Use of new peritoneal dialysis solutions in children

Transcription

1 Standard peritoneal dialysis (PD) solutions with low ph and containing high concentrations of lactate and glucose have been demonstrated to negatively affect the peritoneal membrane, mesothelial cell viability, residential peritoneal cells and also to inhibit phagocytic functions. 1 5 An increasing body of experimental evidence supports the idea that the peritoneal hypervascularization and fibrosis observed in long-term PD are causally related to the acute and chronic toxicity of conventional PD solutions. 6,7 Metabolic and cardiovascular burden arising from many sources, including glucose degradation products, 8 vascular volume control, 9 oxidative stress, 10 and glucose load 11 have been implicated in exacerbating the decline of residual renal function, a major determinant of patient outcome 12 that strongly influences morbidity and mortality of PD patients. 13 The development of second generation PD solutions such as Extraneal (7.5% icodextrin) is expected to reduce these disease implications due to increased biocompatibility, removal of glucose, and reduced GDP. 14 A Physioneal (lactate/bicarbonate mixed buffer ph 7 7.4), Physioneal, Extraneal, Nutrineal (1.1% amino-acid-containing solution) regimen, for example, offers a significant reduction in carbohydrate load (approximately 40 50%), lower exposure to and absorption of GDPs, reduced oxidative stress, and improved volume control when compared with a firstgeneration DDDD (4 Dianeal) regimen. 15 The nighttime automated peritoneal dialysis (APD) regimes with short cycles fit in well with the characteristics of the peritoneal membrane transport in children. The preference for APD as the dialytic treatment of choice for children with end-stage renal failure has also largely been a lifestyle choice; indeed, the nighttime APD courses enable children to attend school full time and reduce the impact of the dialysis treatment on the way of life of the patients and their families. Moreover, thanks to the wide range of treatment options available, APD can provide a dialytic schedule, which is tailored to the needs of children of different ages and body sizes. Therefore, during the last decade, APD has progressively replaced continuous ambulatory PD in the pediatric dialysis centers and is nowadays considered the chronic PD modality of choice for pediatric patients. 16,17 Children represent the patient category that may potentially benefit most from the new, more physiological, high ultrafiltration (UF), and nutritive PD solutions, especially if one considers their long-term depenhttp:// & 2008 International Society of Nephrology Use of new peritoneal dialysis solutions in children A Canepa 1, E Verrina 1 and F Perfumo 1 1 Nephrology Department, G Gaslini Institute, Genova, Italy Standard peritoneal dialysis (PD) solutions with low ph and containing high concentrations of lactate and glucose have been demonstrated to negatively affect the peritoneal membrane, mesothelial cell viability, residential peritoneal cells, and also to inhibit phagocytic functions. An increasing body of experimental evidence supports the idea that the peritoneal hypervascularization and fibrosis observed in long-term PD are causally related to the acute and chronic toxicity of conventional PD solutions. A Physioneal (lactate/ bicarbonate mixed buffer ph 7 7.4), Physioneal, Extraneal (7.5% icodextrin), Nutrineal (1.1% amino-acid-containing solution) regimen, for example, offers a significant reduction in carbohydrate load (approximately 40 50%), lower exposure to and absorption of glucose degradation products, reduced oxidative stress, and improved volume control when compared with a first-generation DDDD (4 Dianeal) regimen. The positive aspects of each solution that we have observed in our patients allow a recommendation on the potential benefit of using these solutions in children treated with PD. In fact, data from the literature as well as the results of the studies reported in this paper show that in children the application of neutral ph bicarbonate/lactate-buffered solution for the standard nighttime APD prescription, icodextrin solution for a long daytime dwell, and AA-based solution in malnourished patients is safe and effective. Extended clinical trials should be encouraged to better define the PD schedules for the combined use of these solutions that may be associated with the best clinical efficacy and the highest level of biocompatibility. ; doi: /sj.ki KEYWORDS: icodextrin; amino acids; bicarbonate/lactate; pediatric peritoneal dialysis; PD solutions Correspondence: A Canepa, Nephrology Department, G Gaslini Institute, Genova 16148, Italy. albertocanepa@ospedale-gaslini.ge.it S137

2 dence on a functioning peritoneal membrane in case of a kidney transplant failure and the fact that in APD frequent short cycles continuously expose the peritoneal membrane to a non-physiological and bio-incompatible milieu. There is limited experience of the use of biocompatible PD solutions in children, and it is reported in a variety of pediatric centers. Our goal of this study was to present a brief overview of what has been published so far in this area of pediatric nephrology and, more important, to report our own experience with all three new generation PD solutions (Physioneal, Extraneal, and Nutrineal) in our pediatric population treated with PD at the Institute Gaslini in Genoa, Italy. Physioneal is a glucose-based PD solution buffered with bicarbonate/lactate, Extraneal has icodextrin as an osmotic agent, and Nutrineal has amino acids (AAs) as an osmotic agent. Bicarbonate and bicarbonate/lactate-buffered solutions Both in vitro and ex vivo studies and, more recently also in vivo studies, with bicarbonate-buffered solutions have shown improvements in biocompatibility compared with lactate-buffered solutions. 5,18,23 25 Biocompatibility, UF capacity, and correction of acidosis are three important features in the maintenance treatment of pediatric PD patients. Studies by Jones et al. 25 and Tranaeus 26 have demonstrated improved biocompatibility, UF capacity, and correction of acidosis in adult PD patients treated with bicarbonate/lactate-based PD solutions. Haas et al. 18 reported with a 34 mm bicarbonate solution (BicaVera 170/180/190; Fresenius Medical Care, Bad Homburg, Germany) an improved correction of acidosis with respect to a 35 mm lactate (ph 5.5, CAPD 17/18/19; Fresenius Medical Care), without important modifications in transport kinetics in children undergoing APD. Furthermore, the same authors reported that the peritoneal release of CA-125 increased twofold during bicarbonate APD, which is consistent with recovery of the mesothelial cell layer, indicating improved in vivo mesothelial cell tolerance to high-dose glucose with the neutral ph PD solutions containing reduced GDPs. 18 Fischbach et al., in a pilot study on the effect of PD fluid composition on peritoneal area available for exchange in children, suggest a higher biocompatibility for Physioneal than for Dianeal. They report that the less inflow pain associated with Physioneal induced a lower intraperitoneal pressure, reflecting enhanced fill volume tolerance, and a lower steady-state unrestricted area over diffusion distance reflected less capillary recruitment. They suggest that more biocompatible PD solutions will improve PD therapy, although this conclusion will require verification in extended clinical trials. 21 In our center, we have examined the peritoneal alkali mass balance and UF in children on APD treated with either lactate- or bicarbonate/lactate-buffered PD solutions. The aim of this study was to evaluate the effects of a combined 25 mmol l 1 bicarbonate/15 mmol l 1 lactatebased solution (Physioneal, Baxter SpA, Sesto Fiorentino, Italy) compared with a 40 mmol l 1 lactate-based solution (Dianeal PD4; Baxter Healthcare, Castlebar, Ireland) on the uptake of alkali. The second aim of this study was to investigate if the alkali uptake and UF could be comparable with this new more physiological, that is, bicarbonate/ lactate-based PD solution. RESULTS Daily UF rates did not differ significantly between lactate or bicarbonate/lactate PD solutions ( versus ml), even if there was a tendency to increased UF with the bicarbonate/lactate PD solutions. The results of the peritoneal alkali mass balance are shown in Table 1 and Figure 1. The amount of alkali infused was comparable with the two solutions: mmol with lactate-based solution versus mmol with bicarbonate/lactate-based solution. The lactate losses in the effluent were mmol with lactate-based solution versus mmol with bicarbonate/lactate-based solution; the difference may be explained by the different concentrations of lactate in the two PD solutions. The amount of lactate absorbed was mmol with lactate-based solution versus mmol with bicarbonate/lactate-based solution. The percentage of lactate absorbed of the infused Table 1 Alkali peritoneal mass balance of the children on APD with lactate- or bicarbonate/lactate-based solutions (mean7s.d.) Dianeal PD4, mmol (lactate=40 mmol) Physioneal, mmol (lactate=15 mmol, HCO 3 =25 mmol) (V i LACTATE i ) *** (V i HCO 3i ) *** (V i LACTATE i )+(V i HCO 3i ) (V e LACTATE e ) *** (V e HCO 3e ) *** (V i HCO 3i ) (V e HCO 3e ) ** (V i LACTATE i ) (V e LACTATE e ) *** Mass balance APD, automated peritoneal dialysis; HCO 3e, bicarbonate concentration in the effluent; HCO 3i, bicarbonate concentration in dialysis solution; LACTATE e, lactate concentration in the effluent; LACTATE i, lactate concentration in the dialysis solution; V e, dialysate drained volume; V i, dialysate infused volume. *Po0.05, **Po0.01, ***Po Gain mmol 0 Losses HCO 3 Lactate Alkali mass balance Figure 1 Bicarbonate and lactate mass balance with Dianeal PD4 or Physioneal. Dianeal PD4, & Physioneal. S138

3 amount was 19.7 with lactate-based solution versus 16.6 with bicarbonate/lactate-based solution. Bicarbonate losses in the effluent were mmol with lactate-based solution versus mmol with bicarbonate/lactate-based solution; the difference was due to the different concentrations of bicarbonate in the two solutions. The difference between bicarbonate infused and lost with the bicarbonate/lactate-based solution was mmol, showing that there were no further losses with respect to the infused amount. The peritoneal alkali mass balance showed a slight, but not significant, increase to versus mmol with the bicarbonate/ lactate-based solution. No side effects were observed that could be attributed to the tested PD solutions. CONCLUSION In this study, we found a significant difference in lactate losses in the effluent with lactate- versus bicarbonate/lactatebased solution due to the different concentration of lactate in the two solutions (Table 1 and Figure 1). This difference reflects the fact that with lactate-buffered PD solutions the peritoneal cells are exposed to a much higher lactate concentration (and low ph) for a period of 8 10 h during the APD session. Indeed, it is known that with standard lactate PD solution the peritoneal membrane is exposed to an acidic environment for more than 1 h before peritoneal ph equilibration takes place. 22 Acidity and high lactate concentrations are one of the major inhibitory pathways by which conventional PD solutions modulate cell function. 27 The difference between infused and lost bicarbonate with the bicarbonate/lactate-based solution shows that there were no significant bicarbonate losses in relation to the infused amount when the bicarbonate/lactate-based solution was studied, whereas with the lactate-based solution a significant loss in the effluent ( mmol) of the physiological buffer, that is, bicarbonate was found. When standard lactate PD solutions are infused, lactate is absorbed and converted in the liver to bicarbonate, which diffuses through the peritoneal membrane and is lost into the dialysate. 22,28 In our study, the peritoneal alkali mass balance was comparable between the lactate- and the bicarbonate/lactatebased solution, and there was a reduced exposure to lactate and a tendency to increased UF. These favorable results indicate that pediatric patients may benefit of the use of a bicarbonate/lactate-based PD solution. Icodextrin-based solutions Icodextrin is a glucose polymer with an average molecular weight of Da, an osmolarity of 282 mosm kg 1, and a ph of 5.2. Icodextrin exerts its effect on fluid withdrawal from the blood by a mechanism known as colloid osmosis, through the small pores of the peritoneal membrane, according to the three-pore model of Rippe Posthuma et al. 32 found in adult patients on continuous cycling PD (CCPD) significantly higher UF volumes with icodextrin than with glucose during a 14-h day-time dwell, over a period of 9 months. Experimental data on the time courses of intraperitoneal volume changes caused by transcapillary UF, lymphatic absorption, and resulting in net UF, using 1.36 and 3.86% glucose and icodextrin dialysis solutions, were given by Ho-dac-Pannekeet et al. 33 Transcapillary UF was calculated from the dilution of a volume marker up to 4 h, and then mathematically extrapolated to 9 h. The shape of the curves was markedly different: for the glucose solutions, the study described the standard hyperbolic curve, which can be explained by the decrease in transcapillary UF rate due to the absorption of glucose. In contrast, the icodextrin curve increased almost linearly over time, since icodextrin absorption from the peritoneal cavity is much slower than that of glucose, and an effective colloid osmotic gradient between the peritoneal fluid and the capillary blood is maintained over time. The UF potential of icodextrin solution has led to a series of established clinical indications, and among these, the possibility to obtain positive UF and enhanced solute clearances through a long daytime dwell in CCPD looked particularly useful for pediatric patients. Some interesting information related to the use of icodextrin can be drawn from the APD prescription study performed on the data of the Italian Registry of Pediatric CPD. In 1998, an icodextrin solution was employed for the daytime dwell in 12% of patients on a continuous PD regimen, and during 1999 this percentage increased to 30%. 34 Data for the year 2005 show a further increase to 48% (E Verrina, personal communication). Notwithstanding the reported use of icodextrin PD solutions in children, there are still relatively limited available data on the current clinical use of icodextrin PD solution in pediatric patients on CCPD. The study by de Boer et al. 35 in 11 children on NIPD (nocturnal intermittent PD) confirmed that, during a 12 h dwell, this osmotic agent is able to maintain a net UF, comparable to that obtained with a 3.86% glucose solution. Furthermore, the use of icodextrin during the daytime dwell added to the weekly urea K t /V. In the children examined by de Boer et al., thedailyuseoficodextrinsolutionover6weekssignificantly increased solute removal, was associated with minor side effects, andresultedinanincreaseinserumlevelsoftotalicodextrinand its metabolites comparable to that reported in adults, 30,36 which disappeared after stopping treatment. To assess the need to adapt dietary prescriptions, van Hoeck et al. 37 studied the potential effects of increasing the dialysis dose by adding a daytime icodextrin dwell, in children treated with NIPD, on peritoneal AA and albumin loss, plasma levels of AA, albumin, cholesterol and fibrinogen, and nutritional intake. They found a significant increase of weekly dialysis creatinine clearance and K t /V. However, it is not surprising that an increase in dwell volume and dialysis time improves adequacy parameters. UF increased in all children but not significantly. Although UF might have added clearance, further improving adequacy parameters, it might also have decreased residual renal clearance by dehydration. They concluded that increasing dialysis dose by introducing a S139

4 daytime icodextrin dwell during a week does not affect peritoneal albumin loss, serum albumin, cholesterol, and fibrinogen levels or dietary intake in the short term. They reported a significant increase in essential AA and nonessential AA loss without change in AA plasma levels. Therefore, they suggested monitoring dietary intake when adding a daytime icodextrin dwell in children. By comparing the results of two peritoneal equilibration tests performed in nine pediatric patients using 3.86% glucose or 7.5% icodextrin as a test solution, Rusthoven et al. 38 found that fluid and solute parameters were similar for the two solutions, except for transcapillary UF. This can be explained by differences in fluid kinetics induced by these two osmotic agents; 3.86% glucose gives rise to a rapid UF in the beginning of the dwell, mainly due to crystalloid osmosis, whereas icodextrin induces a slow and sustained UF by means of colloid osmosis, that exerts its effect almost exclusively across the small pores rather than the transcellular pores (aquaporins). For the same reason, the two solutions had a different effect on the change in intraperitoneal pressure during a 4-h dwell; 39 during a peritoneal equilibration test performed with a 3.86% glucose solution, the increase in intraperitoneal pressure was positively correlated with transcapillary UF and inversely correlated with patients body surface area (BSA), while by using an icodextrin solution intraperitoneal pressure hardly increased during the 4-h dwell and no correlation was found with fluid kinetics or patient s BSA. The only limitation of these two very wellconducted studies is that their results were obtained from a 4-h dwell, while icodextrin exerts its osmotic effect for up to h, and in pediatric patients it is usually employed for daytime dwells of such duration. Starting from the proven efficacy and safety of icodextrin solution in children, we were interested in the time course of intraperitoneal volume changes during a long daytime dwell for the children using Extraneal for the first time in our hospital. Therefore, we examined the UF profile in the individual patient and measured the icodextrin absorption rate at the various time points of the daytime dwell. We evaluated a group of seven children (four boys and three girls) with a median age of 9.2 years (range: years), whose underlying renal diseases were nephronophthisis in two cases, renal hypodysplasia in two cases, and focal glomerulosclerosis, cystinosis, and bilateral Wilms tumor in one case each. Patients weight was kg and BSA was m 2. Three patients were anuric, while in the other four the residual daily urine volume was ml. All the patients had been on chronic PD for at least 2 months (median duration of PD: 3 months, range: 2 95 months), were in stable clinical condition, and no episode of peritonitis had been registered during the month preceding the study. All of the patients were on an NIPD regimen, which included 8 10 cycles of 1200 ml m 2 of dialysate for a 10-h treatment duration. None of the patients had been previously treated with icodextrin PD solutions. A written informed permission was obtained from patients parents and a signed consent was also obtained. Thereafter, the CCPD regimen was initiated in these children and Extraneal prescribed for a daytime dwell. The procedure adopted for the evaluation of the intraperitoneal volume was based on the direct volume measurement, as originally described by Stelin and Rippe. 40 At the end of an NIPD session, the patient received a daytime dwell volume of ml m 2 BSA, corresponding to 50% of the night fill volume, of a 7.5% icodextrin solution (2.0 l Extraneal; Baxter Healthcare); 125 mg l 1 cefotaxime and 8 mg l 1 tobramycin were added to the dialysis fluid. The dwell volume adopted for the test corresponded to the dwell volume that is currently employed in our center for children on CCPD; a reduced dwell volume is usually preferred to avoid patient discomfort and to minimize the risk of mechanical complications (for example, hernias, leakage). BSA was calculated by means of the Haycock formula. 41 The scheduled dwell time was 14 h. At 0, 4, 8, and 14 h dwell time, dialysate was accurately and completely drained into a sterile bag, within a closed circuit, and weighed; a 5-ml dialysate sample was drawn from the medical port of the drainage line, which had been previously soaked with a povidone iodine solution for 5 min. At time 0, 4, and 8 h, the drained dialysate was reinfused to the patient. Drainage and infusion periods were kept as short as possible, compatibly with the accuracy of the procedure. The volume of the drained dialysate was determined from the total bag weight corrected for the weight of the empty bag and of the connecting tubings. Drained volumes were corrected for the total volume of the dialysate samples withdrawn during the test. Dialysate samples were tested for glucose, urea, creatinine, sodium,phosphate,albumin,andicodextrin.abloodsampleof glucose, urea, creatinine, sodium, phosphate, and albumin was taken at each time point. Values were corrected for plasma water. The analysis of total icodextrin in spent dialysate was performed after the hydrolysis of polyglucose by the enzyme amyloglucosidase (a1 4 glucosidase; Sigma-Aldrich, St Louis, MO, USA) (Amici et al. Perit Dial Int 2002; 22: 118; abstract). 42 To perform the assay, the dialysate samples were diluted 1:10 to obtain final glucose concentrations within the linear range of glucose analyzers; then, they were incubated with a 1 mg ml 1 amyloglucosidase solution, ph 4.5, for 2 h at 55 1C to ensure the hydrolysis of both the 1,4- and the 1,6- linkages. Glucose was measured before and after the hydrolysis procedure using a clinical chemistry analyzer. Total icodextrin was obtained from generated glucose mass, that is, the difference between total (hydrolyzed þ free) and baseline glucose concentrations. At the four time points of the dwell with icodextrin, the drained volume of dialysate were: ml at time 0; ml at 4 h; ml at 8 h; ml at 14 h. The volume versus time curve (Figure 2) showed an almost linear increase up to 8 h followed by a plateau until the end of the dwell. Mean net UF was ml, which corresponded to % of the infused volume of icodextrin solution. Positive UF was observed in six of seven patients. S140

5 dv (ml) Dwell time (min) Figure 2 Total (dv) drained volume versus time curves. Absorption (%) Dwell time (min) Figure 3 Icodextrin absorption rate during a 14-h dwell. Solute removal was good over the 14-h dwell. Equilibration of dialysate and plasma concentrations of urea and creatinine was reached between the fourth and the eighth hour of the dwell, when the dialysate-to-plasma ratio (D/P) of urea was and D/P of creatinine was At the end of the 14-h dwell, D/P resulted for urea and for creatinine. These D/P ratios higher than 1 could be explained by a solute transport induced by the osmotic force exerted by icodextrin. In fact, in the presence of a solute of high molecular weight, transport of small solute molecules, such as urea and creatinine, may take place even against a concentration gradient, provided the osmotic flow of solute is greater than its diffusive flow in the opposite direction. Sodium D/P with icodextrin solution is usually higher than with glucose solutions due to the reduced sodium sieving associated with the convective transport induced by colloid osmosis through the small pores. 33,43 In our patients, sodium D/P was at 4 h and then remained stable until the end of the dwell ( at 8 and 14 h). Sodium extraction with dialysate was proportional to the amount of net UF, and the curve of D/P sodium concentration during the dwell corresponded to that of drained dialysate volume. Plasma sodium concentration changed from meq l 1 at the start of the dwell to meq l 1 after 14 h. At the end of the 14-h dwell, % of the infused icodextrin was absorbed as a result of the long dwell time and of the relatively small dwell volume. Studies in adult patients reported an icodextrin absorption rate of 20% at 8 h 30 and of 36 42% at 12 h. 44 The total amount of icodextrin absorbed by our patients was g, which corresponded to g per kg body weight and, therefore, to a caloric load of kcal kg 1 day 1, that is, % of the recommended daily allowance of energy for patients chronological age. The curve of icodextrin absorption (Figure 3) showed an almost linear increment with the dwell time. This trend is consistent with a disappearance of icodextrin from the peritoneal cavity, which is independent of molecular size and concentration gradient and is mainly due to the absorption of the solute into the lymphatic system at a rather constant rate. In conclusion, in our pediatric patients, even by using a reduced dwell volume, icodextrin solution proved to be able to obtain sustained UF over a 14-h dwell, good solute clearance performances, and positive sodium extraction. At the same time, the calorie load associated with icodextrin absorption was very limited, and no clinical side effect or complaint was reported. Amino-acid-based solutions Most of the surveys on the nutritional status of children undergoing CPD show that these patients frequently suffer from wasting and/or protein calorie malnutrition The possibility of using PD itself as a source of nutrients in the treatment of malnutrition is an intriguing concept. Several investigators have examined the nutritional benefit of substituting AA for glucose in PD solutions Some studies have reported a significant improvement in some nutritional parameters, while others have shown no significant improvement in the same parameters. With children, clinical experience of medium- and long-term studies is limited. In particular, Hanning et al. evaluated the short-term effectiveness on nutrition in infants and children receiving CAPD, concluding that, compared with glucose, AA dialysate provides reduced but satisfactory fluid and waste removal, maintains normoglycemia, and more than compensates for effluent losses of AA and proteins. 58 Qamar et al. 59 reported the effects of 3 month AA dialysis compared to dextrose in children on CAPD in a prospective randomized crossover study, concluding that AA dialysis was comparable to dextrose dialysis with no additional proven nutritional benefit, was equally effective in UF and creatinine clearance, and produced no adverse clinical on biochemical effects. In a long-term study (6 12 months) on the effects of AA dialysis solution on CAPD children using the same solution, we were unable to show an improved nutrition; the only significant improvement was on the plasma AA profile. 60 In a prospective randomized crossover study in seven children on CCPD treated with single AA (1.1%) daytime dwell for 3 months, Qamar et al. reported an increase in blood urea nitrogen (BUN), total body nitrogen, and appetite. Total plasma albumin and AA levels did not change significantly. 61 Honda et al., 62 using a mixed essential AA and glucose 1.5% solution for a short term, found in children on CAPD a S141

6 decrease of non-essential AA plasma levels after treatment, suggesting that essential AA absorbed from the solutions may have increased uptake of non-essential AA in protein synthesis (PS). Also, Van de Walle et al. proved the safety of using mixed glucose and AA solutions in acute PD (Van de Walle et al. Perit Dial Int 1998; 18(Supp 1): S69; abstract). By using a mixture of glucose and AA for 12 months on a patient on CCPD, Brem et al. 63 reported an improvement of serum albumin, appetite, and growth velocity. There are various possible explanations for the modest nutritional benefits of AA solution. In our experience, we focused our attention on the insufficient simultaneous supply of calories to allow the incorporation of absorbed AA into new proteins, diverting their use for energy production, and leading to the increase of serum blood urea levels, systematically reported by the previous studies on the use of intraperitoneal AA. 50,55,57 60 It is well known that without an energy source, nitrogen will not be effectively incorporated into protein; therefore, in parenteral nutrition the combined infusion of no protein calories and AA has been a key factor in ensuring the best utilization of the AA. APD (considered the chronic PD modality of choice for pediatric patients) is based on the use of cycler and enables different types of solutions to be infused simultaneously. This raises the question of whether APD with a combined intraperitoneal infusion of AA and glucose is a valid means of providing an extra amount of readily available nitrogen and calories, and if an adequate non-protein calorie/nitrogen ratio can prevent the marked increase in BUN, which is usually seen if the AA are administered without glucose. The feasibility of simultaneously infusing glucose- and AAbased PD solutions was tested to determine whether PD children treated at the Gaslini Institute could achieve an adequate nonprotein calorie/nitrogen ratio while preventing a marked increase in BUN, which is usually seen if the AA are administered without glucose. 64 An automatic PD cycler was used to infuse glucose and AA solutions (proportion of 3:1) simultaneously during the night. By this procedure, three favorable conditions for PS could be simultaneously achieved: hyperinsulinemia, hyperaminoacidemia, and an adequate non-protein calorie/nitrogen ratio (115.4:1) of the absorbed glucose and AA. It therefore follows that there is a sound theoretical basis for the use of this procedure, since it could improve utilization of AA for PS as suggested by the lack of increase of the BUN levels with this regimen. To evaluate whether changes in substrate and insulin levels that occur during PD have effects on muscle protein dynamics by studying muscle PS, protein breakdown, and net protein balance by the forearm perfusion method associated with the kinetics of 3 H-phenylalanine in acute, a crossover study in which PD patients served as their own controls has been performed in Genoa by Garibotto s group and ours. 65 The forearm perfusion studies associated with the kinetics of 3 H-phenylalanine were performed (1) in the basal state and during PD with dialysates that contained dextrose alone in different concentrations, (2) during PD with dialysates that contained dextrose alone or dextrose and AA, and (3) in time controls. This study indicated that in PD patients in the fasting state, the moderate hyperinsulinemia that occurs during PD with dextrose alone causes an antiproteolytic action that is obscured by a parallel decrease in AA availability for PS. Conversely, the combined use of dextrose and AA results in a cumulative effect, because of the suppression of endogenous muscle protein breakdown (induced by insulin) and the stimulation of muscle PS (induced by AA availability). The hypothesis therefore is that in patients who are treated with PD, when fasting or when nutrient intake is reduced, muscle mass could be maintained better by the combined use of dextrose and AA. Recently, Tjiong et al., 66 in a single, open label, random order crossover study, compared the effects of a mixture of AA and glucose versus only glucose containing dialysate in 2 periods of 7 days each in 8 APD patients. They concluded that CCPD with dialysate composed of a mixture of AA and glucose acutely improves protein metabolism, and that this gain made during the night persists to a considerable extent for 24 h. This may be promising for long-term improvement of nutritional status in selected groups of patients. We studied the long-term use of simultaneously infusing glucose- and AA-based PD solutions in eight children on APD, for a period of 6 months. 67 We found an improvement of anthropometric parameters, in particular those indicating muscle mass and fat stores: mid-arm circumference increased from mm at baseline to mm after 6 months; mid-arm muscle circumference from mm at baseline to mm at 6 months; arm muscle area from mm 2 at baseline to mm 2 at 6 months; and arm fat area from mm 2 at baseline to mm 2 at 6 months. The weight for height percentile increased from at baseline to at 6 months (Table 2). No modifications of nitrogen waste products were observed. BUN was mg per 100 ml at baseline and mg per 100 ml at 6 months, while urea nitrogen appearance normalized for body weight was g kg 1 day 1 at baseline and g kg 1 day 1 at 6 months. Such findings differ from what was previously reported in adults and children treated with AA solutions. These data support the hypothesis that AAs, when infused simultaneously with glucose, are utilized for PS and not catabolized for energy production. Serum levels of total protein and albumin did not change significantly during the study period: total protein was g per 100 ml at baseline and g per 100 ml at Table 2 Anthropometric parameters T0 T6 T12 D Height (SDS/year) D Weight (SDS/year) BMI Weight for height percentile BMI, body mass index. S142

7 6 months; serum albumin was g per 100 ml at baseline and 3.9 þ 0.2 g per 100 ml at 6 months. However, baseline values of total protein and albumin were within the normal values. The nitrogen balance expressed per kg body weight significantly increased during treatment from mg kg 1 day 1 at baseline to mg kg 1 day 1 at 6 months. During the study period, energy and protein intakes were comparable to those of baseline. Similar and even better changes in caloric and protein balance may be achieved with either nasogastric or gastrostomy feedings, but such procedures are associated with their own set of clinical and psychological problems. The main advantages of administering supplemental AA by the peritoneal route are good compliance without modification of the normal dialysis procedure, and that the supplementary nitrogen by AA carries no additional phosphorus. This last point has to be taken into consideration for its implications on bone metabolism in small children. FINAL CONCLUSION APD is currently employed in the treatment of a large portion of children on chronic dialysis. The availability of new PD solutions significantly increases the possibility of tailoring the APD prescription to the clinical, metabolic, and nutritional needs of this patient population that varies a lot in terms of age, body size, growth velocity, and development stage. The positive aspects of each solution that we have observed in our patients allow a recommendation on the potential benefit of using these solutions in children treated with PD. In fact, data from the literature, as well as the results of the studies reported in this paper, show that in children the application of neutral ph bicarbonate/lactate-buffered solution for the standard nighttime APD prescription of icodextrin solution for a long daytime dwell and of AAbased solution in malnourished patients is safe and effective. Extended clinical trials should be encouraged to better define the PD schedules for the combined use of these solutions that may be associated with the best clinical efficacy and the highest level of biocompatibility. MATERIALS AND METHODS Seven children (five boys and two girls) with a mean age of years on APD for an average of months were studied. Before entering the study at day 0, patients had been on a cycler (HomeChoice or PacExtra; Baxter Healthcare) and treated with Dianeal PD4 for at least 30 days. The study protocol was approved by the G Gaslini Institute Ethical Committee and informed consent was obtained from the parents of the children. The effluents of two exactly alike daily APD prescriptions (that is, number of exchanges, glucose concentration, volume, and dwell time of each exchange), one with a lactate (40 mmol l 1 )-based solution and one with a bicarbonate (25 mmol l 1 )/lactate (15 mmol l 1 )-based solution, were collected on 2 consecutive days. Bicarbonate and lactate concentrations in peritoneal effluent were determined by a hemogasanalyzer (Radiometer ABL505, Copenhagen, Denmark) and by an enzymatic method (Roche, Basel, Switzerland), respectively. The alkali mass balance was calculated according to the following equation: Alkali mass balance ¼ððV i HCO 3i Þ ðv e HCO 3e ÞÞ þððv i LACTATE i Þ ðv e LACTATE e ÞÞ where V i is the dialysate infused volume, V e the dialysate drained volume, HCO 3i the bicarbonate concentration in dialysis solution, HCO 3e the bicarbonate concentration in the effluent, LACTATE i the lactate concentration in the dialysis solution, LACTATE e the lactate concentration in the effluent. Continuous variables are expressed as mean7s.d. Statistical tests were considered significant when Pp0.05. The SPSS statistical software program (SPSS Inc., Chicago, IL, USA) was used for this analysis. DISCLOSURE All of the authors declared no competing interests. 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