J Am Soc Nephrol 13: S104–S116, 2002 Peritoneal Dialysis in the 21st Century: An Analysis of Current Problems and Future Developments

RAM GOKAL Manchester Royal Infirmary, Manchester, United Kingdom.

One major development in the field of kidney diseases in the of death on PD as compared with HD and by and large found 21st century will be in prevention of end-stage renal disease that mortality risk was equal for HD and PD in the various (ESRD). Basic research has made inroads into the understand- studies reported. After this analysis was the report of Bloem- ing of the mechanisms of progression of chronic renal failure, bergen et al. (2), which was based on the US Renal Data including the understanding of the functions of genes activated Systems (USRDS) data on prevalent patients (1987, 1988, and by renal damage. All this may well result in a major reduction 1989). This showed that PD subjects had a 19% higher risk of in the incidence of ESRD. The second important development mortality as compared with patients who used HD. This was will be in transplantation, which will constitute the mainstay of met with considerable consternation in the United States and ESRD treatment in the next century. The clinical introduction probably did the therapy a major disservice. Analysis from the of xenotransplantation and the cloning of one’s own organs via Canadian Organ Replacement Registry on patients starting one’s stem cells may well represent the major areas of replace- RRT between 1990 and 1994 showed that for incident patients, ment therapy. This will reduce dialysis as a method to support the survival with PD was better in the first 2 yr of treatment the main treatments. These predictions will take some time to compared with HD with subsequently no difference up to 4 yr come to fruition. The first few decades in this century will face (3). In addition, it showed that there was a significantly lower an increase, rather than a decrease, in the number of ESRD risk of death in PD patients across all ages, regardless of patients needing dialysis. Peritoneal dialysis (PD) will feature whether or not the patient had diabetes; for ages 0 to 64 yr, the strongly in meeting this need in at least the first two decades of relative risk of death was 0.54 for PD patients without diabetes this century. PD has come a long way since the introduction of continu- (for HD, the relative risk was 1) and 0.73 for patients with ous ambulatory PD (CAPD) as a form of renal replacement diabetes. A further comparative analysis from 11 Canadian therapy (RRT) over the quarter of a century it has been in centers showed that the apparent survival advantage of PD existence. There have been some dramatic improvements in patients was due to lower comorbidity and a lower burden of outcomes in patients treated by PD, such that it is now accepted acute onset end-stage disease at the inception of dialysis; as an equivalent therapy to hemodialysis (HD). In the last 5 yr, survival was otherwise equal (4). CAPD has proven to be as effective a treatment as HD, and in More recent analysis of the USRDS data shows similar some instances may offer advantages over HD. As we move results: 5-yr survival of the 1993 cohort of dialysis patients is into the new millennium, it is clear that PD will feature identical for PD and HD patients (5). The analysis on Medicare strongly in the care and management of patients in ESRD as patients in the United States by Collins et al. (6) on the cohort advances in the understanding of the pathophysiologic mech- of patients 1994 to 1997 concluded that in the first 2 yr of anisms and means to combat the adverse effects of PD are put therapy, short-term PD is associated with superior outcomes into practice. Currently, there are more than 130,000 patients compared with HD at all ages except in elderly women with on PD worldwide, representing approximately 15% of the total diabetes. A further analysis of 17,000 PD patients from the world population requiring dialysis. It is anticipated that this Canadian Organ Replacement Registry database (1981 to number will increase during the next decade, especially in 1997) has shown significant decrease in mortality rates during developing countries. this period (7). Long-term survival from single center analysis shows no difference at 15 yr between PD and HD patients (8). Current Outcomes A reasonable conclusion from all this information is that Several analyses have been undertaken in comparing the mortality is the same for HD and PD when comparing identical outcomes on PD and HD. Nolph (1) analyzed the relative risk types of patients, at least for the first 3 to 4 yr of RRT. Patient survival statistics from long-term studies in PD patients during the 1990s show a 50 to 70% 5-yr survival (5,8). It is likely that the results will continue to improve as the various develop- Correspondence to Dr. Ram Gokal, Department of Renal Medicine, Manches- ments outlined below are incorporated into routine practice. ter Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Phone: 44 161 276 4540; Fax: 44 161 276 8022; E-mail: [email protected] PD to date has proven its utility and has become established in certain areas of care of patients with ESRD. These aspects, 1046-6673/1300-0104 Journal of the American Society of Nephrology which have to be maintained or even further improved in the Copyright © 2001 by the American Society of Nephrology future, are outlined in Table 1. J Am Soc Nephrol 13: S104–S116, 2002 Peritoneal Dialysis in the 21st Century S105

Table 1. Positive points about peritoneal dialysis therapy Peritoneal Infections that have been established beyond doubta Peritonitis remains a problem and a major source of transfer to HD (13,14), even though rates have improved dramatically Lower cost than HD, especially in the Western world. with the advent of technologic improvements related to the Similar survival to HD, and somewhat superior survival in disconnect systems (15). The problem lies in persistent unre- the first 2 to 3 yr (see text). solving peritonitis due to Pseudomonas, fungal, and to a lesser Treatment of choice for infants and younger children, extent Staphylococcus aureus infection (16,17). At present, especially automated PD. there appears no obvious means to prevent gram-negative and Considerable reduction in peritonitis (disconnect systems) fungal infections, and the only option is to develop better and catheter-related infections (exit site treated with therapeutic regimens to improve the outcome of these mupirocin). infections. Adequate solute clearance in all but the largest anuric For S. aureus infection, there is greater reason for optimism. patients. Several studies have shown nasal carriage of S. aureus is Optimal treatment before transplantation. related to increased exit site infection and peritonitis (18,19). a HD, hemodialysis; PD, peritoneal dialysis. Prophylaxis with intranasal mupirocin, exit-site mupirocin, or cyclical rifampicin can dramatically reduce not only S. aureus exit-site infection and peritonitis, but also infections from other Current Problems Requiring Improvement organisms (20,21). Mupirocin routinely administered to exit Technique Failure and Long-Term PD sites is now advocated in published guidelines (22) and is If PD is going to achieve wider acceptance, then several likely to favorably affect infection rates and survival. outstanding problems that currently detract from greater accep- Patient dropout after persistent peritonitis remains a prob- tance need to be overcome. Two major issues are the higher lem, and those who require catheter removal for cure do not technique failure in PD compared with HD (still related in a return to PD. More research needs to be done into techniques third of dropouts to HD to peritoneal infections) and the low for safer catheter removal and reimplantation in the presence of rate of achieving long-term PD. The latter is to a large extent persistent peritonitis to avoid interruption of PD. Prevention of related to long-term changes in peritoneal membrane structure adhesions, which are extensive in some patients with persistent and function. In the analysis by Davies et al. (9), technique peritonitis, is also important. survival in the seven studies in the 1990s was 30 to 50% at 5 yr. The major causes of dropout derived from these analyses Peritoneal Access are shown in Figure 1. The nonachievement of long-term PD is Transfer of patients to HD for peritoneal access failure is to a large extent related to long-term changes in peritoneal now reduced to approximately 5 to 10% (Figure 1). Access- membrane structure and function. Long-term (more than 10 yr) related dropout is low, and the improvement in catheter-related PD is limited to a small percentage of those who start PD (10), infections from mupirocin prophylaxis augur well for the con- and single-center analysis shows that survival for those who tinuing improvement in peritoneal infection. The type of cath- use PD is 20% at 10 yr (8). The major cause of failure in eter and method of implantation are probably less important long-term studies is ultrafiltration failure, inadequate solute than the meticulous care taken during implantation and subse- clearance, and peritonitis (11). In data from Japan (12) long- quent care with immobilization and exit-site care; these aspects term survival from a cohort of 242 patients was for a median are reviewed in the catheter guidelines of the International of 5.8 yr, with patients’ failure to respond to this technique Society of Peritoneal Dialysis (23). related to membrane problems. Adequacy of Solute Removal In spite of the original description by Popovich et al. (24) and the theoretical work of Teehan et al. (25) suggesting prescription formulations, CAPD has remained standardized to daily 4 ϫ 2-L regimen with little, if any, individualization (26). This is disconcerting, because such a standard prescription simply cannot be applied to patients of varying size, residual renal function, and peritoneal permeability. It is now clear that a prescription needs to take these three factors into account. Adequate dialysis regimens need to be arrived at by variation in the number, volume, and strength of exchanges and the dwell time of each exchange. Guidelines on targets for solute clearance have now emerged, the most prominent of which has been the National Figure 1. Reasons for therapy change to hemodialysis in long-term Kidney Foundation–Dialysis Outcomes Quality Initiative peritoneal dialysis patients in the 1990s. Percentages are averaged (NKF-DOQI) guidelines (27). The NKF-DOQI targets are a from seven outcome studies (3,9,65,150–153). weekly Kt/Vurea of 2.0 and a creatinine clearance of 60 L per S106 Journal of the American Society of Nephrology J Am Soc Nephrol 13: S104–S116, 2002 week per 1.73 m2 for CAPD and slightly higher targets on has led to the development of newer PD solutions and paved automated PD (APD) regimens. These have been modified to the way for better treatment of patients undergoing PD with lower the targets for creatinine clearance in low transporters to improved outcomes and longevity. 50 L per week, in line with the Canadian guidelines; high The peritoneal membrane, consisting of the mesothelium transporters have a poorer outcome (28). These have been and the underlying connective tissue, is a highly developed based predominantly on the Canada-USA study (29), which organ that provides structural support, regulates transperitoneal showed that the greater the solute clearance at start of dialysis, transport, and mediates peritoneal defense and repair. The if maintained over the duration of the CAPD, the better the mesothelium acts as a highly dynamic surface; it is involved in outcome. Although there is still considerable debate surround- the production of peritoneal lubricants; in solute and fluid ing the evidence for such targets (30), it is generally accepted transport; in coagulation and fibrinolysis; and in the production that higher target values are desirable and should be achieved and remodeling of the extracellular matrix and host defense (33). if at all feasible (31). A Kt/Vurea of 1.7 and a creatinine Solutes passing from the blood in the peritoneal capillaries clearance of 50 L/wk are absolute minimal targets, and all to the dialysate-filled peritoneal cavity have to pass at least patients should be above these. three structures that can offer resistance: the capillary wall In developing countries, financial constraints have not yet (probably the most important), the interstitial tissue, and me- allowed liberalization of prescriptions to meet these targets. sothelial cell layer. Diffusion and transcapillary ultrafiltration However, results from Hong Kong suggest that lesser total occur in two directions across these resistances. It is now daily exchange volumes can produce good outcomes (32). The recognized that there are effectively three pores that explain the new millennium will see more studies and data from these capillary transport (34). This three-pore theory recognizes ul- countries to verify the needs of their patients in terms of trasmall pores, small pores, and large pores. First, ultrasmall adequacy and prescription-setting. pores (3 to 5 Å; aquaporin-1) allow the transport of water but not solutes. These have been identified in the mesothelium and Automated PD the capillary endothelium (35). Glucose is effective as a crys- One way of achieving increased dialysis is by the use of talloid osmotic agent in spite of its small size of 2 to 3 Å,asit APD. Use of APD is increasing rapidly—indeed, it is the predominantly acts at this level. Approximately 50% of trans- fastest-growing mode of dialysis. APD is a major advantage in capillary ultrafiltration occurs through these pores. Second, patients with a hyperpermeable peritoneal membrane (high colloid osmosis occurs at the level of small pores (40 to 50 Å). transporters) because these patients are unable to ultrafilter Interendothelial clefts have been considered the equivalent of adequately on long-dwell regimens and experience fluid over- the small pores. Third, large pores (Ͼ150 Å; probably less than load on standard CAPD. The short-dwell exchanges on APD 0.1% of total pore count) are involved in macromolecular can overcome the loss of ultrafiltration. Clearly, achieving transport. In addition, there is lymphatic absorption from the targets of solute and fluid clearance is likely to favorably affect peritoneal cavity (36). outcomes. Diffusion and convection are the mechanisms for solute APD has also major advantages for the patient from the transport, which is also bidirectional. Because of the complex psychosocial point of view, and this is partly the reason for its structure of the various barriers to the peritoneal transport of popularity. In the West, there is a growing trend toward higher solutes and fluid, it is simpler to regard this system as one targets. These trends reflect the increasing emphasis on ade- membrane. In practical terms, the transport of low molecular quacy, and the practice of PD is bound to change with this weight substances across this membrane under defined condi- increased emphasis on prescription setting to meet targets of tions gives rise to dialysate/plasma ratios over the 4-h stan- adequacy; variations in the various regimens available to dardized dwell (peritoneal equilibration test). This defines the achieve these will considerably facilitate achievement of solute transporter status of the patient from high (hyperpermeability) clearance targets. It would be interesting to see how these to low (hypopermeability) and has distinct and important im- increased prescriptions are going to affect outcomes. plications for setting the prescription (37). The permeability, Questions where controversies exit and where prospective combined with the surface area, gives rise to the mass transfer controlled studies are required include the following: (1) renal area coefficient, which is a measure of the diffusive perme- versus peritoneal clearances and the equivalence; (2) small ability of the peritoneum, taking into account the surface area solute clearance measured via creatinine clearance and Kt/ and the concentration gradient.

Vurea—which is better?; and (3) solute clearance targets—are Glucose is well recognized to have several deficiencies that they the same or different for special patient groups, such as makes it an unsuitable agent for standard, long-dwell PD for patients with diabetes, children, the elderly, and underweight reasons of ultrafiltration, metabolic side effects, and effect on and obese subjects? the integrity of peritoneal membrane, especially in long-term PD use. With PD, morphologic changes do take place; func- Peritoneal Physiology and Changes with tional derangement is the result. These morphologic-functional Long-Term PD relationships are therefore vitally important. The use of un- In the last 25 yr, enormous strides have been made in the physiologic PD solutions and episodes of infection and inflam- understanding of peritoneal morphology and its related physi- mation (38–40) lead to changes in the mesothelial layer, ology in terms of solute and fluid transport. This understanding disorganization of the interstitium (collagen fiber disruption J Am Soc Nephrol 13: S104–S116, 2002 Peritoneal Dialysis in the 21st Century S107 and “fibrosis”), and duplication of the basement membrane tions with neutral pH and low carbonyl stress, prevention of both in the capillary endothelium and the mesothelial basement angiogenesis in the peritoneal membrane by use of intraperi- membrane (41). This tendency to fibrosis has been reported in toneal or systemic medications against formation, and deposi- long-term dialysis patients (42,43) and this is partly related to tion of advanced glycation end products. Other areas of re- advanced glycation end products in the peritoneum (44) from search include the study of free radical scavengers glucose-protein reactions in the peritoneum. The end results of administered by mouth or intraperitoneally. the changes are sclerosing-encapsulating peritonitis, which is infrequent (45). The Australian data reported 1.9 to 4.2% of patients with this syndrome (46), whereas the Japanese study Other Problem Areas reports a smaller incidence of 0.9 to 1.7% (47). Only a small percentage of patients remain on CAPD-APD Loss of ultrafiltration is the most common peritoneal trans- for more than 8 yr (10). Furthermore, as in HD, these patients port abnormality in long-term PD (48–50). The major causes show an increased cardiovascular mortality and can develop of ultrafiltration failure are the presence of large vascular malnutrition. These are important reasons for failing to achieve peritoneal surface area and decrease in osmotic conductance to long-term PD. Patient fatigue is a significant area of concern in glucose related to decreased aquaporin function or decrease in the long-term management on PD. Maiorca et al. (65) found the ultrafiltration coefficient of the peritoneum (changes in the that patient fatigue and psychosocial factors accounted for interstitial tissues) (51,52). Long-term PD thus produces a about half the total number that changed to HD in long-term large vascular surface area, and the fibrosis may well affect PD patients. This may in part be related to the acceptance of aquaporin function. elderly high-risk patients, whose comorbidity and infirmity is Apart from the metabolic side effects (obesity, glucose in- likely to increase with time on dialysis and will enhance the tolerance, hyperinsulinemia, and reduced peripheral sensitivity difficulties of performing the dialysis procedures on a daily to insulin, hyperlipidemia [53,54]), there are major issues basis. related to the bioincompatibility. There are several pathogenic There is a need to develop methods to identify patients prone factors responsible for changes in the peritoneal membrane. to fatigue. The liberal use of home care in selected patient These appear to be the following: (1) continuous exposure to groups, such as the elderly, and the use of PD in nursing homes bioincompatible dialysis fluids (shown to be toxic in vitro could reduce the incidence of patient fatigue. Currently, some [55–58])—the factors that are important are a combination of of these patients are managed in a nursing home environment low pH and lactate and glucose itself, through its metabolism (66,67); an estimated 2000 to 3000 patients with ESRD are via the polyol pathway (59), and molecular mechanisms such admitted to nursing homes annually in the United States, with as cytokines, growth factors, and nitric oxide synthase activity 13 to 15% managed on PD (68). The use of APD may be (60); (2) glucose exposure leading to vascular changes of advantageous in some of these patients when relatives are neovascularization and deposition of type IV collagen in the involved in their dialysis. The development of respite services interstitium (61); (3) formation of advanced glycation end once or twice a year may well prevent burnout of relatives. The products in peritoneal tissue (44,62,63); and (4) the presence of development of cyclers that are much simpler to operate than glucose degradation products (GDP) generated during steam the current models could be of great importance in preventing sterilization, which induces direct cytotoxicity and also accel- burnout. erates the process of the formation of advanced glycation end It is well recognized that cardiovascular mortality is in- products (55,62–64). creased severalfold in these patients. The reasons are multifac- Glucose exposure is now regarded as a significant pathoge- torial. There are the traditional factors increasing the risk (e.g., netic factor in peritoneal membrane alteration. The goal for the atherogenic lipid profile, left ventricular hypertrophy, conges- clinician is to identify how to reduce patient exposure to tive cardiac failure, smoking) and several factors related to the glucose, minimize the total amount of glucose absorbed, and dialysis therapy itself. For PD, the established risk relates to the avoid the hyperosmolar stress and high glucose and GDP development of a hyperpermeable membrane (29). Less clear exposure to the peritoneum. Fortunately, nonglucose-based PD is the role of an inflammatory milieu giving rise to malnutrition solutions as well as lower GDP containing solutions are now and atherosclerosis (MIA syndrome) (69,70) and disordered becoming available in Europe and offer a positive step calcium-phosphate metabolism and vascular calcification (71). forward. The serum of PD patients is more atherogenic than the serum There is also a need to develop sensitive means for early of HD patients (72). Relevant research should include prospec- diagnosis of membrane damage. Further research needs to be tive, controlled studies on the effects of statins, aspirin, folic done to assess the role of CA125 (a measure of mesothelial acid, antioxidants, and strict control of serum calcium and mass), parameters of ultrafiltration changes (peritoneal equili- phosphorus in the prevention of cardiovascular mortality. Also bration test, standard permeability analysis), and serial perito- needed are studies on the effects of glucose-free dialysis solu- neal biopsies in assessing membrane damage and to establish tions and the role and prevention of chronic inflammation in whether new solutions containing additives may prevent fibro- the production of atherosclerosis and malnutrition. The identi- sis. Potential research in this area includes the study of addition fication of elevated levels of adhesion molecules expressed on of hyaluronic acid to the dialysate, use of glucose-free solu- the surface of vascular endothelial cells in response to proin- tions (glycerol, amino acid, icodextrin), use of dialysis solu- flammatory cytokines have already been found in malnour- S108 Journal of the American Society of Nephrology J Am Soc Nephrol 13: S104–S116, 2002 ished predialysis patients, and these are independent predictors randomized, prospective study. I suspect that as is the case with of mortality (73). solute clearance targets, the practice will evolve to start pa- Severe malnutrition is present in 8 to 10% of the PD pa- tients earlier and earlier than is the current practice, in the hope tients, and another 30% have mild malnutrition (74). The goal that better outcomes will result. If this becomes the de facto should be to prevent this complication, which is a strong practice, then better patient education and involvement in predictor of poor outcome. Future research will need to con- decision-making will be crucial for success of early initiation, centrate on the relationship between malnutrition and small as will the need for earlier referral. solute clearances and the role of chronic inflammation on the development of malnutrition. There is some evidence that Use of PD as an Initial Therapy in an Integrated malnutrition is associated with chronic inflammation and high RRT Program peritoneal solute transport (75), but this has not found to be so The survival results on PD are better than on HD in the by others (76). Further research is needed to clarify the asso- initial years of therapy (3), and technique survival on long-term ciation between chronic inflammation, high transport, and mal- PD is improving (9). It is appealing, therefore, to advocate PD nutrition, as is the reported suggestion of an association be- as an initial therapy (98,99). If PD therapy fails for whatever tween hypoalbuminemia and atherosclerosis (77). reason (usually peritonitis, inadequate dialysis, or patient-re- PD patients are more prone to low-turnover bone disease lated factors), then a switch from PD to HD should be consid- (adynamic bone), which is associated with hypercalcemia and ered. This approach is cost-effective and has shown better metastatic calcification from its inability to handle calcium outcome results. In a Belgian study (100), this approach re- load (78,79). A high calcium-phosphate product has been sulted in better survival in patients starting with PD than HD; linked to increased mortality (80) and coronary vessel calcifi- it showed that patient outcome is not jeopardized by starting cation, which is progressive in young HD patients studied with patients on PD, provided patients are transferred in a timely the new electron-beam computed tomography (81). These are manner when PD-related problems arise. There are several exciting new findings, and there is a need to establish this in advantages to commencing PD as an initial therapy (Table 2) PD patients and assess the link between the higher prevalence pertaining to better residual renal function preservation (101), of adynamic lesion on PD and cardiovascular outcomes. decreased incidence of hepatitis C compared with HD (102), preservation of vascular access sites (98), better initial BP New Trends and Future Developments control and less cardiac dysfunction (103), and better results Early Start with Incremental Dialysis after transplantation (104,105). The discontinuation of PD and Even though targets have been set for solute clearance on transfer to HD at an appropriate time optimizes outcome; the dialysis, patients with chronic renal failure are allowed to failure to do so can lead to poorer outcome (9,106). dwindle to clearances far below these targets before dialysis is There are considerable obstacles to this approach that are initiated (82–84). It does not seem logical to allow patients to almost entirely nonmedical (physician biases, funding and re- fall below minimal targets of adequacy and then have to imbursement policies) (107). The nephrology community increase dialysis to meet these accepted levels. In addition, this needs to be better informed on the current outcomes and practice has major drawbacks: progressive renal failure leads to advances in PD. Other factors also affect modality selection. nutritional decline (85,86); in addition, the worse the small Time of referral is another important determinant. Patients that solute clearance (87,88), the worse the nutritional status at the are referred late are more likely to go on to HD and remain on time of initiation of dialysis, which leads to a poor outcome it (108,109). It is important, therefore, that there is early (89,90). Keshaviah et al. (91) addressed the issue of timely initiation of dialysis and predicted that CAPD in a hypothetical average-sized patient with high average peritoneal transport Table 2. Factors favoring peritoneal dialysis as the initial could be maintained for approximately 8 mo with a single dialytic therapy for patients with end-stage renal a 2.5-L exchange and from 8 to 17 mo with 2 nocturnal ex- disease changes of 2.5 L each. Better survival than HD in the first 2 to 3 yr of therapy. The NKF-DOQI guidelines advocated starting dialytic ther- Better BP and fluid control in first few years of dialysis. apy when the residual Kt/V reaches 2.0; use of incremental urea Better preservation of residual renal function versus HD. dialysis will achieve solute clearance targets by compensating Higher hemoglobin levels, less use of rHuEPO. for the declining residual renal function as occurs with time. Better outcomes after transplant. This incremental approach is possible (92,93) by performing Less risk of acquiring a blood-borne virus (hepatitis C). PD only during the night or by using an exchange of icodex- Patient benefits, including more flexible holidays and travel trin, which has prolonged ultrafiltration characteristics. and higher employment rates. Anecdotal experience of early start (sometimes called Ability to expand patient numbers in a dialysis center with “healthy start”) has been reported (94–96) and reviewed in an limited need for resources and major capital investments. editorial (97). The reports show that it is possible to start early Lower staff-to-patient ratio than center HD. with incremental dialysis, but the experiences do not allow any Less costly than center HD. firm conclusions to be drawn, and the case for early start with incremental dialysis needs to be substantiated with a large, a HD, hemodialysis; rHuEPO, recombinant human erythropoeitin. J Am Soc Nephrol 13: S104–S116, 2002 Peritoneal Dialysis in the 21st Century S109 referral of patient with chronic renal failure to a renal center, longer periods of time, giving rise to prolonged ultrafiltration where the patient will undergo an unbiased education program. of at least 12 h (113,114). It is also isosmotic to uremic plasma Experience in the United States indicates that when patients and shows considerably less glycation and calorie absorption were appraised of all treatment options, the percentage starting (115). Its use in patients with a hyperpermeable membrane and PD was higher than the national average. The USRDS in 1997 loss of ultrafiltration has extended the time on PD by a mean reviewed the patient-reported process of modality choice of 22 mo in patients who would otherwise have switched to HD (110). Of 1174 HD patients assessed, 17% chose this dialysis (116). These are also the patients who would benefit by trans- modality when the decision was patient led (35% of 1049 PD ferring to APD; increasingly, patients need a daytime exchange patients), 53% when it was medical team led (16% for PD), and or exchanges to meet solute clearance targets. Icodextrin is 30% when it was joint patient–medical team decision (49% for ideally suited for this prolonged dwell of 10 to 14 h (117). PD). In a scenario where full patient choice is available with a There is early evidence that BP control may be improved with scheme that provides for unbiased patient education, PD would icodextrin (118), and there may be less hyperlipidemia (119). appear to be the first option if medically suitable (99) (Figure Future areas of clinical research with icodextrin include sub- 2). This may well turn out to be an ever-increasing trend in the stantiating some of the above, use of icodextrin as part of early new millennium. start dialysis prescription (97), use in specialist patient groups (people with diabetes, cardiovascular instability, high trans- Recent and Future Innovations in PD Solutions porters), its use in combination with other osmotic agents, As described in more detail above, there is now a greater long-dwell (14 to 16 h) use (120), and 2 exchanges per day in appreciation of the deleterious effect of current solutions, es- combination with short exchanges. The only substantial side pecially glucose, in damaging the peritoneal membrane (111). effect from its use is skin reactions, which are severe enough Approaches to minimizing glucose exposure should benefit the (exfoliative dermatitis) for discontinuation of icodextrin in less patient. This has been shown in anecdotal studies; in patients than 1% of patients (121). with ultrafiltration failure, total avoidance of glucose (use of glycerol and icodextrin) has shown a return of ultrafiltration Bicarbonate as Buffer (112). This forms only one strategy in improving outcomes in Newer solutions have been recently introduced to minimize PD and forms the basis for a rational approach to using the the affect of the peritoneal membrane. One such solution is various solutions available (Table 3). bicarbonate based, replacing lactate as the buffer. Low pH and lactate are regarded to be deleterious to the peritoneum (57). Icodextrin The introduction of bicarbonate solutions into clinical practice The development with the greatest potential for impacting was based on in vitro studies (58). Advances in sterilization on PD therapy is the introduction of icodextrin. This glucose methods and delivery systems have enhanced the feasibility of polymer is able to maintain a colloid osmotic gradient for producing a bicarbonate-based solution. Several studies have reported clinical experiences with these solutions, either as bicarbonate alone or as a combination of bicarbonate and lactate (122–124). Evidence is not yet available that bicarbonate solutions impart benefit to patients in terms of peritoneal transport and preserving peritoneal membrane integrity. However, patients who experience pain at infusion of PD fluid related to pH and lactate have been shown, in a randomized trial, to improve dramatically on bicarbonate and bicarbonate/lactate solutions (125). The solutions currently available are entirely bicarbon- ate or a lactate/bicarbonate mixture.

Amino Acids Although amino acids have been studied for more than 20 yr as an osmotic agent, the current interest is largely due to the identification of significant malnutrition in the PD population; amino acids may be used to alleviate this problem. In addition, Figure 2. Schematic representation of the role of peritoneal dialysis because it will replace one to two glucose exchanges per day, (PD) in an integrated renal replacement therapy program where (A) the glucose sparing advantage should not be dismissed. patients are referred early, receive full education and therapy choice, The effects of amino acid solutions on nutritional state have and, on the basis of medical conditions and patient choice, are perhaps managed initially by PD. Early start may also be undertaken (B), been investigated by a number of groups. Most show a benefit especially in patients with diabetes; this is also feasible by using a when used in malnourished patients (126–128), but this has not single exchange of icodextrin overnight and by increasing the number been found in other studies (129,130). Use of amino acid of exchanges as the residual renal function declines (incremental solutions is accompanied by a rise in serum urea nitrogen and dialysis). a mild degree of metabolic acidosis, which is enhanced with S110 Journal of the American Society of Nephrology J Am Soc Nephrol 13: S104–S116, 2002

Table 3. A rational approach to using newer peritoneal dialysis solutions according to needs and aimsa

Function Type of PD Fluid

Maintain UF Icodextrin Glucose-free dialysis (glycerol ϩ amino acid ϩ icodextrin) APD ϩ icodextrin (high transporters) Enhance solute clearance Icodextrin (UF related, especially in APD) Treat protein malnutrition Amino acid PD fluid Minimize metabolic problems Icodextrin (less carbohydrate absorbed; perhaps lowers lipids) Protect membrane function Bicarbonate (pH 7.2) Icodextrin (iso-osmolar) Double/triple-chambered glucose fluids low in GDP (pH 6.2) Lower GDP Icodextrin Bicarbonate/lactate Double/triple-chambered glucose fluids low in GDP

a PD, peritoneal dialysis; UF, ultrafiltration; APD, automated peritoneal dialysis; GDP, glucose degradation products. the use of two exchanges per day (126); amino acid solutions will allow for better efficacy and less side effects in the future. can only be used in one to two exchanges per day. Glucose and amino acids, amino acids and glycerol, icodextrin Current emphasis on amino acid use in PD, other than the and amino acids, and icodextrin and glycerol have all been above indications, appears to be in providing a protein source tested in vitro or in patients in a limited way (135). In combi- in people whose ingestion is limited, in catabolic situations nation with bicarbonate, these would approach an ideal. One such as peritonitis, and in minimizing glucose exposure. There can imagine a daily regimen for CAPD consisting of an ex- is no evidence that its use prevents the development of change of amino acids, two exchanges of bicarbonate/glucose, malnutrition. and an overnight exchange of icodextrin. This combination is possible now, but clinical trials are needed to assess its Other Modifications efficacy. Another modification has been to bring about a reduction in the content of GDP, which is produced during heat sterilization Future Strategies and which is cytotoxic (131). Nonglucose-based PD solutions Existing PD solutions were formulated for the maintenance most effectively address all aspects of both systemic and local of fluid and electrolyte balance, removal of metabolic waste, glucotoxicity. However, because glucose-based solutions can- and correction of acidosis. Recent emphasis has been on im- not be used for all exchanges in CAPD or APD therapy, they proving the biocompatibility to enhance peritoneal membrane are still required for at least part of the dialysis regimen. The integrity and improve long-term outcomes; in addition, strate- recent development of two-chamber bags permits separation of gies for reduction in glucose use are available (136). Future glucose from other solution components, thereby allowing solutions will address major clinical needs related to the main- glucose to be sterilized at a lower pH than is possible in tenance of adequate nutrition, improvement in cardiovascular single-chamber bags. Mixing of the two compartments results comorbidity, preservation of peritoneal membrane function, in a raising of the pH, which in the case of bicarbonate- and achievement of adequacy of dialysis. Additives (procys- containing formulations can attain a neutral pH. The resulting teine, sulodexide) may help maintain various peritoneal func- solution has a pH of 6.3 and is less cytotoxic (131,132). tions and enhance adequacy (hyaluroan, atrial natruretic pep- In a pilot study, PD transport characteristics were similar to tide) (137). Increasing automation will reach its peak with glucose, but daily CA125 (a marker of mesothelial mass) was dialysate regeneration (138) and the design of on-line systems significantly increased (133), suggesting that mesothelial tox- to compound PD solutions that have been prescribed to provide icity ascribed to glucose may be related to GDP. For bicarbon- not only toxin and fluid removal, but also nutritional and other ate/lactate-buffered two-chamber systems, sterilization of glu- clinical support. cose at lower pH than currently performed today causes a reduction in most of the identified GDP, including acetalde- Henderson’s “Perpetual Hamburger:” Recycling Waste hyde, 3-deoxyglucosone, and methylglyoxal. Some appear to Henderson (139,140) believes that machine-based options be unchanged (e.g., glyoxal), whereas others are increased may in the future gradually give way to gene therapy that uses (e.g., 5-hydroxymethyl furfural, which appears to be innocuous the mesothelial cells as a site for the placement of nitrogen- in cytotoxicity assays). In vitro cytotoxicity and formation of fixing metabolic architecture that is now resident in both pro- advanced glycation end products are also significantly reduced karyotic and eukaryotic microorganisms (141,142). Presum- in such formulations (57,134). ably urea, uric acid, creatinine, and other organic sources of Because no solution is ideal, combinations of osmotic agents nitrogen, as well as inorganic toxins such as sulfate, phosphate, J Am Soc Nephrol 13: S104–S116, 2002 Peritoneal Dialysis in the 21st Century S111 and hydrogen, will be consumed to synthesize amino acids, National funding policies also determine the PD penetration polypeptides, or proteins with energy derived from carbohy- and use. Privately funded health care uses the smallest percent- drate metabolism. These anabolites will be swept to the blood- age of PD; publicly funded countries have the highest PD stream by the subdiaphragmatic lacunae that provide entrance penetration; and mixed economies are intermediate (143). This to the lymphatic system for macromolecular structures such as is in spite of consistent data from many Western countries that albumin and globulin. The peritoneal catheter in this instance show that PD is certainly cheaper than is center-based HD might logically be used to introduce energy-containing bathing (144,145). Now that the outcomes have shown to be equivalent solutions for use by the mesothelial cell layer. One may then to those of HD in terms of survival and quality of life imagine a “perpetual hamburger” that after initial ingestion (146,147), it is surprising to see that PD, in some countries, has would in its molecular components be infinitely recycled. limited use (148). In the future, funding bodies, both private In addition, it may be possible that the technologies of HD and public, would need to recognize this, and such recognition and automated PD will coalesce in such a way that a single could be a stimulus to the further use of PD—a phenomenon machine will serve to accomplish either therapy with sterile that is already happening in developing countries. pyrogen-free dialysis fluid that is compounded on line in There is no question that the next decade will see an enor- response to closed-loop sensors that use tap water and salt mous growth in the worldwide dialysis population; in particu- concentrates. lar, older and sicker patients will be accepted onto dialysis. It is likely, therefore, that worldwide pressures related to cost Gene Therapy containment will dictate the use of a cost-effective therapy, Henderson (139) first postulated that machine-based options which PD is proving to be. PD will continue to increase in use, for automated PD would gradually give way to gene therapy but only if its efficacy continues to improve without eroding its that uses mesothelial cells. New approaches to preserving the economic benefits over HD (149). The challenge for the mil- peritoneal integrity have been investigated (38). These include lenium and beyond is to develop PD therapy so that it opti- molecular genetic approaches by which the use of genetically mizes patient medical and psychosocial outcomes and mini- modified mesothelium is used to deliver potentially therapeutic mizes costs; this, I believe, is the future, and we need to strive recombinant proteins that might serve to preserve or improve to deliver this promise. Currently, only 15% of the world the performance of the peritoneal membrane in long-term PD. population that requires dialysis is managed by PD. This may In vitro studies on the methodologies have evolved and include well increase as therapy improves. Growth will be fastest in expression of a cytoplasmic reporter gene in rat mesothelial developing countries, and the escalating costs of dialysis treat- cells, delivery of a secreted recombinant protein, regulation of ments will push those who foot the bill to opt for more mesothelial cell-mediated transgene delivery, and delivery of a cost-effective treatment options. membrane-bound recombinant protein. The ability to genetically modify the peritoneal mesothelium References by ex vivo and in vivo strategies demonstrates that the perito- 1. Nolph KD: Why are reported relative mortality risks for CAPD neum is a modifiable membrane. This could then be used to and HD so variable? Perit Dial Int 16: 15–18, 1996 preserve or enhance the performance and integrity of the mem- 2. Bloembergen WE, Port FK, Mauger EA, Wolfe RA: A compar- brane for long-term use. 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