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http://www.kidney-international.org & 2007 International Society of Nephrology
Update on peritoneal dialysis solutions CW McIntyre1,2 1
Division of Vascular Medicine, School of Medical and Surgical Sciences, University of Nottingham Medical School, Derby, UK and 2Department of Renal Medicine, Derby Hospitals, NHS Foundation Trust, Derby, UK
Since the widespread introduction of peritoneal dialysis (PD) into the standard care of patients with chronic kidney disease there has been a shift from the initial focus on technique survival to refinement of the therapy to enhance biocompatibility and improve both the local peritoneal and systemic consequences of PD. One of the most significant contributions to these advances has been the development of novel PD solutions. The use of new manufacturing techniques, buffer presentation, and new osmotic alternatives to glucose have allowed potentially improved peritoneal survival (in terms of structure and function) and improved subjective patient experience. Additional benefits have also included, enhanced management of salt and water removal, supported nutritional status and improvement in the systemic metabolic derangements associated with conventional PD treatment, based on glucose-containing lactate-buffered solutions. The selection of suitable targets for modulation of therapy continues to be hampered by our continued relative ignorance of the local and particularly systemic effects of PD compounded by the dearth of quality, outcome-based studies. The aim of this review is to summarize the characteristics of the next generation of PD fluids currently available, and then to evaluate their possible place in treatment by considering the difference in their effects in a series of structural and functional areas potentially relevant to improving patient outcomes. Kidney International (2007) 71, 486–490. doi:10.1038/sj.ki.5002109; published online 14 February 2007 KEYWORDS: chronic kidney disease; peritoneal dialysis; glucose degradation products; glucose; AGEs
Correspondence: CW McIntyre, Department of Renal Medicine, Derby City General Hospital, Uttoxeter Road, Derby, UK. E-mail:
[email protected] Received 24 May 2006; revised 11 December 2006; accepted 12 December 2006; published online 14 February 2007 486
NEW PD SOLUTIONS
The choices made in the design of conventional peritoneal dialysis (PD) fluids were based on attempting to mimic normal plasma, tempered by a series of compromises to allow production, and ultimate stability under storage conditions of the fluids. These imperatives resulted in glucose being used as the main osmotic agent, buffered with lactate alone (to produce a low pH). This allowed sterilization of the fluids by heat and avoid caramalization of the glucose. The use of glucose in PD fluid (and in particular the higher concentrations required to provide enhanced ultrafiltration) has direct deleterious effects on peritoneal structure (diabetiform change)1,2 and function. Low pH results in increased infusion pain3 and directly effects neoangiogenesis and mesothelial cell damage.4 In combination with the commercial manufacturing process these factors also result in the production of glucose degradation products (GDPs).5 These possess welldefined local toxicities to the peritoneal membrane and are also systemically absorbed (with a range of currently inadequately defined biological effects). GDPs also enhance the local and systemic production of advanced glycation end products by the reaction of the aldehyde form of glucose, in the presence of amines or proteins, to produce Amadori glycosolation products.6 Advanced glycation end product accumulation has been implicated in the development of structural damage of the peritoneum and vasculature.7 The newer generations of PD solutions have sought to utilize more physiological intraperitoneal pH, and reduce GDP production by a combination of this reduced pH with improved manufacturing and product presentation. The choice of glucose alternatives further reduces the potential to generate GDPs. Enhanced biocompatibility is achieved to varying degrees depending on the approaches used. The avoidance of hypertonic glucose itself has emerged as a therapeutic aim for both local peritoneal and systemic exposure reasons. The use of alternatives that are absorbed (amino acids) has also been developed to enhance nutrition in depleted patients. There are two main groups of products currently commercially available. Multibag systems separate out the buffer (either lactate or bicarbonate/lactate mix). This allows the glucose to be stored at a low pH and minimizes degradation during protracted storage.8 It also prevents the precipitation that would result in the mixing of a bicarbonate buffer and magnesium and calcium in solution. Both Baxter Kidney International (2007) 71, 486–490
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and Fresenius produce two bag systems resulting in a more physiological intraperitoneal pH. Physioneals fluids from Baxter utilize a lactate/bicarbonate mixed buffer (ph 7–7.4). The use of bicarbonate/lactate mix (25 mmol/l bicarbonate with 15 mmol/l lactate) was favored over pure bicarbonate buffering owing to lower infusion pain scoring.3 The Fresenius Stay Safe Balances system separates glucose and electrolytes from a lactate buffer and results in a neutral pH once mixed. The bicaVeras system utilizes a pure bicarbonate buffer (34 mmol/l), which although does not result in a more physiological pH, does avoid potentially deleterious local effects attributable to lactate. Gambro produce Gambrosol Trios (a lactate-buffered three bag system) which also separates the hypertonic glucose component, allowing a solution of differing tonicity to be mixed before use, depending on the ultimate combination of compartments performed. Although lactate buffered this still results in a higher pH than characteristically seen with earlier generation low biocompatibility solutions (pH 6.5 c.f. 5.5). There are currently no quality data comparing these newer generation of lower GDP-containing glucose-based solutions against each other in clinical practice. The second group consist of alternatives to glucose as an osmotic agent. Baxter market Extraneals (7.5% icodextrin). This contains a glucose polymer that is only absorbed after having undergone a degree intraperitoneal hydrolysis (ultimately to maltose). Currently this is buffered with lactate alone (although a lactate/bicarbonate-buffered alternative is undergoing formal clinical evaluation), and has a lower GDP content than conventional PD fluids.9 This provides an ultrafiltration capacity broadly similar to 2.27% glucose-containing solutions, but owing to a reduced back diffusion from intraperitoneal cavity into the circulation allows longer sustained ultrafiltration, particularly suited to long dwells.10 Concerns about higher levels of circulating maltose limit use of these solutions to a single daily exchange. Hypersensitivity can occur.11 Baxter also produces Nutrineals (1.1% amino-acid-containing solution). This is presented as a single bag lactate-buffered fluid (40 mmol/l) and has the equivalent ultrafiltration capacity of 1.36% glucose-containing fluids. It’s use further avoids glucose exposure, and contains no GDPs. It has been demonstrated to enhance nutrition in hypoalbuminemic continuous ambulatory peritoneal dialysis patients,12 but is also limited to single daily use owing to the potential for increased symptomatic uremia and acidosis with increased exposure.13 POTENTIAL BENEFITS OF NEW PD SOLUTIONS Local peritoneal effects
The majority of direct toxicity to the peritoneum appears to be attributable to GDPs rather than pH, lactate, osmolality, or glucose per se. A variety of GDPs are characteristically formed but they appear to have differing toxic potential.14 Mesothelial toxicity is attributable both directly to GDPs and as a result of local advanced glycation end product formation.15 advanced glycation end products accumulate Kidney International (2007) 71, 486–490
in the peritoneal membrane and contribute to angiogenesis and subsequent diabetiform change.16 Use of low GDPcontaining solution (Fresenius Balances) was associated with improved viability and proliferation of mesothelial cells, as evidenced by increased levels of Ca-125 and fibronectin in peritoneal effluent, in medium comparative study against conventional PD fluids.17 Experimental data also suggest that lower GDP-containing solutions are associated with improved mesothelial-based healing.18 Similar effects have also been reported with other low GDP-containing glucose-based fluids. Extraneals usage compared to higher hypertonic glucose exposure has also been demonstrated to be associated with improved preservation of peritoneal function.19 Nutrineals has been inadequately evaluated in man in this respect, but some data exist that suggest that it has a similarly protective effective on the peritoneum.20 Low GDP-containing solutions also appear to reduce intraperitoneal inflammation21 and be associated with better maintenance of macrophage function. Whether or not these effects are associated with reduced peritonitis rates is still awaiting robust randomized controlled trial-based study. However data from registry sources suggests that peritonitis rate was significantly reduced in patients receiving Physioneals compared to standard PD solutions.22 Use of Physioneals is certainly associated with reduced infusion pain3 and improved sleep when used as a part of an automated PD regimen.23 SYSTEMIC EFFECTS Salt and water removal
The adequate control of total body water and sodium are key therapeutic targets for effective renal replacement therapy. Failure to do so leads to hypertension and chronic volume overload. These effects on left ventricular mass have been well established as being an independent cardiovascular risk factor in this patient group.24 The two key elements to achieving this in PD patients are the effects of the dialysis solution itself on sustained ultrafiltration, and any effects on the maintenance of residual renal function (RRF) (Tables 1 and 2). The use of icodextrin-based fluids is associated with an improved fluid status in prospective study.25 Extracellular water and total body water were better controlled compared to patients relying exclusively on the use of high glucose concentration fluids. Icodextrin was also associated with better maintenance of residual urine output. Earlier reports that icodextrin use is associated with a more rapid loss of RRF appear to be owing to the effects of inappropriate fluid reduction in a small sub group of patients, resulting in a clinical underhydration.26 Icodextrin use is also associated with an increased mass transfer area coefficient and an increased convective contribution to small solute and free water removal.27 Low sodium dialysate, to enhance diffusive removal, is currently under evaluation. Results are not yet available form this therapeutic approach. Initial study of bicarbonate/lactate-buffered PD solutions suggested that net ultrafiltration at peritoneal equilibration 487
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Table 1 | Summary of the characteristics of currently widely available multibag PD solutions Manufacturer
Potential drawbacks
Potential benefits
Lactate buffered Balances Gambrosol Trios
Fresenius Gambro
More physiological pH, but not neutral Local and systemic glucose exposure
Lactate/bicarbonate buffered Physioneals
Baxter
Local and systemic glucose exposure Does not eliminate peritoneal lactate exposure
Bicarbonate buffered BicaVeras
Fresenius
Local and systemic glucose exposure
Lower GDP levels More physiological pH Improved peritoneal membrane biocompatibility Preserved membrane defence Lower GDP levels More physiological pH Improved peritoneal membrane biocompatibility Preserved membrane defence Reduced infusion pain Lower GDP levels More physiological pH Improved peritoneal membrane biocompatibility Preserved membrane defence Improved correction of acidosis
GDP, glucose degradation product; PD, peritoneal dialysis.
Table 2 | Summary of the characteristics of currently widely available single bag PD solutions Manufacturer
Potential drawbacks
Potential Benefits
Lactate-buffered glucose containing Dianeals
Baxter
Ease of manufacture Low cost
Icodextrin-containing Lactate buffered
Baxter
Low pH High GDP content Poor peritoneal membrane biocompatibility Infusion pain Local and systemic glucose exposure Hypersensitivity Low pH Licensed for single daily use only Lactate containing
Amino-acid containing Nutrineals
Baxter
Low pH Licensed for single daily use only (avoid exacerbation of uremic symptoms and acidosis)
Sustained ultrafiltration Preservation of RRF Hypertonic glucose replacement Reduced hyperglycemia Improved short term systemic hemodynamic profile Desirable effects on metabolic profile and body composition No GDPsAvoid systemic and peritoneal glucose exposure Peritoneal membrane protection Enhance nutrition
GDP, glucose degradation product; PD, peritoneal dialysis; RRF, residual renal function.
test after 6-month follow-up was higher than with conventional-buffered glucose-containing fluid usage.28 A combination of bicarbonate/lactate-buffered solutions with icodextrin and amino-acid-containing fluids, when studied against conventional fluids, resulted in a lesser reduction in residual creatinine clearance, after 6 months of use. However this effect on RRF was not seen consistently throughout all components of the study, and some differences in RRF between the groups did exist on inclusion. The overall effects of fluid biocompatibility c.f. glucose exposure reduction is not possible to determine from this study.29 The GDP, 3,4dideoxyglucosone-3-ene is toxic to cultured tubular cells at biologically relevant concentrations,30 and this may be a potential mechanism in RRF loss. Metabolic effects and cardiovascular risk modification
Other than the modulation of overall hydration, the effects that PD fluids are capable of having beyond the membrane are largely determined by the absorption of the osmotic agent (glucose or amino acids) and the systemic exposure to GDPs. 488
These effects result in profound metabolic, body compositional, lipid, endocrine, and cardiovascular structural/ functional perturbations. Metabolic effects
Intraperitoneal glucose exposure is associated with poorer glycemic control in diabetic continuous ambulatory peritoneal dialysis patients. Substitution of glucose-based conventional fluids for a regimen based on bicarbonate/lactate buffered 1.36% glucose, icodextrin and amino-acid-based solutions resulted in improved blood glucose levels and a reduction in hyperglycemic excursions. The use of similar glucose exposure in a more biocompatible Physioneals format c.f. standard solutions was also associated with a small improvement in mean blood glucose levels.31 The mechanisms for this are unknown. Intraperitoneal glucose exposure results in significant amounts of absorption. This results in loss of the osmotic gradient (with impaired ultrafiltration). Furthermore higher glucose concentration use also results in hyperglycemia with Kidney International (2007) 71, 486–490
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associated hyperinsulinemia (even in non-diabetic patients).32 Hyperinsulinemia is a well-recognized additional cardiovascular risk factor. It is also associated with systemic cardiovascular functional changes and results in increased stroke volume with a significant hypertensive response. These changes seen with hypertonic glucose are not related to alterations in cardiac filling.33 In the longer term the increased carbohydrate load also predisposes to abnormalities of lipid metabolism, and increased insulin resistance. The substitution of hypertonic glucose with icodextrin appears to be capable of ameliorating these effects.34 Body composition
Use of higher concentrations of glucose in PD regimens is associated with an increase in drained body weight, as a result of increased fat mass.25 Avoidance of hypertonic glucose, with substitution by either icodextrin or amino-acid-based PD fluids, has been reported to abrogate most of these effects. Patients with chronic kidney disease exhibit muscle wasting,35 and this is associated with poorer long-term outcomes. PD patients exhibit greater degrees of muscle mass loss over a 12 month follow-up period than chronic kidney disease 4 or established hemodialysis patients of similar dialysis vintage.36 Furthermore, initiation of dialysis with PD resulted in a greater incremental decline in functionally significant muscle mass than those commencing hemodialysis. Patients with PD regimens with a higher exposure to glucose had proportionately more muscle wasting and increased fat accumulation than those with lower weekly glucose exposure. This may be as a result of altered intramuscular insulin-like growth factor signalling in the setting of hyperinsulinemia. Whether or not this is amenable to glucose substitution awaits further prospective study. Amino-acid-containing PD solution usage increases muscular amino-acid utilization37 and is related to an increase in serum albumin, in short to medium term study of hypoalbuminemic PD patients.38 Whether or not this is capable of meaningfully retaining muscle mass and improving outcomes in malnourished PD patients has not been directly studied. Cardiovascular structure and function
The undesirable cardiovascular status of PD patients is further worsened by a deleterious increase in serum leptin and relative reduction in adiponectin.39 These are modulated by visceral fat in particular, but significant changes occur early after therapy initiation before significant changes in body composition.40 In vitro work has suggested that high glucose PD fluids are capable of directly modulating adipokine release from adipocytes41 and use of glucose-free alternatives may modulate these levels in vivo.42 Vascular calcification is increasingly appreciated as being an important driver of cardiovascular mortality in chronic kidney disease patients. PD is associated with a lower calcification burden as compared with matched hemodialysis patients.43 Indeed progression over a 1-year period was Kidney International (2007) 71, 486–490
similar to that seen in chronic kidney disease 4 patients, and significantly less than those on hemodialysis. These changes in peripheral vascular calcification were proportional to changes in arterial stiffness over the corresponding period.44 Multivariate assessment of the factors associated with the change in calcification score revealed that not only dialysis modality was important, but also a maintained ability to eliminate calcium. Maintenance of RRF and sustained peritoneal removal of calcium (highly dependant on ultrafiltration volumes) may be important.45 Use of icodextrinbased fluids may have an advantage in this respect over conventional choices. Serum phosphate is also a major risk factor in the development of arterial calcification. Provision of dietary protein with intraperitoneal amino acids (around 30% of daily requirement), without the delivered phosphate load attendant with oral complex protein may also be potentially significant.46 The systemic effects of absorbed GDPs are largely unknown. They appear to have some ability to modulate cardiovascular performance though. Our group has demonstrated significant differences in the cardiac output changes associated with PD exposure to 3.86% glucose dependant on the biocompatibility of the fluid presentation. No differences in venous bicarbonate were observed. GDP content was therefore the only significant differences between the two phases of study.33 The clinical significance of these observations is still to be determined. CONCLUSION
Registry-based study does suggest survival benefit associated with the use of low GDP biocompatible glucose-based solutions.47 There are a plethora of peritoneal and systemic structural, metabolic, and functional abnormalities that are related to the use of conventional fluids. Many of these adverse profiles can be addressed by the use of some or all of the expanding range of PD fluids. Potentially the optimal therapeutic approach may involve the combination of a variety of products, to gain the maximum potential benefits of high biocompatibility and maximum glucose substitution. The evidence is compelling that there are clear benefits for the patient. The major barrier to more widespread adoption of the current generation of PD fluids is related to increased acquisition costs. The difficult choices that health-care providers need to make are severely hampered by the lack of quality prospective outcome-based studies of these solutions directly compared to conventional glucose/lactate-based products. The design and execution of such appropriately powered hard outcome-based studies remains an urgent priority. REFERENCES 1. 2.
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