Adequacy of haemodialysis and nutrition in maintenance haemodialysis patients: clinical evaluation of a new on-line urea monitor

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Nephrol Dial Transplant (1996) 11: 1568-1573 Original Article IMephrology Dialysis Transplantation Adequacy of haemodialysis and nutrition in maintenance haemodialysis patients: clinical evaluation

1 Nephrol Dial Transplant (1996) 11: Original Article IMephrology Dialysis Transplantation Adequacy of haemodialysis and nutrition in maintenance haemodialysis patients: clinical evaluation of a new on-line urea monitor P. Chauveau, C. Naret, J. Puget, B. Zins and J. L. Poignet Edouard Rist Medical Center, 14 rue Boileau, Paris, France Abstract Background. Recent developments in urea sensing monitoring show a good agreement between on-line and direct dialysis quantification which permits evaluation of both effective dialysis efficiency and protein catabolic rate of dialysis patients. Methods. Fifty chronic haemodialysis patients were enrolled in a prospective study using an automatic urea sensing monitor operating on spent dialysate (U.M. 1000, Baxter). Dietary protein intake (DPI) and energy intake (DEI) were carefully evaluated by a skilled dietitian over 1 week. During this run U.M was used to provide urea mass removed, effective KJV, and normalized npcr. Blood samples were drawn pre- and post-dialysis for classical bloodbased single pool KJV calculations at each session. Results. For all patients results were as follows (mean + SD): Effective KJV , npcr g/kg/day, DPI g/kg/day and DEI Kcal/kg/day; blood-based single pool KJV A strong correlation was found between npcr and DPI for the 50 patients over 1 week (r = 0.75, P< ) and between effective KJV and single pool calculated KJV (r = 0.76). Conclusions. Urea Monitor 1000 is easy and convenient to use and there was a good correlation of the predialysis BUN and effective KJ V with standard bloodside measurements. In stable haemodialysis patients who are not strongly catabolic or anabolic, the urea monitor measurement of npcr correlated with DPI measured by a 7-day dietary record. Key words: adequacy of dialysis; dietary protein intake; haemodialysis; nutrition; on-line urea monitor; protein catabolic rate Introduction Protein and energy malnutrition is common in maintenance dialysis patients and may be a consequence of Correspondence and offprint requests to: Dr Philippe Chauveau, Clinique medicale Edouard Rist, 14 rue Boileau, Paris, France. multiple factors of which underdialysis seems to be a major one [ 1 ]. In addition, nausea and vomiting during and immediately after hemodialysis which are frequently associated with cardiovascular instability and post-dialysis fatigue, may lead to the reduction of food intake during the dialysis day [2]. Direct dialysis quantification (DDQ), based on total dialysate collection allows evaluation of both effective dialysis efficiency and protein catabolic rate (PCR) of the dialysis patient [3,4]. It has been demonstrated that PCR and the dietary protein intake (DPI) are positively correlated in patients who are metabolically stable [5,6]. Recent developments in automated urea sensing have shown good agreement between direct dialysis quantification and on-line dialysate analysis [7,8]. The aim of this clinical investigation was to determine the relationship between protein catabolic rate (PCR) assessed by means of urea kinetic modeling using a new on-line monitor and the protein intake (DPI) evaluated by a skilled dietician, and then to propose a simple approach to dialysis protein nutrition in haemodialysis patients. Patients The study was performed prospectively on 50 chronic haemodialysis (HD) patients after informed consent had been obtained. Twenty seven were male and 23 female with a mean age (±SD) of years (range years). All patients were ambulatory in good clinical condition and were free from intercurrent illness, active liver disease, diabetes, or systemic disease. None were treated with corticosteroid or androgenic agents. Patients unable to answer to a dietary recall and diaries were withdrawn. All patients were being treated with maintenance HD in our unit with a mean duration of treatment of 93 ± 75 months (range months). HD was performed thrice weekly, with low-flux membranes (cellulose acetate, 17 patients), or high-flux membranes (cellulose triacetate, 13 patients; polysulfone, 14 patients; polyacrylonitrile, 6 patients). Urea sensor Urea Monitor 1000 (U.M. 1000, Baxter, US) automatically measures on-line the urea concentration in the effluent dialys European Dialysis and Transplant Association-European Renal Association

2 Clinical evaluation of a new on-line urea monitor ate using an amonium ion electrode fitted with a ureaseimpregnated membrane. Samples are drawn every 5 min during the first half-hour and every 10 min thereafter throughout the entire dialysis session. An integrated microprocessor performs dialysate-based two-pool urea kinetic modeling calculations. User entries are: dialysate flow rate, patient dry weight, expected ultrafiltration, dialysate composition, treatment schedule, and day of week. Pre-dialysis blood urea is measured at the beginning of dialysis by a procedure which allows equilibration of dialysate to blood. Values of K, KJV urea are derived from the curve and V is then back-calculated by separating A" and Kfrom KJV. Total net amount of urea removed is calculated during the treatment. From these data the solute removal index (SRI) defined as net urea removal/pre-dialysis urea content x 100 is determined. By knowing the urea removal for a given treatment-day of the week, the U.M calculates the weekly removal: total weekly removal/10080 min = urea generation rate (G u ). Protein catabolic rate: PCR = 9.35 x G u + (0.29 x V) is then adjusted for weight; npcrw = PCR/dry weight (g/kg/day) or volume npcrv = PCR/Kx0.58 (g/kg/day). Results are available at the end of the session and printed or transferred to a computer with a specific software package. Study design Study protocol was performed over 1 week duration of three dialysis sessions for each patient, on standard bicarbonate dialysate generator (Fresenius 2008C, Germany). The duration of the dialysis procedure ranged from 240 to 300 min, blood flow rate measured by calibrated pumps averaged ml/min with arterio-venous fistulae in biponction in all patients. Non recirculating dialysate flow rate was fixed at ml/min. The residual renal urea clearance was less than 0.5 ml/min in all patients. Blood samples were drawn at the beginning and at the end of each session for blood urea determination (enzymatic urease methodology, Boehringer Mannheim ) in order to calculate classical bloodbased single pool KJV. Effective KJV calculated by the monitor (KJVU. M.) was compared with KJV estimated by two different methods based on single-pool urea modelling, previously described and compared by Daugirdas [9]: K,/Kl = 1.2xln(Co/Cf) KJ V2 = - In (Cf/Co t - ABW/BW) where Co and Cf represent blood urea concentration before and after dialysis session, BW is body weight before dialysis and ABW difference in BW before and after dialysis. One week prior to the study a 2-day dietary recall was carefully evaluated by a skilled dietitian to collect information about patient's habits and ensure good comprehension of the dietary diaries. A prospective 7-day dietary history was undertaken during the week studied with recall by the same dietitian at every dialysis session. Patients were instructed to eat normally and to record and weigh all food. Calories and protein intake were calculated by a diet computer software based on a french composition table (Ciqual) Student's /-test and graphical Bland & Altman method for assessing agreement between two methods of clinical measurement: comparison of the difference versus the average of two measurements [10]. Results Urea measurements The relationship between pre-dialysis urea concentration from the urea monitor and pre-dialysis blood urea samples is shown in Figure 1. A good correlation exists and linear regression curve is close to the line of identity with a r 2 coefficient of KJV The average urea KJV calculated by the different methods were as follows: KJVU. M. = , KJV 1 = , KJV2= Regression analysis shows a good correlation between KJV U. M. vs KJV l(r = 0.81), and KJV U. M. vs KJV2(r=0.&3, i><0.001 for all). Overestimation of KJV measured by single pool formulae is assessed by a significant mean difference of and KJV units, for KJV U. M. vs KJV 1 and KJV 2, respectively (paired Mest and Bland & Altman test for difference to the identity line, / ) <0.001) (Figure 2). Nutritional status Age, sex, body weight, and body mass index (BMI) ([Kg/height in metres] 2 ), biological, and nutritional data are reported in Table 1. Mean caloric intake (DEI) was Kcal/ kg per day and mean protein intake (DPI) was g/kg per day (range Kg). Repartition of the population according to mean DPI or npcr is reported in Table 2. Twelve patients (24%) had a good Statistics Values are expressed as mean + SD. Statistical analysis was performed using regression analysis and comparison between the different KJV calculations were evaluated using paired Blood urea Fig. 1. Relationship between pre-dialysis urea concentration measured by U.M and pre-dialysis blood urea.

3 P. Chauveau et at. 0.5 (Kt/V UM + Kt/Vl)/2 (Kt/V UM Kt/V2)/2 Fig. 2. Plot of the difference between KJV measured by U.M and blood-based single-pool calculations, Bland & Altman graphical representation. Table 1. All patients HF patients LF patients Number Age (years) Sex ratio (M/F) Dry weight (Kg) Body mass index (Kg/m 2 ) Blood urea (mmol/1) Protein (G/L) Albumin (G/L) Dietary protein intake (G/Kg/day) Calories (Kcal/Kg/day) ± / ± ± / ± ± ± ± / ±7.O ± Clinical and nutritional parameters (mean + 1 SD). HF: high-flux membrane, LF: low-flux membrane. Table 2. Repartition of the population according to dietary protein intake or npcr (number of patients). Dietary protein intake (g/kg/day) <1 Calories 5= 35 Kcal Calories ^35 Kcal npcr/dpi ratio Total patients ± ± C 2 protein/calorie ratio with sufficient protein and calorie intake. Thirteen (26%) had a good protein intake but calories less than 35 Kcal/Kg/day. Twenty five patients (50%) ate less than the actual recommendations for dialysis population but 17 of them had a protein intake up to 1 g/kg/day and only 8 (16%) had DPI less than 1 g/kg/day and calories less than 30 Kcal/Kg. Average normalized protein catabolic rate correlated with average dietary protein intake over the week studied (analysis of variance, residual analysis: F-test, / > =0.0001) and is represented in Figure 3. Analysis of the repartition did not show statistical jj Q 0.5 npcr (UM 1000) Fig. 3. Correlation between average npcr (g/kg/day) calculated by U.M and average dietary protein intake (DPI) over 1 week.

Clinical evaluation of a new on-line urea monitor Table 3. Analysis of variance, residual /'-test between Kt/V, npcr, DPI and calorie intake. KJVV. M. KJVV. KJV2 npcr DPI M. KJV 2 0.001 npcr 0.0001 0.

4 Clinical evaluation of a new on-line urea monitor Table 3. Analysis of variance, residual /'-test between Kt/V, npcr, DPI and calorie intake. KJVV. M. KJVV. KJV2 npcr DPI M. KJV npcr DPI Calories tendancy to overestimate protein intake by the npcr calculation but npcr/dpi ratio was higher in the group of patients ingesting less than 1 g/kg/day than in the group of patients ingesting more than 1 g/kg/day of protein. Regression analysis Relationship was observed between average KJV U. M. and average npcr, DPI or caloric intake over 1 week, as reported in Table 3, using regression analysis. These relations were less significant between single-pool KJV and npcr or DPI. Analysis of the slopes, after separation of patients treated with low or high flux membranes, exhibited no difference. Discussion Urea kinetic modeling (UKM) is the most common method currently used to measure and deliver the optimal dose of haemodialysis for each patient but because of complexity, quantification of patient therapy is not universally practiced among dialysis centers [11-13]. Simplified methods for measuring KJV and PCR have been developed. Direct dialysis quantification produces accurate measurements [3,14], but since it involves collection of of dialysate per treatment, this procedure cannot be recommended as a routine method. By diverting a small fixed fraction of the spent dialysate volume, a partial dialysate volume is collected and Garred has recently shown a good accuracy for this method [7]. More recently a new on-line monitor for dialysis adequacy has been proposed [8,15]. The convenience and ease of use of an on-line monitor facilitates individualization and tailoring of therapy prescription without the need for blood samples, laboratory determinations, computers, and specialized software. Dialysate is automatically sampled during the session and urea concentration in the effluent dialysate is determined using an amonium ion electrode fitted with a urease-impregnated membrane. Our results show a good correlation between predialysis urea concentration from the urea monitor and pre-dialysis blood urea samples. A few points were out of the correlation curve due to technical problems during the equilibration phase. This indicates that the 1571 on-line monitor is easy to use but a well respected protocol especially during the equilibration phase is necessary even though this does not affect KJV results which is derived from the curve. A good correlation exists between KJV estimated by usual formulae based on single-pool urea kinetic modeling and KJV estimated from a double-pool estimation by U. M. 1000, but classical formula overestimated KJV by an average of KJV units. Our results are in agreement with Keshaviah who reported a strong correlation between blood-based single-pool KJV and the on-line KJV and showed a significant overestimation of the single-pool approach by an average of 0.2 units [15]. Values directly calculated from pre and post-dialysis contain systematic errors, introduced by ignoring the effects of intradialytic urea generation and by the single-pool UKM approach, notably when high efficiency dialysers are used [16,17]. The single-pool model assumes that urea is distributed in a single well-mixed body water pool. It has been noted that immediately following the cessation of dialysis a significant rebound in urea is noted over a period of min and this may lead to an overestimate of KJV by 10-15% when blood samples were drawn immediately post-dialysis. A two-pool model is more accurate to estimate dialysis efficacy [14,18]. In our study, values of KJV calculated with the urea-monitor, based on effluent dialysate with a 2-pool urea kinetic calculation, appear to be more precise than KJV estimated by single-pool urea kinetic. Calculations of PCR derived from UKM demonstrated considerable variation in the values derived from different methods [3,4]. If DDQ is considered the standard, UKM-derived analysis of PCR shows a mean of 55% variation and cannot be considered an accurate and reproducible measure of protein nutrition [3]. Garred has shown that urea sensor technology offers an alternative mean of determining PCR accurately even when multipool effects are present. npcr reflects protein catabolic rate normalized to body weight and for most stable patients, npcr can be reasonably used to approximate PCR and DPI [7,19-21]. In the NCDS study and in classical UKM, parameters are determined during 1 day which are supposed to be representative of the dialysis efficacy and nutrition of the patients through PCR calculation. Recently, Kloppenburg et al. demonstrated that changes in protein intake are immediately followed by changes in urea generation rate and that PCR only reflects recent protein intake, using a [ 13 C] urea isotope technique [22]. Like others, for better estimation of PCR which fluctuate from day to day, we performed a 7-day survey period [7,23]. In our study protein intake was evaluated by a skilled dietitian and dietary surveys were carried out over 2 periods: 2 days before the study and during the 7-day study period. A good accuracy of these type of dietary protocols has been demonstrated in chronic renal failure [21,24] and in haemodialysis patients [25]. Mean DPI correlated significantly with the PCR estim-

5 1572 ated by urea monitor. npcr does not exactly reflect protein intake in some patients. The npcr/dpi ratio is higher in patients ingesting less than 1 g/kg/day of protein, indicating an overestimation of DPI by npcr. Conversely in most patients ingesting more than 1.2g/Kg/day, DPI is underestimated by npcr. Moreover, low protein intake is associated with low calorie intake. These findings had been demonstrated in two recent studies: Panzetta suggests that the quantity of dietary protein intake could directly influence the rate of protein catabolism by modulating nitrogen balance status [6,26]. Our results suggest that in metabolically stable haemodialysis patients in protein balance who are not strongly catabolic or anabolic, npcr from the on-line monitor may be used to obtain an average estimation of the protein intake during a week. Energy intake is an important determinant for adequate nitrogen balance. Twenty-six per cent of the population had a good protein intake but a low calorie intake. This points out the fact that an adequate calorie intake is necessary to ensure a good protein utilization [6,20]. Dietary recall and recommendations are always necessary even if we can approach protein intake by measurement of npcr. Lindsay et al. showed a linear relationship between protein catabolic rate and KJV urea [27] and review of the data suggests that to obtain a protein catabolic rate of 1 g/kg/day, a KJV urea value of 1 must be prescribed when using a cellulose acetate dialysis membrane [2]. We found the same relationship between KJV and PCR or DPI, by using a 7-day observation period. A better correlation exists between npcr, DPI and KJV urea estimated by urea monitor from a double-pool model than with classical UKM. Some authors pointed out the fact that a mathematical relationship exists between KJV and PCR in classical UKM. In our experience the average weekly protein intake and KJ V values exhibit a physiological relationship. Moreover, we performed a survey of two patients over a period of up to 3 months during which npcr values varied with protein intake whereas KJV remained stable. In our study we could not exhibit any influence on the membranes. The mean KJV in our study was 1.5 and the mean protein intake, over a wide range of age, comes close to that of the french population [28]. Either KJV is sufficient to assure a relative good nutrition, or the number of patients in each group was too low to demonstrate a membrane influence. In conclusion, the on-line urea monitor (U.M. 1000) a non-invasive method, offers a routine and easy direct dialysis quantification for measurement of patient BUN, PCR and KJV without any need for blood or dialysate sampling, or user computations. In metabolically stable patients, npcr from the on-line monitor strongly correlates with the DPI evaluated by a skilled dietitian over a 1-week period and may be used to estimate protein intake. References P. Chauveau et al. 1. Bergstrdm J. Nutrition and mortality in hemodialysis. J Am Soc Nephrol 1995; 6: Lindsay R, Bergstrom J. Membrane biocompatibility and nutrition in maintenance haemodialysis patients. Nephrol Dial Transplant 1994; 9: Barth R. Urea modeling and KJV: a critical appraisal. Kidney Int 1993; 43: S252-S Depner T. Assessing adequacy of haemodialysis: Urea modeling. Kidney Int 1994; 45: Bergstrom J, Furst P, Alvestrand A, Lindholm B. Protein and energy intake, nitrogen balance and nitrogen losses in patients treated with continuous ambulatory peritoneal dialysis. Kidney Int 1993; 44: Lorenzo V, De Bonis E, Rufino M, Hernandez D, Rebello S, Rodriguez A, Torres A. Caloric rather than protein deficiency predominates in stable chronic haemodialysis patients. Nephrol Dial Transplant 1995; 10: Garred L, Canaud B, McCready W. Optimal hemodialysis. The role of quantification. Seminars in Dialysis 1994; 7: Depner T, Collins A, Jindal K, Lazarus J, Nissenson A, Hossli S, Ebben J, Keshaviah P. Multicenter clinical validation of an on-line urea monitor. J Am Soc Nephrol 1993; 4: Daugirdas J. Rapid methods of estimating Kt/V: Three formulas compared. ASAIO Transactions 1990; 36: Bland J, Altaian D. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: Gotch F, Sargent J. A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int 1985; 28: Barth R. Direct calculation of Kt/V: a simplified approach to monitoring of hemodialysis. Nephron 1988; 50: Hakim R. Assessing the adequacy of dialysis. Kidney Int 1990; 37: Gabriel J, Fellay G, Descombes E. Urea kinetic modeling: an in vitro and in vivo comparative study. Kidney Int 1994; 46: Keshaviah P, Ebben J, Luhring D, Emerson P, Collins A. Clinical evaluation of a new on-line monitor of dialysis adequacy. J Am Soc Nephrol 1992; 3: Smye S, Dunderdale E, Brownridge G, Will E. Estimation of treatment dose in high-efficiency hemodialysis. Nephron 1994; 67: Hakim R. Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 1993; 44: Keshaviah P, Star R. A new approach to dialysis quantification: An adequacy index based on solute removal. Semin. Dial 1994; 7: Harty J, Boulton H, Curwell J, Heelis N, Uttley L, Venning M, Gokal R. The normalized protein catabolic rate is a flawed marker of nutrition in CAPD patients. Kidney Int 1994; 45: Bergstrom J, Lindholm B. Nutrition and adequacy of dialysis. How do hemodialysis and CAPD compare. Kidney Int 1993; 43: S39-S Stegeman C, Huisman R, De Rouw B, Joostema A, De Jong P. Determination of protein catabolic rate in patients on chronic intermittent hemodialysis: urea output measurements compared with dietary protein intake and with calculation of urea generation rate. Am J Kidney Dis 1995; 25: Kloppenburg W, Wolthlers B, Tepper T, Stegeman C, De Jong P, Huisman R. Fluctuations of urea generation rate following protein intake in haemodialysis patients measured using l3 C urea. J Am Soc Nephrol 1995; 6: Teschan P. What is the role of KJV in chronic dialysis. Semin. Dial. 1990; 3: Laxton J, Harrison S, Shaw A. Assessment of protein intake in early progressive renal disease. Nephrol Dial Transplant 1991; 6: Kloppenburg W, Stewart R, Stegeman C, De Jong P, Huisman R. Assessing hemodialysis and efficiency and dietary

6 Clinical evaluation of a new on-line urea monitor 1573 intake in the individual patient: how many measurements are 27. Lindsay R, Spanner E, Heidenheim P, Kortas C, Blake P. PCR, required? (Abstract). J. Am Soc Nephrol 1995; 6: 605 KJV and membrane. Kidney M 1993; 43: S268-S Panzetta G. Protein intake does not depend on the dose of 28. Vol S, Doctoriarena A, Le Clesiau H, Tichet J. Comportement dialysis delivered-provided Kt/V is adequate. Nephrol Dial alimentaire des adultes en France. Presse Med 1992; 21: Transplant 1995; 10: Received for publication: Accepted in revised form:

Protein nitrogen appearance in CAPD patients: what is the best formula?

Nephrol Dial Transplant (996) : 9-96 Original Article IMephrology Dialysis Transplantation Protein nitrogen appearance in CAPD patients: what is the best formula? S. Mandolfo, A. Zucchi, L. Cavalieri D'Oro,