Mechanisms of Transport
Peritoneal transport of solutes and water depends on four simultaneously occurring mechanisms: Diffusion, osmosis, convection and fluid absorption.
Electrolyte and Solute Transport
The process of diffusion results in the net movement of solute molecules from an area where they are in high concentration to an area where
their concentration is low, across a semipermeable membrane. Although solute moves randomly in both directions, there is more solute moving from a high to a low concentration than in the opposite direction. Eventually, the concentrations become equal on both sides of the membrane, and the net movement in each direction is zero. An important concept is that the movement of solute molecules is random and driven by thermal energy that increases proportional the higher the temperature is above absolute zero (–273 degrees centigrade). This thermal energy is transformed to kinetic energy, which is the product of mass and velocity. Since this energy is the same for different sized molecules at the same temperature, larger molecules tend to move slower than smaller ones. In addition to the concentration gradient, peritoneal diffusion depends on the peritoneal surface area available for transport, the intrinsic resistance of the membrane, and the molecular weight of the solute to be transported.
Diffusion is by far the most important process involved in the transport of electrolytes and solutes in peritoneal dialysis (PD). Examples of such solutes include: Urea, Creatinine, K+, H+, HCO3-, Phosphate, Albumin, proteins and toxins3,7. Diffusive transport of Na+ and Ca2+ is minimal.
Diffusive flux is highest in the first hour and decreases over time. For instance, as shown in Figure 1, urea is > 90% equilibrated by 4 hours, and creatinine is > 60% equilibrated. Further small solute transport is minimal, and long dwells are more important for the removal of the larger molecular weight (MW) solutes such as β-2 microglobulin and albumin9.
In convective transport, the solvent (i.e. water) carries dissolved solutes through all of the membrane pores except the Aquaporins-1. This is more pronounced if higher concentrations of osmotic agents are used in the dialysate.
Osmosis and Ultrafiltration
Osmosis can be defined as the movement of a solvent (i.e., water) from an area of low solute concentration to an area of higher solute concentration across a semi-permeable membrane3. In peritoneal transport, water movement occurs equally via the small pores and Aquaporins-1, as described by the three-pore model (link out).
Ultrafiltration is the process that occurs as a result of the osmotic gradient (i.e., osmotic pressure) created between the relatively hypertonic dialysis solution and the relatively hypotonic peritoneal capillary blood. With the use of hypertonic dialysis solutions, ultrafiltration can lead to fluid removal and convective removal of solutes, especially medium-sized molecules. However, the effectiveness of ultrafiltration can be affected by various factors. These include the hydraulic conductance of the peritoneal membrane, the reflection coefficient for the osmotic agent, the osmotic agent used, osmotic concentration and gradient, the effective peritoneal surface area, the dwell time, and the hydrostatic pressure gradient, which are discussed in more detail below.
• Hydraulic conductance of the peritoneal membrane
- Reflects the density of small pores and ultra-small pores in the peritoneal capillaries, and the distribution of distances of capillaries from the mesothelium3.
- Differs between patients
• Reflection coefficient for the osmotic agent
- Ranging from 0 and 1, the reflection coefficient reflects the osmotic agent’s effectiveness to diffuse out of the dialysis solution into the peritoneal capillaries. Lower values indicate that the osmotic agent will diffuse out of the dialysis solution into the patient’s body at faster rates, leading to less sustained ultrafiltration. The reflection coefficient for glucose is approximately 0.3, while newer polyglucose formulations have values close to 13.
• Osmotic agent used/ osmotic concentration and gradient
- Dextrose at concentrations of 0.5%, 1.5%, 2.5%, and 4.25% (296, 347, 397, and 485 mOsm/L respectively) are commonly used. Another osmotic agent used is polyglucose 7.5% (isoosmolar). The osmotic concentration of the dialysate relative to the blood determines to what extent fluids are exchanged between the PD solution and the blood. A high osmotic concentration in the dialysate creates a high gradient. Dextrose is continuously absorbed during dialysis which reduces the osmotic gradient and leads to a decline in ultrafiltration over time of the dwell. Polyglucose is absorbed at a slower rate than glucose, which makes it suitable for long dwells. (Figure 2).
Figure 2 above shows a computer simulation of the net ultrafiltration obtained with the use of various dextrose concentration PD solutions and with polyglucose over a 14-hour period. Based on this simulation, a single 12-hour polyglucose dwell provides 600 mL of UF. Glucose is best used for shorter dwell times. With a single 6-hour dwell of 2.5% dextrose, an average of 400 mL of UF can be achieved. Compared to one 12 hours long dwell with polyglucose, two 6 hours dwells of 2.5% dextrose result in about 30% higher UF and about double the solute clearance. A 4.25% dextrose solution can further increase UF, but may not be necessary.
• Effective peritoneal surface area
- The effective peritoneal surface area is determined by the area of the membrane in direct contact with the dialysate and the number of perfused peritoneal capillaries, which varies widely from patient to patient. In practice, a peritoneal equilibration test (PET – link out) can be used to assess solute transport capabilities of the peritoneal membrane2.
• Dwell time
- Transport of solutes occurs more rapidly in the early stages of PD until equilibrium is reached. For this reason, shorter and more frequent dwell times are theoretically more effective in PD. Time without effective dialysis during outflow and inflow of each exchange has a limiting role on how short and frequent the exchanges can be still effective. Too long dwell time reduces the effectiveness of ultrafiltration as fluid may transport back from the peritoneal cavity into the patient’s body via the lymphatic system. Long dwells may also reach maximum equilibration of solutes after which no further effective clearance is achieved.
• Hydrostatic pressure gradient
- Ultrafiltration can also occur as a result of hydrostatic pressure gradients. By increasing the volume of the peritoneal dialysis solution the hydrostatic pressure gradient will also increase. Theoretically, water will be pushed from the dialysis solution into the patient’s body, reducing net ultrafiltration. In PD, the effects of hydrostatic ultrafiltration seem of minor importance.
Each solute has a sieving coefficient that depends on the molecular weight and charge. Higher sieving coefficients indicate greater permeability of the solute. A disadvantage of sieving is that makes clearance of solutes less effective. On the other hand, sieving maintains the osmotic gradient that is necessary glucose-induced ultrafiltration to occur. Sieving has also a particular role in water transport across the peritoneal membrane into the peritoneal cavity via the ultra-small pores, the Aquaporins-1. These pores are only permeable for water, while sieving occurs for all the solutes. As a result, solutes such as sodium do not move across the membrane in the same proportion as water and can accumulate in the body. This effect is called sodium sieving and especially occurs during the early phase of PD and is more pronounced with dialysates of high osmotic agent concentrations. In case of sodium, sieving is especially relevant since PD solutions usually have a near physiological sodium concentration that does not create a sufficient diffusive gradient for effective sodium removal.
Fluid absorption of water and solute constantly occurs directly and indirectly from the peritoneal cavity into the lymphatic system. The average absorption of peritoneal fluid is 1-2 mL/min of which 0.2-0.4 mL/min is directly absorbed into the lymphatics3. Constant fluid absorption during PD limits the duration of the PD session since fluid from the peritoneal cavity will be transported into the patient’s body.
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