Automated peritoneal dialysis (APD) has, in recent

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1 VIIth International Course on Peritoneal Dialysis May 23 26, 2000, Vicenza, Italy Peritoneal Dialysis International, Vol. 20, Suppl /00 $ Copyright 2000 International Society for Peritoneal Dialysis Printed in Canada. All rights reserved. AUTOMATED PERITONEAL DIALYSIS: CLINICAL PRESCRIPTION AND TECHNOLOGY Claudio Ronco, 1 Alan S. Kliger, 2 Gianpaolo Amici, 3 Giovambattista Virga 4 Renal Research Institute, 1 Division of Nephrology and Hypertension, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, U.S.A.; Renal Research Institute, 2 Yale University School of Medicine, New Haven, Connecticut, U.S.A.; Nephrology Division, 3 S. Maria dei Battuti Hospital, Treviso, Italy; and Nephrology Service, 4 P. Cosma Hospital, Camposampiero, Italy KEY WORDS: Automated peritoneal dialysis; cyclers; adequacy; prescription. Correspondence to: C. Ronco, Renal Research Institute, 207 East 94 Street, Suite 303, New York, New York U.S.A. S70 Automated peritoneal dialysis (APD) has, in recent years, grown faster than any other dialysis treatment. The growth in APD has been paralleled by the development of new automatic machines. The machines and the newer APD schedules have permitted personalized prescription and improved compliance to the prescribed regimens. Starting in 1960, machines were introduced to perform semiautomatic or fully automatic PD treatment. In the early days, peritoneal dialysis was mostly intermittent (IPD), featuring a total of 24 hours of treatment per week divided into three or more sessions. Low clearance volumes limited the efficacy and the clinical success achievable with these treatments (1). More recently, the knowledge derived from the equilibration dialysis concept of continuous ambulatory peritoneal dialysis (CAPD) and the availability of plastic bags (2) have contributed to a rediscovery of intermittent peritoneal dialysis techniques. APD today is a daily home treatment with automated nightly exchanges [nightly intermittent peritoneal dialysis (NIPD) or continuous cycling peritoneal dialysis (CCPD)] (3,4). The development of easy-to-use machines with a simple operator interface (cyclers) represented a further key factor in this process of evolution (1). Microchips and computers represent another important step. These components, incorporated into PD cyclers, provide greater programming flexibility, making it possible to prescribe individualized fill volumes, variable tidal volumes, and additional automated exchanges during the day. Teledialysis and remote delivery control are also possible. Finally, miniaturization of all components now produces fully portable cyclers with reduced dimensions and light weight (5). In the U.S., 31.9% of all PD patients use APD, including patients using daytime dwell mode, daytime empty mode, and schedules with one or more additional hand exchanges (6). APD seems to represent a possible answer to keeping patients on PD and to increasing the treatment dose when residual renal function is declining and CAPD results may be inadequate. APD seems to more easily meet higher adequacy targets and expectations for improved quality of life. The possibility of using newer dialysis solutions represents a further step in the increased application of APD techniques. APD TECHNIQUES Various acronyms are used to define slightly different APD treatment schedules: Automated peritoneal dialysis (APD): This broad term includes every type of peritoneal dialysis performed with the aid of a cycler (1,7). Nightly intermittent peritoneal dialysis (NIPD): NIPD describes APD performed only at night with complete fill and drain of the peritoneal cavity (1,7). Nightly tidal peritoneal dialysis (NTPD): NTPD describes APD performed only at night with partial fill and drain of the peritoneal cavity (tidal volume is variable) (1,7). Continuous cycling peritoneal dialysis (CCPD): CCPD describes APD performed at night, but with the addition of one (CCPD1) or two (CCPD2) daytime dwells (1,7). Continuous tidal peritoneal dialysis (CTPD): CTPD describes APD performed at night (tidal modality), with the addition of one (CTPD1) or two (CTPD2) daytime dwells (1,7). These latest two modalities are also called PD Plus therapy. Intermittent peritoneal dialysis (IPD): IPD de-

2 PDI MAY 2000 VOL. 20, SUPPL. 2 APD PRESCRIPTION scribes APD treatment prescribed mainly for a total duration of 24 hours per week divided into three or more sessions. The dialysate flow is with or without short dwells (1,7). Borderline techniques: This term describes CAPD with one or more automated exchanges using simple machines without all the characteristics of a modern cycler. These techniques reduce the number of connections and can aid patients performing additional exchanges (8,9) PRESCRIPTION AND DELIVERY OF APD The efficiency of APD is affected by fill volumes (10,11), individual peritoneal transport characteristics (12,13), and total prescribed dialysate volume per session. These factors may also limit the application of APD. Using NTPD only, patients with a 4-hour creatinine (Cr) D/P > 0.65 and total volumes of L per session can achieve a weekly peritoneal creatinine clearance (C Cr ) higher than 50 L per week (14). This result is confirmed by Twardowski, who found an average C Cr = 47 L per week in NTPD patients with a mean Cr D/P = 0.66 (15). Using CTPD2 (two diurnal dwells) in anuric patients, only those with a Cr D/P > 0.65 can reach both DOQI targets (Kt/V = 2.1 and C Cr /1.73m 2 = 63 L per week). However, these patients require total dialysis volumes of more than 20 L/1.73 m 2 per session (16). NIPD with a mean total volume of 14 L per session achieved a mean C Cr of 27 L per week in 7 patients (74 kg, 1.8 m 2 ), with a mean Cr D/P = 0.68 (17). Another study demonstrated a C Cr of 42.5 L per week and a Kt/V urea of 1.55 in 9 NIPD patients (75 kg mean body weight) with a total volume per session of about 10 L (18). Both studies demonstrated that when dialysate exchange volumes below 20 L per session are used for NIPD, inadequate results are likely to be expected. Thus, for all APD techniques, only patients with a peritoneal permeability higher than the mean (high and high average) can reach adequacy targets with a total volume per session not less than 20 L. Tidal dialysis, usually prescribed at 50% exchange volume, has theoretic advantages over non tidal modalities using the same dialysis time and volume (14,19 21). However, recent studies failed to show superior clearances for tidal dialysis when compared with CCPD. Nevertheless, many patients experience pain or abdominal discomfort at the termination or initiation of a dialysis exchange with standard CCPD, and these patients can benefit from a tidal dialysis regimen (22). Any attempt to increase peritoneal clearance in APD implies tailored fill volumes. Intra-abdominal pressure is higher in the sitting position than in the upright and supine positions (23). Thus, larger volumes of dialysate are better tolerated while the patient is supine at night. Increased dwell volumes permit longer dwell times and increase clearances in patients with a peritoneal permeability lower than the mean. Common dwell volumes in APD are 40 ml/kg (21) or 2.5 L/1.73 m 2 (9,10). Increased intra-abdominal pressure can reduce ultrafiltration and the expected increase in clearance; for this reason, it has been suggested that intra-abdominal pressure values should be below 18 cmh 2 O (11,24). The use of computer-assisted kinetic modelling may also help to achieve an optimal APD prescription (25). Programs for this purpose are easily available [PD Adequest (Baxter Healthcare Corporation, Deerfield, Illinois, U.S.A.), Pack PD (Fresenius Medical Care, Bad Homburg, Germany), PDC (Gambro Lundia AB, Lund, Sweden)]. All of these programs have in common a reliable mathematical model and an individual peritoneal function test as data entry (26 33). With these programs, various APD regimens can be simulated and the desired optimization achieved in each patient. TREATMENT MONITORING Catheter malfunction, changes in peritoneal transport, and poor patient compliance can produce a discrepancy between the prescribed treatment dose and the dose effectively delivered. Catheter malfunction can be detected by periodically measuring inflow and outflow times. Changes in peritoneal transport can be suspected if serum creatinine values rise in the presence of a constant PD regimen. Such a rise may be caused by falling endogenous renal function or by decreased peritoneal transport. A peritoneal equilibration test (PET) should therefore be prescribed and compared to previous results. A change in the patient s adherence to the prescribed dialysis regimen (patient compliance) can be more difficult to detect. Cycler function and patient compliance can be assessed electronically or the human way, with frequent home visits. Removable memory that registers all of the data about sessions at home are now available, as are telecommunication systems between the center and the cycler at the patient s home. Frequent home visits provide an opportunity for the dialysis staff to assess many factors affecting a dialysis patient s health, including the cleanliness of the home, the dialysis technique, and family interactions; but a machine-based data collection device can provide more precise and continuous information about dialysis kinetics. The expansion of data transfer via cable or satellite promises a future of increasing teledialysis and more precise information about solute clearance and ultrafiltration. S71

3 RONCO et al. MAY 2000 VOL. 20, SUPPL. 2 PDI S72 However, the direct measurement of clearances is crucial in the assessment of treatment adequacy. Creatinine and urea clearances are the most widely used adequacy indexes in APD. Creatinine clearance is normalized to body surface area (C Cr /1.73 m 2 ), and urea clearance to body water (Kt/V). Both are expressed on a weekly basis. In steady state, clearance is calculated by measuring the solute removed in the total effluent fluid collection, and the plasma concentration of the solutes (34). The intermittency of the therapy causes a compartmental disequilibrium effect that manifests as a fluctuation in plasma concentration from the pre-dialytic (evening) value to post-dialytic (morning) value (16,18). The difference is more marked for urea than for creatinine (18). The use of the post-dialytic plasma value in clearance measurement significantly overestimates Kt/V by 6% 14% (16 18). The variability in overestimation is a result of the variable efficiency of APD and, consequently, to varied compartmental effects. To standardize measures of Kt/V, the blood sample is obtained during the day at a time equidistant from the previous and the subsequent nocturnal APD session (35). Because clearances may be overestimated in intermittent peritoneal dialysis regimens, it has been suggested that optimal adequacy targets should be higher in NIPD (Kt/V = 2.2 and C Cr /1.73 m 2 = 66 L) than in CCPD (Kt/V = 2.1 and C Cr /1.73 m 2 = 63 L), and that both should be higher than in CAPD (Kt/V = 2.0 and C Cr /1.73 m 2 = 60 L) (34 36). Treatments that vary in intermittency and intensity may produce different blood profiles, independent of total body composition. Intermittent dialysis produces variable nonlinear dynamic compartmental disequilibrium. Moreover, pre-dialysis blood concentration of solutes is markedly different in intermittent and continuous treatments (34,37 39). Several kinetic models have been proposed to describe dialysis adequacy. While the peak concentration hypothesis helped relate peritoneal to hemodialysis, the solute removal index (SRI) may minimize the problem of solute compartmentalization. The rationale of SRI is that the removed solute mass is normalized for the pre-dialysis compartment (body) content. Pre-dialysis urea and creatinine compartments are at or near equilibrium because they are as distant as possible from the end of the previous treatment (37 42). Thus the pre-dialysis blood is representative of total body water solute concentration. Kt/V and C Cr target discrepancies have been reported in several papers, both for APD (16,42) and for CAPD (43,44). The most common finding is that Kt/V easily reaches the adequacy target, while C Cr does not. Factors affecting this discordance are the intermittent nature of APD treatment (42), the degree of residual renal function (43), and the peritoneal transport characteristics (15,44). In cases of discordance between the two indices, some believe that Kt/V should be given primacy (36,45); however, no clear evidence exists to show which index correlates best with clinical outcomes. Previous studies have shown considerable day-today variability in measured peritoneal clearances. Consequently, when single measurements are close to adequacy targets, it is advisable to repeat them to assure adequate delivered dialysis dose (46,47). The CANUSA study was very helpful in correlating dialysis dose with clinical outcomes in CAPD (48). However, that study was conducted without prospective randomization into different dose groups, and consequently it does not answer all questions about PD adequacy. Moreover, because no APD patients were studied, comparisons between APD and CAPD cannot be made. Future clinical trials that compare adequacy measurements in various APD and CAPD techniques should use indices, such as the SRI, that are not influenced by compartmental effects. PATIENT SELECTION CRITERIA FOR APD APD provides a practical way for patients to use higher total volumes of dialysate. Higher volumes are frequently necessary to achieve adequate dialysis clearance, particularly in larger patients and in those with declining endogenous renal function. However not all patients benefit from such frequent PD exchanges. Solute removal in patients with low or lowaverage peritoneal transport may not rise, and might even fall, when more frequent exchanges are performed. When a peritoneal equilibration test (PET) is done, 6% of patients show low transport, and 31% show low-average transport. These patients are often unable to reach adequate clearances using APD (14,16). In their case, conventional continuous therapies should be used first (9). In contrast, clearances can be enhanced substantially with high-volume APD in high-average and high transporters (53% and 10% of PD patients, respectively) (9). CCPD is often an excellent choice for these patients. The use of tidal modality can increase dialysate flow and reduce drain and fill times. Coupled with larger volumes, it can raise clearances in high or high-average transporters (14,19 22). Moreover, tidal APD can increase clearances in patients with catheter malfunction. CTPD may be the only way that some larger or anephric patients can achieve target clearance rates (16). CCPD or CTPD are indicated in high-average transport patients. These patients generally cannot reach adequate clearances with NIPD or NTPD even

4 PDI MAY 2000 VOL. 20, SUPPL. 2 APD PRESCRIPTION at high volumes (14,16). With the addition of a long daytime dwell, the efficiency of APD is greatly increased in these subjects; a further increase can be achieved with two daytime dwells (9,16,49). NIPD or NTPD (with dry day) can give adequate results only in high transport patients (9). Moreover, NIPD or NTPD are strictly indicated in high transporters because these techniques can reduce protein loss, glucose absorption, and fluid retention. APD can be an excellent choice for the first treatment of a patient with end-stage renal disease, before studies of the peritoneal transport characteristics are made. We often make this choice in anuric patients with a big body size (> 80 kg) who cannot reach adequacy targets with CAPD. In this case, a continuous APD technique (CCPD2, CTPD2, or PD Plus therapy) with large, tailored fill volumes is indicated. APD as a first-choice treatment is also indicated in patients with limited self-sufficiency, in children, in patients with hernias or leaks, and finally for lifestyle requirements. APD as second-step treatment can be useful in CAPD patients with burnout (those who no longer can tolerate frequent daily manual dialysis exchanges) or in patients with increased peritoneal permeability. In these situations, APD can effectively continue peritoneal dialysis and minimize the need for patients who prefer PD to transfer to the hemodialysis modality. APD can further reduce the dropout rate owing to a possibly lower rate of infectious episodes (50) and a generally better acceptance of the technique by the patient (5). NEW CLINICAL ASPECTS AND FUTURE TRENDS OF APD The use in APD of new solutions with alternative osmotic agents, nutritional integration, reduced sodium content, and alternative buffers seems very promising (51,52). Peritoneal dialysis solutions mixed and tailored to the needs of individual patients will require new solution bags and connections for APD. Dialysate composed of amino acids together with glucose has the advantage of simultaneous absorption of calories and nitrogen for protein anabolism. The optimal proportion of glucose to amino acids in the mixture can be 7:1, giving an approximate intake of 1 g of nitrogen for every 112 kcal. This mixture has been used in a long-term study on children with favourable results (53). Glucose-free APD may be used in the future, employing a mixture of glycerol and amino acids during the night and icodextrin during the day for ultrafiltration failure type I. The former dialysate may be particularly suited to the short dwell of APD, because small osmotic agents such as glycerol and amino acids enhance ultrafiltration in short, APD-like dwells, while the latter dialysate can be used in the daytime dwell to achieve better ultrafiltration. Moreover, a period of glucose-free PD could permit the recovery of a membrane with type I ultrafiltration failure (reduction, exhaustion, or glycosylation of aquaporins). Bicarbonate-based APD solutions will soon be available, with on-line mixing of the dialysate to avoid carbonate precipitation, as in hemodialysis. The bicarbonate solution now available in two-chambered bags may provide satisfactory stability once the two solutions are mixed together. In fact, a bicarbonate solution with stable electrolytes and glucose has been demonstrated (54), and no precipitation occurred for up to 72 hours. A mixture of amino acids and bicarbonate-buffered solutions can give good results because of better acid buffering and enhanced protein anabolism. In the future, continuous flow peritoneal dialysis using a specifically designed double-lumen peritoneal catheter may be possible. One promising design uses recirculated dialysate in a cycler using a double pump and on-line monitoring of intraperitoneal pressure (55). Biosensors can be placed on cyclers for many purposes. The intraperitoneal pressure can be measured continuously for on-line optimization of fill volume. Dialysate flow speed can be measured for on-line optimization of exchange times. In the peritoneal fluid, po 2, pco 2, ph can be measured for on-line bicarbonate mixing, and acid base and oximetry monitoring. These measurements may be useful to detect and treat sleep apnea. Urea and dialysate conductivity can easily be monitored on-line, and these values may be useful to standardize on-line dialysis fluid production. Lastly, white blood cells in dialysate can be monitored on-line for early diagnosis of peritonitis (56). Segmental bioimpedance may further help in measuring intraperitoneal fill volumes and ultrafiltration during rapid APD exchanges. Advancing machine technology will also improve the patient machine interface for the APD cyclers of the future (57). When a peritoneal cycling machine is placed in a patient s home, the need for simplicity of troubleshooting and service is more demanding than for a hospital product. Data connections and information transfer, data management and the creation of useful clinical information, and communication can all be implemented efficiently and at low cost, by adapting the evolving hardware and software. Because peritoneal dialysis is a home-based, selfcare therapy, and often the first form of dialysis that renal failure patients come into contact with, the most important requirement for PD products is ease of use and a simple interface. CAPD products fulfill these S73

5 RONCO et al. MAY 2000 VOL. 20, SUPPL. 2 PDI requirements. APD products, however, are under constant challenge to balance what is technically possible and clinically desirable with what is achievable in practice. Patient satisfaction should therefore be the most important design criterion for PD cyclers. A second goal is the ability of the medical team to individualize the prescription and to measure delivered dialysis dose and patient compliance. There should be flexibility in the choice of modes and solution composition, so that new ideas and medical progress can be accommodated. Most important, treatment cost must be contained. Safety, according to local and global standards, is a basic, mandatory characteristic of any medical device and must also apply to APD cyclers. A design philosophy is a dynamic vision of a future goal, into which medical and technical events and demands are continually integrated. With this consideration in mind, the ideal machine should not only be able to perform all treatment schedules, but it should also be able to optimize the performance of a selected treatment strategy. For example, on-line pressure and flow sensors should be integrated to provide accurate information on patient response to a given treatment regimen. Catheter malfunction or other complications such as excessive intra-abdominal pressure should not only be immediately detected, but the machine should also propose or perhaps even automatically attempt an appropriate solution. For example, during tidal dialysis, the tidal volume, and the inflow and outflow volumes and rates must be measured accurately. During the outflow cycle, the ideal machine would be able to measure intra-abdominal pressure and dialysate flow rate. When the pressure and flow display a break point and the trend is no longer linear, outflow should cease and inflow should start immediately. In this case, the tidal volume is not fixed throughout the treatment; it may vary at each exchange, reducing drainage and inflow times. On-line detection of net ultrafiltration related to fluid osmolality, dwell time, and cycle volume should provide automatic feedback for fluid composition in the next cycle. Segmental bioimpedance might provide the technology for this purpose. Sodium and glucose concentrations can be instantaneously varied by such a feedback loop, providing fine control of net ultrafiltration. On-line fluid preparation should be possible; the cycler will then become an intelligent unit. Some of these innovations have been made possible in hemodialysis. However, while the primary target in hemodialysis is the clinical tolerance to ultrafiltration, in peritoneal dialysis, these efforts should be primarily oriented toward maximal safety of the solution and maximal use of the peritoneal membrane. The permeability of the peritoneum, the S74 behavior of the abdominal cavity, the biological response to dialysis fluids, and the function of the peritoneal catheter determine many of the variables in peritoneal dialysis treatment performance. The machine can probably control all the other variables. We are entering an exciting era, when technological advances and increased understanding of the interface between machines and patients will make advanced APD available soon, improving the quality of life for patients with end-stage renal failure. REFERENCES 1. Diaz Buxo JA, Suki WN. Automated peritoneal dialysis. In: Gokal R, Nolph KD, eds. The textbook of peritoneal dialysis. Dordrecht: Kluwer Academic Publishers; 1994: Popovich RP, Moncrief JW, Nolph KD, Ghods AJ, Twardowski ZJ, Pyle WK. Continuous ambulatory peritoneal dialysis. Ann Intern Med 1978; 88: Diaz Buxo JA, Farmer CD, Walker PJ, Chandler JT, Holt KL. Continuous cyclic peritoneal dialysis: A preliminary report. 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7 RONCO et al. MAY 2000 VOL. 20, SUPPL. 2 PDI Bernardini J, Malhotra D, et al. Peritoneal urea and creatinine clearance in continuous peritoneal dialysis patients with different types of peritoneal solute transport. Kidney Int 1998; 53: Mehrotra R, Saran R, Nolph KD, Moore HL, Khanna R. Evidence that urea is a better surrogate marker of uremic toxicity than creatinine. ASAIO J 1997; 43(5):M Amici G, Mastrosimone S, Virga G, Da Rin G, Bocci C. Variability of adequacy indices derived from 24h collections in APD [Abstract]. Perit Dial Int 1998; 18(1): Rodby RA, Firanek CA, Cheng YG, Korbet SM. Reproducibility of studies of peritoneal dialysis adequacy. Kidney Int 1996; 50(1): Churchill DN, Taylor DW, Keshaviah PR, and the CANUSA Peritoneal Dialysis Study Group. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: Association with clinical outcomes. J Am Soc Nephrol 1996; 7: Diaz Buxo JA. Enhancement of peritoneal dialysis: The PD Plus concept. Am J Kidney Dis 1996; 27(1): Korbet SM, Vonesh EF, Firanek CA. Peritonitis in an urban peritoneal dialysis program: An analysis of infecting pathogens. Am J Kidney Dis 1995; 26(1): Vande Walle J, Raes A, Castillo D, Lutz Dettinger N, Dejaegher A. Advantages of HCO 3 solution with low sodium concentration over standard lactate solutions for acute peritoneal dialysis. In: Khanna R, ed. Advances in peritoneal dialysis. Toronto: Peritoneal Dialysis Publications, 1997; 13: Struijk DG, Douma CE. Future research in peritoneal dialysis fluids. Semin Dial 1998; 11(4): Canepa A, Perfumo F, Carrea A, Verrina E, Menoni S, Trivelli A, et al. Long-term effects of amino acid solutions in children on automated peritoneal dialysis [Abstract]. J Am Soc Nephrol 1996; 7(9): Leblanc M, Moreno L, Robinson O, Tapolyai M, Paganini EP. Bicarbonate dialysate for continuous renal replacement therapy [Abstract]. J Am Soc Nephrol 1995; 6(3): 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(4): Steele M, Kwan JT. Potential problem: Delayed detection of peritonitis by patients receiving home automated peritoneal dialysis. Perit Dial Int 1997; 17(6): Ronco C, Brendolan A, Zanella M. Evolution of machines for automated peritoneal dialysis. Contrib Nephrol 1999; 129: S76