STUDIES ON ULTRAFILTRATION IN PERITONEAL DIALYSIS: INFLUENCE OF PLASMA PROTEINS AND CAPILLARY BLOOD FLOW

Transcription

1 STUDIES ON ULTRAFILTRATION IN PERITONEAL DIALYSIS: INFLUENCE OF PLASMA PROTEINS AND CAPILLARY BLOOD FLOW ABSTRACT Claudio Ronco Alessandra Brendolan Luisa Bragantini Stefano Chiaramonte Mariano Feriani Aldo Fabris and Giuseppe La Greca This study has evaluated the influence of peritoneal blood flow and plasma protein concentration on the peritoneal ultrafiltration rate. In vitro and in vivo experiments were done to assess the effective peritoneal capillary blood flow. Based on the assumption that one can compare the behavior of an hollow fiber hemofilter with the peritoneal dialysis system, we have compared the opera tional characteristics of the two systems. After demonstrating that there was filtration pressure equilibrium in the filter, the plasma protein concentration was measured in the venous site of the filter at different applied transmembrane pressures. The nomogram, so obtained, was used to calculate the plasma-protein concentration in the blood leaving the peritoneal capillary during exchanges with an established glucose concentration (and therefore at a given transmembrane pressure), and to calculate the filtration fraction. From the Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy. Key Wards: Ultrafiltration, Plasma proteins, Transmembrane pressure, Filtration fraction, Blood flow, Maximal ultrafiltration. Once that fraction had been calculated, based on the value of the ultrafiltration rate, one can calculate the importance of the plasma flow and then the blood flow. In this study the filtration fraction ranged between 45 and 55% and the blood flow ranged between 21 and 27 ml/min. It was concluded that the blood flow may be very low and hence may limit ultrafiltration. The rate of ultrafiltration in peritoneal dialysis depends mainly on the glucose concentration in the dialysate and on the consequent osmotic gradient, which moves water from blood to the peritoneal cavity ( 1).Other factors contribute to the final transmembrane pressure (TMP) such as the mean arterial pressure (MAP), hematocrit (Hct), blood viscosity and plasma protein oncotic pressure ( π ).The final peritoneal TMP reaches a level of hundreds of mmhg. As Ronco et al have demonstrated (2), a dialysis solution with 2.5% glucose generates an average TMP of about 1000 mmhg in a standard subject, (MAP = 90 mmhg, viscosity = 4cps, Hct = 30%, and π = 25 mmhg). All these calculations assume a conversion factor for pressure calculated as I mosm = 15 mmhg and a reflection coefficient for glucose = In these conditions the peritoneal ultrafiltration rate (Qf) appears to be small when compared to other dialysis membranes (3) and the ultrafiltration coefficient (K) shows a very narrow range with small values. The aiiii of this study was to estimate the maximal ultrafiltration rate, which can be achieved in humans and to assess some of the factors that may act to limit this rate. We might hypothesize that the phe nomenon of maximum ultrafiltration is surface-area limited or dependent upon membrane permeability however, peritoneal membrane surface area and permeability characteristics should not be factors directly involved in the ultrafiltration limitation: the total surface area is in the range of 1 to 2 sq. meters, and even when the number of "pores" are limited it can achieve adequate clearance of small and middle molecules demonstrating a remarkable permeability (4). We propose that the factor primarily limiting peritoneal ultrafiltration is the low blood flow of the peritoneal capillary network. If we can obtain reasonable proof that filtration pressure equilibrium occurs inside the peritoneal capillary, this might suggest that ultrafiltration stops at a certain point inside the capillary and no more fluid can be obtained from that volume of blood passing through the peritoneal capillary during the duration of one exchange at a given pressure gradient (average osmotic gradient during one exchange). The calculation of the peritoneal filtration fraction (FF) should allow (testing indirectly this hypothesis) the estimation of the "effective peritoneal blood flow (Qb)" (5). Furthermore, a high plasma protein concentration might draw the point of filtration pressure equilibrium close to the pressure on the arterial side of the capillary causing a further reduction in ultrafiltration. If we can support this hypothesis and demonstrate the existence of filtration pressure equilibrium, we might explain the low values of ultrafiltration coefficient and the Qf Max for the peritoneal dialysis + system on the basis of the low blood flow available for peritoneal exchanges.

2 METHODS In viva and in vitra studies were done to establish the following points: a) Absolute value of peritoneal ultrafiltration coefficient (K) and the maximal value of peritoneal ultrafiltration rate (Qf max). b) the presence of filtration pressure equilibrium in the peritoneal capillary c) calculate the peritoneal filtration fraction d) calculate the effective peritoneal blood flow e) estimate the influence of plasmaprotein concentration on ultrafiltra tion rate. For these purposes, it was necessary to determine the plasma protein concentration in blood leaving the capillary at different applied TMP; earlier in vitra studies had supplied indirect methods for this calculation. In Vitra Studies: Figure 1 shows the apparatus used for our in vitra experiments, which were intended to compare the behaviour of an hollow fiber hemofilter under special conditions of blood flow and TMP with the peritoneal capillary network. The first approach was to demonstrate that filtration pressure equilibrium occurs in the hollow fiber system under particular conditions, as it happens in several capillary networks in the body (6). Experiment I: the blood was pumped through the hemofilter (polysulphon AMICON D-20) in a single pass at different Qb ( ml/min). Different TMP were applied for each blood flow (from 20 to 1200 mmhg). Pre and post filter blood samples were taken for each 10 min period, in which stable TMP and Qb were applied. Hct and plasma protein concentration were measured in each sample. At the same time Qf and FF were also measured. Experiment 2: blood was recirculated in the same circuit, adjusting the staning protein concentration to the same value of the first experiment. A stirrer and a heater provided mixing and thermostability at 37 C of the blood. The same Qb and TMP were also used for this experiment. For each period the blood was recirculated until there was no more ultrafiltration: this situation was accepted as filtration pressure equilibrium for that Qb and TMP. Pre and post-filter blood samples were taken for Hct and plasma protein measurements to compare inlet and outlet values. Each group of experiments was done three times. The protein concentrations, at a given Qb and TMP, were compared between experiment 1 and 2. When the two values didn't differ significantly, we accepted this as showing that filtration pressure equilibrium had been achieved in the filter also in single pass conditions. The values of outlet protein concentration obtained in conditions of filtration pressure equilibrium at different TMP were used to draw a curve which depicts the relationship between the plasma protein concentration and the relative oncotic force (Fig 2). In Viva Experiments: a) Several exchanges were performed in five patients with dwell time = 0 and different glucose concentration in the dialysis solution. The dialysate osmolality was increased progressively from 300 to 700 mosm, and the relative ultrafiltration rate was measured according to the formula: where V do and V di are the outlet and inlet volumes of dialysate while Rv2 and Rvl are the residual intraperitoneal volumes of fluid after and before the exchange, measured by the dilution of a nondiffusible isotope (SARI 131). b) Hourly measurements of peritoneal ultrafiltration were performed during IPD session in five patients with 2 L exchanges, dwell = 0, 2.5% and 1.5% glucose solutions. We also recorded the behavior of peritoneal ultrafiltration in the same patients under a) baseline conditions, b) after acute extracorporeal dehydration (at least 2.5 kg) and c) after restoration of the normal body weight by saline infusion. Venous blood samples were taken at the beginning and at the end of each session for measurements of glucose, electrolytes, total plasma proteins and hematocrit. Systemic blood values were considered identical to the peritoneal capillary inlet concentration. CALCULATIONS The calculations of peritoneal ultrafiltration coefficient, TMP, FF, Qb and Qp ali were made according to the formuias reported in the appendix. RESULTS In Vitra Studies: The first in vitra experiment allowed us to draw the curve shown in Fig 2. The curve displays the exponential relationship between the protein concentration at the outlet of the filter and the hydrostatic pressure applied to the system to obtain that concentration. These protein concentrations were not significantly different trom those found in the second experiment under conditions of recirculation at the same blood flows and TMP (Table 1). This observation

3 was accurate up to 150 ml/min of blood flow. At blood flows higher than 150 ml/min, discrepancy was seen between the protein concentration obtained in single pass and that during recirculation. When the protein concentrations were identical, it was considered that we had achieved the condition of filtration pressure equilibrium. In this system, the upper limit for filtration pressure equilibrium was 150 mllmin of Qb.Under the conditions of equilibrium, the protein concentration in the venous line must generate an oncotic pressure able to balance the hydrostatic pressure applied to the system. I hus, with a semipermeable membrane working at equilibrium, one can predict the protein concentration leaving the system when he knows the overall 1 MP and tje IIIlet protein concentration. At the same time, It we know the concurrent ultraflltration rate we can calcuiate the tlltration traction and plasma flow. in v IVO Experlments: Figure 3 ShOWS the effects or alalysate OSmOlality on peritoneal ultrafiltration during rapid exchanges with different osmotic gradients. It is evident that the ultrafiltration rate reaches a plateau. The point at which a further increase in dialysate osmolality does not produce a direct increase in Qf describes the max1mal capacity for ultrafiltration in the time period allowed by the peritoneal dialysis system (Qf Max). The concentration of glucose in the effluent was less than in the inflowing dialysate. In our patients, the back diffusion of glucose, which averaged 5-10%, was considered in the final calculation of the average osmotic gradient. Also taken into account when measuring the average effective osmotic gradient throughout the exchange was the effect of dilution by the ultrafiltrate. When this grad1ent is converted into total transmembrane pressure by the formula described III the appendix, the calculation ot the peritoneal ultratlltration coefficlent appears to be reproducible and ranges between and As shown in Fig 4, th1s value is very low when comparea WIth other dlalysls systems, and the Qt max averages 15 mllmiii. ; ne residual thtraperitoneal volumes showed a high variability ftrom 45 to 890 ml) and hence 1t IS 1mportant to take this parameter into account when calculatthg ultratlitration rate. a) 1 ne peritoneal uitratlltratlon rate decreased significantly (trom 10.5 to 7.1 mllmin) trom the beginning to the end of a six-hour session performed with rapid exchanges and 2.5%0 glucose solution. A parallel increase was noted in plasma protein concentration from 6.5 to 7.8 g/dl. b) After acute dehydration obtained by extracorporeal ultrafiltration, the peritoneal Qf showed a permanently low values during a sixhour hr PD session (4.5 ml/min). The initial plasma-protein concentration was 7.9 (because of the extracorporeal ultrafiltration) and remained stable during the session. c) After the reinfusion of fluid, the protein concentration decreased to 6.6 g/dl and peritoneal Qf, tested during a new session was restored to 9.9 ml/min. These data suggest that peritoneal ultrafiltration rate has a remarkable effect on protein concentration. CALCULATIONS: To calculate the peritoneal filtration fraction and effective blood flow, we carried out rapid exchanges in the five patients with 2.5% glucose solution. After conversion from the osmotic gradient to the overall TMP assuming filtration pressure equilibrium, we calculated the oncotic pressure and the relative protein concentration of the plasma leaving the peritoneal capillary from the nomogram in Fig 2. As showh in Table II, the average TMP vaned from 690 to 850 mmhg and the calculated outflow protein concentration varied from 13.5 to 14.2 gr/dl. The peritoneal filtration fraction ranged between 45.9 and 51.8%. Figure 5 makes it possible to compare these filtration fractions with those achieved in other treatments. In peritoneal dialysis the filtration fraction was high and, when plotted against the ultrafiltration rate obtained in our patients, 1t allowed us to calculate plasma flow in the peritoneal capillary network, which ranged from 15.7 to 19.6 ml/min. Finally the correction for Hct permits one to calculate the..eftective blood tlow" in the peritoneal capillary network and available tor dialysis. It IS evident from Table II that, despite a certain variation in the total transmembrane gradient due probably to IndIvIdual variabllity in peritoneal permeability to giucose and in its retlection coeftlclent, the filtratlon fractions definitely are high and the calculated blood flows are extremely low. Even considering errors in calculation, the ultrafiltration during peritoneal dialysis seems relatively high

4 considering the local blood flow however, such low blood flow does not allow for increases in ultrafiltration rate even in the presence of greater osmotic gradients. DISCUSSION Several previous studies (7-8) demonstrated that the splanchnic blood flow ranges between 1300 and 1600 ml/min. On the basis of these data, it has been assumed that the peritoneal blood flow is not a factor limiting clearances and ultrafiltration in peritoneal dialysis. Only a few workers have attempted direct measurement of the peritoneal capillary blood flow (9) and the values so obtained were surprisingly low. In any event the general view is that blood flow is not a factor limiting the efficiency of peritoneal dialysis. However many points remain to be clarified concerning the kinetics of ultrafiltration. Measurements of peritoneal ultrafiltration coefficient appear to be inaccurate if it is considered as the ratio between Qf and the simple osmotic gradient. Several other factors affect Qf and may change the ratio QfΔOsm over a shorter period. The low values of ultrafiltration we obtained after acute dehydration showed that slight changes in protein concentration may produce significant changes in the ultrafiltration rate, even when the osmotic gradient is constant. However, when the peritoneal ultrafiltration coef ficient (K) is calculated as Qf/TMP (where TMP takes into account all the factors involved in the final effective transmembrane gradient), the value of K is stable and reproducible. This value might even be used as an index of peritonealmembrane efficiency in the same subject over a prolonged period. However it is not clear why the value of K in the peritoneal membrane is so low. The surface area of the membrane is large and its permeability allows for clearances of middle molecules better than other membranes. The curve of function K may explain the low value of K. As depicted in Fig 6, the function K is linear only under conditions of "unlimited" membrane area or blood flow. When the function is measured under different conditions, it becomes

5 non-linear and the limiting effect of blood flow or surface area is evident. There is good evidence that peritoneal dialysis works under conditions of filtration pressure equilibrium as do many other systems in the body. Several models have suggested that fluid even may be reabsorbed in the venous side of the capillary (10). The high pressure gradient generated by the glucose solution certainly favors the establishment of pressure equilibrium in the capillary.under these conditions, it is easy to calculate the protein concentration of blood leaving the capillary and, hence the filtration fraction. Our results suggest that the peritoneal dialysis system operates at filtration fractions higher than 40%. Consequently, the ultrafiltration rate achieved during rapid exchanges may be low because of the small volume of blood passing through the capillary in that short period. The blood flow in the peritoneum might be greater, but our calculation gives the "effective blood flow" contributing to the exchanges at a given moment. It could be argued that solute clearance sometimes exceeds the volume of plasma flow in our experiments; however, it should be noted that we do not know whether diffusion between different compartments (bloodcell-interstitiurn; fluid layers etc.) affects the final concentration of solutes in the dialysate and hence the final clearance value. Concerning the possibility of a significant reabsorption of fluid from the peritoneal cavity via the lymphatic flow, several workers have demonstrated the importance of the lymphatic reabsorption from the peritoneum; however, while the absolute volume amount of fluid reabsorbed during a CAPD exchange can be high, the rate of resorption may be quite low and therefore its effect would decrease during rapid IPD exchanges. Furthermore, we measured peritoneal ultrafiltration in terms of the dilution of a non diffusable isotope. Thus, if the volume of fluid resorbed during one 20-min exchange was relevant, the concentration and absolute amount of isotope recovered from the effluent should have been lower. Taking these facts into account it seems unlikely that the peritoneal Qf is excessively high but the final value is unduly low due to a lymphatic resorption. In conclusion, it must be emphasized that most of these calculations are based on assumptions that may be controversial. Other hypothesis have been based on different assumptions. We hope that the critical evaluation of this hypothesis by others will help to improve our understanding of the basic physiology of the peritoneal membrane. REFERENCES 1. Nolph KD, Twardowski ZJ. The peritoneal dialysis system. In: Nolph KD ed. Peritoneal dialysis. Martinus NijhoffPublisher. 1985; pp Ronco C, Brendolan A. Bragantini L et al. The peritoneal coefficient of ultrafiltration as an index of the peritoneal membrane permeability.proc Int Symp Perit Dial, Washington. D.C (in press). 3. Ronco C. Factors affecting the peritoneal dialysis efficiency. Proc 2nd Int Course on Perit Dial, Vicenza, Italy, 1985 (in press). 4. Henderson L W.The problem of peritoneal membrane area and permeability. Kidney Int 1973;3: Lauer A. Saccaggi A, Ronco C et al. Continuous arterio-venous hemofiltration in the critically ill patient. Ann Intern Med 1983;99: Wade OL, Combes B, Childs AW et al. The effect of exercise on the splanchnic blood flow and splanchnic blood volume in normal man. Clin Sci 1956;15: Nolph KD. Anatomy, physiology and kinetics of peritoneal transport during peritoneal dialysis. Proc. Ist Int Symp on CAPD. Excerpta Medica, Amsterdam 1980; pp Nolph KD, Ghods AJ, Van Stone J et al. The effect of intraperitoneal vasodilators on peritoneal clearances. Trans ASAIO 1976;22: Aune S. Transperitoneal exchanges, II: Peritoneal blood flow estiiiiated by hydrogen gas clearance. Scand J GastroenteroI1970;5: Nolph KD, Popovich RP, Ghods AJ et al. Determinants of low clearances of small solutes during peritoneal dialysis. Kidney Int 1978; 13:

6 APPENDIX