PD solutions - Wiley Online Library

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Aug 2, 2011 - good patient tolerance, manufacturing ... Peritoneal dialysis (PD) solutions have evolved since Boen ...... Lee HY, Park HC, Seo BJ, et al.
PD Solutions: New and Old Jose A. Diaz-Buxo, MD; Dixie-Ann Sawin, PhD; Rainer Himmele, MD The authors are with Fresenius Medical Care North America, Waltham, Massachusetts.

Peritoneal dialysis (PD) solutions have evolved since Boen described the appropriate composition of a suitable fluid comprising an osmotic agent, electrolytes, and buffer substance in 1969. New solutions introducing alternative osmotic agents and bicarbonate as an alternative to lactate-buffered solutions have been developed. These so-called biocompatible solutions belong to a very heterogeneous group of PD fluids that share some features but are distinct in other aspects. All biocompatible solutions have a substantially reduced level of toxic glucose degradation products (GDPs). However, the new solutions differ in their absolute GDP content, osmotic agent, buffer substance, and pH. The differences from the conventional solutions and the characteristics of the distinct new solutions are presented in this review together with a discussion of their potential clinical benefits and implications.

A

growing understanding of the physiology of the peritoneal membrane together with the evolution of innovative manufacturing techniques resulted in the introduction of a variety of new and more biocompatible peritoneal dialysis (PD) solutions. This development is just the latest in a long history of innovations in PD fluids. The first infusion of fluid into the peritoneal cavity for therapeutic purposes involved red wine and was performed by Warrick in 1744.1 Ganter later used physiological saline for his first PD treatment in 1923.2 Heusser improved ultrafiltration (UF) by adding dextrose in 1927,3 and Rhoads added lactate as a source of bicarbonate in 1938.4 In 1969, Boen’s dialysate consisted of an acetate-based solution of 35 mEq/L with 130-140 mEq/L of sodium and 1.55 g/dL of glucose.5 By then it had become evident that a PD solution should contain a buffer, electrolytes, and an osmotic agent. Lactate and acetate have been traditionally used as buffers in PD solutions, as they both have similar effects on maintaining the acid-base balance. However, over the years lactate became the preferred buffer over acetate, since the use of acetate was potentially associated with high serum acetate levels, while lactate provided safer and more stable blood pH and bicarbonate concentrations.6 The electrolytes present in PD solutions include sodium, calcium, magnesium, 356 Dialysis & Transplantation August 2011

and chloride, but no potassium, and are listed along with their typical concentrations in Table I. The ideal osmotic agent should effectively induce UF and should be easy to manufacture; it should be biocompatible, not absorbed, and inexpensive. Although not ideal, glucose has been the osmotic agent of choice for PD for more than a century, and concentrations applied vary depending on UF requirements and techniques used. PD solution formulations have remained relatively standard for many decades probably due to the relatively good patient tolerance, manufacturing limitations, and poor understanding of the effects of the chemical compositions and physical characteristics of PD solutions on the microcirculation and mass transport mechanism.7 However, an increasing awareness of biocompatibility issues and the occurrence of adverse effects experienced with conventional PD solutions mandated changes in the formulations of these solutions.

Conventional or Standard Solutions Composition Current conventional PD solutions consist of a lactate-based buffer, electrolytes, and an osmotic agent that are present in singlechamber bags at a pH of approximately 5.5. The glucose concentrations of these

dialysis solutions are mostly specified as g/L or percent of monohydrous or anhydrous glucose. Available compositions include 1.5% (345 mOsm/L), 2.5% (395 mOsm/L), and 4.25% (484 mOsm/L) of monohydrous glucose, for which the anhydrous compositions are 1.36%, 2.27%, and 3.86%, respectively. If the glucose content is specified as monohydrous instead of anhydrous, the concentrations is rated about 10% higher; however, the glucose content is the same. The general composition of these standard or conventional solutions is given in Table I.

Safety and Efficacy Successful PD depends on long-term preservation of the peritoneal membrane; however, long-term PD has deleterious effects on the peritoneum that correlate with increasing small-solute permeability, as well as reduced UF capacity and residual renal function (RRF). The observation that these changes occurred under chronic exposure to conventional PD solutions has led to the conclusion that the bioincompatible composition of conventional PD solutions might be responsible for these adverse effects.8,9 In particular, concerns that relate to extended exposure to glucose have arisen with the use of these solutions. Glucose exposure can increase caloric load and insulin secretion.10 It is absorbed relatively quickly, leading to dissipation of the osmotic gradient and loss of UF.11 DOI: 10.1002/dat.20601

TABLE I. Typical composition of conventional PD solutions. Component

Concentration

Electrolytes Sodium

132–134 mEq/L

Potassium

None

Calcium

1.5–3.5 mEq/L

Chloride

95–102.5 mEq/L

Magnesium

0.5–1.5 mEq/L

Buffer Sodium lactate

New Biocompatible Solutions 35–40 mmol/L

Osmotic agent Dextrose (glucose monohydrate)

This high rate of peritoneal absorption can precipitate hypertriglyceridemia, hyperinsulinemia, obesity, and significant fluctuations in blood glucose levels.12,13 High glucose concentrations have been shown to be toxic to peritoneal cells and to affect phagocytic responses adversely.14 Glucose is also the precursor of bioincompatible glucose degradation products (GDPs).15 Studies have shown that GDPs have even a higher toxic potential than pure glucose16,17 and that they are important catalysts for the formation of advanced glycation end products (AGEs). In vivo studies found a significant increase in the levels of AGEs in the myocardium and aorta of rats, as well as higher oxidative stress and increased apoptosis.18 The authors concluded that systemic GDPs can cause toxicity in cardiovascular tissues. AGEs (specifically carboxymethyl lysine [CML] and pentosodine) were also detectable by immunohistochemistry in the fatty streaks and proliferative intima of arteries from patients with diabetic nephropathy19 and in the intramyocardial blood vessels of patients who experienced a myocardial infarction (MI).20 In vitro, ex vivo, and in vivo animal data have also indicated that conventional PD fluids negatively impact host defense mechanisms and have a profibrotic effect on the peritoneal membrane.21,22 These studies have been corroborated clinically: longterm exposure to conventional PD solutions has produced negative histopathological changes in the peritoneal membrane that include loss of the mesothelial monolayer,

adverse outcomes over time. This is mostly due to the combination of glucose as an osmotic agent and suboptimal manufacturing compromises, which lead to high concentrations of toxic GDPs in an acidic PD solution. Since glucose absorption occurs rapidly during a dialysate dwell, UF is suboptimal during long dwells, especially in patients who are high or high-average transporters.32

1.5–4.25%

thickening of the submesothelial compact collagenous zone, neovascularization, and additional vascular changes including subendothelial hyalinization of post-capillary venules, with accompanying obliteration or narrowing of the vascular lumen.8,23 Most of these bioincompatible effects appear to be due to the acidic pH and high concentrations of GDPs of the standard solutions following heat sterilization or periods of extended storage.16,17,24-28 Sterilization of glucose-containing PD solutions in buffer at a pH of 5.5, which is typical for conventional standard solutions, unfortunately is far from optimal and leads to a significant amount of GDPs.29,30 Data suggest that the acidic pH that is a feature of all conventional and some new solutions has toxic effects. Investigating the cytotoxicity of different components of standard PD solutions, Wieslander showed that a pH of 5.5 inhibited cell growth to 100%, while lactate at neutral pH had no significant adverse effect.16 Other clinical symptoms such as increased peritoneal permeability, induction of oxidative stress, and infusion pain have been associated with low pH solutions. However, it is difficult to say to what extent these effects can be attributed to pH alone, or may be partly due to a combination of low pH and other bioincompatible components such as buffer base, GDP and AGE content, osmolality, or choice of osmotic agent.31

Limitations In general, standard PD solutions have unfavorable characteristics that may lead to

Compared with conventional PD solutions, new biocompatible solutions consist of the same basic components—buffer, electrolytes, and an osmotic agent. In general, the electrolyte composition is similar to that of conventional solutions. Innovations include the use of alternative osmotic agents, buffer substances and advanced manufacturing practices that lead to low GDP concentrations and neutral pH. The new more biocompatible solutions are not uniform but represent a whole spectrum of different solutions with distinct combinations of the innovations described.

New Osmotic Agents New solutions can contain glucose or an alternative osmotic agent in the form of polyglucose (icodextrin [Extraneal]) or amino acids (Nutrineal). Icodextrin. Currently in the United States, polyglucose is available as an alternative to glucose as an osmotic agent. The polyglucose polymers are of varying lengths and are derived from corn starch.33 The solution has a pH of 5.5-6 and contains 7.5% polyglucose (MW 15-17 kDa), sodium (133 mEq/L), calcium (1.75 mEq/L), magnesium (0.5 mEq/L), chloride (96 mEq/L), and lactate (40 mEq/L) as the buffer. Thus, although icodextrin is considered a biocompatible solution, it still has a relatively acidic pH. The use of polyglucose circumvents the issue of fast absorption of glucose experienced with conventional solutions. Absorption of polyglucose is slower than that of glucose, making it more suitable for long dwells. The International Society of Peritoneal Dialysis (ISPD) Ad Hoc Committee on Ultrafiltration Management in Peritoneal Dialysis recommended that icodextrin be used for the long dwell (13-15.5 hours) in August 2011 Dialysis & Transplantation 357

PD Solutions

high transporter patients with a net peritoneal ultrafiltration of less than 400 mL/ 4 h34; this long dwell may be at night in continuous ambulatory PD (CAPD) patients or during the day in continuous cycling PD (CCPD) patients. However, a considerable amount of polyglucose is absorbed during long dwells. The absorption rate of polyglucose has been reported to be 14.4% at 6 hours and 28.1.% at 12 hours.35,36 In a single-dose pharmacokinetic study using icodextrin (n ⫽ 13), a median of 40% (60 g) of the instilled icodextrin was absorbed from the peritoneal solution during a 12-hour dwell. Reduction of volume overload due to increased UF has been shown in several studies. A recent study by Cho et al. demonstrated that there was less gain in body weight between CAPD patients on polyglucose versus conventional PD solutions over a 3-year period, indicating a positive effect on water removal.37 Takatori et al. conducted a randomized controlled study on 41 patients with diabetic nephropathy and end-stage renal disease. Patients were randomized to 8 L of 1.5% or 2.5% glucose solution or to 1.5 or 2.0 L of 7.5% icodextrin-containing solution.38 Their results demonstrated that technique survival was 71.4% in the icodextrin group compared to 45.0% in the glucose-containing group, with most of the technique failure due to volume overload. Declines in urine volume and RRF were not significant, even though they appeared to be greater in the icodextrin group. The labeled use of icodextrin is limited to a single exchange in each 24-hour period. The recently published Canadian Society for Nephrology Guideline on peritoneal adequacy mentions that use of icodextrin twice daily may be safe and may enhance UF in patients with evidence of UF failure, but that these strategies require further research.39 However, this suggestion was based on three small, low-powered studies.40-42 Another study by Jeloka et al. showed that UF does not increase after a 10-hour dwell with icodextrin.43 Based on this, Dousdampanis and colleagues hypothesized that two 8-hour exchanges with icodextrin could produce more UF than a single 15-16hour exchange.44 In their study (n ⫽ 9), they stated that none of the parameters tested were significant and that caution 358 Dialysis & Transplantation August 2011

should be exercised when using twicedaily icodextrin as RRF may decrease due to increased peritoneal UF, there may be increased inflammatory responses as well as increased cost and there may be possible long-term effects of glucose polymer and maltose accumulation.45 Due to the potential risks of increased icodextrin dose, we certainly agree that further longterm controlled studies and regulatory assessment to establish efficacy and safety are required before recommending the use of twice-daily icodextrin. Amino acids. Another alternative to glucose as an osmotic agent is amino acids, available commercially as Nutrineal (pH ~6.7), although not in the United States. Use of amino acids as an osmotic agent was initially proposed by Gjessing.46 Oreopoulos and colleagues studied the effects of amino acid-containing solutions in an attempt to reduce amino acid losses from the peritoneal effluents and prevent hypertriglyceridemia and obesity.47,48 These early studies suggested that amino acids could be potential osmotic agents without interfering with nitrogenous waste removal. Increased levels of albumin, pre-albumin, and transferrin have been observed after 1-3 months of treatment with amino acid dialysate in hypoalbuminemic PD patients. 49 Studies have shown that 80-91% of the amino acids in 1.1% amino acid dialysate could be absorbed across the peritoneum, which resulted in improved serum amino acid profile and protein synthesis.50,51 However, the observation that single amino acid levels, such as methionine, increase up to threefold might affect the normal ration of essential and non-essential amino acids. This might impair the nitrogen balance, which is highly dependent on a normal ratio of essential and non-essential amino acids in the plasma.54-56 To date, only one randomized, prospective, controlled trial has investigated the long-term effects of amino acid dialysate in CAPD patients.52 In this 3-year study, 60 malnourished Chinese CAPD patients were randomly assigned to replace one daily exchange with the amino acid dialysate or to continue with the dextrose dialysate. While total and oral caloric intake decreased with time in both treatment groups, dietary protein intake increased

after 6 months in the amino acid group, although the between-group difference did not reach statistical significance. However, patients on amino acid dialysate showed higher serum albumin and cholesterol concentrations. Of note, the authors state that L-methionione levels were as high as in the study by Brulez et al., which might potentially induce an adverse increase in plasma homocysteine levels.51 In addition, significant and progressive increase in blood urea nitrogen (BUN) concentrations and the possible development of clinical metabolic acidosis have been observed with the use of amino acidcontaining PD solutions.47,53-56 Glucose-based biocompatible solutions. New glucose-based biocompatible solutions are available in double- or triple-chamber bags, where the glucose is separated from the buffer and electrolyte components. These include Balance, Bicavera, Gambrosol Trio, Physioneal, and Delflex Neutral pH. Delflex Neutral pH solution is the only neutral-pH biocompatible solution approved by the U.S. Food and Drug Administration (FDA), but it is not yet available in the United States.30,57 In these solutions, the buffer consists of lactate and/or bicarbonate. The pH of the glucose-containing compartment is very low, ideally about 2-3, allowing for the separate sterilization of glucose at a low enough pH such that GDP generation is minimized.58 Keeping the electrolytes in the acid compartment prevents precipitation of calcium and magnesium. The buffer, electrolytes, and glucose are mixed prior to use, resulting in a final solution consisting of an ultralow GDP concentration at neutral pH. The compositions of the various commercially available biocompatible solutions are given in Table II. Although the GDP content of these new solutions is much lower than in the conventional ones, there is still much variability among them. Recently, we and others compared the monocarbonyl, dicarbonyl, and total GDP content among these newer biocompatible PD solutions.57,59 Delflex Neutral pH, Balance, Bicavera, and Gambrosol Trio exhibited similar low total GDP concentrations, while that of Physioneal was considerably higher. Compared with glucose-based low GDP solutions, the total amount of GDPs in Extraneal, being a polyglucose solution,

TABLE II. Composition of new/biocompatible solutions.a Vol. (L)

Osmotic Agent

2

1.5 2 2.5 3

Bicavera

2

1.5 2 2.5 3

Extraneal (icodextrin)

1

2 3

Gambrosol Trio 10b

3

Solution

Chambers

Balance

Gambrosol Trio 40b

Strength (%)

Buffer

pH

Na+

Ca2+

Mg2+

Cl–

Glucose

1.5 2.5 4.25

Lactate (35)

7.0

134

1.25 1.75

0.5

101.5, 100.5

Glucose

1.5 2.5 4.25

Bicarbonate (34 or 39)

7.4

134

1.75

0.5

104.5

Polyglucose

7.5

Lactate (40)

5.0–6.0

132

1.75

0.25

96

2 2.5 3 5

Glucose

1.5 2.5 3.9

Lactate (39-41)

5.5–6.5

133

1.79

0.26

96.2

1.38

95.4

Physioneal

2

1.5 2 2.5 3 4.5 5

Glucose

1.5 2.5 4.25

Lactate (10 or 15) and Bicarbonate (25)

7.4

132

1.25

0.25

95

Nutrineal

1

0.5, 1, 1.5 2 2.5 3

Amino acids

1.1

Lactate (40)

6.7

132

1.25

0.25

105

Delflex NpHc

2

2 3

Glucose

1.5 2.5 4.25

Lactate (31.5 or 36.5) and Bicarbonate (3.5)

7.0 ± 0.4

132

1.25 1.75

0.25, 0.75

95, 96, 102

aStrength

is presented as percent monohydrous glucose. Buffer and electrolyte concentrations are presented in mmol/L. electrolyte concentrations for the Gambrosol Trio 1.5% solutions. cFDA approved but not yet available. bShows

was slightly lower than that in the 4.25% glucose solution, but higher than in the 1.5% and 2.5% glucose solutions. Extraneal additionally showed a different GDP distribution pattern compared with the twochamber bag glucose solutions due to the sterilization in a single-chamber bag at higher pH.

Does Biocompatibility Make a Difference? Several studies have been performed that strongly support the use of new biocompatible solutions. Accumulating data from in vitro, ex vivo, and in vivo animal data have generally shown that use of newer biocompatible PD solutions results in sig-

nificant changes in effluent markers suggestive of improved membrane integrity.60 These studies have demonstrated improved leukocyte and macrophage cell function, improved cell viability and function, stabilization of peritoneal hemodynamics, reduced angiogenesis, reduced fibrosis, reduced bacterial survival, and reduced plasma AGE levels.61-68 Zeier et al. showed that in PD patients GDPs are absorbed from the dialysate during PD and that plasma AGE concentration (fluorescence and plasma CML concentration) was significantly higher after treatment with conventional standard versus biocompatible glucose solutions.69 The question of how strongly lower systemic levels of toxic GDPs and AGEs

impact patient outcomes has not yet been finally answered due to the lack of highly powered prospective randomized controlled trials (RCTs) regarding long-term patient survival. However, the majority of trials covering various clinical aspects and outcomes seem to strongly indicate the benefit of the new solutions. The available data pertaining to specific clinical outcomes are summarized below.

Peritonitis Reduction in peritonitis rates has not been proved in prospective, randomized trials. Recent studies have reported mixed results. In a retrospective study, Furkert et al. determined that the use of low-GDP dialysis solutions resulted in significantly lower August 2011 Dialysis & Transplantation 359

PD Solutions rates of peritonitis (p ⫽ 0.002) and exit-site infections (p ⫽ 0.02).70 Patients on the biocompatible solutions experienced one peritonitis/exit-site infection in 48/34 months compared with one in 20/23 months on the standard solutions. Analysis of 121 peritonitis cases in one hospital during 2002–2005 also identified a lower peritonitis rate in patients treated with a biocompatible solution compared with standard solutions (one episode per 52.5 patient months versus one episode per 26.9 patient months).71 These results were supported by a study by Montenegro et al. in another retrospective study showing that use of a low-GDP, pH-neutral bicarbonate solution was associated with significantly lower peritonitis rates, i.e., one episode per 36 patientmonths versus 21 patient months with the lactate dialysis fluid (OR 0.58, 95% CI 0.37-0.91, p ⫽ 0.017).72 However, other studies with low-GDP solutions did not show any difference in peritonitis rates.73,74 A major limitation of some of these studies is that they were not adequately powered to detect a significant effect of the new solutions on peritonitis rates due to the infrequent rates of peritonitis in that particular population of patients, short observation periods, and small numbers of patients.

Preservation of the Peritoneal Membrane Evidence describing clinical experiences with newer PD solutions supports less inflammation and better peritoneal mesothelial mass preservation.75 Also, there are some data to suggest stabilization of peritoneal transport rates with some biocompatible solutions.76 Two prospective, randomized studies using a bicarbonate and lactate-based glucose solution instead of a standard lactate PD solution resulted in decreased interleukin-6 (IL-6) levels in the dialysate.77,78 In contrast, the use of polyglucose solution was shown to increase dialysate levels of IL-6.79 Other studies have demonstrated reduced intraperitoneal hyaluronan levels with the use of newer, more biocompatible solutions, suggesting reduced irritation of the peritoneal membrane.73,74,80,81 In vitro tests as well as clinical trials in PD patients using newer PD solutions have shown increased concentration of cancer antigen 125 (CA125) in effluent 360 Dialysis & Transplantation August 2011

fluid. Although the clinical significance of CA125 is not entirely clear, it is likely that CA125 levels reflect mesothelialcell mass and intact peritoneal membrane function; thus, increased levels may indicate better preservation of the peritoneal membrane. 37,79,80-84 With respect to peritoneal transport, the effect of newer PD solutions is less clear. Stabilization of peritoneal transport rates was shown in CCPD patients with RRF using a daytime polyglucose exchange, but there was no statistically significant difference from the patients who used standard solutions for the daytime exchange.85,86 The prospective European Automated Peritoneal Dialysis Outcomes Study (EAPOS) showed that polyglucose solution slows the development of high peritoneal membrane permeability in anuric patients.87 This study, however, was not randomized. Other studies with newer, biocompatible PD solutions showed no advantage over conventional solutions in relation to peritoneal membrane transport.80,81,88

Preservation of RRF The randomized, crossover EuroBalance trial (n ⫽ 71, 22 centers) showed that use of biocompatible PD fluids compared with conventional solutions resulted in better preservation of RRF (increased urine volume and urine creatinine clearance) and lower levels of circulating AGEs.74 At the same time the gain in RRF was accompanied by less peritoneal UF. A study by Fan et al. failed to show any change in rate of decline in RRF with low-GDP solutions, but the analysis of this study was underpowered (inadequate numbers of patients) to detect a clinically significant difference in change in RRF.89 Another potential issue in this study was the inclusion of patients on Physioneal (~85%) in the biocompatible group. Physioneal contains considerable amounts of 3,4-DGE (11 µM), the most toxic and biologically active GDP present in PD compared with other new, biocompatible solutions.57,90 Several studies in Korea have examined the effects of low-GDP PD solutions on residual renal function. In a randomized, intention-to-treat (ITT) controlled trial, Kim et al. reported a slower rate of decline in RRF with Balance compared with conventional solution.91 The per

protocol (PP: as treated) analysis was also consistent with better preservation of RRF using Balance, but the difference did not reach statistical significance. The authors also reported a significant preservation of renal function by ITT and PP analysis in a subset of patients whose initial glomerular filtration rate (GFR) exceeded 2 mL/min. As with the Fan study from the United Kingdom, however, the analysis was underpowered. A report from the DIUREST study group compared rate of RRF decline in patients using Gambrosol Trio solution (low GDP) with patients using standard PD fluids.92 In this multicenter approach, 80 patients were randomly assigned to treatment with either Gambrosol Trio, a multicompartment bag with minimal amounts of GDPs (3,4-DGE < 1 µM) or standard PD solutions from different manufacturers in single-compartment bags, all containing significant amounts of GDPs. Clearances were assessed at study entry and every 4-6 weeks over an 18-month study period. The final sample size was based on the possibility of showing 1 mL/min/1.73 m2/y difference between the groups in the slope of RRF decline, with a power of 0.8 and a significance level of 0.05. This prospective study demonstrated a significant effect on the preservation of RRF and urine volume of using a PD fluid with low GDP levels, suggesting that GDPs might affect patient outcome related to RRF (RRF change: ⫺1.5% [95% CI ⫽ ⫺3.07% to +0.03%] with low GDP (43 patients) versus ⫺4.3% [95% CI ⫽ ⫺6.8% to ⫺2.06%] with standard fluids [26 patients; p ⫽ 0.0437]; 24-hour urine volume: 12 [low GDP] versus 38 [standard] mL/mo; p ⫽ 0.0241]). Results from the on-going prospective randomized controlled balANZ trial are eagerly awaited. The main hypothesis of this study is that neutral pH, low-GDP PD fluid better preserves residual renal function in PD patients over time compared with conventional dialysate.28

Survival According to 2010 figures of the U.S. Renal Data System (USRDS), the adjusted rates of all-cause mortality are 6.4-7.8 times higher for dialysis patients than for individuals in the general population.93 Thus, efforts focus on improving these

rates. The use of more biocompatible dialysis solutions has been associated with better patient survival and may be due to better preservation of RRF in the patients treated with more biocompatible solutions.92 Mortality rate was shown to be significantly lower in patients who used polyglucose PD solution instead of glucose for the daytime exchange during a 2-year treatment period.95 In contrast, mortality rates were identical in malnourished Chinese patients using or not using an amino acid dialysate for 3 years.52 A large Korean study showed lower mortality rates in patients using lactate-buffered, neutral pH, lowGDP solutions compared with standard lactate solutions; furthermore, when they used a multivariate Cox regression model, including age, diabetes, and gender, the survival advantage of the more biocompatible solution persisted.96 In a 3-year prospective, albeit not randomized study, mortality was also determined to be lower with a biocompatible solution that had a pH of 7.4 and low GDP content compared with a standard dialysis solution.72 Cumulatively, these studies suggest that the newer, more biocompatible solutions may decrease mortality, but more prospective, randomized studies are required for confirmation. A large (n ⫽ 1,162) observational study in Korea also reported superior patient survival for patients treated with Balance compared with standard PD fluids.95 However, this study elicited much editorial comment, mostly justified, questioning whether the groups were adequately matched and pointing out that the superior survival was only identified for as-treated as opposed to intention-to-treat analysis. In another study from Korea, comparison of low-GDP and standard solutions also provided evidence suggesting that RRF declined less rapidly with Balance compared with standard solutions.96 However, the analysis was very underpowered and the statistical methods used for the analysis were not optimal. Han et al. also reported improved survival rates in patients treated with biocompatible PD fluids compared with conventional solutions (HR: 0.70; 95% CI: 0.50-0.98; p ⫽ 0.04).97 However, there were major study limitations including that the study was an observational retrospective analysis; there was also a lack of

laboratory data and unknown indications for use of biocompatible solution. Although the prognosis of patients with diabetes on dialysis has greatly improved, survival and medical rehabilitation rates continue to be significantly worse than for non-diabetic patients, primarily due to pre-existing, severely compromised cardiovascular conditions,98 and diabetes was shown to be independently associated with all-cause mortality in incident dialysis patients.99 The 2010 USRDS reports that among diabetic patients, the unadjusted 1-year survival in PD populations is 0.86 compared with 0.88 in non-diabetics.93 Diabetic patients on peritoneal dialysis with standard PD solutions are at an increased risk of obesity, hyperlipidemia, loss of UF, increased peritoneal membrane permeability, and overhydration compared with non-diabetics.12,13 Lee and co-workers showed that survival of diabetic patients treated with the new PD solution was identical to that of the non-diabetic patients treated with standard PD solutions, but treatment with low-GDP solutions independently reduced the relative risk (RR) of death (RR ⫽ 0.613; CI 0.50-0.74; p < 0.00001) in a proportional hazards model with age, diabetes, and center experience as variables. In a univariate analysis, the low-GDP PD solution was also associated with a longer technique survival (p ⫽ 0.049), as defined by time until change to HD censored for transplant and death, but this effect was not significant in multivariate analysis.100 Thus, the use of newer PD solutions could be beneficial in these patients, but more studies are needed for confirmation.

Conclusions Recent innovations led to a variety of new PD solutions featuring glucose or an alternative osmotic agent and bicarbonate as an alternative buffer substance in conjunction with lactate or by itself. Compared with conventional or standard solutions, the level of toxic GDPs has been decreased substantially, and some new solutions additionally offer a neutral pH. This is without doubt a good development. How important these improvements will ultimately be for hard clinical outcomes is still a matter for controversial discussion. The in vitro and

pre-clinical data are most encouraging and indicate significant progress regarding the better biocompatibility of low-GDP solutions. The evidence from clinical studies is diverse, and its interpretation is complicated by many confounding factors pertaining to each trial. However, the balance of evidence, specifically in regard to the preservation of residual renal function, seems most suggestive of a real clinical benefit for some of the new biocompatible solutions. D&T

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