Physiology of the Peritoneum: Implications for Peritoneal Dialysis

002.5-7125/90 80.00 + .20

Renal Disease

Physiology of the Peritoneum Implications for Peritoneal Dialysis

John F. Maher, ."'1D*

STRUCTURE AND FUNCTION OF THE PERITONEAL MEMBRANE

A monocellular layer of membrane lines the inner surface of the abdominal wall and reflects over the visceral organs, covering them and creating a space, the peritoneum. In health, the peritoneal cavity contains a small volume of lipid-rich fluid that serves to cushion the abdominal viscera. When aqueous solutions are instilled into the peritoneal cavity, their solute composition approaches Gibbs-Donnan equilibrium with plasma by diffusion along electrochemical concentration gradients (Fig. 1). This is the major mechanism of solute transfer during peritoneal dialysis and the rationale underlying its clinical use. Concurrently, iso-osmotic solutions arc absorbed into the circulation predominantly through the diaphragmatic lymphatics at a rate faster than the rate of ultrafiltration, which is induced by the transcapillary hydrostatic pressure gradient alone. To achieve net ultrafiltration, a slowly or nondiffusible solute must be added to the solution instilled into the peritoneum to serve as an osmotic agent. These two processes, diffusion and osmotic ultrafiltration, govern peritoneal dialysis, although net solute and water removal are reduced by the absorption of solution through lymphatics. Solutes such as fatty acids atypically enter peritoneal dialysate through metabolic production, whereas others may undergo hepatic biotransformation during absorption. The volume of peritoneal dialysis solution per exchange is typically *Professor of Medicine and Director. ;\Iephrology Division, Uniformed Services University of the Health Sciences, Bethesda, Maryland The opinions and assertions contained herein are the private views of the author and will not be construed as official or as necessarily reflecting the views of the USUHS or DoD.

Medical Clinics of North America-Vol. 74, No. 4, July 1990

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concentration profile Figure 1. Peritoneal dialysis volume relationships. The volume of total body water considerably exceeds that of peritoneal dialysate. Hence, as dialysis proceeds, a highly diffusible solute accumulates in dialysate rapidly while the plasma level changes inconsequentially.

only about 5% of total body water (see Fig. 1), unlike hemodialysis, in which much higher volumes are used, perfusing the dialyzer at 500 ml/min or more. Hence, solute equilibration between plasma water and peritoneal dialysate occurs rather quickly. As a consequence, in order to achieve maximal transport per minute, the dialysate must be exchanged reasonably rapidly, despite a relatively low blood flow to the peritoneum. The peritoneal diffusion barrier consists of the fluid films in the blood and in the dialysate, the endothelium, the mesothelium, their basement membranes, and the intervening interstitium. 21 Knowledge about the role of each barrier in hindering diffusion of solutes of particular physical characteristics is meager, however. There is abundant evidence favoring the concept that during peritoneal dialysis solutes transfer through intercellular channels; transcellular transport is not considered quantitatively important. It is noteworthy that dialysate potassium and sodium equilibrate with the concentrations in extracellular fluid, not with concentrations within cells. 2 Moreover, when ultrafiltration into peritoneal dialysate is induced by an osmotic gradient, the mesothelial cells resist loss of potassium in contrast to the potassium flux that occurs when intravascular hyperosmolality is induced. 18 In addition, the disruption of intercellular junctions, e. g., by the intraperitoneal instillation of cytochalasin D, increases the solute mass transport rate, concurrently decreasing the net ultrafiltration rate because the osmotic gradient dissipates more rapidly than normally.ll

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The diffusion of large solutes is limited predominantly by the dimensions of the intercellular pores of the capillary wall, but movement of small solutes is restricted by stagnant fluid films of the blood, dialysate, and interstitium. The blood flow rate and dialysis fluid volume and exchange rate affect these fluid films to a great extent. Higher peritoneal blood flow rates are ordinarily accompanied by higher splanchnic blood volume, which should increase capillary pore dimensions, also accelerating transport rates.

SOLUTE KINETICS ACROSS THE PERITONEAL MEMBRANE The rate of diffusion across the peritoneum is determined by the surface area and the chemical concentration gradient. Corrected for these two factors, the diffusion rate is constant. Solute transport per minute divided by the plasma concentration or, more precisely, by the concentration gradient, yields a clearance somewhat analogous to renal clearance. The peritoneal clearance is quite useful clinically for assessing the functional integrity of the peritoneum, but it differs from the rate of diffusion. Ultrafiltration adds solutes convectively to peritoneal dialysate (or dilutes those already present). For example, if the dialysate volume doubled over a time interval, the concentration of a nondiffusible solute already present should decrease to about half. It would be inappropriate to interpret this as inward diffusion. Formulas that correct for the concentration gradient and the rate of (net) ultrafiltration yield a mass transfer coefficient that is much closer to the rate of diffusion. Obviously, the gross rate of ultrafiltration (net plus absorption) contributes to the convective dilution of dialysate. For a simpler assessment, peritoneal clearances are preferred. Provided that the interval is brief so that the gradient persists somewhat and the rate of ultrafiltration is modest, they assess peritoneal function acceptably.

FACTORS AFFECTING EFFICACY OF PERITONEAL DIALYSIS Many physiologic variables influence transport rates into and out of the peritoneal cavity. Some of these can be manipulated easily. Increased peritoneal clearances of a small solute such as urea can be achieved by increased mixing of the dialysate,27 more rapid fluid cycling, or an increased volume of dialysate. 30 Increased surface contact of dialysate may contribute to the augmented transport rates that are induced by these maneuvers, which are designed to lower dialysate resistance. Because of its length, the interstitium is a major diffusion barrier for small solutes. It has been postulated that aqueous channels permeate the gelatinous interstitium and that these channels become distorted by dehydration, thereby delaying solute transit. 31 To date, a technique for lowering the blood resistance has not been devised. Increasing blood flow rate has other effects on mass transfer rates and, unless turbulence is induced, may raise the blood film resistance by widening the path as it simultaneously lowers the endothelial resistance.

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Influence of Vasoactive Drugs Peritoncal blood flow rates have been manipulated by a variety of maneuvers, usually by the administration of vasoactive agents intraperitollCally, or by intravenous administration of one of those few substances that affcct the splanchnic vasculature preferentially.12 Care must be taken, however, that anesthetic drugs are not used concurrently, because drug combinations may simply represent inhibitory effects rather than a primary influence on the peritoneal diffusion barrier. Vasodilators incrcase flow proportionately more than clearances increase, and reductions in peritoneal blood flmv by disease or vasoconstrictors are proportionately greater than the fractional lowering of mass transfer rates. 4 , 22 Moreover, the greater effect of vasoactive drugs on larger solutes than on smaller compounds suggests that these agents affect membrane permeability, not merely solute delivery. Effect of Splanchnic Blood Volume Recent evidence suggests that the peritoneal capillary blood volume, rather than its flow rate, may be the more important determinant of solute mass transfer rates. After intravenous administration of dihydroergotamine, which induces somatic capillary ultrafiltration, thereby decreasing blood volume and accelerating flow, peritoneal solute clearances decrease. 25 In contrast, when intrahepatic sinusoidal obstruction is induced, causing portal venous congestion, a decreasing flow rate, but an increasing volume, peritoneal ultrafiltration and mass transfer coefficients increase. These observations are consistent with a predominant effect of splanchnic volume, not blood flow, on hydraulic and solute permeability of the peritoneum. Furthermore, acute extracellular volume expansion with hypertonic dextrose given intraperitoneally or with isotonic dextrose administered intravenously increases solute clearances. I, Extracellular volume expansion appears to be a more important mechanism underlying the augmented transport induced by hypertonic dextrose dialysis solution than a direct effect of dextrose on the membrane itself. Changes in peritoneal capillary blood volume may correlate directly with the endothelial surface perfused and, by stretching capillary walls, with the dimensions of intercellular pores as wcll. Pore Dimensions and Characteristics and Solute Size The capillary wall appears to be the dominant resistance to the transfer of large solutcs. The mesothelium impedes their movement to a lesser extent. The relative clearances of polydispersed neutral dextrans suggest that the radius of most of the pores in the peritoneal cavity is about 50 A. 9 Solutes of larger dimensions are transported at a very slow rate (about 5 J-Ll/kg/minl, possibly by pinocytosis or through a few large pores. Up to about 25 A, the mass transfer rate has been shown to be comparable to the rate of free diffusion of the solute in water. 14 The capillary wall merely restricts the available area through which diffusion can occur. Recent evidence supports the concept that anionic charges exist within the peritoneal diffusion barrier. 7 Ruthenium red stains such charges on the

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capillary wall, in the interstitium, and on the mesothelium. These charges should restrict passage of anionic solutes, repelling them from por~s; however, reported protein clearances have been in accord with values that are predicted by dextran clearance and solute size, not lower, as should occur if charge repelling were impeding transport. The effects of differences in solute shape between test solutes and the influence of pinocytosis on these data remain to be elucidated. Preliminary data suggest lower peritoneal clearances of anionic dextrans than of neutral dextrans of similar mass, confirming the concept of ionic charge repelling. Moreover, the transport rates of smaller anions are less than the rates that are predicted from their molecular radii. 15 At present, there is little information regarding the effects of peritoneal pathology on the anionic composition of the peritoneum. It is known, however, that chemical peritonitis, which has been induced by sodium desoxycholate, increases both protein loss and the transfer rates of neutral dextrans. lO Hence, a mechanism unrelated to anionic charges must contribute to excessive protein loss. Hyperpermeability Mediated by Prostaglandins Intraperitoneal administration of vasoconstrictor prostaglandins such as PGF 2" decreases peritoneal solute transfer rates, whereas the vasodilator PGE z increases permeability of the peritoneum of experimental animals. Excessive permeability of the peritoneum is disadvantageous because protein loss can become detrimental and because of rapid dissipation of the osmotic gradient. Any cause of peritoneal inflammation may induce hyperpermeability with loss of ultrafiltration capacity and inordinate protein depletion. This most commonly results from infectious peritonitis, and the functional aberration is mediated by vasodilator prostaglandins. ZG Indeed, the prostaglandin synthetase inhibitor, indomethacin, blocks this exaggerated permeability. 26 A controlled clinical trial is needed to establish whether indomethacin or its analogues would benefit patients with peritonitis. In studies in animals, we showed that histamine increases peritoneal permeability and protein loss, an effect that was decreased by histamine HI receptor antagonism and eliminated by H z receptor antagonists. 24 The antagonists alone did not lower permeability, suggesting insignificant baseline histamine activity. A trial of histamine antagonists can be justified for hypersensitivity peritonitis with distorted permeability, but ranitidine did not block the protein loss induced by peritonitis secondary to a chemical irritant. 24 Absorption of Peritoneal Dialysate The absorption of small solutes from peritoneal dialysate to blood can occur by diffusion along concentration gradients. This mechanism accounts for most of the absorption of calcium, glucose, and anionic buffers such as lactate. Large solutes, however, are absorbed exclusively via lymphatics,5 and their disappearance from dialysate has been taken to equal lymphatic flow rate. 1:] Lymphatic absorption causes transport asymmetry of large solutes, the inward clearance exceeding the transfer rate into the peritoneum. Hence, the equilibrium concentration of macromolecules such as

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protein in dialysate or ascitic fluid is ordinarily much lower than that in plasma, usually about half. Lymphatic absorption of peritoneal dialysate negatively affects the net ultrafiltration ratc across the peritoneum. 11 Thc influence of numerous physiologic and pharmacologic variables on lymphatic absorption is just beginning to be investigated. Although lymphatic absorption does not greatly diminish high rates of ultrafiltration during short-term exchanges, it decreases net fluid flux appreciably during long dwells of dialysate (Fig. 2). Dialysate volume affects the rate of dialysate absorption positively, whereas dialysate osmolality influences it negatively. 1 The rate of radiolabe led albumin absorption is also faster in animals with renal failure compared to normal animals. Faster absorption might be attributed to acidosis, a known stimulant of the lymphatic flow rates. 15 fluid fluxes

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Figure 2. Peritoneal ultrafiltration. During; peritoneal dialysis, the rate of osmotic ultrafiltration decreases exponentially as the dextrose concentration gradient dissipates. The absorptive rate varies as dialysate volume does, but it decreases more slowly than the ultrafiltration rate does. With prolonged dialysate dwell, lymphatic absorption impacts negati\'ely to Cl large extent on dialysate volume.

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ULTRAFILTRATION Peritoneal ultrafiltration occurs because osmotic equilibrium is approached between plasma and dialysate, to which a slowly diffusible solute, usually dextrose, has been added. The rate of fluid flux is high compared to the inward diffusion rate. Hence, the dextrose osmotic concentration diSSipates slowly enough to achieve a high rate of ultrafiltration. A variety of other osmotic agents have been studied,8, 29 but dextrose, despite its disadvantageous caloric excess, remains preferred because rapid metabolism of plasma glucose maintains the osmotic gradient and its toxicity is low. Insulin is necessary for maintenance of the maximal osmotic gradient by promoting the metabolism of glucose. The ultrafiltration rate is proportional to the dialysate dextrose concentration, but a maximum rate may be achieved that has been attributed to a very high filtration fraction, eventually raising oncotic pressure to a level that offsets ultrafiltration forces. 23 Using an assumed filtration fraction, the maximal ultrafiltration rate would indicate a low peritoneal blood flow rate of about 40 mllmin/l. 73 m 2 . Alternative explanations for an ultrafiltration limit, such as concentration polarization and back flux, would alter this calculation upward. Prolonged dwell of dialysate with high dextrose concentrations when osmotic equilibrium has almost been approached achieves minimal ultrafiltration at the expense of considerable dextrose absorption. 19

LOSS OF ULTRAFILTRATION CAPACITY Although solute transfer rates tend to remain steady after months or years, prolonged treatment by peritoneal dialysis is often complicated by loss of ultrafiltration capacity. This loss can be associated with an increased rate of solute transport dissipating the osmotic gradient, with decreased transport suggesting loss of membrane surface, with augmented lymphatic absorption or without a detectable change in solute kinetics. The usual clinical approach to this problem is to use increasing concentrations of dextrose in dialysis fluid. Higher dextrose concentrations will increase ultrafiltration, but the price paid is a large quantity of dextrose absorbed. As intraperitoneal dwell is prolonged, the rate of ultrafiltration declines faster than glucose mass transport does, and ultrafiltration per gram absorbed decreases. Short-term exposure to high dextrose concentrations is more efficient in removing fluid expressed as volume/time or volume/ glucose absorbed. When patients lose ultrafiltration capacity, a deficiency of phosphatidylcholine in dialysate may be detected. 3 Replenishing this lecithin increases the ultrafiltration rate toward normal in these patients.

EFFICACY OF CAPD AND COMPARISONS WITH HEMODIALYSIS Over the past decade, much has been learned about peritoneal transport physiology. This has coincided with the growth of continuous ambulatory peritoneal dialysis (CAP D) and with numerous clinical obser-

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vations, many of which have been tested by experimental protocols. Because CAPD is performed for 168 hr/week, the total weekly clearances of small solutes approach those of standard hemodialysis performed 12 hr/week or high-flux hemodialysis performed more briefly, even though the elimination rate per minute is much less than that of the intermittent treatments. Attempts at high-flux peritoneal dialysis for repeated short intervals require more frequent fluid exchanges and are less efficient, as assessed by the weekly clearance. Patients with cardiovascular disease and diabetes mellitus and the elderly and small children do well with peritoneal dialysis treatment. It may also be preferred because of factors such as distance from the medical center and occupation. Those with extensive abdominal surgery, severe pulmonary disease, lumbar disc problems, blindness, or numerous diverticuli are more likely to flourish with hemodialysis. It has long been recognized that the peritoneum is more porous than conventional hemodialysis membranes. Accordingly, the inverse slope that relates the mass transfer coefficient to solute size is less steep with peritoneal dialysis than with hemodialysis. 15 Because large solutes do not accumulate in dialysate sufficiently to lower their chemical concentration gradients appreciably, their transfer rate is not impeded by prolonged dialysate dwell. Hence, CAPD may remove large solutes more efficiently than some hemodialysis regimens do, depending on the porosity of the hemodialysis membrane and duration of treatment. Until we can quantify the toxicity of the manv substances retained in renal failure and understand the hazards of loss ~f essential solutes across dialysis membranes, however, it is speculative to proclaim that higher removal of a solute of any particular size is a therapeutic gain of a given magnitude. ADVANTAGES AND DISADVANTAGES OF CAPD Continuous dialysis techniques achieve steady-state concentrations, which are presumably advantageous compared to the fluctuating levels seen with intermittent therapy (Table 1). Yet, the persistence of moderately high solute levels or of activated compensatory mechanisms could be worse than more complete correction of severe abnormalities, albeit transiently. It is known, however, that rapid correction of severe azotemia can itself induce Table 1. Some Benefits and Limitations of CAPD ADYANTAGES

DISADVANTAGES

Steady-state homeostasis Hemodynamic tolerance Highly permeable membrane remoyes peptides Simplicity Freedom from machine dependence Ease of training Lower extracellular fluid volume Improved nutritional indices

Excessive glucose load Continued necessity for sterile exchange Time-consuming fluid exchange Boredom with technique Marginal elimination efficiency Delicate peritoneum vulnerable to injury Protein loss

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symptoms. Rapid fluid shifts frequently are poorly tolerated hemodynamically. Moreover, high-efficiency hemodialyzers can function at rates that exceed metabolic tolerance, e.g., of absorbed acetate, suggesting that for limiting morbidity, steady-state control is preferable. The energy expenditure for conversion of lactate or acetate to bicarbonate is considerable, and the weekly load of anionic buffer precursors with CAPD is less than half that of conventional hemodialysis. In contrast to peritoneal dialysis, the glucose load with hemodialysis is negligible; glucose absorption may range from 100 to 300 g daily with CAPD, especially when hypertonic dextrose is required to remove excess fluid. Prolonged dwell of dialysate promotes continued dextrose absorption while diminishing ultrafiltration, lowering the cost-benefit ratio when expressed as volume ultrafiltered per gram absorbed. 21 Obvious consequences of dextrose absorption are the obesity and anorexia that ensue and often limit protein intake. Of long-term concern are the metabolic consequences that may promote atherosclerosis. Most patients achieve adequate ultrafiltration to yield a normal or even low extracellular fluid volume, and acutely, the glucose load is well tolerated even by diabetic patients. Indeed, when corrected for about 20% absorption, insulin can be given intraperitoneally and can achieve euglycemia. Alternatives to dextrose as osmotic agents have not yet proved preferable, but new agents continue to be investigated. 23, 2B,32 Larger solutes would seem to be advantageous as osmotic agents because their rate of absorption by diffusion would be slower than that of dextrose. However, their absorption by convection via the lymphatics would remain constant, and removal by back flux into dialysate would be very slow. The metabolic disposition of an osmotic agent may be the factor limiting its use. The high permeability of the peritoneum disadvantageously promotes protein elimination into the dialysate, The protein loss often exceeds 5.0 g/ day; several grams of peptides are also lost in the dialysate. This deficit is overcome by ensuring a protein intake exceeding 1.0 g/kg/day. Otherwise, protein malnutrition occurs rapidly, particularly when losses are aggravated by peritonitis. Understanding the mechanisms of transperitoneal protein transfer could lead to methods for selective inhibition of the protein loss while maintaining maximal transfer rates of smaller solutes. Most patients show nutritional indices that are closer to normal than those of uremic patients not undergoing dialysis or treated by hemodialysis. The efficiency of the peritoneum in solute removal is marginal enough that inadequate dialysis can result unless sufficient fluid volumes are exchanged and the peritoneum remains functionally intact. The reduction in dialysis to only three or four nocturnal exchanges without a diurnal dwell may be inadequate to control uremia. Even three evenly spaced circadian exchanges may control uremia insufficiently in anuric patients; hence, pharmacologic methods to accelerate solute mass transfer and augment fluid flux continue to be studied. 16 Isoproterenol and nitroprusside given intraperitoneally have had some clinical trials, but these efforts remain investigative. It is well to remember, however, that dipyridamole, when given orally to patients with increased platelet aggregation, will accelerate peritoneal transport, even though salutary effects in those with normal vascu-

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lature and coagulation indices are only marginal. Moreover, when vasopressors are required, norepinephrine should be expected to decrease peritoneal transport parameters, unlike dopamine, which may even increase them. 12 The simple expedient of raising the dialysis fluid exchange volume from 2.0 to 2.5 or 3.0 L when tolerated increases efficiency by 25 to 50%, or even higher when this increases the fluid contact with the peritoneum. 30 Increased dialysate volume is tolerated by most patients, although hernia occasionally complicates CAPD. Physicians must be aware of indices of adequacy of dialysis as applied to CAPD by Teehan et al. 28 Increased dialysate volume, more frequent exchanges, or pharmacologic augmentation of transport rate may be required to insure appropriate treatment. SURVIVAL ON CAPD AND COMPLICATIONS

Despite treatment of numerous high-risk patients and many limitations of the peritoneal dialysis technique, the results of CAPD can be considered hlvorable. 20 Cumulative mortalitv rates are below 20% at 12 months, less than 30% at 24 months, and u~der 40% at 36 months. A number of additional patients withdraw to other treatments. After several years, however, 50% of patients remain on CAPD, with the mortality and withdrawal rates highest in the first year. Although poor dialysis efficiency can contribute to mortality, to complications, or to transfer to an alternative treatment, the major problem complicating peritoneal dialysis and leading to mortality or to discontinuation of this form of treatment is peritonitis. Most reports now report an incidence of peritonitis of one episode every 9 to 24 months, many of which are caused by Staphylococcus epidermidis and resolve with antibiotic treatment without sequelae. Other organisms resist treatment and more likely lead to catheter replacement or withdrawal from peritoneal dialysis. Technologic improvements in the sterile fluid-exchange technique and training in meticulous care have lowered appreciably the incidence of infection within the past several years. These improvements justifY a stronger focus on the limitations of peritoneal dialysis imposed by low transfer efficiency and on methods to augment peritoneal transfer rates. Other complications of chronic peritoneal dialysis include hernia, which relates to intraperitoneal volume and pressure, as do dialysate leaks and back pain. Chronic volume depletion may lead to chronic hypotension and exacerbation of peripheral vascular disease. The membrane may deteriorate, leading to loss of surface area and poor solute transfer or to loss of ultrafiltration with hyperpermeability or to sclerosing peritonitis. Protein malnutrition, hypertriglyceridemia, obesity, and carbohydrate intolerance may also ensue with the chronic use of peritoneal dialysis. Finally, the patient may sense burnout and become depressed. Like other dialysis procedures, CAPD is an imperfect treatment. Methods to reverse renal injury or to insure successful renal transplantation safely are more desirable goals than improvements in long-term dialysis treatment. Because renal failure often progresses despite our best efforts. terminal renal failure usually is not reversible. Moreover, transplant recip(i

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ients are a limited, select group. Hence, dialysis continues to be required for managing most patients with end-stage renal failure, and CAPD has taken its place as a successful form of dialysis. Unless major unforeseen advances in hemodialysis treatment occur, it is unlikely that CAPD will disappear as a treatment option during the foreseeable future. The potential for greater preference for this treatment relates to solving some of the problems of CAPD, such as low efficiency and peritonitis. The excellent results achieved at many centers worldwide do not justify a bias against this method of dialysis.

REFERENCES 1. Breborowicz A, Rodela H, Oreopoulos DG: Effect of various factors on peritoneal lymphatic Row in rabbits. Peritoneal Dial Bull 9:85-90, 1989 2. Brown ST, Ahearn DJ, Nolph KD: Potassium removal with peritoneal dialysis. Kidney lnt 4:67-69, 1973 3. Di Paolo N, Buoncristiani V, Gaggiotti E, et al: Improvement of impaired ultrafiltration after addition of phosphatidylcholine in patients on CAPD. Peritoneal Dial Bull 6:4445, 1986 4. Felt J, Richard C, McCaffrey C: Peritoneal clearance of creatinine and inulin in dogs: Effect of splanchnic vasodilators. Kidney Int 16:459-469, 1979 5. Flessner MF, Dedrick HL, Schultz J: Exchange of macromolecules between peritoneal cavity and plasma. Am J Physiol 248:HI5-H25, 1985 6. Gokal R, Baillod R, Bogie S, et al: Multicentre study on outcome of treatment in patients on continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2:172-178, 1987 7. Gotloib L, Shostak A, Jaichenco J: Huthenium red stained anionic charges of rat and mice mesothelial cells and basal lamina. The peritoneum is a negatively charged dialyzing membrane. Nephron 47:22-28, 1987 8. Heaton A, Johnston DG, Ward MK, et al: Glycerol instead of dextrose as an osmotic agent in CAPD. In Maher JF, Winchester JF (eds): Frontiers in Peritoneal Dialysis. Field, Rich and Assoc, New York, 1986, pp 255-260 9. Hirszel P, Chakrabarti EK, Bennett RR, et al: Perms electivity of the peritoneum to neutral dextrans. Trans Am Soc Artif Intern Organs 30:625-628, 1984 10. Hirszel P, Chakrabarti E, Maher JF: Exaggerated protein loss complicating peritoneal dialvsis results from increased diffusion. Peritoneal Dial Bull 6:141-143, 1986 11. Hirsz~1 P, Dodge K, Maher JF: Acceleration of peritoneal solute transport by cytochalasin D. Uremia Invest 8:85-88, 1984 12. Hirszel P, Maher JF: Pharmacological alteration of peritoneal transport. In Nolph KD (ed): Peritoneal Dialysis. Boston, Kluwer Academic Publishers, 1989, pp 184-198 13. Khanna R, ~Iactier R, Twardowski ZJ, et al: Peritoneal cavity Iymphatics. Peritoneal Dial Bull 6:113-121, 1986 14. Krediet RT, Koorman GCM, Koopman MG, et al: The peritoneal transport of serum proteins and neutral dextran in CAPD patients. Kidney Int 35:1064-1072, 1989 1.5. Lasrich M, Maher JM, Hirszel P, et al: Correlation of peritoneal transport rates with molecular weight. A method for predicting clearance. ASAIO J 2:107-113, 1979 16. Maher JF: Peritoneal transport rates: Mechanisms, limitations and methods for augmentation. Kidnev Int 18:S117-S120, 1980 17. "Iaher JF, Ben~ett HH, Hirszel P, et al: The mechanism of dextrose-enhanced peritoneal mass transport rates. Kidney Int 28:16-20, 198.5 18. ~Iaher JF, Chakrabarti E: Ultrafiltration by hyperosmotic peritoneal dialysis Rnid excludes intracellular solutes. Am J Nephrol 4:169-172, 1984 19. Maher JF, Hirszel P, Shostak A, et al: Prolonged intraperitoneal dwell decreases ultrafiltration coefficient in rabbits. Am J Kidney Dis 12:62-65, 1988 20. Maiorca R, Cancarini G, Manili L, et al: Comparative analysis after 6 years of results obtained with continuous ambulatory peritoneal dialysis and hemodialysis. Contrib NephroI5.5:221-230, 1987

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21. Nolph KD, Miller F, Rubin J, et al: New directions in peritoneal dialysis concepts and applications. Kidney lnt 18 (suppl 1O):SI11-S116, 1980 2 0 Nolph KD, Stoltz M, Maher JF: Altered peritoneal permeability in patients with systemic vaculitis. Ann Intern Med 75:753-755, 1971 23. Ronco C, Brendolan A, Braganatini L, et al: Studies on ultrafiltration in peritoneal dialysis: Influence of plasma proteins and capillary blood flow. Peritoneal Dial Bull 6:93-98, 1986 24. Shostak A, Chakrabarti E, Hirszel P, et al: Effects of histamine and its receptor antagonist on peritoneal permeability. Kidney Int 34:786-790, 1988 25. Shostak A, Hirszel P, Chakrabarti E, et al: Dihydroergotamine lowers peritoneal transfer rates: A hypervolemic transport decrease. Peritoneal Dial Bull 7:S69, 1987 26. Steinhauer HB, Schollmeyer P: Prostaglandin mediated loss of proteins during peritonitis in continuous ambulatory peritoneal dialysis. Kidney Int 29:584-590, 1986 27. Stephen RL, Atkins-Thor E, KolffWJ: Recirculating peritoneal dialysis with subcutaneous catheter. Trans Am Soc Artif Intern Organs 22:575-584, 1976 28. Teehan BP, Schleifer CM, Sigler MH, et al: A quantitative approach to the CAPD prescription. Peritoneal Dial Bull 5:152-156, 1985 29. Twardowski ZJ, Khanna R, Nolph KD: Osmotic agents and ultrafiltration in peritoneal dialysis. Nephron 42:93-101, 1986 30. Twardowski ZJ, Prowant BF, Nolph KD, et al: High volume low frequency continuous ambulatory peritoneal dialysis. Kidney Int 23:64-70, 1983 31. Wayland H: Transmural and interstitial molecular transport. In Legrain M (ed): Continuous Ambulatory Peritoneal Dialysis. Amsterdam, Excerpta Medica, 1980, pp 18-27 32. Winchester JF, Stegink LD, Ahmad S, et al: A comparison of glucose polymer and dextrose as osmotic agents in CAPD. In Maher JF, Winchester JF (eds): Frontiers in Peritoneal Dialysis. Field, Rich and Assoc, New York, 1986, pp 231-240

Address reprint requests to John F. Maher, MD Nephrology Division Uniformed Services U niversitv of the Health Sciences 4301 Jones Bridge Road . Bethesda, MD 20814-4799