continuous-flow peritoneal dialysis

VIIth International Course on Peritoneal Dialysis May 23–26, 2000, Vicenza, Italy Peritoneal Dialysis International, Vol. 20, Suppl. 2

0896-8608/00 $3.00 + .00 Copyright © 2000 International Society for Peritoneal Dialysis Printed in Canada. All rights reserved.

CONTINUOUS-FLOW PERITONEAL DIALYSIS

Richard Amerling,1 Claudio Ronco,1,2 Nathan W. Levin2 Beth Israel Medical Center,1 Renal Research Institute,2 New York, New York, U.S.A.

KEY WORDS: Continuous-flow peritoneal dialysis; fluid regeneration; sorbents. Correspondence to: R. Amerling, Division of Nephrology and Hypertension, Beth Israel Medical Center, 16th Street and 1st Avenue, New York, New York 10003 U.S.A. S172

the dwell time requires an increase in the rate of fluid exchanges. The typical acute PD prescription of 2 L each hour is about 30 mL/min. Reducing the flow rate to 15 mL/ min decreases urea clearance by 35%; increasing the flow rate to 50 mL/min augments urea clearance by 50% (1). However, in practice, 2 L each hour is not 30 mL/min. The combination of inflow and outflow times reduces the effective dwell time to perhaps 40 minutes, meaning that the effective flow rate is cut by a third, to 20 mL/min. This “down time” is inherent in traditional PD and constitutes a real barrier to increasing dialysate flow rate by adding exchange cycles. The solution to this problem is continuous flow. HISTORY OF CONTINUOUS-FLOW PD

In 1965, James Shinaberger et al (4) performed a series of studies comparing standard intermittent PD (IPD) with continuous-flow PD (CFPD). He used two intraperitoneal catheters, and he used a pump to recirculate dialysate between the catheters at flow rates of 20 – 300 mL/min. The dialysate was cleansed externally by twin dialysis coils bathed in a 100 L vat of dialysis solution, which was replaced every eight hours (Figure 1). Urea and creatinine clearances were measured and compared with standard treatments, each patient serving as a personal control. Five patients are reported, one of whom had three separate studies. At recirculation rates of 20 – 75 mL/min, urea clearances were only slightly greater than with IPD: they averaged 22 mL/min versus 15 mL/min for IPD. When the recirculation rate was increased to 100 mL/min, clearances jumped into the 30 – 50 mL/min range. When the recirculation was pushed to 200 – 300 mL/ min, urea clearances increased further. They were reported to be 50 – 125 mL/min! Considerable variability was seen, even when the procedure was performed on the same patient. In one patient, over five sessions with a recirculation rate of 300 mL/min, the urea clearance varied from 46 – 125 mL/min. Four of the five sessions were in the 46 –

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eritoneal dialysis (PD) is losing market share to hemodialysis in the United States (1). This situation is surprising, given that dialysis financing in the U.S. heavily rewards home treatment. Units with large numbers of home patients are very profitable. Why has PD failed to catch on? After more than twenty years of experience with continuous ambulatory peritoneal dialysis (CAPD) and continuous cycling peritoneal dialysis (CCPD), a consensus is emerging that these treatments are failing owing to their inherent inefficiency. Adequate levels of solute clearance for normal-sized, anephric patients can be achieved only with inordinate numbers of fluid exchanges, or hernia-provoking intraperitoneal volumes, or both. Once residual renal function is lost, many patients become under-dialyzed. Why is PD so inefficient? Peritoneal membrane surface area is roughly equal to total body surface area, about 1 – 2 m2 (2). This area is comparable to that of commonly used hemodialysis filters. Peritoneal blood flow is not known. Even if the blood flow is only 10% of splanchnic flow, which can exceed 1200 mL/min, it should be more than enough. Much indirect evidence exists to suggest that peritoneal blood flow does not limit maximal peritoneal solute clearance (1). Though peritoneal membrane permeability may limit transfer of large molecular solutes, it is unlikely to be a significant barrier to small-solute movement (1). Peritoneal clearance is exquisitely sensitive to intraperitoneal dwell time. Increased dwell time decreases peritoneal clearance by reducing the diffusive gradient for solute exchange. Alterations of between 10 and 60 minutes in dwell time significantly influence clearance rates (3). Solute transfer is slowed after as little as 10 minutes of dwell time. Reducing

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Figure 1 — Continuous-flow peritoneal dialysis according to Shinaberger et al (4).

66 mL/min range. It is clear that ultrafiltration occurred in a more or less uncontrolled fashion and that this situation may explain some of the variance. Ultrafiltration adds to the total clearance arithmetically and can confuse the analysis. It was also noted that when the intraperitoneal volume dropped below a certain level, high flow rates were unobtainable and clearances suffered. Shinaberger demonstrated the potential of the continuous-flow technique and clearly spelled out the inefficiencies of intermittent exchanges: “The potential increase in efficiency obtained by using a more rapid solution exchange rate in IPD is self-limited by a proportionate loss of effective dialysis time during filling and draining of the peritoneal cavity.” And further: “The rate of transfer of dialyzable substances across the peritoneal membrane is dependent on the blood to intraperitoneal fluid gradient. In intermittent dialysis at any exchange rate this gradient declines with duration of intraperitoneal stay. The high effective dialysate flow rate which can be obtained with the closed, constant volume recirculation technique maintains this gradient near optimum at all times allowing the maximum diffusion capacity of the peritoneal membrane to be fully exploited” (1). In 1968, Kurt Lange et al published a study of continuous-flow PD (5). The group studied 52 patients during 73 sessions using an ingenious dual-catheter

system. Sterile dialysate was pumped through at rates of 4 – 6 L/hour. At 4 L/hour, the researchers reported urea clearances that varied between 29 mL/min and 45 mL/min. Interestingly, they claimed no improvement at higher flow rates (6 L/hour). This result suggests that the small-solute transfer capability of the peritoneal membrane is limited to 45 mL/min. It is also possible that the catheter design did not permit adequate intraperitoneal mixing. From 1976–1983, several trials of CFPD were published. In 1976, Stephen et al reported a comparison of IPD with CFPD using a novel, completely subcutaneous dual-lumen catheter (6). The IPD study used 2-L exchange volumes at 4 L/hour. The CFPD apparatus consisted of an external dialyzer in series with a charcoal filter. The external circuit used 20 L of non sterile dialysate (Figure 2). Dialysate flow rates of 150 – 250 mL/min were used. Urea clearance averaged 26 mL/min with high-flow IPD, and 33 mL/min with CFPD. Owing to the limited extracorporeal clearance capability provided by a fixed amount of dialysate, urea clearances fall from an initial value of 40 mL/min. Unfortunately, the interesting catheter design was doomed by a high infection rate. In 1976, Raja et al described a continuous-flow technique in dogs using the Redy sorbent (Sorb Technology, Oklahoma City, Oklahoma, U.S.A.) cartridge (7). The anesthetized animals were rendered “uremic” S173


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Figure 2 — Continuous-flow peritoneal dialysis according to Stephen et al (6).

with continuous infusions of urea and creatinine. IPD was performed using 2 L exchanges every 20 minutes. CFPD was performed using two peritoneal catheters, a 2.5 L intraperitoneal volume, and recirculation rates of 66 – 250 mL/min. Clearances and mass transfer rates were calculated for urea and creatinine. Solute transport rate was higher with recirculation PD than with IPD at comparable flow rates. At higher flow rates (150, 200, and 250 mL/min), which were unobtainable with IPD owing to restrictions in gravity drainage and filling, urea clearances increased to 27 – 32 mL/min. Peritoneal mass transfer rates for urea and creatinine were higher for CFPD at all flow rates, and increased almost linearly up to recirculation rates of 200 mL/min. As recirculation rates increased, the researchers also noted a fall in the concentration of urea and creatinine in the precartridge fluid. Their conclusion was that, by rapidly removing solute from the peritoneal cavity, the recirculation technique maintained a higher transmembrane concentration gradient. The higher gradient resulted in a twofold to threefold increase in mass transfer rate. The authors suggested that a recirculating system with sorbent regeneration of dialysate could form the basis of an efficient, wearable artifiS174

cial kidney. Roberts and others later advanced this concept (8). Also in 1976, Gordon et al studied a recirculation PD model with sorbent regeneration of dialysate in dogs (9). The animals were rendered uremic by nephrectomy. CFPD was performed through two peritoneal catheters at flow rates of 40 – 120 mL/min. Solute clearance by the Redy cartridge was 100%. Therefore, the solute clearance was equal to the solute concentration in the fluid leaving the peritoneal cavity, times the flow rate, divided by the serum concentration. At flow rates of 100 – 120 mL/min, clearance values were 2 – 3 times greater than those at flow rates of 40 – 60 mL/min. Urea clearance averaged 35 mL/min at the higher flow rates. In 1978, Warden et al published a paper reporting on the use of a variant of continuous-flow PD: reciprocating PD (RPD) (10). This group used a singlelumen version of the Stephen subcutaneous catheter, cannulated transcutaneously with a 14-gauge needle. Intraperitoneal volumes of 2 L and 2.5 L and “stroke volumes” of 300 – 1500 mL were used. Inflow and outflow rates were varied from 150 – 400 mL/min and were adjusted empirically to achieve optimal clearance in 3 patients out of 27 studied (Figure 3). The mean urea clearance was 29.7 mL/min, with a maximum result of 41.5 mL/min. Twenty patients were maintained on RPD, 7 at home, 13 in-center. This group had a very high mortality—50%. Four of ten died following transplantation, and three elected to stop dialysis. Two others died from anesthesia complications following surgery. Catheter-related infections, however, were much lower in the RPD group (0.66% vs 2.5% for IPD), which suggests that this group may have been better dialyzed. Kablitz, working with Stephen, published another paper in 1978 based on the same patient experience (11). No further clinical trials of CFPD appear in the English-language medical literature until 1983. One can only surmise that technical obstacles deterred others from trying to duplicate the results of Shinaberger. In 1968, the Tenckhoff catheter was introduced (12), spurring the use of IPD at home. Various delivery systems were devised and sterile solution was more readily available. In 1976, Popovich and Moncrief described equilibration PD (13), which would eventually be renamed CAPD (14). The simplicity and apparent efficacy of CAPD, together with enthusiastic industry support, overwhelmed the continuousflow movement and left it in the dust. The next reported study of CFPD was published by Kraus et al in 1983 (15). They treated four patients using dual-lumen catheters and a constant intraperitoneal volume of 2 L. The dialysate was recirculated at 200 mL/min and externally regenerated by


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Figure 3 — Reciprocating peritoneal dialysis according to Warden et al (10).

passage through a commercially available hemodialysis system. At external dialysate flow rates of 500 – 600 mL/min, urea clearances of 45 – 101 mL/min were obtained. Treatments were limited by abdominal pain. The researchers also assessed the role of ultrafiltration by discarding spent peritoneal dialysate and replacing it with fresh solution. The ultrafiltrate volume is added to the diffusive clearance and enhances total solute clearance. The 1990s witnessed a revival of CFPD in the form of dog studies by Mineshima (16), Uechi (17), and Ash (18). Mineshima, in addition to working out mathematical models of peritoneal and extracorporeal clearance, contributed a dual-lumen Silastic catheter that functioned well. The researchers’ animal model used an intraperitoneal dialysate volume of 820 mL, a recirculation rate of 100 mL/min, and an extracorporeal dialysate flow rate of 200 mL/min. The clearance data is somewhat difficult to interpret because intraperitoneal urea was used. Based on the observations and models, the time-averaged concentration of urea (TACUrea) for a 60-kg patient with 1 L of daily fluid gain receiving CFPD for 8 hours each day was predicted to be about 34 mg/dL. This result is lower than

the TACUrea predicted for 12 hours of hemodialysis weekly (45 mg/dL). Uechi performed studies on 15 dogs rendered anephric by ligation of both renal arteries and veins. Two separate catheters were used to recirculate 2 L of dialysate at flow rates of 30 – 120 mL/min. The dialysate was not regenerated externally. Urea clearance increased with increased flow rates and ranged from 5.1 – 14.1 mL/min. These values compared favorably with those obtained from standard PD using similar volumes (3.3 mL/min). The authors conclude that the flow-through technique greatly increased efficiency without adding much complexity. Ash investigated IPD, CAPD, tidal PD (TPD), and CFPD in non uremic dogs and estimated urea clearance by measuring the rate of glucose reabsorption through the peritoneum. He used a flow-through technique with two separate catheters, and, like Uechi, did not regenerate the dialysate externally. The results show that glucose clearance increased with flow rate and achieved 16 mL/min at dialysate flow rates of 100 – 120 mL/min. This result corresponds to a urea clearance of approximately 33 mL/min. The conclusion was that CFPD is the most effective PD technique for small-solute clearance. S175


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RECENT WORK AND CURRENT TRENDS

CONCLUSION The renewed interest in CFPD stems from the growing awareness that PD is failing owing to inadequate small-molecule clearance. But traditional thrice-weekly hemodialysis is also under review, given the poor mortality and morbidity data. Alarm is growing at the number of under-dialyzed patients on hemodialysis. Daily or nightly home hemodialysis is attracting a following (22). CFPD could be an attractive alternative to home hemodialysis. If a suitable system can be devised, it is inherently safer. The major risk would still be peritonitis; but home hemodialysis has risks of hemorrhage, sepsis, and air embolism. CFPD offers the possibility of high weekly Kt/V with 8 hours or less of dialysis, 5 – 7 nights per week. Clearances of 40 mL/min over 8 hours gives almost 60 L of dialysis. Five such treatments would provide a weekly Kt/V of 7.5 for an average-sized person with a V of 40 L. On-line production of non sterile dialysate would cost much less than the sterile solutions currently used in increasing amounts. Protein loss would be minimal with the recirculation technique as opposed to a flow-through system. Technical problems will be related to catheter design and function, and to maintaining and controlling ultrafiltration in a way that preserves a large intraperitoneal volume. S176

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Expected clearances for CFPD are in the range of those provided by many continuous veno-venous hemofiltration (dialysis) [CVVH(D)] systems and could be an alternative therapy for serious acute renal failure. REFERENCES 1. Blake PG, Bloembergen WE, Fenton SS. Changes in the demographics and prescription of peritoneal dialysis during the last decade. Am J Kidney Dis 1998; 32(Suppl 4):S44–51. 2. Nolph KD, Twardowski ZJ. The peritoneal dialysis system. In: Nolph KD, ed. Peritoneal dialysis. Third edition. Dordrecht: Kluwer Academic Publishers; 1989: 13–27. 3. Korthuis RJ, Granger DN. Role of the peritoneal microcirculation in peritoneal dialysis. In: Nolph KD, ed. Peritoneal dialysis. Third edition. Dordrecht: Kluwer Academic Publishers; 1989: 28–47. 4. Shinaberger JH, Shear L, Barry KG. Peritoneal–extracorporeal recirculation dialysis: A technique for improving efficiency of peritoneal dialysis. Investig Urol (Berl) 1965; 2:555–65. 5. Lange K, Treser G, Mangalat J. Automatic continuous high flow rate peritoneal dialysis. Arch Klin Med 1968; 214:201–6. 6. Stephen RL, Atkin–Thor E, Kolff WJ. Recirculating peritoneal dialysis with subcutaneous catheter. ASAIO Trans 1976; 22:575–85. 7. Raja RM, Kramer MS, Rosenbaum JL. Recirculation peritoneal dialysis with sorbent Redy cartridge. Nephron 1976; 16:134–42. 8. Roberts M, Niu PC, Lee DBN. Regeneration of peritoneal dialysate: A step towards a continuous wearable artificial kidney [Abstract]. J Am Soc Nephrol 1991; 2:367. 9. Gordon A, Lewin AJ, Maxwell MH, Morales ND. Augmentation of efficiency by continuous-flow sorbent regeneration peritoneal dialysis. ASAIO Trans 1976; 22:599–604. 10. Warden GD, Maxwell G, Stephen RL. The use of reciprocation peritoneal dialysis with a subcutaneous peritoneal catheter in end-stage renal failure in diabetes mellitus. J Surg Res 1978; 24:495–500. 11. Kablitz C, Stephen RL, Jacoblsen SC, Kirkham R, Kolff WJ. Reciprocating peritoneal dialysis. Dialysis and Transplantation 1978; 7:211–14. 12. Tenckhoff H, Schechter H. A bacteriologically safe peritoneal access device. ASAIO Trans 1968; 14:181–6. 13. Popovich RP, Moncrief JW, Decherd JF, Bomar JB, Pyle WK. The definition of a novel portable/wearable equilibrium dialysis technique [Abstract]. ASAIO Trans 1976; 5:64. 14. Popovich RP, Moncrief JW, Nolph KD, Ghods AJ, Twardowski ZJ, Pyle WK. Continuous ambulatory peritoneal dialysis. Ann Intern Med 1978; 88:449–56. 15. Kraus MA, Shasha SM, Nemas M, Better OS, Khoushy A. Ultrafiltration peritoneal dialysis and recirculating peritoneal dialysis with a portable kidney. Dialysis and


Cosme Cruz (19) has performed flow-through studies in several patients who, for various clinical reasons, had two peritoneal catheters for a short period of time. Flow rates of 6 – 12 L/hour produced urea clearances in the 40 – 60 mL/min range. Mineshima’s group (20) recently published results of continuous recirculating PD with three patients. Using a dual-lumen catheter, an intraperitoneal volume of 1 L, a recirculation rate of 100 mL/min, and an external dialysate flow of 400 mL/min, they achieved 13.7% urea reduction after four hours of treatment. We recently studied continuous-flow PD in a patient with chronic renal failure who transiently had two peritoneal catheters (21). With a recirculation rate of 300 mL/min, a dialysate flow rate of 100 mL/min, and the Fresenius 2008H machine with an AV400 hemofilter (Fresenius Medical Care, Lexington, Massachusetts, U.S.A.), we achieved 18% urea reduction over four hours. It is clear that the success of CFPD will depend on a catheter design that establishes an intraperitoneal “current” that enhances the mixing of regenerated dialysate and solicits a large peritoneal surface area. Likewise, the problem of controlling external ultrafiltration in a way that maintains a relatively constant intraperitoneal volume will have to be solved.

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Transplantation 1983; 12:385–8. 16. Mineshima M, Watanuki M, Yamagata K, Era K, Nakazato S, Suga H, et al. Development of continuous recirculation peritoneal dialysis using a double lumen catheter. ASAIO J 1992; 38:M377–81. 17. Uechi M, Iida E, Watanabe T, Kuwajima S, Nakayama T, Kano Y, et al. Peritoneal dialysis using a recycling system in dogs. J Vet Med Sci 1993; 55:723–7. 18. Ash SR, Janle EM. Continuous-flow-through peritoneal dialysis (CFPD): Comparison of efficiency to IPD, TPD, and CAPD in an animal model. Perit Dial Int 1997; 17:365–72. 19. Cruz C, Molendez A, Gotok F, Folden T, Levin NW,

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Crawford T, et al. Continuous flow peritoneal dialysis (CFPD): Preliminary clinical experience [Abstract]. Perit Dial Int 2000; 20(Suppl 1):S6. 20. Mineshima M, Suzuki S, Sato Y, Ishimori I, Ishida K, Kaneko I, et al. Solute removal characteristics of continuous recirculation peritoneal dialysis in experimental and clinical studies. ASAIO J 2000; 46:95-8. 21. Amerling R, DeSimone L, Gotch F. Continuous flow PD (CFPD) with the Fresenius 2008H: First clinical trial [Abstract]. ASAIO J 2000; 46:218. 22. Neumann ME. Daily home hemodialysis takes center stage at PD conference. Nephrology News and Issues. 1995; March:12,32.


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