Blood Purif 1992:10:136-147
Laboratory of Kidney and Electrolyte Metabolism, National Institutes of Health, Bethesda. Md„ USA
KeyWords Peritoneum Peritoneal dialysis Ultrafiltration Membrane transport Convection Interstitium
Net Ultrafiltration in Peritoneal Dialysis: Role of Direct Fluid Absorption into Peritoneal Tissue
Abstract ‘Net ultrafiltration’ in peritoneal dialysis refers to the differ ence between the osmotically induced ultrafiltration into the peritoneal cavity and the fluid loss from the cavity during dial ysis. Recent research has demonstrated that, during a 3- to 4-hour experimental dialysis, 5-25% of the total fluid loss is via lymphatics and the remaining fluid is absorbed directly into the tissue surrounding the peritoneal cavity. The driving force for this convection into tissue is the hydrostatic pressure gradient between the peritoneal cavity and the tissue, which ranges from 2 to 8 mm Hg during the typical 2-Iiter dialysis in humans. Because the convection from the cavity occurs dur ing periods of a positive net ultrafiltration, the peritoneum and its underlying tissue cannot be represented as a single membrane but function as a composite of ‘tight’ and ‘loose’ membranes. More data on the mechanical properties of the peritoneal tissue space and its response to hydrostatic pressure in the cavity are required before we fully understand fluid transport at the tissue level.
Introduction Early practitioners of peritoneal dialysis noted that an isotonic salt solution was ab sorbed into the body during the procedure. In order to withdraw fluid from patients, they added 2-5% glucose to make the solution hypertonic [1, 2], Since that time, nephrolo-
gists have adjusted the hypertonicity by vary ing the glucose concentration in dialysis solu tions in accordance with the fluid balance of their patients. The term ‘net ultrafiltration' refers to the volume of fluid drained from a dialysis patient which is in excess of the amount instilled. This net transport of fluid equals the difference between osmotically
Michael F. Flessner. MD. PhD Nephrology Unit, Department of Medicine tJ diversity o f Rochester School of Medicine 601 Elmwood Ave Rochester. NY 14642 (USA)
© 1992 S. Karger AG. Basel 0253-5068/92/ 0104-0136S2.75/0
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Michael F. Flessner
Background A nim al Studies
Courtice and Steinbeck [6] demonstrated that plasma or isotonic solutions containing protein were absorbed without sieving at the peritoneum. Their experiments utilized low volumes and were designed to examine lym phatic removal of fluid and protein from the cavity. When thay tied off the parasternal lymphatics, the rates of absorption decreased by more than 50%. They were the first to demonstrate that the subdiaphragmatic lym phatic system, which flows to the parasternal lymphatics, was a major route of fluid re moval from the peritoneal cavity. Zink and Greenwav [7] showed that the rate of fluid absorption from the cavity is directly proportional to the intraperitoneal hydrostatic pressure. The rate of absorption
i.p. protein concentration, g/100 ml
Fig. 1. Bidirectional transport rates of labelled se rum albumin between the blood and peritoneal cavity, i.p. hydrostatic pressure was held constant at 15 mm Hg. The i.p. concentration of serum albumin was varied between l and 8% (by weight) [from 8).
was unaffected by the presence of protein (0 or 8% bovine serum albumin. BSA). and there was no apparent sieving of the protein by the peritoneum. McKay et al. [8] extended these findings by carrying out experiments in which the intraperitoneal (i.p.) pressure was held constant, the i.p. protein concentration was varied between l .4 and 8% BSA, and the bidi rectional transport of labelled BSA was stud ied. As shown in figure l, the rate of protein disappearance was directly proportional to the protein concentration in the cavity. They also found that the rate of protein disappear ance was proportional to the rate of fluid absorption and that neither rate changed from hour to hour over a total of 6 h. The low rate of entry of intravenously administered pro tein into the peritoneal cavity was unaffected by the protein content in the cavity. This dis counted the possibility of significant recircu lation of labelled protein in these experi ments. Nolph et al. [9] showed that protein moved out of the peritoneal cavity at the same rate whether the dialysis solution was isotonic or
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driven water transport into the cavity and fluid loss from the cavity. The flux of fluid into the cavity presumably results from the osmotic extraction of water from blood ves sels in the tissue surrounding the peritoneal cavity. Fluid loss from the peritoneal cavity, which is thought to be due to a combination of direct absorption into the surrounding tissue and peritoneal lymph flow [3], decreases the net ultrafiltration and the dialysate recovery. In the following, the physiologic mecha nisms which underlv net ultrafiltration will be discussed. Recent studies have pointed to the importance of the intraperitoneal hydrostatic pressure as a major force in the peritoneal fluid absorption. While the direct passage into lymph from the cavity is significant, most of the fluid loss results from direct absorption into the surrounding tissue [4, 5], These stud ies have generated new questions concerning the true structure and function of the anatom ical peritoneum and of its underlying tissue.
Blood capillary
I
Fig. 2. Two-compartment model of protein trans port between the blood and the peritoneal cavity.
Fig. 3. Pathways of solute and water absorption from the peritoneal cavity.
hypertonic (15% dextrose). However, they did not measure the hydrostatic pressure in the cavity. They assumed that protein (and presumably water) passed directly into subdiaphragmatic lymphatics, since the massive influx of fluid into the cavity in the case of hypertonic dialysis did not seem to slow the rate of protein removal from the cavity. These findings show that removal of pro tein solutions from the peritoneal cavity in volves the subdiaphragmatic lymphatics. The rate of fluid absorption is dependent on the intraperitoneal hydrostatic pressure but inde pendent of the i.p. osmotic pressure. Protein in solution in the peritoneal cavity is a marker of peritoneal fluid movement, because it is not sieved as it is being removed. In each of these studies, the authors did not measure transport of protein into tissue or into plasma. They made the assumption that the rate of protein removal from the cavity was equal to the rate of lymph flow.
and the peritoneal cavity, separated by a hy pothetical ‘membrane' [ 10], Figure 2 illus trates a two-compartment version of this model for protein transport. The membrane which separates the blood and the cavity allows a capillary leak or some means for a slow rate of protein entry. The only pathway for protein transport from the cavity is as sumed to be the lymphatic system. In general, the function of the lymphatics is to transfer water, solutes, protein and cells from the tis sue interstitium to the blood. In the case of the peritoneal cavity, all the authors cited above used some form of the model in figure 2 and made the assumption that what left the perito neal cavity arrived in the blood in a relatively short amount of time. None of them, how ever, confirmed their assumption by complet ing the mass balance between the cavity and the blood for the protein being transported.
Peritonea! Membrane Hypothesis and Lymph Flow
Since its beginnings, peritoneal dialysis has been modelled as transport between the blood
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Clinical Studies Several investigators have carried out stud ies of protein removal from the cavity of peri toneal dialysis patients [11. 12] and patients with ascites [13]. Radiolabelled serum albu min was included in the dialysis solution [11,
Absorption from the Peritoneal Cavity
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I
Disappearance from the peritoneal cavity, ml/h
Appearance in the plasma, ml/h
n
Patient type
Reference
90.7 ± 10.9 59.7 ± 7.5 2 0 l ± l 13
21.0± 1.6 11.1 ± 1.4 32.7 ±6.7
7 10 6
CAPD CAPD Cirrhosis
11 12 13
12] or injected into the ascitic fluid [ 13], Both the disappearance from the cavity and the uptake into the blood compartment were monitored, in order to complete the mass bal ance. Table 1 summarizes the findings of these studies. The data demonstrate the marked discrepancy between disappearance of the tracer from the peritoneal cavity and its appearance in plasma and indicate that the assumption of equal rates of protein loss from the peritoneal cavity and uptake by the blood is not correct. The "peritoneal membrane’ model would therefore appear to be of limited usefulness in describing protein removal from the peritoneal cavity.
Protein Transport into Peritoneal Tissue Protein Transport at the Tissue Level The peritoneal membrane hypothesis (fig. 2) has recently been challenged on ana tomical grounds [14], theoretical arguments [ 15], and physiologic considerations [ 16]. Fig ure 3 depicts the pathways for absorption of water and solutes from the peritoneal cavity into all surrounding tissue, with the exception of the diaphragm. (The subdiaphragmatic lymphatics are a specialized system of stoma ta. lacunae, and collecting lymphatics, which function with the contraction and relaxation of the diaphragmatic muscle [17, 18].) Al though pathophysiologic animal models of
peritonitis have demonstrated increased rates of glucose loss and protein appearance in the cavity after mechanical injury to the mésothé lium, changes to the underlying tissue could not be excluded [ 19], In studies of normal ani mals. the mésothélium provides little resis tance to the transport of protein or fluid, but the tissue interstitium presents a significant barrier [16], While small solutes and water readily transfer between the blood capillary lumen and the interstitium. protein transport from the interstitium into the blood capillar ies is very restricted [20]. The major route for removal of protein from the interstitium is the intratissue lymphatic capillary. Once the protein is in the lymph vessel, its transit time to the blood is in the order of minutes [approximatelylO min in rats, 21], The protein is cleared from the tissue at different rates, de pending on the density and distribution of the lymphatic capillaries. To summarize, if there is a protein solu tion in the peritoneal cavity, the interstitium of each tissue surrounding the cavity becomes a site of absorption of fluid, small solutes, and protein. Evidence o f Direct Protein Transport into Peritonea! Interstitium
Studies in rats [21,22] have demonstrated that proteins are directly transported from the peritoneal cavity into the surrounding inter stitium.
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Table 1. Comparison of tech niques for measuring transport of l2sI-serum albumin injected i.p. in humans
ttttttt
TTTTT
& jl _ t i _ j- v =
i.p. absorption of ,25I-HSA in Krebs-Ringer
A V y ^
0.1-1
0.01
1 Î
a 7 A .
5 5 ^
t
n
T
-
250 500 750 Distance from peritoneum, pm
■ Abdominal wall (n = 7) a
Liver (n = 3)
1.000
o Diaphragm (n = 3) y Small intestine (n = 11)
Fig. 4. Concentration profiles (mean ± SE. based on total tissue volume, measured by quantitative autoradioagraphy of freeze-dried, whole-body sections) of labelled human serum albumin (HSA) in tissue sur rounding the peritoneal cavity of rats. Concentrations were measured by quantitative autoradiography of freeze-dried, whole-body sections. The values are based on total tissue volume and normalized by the initial concentration in the cavity. Dialysis time w'as 120 min. Dialysis solution was an isotonic KrebsRinger solution with 5% BSA[from 22], I = 200 min.
The loss of l25I-fibrinogen in an isotonic salt solution from the peritoneal cavity of anesthetized rats was observed under condi tions of varying intraperitoneal hydrostatic pressures [21]. Rates of fibrinogen and vol ume loss from the cavity were directly propor tional to the intraperitoneal hydrostatic pres sure. and these findings verified the earlier
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Absorption from the Peritoneal Cavity
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1 0 -,
data of Zink and Greenway [7], The authors also measured the plasma appearance of the tracer in order to estimate the lymph flow. [Plasma appearance may actually overesti mate the true lymph flow if some tracer enters the bloodstream directly; pers. commun.. Johnston.] They found that the rate of fibrino gen appearance in the plasma was indepen dent of intraperitoneal pressure and was only 5-25% of the total rate of fibrinogen disap pearance from the peritoneal cavity. Most of the labelled protein which had been trans ferred from the cavity but had not arrived in the blood was recovered in the surrounding tissues. One third of this protein was found in the anterior abdominal wall. Measurements of tissue concentration pro files of serum albumin absorbed from the peritoneal cavity have demonstrated that a hydrostatic pressure-driven convection is the most likely mechanism underlying this pro cess [22]. Figure 4 illustrates these concentra tion profiles (based on total tissue volume), which were measured with quantitative auto radiography of freeze-dried, whole-body sec tions of the peritoneal cavity after a 2-hour dialysis with an isotonic Krebs-Ringer solu tion containing unlabelled BSA (5%) and la belled human serum albumin. Concentra tions in the diaphragm would be anticipated to be high, because of the specialized lym phatic system [17, 18], which includes an extensive system o f ‘stomata" opening to subdiaphragmatic compartments called ‘lacunae" and which drain 70-80% of the peritoneal lymph [21]. Visceral tissue profiles displayed decreasing concentrations with increasing dis tance from the peritoneal surface. Protein en try into these tissues is evidently more re stricted than into the diaphragm and their lymphatic systems transport protein away from the interstitium as it enters [23]. The high concentrations in the anterior abdominal wall were something of a surprise.
Unlike the visceral tissue, the abdominal wall has few intratissue lymphatics [24], and protein transporting into its interstitium may take 24-36 h to transport into lymphatics [25]. Therefore the resulting profile is much flatter than in the viscera. The abdominal wall also has a measurable pressure gradient di rected from inside the cavity to the exterior of the skin (equal to the i.p. hydrostatic pres sure), which can drive convection of fluid and solutes from the cavity into the tissue [16,22]. That the observed transport into the abdomi nal wall is primarily convective is evidenced by the large concentration shown in figure 4. Diffusion is the passive process by which sol utes move from areas of higher concentration to areas of lower concentration. Since the vol ume fraction of whole tissue which is avail able to serum albumin is 10-30% [26-28]. the concentration profile of the tissue should not rise above 0.3 of the peritoneal concentration if the dominant transport process is diffusion. However, protein can be concentrated if it is dragged along by convection (fluid move ment) and then sieved within the tissue at the capillary endothelium. As shown in figure 4, the tissue concentration profile in the abdom inal wall is nearly equal to the peritoneal con
Osmotic pressure-driven convection
Blood capillary exchange
centration. Since there was no evidence of extraordinary edema, the interstitial concen tration must be at least 3 times the peritoneal concentration. This high interstitial concen tration can only result from direct convection into the tissue. An alternative model of transport to fig ure 2, which includes the tissue space, is shown in figure 5. The diagram illustrates the major routes of fluid exchange between the peritoneal cavity and the blood. (From fig ure 3 we know that, anatomically, a portion of the blood compartment is contained within capillaries distributed throughout the perito neal tissue. In order to keep the diagram sim ple. the capillaries have been removed from the tissue compartment.) Fluid is transported from the cavity by diaphragmatic lymphatics (and various other lymph channels) directly into the blood or by hydrostatic pressuredriven convection into the tissue. Fluid and solute which are transported into the tissue can be transferred to the blood via intratissue lymphatics or blood capillary exchange. Fluid can also enter the peritoneal cavity during peritoneal dialysis with a hypertonic solution, which induces a convection from blood vessels within the tissue into the peritoneal cavity.
Ml
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Fig. 5. Three-compartment model of fluid transport between the peritoneal cavity and the blood.
Table 2. Protein solution absorption in rats
Dialysis solution
Isotonic Hypertonic
Fluid Fluid Estimated lymph absorption rate1 absorption rate2 flow rate3 pl/min pl/min pl/min 32 ±2.0 -21.2 ±10.5
39.5 ±5.9 38.7 ±3.2
8.5 ±0.5 8.6 ±1.0
Effect o f Hypertonic Dialysate on Protein Transport
All of the experiments described in the sec tion above were performed with isotonic dial ysis solutions. These solutions result in fluid absorption from the peritoneal cavity into the body. Hypertonic solutions, however, induce an osmotically driven fluid flux into the cavi ty. If protein transport from the peritoneal cavity is primarily convective, then a fluid flux in the opposite direction should decrease or reverse the protein transport. Nolph et al. [9], however, observed that protein was re moved from the peritoneal cavity of rats dur ing a hypertonic dialysis at the same rate as protein in an isotonic dialysis. They did not measure uptake in the blood or the peritoneal tissue, so the mechanism of protein transport was not clear. Recent studies in rats [4, 5] were specifi cally designed to investigate the protein trans port phenomena observed by Nolph et al. [9], within the context of the model presented in figure 5. Transport of labelled immunoglobu lin into tissue was measured in experiments in which the i.p. hydrostatic pressure was the same for each case, but the initial dialysate osmolality was varied between 300 and 450 mOsm/kg H^O by the addition of manni tol. This experiment was designed to cause fluid to be driven into the tissue at the same
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rate with each dialysate type, by maintaining the equivalent i.p. hydrostatic pressure in each case. The hypertonic solution would in duce an osmotic water flux in the opposite direction, i.e.. from blood vessels within the tissue into the cavity. Table 2 compares the calculated absorption rates of fluid removal based on observed volume and protein losses with the estimated lymph flow rate based on protein appearance in the plasma. The results for IgG in an isotonic solution are analogous to those of previous studies with fibrinogen [21], The results from the hypertonic dialysis solution confirm the findings of Nolph et al. [9], but also demonstrate that the transfer of protein to the plasma (estimated lymph flow) is unaffected by the hypertonicity of the dialy sis solution. As shown in figure 6, protein con centrations in tissue increase with time. With the exception of the anterior abdominal wall, there are only small differences between con centrations obtained with either isotonic or hypertonic solution at 20 min (following the time of peak osmotic water influx). There are essentially no differences between the results for each solution at 200 min. Figure 7 illus trates the corresponding tissue concentration profiles in intestinal tissue. Because the water influx into the cavity dilutes the protein in the cavity, the concentration profiles of intestinal tissue in figure 7 have been normalized by the
Absorption from the Peritoneal Cavity
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1 Based on observ ed volume loss. 2 Based on observed protein loss. 3 Based on plasma appearance.
0.500 -i
0.400
Isotonic dialysate: Krebs-Ringer + 5% BSA Hypertonie dialysate: Krebs-Ringer + 5% BSA + 4% mannitol
20-min isotonic Hl 20-min hypertonic
□ □
200-min isotonic 200-min hypertonic
I
ö 0.300-
I 1
0.200
0.100-
am Liver
Spleen
Stomach
Sm Int
L Int Tissue
Cecum
Diaph
Ant Wall
Ret Mus
Fig. 6. Accumulation of IgG in tissues surrounding the peritoneal cavity during dialysis in rats. Data is expressed in concentration (mean ± SE. based on total tissue volume and nor malized by the initial concentration in the peritoneal cavity). Experiments were performed with either isotonic or hypertonic dialysate; data was taken at 20 and 200 min. Sm Int = Small intestine: L Int = large intestine: Diaph = diaphragm: Ant Wall = anterior abdominal wall: Ret Mus = retroperitoneal muscle [from 4], l25I-IgG (human) was added to each dialysate.
hypertonic case were shown to be due pri marily to dilution of the peritoneal contents by the incoming water. Diffusion of protein was calculated to play only a minor role in the tissue deposition of protein [see 4. 5. for details]. Hypothesis concerning the Nature o f the Peritoneum
The preceding discussions have indicated that there are two relatively independent con vective processes occurring during a hyper-
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final peritoneal concentration. The results demonstrate minor differences in protein concentration between the isotonic and hy pertonic dialysate cases at 20 min near the peritoneal surface. However, in general, the 20- and 200-min curves are nearly superim posed. This means that protein transport deep into the surrounding tissue occurs in the hy pertonic case at nearly the same rate as in the isotonic case. This movement is in the face of an apparent flux of water from the tissue. The lower concentrations at 20 and 200 min in the
tonic dialysis, which move fluid in opposite directions. As shown in figure 5, there is a hydrostatic pressure-driven flux which causes fluid and solutes to move into the tissue, and there is an osmotically driven flux, which draws water into the cavity but apparently does not block the water flux out of the cavity. One possible mechanism for these two pro cesses is shown in figure 8. This drawing por trays a hypothetical mesothclium. which sep arates the peritoneal cavity and the underly ing tissue. It is functionally analogous to a het erogeneous membrane, which has been used to model the capillary endothelium [20], In this hypothesis, over most of the perito neal area there exist relatively large gaps be tween mesothelial cells. These gaps permit peritoneal water, small solutes and protein to have ready access to the underlying tissue space. The gaps are so large that there is no osmotic pressure difference between the tis sue and the cavity. The only force which can
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Fig. 8. Hypothetical peritoneal structure to explain how osmotically driven convection into the cavity can occur simultaneously with hydrostatic pressure-driven fluid and protein removal from the cavity. P = Hydro static pressure; n = osmotic pressure. Large circles represent protein: small circles, glucose or small mole cules. Arrows indicate the direction of movement. Sec text for details.
Absorption from the Peritoneal Cavity
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Fig. 7. Concentration profiles (mean ± SE) of IgG in intestinal tissue surrounding the peritoneal cavity. Data was obtained by quan titative autoradiography of freezedried, whole-body sections of the rat peritoneal cavity. Concentra tions are based on total tissue vol ume and normalized by the final peritoneal concentration. Experi ments were performed under the same conditions as in figure 6 [from 5]. ,25I-IgG (human) was added to each dialysate.
Fig. 9. Hydrostatic pressure in the peritoneal cavity of dialysis pa tients as a function of i.p. volume and position. Reference points were chosen as the highest anatom ical point in the cavity. 1 = Accord ing to Twardowski et al. [30]: 2 = according to Gotloib et al. [31],
Clinical Implications and Design of Future Experiments Research in animals [4-9. 21. 22] and in humans [11-13] has shown that fluid and large solutes are removed from the peritoneal cavity at equivalent rates. While 5-25% of the solution leaving the cavity passes directly into the lymphatics, the remainder is transported directly into the surrounding tissue interstitium. The water and solutes which have trans ferred into the interstitium will be taken up byblood or lymph capillaries in accordance with the local Starling's forces and the intratissue blood and lymph capillary distribution. The driving force for the convective movement into tissue is intraperitoneal hydrostatic pres sure. Figure 9 displays the correlations from two sets of data for intraperitoneal pressure versus intraperitoneal volume in human subjects [30. 31], Reference points in each study were chosen to be the highest point in the abdo men; this would result in the lowest pressure. For a given dialysis volume, the pressure is
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drive fluid in either direction is hydrostatic pressure. Because of the near-zero hydrostatic pressure and the compliance properties of the interstitium [16], there will be a pressure gra dient during dialysis to drive solution from the cavity to the tissue. The fluid and small solutes which transport into the tissue will be taken up by blood capillaries distributed throughout the space in accordance with the local Starling forces. Large proteins will be taken up by intratissue lymphatics. In other regions of the peritoneum, there exist functionally tight membranes near the mésothélial surface, such as superficial blood capillaries in the mesentery and intestinal loops. Small solutes can induce osmotic pres sure gradients across these vessels, which re sult in a relatively solute-free water flux into the cavity. Since these exchange capillaries probably cover less than 10-20% of the total mésothélial area [29], this flux would prevent convection into only a small total area of tis sue. The amount of heterogeneity of protein deposition would likely go unnoticed in the experimental studies discussed above [4. 5],
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magnitude to those experienced by humans. Many investigators extrapolate dialysis vol umes used in humans (generally about 2 li ters) by multiplying by a ratio of body weights. For example, for a 200-gram rat. the volume would be 5.7 ml [(200/70,000) X 2.000 ml]. This volume produces almost no measurable intraperitoneal pressure in the rat. Other groups [ 12] have advocated using the body weight to the 0.7 power: for the 200gram rat. this results in a volume of 30.2 ml [(200/70.000)0-7 X 2.000 ml]. This larger vol ume in a supine, anesthetized rat produces pressures of 2-5 mm Hg [ 18], which is in the range for supine patients (fig. 9). This latter factor (BW°-7) or the actual recorded i.p. pres sure is a more appropriate scaling factor when the purpose is the examination of the trans port forces governing peritoneal absorption. Further, the mass transfer coefficient (PA) for small hydrophilic molecules varies as about the 0.7 power of the body weight [15]. Thus the time scale of small molecule transport (peritoneal volume/permeability-area prod uct) is similar across species if BWU7scaling is used. There is much that is not known about the tissue space surrounding the peritoneal cavi ty. The hypothetical representation of the peritoneum presented in figure 8 may or may not be correct, and the mechanisms of net ultrafiltration warrant further investigation. There is little data on the mechanical proper ties of the peritoneal interstitium that deter mine rates of convection. A convective driv ing force exists which drives significant amounts of fluid and protein into the anterior abdominal wall. However, the intratissue pressure profile has not yet been measured. Detailed knowledge of the mechanisms of convection in the abdominal wall may lead to therapies capable of manipulating pressure gradients in order to obtain larger net ultrafil tration [32].
Absorption from the Peritoneal Cavits
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dependent on the position of the patient. From these curves, the pressure in the cavity of a supine patient during a 2-liter dialysis will average between 2 and 8 mm Hg. The pres sure will rise as the patient gets up and moves about. This pressure provides the driving force necessary to cause fluid absorption from the peritoneal cavity and the apparent loss in net ultrafiltration. Therefore this pressure should be measured in any experiment in which the goal is the study of peritoneal trans port. The curves of figure 9 are quite different, depending on the group which conducted the study. It is possible that the two patient popu lations in which these studies were performed may have had very different compliance properties of the abdominal wall and this might have accounted for the differences in slope of the curves. But since the reference point and measurement device were equiva lent in each study, the i.p. pressure at zero vol ume should be the same. However in figure 9. the intercept of the curves for supine subjects with the y-axis for zero volume in the cavity are so different ( - I m m H g [30] vs. +1 mm Hg [31 ]) that it is likely the techniques of the groups were different. The variance in data demonstrates the difficulty of carrying out these studies. Careful consideration should be given to the goal of the pressure measurement prior to selection of the refer ence point. Patency of the catheter and low resistance to flow must be insured during all measurements, especially when the patient’s position is varied. Another major consideration in experi mental design is the scaling factor used to compare results obtained in different-sized species or to extrapolate from one species to another. In mammalian transport studies which are intended to simulate human pro cesses, it is important that the scaling process result in driving forces which are similar in
References 11 Daugirdas JT. Ing TS. Gandhi VC. l lano JE. Chen WT. Yuan L: Kinet ics of peritoneal fluid absorption in patients with chronic renal failure. J Lab Clin Med 1980:85:351-361. 12 Rippe B. Stelin G. Ahlmen J: Lymph flow from the peritoneal cavity in CAPD patients: in Maher JF. Winchester J F (eds): Frontiers in Peritoneal Dialysis. New York. Field. Rich. 1986. pp 24-30. 13 Dykes PW. Jones JH; Albumin ex change between plasma and ascites fluid. Clin Sci 1964:34:185-197. 14 Nolph DK. Miller F. Rubin J. Popo vich RP: New directions in perito neal dialysis concepts and applica tions. Kidney Int 1980:18(suppl 10): SI 11— SI 16. 15 Dedrick RL, Flessner MF. Collins JM. Schultz .IS: Is the peritoneum a membrane? ASAIO J 1982:5:1-8. 16 Flessner MF: Peritoneal transport physiology: Insights from basic re search. J Am Soc Nephrol 1991:2: 122-135. 17 Bettendorf U: Lymph flow mecha nism of the sub-peritoneal diaphrag matic-lymphatics. Lymphology 1978; 11:111-116. 18 Leak LV. Rahil K: Permeability of the diaphragmatic mésothélium: The ultrastructural basis for stoma ta'. Am J Anal 1978:151:557-594. 19 Verger C. Luger A. Moore HL. Nolph KD: Acute changes in perito neal morphology and transport properties with infectious peritoni tis and mechanical injury. Kidney Int 1983;23:823-831. 20 Rippe B. Haraldsson B: Fluid and protein fluxes across small and large pores in the microvasculature. Ap plication of two-pore equations. Acta Physiol Scand 1987:131:411428. 21 Flessner MF. Parker RJ. Sieber SM: Peritoneal lymphatic uptake of fi brinogen and ery throcytes in the rat. AraJ Physiol I983:244:H89-H96. 22 Flessner MF. Fenstermacher JD. Dedrick RL. Blasberg RG: Perito neal absorption of macromolccules studied by quantitative autoradiog raphy. Am J Physiol I985:248:H26H32.
23 Barrowman JA: Physiology of the Gastro-lntestinal Lymphatic Sys tem. Cambridge, Cambridge Uni versity Press. 1978, pp3-10. 24 Pearson CM: Circulation in skeletal muscle: in Abramson DI (ed): Blood Vessels and Lymphatics. New York. Academic Press. 1962. pp 520—521. 25 Bill A: Plasma protein dynamics: Al bumin and IgG capillary' permeabil ity. cxtravascular movement and re gional blood flow in unanesthetized rabbits. Acta Physiol Scand 1977; 101:28-42. 26 Bell DR. Watson PD. Renkin EM: Exclusion of plasma proteins in interstitium of tissues from the dog hind paw. Am J Physiol 1980:239: H532-H538. 27 Bell DR. Mullins RJ: Effects of in creased venous pressure on albu min- and lgG-excluded volumes in muscle. Am J Physiol 1982:242: H1044-H1049. 28 Mullins RJ. Bell DR: Changes in interstitial volume and masses of al bumin and IgG in rabbit skin and skeletal muscle after saline volume loading. Circ Res 1982:51:305-313. 29 Intaglietta M. Zweifach BW: Geo metrical model of the microvascula ture of the rabbit omentum from invivo measurements. Circ Res 1971: 28:593-600. 30 Twardowski ZJ. Prowant BF. Nolph KD: High volume, low frequency continuous ambulatory peritoneal dialysis. Kidney Int 1983:23:64-70. 31 Gotloib L. Mines M, Garmizo L, Varka 1: Hemodynamic effects of in creasing intra-abdominal pressure in peritoneal dialysis. Periton Dial Bull 1981:1:41-43. 32 Okamoto SN. Fox SD. Leypoldt JK. Henderson LW: Abdominal com pression (AC) reduces fluid absorp tion during peritoneal dialysis in the rabbit (abstract). 21st Annu Meet Am Soc Nephrol. San Antonio. 1988. p 126A.
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1 Heusser H. Wcrder H: Untersuchungen iibcr Peritonealdialyse. Bruns Beilr Klin Chir 1927; 141:3849. 2 Fine J. Frank H, Seligman AM: The treatment of acute renal failure by peritoneal irrigation. Ann Surg 1946:124:857-875. 3 Nolph KD. Twardowski ZJ: The peritoneal dialysis system: in Nolph KD (cd): Peritoneal Dialysis . ed 3. Boston. Kluwer Academic Publ. 1990. p 25. 4 Flcssner MF. Dedrick RL Reynolds JC: Bidirectional peritoneal trans port of immunoglobulin in rats: Compartmental kinetics. Am J Physiol 1992:262:F275-F287. 5 Ressner M. Dedrick RL. Reynolds JC: Bidirectional peritoneal trans port of immunoglobulin in rats: Tis sue concentration profiles. Am J Physiol 1992:263:FI 5— F23. 6 Courtice FC. Steinbeck AW: Ab sorption of protein from the perito neal cavity. J Physiol 1951:114: 336-355. ’ 7 Zink J. Greenway CV: Control of ascites absorption in anesthetized cats: Effects of intraperitoneal pres sure. protein, and furosemide diure sis. Gastroenterology 1977:73: 1119-1124. 8 McKay T. Zink J. Greenway CV: Relative rates of absorption of fluid and protein from the peritoneal cav ity in cats. Lymphology 1978; 11: 106-110. 9 Nolph KD. Mactier R. Khanna R. Twardowski ZJ. Moore H. McGary T: The kinetics of ultrafiltration during peritoneal dialysis: The role of lymphatics. Kidney Int 1987:32: 219-226. 10 Babb AL. Johansen PH. Strand MJ. Tcnckhoff H. Scribner BH: Bidirec tional permeability of the human peritoneum to middle molecules. Proc 10th Congr Eur Dial Trans plant Assoc 1973:10:247-262.
Laboratory of Kidney and Electrolyte Metabolism, National Institutes of Health, Bethesda. Md„ USA
KeyWords Peritoneum Peritoneal dialysis Ultrafiltration Membrane transport Convection Interstitium
Net Ultrafiltration in Peritoneal Dialysis: Role of Direct Fluid Absorption into Peritoneal Tissue
Abstract ‘Net ultrafiltration’ in peritoneal dialysis refers to the differ ence between the osmotically induced ultrafiltration into the peritoneal cavity and the fluid loss from the cavity during dial ysis. Recent research has demonstrated that, during a 3- to 4-hour experimental dialysis, 5-25% of the total fluid loss is via lymphatics and the remaining fluid is absorbed directly into the tissue surrounding the peritoneal cavity. The driving force for this convection into tissue is the hydrostatic pressure gradient between the peritoneal cavity and the tissue, which ranges from 2 to 8 mm Hg during the typical 2-Iiter dialysis in humans. Because the convection from the cavity occurs dur ing periods of a positive net ultrafiltration, the peritoneum and its underlying tissue cannot be represented as a single membrane but function as a composite of ‘tight’ and ‘loose’ membranes. More data on the mechanical properties of the peritoneal tissue space and its response to hydrostatic pressure in the cavity are required before we fully understand fluid transport at the tissue level.
Introduction Early practitioners of peritoneal dialysis noted that an isotonic salt solution was ab sorbed into the body during the procedure. In order to withdraw fluid from patients, they added 2-5% glucose to make the solution hypertonic [1, 2], Since that time, nephrolo-
gists have adjusted the hypertonicity by vary ing the glucose concentration in dialysis solu tions in accordance with the fluid balance of their patients. The term ‘net ultrafiltration' refers to the volume of fluid drained from a dialysis patient which is in excess of the amount instilled. This net transport of fluid equals the difference between osmotically
Michael F. Flessner. MD. PhD Nephrology Unit, Department of Medicine tJ diversity o f Rochester School of Medicine 601 Elmwood Ave Rochester. NY 14642 (USA)
© 1992 S. Karger AG. Basel 0253-5068/92/ 0104-0136S2.75/0
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Michael F. Flessner
Background A nim al Studies
Courtice and Steinbeck [6] demonstrated that plasma or isotonic solutions containing protein were absorbed without sieving at the peritoneum. Their experiments utilized low volumes and were designed to examine lym phatic removal of fluid and protein from the cavity. When thay tied off the parasternal lymphatics, the rates of absorption decreased by more than 50%. They were the first to demonstrate that the subdiaphragmatic lym phatic system, which flows to the parasternal lymphatics, was a major route of fluid re moval from the peritoneal cavity. Zink and Greenwav [7] showed that the rate of fluid absorption from the cavity is directly proportional to the intraperitoneal hydrostatic pressure. The rate of absorption
i.p. protein concentration, g/100 ml
Fig. 1. Bidirectional transport rates of labelled se rum albumin between the blood and peritoneal cavity, i.p. hydrostatic pressure was held constant at 15 mm Hg. The i.p. concentration of serum albumin was varied between l and 8% (by weight) [from 8).
was unaffected by the presence of protein (0 or 8% bovine serum albumin. BSA). and there was no apparent sieving of the protein by the peritoneum. McKay et al. [8] extended these findings by carrying out experiments in which the intraperitoneal (i.p.) pressure was held constant, the i.p. protein concentration was varied between l .4 and 8% BSA, and the bidi rectional transport of labelled BSA was stud ied. As shown in figure l, the rate of protein disappearance was directly proportional to the protein concentration in the cavity. They also found that the rate of protein disappear ance was proportional to the rate of fluid absorption and that neither rate changed from hour to hour over a total of 6 h. The low rate of entry of intravenously administered pro tein into the peritoneal cavity was unaffected by the protein content in the cavity. This dis counted the possibility of significant recircu lation of labelled protein in these experi ments. Nolph et al. [9] showed that protein moved out of the peritoneal cavity at the same rate whether the dialysis solution was isotonic or
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driven water transport into the cavity and fluid loss from the cavity. The flux of fluid into the cavity presumably results from the osmotic extraction of water from blood ves sels in the tissue surrounding the peritoneal cavity. Fluid loss from the peritoneal cavity, which is thought to be due to a combination of direct absorption into the surrounding tissue and peritoneal lymph flow [3], decreases the net ultrafiltration and the dialysate recovery. In the following, the physiologic mecha nisms which underlv net ultrafiltration will be discussed. Recent studies have pointed to the importance of the intraperitoneal hydrostatic pressure as a major force in the peritoneal fluid absorption. While the direct passage into lymph from the cavity is significant, most of the fluid loss results from direct absorption into the surrounding tissue [4, 5], These stud ies have generated new questions concerning the true structure and function of the anatom ical peritoneum and of its underlying tissue.
Blood capillary
I
Fig. 2. Two-compartment model of protein trans port between the blood and the peritoneal cavity.
Fig. 3. Pathways of solute and water absorption from the peritoneal cavity.
hypertonic (15% dextrose). However, they did not measure the hydrostatic pressure in the cavity. They assumed that protein (and presumably water) passed directly into subdiaphragmatic lymphatics, since the massive influx of fluid into the cavity in the case of hypertonic dialysis did not seem to slow the rate of protein removal from the cavity. These findings show that removal of pro tein solutions from the peritoneal cavity in volves the subdiaphragmatic lymphatics. The rate of fluid absorption is dependent on the intraperitoneal hydrostatic pressure but inde pendent of the i.p. osmotic pressure. Protein in solution in the peritoneal cavity is a marker of peritoneal fluid movement, because it is not sieved as it is being removed. In each of these studies, the authors did not measure transport of protein into tissue or into plasma. They made the assumption that the rate of protein removal from the cavity was equal to the rate of lymph flow.
and the peritoneal cavity, separated by a hy pothetical ‘membrane' [ 10], Figure 2 illus trates a two-compartment version of this model for protein transport. The membrane which separates the blood and the cavity allows a capillary leak or some means for a slow rate of protein entry. The only pathway for protein transport from the cavity is as sumed to be the lymphatic system. In general, the function of the lymphatics is to transfer water, solutes, protein and cells from the tis sue interstitium to the blood. In the case of the peritoneal cavity, all the authors cited above used some form of the model in figure 2 and made the assumption that what left the perito neal cavity arrived in the blood in a relatively short amount of time. None of them, how ever, confirmed their assumption by complet ing the mass balance between the cavity and the blood for the protein being transported.
Peritonea! Membrane Hypothesis and Lymph Flow
Since its beginnings, peritoneal dialysis has been modelled as transport between the blood
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Clinical Studies Several investigators have carried out stud ies of protein removal from the cavity of peri toneal dialysis patients [11. 12] and patients with ascites [13]. Radiolabelled serum albu min was included in the dialysis solution [11,
Absorption from the Peritoneal Cavity
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I
Disappearance from the peritoneal cavity, ml/h
Appearance in the plasma, ml/h
n
Patient type
Reference
90.7 ± 10.9 59.7 ± 7.5 2 0 l ± l 13
21.0± 1.6 11.1 ± 1.4 32.7 ±6.7
7 10 6
CAPD CAPD Cirrhosis
11 12 13
12] or injected into the ascitic fluid [ 13], Both the disappearance from the cavity and the uptake into the blood compartment were monitored, in order to complete the mass bal ance. Table 1 summarizes the findings of these studies. The data demonstrate the marked discrepancy between disappearance of the tracer from the peritoneal cavity and its appearance in plasma and indicate that the assumption of equal rates of protein loss from the peritoneal cavity and uptake by the blood is not correct. The "peritoneal membrane’ model would therefore appear to be of limited usefulness in describing protein removal from the peritoneal cavity.
Protein Transport into Peritoneal Tissue Protein Transport at the Tissue Level The peritoneal membrane hypothesis (fig. 2) has recently been challenged on ana tomical grounds [14], theoretical arguments [ 15], and physiologic considerations [ 16]. Fig ure 3 depicts the pathways for absorption of water and solutes from the peritoneal cavity into all surrounding tissue, with the exception of the diaphragm. (The subdiaphragmatic lymphatics are a specialized system of stoma ta. lacunae, and collecting lymphatics, which function with the contraction and relaxation of the diaphragmatic muscle [17, 18].) Al though pathophysiologic animal models of
peritonitis have demonstrated increased rates of glucose loss and protein appearance in the cavity after mechanical injury to the mésothé lium, changes to the underlying tissue could not be excluded [ 19], In studies of normal ani mals. the mésothélium provides little resis tance to the transport of protein or fluid, but the tissue interstitium presents a significant barrier [16], While small solutes and water readily transfer between the blood capillary lumen and the interstitium. protein transport from the interstitium into the blood capillar ies is very restricted [20]. The major route for removal of protein from the interstitium is the intratissue lymphatic capillary. Once the protein is in the lymph vessel, its transit time to the blood is in the order of minutes [approximatelylO min in rats, 21], The protein is cleared from the tissue at different rates, de pending on the density and distribution of the lymphatic capillaries. To summarize, if there is a protein solu tion in the peritoneal cavity, the interstitium of each tissue surrounding the cavity becomes a site of absorption of fluid, small solutes, and protein. Evidence o f Direct Protein Transport into Peritonea! Interstitium
Studies in rats [21,22] have demonstrated that proteins are directly transported from the peritoneal cavity into the surrounding inter stitium.
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Table 1. Comparison of tech niques for measuring transport of l2sI-serum albumin injected i.p. in humans
ttttttt
TTTTT
& jl _ t i _ j- v =
i.p. absorption of ,25I-HSA in Krebs-Ringer
A V y ^
0.1-1
0.01
1 Î
a 7 A .
5 5 ^
t
n
T
-
250 500 750 Distance from peritoneum, pm
■ Abdominal wall (n = 7) a
Liver (n = 3)
1.000
o Diaphragm (n = 3) y Small intestine (n = 11)
Fig. 4. Concentration profiles (mean ± SE. based on total tissue volume, measured by quantitative autoradioagraphy of freeze-dried, whole-body sections) of labelled human serum albumin (HSA) in tissue sur rounding the peritoneal cavity of rats. Concentrations were measured by quantitative autoradiography of freeze-dried, whole-body sections. The values are based on total tissue volume and normalized by the initial concentration in the cavity. Dialysis time w'as 120 min. Dialysis solution was an isotonic KrebsRinger solution with 5% BSA[from 22], I = 200 min.
The loss of l25I-fibrinogen in an isotonic salt solution from the peritoneal cavity of anesthetized rats was observed under condi tions of varying intraperitoneal hydrostatic pressures [21]. Rates of fibrinogen and vol ume loss from the cavity were directly propor tional to the intraperitoneal hydrostatic pres sure. and these findings verified the earlier
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Absorption from the Peritoneal Cavity
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1 0 -,
data of Zink and Greenway [7], The authors also measured the plasma appearance of the tracer in order to estimate the lymph flow. [Plasma appearance may actually overesti mate the true lymph flow if some tracer enters the bloodstream directly; pers. commun.. Johnston.] They found that the rate of fibrino gen appearance in the plasma was indepen dent of intraperitoneal pressure and was only 5-25% of the total rate of fibrinogen disap pearance from the peritoneal cavity. Most of the labelled protein which had been trans ferred from the cavity but had not arrived in the blood was recovered in the surrounding tissues. One third of this protein was found in the anterior abdominal wall. Measurements of tissue concentration pro files of serum albumin absorbed from the peritoneal cavity have demonstrated that a hydrostatic pressure-driven convection is the most likely mechanism underlying this pro cess [22]. Figure 4 illustrates these concentra tion profiles (based on total tissue volume), which were measured with quantitative auto radiography of freeze-dried, whole-body sec tions of the peritoneal cavity after a 2-hour dialysis with an isotonic Krebs-Ringer solu tion containing unlabelled BSA (5%) and la belled human serum albumin. Concentra tions in the diaphragm would be anticipated to be high, because of the specialized lym phatic system [17, 18], which includes an extensive system o f ‘stomata" opening to subdiaphragmatic compartments called ‘lacunae" and which drain 70-80% of the peritoneal lymph [21]. Visceral tissue profiles displayed decreasing concentrations with increasing dis tance from the peritoneal surface. Protein en try into these tissues is evidently more re stricted than into the diaphragm and their lymphatic systems transport protein away from the interstitium as it enters [23]. The high concentrations in the anterior abdominal wall were something of a surprise.
Unlike the visceral tissue, the abdominal wall has few intratissue lymphatics [24], and protein transporting into its interstitium may take 24-36 h to transport into lymphatics [25]. Therefore the resulting profile is much flatter than in the viscera. The abdominal wall also has a measurable pressure gradient di rected from inside the cavity to the exterior of the skin (equal to the i.p. hydrostatic pres sure), which can drive convection of fluid and solutes from the cavity into the tissue [16,22]. That the observed transport into the abdomi nal wall is primarily convective is evidenced by the large concentration shown in figure 4. Diffusion is the passive process by which sol utes move from areas of higher concentration to areas of lower concentration. Since the vol ume fraction of whole tissue which is avail able to serum albumin is 10-30% [26-28]. the concentration profile of the tissue should not rise above 0.3 of the peritoneal concentration if the dominant transport process is diffusion. However, protein can be concentrated if it is dragged along by convection (fluid move ment) and then sieved within the tissue at the capillary endothelium. As shown in figure 4, the tissue concentration profile in the abdom inal wall is nearly equal to the peritoneal con
Osmotic pressure-driven convection
Blood capillary exchange
centration. Since there was no evidence of extraordinary edema, the interstitial concen tration must be at least 3 times the peritoneal concentration. This high interstitial concen tration can only result from direct convection into the tissue. An alternative model of transport to fig ure 2, which includes the tissue space, is shown in figure 5. The diagram illustrates the major routes of fluid exchange between the peritoneal cavity and the blood. (From fig ure 3 we know that, anatomically, a portion of the blood compartment is contained within capillaries distributed throughout the perito neal tissue. In order to keep the diagram sim ple. the capillaries have been removed from the tissue compartment.) Fluid is transported from the cavity by diaphragmatic lymphatics (and various other lymph channels) directly into the blood or by hydrostatic pressuredriven convection into the tissue. Fluid and solute which are transported into the tissue can be transferred to the blood via intratissue lymphatics or blood capillary exchange. Fluid can also enter the peritoneal cavity during peritoneal dialysis with a hypertonic solution, which induces a convection from blood vessels within the tissue into the peritoneal cavity.
Ml
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Fig. 5. Three-compartment model of fluid transport between the peritoneal cavity and the blood.
Table 2. Protein solution absorption in rats
Dialysis solution
Isotonic Hypertonic
Fluid Fluid Estimated lymph absorption rate1 absorption rate2 flow rate3 pl/min pl/min pl/min 32 ±2.0 -21.2 ±10.5
39.5 ±5.9 38.7 ±3.2
8.5 ±0.5 8.6 ±1.0
Effect o f Hypertonic Dialysate on Protein Transport
All of the experiments described in the sec tion above were performed with isotonic dial ysis solutions. These solutions result in fluid absorption from the peritoneal cavity into the body. Hypertonic solutions, however, induce an osmotically driven fluid flux into the cavi ty. If protein transport from the peritoneal cavity is primarily convective, then a fluid flux in the opposite direction should decrease or reverse the protein transport. Nolph et al. [9], however, observed that protein was re moved from the peritoneal cavity of rats dur ing a hypertonic dialysis at the same rate as protein in an isotonic dialysis. They did not measure uptake in the blood or the peritoneal tissue, so the mechanism of protein transport was not clear. Recent studies in rats [4, 5] were specifi cally designed to investigate the protein trans port phenomena observed by Nolph et al. [9], within the context of the model presented in figure 5. Transport of labelled immunoglobu lin into tissue was measured in experiments in which the i.p. hydrostatic pressure was the same for each case, but the initial dialysate osmolality was varied between 300 and 450 mOsm/kg H^O by the addition of manni tol. This experiment was designed to cause fluid to be driven into the tissue at the same
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rate with each dialysate type, by maintaining the equivalent i.p. hydrostatic pressure in each case. The hypertonic solution would in duce an osmotic water flux in the opposite direction, i.e.. from blood vessels within the tissue into the cavity. Table 2 compares the calculated absorption rates of fluid removal based on observed volume and protein losses with the estimated lymph flow rate based on protein appearance in the plasma. The results for IgG in an isotonic solution are analogous to those of previous studies with fibrinogen [21], The results from the hypertonic dialysis solution confirm the findings of Nolph et al. [9], but also demonstrate that the transfer of protein to the plasma (estimated lymph flow) is unaffected by the hypertonicity of the dialy sis solution. As shown in figure 6, protein con centrations in tissue increase with time. With the exception of the anterior abdominal wall, there are only small differences between con centrations obtained with either isotonic or hypertonic solution at 20 min (following the time of peak osmotic water influx). There are essentially no differences between the results for each solution at 200 min. Figure 7 illus trates the corresponding tissue concentration profiles in intestinal tissue. Because the water influx into the cavity dilutes the protein in the cavity, the concentration profiles of intestinal tissue in figure 7 have been normalized by the
Absorption from the Peritoneal Cavity
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1 Based on observ ed volume loss. 2 Based on observed protein loss. 3 Based on plasma appearance.
0.500 -i
0.400
Isotonic dialysate: Krebs-Ringer + 5% BSA Hypertonie dialysate: Krebs-Ringer + 5% BSA + 4% mannitol
20-min isotonic Hl 20-min hypertonic
□ □
200-min isotonic 200-min hypertonic
I
ö 0.300-
I 1
0.200
0.100-
am Liver
Spleen
Stomach
Sm Int
L Int Tissue
Cecum
Diaph
Ant Wall
Ret Mus
Fig. 6. Accumulation of IgG in tissues surrounding the peritoneal cavity during dialysis in rats. Data is expressed in concentration (mean ± SE. based on total tissue volume and nor malized by the initial concentration in the peritoneal cavity). Experiments were performed with either isotonic or hypertonic dialysate; data was taken at 20 and 200 min. Sm Int = Small intestine: L Int = large intestine: Diaph = diaphragm: Ant Wall = anterior abdominal wall: Ret Mus = retroperitoneal muscle [from 4], l25I-IgG (human) was added to each dialysate.
hypertonic case were shown to be due pri marily to dilution of the peritoneal contents by the incoming water. Diffusion of protein was calculated to play only a minor role in the tissue deposition of protein [see 4. 5. for details]. Hypothesis concerning the Nature o f the Peritoneum
The preceding discussions have indicated that there are two relatively independent con vective processes occurring during a hyper-
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final peritoneal concentration. The results demonstrate minor differences in protein concentration between the isotonic and hy pertonic dialysate cases at 20 min near the peritoneal surface. However, in general, the 20- and 200-min curves are nearly superim posed. This means that protein transport deep into the surrounding tissue occurs in the hy pertonic case at nearly the same rate as in the isotonic case. This movement is in the face of an apparent flux of water from the tissue. The lower concentrations at 20 and 200 min in the
tonic dialysis, which move fluid in opposite directions. As shown in figure 5, there is a hydrostatic pressure-driven flux which causes fluid and solutes to move into the tissue, and there is an osmotically driven flux, which draws water into the cavity but apparently does not block the water flux out of the cavity. One possible mechanism for these two pro cesses is shown in figure 8. This drawing por trays a hypothetical mesothclium. which sep arates the peritoneal cavity and the underly ing tissue. It is functionally analogous to a het erogeneous membrane, which has been used to model the capillary endothelium [20], In this hypothesis, over most of the perito neal area there exist relatively large gaps be tween mesothelial cells. These gaps permit peritoneal water, small solutes and protein to have ready access to the underlying tissue space. The gaps are so large that there is no osmotic pressure difference between the tis sue and the cavity. The only force which can
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Fig. 8. Hypothetical peritoneal structure to explain how osmotically driven convection into the cavity can occur simultaneously with hydrostatic pressure-driven fluid and protein removal from the cavity. P = Hydro static pressure; n = osmotic pressure. Large circles represent protein: small circles, glucose or small mole cules. Arrows indicate the direction of movement. Sec text for details.
Absorption from the Peritoneal Cavity
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Fig. 7. Concentration profiles (mean ± SE) of IgG in intestinal tissue surrounding the peritoneal cavity. Data was obtained by quan titative autoradiography of freezedried, whole-body sections of the rat peritoneal cavity. Concentra tions are based on total tissue vol ume and normalized by the final peritoneal concentration. Experi ments were performed under the same conditions as in figure 6 [from 5]. ,25I-IgG (human) was added to each dialysate.
Fig. 9. Hydrostatic pressure in the peritoneal cavity of dialysis pa tients as a function of i.p. volume and position. Reference points were chosen as the highest anatom ical point in the cavity. 1 = Accord ing to Twardowski et al. [30]: 2 = according to Gotloib et al. [31],
Clinical Implications and Design of Future Experiments Research in animals [4-9. 21. 22] and in humans [11-13] has shown that fluid and large solutes are removed from the peritoneal cavity at equivalent rates. While 5-25% of the solution leaving the cavity passes directly into the lymphatics, the remainder is transported directly into the surrounding tissue interstitium. The water and solutes which have trans ferred into the interstitium will be taken up byblood or lymph capillaries in accordance with the local Starling's forces and the intratissue blood and lymph capillary distribution. The driving force for the convective movement into tissue is intraperitoneal hydrostatic pres sure. Figure 9 displays the correlations from two sets of data for intraperitoneal pressure versus intraperitoneal volume in human subjects [30. 31], Reference points in each study were chosen to be the highest point in the abdo men; this would result in the lowest pressure. For a given dialysis volume, the pressure is
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drive fluid in either direction is hydrostatic pressure. Because of the near-zero hydrostatic pressure and the compliance properties of the interstitium [16], there will be a pressure gra dient during dialysis to drive solution from the cavity to the tissue. The fluid and small solutes which transport into the tissue will be taken up by blood capillaries distributed throughout the space in accordance with the local Starling forces. Large proteins will be taken up by intratissue lymphatics. In other regions of the peritoneum, there exist functionally tight membranes near the mésothélial surface, such as superficial blood capillaries in the mesentery and intestinal loops. Small solutes can induce osmotic pres sure gradients across these vessels, which re sult in a relatively solute-free water flux into the cavity. Since these exchange capillaries probably cover less than 10-20% of the total mésothélial area [29], this flux would prevent convection into only a small total area of tis sue. The amount of heterogeneity of protein deposition would likely go unnoticed in the experimental studies discussed above [4. 5],
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magnitude to those experienced by humans. Many investigators extrapolate dialysis vol umes used in humans (generally about 2 li ters) by multiplying by a ratio of body weights. For example, for a 200-gram rat. the volume would be 5.7 ml [(200/70,000) X 2.000 ml]. This volume produces almost no measurable intraperitoneal pressure in the rat. Other groups [ 12] have advocated using the body weight to the 0.7 power: for the 200gram rat. this results in a volume of 30.2 ml [(200/70.000)0-7 X 2.000 ml]. This larger vol ume in a supine, anesthetized rat produces pressures of 2-5 mm Hg [ 18], which is in the range for supine patients (fig. 9). This latter factor (BW°-7) or the actual recorded i.p. pres sure is a more appropriate scaling factor when the purpose is the examination of the trans port forces governing peritoneal absorption. Further, the mass transfer coefficient (PA) for small hydrophilic molecules varies as about the 0.7 power of the body weight [15]. Thus the time scale of small molecule transport (peritoneal volume/permeability-area prod uct) is similar across species if BWU7scaling is used. There is much that is not known about the tissue space surrounding the peritoneal cavi ty. The hypothetical representation of the peritoneum presented in figure 8 may or may not be correct, and the mechanisms of net ultrafiltration warrant further investigation. There is little data on the mechanical proper ties of the peritoneal interstitium that deter mine rates of convection. A convective driv ing force exists which drives significant amounts of fluid and protein into the anterior abdominal wall. However, the intratissue pressure profile has not yet been measured. Detailed knowledge of the mechanisms of convection in the abdominal wall may lead to therapies capable of manipulating pressure gradients in order to obtain larger net ultrafil tration [32].
Absorption from the Peritoneal Cavits
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dependent on the position of the patient. From these curves, the pressure in the cavity of a supine patient during a 2-liter dialysis will average between 2 and 8 mm Hg. The pres sure will rise as the patient gets up and moves about. This pressure provides the driving force necessary to cause fluid absorption from the peritoneal cavity and the apparent loss in net ultrafiltration. Therefore this pressure should be measured in any experiment in which the goal is the study of peritoneal trans port. The curves of figure 9 are quite different, depending on the group which conducted the study. It is possible that the two patient popu lations in which these studies were performed may have had very different compliance properties of the abdominal wall and this might have accounted for the differences in slope of the curves. But since the reference point and measurement device were equiva lent in each study, the i.p. pressure at zero vol ume should be the same. However in figure 9. the intercept of the curves for supine subjects with the y-axis for zero volume in the cavity are so different ( - I m m H g [30] vs. +1 mm Hg [31 ]) that it is likely the techniques of the groups were different. The variance in data demonstrates the difficulty of carrying out these studies. Careful consideration should be given to the goal of the pressure measurement prior to selection of the refer ence point. Patency of the catheter and low resistance to flow must be insured during all measurements, especially when the patient’s position is varied. Another major consideration in experi mental design is the scaling factor used to compare results obtained in different-sized species or to extrapolate from one species to another. In mammalian transport studies which are intended to simulate human pro cesses, it is important that the scaling process result in driving forces which are similar in
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