235 antigen 125 (CA 125) levels in keeping with recovery of the mesothelial cell layer and improved in vivo mesothelial cell tolerance to high glucose concentrations [50] Schmitt et al subsequently co[.]
14 Peritoneal Dialysis Solutions antigen-125 (CA-125) levels in keeping with recovery of the mesothelial cell layer and improved in vivo mesothelial cell tolerance to high glucose concentrations [50] Schmitt et al subsequently compared the efficacy of two neutral pH and low GDP solutions (Balance™ 35 mmol/L lactate and Bicavera™ 34 mmol/L bicarbonate) in children on APD and demonstrated equal acidosis control [51] However, the bicarbonate solution was associated with better preservation of ultrafiltration Alkalosis is common in children treated with pure bicarbonate or bicarbonate/lactate solutions on APD, especially with an icodextrin day dwell [52] There are no published studies specifically using Balance™ in children Of potential relevance is a study of adults on APD comparing Balance™ to cPDS. Balance™ was associated with a higher effluent CA125 rate of appearance and concentration, suggesting improved biocompatibility [53] Published pediatric guidelines suggest the use of a neutral pH and low GDP solution in children, with the choice of buffer dependent on local availability and automated delivery system, and buffer concentration tailored to the patient’s acid basis status to correct acidosis and avoid alkalosis [54] A pediatric PD program thus requires a variety of solutions with varying base type and concentration to meet the metabolic needs of growing children Osmotic Agent Removal of excess salt and water to achieve euvolemia and improve blood pressure control is a critical component of PD. To that end, the PDS must contain an osmotic agent to achieve fluid removal Osmotic agents in the currently available PDS include glucose (dextrose), icodextrin, and amino acids Experimental solutions such as carnitine and polyglucose will be reviewed later Glucose Glucose in supraphysiological concentrations to achieve an osmolality higher than uremic serum remains the most widely used osmotic agent worldwide Solutions containing 1.5%, 235 2.5%, and 4.25% glucose were introduced with the advent of PD and were found to produce ultrafiltration in children on CAPD [55, 56] With instillation of a volume of PDS of 1100 ml/m2 BSA in children above approximately 2 years of age, it has been demonstrated that children and adults have comparable peritoneal kinetics for glucose absorption and UF [57, 58] Glucose works to achieve UF largely through the ultrasmall pores or aquaporins [59] While it is an effective osmotic agent, glucose is readily absorbed across the peritoneal membrane, contributing to hyperglycemia, obesity, insulin resistance, anorexia, and dyslipidemia in PD patients Additionally, hyperosmolar glucose- containing solutions and GDPs are key players in the structural alterations in the peritoneal membrane seen with long-term PD The creation of the multichamber bag for PDS resulted in the manufacture of solutions low in GDPs and with neutral pH. A crossover comparison of a lactate single chamber versus bicarbonate two-chamber solution in 25 children demonstrated similar UF and peritoneal transport kinetics for the two solutions, with a 10% lower removal of creatinine and phosphate with the bicarbonate-based solution [44] A subsequent study of 21 children comparing the two solutions over 12 weeks each demonstrated rapid absorption of GDPs across the peritoneal membrane and a reduction in AGEs in children treated with the two-chamber bicarbonate-based, low GDP solution [60] As a result, the 2011 European Pediatric PD guidelines endorsed the use of multichamber PD fluids for use in children [54], along with the lowest concentration of glucose and lowest number of cycles possible to achieve euvolemia With loss of residual renal function, patients require more hypertonic solution to maintain UF and solute clearance, placing them at risk for alteration in body composition However, one longitudinal study in 136 anuric adults on PD demonstrated no increase in body fat, no loss of fat-free muscle mass, and maintenance of normalized protein catabolic rate (nPCR) despite increasing exposure to hypertonic dialysate [61] 236 By contrast, tube-fed anuric, or oliguric infants are frequently obese, with contributing factors being delayed motor milestones, excessive glucose exposure to achieve UF, and uremic inhibition of endogenous growth hormone One source of confusion in the literature and in clinical practice is the different labeling of the glucose content in PD solutions between North America and Europe European labeling is for anhydrous glucose equivalent, while in North America, solutions are labeled for dextrose content Thus a 1.36% Physioneal™ solution contains 15 G/L of glucose monohydrate, equivalent to anhydrous glucose of 13.6 G/L; a 2.27% solution contains 25 G/L of glucose monohydrate or 22.7 G/L anhydrous glucose; and a 3.86% solution contains 42.5 G/L glucose monohydrate or 38.6 G/L of anhydrous glucose The carbohydrate content and UF capacity of these solutions are equivalent to North American labeled solutions of 1.5%, 2.5%, and 4.25% dextrose, respectively E Harvey First introduced into clinic care in the early 1990s, icodextrin gained widespread use for the long overnight dwell in adults on CAPD [64] and was subsequently adopted for the long day dwell in children on APD [54, 65, 66] In adults, icodextrin has been shown to be associated with improved UF and mitigation of uncontrolled fluid overload independent of peritoneal transport type [67, 68], improved preservation of residual renal function [69], reduction in insulin resistance in nondiabetic patients [70], improved atherogenic lipid profiles [71], and reduced technique failure [72] Glucose-sparing regimens incorporating icodextrin, amino acid dialysate, and conventional glucose-containing PDS have also been shown to improve atherogenic lipid profiles compared to regimens with only glucose-based PD fluids [73] Twice daily icodextrin exchanges and the use of “bimodal” or combined icodextrin/glucose solutions have also been associated with improved UF in adults [63, 74, 75] However, the latter combined solutions are not currently commercially available and have not been studied in Icodextrin (Extraneal™) Icodextrin is a children Although used as part of a membrane- polyglucose solution derived from starch with sparing strategy, icodextrin use has been associan average molecular weight of 16,200 daltons ated with EPS and with markers of peritoneal It is an isosmolar (284 mOsm/L), non-glucose- fibrogenesis [76] More recently, a dual-chamber containing, lactate-buffered (40 mmol/L) solu- neutral icodextrin solution (pH ~ 6.8) has become tion with a pH of 5.2 and low GDPs (Table 14.1) available in Japan Preliminary clinical evaluaIt exerts UF through colloid osmosis, resulting tion in adults suggests equivalent salt and water in salt and water removal through the small removal but improved biocompatibility similar to pores, without activation of aquaporins, and other neutral pH PD solutions based on mesothewithout sodium sieving Approximately lial cell proliferation assays [77] 20–40% is absorbed from the peritoneal cavity through the lymphatics over an 8–12-hour Pediatric Studies Early pediatric experience dwell, resulting in a sustained gradient for demonstrated UF similar to 3.86% glucose over a UF. Icodextrin is metabolized by α-amylase to 12-hour dwell and serum icodextrin metabolites maltose, maltotriose, and maltotetraose Serum comparable to those seen in adults [65] Addition metabolites reach steady state in 7–10 days and of a single day dwell of icodextrin, approximately disappear within the same time frame when the 1100 ml/m2, provided an increased Kt/V of solution is discontinued Approximately 20% 0.52 ± 0.07 weekly [45] A second study using a of icodextrin and its metabolites are removed day dwell of 1100 ml/m2 confirmed an increase through dialysis or via the urine Tissue malt- in weekly Kt/V from 1.99 to 2.54 and weekly ases convert the metabolites to glucose within creatinine clearance from 35 to 65 L/1.73m2, the cells, without producing hyperglycemia, without increased loss of albumin but with an unlike conventional glucose- based solutions increased loss of essential and nonessential [62–64] amino acids [66] 14 Peritoneal Dialysis Solutions Using a long day dwell volume of 630 ± 191 ml/m2, Canepa et al demonstrated a linear increase in fluid removal up to 8 hours, with a plateau until the end of the dwell [45] The disappearance of icodextrin from the peritoneal cavity was compatible with removal via lymphatic absorption, with an average of 45% absorption The caloric value of the absorbed icodextrin was low, approximately 3.4% of recommended daily caloric intake A subsequent report on eight children suggested an inverse relationship between UF and age, with infants more likely to absorb icodextrin rather than achieve UF [78] However, UF was not correlated with infused volume A retrospective study of 50 children on automated PD treated with an icodextrin day dwell showed a linear correlation between fill volume and net ultrafiltration, with a fill volume of ≥550 ml/m2 associated with UF in 88% of children [79] Clinical Considerations There are several clinical considerations that must be appreciated when using icodextrin, as outlined in the excellent review by Silver et al [62] Rash Skin rash occurs in 5–10% of patients Acute generalized pruritic exfoliative rash may occur early after starting icodextrin, necessitating discontinuation, with rapid resolution of symptoms Milder forms involving peeling of the palms and soles may not require icodextrin withdrawal unless distressing to the patient A later blistering rash in sun-exposed areas occurring 3–6 months after exposure has also been described, taking several weeks to resolve after removal of icodextrin Falsely Elevated Glucose Measurements The accumulation of non-glucose sugars (icodextrin metabolites) may interfere with glucose measurements by nonspecific methods such as commonly employed glucose strips or glucometers [80] This has resulted in hypoglycemia in diabetics whose insulin was adjusted on the basis of a spuriously elevated reading This risk exists while the patient is on icodextrin and for up to weeks after discontinuation Serum glucose should 237 therefore be measured by glucose-specific assays in patients utilizing icodextrin Amylase Interpretation for Diagnosis of Pancreatitis Serum amylase activity is reduced in patients receiving icodextrin This appears to be due to a competitive interaction with amylase substrate resulting in a low serum amylase, which may mask the diagnosis of pancreatitis in PD patients Lipase should be measured in PD patients on icodextrin suspected of having pancreatitis Sterile Peritonitis The early use of icodextrin was associated with the development of sterile peritonitis, subsequently linked to contamination with a peptidoglycan produced by Bacillus acidocaldarius, a bacterium which may contaminate starch Improved manufacturing has reduced but likely not completely eliminated this contaminant Miscellaneous Side Effects Clinically insignificant mild hyponatremia and mild elevation in alkaline phosphatase have both been described with the use of icodextrin Pediatric-Specific Contraindications Icodextrin should not be used in patients with glycogen storage disease or lactic acidosis Antibiotic Stability Of relevance to pediatrics where a significant proportion of patients are on overnight cycling is the stability of antibiotics in icodextrin Cefazolin, tobramycin, cotrimoxazole, and vancomycin have been shown to be stable for 24 hours in Physioneal™ and Extraneal™ under conditions mimicking CCPD [81] Ceftazidime is stable for 24 hours in Extraneal™, but not in Physioneal™ Amino Acid (Nutrineal™) Nutrineal™ (Baxter Corporation) is a 1.1% amino acid dialysis solution with UF capacity similar to a 1.36% (1.5%) glucose-based PDS [82–84] It contains both essential (valine, leucine, lysine, isoleucine, methionine, histidine, threonine, phenylalanine, tryptophan) and nonessential (arginine, alanine, 238 proline, glycine, serine, tyrosine) amino acids The preparation currently available in North America is a high lactate (40 mmol/l), low calcium (1.25 mmol/L), and low magnesium (0.25 mmol/L) solution (Table 14.1) However, solutions with higher calcium and magnesium and lower lactate were initially available, with modification of buffer and amino acid content in response to early clinical studies [85] Peritoneal solute transport characteristics of Nutrineal™ are similar to glucose solutions [84] Nutrineal™ was first introduced in the 1980s in response to concerns about protein losses and malnutrition in PD patients Early pediatric studies using a single exchange in CAPD patients showed absorption of 80–86% of the amino acid from a single dwell, net positive nitrogen balance for a 24-hour period [83, 86], and reduced losses of amino acids not contained in the amino acid solution Administration of a single daily dwell for 6–12 months in eight children on CAPD demonstrated improvement of plasma essential amino acid levels but elevated urea and minimal improvement in cellular amino acid levels [87] Adult studies showed mixed results in terms of nutritional benefit from a single daily dwell, with acidosis and elevated urea as common side effects A more recent retrospective study has shown similar improvement in nutritional parameters in adults using either oral essential amino acid supplementation or a single daily exchange of amino acid dialysate [88] Anorexia and decreased caloric intake are common in PD patients, and many receive overnight tube feeds If an amino acid dialysate (AAD) is utilized as a day dwell in this situation, the amino acids are utilized as calories, resulting in acidosis and elevated urea [89] Working on the theory that an AAD coupled with adequate glucose administration would allow for better incorporation of amino acids into protein, Canepa et al studied AAD as part of a cyclic dialysis regimen They utilized a mixture of ¼ Nutrineal™, ½ 2.27 (2.5) % dextrose, and ¼ 3.86 (4.25)% dextrose during CCPD in ten children [90] The solution was well tolerated, and despite absorption of approximately 50% of the infused E Harvey amino acids, elevation in urea was not seen, suggesting improved utilization of the amino acids This short-term study achieved the three requisites for improved protein synthesis, namely, hyperinsulinemia, elevated plasma amino acid levels, and a favorable nonprotein calorie/nitrogen intake ratio The use of this regimen for 1 year resulted in positive nitrogen balance, a rise in serum albumin, and improved linear growth [91] Subsequently Tjiong et al have shown improved protein synthesis using amino acid plus glucose solutions in fed adult CAPD patients [92] and also in adults on automated PD [93], supporting the notion of “dialysate as food” [94] The product monograph states that Nutrineal™ is contraindicated in patients with known hypersensitivity to any of the amino acids or excipients in the solution, an elevated urea above 38 mmol/L (106 mg/dL), symptoms of uremia, metabolic acidosis, liver insufficiency, severe hypokalemia, and, most importantly for pediatrics, inborn errors of amino acid metabolism A multicenter outbreak of sterile peritonitis from a single batch of Nutrineal™ was reported in 2011 in adults [95, 96], with no etiology reported Several patients were able to resume Nutrineal™ from a different lot without recurrence of the chemical peritonitis Similarly, in a study in children using a 1:1 dilution of Nutrineal™ and glucose dialysate, five of seven children developed sterile peritonitis which did not respond to antibiotics but which resolved with cessation of Nutrineal™ [97] Nutrineal™ has been used as part of the “PEN” membrane-sparing regimen which utilizes Physioneal™, Extraneal™, and Nutrineal™ (discussed below) [98] As noted, Nutrineal™ is a lactate-buffered AAD. Aminobic™ (Fresenius Medical Care) is a bicarbonate-buffered 1% amino acid dialysate with bicarbonate 24 mmol/L, Mg 0.5 mmol/L, calcium 1.25 mol/L, and pH of 7.2–7.6 [99] In comparison to a lactate-based glucose-containing PDS of similar osmolality with pH 5.5, Aminobic™ was associated with improved viability and reduced cellular stress response in human peritoneal mesothelial cells [99] In one in vivo study, Aminobic™ was associated with a 14 Peritoneal Dialysis Solutions small but significant increase in permeability to larger proteins, notably β2 microglobulin, albumin, and IgG [100] However, no comparison of Nutrineal™ and Aminobic™ exists, and Aminobic™ does not appear to be commercially available currently Electrolyte Composition Sodium Removal of excess salt and water to control hypertension and normalize extracellular volume status is one of the basic goals of peritoneal dialysis Sodium concentrations in cPDS average 132 mmol/L (132 mEq/L) Hence, sodium removal is primarily by convection through ultrafiltration (UF), due to the low concentration gradient for diffusion between the PDS and serum Sodium removal and UF rate are thus proportional and related to the mechanics of dialysis and the PDS, with typical sodium removal of 100 mmol/L UF in CAPD, 80 mmol/L UF in APD, and 130 mmol/L UF with a long icodextrin dwell [1] Low-Sodium Solutions Despite two decades of published experimentation with low-sodium PDS, they are not yet commercially available, and the ideal solution or number of exchanges has not been fully elucidated Lowering the dialysate sodium concentration results in greater diffusive sodium removal but loss of ultrafiltration due to a lower osmolar gradient Low-sodium solutions must therefore be compensated with the addition of more glucose [1, 101, 102] Pediatric Considerations In infants and children on PD, hyponatremia is relatively common, especially in patients with high output renal impairment due to urinary sodium loss [103] and in anuric or anephric infants due to dialytic sodium loss in excess of intake [104] These patients require sodium supplementation Additionally, growing children require a positive salt balance to prevent worsening growth impairment A subset of children on APD may have hypernatremia when treated with hypertonic glucose and short dwell times [105], due to sodium 239 sieving, as described in intermittent peritoneal dialysis [106] These patients might benefit from a lower sodium dialysate In general, low-sodium PDS likely has a minimal role in pediatric PD Calcium The original commercially available PD solutions contained a calcium concentration of 1.62– 1.75 mmol/L (3.2–3.5 mEq/L), and these remain available throughout the world Mass transfer studies demonstrated net absorption of calcium from these high calcium (HC) solutions, with greater absorption with lower glucose concentrations due to convective removal of some calcium during ultrafiltration [107] With the advent of calcium carbonate as a non-aluminum phosphate binder, hypercalcemia became common, so lower calcium (LC) PDS with calcium 1.25 mmol/L (2.5 mEq/L) and lower magnesium 0.25 mmol/L (0.5 mEq/L) (see below) were developed and became widely used in the early 1990s Mass transfer studies showed a negative or neutral calcium balance with greater removal with higher glucose solutions as expected, allowing for supplementation with oral calcium to achieve phosphate control while preventing hypercalcemia [108–110] What is clear in all the subsequent studies is that patients on a LC PDS tolerated higher doses of calcium containing phosphate binders with fewer episodes of hypercalcemia [111] However, longitudinal studies showed conflicting results, with some demonstrating good tolerance with maintenance of normal serum Ca, Mg, and PTH levels [110, 112, 113], while others documented a fall in ionized calcium and a persistent rise in serum PTH [114– 116], highlighting the need to individualize the PDS prescription for any given patient [117] More recent studies suggest that whether a LC PDS is beneficial or not relates to the target outcome In a retrospective study of 236 adults on PD, Kang et al noted that patients on a low calcium (LC) dialysate (1.25 mmol/L, 2.5 mEq/L) had a greater decrease in bone mineral density and higher PTH and alkaline phosphatase levels compared to those treated with a high calcium E Harvey 240 (HC) dialysate (1.75 mmol/L, 3.25 mEq/L) [118] By contrast, Wang et al showed better left ventricular diastolic function and preservation of residual renal function in adults using a LC versus HC solution [119] Haris et al demonstrated reversal of adynamic bone disease in adults using a LC PDS [120] Zhao et al found the combination of a LC and HC solution to provide the best control of serum calcium and PTH [121] Commercially available PDSs have the same calcium concentration regardless of the glucose content However, kinetic modeling and clinical studies show that calcium transfer across the peritoneum is dependent on serum-ionized calcium, PDS calcium content, and PDS glucose concentration which determines UF. Higher degrees of UF result in increased removal of calcium [122] Rippe suggests that in order to maintain neutral calcium balance during a 4-hour dwell, there should be higher calcium concentrations in higher glucose solutions He proposes calcium of 1.38 mmol/L (2.76 mEq/L) for 1.5% glucose, 1.7 mmol/L (3.4 mEq/L) for 2.5% glucose, and 2.2 mmol/L (4.4 mEq/L) for 4.25% glucose Thus, patients requiring larger amounts of UF are at risk for more negative calcium balance Pediatric Considerations Mass transfer calcium studies have been done almost exclusively on adults on CAPD, and a paucity of data exists for children or for automated PD. A further consideration in children is the need for net positive calcium balance during growth Hypocalcemia and secondary hyperparathyroidism are common in infants on APD, especially if they are on LC PDS, are receiving renal formulas low in phosphate, and thus are not receiving large doses of calcium-containing phosphate binders [123, 124] Thus, the calcium content of the PDS used must take into account the locally available PDSs and the individual needs of the patient, including their UF requirements Maintenance of normal calcium, phosphate, and PTH requires coordination between the dialysis prescription, PDS, diet, supplements, phosphate binders, and activated vitamin D. A pediatric program should have available both HC and LC PDS to meet the needs of all patients Magnesium The original commercially available PD solutions contained a magnesium concentration of 0.75 mmol/L (1.5 mEq/L) A number of factors lead to the development of lower-magnesium PD solutions It was recognized that hypermagnesemia was common in patients with ESRD due to an imbalance between gut absorption and dialytic removal The realization of the toxicity of aluminum containing phosphate binders in patients with ESRD led to the use of alternate phosphate- binding agents, including calcium carbonate and magnesium carbonate Finally, an association between higher serum magnesium levels and low PTH and adynamic bone disease was suggested [125] Thus, PDSs with a lower magnesium content of 0.25 mmol/L (0.5 mEq/L) were introduced, were shown to maintain serum magnesium in the normal range, and gained widespread popularity [110, 126], despite concerns about potential depletion of tissue magnesium [127] Subsequently, reports of hypomagnesemia in PD patients emerged, necessitating magnesium supplementation [128] or a switch to higher- magnesium PD fluids [129] More concerning is the accumulating data that a higher serum magnesium may be protective against vascular and coronary calcification and may contribute to suppression of PTH [130] Newer solutions such as Balance™ have an intermediate magnesium concentration of 0.5 mmol/L (1 mEq/L) (Table 14.1) Thus, the optimal PDS magnesium concentration remains unknown, but accumulating evidence is in favor of either a reversion to higher magnesium solutions or oral supplementation with magnesium as needed to maintain a high normal serum magnesium ... glucose strips or glucometers [80] This has resulted in hypoglycemia in diabetics whose insulin was adjusted on the basis of a spuriously elevated reading This risk exists while the patient is... Tissue malt- in weekly Kt/V from 1.99 to 2.54 and weekly ases convert the metabolites to glucose within creatinine clearance from 35 to 65 L/1.73m2, the cells, without producing hyperglycemia, without... reach steady state in 7–10 days and of a single day dwell of icodextrin, approximately disappear within the same time frame when the 1100 ml/m2, provided an increased Kt/V of solution is discontinued