compare minimum dialysis targets using alternative scaling parameters, weekly Kt was calculated as Kt ¼ 1.7 multiplied by V. Corresponding target values of Kt/BSA, Kt/REE, and Kt/TEE were calculated by dividing daily Kt by the respective parameters. Ethical approval of the study was granted by the UK National Research Ethics Committee–Essex, and the study was registered in UK Clinical Research Network portfolio number 14018. All patients provided written informed consent in keeping with the Declaration of Helsinki. Statistical analysis
Statistical analysis was performed using the Student t test or Mann-Whitney U test, analysis of variance, the Kruskal-Wallis test with appropriate post hoc correction, the Pearson or Spearman test for univariate correlation (GraphPad Prism, version 6.0, San Diego, CA), and step backward linear regression of variables on univariate analysis of P < 0.1 and those considered to be clinically relevant, with log transformation of variables that were not normally distributed and removal of variables that were not statistically significant unless they improved model fit. Models were checked for collinearity using SPSS, version 22 (SPSS Inc., Chicago, IL) and the Bland-Altman comparison (Analyse-It Software, version 3.0, Leeds, UK). Data are presented as the mean SD, median (interquartile range), mean and 95% confidence limits (CL), or percentage. DISCLOSURE
All the authors declared no competing interests. ACKNOWLEDGMENTS
The study was funded by a grant from the British Renal Society. SE-K was awarded an International Society for Nephrology fellowship. SUPPLEMENTARY MATERIAL Supplementary Appendix. Resting energy expenditure (REE) was estimated from a newer novel predictive equation that was derived and validated in a cohort of hemodialysis patients.18 Supplementary material is linked to the online version of the paper at www.kidney-international.org. REFERENCES 1. Woodrow G, Davies SJ. Peritoneal Dialysis (PD) (Guidelines PD 3.1 – 3.3). Available at: http://www.renal.org/guidelines/modules/peritonealdialysis-in-ckd#sthash.Br67xjah.dpuf. Accessed July 25, 2016. 2. Jansen MA, Termorshuizen F, Korevaar JC, et al. Predictors of survival in anuric peritoneal dialysis patients. Kidney Int. 2005;68:1199–1205. 3. Paniagua R, Amato D, Vonesh E, et al.; Mexican Nephrology Collaborative Study Group. Effects of increased peritoneal clearances on mortality
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