METABOLIC EFFECTS OF INCREMENTAL DOSES OF INTRAPERITONEAL AMINO ACIDS ON AUTOMATED PERITONEAL DIALYSIS

Peritoneal Dialysis International, Vol. 30, pp. 201–207 doi: 10.3747/pdi.2009.00040

0896-8608/10 $3.00 + .00 Copyright © 2010 International Society for Peritoneal Dialysis

METABOLIC EFFECTS OF INCREMENTAL DOSES OF INTRAPERITONEAL AMINO ACIDS ON AUTOMATED PERITONEAL DIALYSIS

Brendan B. McCormick,1,2 Salim Mujais,3 Francine Poirier,2 Nicole Page,2 and Susan Lavoie1,2 Division of Nephrology,1 Department of Medicine, The University of Ottawa; The Ottawa Hospital Centre for Kidney Disease,2 Ottawa, Ontario, Canada; Astellas Pharma Global Development Inc.,3 Deerfield, Illinois, USA

Perit Dial Int 2010; 30:201–207 www.PDIConnect.com epub ahead of print: 11 Feb 2010 doi: 10.3747/pdi.2009.00040

Correspondence to: B.B. McCormick, Division of Nephrology, 1967 Riverside Drive, Ottawa, Ontario, K1H 7W9 Canada. [email protected] Received 22 February 2009; accepted 4 June 2009.

KEY WORDS: Automated peritoneal dialysis; amino acids; Nutrineal; glucose sparing; ultrafiltration; metabolic acidosis.

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t has long been recognized that amino acids may be an effective osmotic agent to achieve ultrafiltration in peritoneal dialysis (PD) (1). Most of the interest to date in amino acid dialysis solutions has focused on their potential to treat protein-energy malnutrition. The efficacy of amino acid dialysis solutions as a nutritional supplement to treat malnutrition on continuous ambulatory PD (CAPD) remains controversial. Many studies have demonstrated an improvement in biochemical parameters with amino acid dialysate but have failed to show meaningful clinical improvements (2–4). The use of amino acid dialysate may induce a small decrease in serum bicarbonate level and this could mitigate the anabolic effect of the amino acids and could account for an inconsistent improvement in nutritional status (5,6). It has been hypothesized that provision of amino acid solution mixed with glucose on the cycler is preferable as the caloric load provided by the glucose maximizes the anabolic effects of the amino acids (7). Recently, it was shown that delivery of up to 2.5 L 1.1% amino acid solution via an automated PD (APD) cycler is associated with a net increase in protein anabolism as assessed by whole body protein turnover (7). It is unknown if the provision of larger quantities of amino acids via APD is safe or efficacious. Amino acid dialysate is also a subject of interest for its potential to spare peritoneal glucose exposure. It has been used in regimes with icodextrin and bicarbonatebuffered glucose-based dialysate in CAPD and this combination has been shown to significantly reduce glucose exposure compared to standard solutions (8). It is unknown if a mixture of glucose and amino acids delivered by APD would be glucose sparing as the use of amino acid

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♦♦Background: The use of amino acid (AA) dialysate to ameliorate protein-energy malnutrition has been limited by adverse metabolic effects. ♦♦Objective: We undertook this study to examine the acute metabolic effects of escalating doses of AAs delivered with lactate/bicarbonate dialysate on automated peritoneal dialysis (APD). ♦♦Patients and Methods: 12 APD patients were treated with conventional lactate-buffered dialysate (week 1), followed by lactate/bicarbonate-buffered dialysate (week 2), then 2 – 2.5 L 1.1% AA solution were added (week 3), and then an additional 2 – 2.5 L 1.1% AA were added (week 4). The primary outcomes were change in serum bicarbonate and pH, change in protein catabolic rate (PCR), and change in normalized ultrafiltration (milliliters/gram of carbohydrate infused). ♦♦Results: Serum bicarbonate rose from week 1 to week 2 (28.9 ± 3.2 vs 26.9 ± 4.1 mmol/L, p = 0.03). Addition of one bag of AAs led to a decline in plasma bicarbonate (26.9 ± 2.1 vs 28.9 ± 3.2 mmol/L, p < 0.01), which was further magnified by the addition of the second bag of AAs (23.8 ± 2.7 vs 26.9 ± 2.1 mmol/L, p < 0.01). Serum bicarbonate fell significantly by week 4 compared to week 1 (23.8 ± 2.7 vs 26.9 ± 3.2 mmol/L, p < 0.01) although there was no significant change in venous pH or PCR when week 4 was compared to week 1. Normalized ultrafiltration was stable for the first 3 weeks but rose significantly in week 4 compared to week 1 (5.32 ± 2.30 vs 4.14 ± 1.58 mL/g, p = 0.03). ♦♦Conclusions: Higher doses of AAs mixed with newer bicarbonate/lactate dialysate on APD result in a small decrease in serum bicarbonate but improved normalized ultrafiltration. This merits further study as both a nutritional supplement and a glucose-sparing strategy.

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dialysate may increase peritoneal membrane permeability to small molecules, including glucose (9,10). We undertook this pilot study to assess the acute metabolic effects of incremental doses of amino acid dialysate delivered by APD. We hypothesized that converting APD patients from conventional lactate-buffered acidic dialysis solution (Dianeal; Baxter Healthcare, Deerfield, IL, USA) to lactate/bicarbonate-buffered physiologic pH dialysis solution (Physioneal, Baxter Healthcare) would mitigate the acidemic effect of higher doses of amino acids. The primary outcomes studied were changes in serum bicarbonate and venous pH, change in protein catabolic rate (PCR), and change in ultrafiltration (normalized to grams of carbohydrate infused). MATERIALS AND METHODS

Twelve adult patients were recruited from the pool of prevalent APD patients at The Ottawa Hospital. Inclusion criteria were treatment with PD for greater than 3 months, a peritoneal equilibration test within 6 months, ability to achieve prescribed dry weight, weekly total Kt/V ≥ 2.0, APD overnight volume ≤ 17.5 L, dwell volumes 1.5 – 2.5 L, and baseline serum bicarbonate level > 20 mmol/L. Exclusion criteria were severe comorbid disease including active malignancy, infection, systemic inflammatory diseases, severe coronary artery disease (Canadian Cardiovascular Society class 3 angina) or severe congestive heart failure (New York Heart Association class 3 or 4), peritonitis, or hospitalization for any reason within the previous 30 days. The study was approved by the hospital Research Ethics Board and written informed consent was obtained from all patients. STUDY DESIGN

The study was a single center, open label, crossover study of 4 weeks’ duration. All patients performed APD with Dianeal (40 mmol/L lactate, 1.5% – 4.25% dextrose) in week 1, switched to Physioneal (25 mmol/L bicarbonate, 15 mmol/L lactate, 1.36% – 3.86% glucose) in week 2, added one 2.5 L bag of Nutrineal (1.1% amino acid, lactate 40 mmol/L; Baxter Healthcare) in week 3, and substituted a second 2.5 L bag of Nutrineal in week 4 (removing one 2.5 L bag of Physioneal). The patients were seen in the Home Dialysis Unit weekly at the end of each week. On the seventh day of each cycle, blood samples were obtained and a 24-hour collection of urine and dialysate was obtained for measurement of ultrafiltration and adequacy. On a daily basis, each patient recorded the choice of solution 202

strength, body weight, and ultrafiltration volume from the cycler readout. Peritoneal and renal urea and creatinine clearances and PCR were calculated using the Baxter Adequest program (Baxter Healthcare). The primary outcomes were change in serum bicarbonate and venous pH from week 1 to week 4, change in PCR from week 1 to week 4, and changes in overnight normalized ultrafiltration (expressed as milliliters of ultrafiltration per gram of carbohydrate infused). Exploratory analyses comparing changes from weeks 2 and 3 to week 4 were also performed. DIALYSIS PROCEDURE

During the study, the APD and daytime exchange schedules and volumes delivered for each patient were identical to those used before the study to achieve adequacy and ultrafiltration targets. Dwell volume, dwell time, and number of overnight exchanges were kept constant for each patient throughout the 4 weeks. Those patients with glucose-based daytime exchanges used Dianeal in week 1 and Physioneal in weeks 2 through 4. Those with daytime icodextrin exchanges continued to use icodextrin during all 4 weeks. Automated PD was performed using the HomeChoice cycler (Baxter Healthcare). During weeks 2 through 4, the heater bag was empty and the undersides of all hanging bags were maintained at the same level to ensure even mixing of glucose and amino acids by drawing equally from the hanging bags. This technique is similar to that previously described for mixing amino acid and glucose dialysate on APD (7). The adequacy of this mixing technique was assessed by observing and weighing the hanging bags between exchanges using a mock setup. At the completion of the study all patients returned to their original APD prescriptions. CALCULATION OF CARBOHYDRATE LOAD AND NORMALIZED ULTRAFILTRATION

Carbohydrate load was calculated on a nightly basis as total grams of glucose or dextrose infused during the overnight period, not including the last fill. Ultrafiltration was recorded by the cycler and did not include the initial drain volume from the day dwell. Means for each week were recorded for each patient. For each night, total carbohydrate (CHO) load and normalized ultrafiltration were calculated as follows: CHO load (g) = [total volume of fluid infused (L) × total CHO of all solutions hung (g)] / total volume of all solutions hung (L);

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PATIENTS

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AMINO ACID DIALYSATE ON APD

Normalized ultrafiltration (mL/g) = overnight ultrafiltration (mL) / total overnight CHO load (g). STATISTICAL ANALYSIS

All data are expressed as mean ± standard deviation. Differences in biochemistry, adequacy, normalized ultrafiltration, and carbohydrate load between weeks were analyzed using a paired t-test. A two-sided p value less than 0.05 was considered statistically significant. RESULTS Of the 12 patients enrolled, 1 was withdrawn in week 2 due to need for hospitalization for an infected foot. Table 1 shows the characteristics and baseline APD prescriptions of the 11 patients that completed the study. Mean age was 53 years, mean time on dialysis was 26 months, 1 patient was anuric. Four patients were treated with nocturnal intermittent PD (NIPD), 5 with conventional continuous cyclic PD (CCPD), and 2 with enhanced CCPD. One patient developed nausea during the fourth week but completed the study.

ULTRAFILTRATION

As shown in Table 3, mean daily weight, and 24-hour urine output remained stable over the course of the 4 weeks. Mean overnight ultrafiltration trended down from weeks 2 through 4 and ultrafiltration in week 4 was significantly lower than in week 2 (831 ± 448 vs 986 ± 481 mL, p = 0.02). In week 3, mean delivered amino acid dose was 21.1 ± 2.7 g (range 17.2 – 26.6 g) and in week 4 mean delivered amino acid dose was 42.2 ± 5.5 g (range 34.4 – 53.2 g).

BIOCHEMISTRY AND ADEQUACY

Table 2 shows the trend in biochemistry values and adequacy over the 4 weeks. Peritoneal creatinine and urea clearances and residual glomerular filtration rate (GFR) remained stable over the 4 weeks. Serum

TABLE 1 Patient Characteristics

Patient 1 2 3 4 5 6 7 8 9 10 11

Cause of ESRD

Time on dialysis (months)

Myeloma Glomerulonephritis Polycystic Glomerulonephritis Diabetes Unknown Post nephrectomy Diabetes Diabetes Glomerulonephritis Reflux

46 46 7 9 20 32 5 41 24 10 44

Gender

Age (years)

Membrane typea

Cycler volume (L)

Last fill volume (L)

Daytime exchange volume (L)

F F M F M M F F M F F

37 53 62 36 44 76 75 71 69 36 29

LA HA HA LA LA LA LA HA H LA L

9.0 11.0 9.6 8.2 13.2 14.0 10.0 10.0 14.0 11.5 12.7

0 2.0 0 1.5 0 0.5 0 1.5 2.5 2.0 1.5

0 2.0 0 0 0 0 0 0 0 2.0 0

ESRD = end-stage renal disease. a Membrane transport as determined by standard peritoneal equilibration test. Membrane classified as low (L), low average (LA), high average (HA), or high (H) according to published criteria (11). This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]

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urea exhibited a significant rise from week 1 to week 4 (20.3 ± 3.4 vs 23.3 ± 3.4 mmol/L, p < 0.007) and PCR exhibited a similar rise although the change was statistically significant only when week 2 was compared to week 4 (0.84 ± 0.26 vs 0.94 ± 0.19, p = 0.04). Serum albumin did not change over the course of the 4 weeks. Serum bicarbonate rose signif icantly in week 2 after Physioneal was substituted for Dianeal (28.9 ± 3.2 vs 26.9 ± 4.1 mmol/L, p = 0.03) but then trended down and was significantly lower than baseline by week 4 (23.8 ± 2.7 vs 26.9 ± 4.1 mmol/L, p < 0.01). Venous pH rose significantly in week 2 (7.36 ± 0.03 vs 7.33 ± 0.05, p = 0.05) and then trended down in weeks 3 and 4. Overall, there was no significant difference between venous pH when week 4 was compared to week 1 due to adaptive changes in the partial pressure of carbon dioxide. There were no changes in calculated anion gap, potassium, or phosphate (data not shown).

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TABLE 2 Biochemistry and Adequacya

Venous pH Bicarbonate (mmol/L) Anion gap (mmol/L) Urea (mmol/L) Creatinine (µmol/L) Albumin (g/L) Weekly peritoneal Kt/V Weekly peritoneal CrCl (L/1.73 m2) Residual GFR (mL/min) Protein catabolic rate (g/kg/24 hours)

Week 1

Week 2

Week 3

Week 4

7.33±0.05 26.9±4.1 14.9±2.0 20.3±3.4 821±220 39.6±3.1 1.64±0.45 36.2±12.7 2.9±1.8 0.88±0.19

7.36±0.03b 28.9±3.2c 14.2±2.4 19.2±4.8 854±222 39.1±3.5 1.56±0.44 34.8±11.6 3.1±2.0 0.84±0.26

7.34±0.05 26.9±2.1 14.7±2.5 21.2±3.3 858±221 39.1±2.7 1.54±0.40 34.5±10.8 3.0±2.0 0.90±0.20

7.32±0.07 23.8±2.7d,e,f 15.5±2.4 23.3±3.4g,h,i 846±197 40.2±2.8 1.65±0.43 34.8±10.7 2.6±1.8 0.94±0.19 j

TABLE 3 Carbohydrate (CHO) Infused and Ultrafiltration (UF)a

Overnight UF (mL) Weight (kg) 24-hour urine output (mL) Overnight CHO infused (g) Overnight amino acids infused (g) Overnight normalized UF (mL/g CHO)

Week 1

Week 2

Week 3

Week 4

936±411 76.1±12.6 559±436 222±64

986±481 76.4±11.9 629±478 226±71

4.14±1.58

4.31±1.60

835±431 76.9±11.6 614±431 185±60b 21.1±2.7 4.45±2.17

831±448c 76.9±11.5 543±487 154±57d,e,f 42.2±5.5g 5.32±2.30h,i,j

a

Data are expressed as mean±standard deviation. p = 0.0003 for week 3 versus week 1. c p = 0.02 for week 4 vs week 2. d p < 0.0001 for week 4 vs week 1. e p < 0.0001 for week 4 vs week 2. f p < 0.0001 for week 4 vs week 3. g p < 0.0001 for week 4 vs week 3. h p = 0.03 for week 4 vs week 1. i p = 0.03 for week 4 vs week 2. j p = 0.02 for week 4 vs week 3. b

Compared with week 1, the overnight carbohydrate load decreased significantly at week 3 (185 ± 60 vs 222 ± 64 g, p < 0.001) and week 4 (154 ± 57 vs 222 ± 64 g, p < 0.0001). Normalized ultrafiltration, expressed as milliliters of ultrafiltration per gram of carbohydrate infused, 204

was not different at weeks 2 or 3 compared with week 1 but was significantly higher at week 4 compared with week 1 (5.32 ± 2.30 vs 4.14 ± 1.58 mL/g, p = 0.03). As shown in Table 3, normalized ultrafiltration was also higher when week 4 was compared to weeks 2 and 3.

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CrCl = creatinine clearance; GFR = glomerular filtration rate. a Data are expressed as mean±standard deviation. b p = 0.05 for week 2 versus week 1. c p = 0.03 for week 2 vs week 1. d p = 0.004 for week 4 vs week 1. e p < 0.0001 for week 4 vs week 2. f p < 0.0001 for week 4 vs week 3. g p = 0.007 for week 4 vs week 1. h p < 0.0001 for week 4 vs week 2. i p = 0.001 for week 4 vs week 3. j p = 0.04 for week 4 vs week 2.

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DISCUSSION

been reported that approximately 47% of amino acids were absorbed using a similar APD program and that this was associated with significant protein anabolism (7). Thus, a possible explanation for the small rise in PCR is that the nitrogen appearance rate did not rise significantly due to protein anabolism. The observed fall in serum bicarbonate does, however, suggest that some of the amino acids were oxidized and were not entirely used for protein synthesis. More detailed nitrogen balance studies, similar to those reported by Tjiong and colleagues (7), are required to determine if higher than conventional doses of amino acids lead to increased protein anabolism. The absence of a glucose-sparing effect in week 3 was also unexpected. Normalized ultrafiltration was no different in week 3 compared to weeks 1 and 2, suggesting that the amino acids in week 3 were not acting as effective osmols. It is possible that an increase in small molecule transport induced by the amino acids caused more rapid glucose absorption and that the loss of glucose osmols is not mitigated by the relatively small osmotic effect of the amino acids present during week 3. During week 4, a greater proportion of the osmols are amino acids and thus an accelerated dissipation of the glucose gradient would have less effect on ultrafiltration than in week 3. It is also possible that a significant glucosesparing effect was missed in week 3 due to the underpowered nature of this pilot study to detect small differences in normalized ultrafiltration. More specific studies of the effect of varying amino acid concentrations on glucose transport and peritoneal ultrafiltration are required to explain this interesting observation. Our results are important as protein malnutrition remains a significant problem among chronic PD patients and we have shown that a strategy of increasing the amino acid dosage on APD is well tolerated overall in the short term. The 1 patient in our study who developed nausea (Patient 1) was on NIPD and had a rapid loss of residual GFR over the 4 weeks of the study, resulting in a low Kt/V (1.64) by week 4. We speculate that the higher doses of amino acids may have aggravated or unmasked her uremic symptoms. None of the other 10 patients, all of whom had adequate dialysis, developed nausea or significant loss of residual GFR over the study period. It remains to be demonstrated whether our strategy would lead to improvement in clinically meaningful nutritional indices but preliminary data using lower doses of amino acids in APD are encouraging (7). The glucose-sparing implications of amino acid dialysate are also important as glucose-sparing strategies are increasingly being examined as a means to reduce weight gain and metabolic complications associated with PD

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This pilot study is the first to systematically examine the effect of higher than conventional doses of amino acid dialysate delivered by APD on metabolic parameters and ultrafiltration. We find that the use of Physioneal instead of Dianeal mitigates against a fall in serum bicarbonate with a conventional dose of amino acids in week 3, although there was a significant fall in serum bicarbonate with the higher dose used in week 4. The more biocompatible solution Physioneal does not appear to result in better ultrafiltration than conventional Dianeal, and conventional doses of amino acids are not associated with any significant glucose-sparing effect. Higher doses of amino acids are associated with greater normalized ultrafiltration, in keeping with a glucosesparing effect of approximately 29%. The decrease in serum bicarbonate with higher doses of amino acids is not unexpected as the metabolism of lysine, arginine, and methionine releases hydrogen ions. As anticipated, the use of the bicarbonate/lactate-buffered Physioneal in week 2 resulted in higher serum bicarbonate levels compared to Dianeal alone in week 1. Improved acid–base status with Physioneal has been reported before and, were it not for the addition of Physioneal to the regime in week 2, the fall in serum bicarbonate in weeks 3 and 4 would likely have been much more profound (12,13). It is noteworthy that, due to adaptive changes in pCO2, there were only minor changes in venous pH over the course of the study. Also, despite a significant decrease from week 2 to week 4, serum bicarbonate remained within normal range at the end of week 4. The decrease in serum bicarbonate with the higher dose amino acid dialysate was of a magnitude that has been associated with suboptimal protein metabolism (6). Small changes in acid–base balance may have large implications for nutritional indices so the use of higher doses of amino acid dialysate on APD should be accompanied by the use of oral alkali therapy if there is a fall in serum bicarbonate (6,14). If the use of amino acid dialysate on APD is to become widespread, new solutions must be developed in which the amino acids are premixed with glucose in cycler bags for ease of use and a higher lactate/bicarbonate concentration should be used to prevent acidosis. The rise in PCR with increasing doses of amino acids was less than expected and was significant only when week 4 was compared to week 2. Patients were advised to follow a consistent diet throughout the study but it is possible that patients inadvertently decreased their protein intake as the study progressed. It has previously

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DISCLOSURE This study was supported by an unrestricted grant from Baxter Healthcare. Dr. Brendan McCormick has received consulting fees and honoraria from Baxter Healthcare in the past. Dr. Salim Mujais was previously employed by Baxter Healthcare but has no current financial conflicts of interest to disclose. The other authors have no financial conflicts of interest to disclose. 206

REFERENCES 1. Khanna R, Twardowski ZJ, Oreopoulos DG. Osmotic agents for peritoneal dialysis. Int J Artif Organs 1986; 9:387–90. 2. Maurer O, Saxenhofer H, Jaeger P, Casez JP, Descoeudres C, Horber FF. Six-month overnight administration of intraperitoneal amino acids does not improve lean mass. Clin Nephrol 1996; 45:303–9. 3. Jones M, Hagen T, Boyle CA, Vonesh E, Hamburger R, Charytan C, et al. Treatment of malnutrition with 1.1% amino acid peritoneal dialysis solution: results of a multicenter outpatient study. Am J Kidney Dis 1998; 32:761–9. 4. Li FK, Chan LY, Woo JC, Ho SK, Lo WK, Lai KN, et al. A 3-year, prospective, randomized, controlled study on amino acid dialysate in patients on CAPD. Am J Kidney Dis 2003; 42: 173–83. 5. Kopple JD, Bernard D, Messana J, Swartz R, Bergstrom J, Lindholm B, et al. Treatment of malnourished CAPD patients with an amino acid based dialysate. Kidney Int 1995; 47:1148–57. 6. Pickering WP, Price SR, Bircher G, Marinovic AC, Mitch WE, Walls. Nutrition in CAPD: serum bicarbonate and the ubiquitin-proteasome system in muscle. Kidney Int 2002; 61:1286–92. 7. Tjiong HL, van den Berg JW, Wattimena JL, Rietveld T, van Dijk LJ, van der Wiel AM, et al. Dialysate as food: combined amino acid and glucose dialysate improves protein anabolism in renal failure patients on automated peritoneal dialysis. J Am Soc Nephrol 2005; 16:1486–93. 8. le Poole CY, Welten AG, Weijmer MC, Valentijn RM, van Ittersum FJ, ter Wee, PM. Initiating CAPD with a regimen low in glucose and glucose degradation products, with icodextrin and amino acids (NEPP) is safe and efficacious. Perit Dial Int 2005; 25(Suppl 3):S64–8. 9. Waniewski J, Werynski A, Heimburger, Park MS, Lindholm B. Effect of alternative osmotic agents on peritoneal transport. Blood Purif 1993; 11:248–64. 10. Olszowksa A, Waniewski J, Werynski A, Anderstam B, Lindholm B, Wankowicz Z. Peritoneal transport in peritoneal dialysis patients using glucose-based and amino acidbased solutions. Perit Dial Int 2007; 27:544–53. 11. Twardowski Z, Nolph KO, Khanna R, Prowant BF, Ryan LP, Moore HL, et al. Peritoneal equilibration test. Perit Dial Bull 1987; 7:138–48. 12. Vande Walle JG, Raes AM, Dehoorne J, Maneul R. Use of bicarbonate/lactate-buffered dialysate with a nighttime cycler, associated with a daytime dwell with icodextrin, may result in alkalosis in children. Adv Perit Dial 2004; 20: 222–5. 13. Dratwa M, Wilkie M, Ryckelynck JP, ter Wee PM, Rutherford P, Michel C, et al. Clinical experience with two physiologic bicarbonate/lactate peritoneal dialysis solutions in automated peritoneal dialysis. Kidney Int Suppl 2003; 88:S105–13. 14. Szeto CC, Wong TY, Chow KM, Leung CB, Li PK. Oral sodium

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(8,15,16). The majority of PD patients in North America are currently treated with APD, and glucose-sparing strategies with this modality are particularly important due to the high glucose load associated with APD. The 29% improvement in normalized ultrafiltration with higher doses of amino acids should result in a reduction in overnight glucose load by 29% if the patient remains in steady state. The potential now exists to combine overnight amino acid dialysate with other glucose-sparing strategies, such as a daytime icodextrin dwell and high dose oral diuretic, to produce significant reductions in 24-hour glucose load for APD patients (15–17). Our study has a number of important limitations. It was a short-term study and it is possible that longer-term exposure to amino acid dialysate could alter membrane permeability in such a way to change glucose transport, thereby affecting ultrafiltration. Also due to its shortterm nature, our study does not report on clinically important nutritional outcomes such as Subjective Global Assessment or anthropometric measurements. The crossover design was nonrandomized because we wanted to assure tolerance to lower dose amino acid dialysate in each patient prior to increasing the dose. We report normalized ultrafiltration as we measured only glucose instilled and not glucose absorbed, thus we cannot report the more conventional ultrafiltration efficiency measure (18). In conclusion, we have demonstrated that higher than conventional doses of amino acids mixed with glucose can be tolerated on APD with relatively minor changes in acid–base status provided that a bicarbonate/lactatebuffered solution is used. We also found that higher than conventional doses of amino acids improve normalized ultrafiltration by approximately 29%. This suggests that a higher dose amino acid dialysate may be an effective strategy to treat protein energy malnutrition as well as reduce nocturnal glucose exposure on APD. Longer-term studies are required to confirm our findings on ultrafiltration and to assess for any clinically important nutritional benefit with this strategy. These studies should be done with a tailor-made dialysate higher in alkali content to counter a fall in serum bicarbonate.

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bicarbonate for the treatment of metabolic acidosis in peritoneal dialysis patients: a randomized placebo-control trial. J Am Soc Nephrol 2003; 148:2119–26. 15. Marshall J, Jennings P, Scott A, Fluck RJ, McIntyre CW. Glycemic control in diabetic CAPD patients assessed by continuous glucose monitoring system (CGMS). Kidney Int 2003; 64:1480–6. 16. Martikainen T, Teppo AM, Gronhagen-Riska C, Ekstrand A. Benefit of glucose-free dialysis solutions on glucose and

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lipid metabolism in peritoneal dialysis patients. Blood Purif 2005; 23:303–10. 17. Medcalf JF, Harris KP, Walls J. Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory peritoneal dialysis. Kidney Int 2001; 59: 1128–33. 18. Holmes C, Mujais S. Glucose sparing in peritoneal dialysis: implications and metrics. Kidney Int Suppl 2006; 103: S104–9.

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