Peritoneal Cavity

Infusion

Drain

Transcellular Pore (Aquaporin) r < 0.5 nm

Small ' Solutes .

Transcellular Forces

osmotic pressure dominates hydrostatic & osmotic pressures large Pore r . 20.0 nm protein INTERSTITIUM

large Pore r . 20.0 nm protein INTERSTITIUM

glycocalyx

CAPILLARY LUMEN

Figure 4 Pore-matrix theory of transendothelial transport. See text for details.

glycocalyx hydrostatic pressure dominates

CAPILLARY LUMEN

Figure 4 Pore-matrix theory of transendothelial transport. See text for details.

multicompartment model that includes this division of the circulation and which is particularly useful in consideration of drug absorption and mathematical modeling.

Peritoneal Microcirculation Involved in Transport

The classic description of the peritoneal microvascula-ture was provided by Chambers and Zweifach more than 50 years ago. The typical capillary network consists of arterioles, terminal arterials, precapillary sphincters, arterial venules and anastomotic thoroughfare channels, capillaries, postcapillary venules, and venules. Blood flows into the capillary system through the arterioles and exits through venules. Arterioles and thoroughfare channels control actual blood flow to the exchange vessels, which are the capillaries and the venules. Although most data have been collected in studies of the mesenteric bed because of the convenience of imaging these vessels, they may not be the best representation of the major microcirculation involved in transperitoneal transport. As discussed earlier, the transport involves vessels within approximately a millimeter of the mesothelial surface. The mesentery is a double-walled fold of the mesothelium with a single layer of sparse vessels making up the mesenteric circulation. The vessels tend to be much greater distances apart than the vessels in the abdominal wall or in the wall of the gut. Because the largest percentage of the anatomic peritoneum is made up of muscle (either smooth muscle of the hollow viscera or the skeletal muscle of the abdominal wall or of the retroperitoneum), it may be better to think of the peritoneal circulation involved with transport to be similar to that of muscle. This circulation is only bathed by solution in the cavity on one side, whereas the mesentery is bathed on both sides of a single layer of vessels. Although nonfenestrated capillaries of the liver and spleen are extremely permeable and are likely a source of protein loss during peritoneal dialysis, the amount of direct exchange is limited because their surface exposure is a small fraction (about 10%) of the potential surface area.

Transendothelial Transport: The Three-Pore Model

Because of the importance of muscle capillaries, the remainder of this discussion will be focused on this type of nonfenestrated capillaries. Rippe and colleagues have recently published a detailed description of the microcirculation and has described the endothelial barrier in terms of a three-pore model as illustrated in Figure 4. One to two percent of the total pore surface area is made up of transcellu-lar pores or "aquaporins" of radius 0.1 to 0.5 nanometers (nm) in diameter that permit only water to cross. Most of the pore surface area (about 95%) is made up of "small pores" with a radius of 4.0 to 6.0nm. The remaining 2 to 3 percent of the total pore area is made up of "large pores" on the order of 20 to 30nm, across which the hydrostatic pressure dominates the transport forces. The figure also depicts the endothelial cells coated on the luminal side with a glycoca-lyx, which is typically 0.1 to 0.2 mm thick but can be as thick as 0.5 mm. The pore-matrix theory hypothesizes that this glycocalyx restricts the passage of molecules across the endothelium and may be responsible for the membrane properties of the "pores." In this theory, the pore sizes, which have been estimated from the transfer of different molecular size solutes across the capillary wall, may be in fact made up of similar-sized interendothelial gaps that are filled with different densities of glycocalyx. Mathematically, each theory can be shown to be equivalent to the other.

Water, which transports during dialysis in response to an osmotic pressure difference across the capillary wall, flows chiefly through endothelial aquaporins, unique structures in the cell membrane that allow only water to pass through the membrane. The portions of endothelium containing these very small pores are perfect semipermeable membranes, and therefore the entire osmotic pressure difference is effectively exerted. In experiments in an aquaporin-knockout mouse, approximately 50 percent of the osmotic filtration during dialysis was eliminated, demonstrating that these water-only pores are responsible for half of the osmosis during dialysis. The remaining 50 percent of the water transport occurs across the small pores and the large pores.

Small pores make up approximately 95 percent of the total pore area and are primarily responsible for transendothelial transport of substances with a molecular weight of less than 5,000. Permeability of the small pore decreases with increasing molecular size up to a radius of 3.0 nm. Larger solutes are excluded from these pathways and pass through the large pore. Since these openings are too large to restrict macromolecules, there is essentially no osmotic pressure difference across these pores. Because the hydrostatic pressure in the capillary or venule lumen is typically higher than in the interstitium, solutes and water are driven out of the bloodstream under hydrostatic pressure-driven convection. Although some have postulated that there is a vesicular transport of macromolecules across the endothelium, this has been discounted by functional studies in which macromolecular transport continued to be observed under conditions in which vesicular transport should be near zero. Additional evidence comes from direct histologic observation in serial thin sections, which demonstrated that the so-called vesicles were actually invaginations in the cell wall.

Blood Flow and Limitations of Transport

In the transfer of solutes and water, there has been disagreement on whether blood flow limits the transport. In theory, very low blood flows may limit transfer of very small solutes such as urea (MW = 60Da). However in experiments in rats, the blood flow perfusion to individual organs was decreased to 20 to 30 percent of its original level without change in the mass transfer rates of urea across the peritoneum of the cecum, stomach, or abdominal wall. The transfer across the liver was significantly altered with a decrease in blood flow. In analogous experiments, water transport was decreased across all of these surfaces, but only approached statistical significance across the liver peritoneum. In another approach to the problem, animals were bled to decrease their blood pressure to shock levels, which resulted in minor but statistically significant changes in rates of mass transfer in small solutes. However, even under these extreme conditions the rate of transfer was sufficient to support dialysis. From these studies it can be concluded that under normal circumstances, there are no significant blood flow limitations for water-soluble molecules, but there may be limitations in removal of water during states of systemic shock.

Peritoneal Lymphatic System

The lymphatic system that drains the peritoneal cavity can be divided up into two parts. In the subdiaphragmatic system, which drains 70 to 80 percent of the lymphatic flow from the peritoneal cavity, the diaphragm acts as a pumping mechanism that pulls fluid from the pelvic regions of the cavity toward itself. As the diaphragm moves upward in expiration, the lymphatic plexus expands and a negative pressure is established in the lymphatic vessels. Penetrations in the basement membrane called lacunae open to take in fluid, solutes, and particles up to 25 mm in diameter. When the diaphragm contracts, the tension in the lymphatic wall is released and the lacunae are closed. The fluid is then propelled upward toward the right lymphatic duct or into the thoracic duct. The remaining 20 to 30 percent of lymph flow from the peritoneal cavity travels through the visceral lymphatics. These drain to the mesenteric lymphatics and ultimately to the cisterna chyli at the base of the thoracic duct. In healthy peritoneal dialysis patients, the total lymph flow has been determined to be between 7 and 21 mL/hour. The capacity of the lymphatic system can increase significantly in states of massive cirrhotic ascites to rates of greater than 30 mL/hour or decrease to near zero with carcinomatous obstruction of the lymph channels.

Subperitoneal Interstitium and Effects of Intraperitoneal Pressure

Although some transport models neglect the presence of interstitium and portray the peritoneal barrier as a capillary endothelium, the interstitial space, which surrounds the blood vessels and parenchyma cells of the subperitoneum, presents a significant barrier to transport. This was demonstrated most clearly by the absorption of inert gases from the peritoneal cavity of pigs, which demonstrated a one-hundredfold range of clearances that correlated with the log of the aqueous diffusivity. If the resistance in the barrier were equivalent to just the blood capillary wall, then the transfer of gas would be limited by blood flow as it is in the lung, and the rates of inert gas absorption would have been the same. Correlation with diffusivity of water implies that the resistance in the tissue interstitium limits the transport of these inert gases.

The space between the cells, termed interstitium, is a very ordered structure of the tissue. At one time the interstitial matrix of molecules was considered an amorphous mixture of interstitial ground substance. However, now it is known to be a highly ordered matrix made up of collagen fibers that are anchored to the surrounding cells by adhesion molecules called integrins. Collagen fibers have been demonstrated to hold the cells and extracellular matrix in active tension that can be disrupted in states of inflammation or tissue damage. Wrapped around the collagen molecules are large hyaluronan molecules, which imbibe water and bind proteoglycans such as chondroitin sulfate, keratin sulfate, and heparin sulfate. The hyaluronan molecules are negatively charged and together with the collagen present a major barrier to the passage of negatively charged proteins. These molecules also restrict proteins to approximately 20 percent of the extracellular space. These interstitial molecules in the subperitoneal tissues link the parenchymal cells, fibroblasts, and other cells and force solutes to take a very tortuous path when transiting from the blood to the peritoneal cavity or vice versa. The presence of the interstitium and cells surrounding the exchange blood vessels in the tissue has the effect of decreasing the rates of diffusive transport from the blood to the peritoneal cavity 30 to 100 times from the rate of free diffusion of the same molecule through water. The greater the distance between the capillary and the peritoneal surface, the more significant the resistance of the interstitium becomes. The portion of resistance attributable to the interstitium in the diffusion of a small solute such as sucrose is estimated to be 20 percent if the capillary is located 50 mm from the peritoneum. However, it increases to more than 80 percent of the total peritoneal resistance if the capillary is located 600 mm from the peritoneum.

During a therapeutic procedure in which a volume of 2 to 3L is infused into the cavity, pressures are 2 to 20 mmHg, depending on the size of the patient, the volume administered, and the position of the patient (sitting position has the highest pressure; supine, lowest). In the abdominal wall, even a relatively low pressure of 4 mmHg causes the extracellular volume of the abdominal wall of the rat to expand by 100 percent, which results in a marked decrease in the resistance to diffusion or convection. Therefore, the interstitial portion of the peritoneal transport system during a large abdominal dwell of fluid can potentially be quite variable in its characteristics.

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