Coles GA, Davies M, Williams JD (eds): CAPD: Host Defence, Nutrition and Ultrafiltration. Contrib NephroJ. Basel, Karger, 1990, vol 85, pp 126- 133
Osmotic Agents in Peritoneal Dialysis Ram Gokal Manchester Royal Infirmary, Manchester, UK
The early concept of osmosis as applied to peritoneal dialysis was based on the principle that a solution, relatively hypertonic to plasma, instilled into the peritoneal cavity, would lead to ultrafiltration. In 1876, Wegner [1] noticed that injection of a hypertonic solution of sugar into the peritoneal cavity led to an increase in the intraperitoneal volume. Subsequent studies, using hyperosmotic solutions of glucose (2-10 gjdl) showed that the greater the osmolality relative to plasma, the greater the ultrafiltration, whilst hypotonic saline solutions led to fluid reabsorption [2]. This confinned that the magnitude of ultrafiltration was directly related to the osmolality gradient. Since low-molecular-weight solutes generate greater osmolality per unit mass, these agents (crystalloids) were regarded as effective osmotic agents. Of a number of low-molecular-weight agents evaluated in animals [3], only glucose appeared to be safe, effective and readily metabolised. These experiences led to the use of glucose as an osmotic agent in peritoneal dialysis. In the 1960s, the use of intennittent peritoneal dialysis (lPD) in the management of patients with end-stage renal failure confinned the long-tenn safety of glucose [4]. Although a rapid decline in osmotic gradient, as a consequent of glucose absorption, was already recognised, it was of little consequence during short dwell (30-60 min) IPD. In 1976, Popovich et al. [5] proposed a radical change in the practice of peritoneal dialysis by extending the duration of dwell time to 4-10 h. This concept of long-dwell dialysis (CAPD), however, highlighted the short duration of effective ultrafiltration (2-3 h) associated with the use of glucose. If ultrafiltration of greater magnitude or duration was required, this was achieved by increasing the osmolality and the concentration of glucose. This shortcoming of glucose in CAPD prompted a closer look at the factors which influence the magnitude and direction of osmotic forces [see chapter 15 by Mistry and Gokal, this vo1.].
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Historical Perspectives
Osmotic Agents in Peritoneal Dialysis
127
Table 1. Characteristics of an 'ideal' osmotic agent
I 2 3 4 5 6 7 8
Physiological pH and osmolality Sustained ultrafiltration Minimal absorption Complete metabolism with nutritional value No metabolic derangement Non-toxic to peritoneum and host defence mechanisms Non-allergenic Low cost and ease of manufacture
An Ideal Osmotic Agent for Continuous Ambulatory Peritoneal Dialysis Whilst there is no readily available, ideal osmotic agent for long-dwell dialysis, its desired characteristics are given in table 1. It is clear that an optimal agent is one providing sustained ultrafiltration with minimal absorption. Albumin (MW 68,000 daltons), impermeable to the capillary wall, is the most effective osmotic agent encountered in biological systems. Even though it is present in low molar concentrations in the circulation (0.66 mmol/l), it maintains sustained osmotic transport between extracellular compartments of virtually identical osmolality (isosmotic flow) by the phenomenon of colloid osmosis. It is negatively charged at physiological pH and therefore influences the distribution of diffusible ions by the Donnan effect, which results in a colloid osmotic pressure 50% greater than that predicted by its molar concentration [6]. Although albumin possesses many of the characteristics required of an ideal osmotic agent, it is prohibitively expensive to be considered a substitute for glucose.
It is well recognized that the peritoneum is a partially permeable membrane and glucose readily permeates through it. Pyle characterised the ultrafiltration profile of glucose-based solutions [7] demonstrating a rapid exponential decline in the ultrafiltration rate with time, in response to a fall in osmotic gradient, due to a combination of glucose absorption and intraperitoneal dilution. Once equilibration of osmotic forces occurs (between 2 and 3 h), ultrafiltration ceases and reabsorption begins. Any prolongation of dwell time beyond this commonly leads to reabsorption of fluid (negative ultrafiltration); this is particularly noticeable in overnight exchanges. In addition, the continuous daily absorption of 150-300 g of
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
Glucose as an Osmotic Agent
Gokal
128
glucose from the dialysate imposes a substantial calorie load, aggravating such long-term metabolic complication as hyperinsulinaemia, hyperlipidaemia and obesity [8]. Other disadvantages of glucose include the low pH of this solution which inhibits polymorph phagocytosis and intracellular killing of bacteria [9], whilst the high osmolality of the solutions may well damage the peritoneum with long-term use [10]. Furthermore, glucose undergoes spontaneous breakdown to a number of reacting metabolites including aldehyde, S-hydroxymethylfurfurol and formic acid. The breakdown process is accelerated by storage; old fluid has been shown to cause loss of ultrafiltration possibly due to these breakdown products [II]. Other Osmotic Agents for Continuous Ambulatory Peritoneal Dialysis
The disadvantages of continuous long-term use of glucose have stimulated many investigators to search for an alternative osmotic agent. Attention has been focused on correcting the metabolic and ultrafiltration problems; this has been attempted in two different ways. Small-M olecular- Weight Agents One line of research has concentrated on minimising the metabolic effects of glucose rather than the ultrafiltration deficiencies by studying agents with molecular size similar to or smaller than glucose (table 2). These have differed from glucose by their ability to utilise alternative metabolic pathways, thereby offering potential advantages such as reduced insulin stimulation and calorie load. In the majority of cases the rate of transperitoneal absorption exceeds the metabolic capacity resulting in a serious hyperosmolar syndrome [12~ IS]. Amongst these, these two agents have been used with limited success in humans.
Amino Acids. Solutions of amino acids appear to be an attractive alternative to glucose. Based on animal studies, Oreopoulos et a1. [20] suggested that amino acids may safely be used as osmotic agents. Subse-
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
Glycerol. Being a smaller molecule than glucose and therefore with higher osmolality per unit mass, it produces greater ultrafiltration than glucose but of shorter duration [16]. It has the advantage of reducing insulin hypersecretion but its rapid absorption can lead to the hyperosmolar syndrome [17]. Long-term use of glycerol has been limited to managing patients with diabetes mellitus, but exacerbation of hypertriglyceridaemia remains a problem [18, 19]. There appears to be no overall advantage over glucose to support its more widespread use.
Osmotic Agents in Peritoneal Dialysis
129
quently, the same group showed that the ultrafiltration patterns of 1 and 2% amino acids solutions were similar to those of 2.5 and 4.25% glucose solutions, respectively [21]. The use of 1% amino acids solution alternating with glucose in 6 patients over a period of 4 weeks led to improved nutritional status without systemic or local side effects [22]. However, the optimal ratio of essential to non-essential amino acids in the PD fluid is yet to be determined. There are rising levels of urea as well as acidosis [23] and there are high manufacturing costs. Dombros et al. [24] in a 6-month study in 5 malnourished CAPD patients (one exchange of I % amino acid with 3 of glucose) found the amino acids ineffective in improving the nutritional status possibly due to the low calorie intake. Steinhauer et al. [25] showed that whilst amino acids may offer a solution to the problems of malnutrition, there is an associated increase in dialysate protein losses, secondary to PGE 2 synthesis. Hence, amino acid solutions still have several disadvantages that need modifying before long-term clinical use can be justified.
Charged and Neutral Macromolecules. Although polyanions and polycation solutions have been effective in vitro, they have been universally toxic to the peritoneum in animal studies [26]. Recently, gelatin has been shown to be effective in single dwell studies in rats, but there are no human data on the metabolism of absorbed gelatin, and the potential allergenicity has precluded its human use [15,26]. Gjessing [27] failed to show significant ultrafiltration using dextrans. However, this is almost certainly due to its use in molar concentrations insufficient to counteract the effects of albumin in the peritoneal capillaries.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
High-Molecular-Weight Agents An alternative approach is to alter the ultrafiltration profile as well as minimising the metabolic disadvantages of glucose by using highmolecular-weight agents. These would be less readily absorbed, giving rise to sustained ultrafiltration with reduced calorie load. The problem with the use of these substances is related to the need to have a much greater mass to achieve the equivalent osmolality gradient of a low-molecular-weight substance. At high concentrations these molecules are less soluble, hyperviscous, non-physiological and can be allergenic [15]. However, one may question the need to have a very high molar concentration of these substances to produce sufficient osmotic forces for ultrafiltration. The phenomenon of 'colloid' osmosis, as highlighted by albumin, could be utilised in peritoneal dialysis. This would have the advantage of achieving sustained ultrafiltration at low molar concentrations of dialysis solutions relative to plasma. Early attempts to emulate this phenomenon using charged and neutral macromolecules (table 2) have not been successful.
Gokal
130
Table 2. Evaluation of potential alternative osmotic agents [adapted from ref. 33, with permission]
Molecular weight
Disadvantages
Low molecular weight Glucose Fructose
182 182
Xylitol
152
Sorbitol Glycerol
122 92
see text similar to glucose, hyperosmolality lactic acidosis, hyperosmolality hyperosmolality short ultrafiltration, hyperosmolality, limited to dia betics no optimal formula, elevated urea levels, acidosis, high costs, protein losses
Amino acids
75-214
High molecular weight Polyanions Polycations
90,000- 500,000 40,000-60,000
Neutral dextran
60,000- 250,000
Gelatin
20,000- 35,000
Glucose polymer
20,000- 22,000
toxic to peritoneum cardiovascular instability (rats) low ultrafiltration, absorption metabolism? allergenic, viscous accumulation/metabolism? accumulation of maltose
References
12 13 14 15-19
20-24
15-25 26 15-25 28-33
Glucose Polymer (GP). Since glucose has proved extremely effective with a remarkable safety record, it seemed natural to consider a macromolecule composed of polymerised glucose as a possible successor to glucose for long-dwell PD. GP are isolated by fractionation of hydrolysed corn starch and consist of oligopolysaccharides of variable chain length, ranging from 4 to > 300 glucose units linked predominantly by a 1-4 linkage. The initial studies with GP (MW 20,000) showed its many advantages over glucose as an osmotic agent [28]; there was sustained ultrafiltration up to 12 h of dwell, substantially lower calorie load per millilitre of ultrafiltration, equivalent solute clearance with a marginal increase related to ultrafiltration, and no insulin response. An important finding during the studies was the demonstration that an isosmotic solution of GP was capable of sustained ultrafiltration through the mechanism of colloid osmosis [29]. In addition, a hypo-osmolar solution of GP was also able to achieve sustained ultrafiltration over a 12-hour period [30]. The
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Agents
Osmotic Agents in Peritoneal Dialysis
131
only problem with its use is the accumulation of the final breakdown product of GP, maltose (disaccharide) at levels six times those already found in uraemic plasma [31]. None of the patients using the single or multiple exchanges experienced any ill effects; no hyperosmolar effects were noted even with continuous use over a 7-day period of one exchange with 3 of glucose [32]. More recently, a 3-month study with GP (I exchange of 12 h 7.5% GP with 3 of 1.36% glucose per day) in 5 patients has shown good ultrafiltration of 500-900 ml over the 12-hour GP exchange and steady state accumulation of maltose and maltotriose without any clinical side effects [Mistry and Gokal, unpubl. data]. These studies are extremely encouraging and auger well for future use of GP in long-dwell PD, where its use may be to replace the overnight hypertonic exchange. In addition, it may be of advantage in diabetic patients, reduce the number of daily exchanges and aid ultrafiltration where necessary.
Future Trends in Osmotic Agents
For short-dwell peritoneal dialysis, low-molecular-weight osmotic agents are most effective and glucose is probably the best and safest agent. However, for long-dwell processes like CAPD, the aims should be to achieve a more physiological isosmotic solution, capable of producing sustained ultrafiltration. Perhaps a combination of low- and high-molecular-weight substances (e.g. glucose + glucose polymer, or amino acid + glucose polymer) with synergistic effects of their different ultrafiltration profiles may be appropriate: the low-molecular-weight substance giving early ultrafiltration which is sustained by the action of the high-molecular-weight agent. The exact proportion of these combinations would be determined by the duration of the exchanges required. As yet, there is no readily available agent to replace glucose.
2 2 3 4
Wegner G: Chirugische Bemerkungen iiber die Peritonealhohle, mit besonderer Beriicksichtigung der Ovariotomie. Arch Klin Chir 1877;20:51-145. Putman J: The living peritoneum as a dialysing membrane. Am J Physiol 1923;63:548565. Cunningham RS: Studies on absorption from serious cavities. III. The effect of dextrose upon the peritoneal mesothelium Am J Physiol 1920;53:458-488. Palmer RA, Quinton WE, Gray JF, et al: Prolonged peritoneal dialysis for chronic renal failure. Lancet 1964;i:700-702.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
References
5 6 7
8 9
10 II 12
13 14 15 16
17 18 19
20
21 22 23 24
25
132
Popovich R, Moncrief J, Denchard J, et al: The definition of a novel protable/wearable equilibrium dialysis technique (abstract). Trans ASAIO 1976;5:64. Guyton AC. The body fluids and kidneys; in textbook of Medical Physiology, ed 6. Philadelphia, Saunders, 1981, pp 358-369. Pyle WK, Popovich RP, Moncrief JW: Mass transfer evaluation in peritoneal dialysis; in Moncrief JW, Popovich RP (eds): CAPO Update. New York, Masson, 1981, pp 35-52. Hain H, Kessel M: Aspects of new solutions for peritoneal dialysis. Nephrol Dial Transplant 1987;2:67-72. Duwe AK, Vas SI, Weatherhead JW: Effect of the composition of peritoneal dialysis fluid on chemiluminescence, phagocytosis and bacterial activity in vitro. Infect Immunity 1981 ;33: 130-135. Ota K, Mineshima M, Watanabe N, et al: Functional deterioration of the peritoneum: Does it occur in the absence of peritonitis? Nephrol Dial Transplant 1987;2:30-33. Henderson I, Gokal R: Loss of ultrafiltration; in Gokal R (ed): Continuous Ambulatory Peritoneal Dialysis. Edinburgh, Churchill-Livingstone, 1986, pp 218-227. Raja RM, Kramer MS, Manchanda R, et al: Peritoneal dialysis with fructose dialysate - prevention of hyperglycaemia and hyperosmolality. Ann Intern Med 1973;79:511-517. Bazzato G, Coli U, Landinis S, et al: Xylitol and low dosage of insulin: New perspectives for diabetic uraemic patients on CAPO. Peri ton Dial Bull 1982;2:161-164. Raja RM, Moros JG, Kramer MS, et al: Hyperosmotic coma complicating peritoneal dialysis with sorbitol dialysate. Ann Intern Med 1970;73:993-994. Twardowski ZJ, Khanna R, Nolph KD: Osmotic agents and ultrafiltration in peritoneal dialysis. Nephron 1986;42:92-101. Heaton A, Ward MK, Johnston DG, et al: Short term studies on the use of glycerol as an osmotic agent for continuous ambulatory dialysis in end stage renal failure. Clin Sci 1984;67:121-130. Matthys E, Dolkart R, Lamieire N: Potential hazards with the use of glycerol dialysate in diabetic CAPD patients. Periton Dial Bull 1987;7:16-20. Matthys E, Dolkart R, Lamieire N: Extended use of a glycerol containing dialysate in the treatment of diabetic CAPO patients. Periton Dial Bull 1987;7:10-15. Heaton A, Ward KD, Johnston DG, et al: Evaluation of glycerol as an osmotic agent for continuous ambulatory peritoneal dialysis in end stage renal failure. Clin Sci 1986;70:23-29. Oreopoulos DG, Crassweller P, Kartirtzoglou A, et al: Amino acids as an osmotic agent in contiuous peritoneal dialysis; in Legrain M (ed): Continuous Ambulatory Peritoneal Dialysis. Amsterdam, Excerpta Medica, 1979, pp 335-340. William PF, Marliss EB, Anderson GH, et al: Amino acid absorption following intraperitoneal administration in CAPO patients. Periton Dial Bull 1982;2:124-130. Oren A, Wu G, Anderson GH, et al: Effective use of amino acids dialysate over 4 weeks in CAPO patients. Periton Dial Bull 1983;3:66-73. Young GA, Dibble JB, Tompkins L, et al: Amino acid based CAPO fluid: A 5-month study. Nephrol Dial Transplant. 1982;2:456. Dombros N, Prutis K, Tong M, et al: Six month overnight intraperitoneal amino acid in CAPO patients: No effect on nutritional status. Nephrol Dial Transplant 1988;3:556. Steinhauer HB, Lubrick-Birker I, Kluthe R, et al: Amino acid dialysate stimulates peritoneal prostaglandin E2 generation in humans; in Khanna R, et al (eds): Advances in CAPO, 1988. Toronto, Peritoneal Dialysis Bulletin, Inc, 1988, pp 2[-26.
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Gokal
Osmotic Agents in Peritoneal Dialysis
27 28 29 30 31 32 33
Twardowski ZJ, Moore H, McGary T, et al: Polymer as osmotic agents in peritoneal dialysis. Periton Dial Bull 1984;4:S125-S131. Gjessing J: Use of dextran as a dialysing fluid in peritoneal dialysis. Acta Med Scand 1969;185:237- 239. Mistry CD, Mallick NP, Gokal R: The advantages of glucose polymer (MW 20,000) as an osmotic agent in CAPO. Proc EDTA 1985;22;415-420. Mistry CD, Gokal R, Mallick NP: Ultrafiltration with an isosmotic solution during long peritoneal dialysis exchanges. Lancet 1987;ii: I 78-182. Mistry CD, Turner K, Uttley L, et al: Can ultrafiltration occur with hyposmolar solution across the peritoneum? Periton Dial Bull 1987;7:553. Mistry CD, Fox JE, Mallick NP, et al: Circulating maltose and isomaltose in chronic renal failure. Kidney Int 1987;32(suppl 22):S210-S214. Mistry CD, Gokal R: The use of glucose polymer in CAPO: A 7day study. Periton Dial Bull 1987;7:S54. Mistry CD, Gokal R: Osmotic agents in CAPO; in Davison (ed): Nephrology, vol II. London, Bailliere-Tindall, 1988, pp 1268-1275.
Ram Gokal, MD, Consultant Nephrologist, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL (UK)
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26
133
Osmotic Agents in Peritoneal Dialysis Ram Gokal Manchester Royal Infirmary, Manchester, UK
The early concept of osmosis as applied to peritoneal dialysis was based on the principle that a solution, relatively hypertonic to plasma, instilled into the peritoneal cavity, would lead to ultrafiltration. In 1876, Wegner [1] noticed that injection of a hypertonic solution of sugar into the peritoneal cavity led to an increase in the intraperitoneal volume. Subsequent studies, using hyperosmotic solutions of glucose (2-10 gjdl) showed that the greater the osmolality relative to plasma, the greater the ultrafiltration, whilst hypotonic saline solutions led to fluid reabsorption [2]. This confinned that the magnitude of ultrafiltration was directly related to the osmolality gradient. Since low-molecular-weight solutes generate greater osmolality per unit mass, these agents (crystalloids) were regarded as effective osmotic agents. Of a number of low-molecular-weight agents evaluated in animals [3], only glucose appeared to be safe, effective and readily metabolised. These experiences led to the use of glucose as an osmotic agent in peritoneal dialysis. In the 1960s, the use of intennittent peritoneal dialysis (lPD) in the management of patients with end-stage renal failure confinned the long-tenn safety of glucose [4]. Although a rapid decline in osmotic gradient, as a consequent of glucose absorption, was already recognised, it was of little consequence during short dwell (30-60 min) IPD. In 1976, Popovich et al. [5] proposed a radical change in the practice of peritoneal dialysis by extending the duration of dwell time to 4-10 h. This concept of long-dwell dialysis (CAPD), however, highlighted the short duration of effective ultrafiltration (2-3 h) associated with the use of glucose. If ultrafiltration of greater magnitude or duration was required, this was achieved by increasing the osmolality and the concentration of glucose. This shortcoming of glucose in CAPD prompted a closer look at the factors which influence the magnitude and direction of osmotic forces [see chapter 15 by Mistry and Gokal, this vo1.].
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
Historical Perspectives
Osmotic Agents in Peritoneal Dialysis
127
Table 1. Characteristics of an 'ideal' osmotic agent
I 2 3 4 5 6 7 8
Physiological pH and osmolality Sustained ultrafiltration Minimal absorption Complete metabolism with nutritional value No metabolic derangement Non-toxic to peritoneum and host defence mechanisms Non-allergenic Low cost and ease of manufacture
An Ideal Osmotic Agent for Continuous Ambulatory Peritoneal Dialysis Whilst there is no readily available, ideal osmotic agent for long-dwell dialysis, its desired characteristics are given in table 1. It is clear that an optimal agent is one providing sustained ultrafiltration with minimal absorption. Albumin (MW 68,000 daltons), impermeable to the capillary wall, is the most effective osmotic agent encountered in biological systems. Even though it is present in low molar concentrations in the circulation (0.66 mmol/l), it maintains sustained osmotic transport between extracellular compartments of virtually identical osmolality (isosmotic flow) by the phenomenon of colloid osmosis. It is negatively charged at physiological pH and therefore influences the distribution of diffusible ions by the Donnan effect, which results in a colloid osmotic pressure 50% greater than that predicted by its molar concentration [6]. Although albumin possesses many of the characteristics required of an ideal osmotic agent, it is prohibitively expensive to be considered a substitute for glucose.
It is well recognized that the peritoneum is a partially permeable membrane and glucose readily permeates through it. Pyle characterised the ultrafiltration profile of glucose-based solutions [7] demonstrating a rapid exponential decline in the ultrafiltration rate with time, in response to a fall in osmotic gradient, due to a combination of glucose absorption and intraperitoneal dilution. Once equilibration of osmotic forces occurs (between 2 and 3 h), ultrafiltration ceases and reabsorption begins. Any prolongation of dwell time beyond this commonly leads to reabsorption of fluid (negative ultrafiltration); this is particularly noticeable in overnight exchanges. In addition, the continuous daily absorption of 150-300 g of
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
Glucose as an Osmotic Agent
Gokal
128
glucose from the dialysate imposes a substantial calorie load, aggravating such long-term metabolic complication as hyperinsulinaemia, hyperlipidaemia and obesity [8]. Other disadvantages of glucose include the low pH of this solution which inhibits polymorph phagocytosis and intracellular killing of bacteria [9], whilst the high osmolality of the solutions may well damage the peritoneum with long-term use [10]. Furthermore, glucose undergoes spontaneous breakdown to a number of reacting metabolites including aldehyde, S-hydroxymethylfurfurol and formic acid. The breakdown process is accelerated by storage; old fluid has been shown to cause loss of ultrafiltration possibly due to these breakdown products [II]. Other Osmotic Agents for Continuous Ambulatory Peritoneal Dialysis
The disadvantages of continuous long-term use of glucose have stimulated many investigators to search for an alternative osmotic agent. Attention has been focused on correcting the metabolic and ultrafiltration problems; this has been attempted in two different ways. Small-M olecular- Weight Agents One line of research has concentrated on minimising the metabolic effects of glucose rather than the ultrafiltration deficiencies by studying agents with molecular size similar to or smaller than glucose (table 2). These have differed from glucose by their ability to utilise alternative metabolic pathways, thereby offering potential advantages such as reduced insulin stimulation and calorie load. In the majority of cases the rate of transperitoneal absorption exceeds the metabolic capacity resulting in a serious hyperosmolar syndrome [12~ IS]. Amongst these, these two agents have been used with limited success in humans.
Amino Acids. Solutions of amino acids appear to be an attractive alternative to glucose. Based on animal studies, Oreopoulos et a1. [20] suggested that amino acids may safely be used as osmotic agents. Subse-
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
Glycerol. Being a smaller molecule than glucose and therefore with higher osmolality per unit mass, it produces greater ultrafiltration than glucose but of shorter duration [16]. It has the advantage of reducing insulin hypersecretion but its rapid absorption can lead to the hyperosmolar syndrome [17]. Long-term use of glycerol has been limited to managing patients with diabetes mellitus, but exacerbation of hypertriglyceridaemia remains a problem [18, 19]. There appears to be no overall advantage over glucose to support its more widespread use.
Osmotic Agents in Peritoneal Dialysis
129
quently, the same group showed that the ultrafiltration patterns of 1 and 2% amino acids solutions were similar to those of 2.5 and 4.25% glucose solutions, respectively [21]. The use of 1% amino acids solution alternating with glucose in 6 patients over a period of 4 weeks led to improved nutritional status without systemic or local side effects [22]. However, the optimal ratio of essential to non-essential amino acids in the PD fluid is yet to be determined. There are rising levels of urea as well as acidosis [23] and there are high manufacturing costs. Dombros et al. [24] in a 6-month study in 5 malnourished CAPD patients (one exchange of I % amino acid with 3 of glucose) found the amino acids ineffective in improving the nutritional status possibly due to the low calorie intake. Steinhauer et al. [25] showed that whilst amino acids may offer a solution to the problems of malnutrition, there is an associated increase in dialysate protein losses, secondary to PGE 2 synthesis. Hence, amino acid solutions still have several disadvantages that need modifying before long-term clinical use can be justified.
Charged and Neutral Macromolecules. Although polyanions and polycation solutions have been effective in vitro, they have been universally toxic to the peritoneum in animal studies [26]. Recently, gelatin has been shown to be effective in single dwell studies in rats, but there are no human data on the metabolism of absorbed gelatin, and the potential allergenicity has precluded its human use [15,26]. Gjessing [27] failed to show significant ultrafiltration using dextrans. However, this is almost certainly due to its use in molar concentrations insufficient to counteract the effects of albumin in the peritoneal capillaries.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
High-Molecular-Weight Agents An alternative approach is to alter the ultrafiltration profile as well as minimising the metabolic disadvantages of glucose by using highmolecular-weight agents. These would be less readily absorbed, giving rise to sustained ultrafiltration with reduced calorie load. The problem with the use of these substances is related to the need to have a much greater mass to achieve the equivalent osmolality gradient of a low-molecular-weight substance. At high concentrations these molecules are less soluble, hyperviscous, non-physiological and can be allergenic [15]. However, one may question the need to have a very high molar concentration of these substances to produce sufficient osmotic forces for ultrafiltration. The phenomenon of 'colloid' osmosis, as highlighted by albumin, could be utilised in peritoneal dialysis. This would have the advantage of achieving sustained ultrafiltration at low molar concentrations of dialysis solutions relative to plasma. Early attempts to emulate this phenomenon using charged and neutral macromolecules (table 2) have not been successful.
Gokal
130
Table 2. Evaluation of potential alternative osmotic agents [adapted from ref. 33, with permission]
Molecular weight
Disadvantages
Low molecular weight Glucose Fructose
182 182
Xylitol
152
Sorbitol Glycerol
122 92
see text similar to glucose, hyperosmolality lactic acidosis, hyperosmolality hyperosmolality short ultrafiltration, hyperosmolality, limited to dia betics no optimal formula, elevated urea levels, acidosis, high costs, protein losses
Amino acids
75-214
High molecular weight Polyanions Polycations
90,000- 500,000 40,000-60,000
Neutral dextran
60,000- 250,000
Gelatin
20,000- 35,000
Glucose polymer
20,000- 22,000
toxic to peritoneum cardiovascular instability (rats) low ultrafiltration, absorption metabolism? allergenic, viscous accumulation/metabolism? accumulation of maltose
References
12 13 14 15-19
20-24
15-25 26 15-25 28-33
Glucose Polymer (GP). Since glucose has proved extremely effective with a remarkable safety record, it seemed natural to consider a macromolecule composed of polymerised glucose as a possible successor to glucose for long-dwell PD. GP are isolated by fractionation of hydrolysed corn starch and consist of oligopolysaccharides of variable chain length, ranging from 4 to > 300 glucose units linked predominantly by a 1-4 linkage. The initial studies with GP (MW 20,000) showed its many advantages over glucose as an osmotic agent [28]; there was sustained ultrafiltration up to 12 h of dwell, substantially lower calorie load per millilitre of ultrafiltration, equivalent solute clearance with a marginal increase related to ultrafiltration, and no insulin response. An important finding during the studies was the demonstration that an isosmotic solution of GP was capable of sustained ultrafiltration through the mechanism of colloid osmosis [29]. In addition, a hypo-osmolar solution of GP was also able to achieve sustained ultrafiltration over a 12-hour period [30]. The
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
Agents
Osmotic Agents in Peritoneal Dialysis
131
only problem with its use is the accumulation of the final breakdown product of GP, maltose (disaccharide) at levels six times those already found in uraemic plasma [31]. None of the patients using the single or multiple exchanges experienced any ill effects; no hyperosmolar effects were noted even with continuous use over a 7-day period of one exchange with 3 of glucose [32]. More recently, a 3-month study with GP (I exchange of 12 h 7.5% GP with 3 of 1.36% glucose per day) in 5 patients has shown good ultrafiltration of 500-900 ml over the 12-hour GP exchange and steady state accumulation of maltose and maltotriose without any clinical side effects [Mistry and Gokal, unpubl. data]. These studies are extremely encouraging and auger well for future use of GP in long-dwell PD, where its use may be to replace the overnight hypertonic exchange. In addition, it may be of advantage in diabetic patients, reduce the number of daily exchanges and aid ultrafiltration where necessary.
Future Trends in Osmotic Agents
For short-dwell peritoneal dialysis, low-molecular-weight osmotic agents are most effective and glucose is probably the best and safest agent. However, for long-dwell processes like CAPD, the aims should be to achieve a more physiological isosmotic solution, capable of producing sustained ultrafiltration. Perhaps a combination of low- and high-molecular-weight substances (e.g. glucose + glucose polymer, or amino acid + glucose polymer) with synergistic effects of their different ultrafiltration profiles may be appropriate: the low-molecular-weight substance giving early ultrafiltration which is sustained by the action of the high-molecular-weight agent. The exact proportion of these combinations would be determined by the duration of the exchanges required. As yet, there is no readily available agent to replace glucose.
2 2 3 4
Wegner G: Chirugische Bemerkungen iiber die Peritonealhohle, mit besonderer Beriicksichtigung der Ovariotomie. Arch Klin Chir 1877;20:51-145. Putman J: The living peritoneum as a dialysing membrane. Am J Physiol 1923;63:548565. Cunningham RS: Studies on absorption from serious cavities. III. The effect of dextrose upon the peritoneal mesothelium Am J Physiol 1920;53:458-488. Palmer RA, Quinton WE, Gray JF, et al: Prolonged peritoneal dialysis for chronic renal failure. Lancet 1964;i:700-702.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 4/8/2017 10:17:47 PM
References
5 6 7
8 9
10 II 12
13 14 15 16
17 18 19
20
21 22 23 24
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Ram Gokal, MD, Consultant Nephrologist, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL (UK)
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