Peritoneal dialysis solutions

INTRODUCTION — Although the ancient Egyptians were the first to describe the peritoneal cavity in approximately 3000 BC, the concept of peritoneal dialysis is relatively new. In the late 19^th century, Wegner, a German investigator, was the first to use peritoneal solutions in animals; he reported that hypertonic solutions increased in volume when injected into the peritoneal cavity. Additional investigations found that hypertonic solutions increased and hypotonic solutions decreased peritoneal fluid volume [1].

Various different investigators subsequently evaluated the efficacy of treating uremia by instilling fluids into the peritoneal cavity:

●Gantar instilled saline solution in the peritoneal cavity of uremic guinea pigs and subsequently treated a uremic woman with peritoneal dialysis solution containing saline.

●Heusser added dextrose to the peritoneal dialysis solution to improve ultrafiltration.

●In 1938, Rhoads added lactate to the peritoneal dialysis fluid to correct acidosis.

Several peritoneal dialysis solutions were subsequently used in the management of uremic patients. Besides saline, they included glucose solutions, gelatin, xylitol, sorbitol, mannitol, glucose polymer (eg, icodextrin), amino acids, and many other agents [2-5].

The Dan Baxter Company made the first commercial dialysis solution available in 1959. Subsequently, there has been very little change in the basic composition of these solutions. A review of peritoneal dialysis solutions will be presented in this topic review.

IDEAL SOLUTION — Peritoneal dialysis solutions consist of water, osmotic agents, electrolytes, and minerals and are sometimes fortified with different substances. An ideal solution should [6]:

●Have a sustained and predictable solute clearance with minimal absorption of the osmotic agents

●Provide deficient electrolytes and nutrients if required

●Correct acid-base problems without interacting with other solutes in the peritoneal dialysis fluid

●Be free of and inhibit the growth of pyrogens and micro-organisms

●Be free of toxic metals

●Be inert to the peritoneum

CONSTITUENTS — Peritoneal dialysis solutions have not significantly changed since they were made available commercially in 1959. The earlier solutions were packaged in glass bottles, but they are currently available in several sizes of collapsible plastic bags. The constituents can be broadly divided into osmotic agents, buffers, and electrolytes [7].

Osmotic agents — Fluid removal is essential in dialysis patients. Osmotic agents, being hyperosmolar, allow net water removal by altering the osmotic pressure gradient between the peritoneal dialysis solution and plasma water (see "Mechanisms of solute clearance and ultrafiltration in peritoneal dialysis"). The initial peritoneal dialysis solutions were saline solutions, but, since the 1940s, dextrose has been commonly used as the osmotic agent. Several investigators have attempted to use other osmotic agents in peritoneal dialysis solutions but have been unable to show any better overall performance.

Properties of an ideal osmotic agent include the following:

●Metabolized easily with nontoxic degradation products

●Poorly absorbed

●Inert and nontoxic to the peritoneal membrane

●Inexpensive

●Effective osmotic agent at low concentration

●No metabolic consequences of absorption

●Must be of nutritional value if absorbed

●Not difficult to manufacture

●Should not inhibit peritoneal defenses

The two major types of osmotic agents that are used in peritoneal dialysis are generally classified as agents with high or low molecular weight.

High-molecular-weight agents — High-molecular-weight agents, such as glucose polymers, polypeptides, dextran, gelatin, and polycations, range in weight from 20,000 to 350,000 DA. With these agents, a high concentration is required to produce an osmolar gradient, which could lead to hyperviscosity, thereby affecting dialysis inflow and outflow.

Glucose polymer-containing solutions (icodextrin) — Glucose polymers (eg, icodextrin) are mixtures of oligo/polysaccharides of variable chain lengths. Initially, low-molecular-weight oligo/polysaccharides with weights of approximately 900 DA were tried with limited success. Larger molecules with weights of 20,000 DA have been introduced in Europe [8]. Icodextrin dialysate (Extraneal) is the major glucose polymer utilized in peritoneal dialysis.

Glucose polymers were introduced to replace glucose-containing solutions by offering the possible advantages of decreased absorption of solute and increased ultrafiltration for a longer period of time.

The use of a glucose polymer as an osmotic agent is particularly appealing as a substitute for glucose solutions, particularly in diabetics, in those who require long dwell, and in patients whose ultrafiltration capacity may need to be enhanced [9-12]. The reduced carbohydrate load also may provide some long-term metabolic advantage. This was suggested by one randomized, controlled trial in which 251 diabetic patients were assigned to a control group (dialyzed using standard dextrose solution) or to a low-dextrose treatment group (dialyzed using a combination of dextrose-based solutions, icodextrin, and amino acids) [13]. At six months, by intention-to-treat analysis, the mean glycated hemoglobin (HbA1C) was improved in the treatment group but not in the control group, with a resulting 0.5 percent difference between groups (95% CI 0.1-0.8). There were also improvements in serum triglycerides, very-low-density lipoprotein (VLDL), and apolipoprotein B in the treatment, but not control, group.

However, there were more deaths and serious adverse events in the treatment group, many of which were related to volume overload. There were 5 deaths in the control group and 11 in the intervention group. These data suggest that, although low-dextrose dialysate may improve metabolic parameters, volume status should be followed closely.

The most commonly used glucose polymer is a 7.5 percent solution. The blood concentrations of maltose, maltotriose, and other oligo/polysaccharides have been shown to increase with these agents, possibly resulting in adverse reactions. Several studies, for example, have reported a relatively high incidence of cutaneous reactions (approximately 15 percent) [14].

The reported incidence of culture-negative peritonitis with glucose polymer solutions ranges from 9 to nearly 50 percent. This is thought to be due to contamination of some batches with a bacterial wall breakdown product, peptidoglycan. The manufacturer subsequently had a voluntary recall of the suspect batches of dialysate, with a resultant decrease in incidence of the peritonitis [15]. (See "Microbiology and therapy of peritonitis in peritoneal dialysis".)

However, a systematic review of five randomized trials (607 patients) showed no increase in the risk of peritonitis with icodextrin [16].

In addition, both icodextrin and maltose can interfere with or cause falsely elevated glucose results, possibly leading to inappropriate therapy [17-19]. Thus, the labeling for icodextrin dialysate includes a warning that "blood glucose monitoring must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose."

In one retrospective study, the use of icodextrin was associated with a lower risk of technique failure related to noncompliance and mortality [20]. In the systematic review cited above, in three randomized trials (290 patients), icodextrin did not alter risk of technique failure; however, none of the included trials were sufficiently powered to show such a difference, and the follow-up time was short [16].

Polypeptides — Polypeptides may be used as osmotic agents by the hydrolysis of a 5 percent solution of a milk protein with the enzymes trypsin and chymotrypsin [21]. Compared with a 2.5 percent glucose solution, this polypeptide solution yielded twice the ultrafiltrate volume after one hour of dwell. Furthermore, only 3 percent of the peptide was absorbed from the solution. In another study, 10 stable continuous ambulatory peritoneal dialysis (CAPD) patients received either 1 percent peptide with 1.36 percent glucose (osmolality of 381 mosmol/kg) or 2.27 percent glucose (osmolality of 404 mosmol/kg) [22]. The peptide solution was well tolerated, resulting in a similar clearance as the 2.27 percent glucose solution. Furthermore, there were no irritant effects of the peptide solution on the peritoneum, and the plasma amino acid profile was similar in both groups. Thus, short-chain polypeptides were absorbed less than glucose, and their ultrafiltration capacity was similar to 2.27 percent glucose. However, long-term studies are needed to evaluate the effects of peptide on the nutritional status of peritoneal dialysis patients.

Dextrans — Neutral dextran had been tried as an osmotic agent since the 1960s. Initially, 6 percent dextran in saline was utilized, but this concentration was unable to achieve good ultrafiltration.

A 10 percent solution provided good ultrafiltration, but 40 to 60 percent of dextran was absorbed over a six-hour dwell time [23]. Accumulation of dextran in the body can result in blockage of the reticuloendothelial system; thus, it is not considered a suitable alternative for peritoneal dialysis solutions [1].

Low-molecular-weight agents — Low-molecular-weight agents, such as dextrose (eg, glucose-containing solutions), amino acids, xylitol, and glycerol, have weights of 90 to 200 DA. Among these agents, dextrose is the most commonly used.

Glucose-containing solutions — Glucose is the most commonly utilized osmotic agent in peritoneal dialysis. It comes in three different dextrose monohydrate concentrations: 1.5, 2.5, and 4.25 percent (see below).

Glucose is not the ideal osmotic agent, because it is easily absorbed, leading to short-lived ultrafiltration. Its absorption can also lead to several metabolic complications, such as hyperinsulinemia, hyperglycemia, hyperlipidemia, and weight gain [24]. Furthermore, the high glucose concentration, low pH, and glucose degradation products (GDPs) of these solutions can affect peritoneal host defense mechanisms by inhibiting phagocytosis and bactericidal activity due in part to overall bioincompatibility [25].

Peritoneal dialysis solutions with neutral pH and low GDPs have been developed in an attempt to improve their biocompatibility [26,27]. The use of such solutions may preserve daily urine volume, though not necessarily residual kidney function [28,29]. Residual kidney function in this setting is defined as solute (eg, urea and/or creatinine) clearance.

One multicenter, randomized trial compared biocompatible dialysate with conventional dialysate among 185 peritoneal dialysis patients with residual kidney function [28]. At two years, there was no difference in the rate of decline in kidney function. However, the use of the biocompatible solution associated with a decreased risk of anuria (adjusted hazard ratio [HR] 0.36, 95% CI 0.13-0.96) and a decreased rate of peritonitis (0.30 versus 0.49 episodes per patient-year) compared with conventional dialysate.

A randomized, open-label study compared three biocompatible dialysate solutions to conventional dialysate solution among 150 incident CAPD patients [29]. At 12 months, patients who used biocompatible solutions had better preservation of daily urine volume compared with those who used a conventional dialysate solution (959 versus 798 mL/day), but there was no difference between groups in the rate of decline of residual kidney function.

One retrospective study of over 2000 patients has suggested a survival benefit associated with a neutral pH low-GDP solution [27]. Randomized, prospective studies are required to accurately determine the possible survival benefits associated with this solution [30,31].

The main advantage of dextrose is that it is cheap, safe, and easily available. Furthermore, nephrologists are comfortable using dextrose solutions as they have been in the market for a long time. To date, no other osmotic agent has proven superior to dextrose-containing solutions.

Amino acid-containing solutions — Nutrition is being increasingly recognized as an important predictor of outcome in dialysis patients [32] (see "Nutritional status and protein intake in patients on peritoneal dialysis"). Malnutrition is common in peritoneal dialysis patients [33] and has been associated with higher mortality and higher hospitalization rates (see "Patient survival and maintenance dialysis"). Whereas several factors are responsible for the low albumin levels in dialysis patients, peritoneal dialysis patients tend to lose significant amounts of protein in the dialysate. It is estimated that up to 15 g of protein and 2 to 4 g of amino acids per day may be lost [34-36].

Amino acid-containing peritoneal dialysis solutions have therefore been utilized to possibly improve nutritional status in peritoneal dialysis patients. The rationale behind this approach was that the absorbed amino acids from the peritoneal dialysis solution might help contribute to protein synthesis [37].

However, early experiences with amino acid solutions were not very successful, with little to no nutritional benefit evident in studied patients. One explanation for the lack of benefit is that earlier amino acid solutions were not well designed for peritoneal dialysis. By comparison, subsequent studies found that 1.1 percent amino acid solutions are as effective an osmotic agent as 1.36 percent dextrose solutions [38]. Such studies have also shown optimal utility when amino acids were administered with a nonprotein energy source.

The amino acid solution used in these studies was a 1.1 percent solution of a combination of essential amino acids and some nonessential amino acids (Nutrineal). The pH of this solution is 6.7, and osmolality is 365 mosmol/kg [39]. In various studies, this solution has been shown to improve the nutritional status of dialysis patients [40]. The common side effects include worsening of acidosis and a rise in blood urea nitrogen (BUN).

The following guidelines should be considered when prescribing amino acid peritoneal dialysis solutions [41] (see "Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis"):

●They are indicated for use only in malnourished or diabetic patients and/or those with recurrent peritonitis.

●A 1.1 percent amino acid solution consisting of predominantly essential amino acids (required by dialysis patients) should be used.

●Sufficient concurrent alternative caloric intake should be guaranteed.

Xylitol-containing solution — Xylitol has been tried as an osmotic agent in diabetic patients. A preliminary study found that its use helped decrease metabolic complications of diabetes, as well as blood glucose levels [42]. However, it is not used, because of several potentially serious side effects, including lactic acidosis, hyperuricemia, carcinogenicity, and deteriorating liver function.

Glycerol-containing solution — Glycerol gained interest as an osmotic agent because of its smaller molecular weight, relatively high osmolality per unit mass, and a higher pH than glucose solutions. It was therefore initially proposed as the alternative solution in diabetic patients.

However, because of rapid diffusion into blood, it produces less ultrafiltration than glucose. In addition, long-term trials found that the insulin requirement was not significantly different after three to four months; furthermore, its regular use may lead to accumulation of glycerol and cause hyperosmolality of the plasma and hypertriglyceridemia. Thus, glycerol solutions have a limited role in diabetic patients [43].

Buffers — Three different agents have been used as buffers to control acidosis in peritoneal dialysis patients. These are acetate, lactate, and bicarbonate [44].

Lactate — Lactate is a commonly used agent to control acidosis [26,45]. It is sometimes associated with inflow pain. Furthermore, occasional, excessive absorption of lactate may lead to encephalopathy. Nonetheless, a lactate buffer is generally quite safe. It is commercially available in concentrations of 35 and 40 mmol/L.

Acetate — Acetate controls the metabolic acidosis of chronic uremia as well as lactate; however, the major drawback is that acetate frequently causes pain during inflow, as well as sclerosing peritonitis, the latter leading to poor ultrafiltration.

Bicarbonate — Compared with other buffers, bicarbonate controls acidosis in a more physiologic fashion. However, it is not compatible with calcium- and magnesium-containing solutions, particularly if stored for a prolonged period. This problem can be circumvented by using two separate bags (one containing bicarbonate and the other containing calcium and magnesium), which mix together at the time of infusing the solutions.

However, this procedure was cumbersome for patients and did not gain popularity. Different concentrations of bicarbonate have been mixed with lactate, with variable results [46-52].

Electrolytes — Commercially available solutions contain sodium, magnesium, calcium, and chloride. In some settings, minerals like iron pyrophosphate [53] or iron dextran [54] have also been added to the peritoneal dialysis solutions (see "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)" and "Treatment of iron deficiency in patients on dialysis"). In addition, potassium can be added to the peritoneal dialysis solution.

Sodium — The sodium concentration in peritoneal dialysis solutions varies from 130 to 137 mmol/L. In North America, the sodium concentration of the dialysate is principally 132 mmol/L. Since fluid removal with peritoneal dialysis is mainly by convection, water removal from the plasma exceeds sodium removal, thereby possibly leading to hypernatremia. Thus, the relatively low sodium concentration in the peritoneal dialysis fluid helps offset the predilection for hypernatremia. Nomograms are available to predict net sodium removal, adjusted for glucose concentration of the solution.

Calcium — In the 1970s, the most commonly used calcium concentration in peritoneal dialysis solutions was 1.75 mmol/L. The optimal peritoneal dialysis calcium concentration is unclear. Hypercalcemia is common in patients using 1.75 mmol/L of calcium in the dialysate, which is due to the concurrent administration of calcium-containing phosphate binders and vitamin D analogs. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

Thus, an increasing number of centers are now using low-calcium concentrations in the dialysate, which can help in the treatment of hyperphosphatemia with calcium-containing phosphate binders. Studies have shown that lower dialysate calcium (1.25 mmol/L) seems to be safe in the majority of patients [55]. However, hypocalcemia may develop in some patients, particularly in those with poor compliance with calcium-containing phosphorus binders [56,57].

Magnesium — Hypermagnesemia is a frequent occurrence in peritoneal dialysis patients. Available peritoneal dialysis solutions contain magnesium at concentrations of 0.5 to 1.5 mEq/L. In most studies, the use of 1.5 mEq/L of magnesium in the dialysate solution resulted in hypermagnesemia. Since persistently elevated magnesium levels may cause bone disease, the 0.5 mEq/L concentration is therefore more commonly used to optimize the serum magnesium concentration. A zero-dialysate magnesium concentration has also been attempted to allow the use of oral magnesium salt as an additional phosphate binder [1].

Potassium — Potassium is usually not added in the commercial dialysate; potassium concentration in commercially available dialysate can vary from 0 to 2 mEq/L. Zero-potassium dialysate tends to maintain serum potassium around 4 mEq/L. Interestingly, 10 to 36 percent of peritoneal dialysis patients develop hypokalemia, which could be corrected by adding 1 to 4 mEq/L of potassium to the dialysate, as required. However, a strongly preferred method is to supplement potassium orally.

AVAILABLE DEXTROSE-BASED SOLUTIONS — Peritoneal dialysis solutions are available in different volumes, dextrose concentrations, and formulations.

Volume — Peritoneal dialysis solutions are commonly available in 1, 2, 2.5, 3, 5, and 6 liter bags. In the United States, these bags were initially available in glass bottles, but they are currently commercially packaged in collapsible plastic bags.

Dextrose concentrations — Three different dextrose concentrations are available: 1.5, 2.5, and 4.25 percent dextrose solutions. The osmolality of these solutions is 346, 396, and 485, respectively. The adequate management of volume status in a peritoneal dialysis patient involves alternating the different concentrations of dextrose-containing solutions to achieve dry weight and blood pressure control.

Formulations — Different peritoneal dialysis formulations are commonly used and are available with different concentrations of dextrose.

Standard solution — The standard solution contains 132 mEq/L of sodium along with 3.5 mEq/L calcium, 1.5 mEq/L magnesium, 35 mEq/L lactate, and 102 mEq/L of chloride (table 1). Although this formulation is commonly referred to as the standard solution, this is not necessarily the most commonly prescribed or the best available formulation. The use of the standard solution has been found to be associated with hypermagnesemia and hypercalcemia, particularly if the patients are on high doses of calcium-containing phosphate binders. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

Modified solutions — The most commonly used modifications to peritoneal dialysis solutions are low-magnesium (0.5 mEq/L) and low-calcium (2.5 mEq/L) dialysate (table 2) [35,36]. Another modification that is available commercially contains low-magnesium (0.5 mEq/L), high-calcium (3.5 mEq/L), and high-lactate concentration.

These various formulations allow clinicians to tailor and individualize the peritoneal dialysis prescription based upon an individual's electrolyte and metabolic profile.

Other additives — Several other additives are often added to the peritoneal dialysis fluid in certain clinical situations. Some of the commonly used additives include insulin, heparin, and antibiotics:

●Insulin is frequently added to peritoneal dialysis solutions in diabetics to help control hyperglycemia and offset the glucose load from the dextrose-containing solutions. Intraperitoneal insulin has been found to be as good as subcutaneous insulin in the management of diabetes in peritoneal dialysis patients. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease".)

●Heparin is frequently added to prevent the formation of fibrin in the peritoneal dialysis fluid. This is particularly important during peritonitis episodes, when there is increased fibrin production, as well as deposition of debris, which could lead to obstruction of the peritoneal dialysis catheter. Intraperitoneal heparin does not lead to systemic anticoagulation in these patients. (See "Noninfectious complications of peritoneal dialysis catheters".)

●Antibiotics are added to the peritoneal fluid to treat peritonitis. They are usually well tolerated, and their absorption through the peritoneal membrane is enhanced during episodes of peritonitis. (See "Microbiology and therapy of peritonitis in peritoneal dialysis".)

SUMMARY

●Components of dialysate – Peritoneal dialysis solutions primarily consist of water, osmotic agents, electrolytes, and minerals. (See 'Ideal solution' above.)

●Osmotic agents – Osmotic agents allow net water removal by altering the osmotic pressure gradient between the peritoneal dialysis solution and plasma water. Dextrose is the most commonly used osmotic agent. Available dextrose concentrations include 1.5, 2.5, and 4.25 percent solutions. Amino acids may be used as an alternative to dextrose to improve nutritional status in peritoneal dialysis patients. (See 'Low-molecular-weight agents' above and 'Dextrose concentrations' above.)

●Buffers – Buffers used to control acidosis include acetate, lactate, and bicarbonate. Lactate buffers are most commonly used and are commercially available in concentrations of 35 and 40 mmol/L. Acetate-based buffers cause pain during inflow and have been associated with sclerosing peritonitis. Bicarbonate-based buffers are not compatible with calcium- and magnesium-containing solutions but can be mixed together immediately before use without problems. (See 'Buffers' above.)

●Electrolyte concentrations – Dialysate contains sodium, calcium, magnesium, and potassium in varying concentrations.

•Sodium – The sodium concentration in peritoneal dialysis solutions varies from 130 to 137 mmol/L. Nomograms are available to predict net sodium removal. (See 'Sodium' above.)

•Calcium – The optimal peritoneal dialysis calcium concentration is unclear. Many centers use low-calcium concentrations (ie, 1.25 mmol/L), which can help in the treatment of hyperphosphatemia with calcium-containing phosphate binders. Hypocalcemia may develop in some patients who use low-calcium dialysate, particularly those that are noncompliant with calcium-containing phosphate binders. (See 'Calcium' above.)

•Magnesium – The magnesium concentrations range from 0.5 to 1.5 mEq/L; the 0.5 mEq/L concentration is more commonly used since higher concentrations may cause hypermagnesemia. (See 'Magnesium' above.)

•Potassium – Potassium is usually not present in the commercial dialysate. Zero-potassium dialysate tends to maintain serum potassium around 4 mEq/L, although some patients may develop hypokalemia. Hypokalemia could be corrected by the addition of 1 to 4 mEq/L of potassium to the dialysate, but the strongly preferred method is to supplement potassium orally. (See 'Potassium' above.)

●Dextrose-based solutions – Peritoneal dialysis solutions are commonly available in 1, 2, 2.5, 3, 5, and 6 liter bags. Three different dextrose concentrations are available: 1.5, 2.5, and 4.25 percent. (See 'Available dextrose-based solutions' above and 'Volume' above.)

●Icodextrin and spurious hyperglycemia – Icodextrin-containing solutions can cause falsely elevated glucose levels. In patients using icodextrin, blood glucose monitoring must be done with glucose-specific methods to prevent falsely elevated levels and subsequent inappropriate treatment of presumed hyperglycemia. (See 'High-molecular-weight agents' above.)