Peritoneal Dialysis in the 21st Century
Authors: Ram Gokal
Journal: Journal of the American Society of Nephrology (2002)

One major development in the field of kidney diseases in the 21st century will be in prevention of end-stage renal disease (ESRD). Basic research has made inroads into the understanding of the mechanisms of progression of chronic renal failure, including the understanding of the functions of genes activated by renal damage. All this may well result in a major reduction in the incidence of ESRD. The second important development will be in transplantation, which will constitute the mainstay of ESRD treatment in the next century. The clinical introduction of xenotransplantation and the cloning of one's own organs via one's stem cells may well represent the major areas of replacement therapy. This will reduce dialysis as a method to support the main treatments. These predictions will take some time to come to fruition. The first few decades in this century will face an increase, rather than a decrease, in the number of ESRD patients needing dialysis. Peritoneal dialysis (PD) will feature strongly in meeting this need in at least the first two decades of this century. PD has come a long way since the introduction of continuous ambulatory PD (CAPD) as a form of renal replacement therapy (RRT) over the quarter of a century it has been in existence. There have been some dramatic improvements in outcomes in patients treated by PD, such that it is now accepted as an equivalent therapy to hemodialysis (HD). In the last 5 yr, CAPD has proven to be as effective a treatment as HD, and in some instances may offer advantages over HD. As we move into the new millennium, it is clear that PD will feature strongly in the care and management of patients in ESRD as advances in the understanding of the pathophysiologic mechanisms and means to combat the adverse effects of PD are put into practice. Currently, there are more than 130,000 patients on PD worldwide, representing approximately 15% of the total world population requiring dialysis. It is anticipated that this number will increase during the next decade, especially in developing countries. Current Outcomes Several analyses have been undertaken in comparing the outcomes on PD and HD. Nolph (1) analyzed the relative risk of death on PD as compared with HD and by and large found that mortality risk was equal for HD and PD in the various studies reported. After this analysis was the report of Bloembergen et al. (2), which was based on the US Renal Data Systems (USRDS) data on prevalent patients (1987, 1988, and 1989). This showed that PD subjects had a 19% higher risk of mortality as compared with patients who used HD. This was met with considerable consternation in the United States and probably did the therapy a major disservice. Analysis from the Canadian Organ Replacement Registry on patients starting RRT between 1990 and 1994 showed that for incident patients, the survival with PD was better in the first 2 yr of treatment compared with HD with subsequently no difference up to 4 yr (3). In addition, it showed that there was a significantly lower risk of death in PD patients across all ages, regardless of whether or not the patient had diabetes; for ages 0 to 64 yr, the relative risk of death was 0.54 for PD patients without diabetes (for HD, the relative risk was 1) and 0.73 for patients with diabetes. A further comparative analysis from 11 Canadian centers showed that the apparent survival advantage of PD patients was due to lower comorbidity and a lower burden of acute onset end-stage disease at the inception of dialysis; survival was otherwise equal (4). More recent analysis of the USRDS data shows similar results: 5-yr survival of the 1993 cohort of dialysis patients is identical for PD and HD patients (5). The analysis on Medicare patients in the United States by Collins et al. (6) on the cohort of patients 1994 to 1997 concluded that in the first 2 yr of therapy, short-term PD is associated with superior outcomes compared with HD at all ages except in elderly women with diabetes. A further analysis of 17,000 PD patients from the Canadian Organ Replacement Registry database (1981 to 1997) has shown significant decrease in mortality rates during this period (7). Long-term survival from single center analysis shows no difference at 15 yr between PD and HD patients (8). A reasonable conclusion from all this information is that mortality is the same for HD and PD when comparing identical 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 developments outlined below are incorporated into routine practice. PD to date has proven its utility and has become established in certain areas of care of patients with ESRD. These aspects, which have to be maintained or even further improved in the future, are outlined in Table 1. Table 1: Positive points about peritoneal dialysis therapy that have been established beyond doubtaCurrent Problems Requiring Improvement Technique Failure and Long-Term PD If PD is going to achieve wider acceptance, then several outstanding problems that currently detract from greater acceptance need to be overcome. Two major issues are the higher technique failure in PD compared with HD (still related in a third of dropouts to HD to peritoneal infections) and the low rate of achieving long-term PD. The latter is to a large extent related to long-term changes in peritoneal membrane structure and function. In the analysis by Davies et al. (9), technique survival in the seven studies in the 1990s was 30 to 50% at 5 yr. The major causes of dropout derived from these analyses are shown in Figure 1. The nonachievement of long-term PD is to a large extent related to long-term changes in peritoneal membrane structure and function. Long-term (more than 10 yr) PD is limited to a small percentage of those who start PD (10), and single-center analysis shows that survival for those who use PD is 20% at 10 yr (8). The major cause of failure in long-term studies is ultrafiltration failure, inadequate solute clearance, and peritonitis (11). In data from Japan (12) long-term survival from a cohort of 242 patients was for a median of 5.8 yr, with patients' failure to respond to this technique related to membrane problems. Figure 1. : Reasons for therapy change to hemodialysis in long-term peritoneal dialysis patients in the 1990s. Percentages are averaged from seven outcome studies (3 , 9 , 65 , 150 – 153).Peritoneal Infections Peritonitis remains a problem and a major source of transfer to HD (13,14), even though rates have improved dramatically with the advent of technologic improvements related to the disconnect systems (15). The problem lies in persistent unresolving peritonitis due to Pseudomonas, fungal, and to a lesser extent Staphylococcus aureus infection (16,17). At present, there appears no obvious means to prevent gram-negative and fungal infections, and the only option is to develop better therapeutic regimens to improve the outcome of these infections. For S. aureus infection, there is greater reason for optimism. Several studies have shown nasal carriage of S. aureus is related to increased exit site infection and peritonitis (18,19). 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 organisms (20,21). Mupirocin routinely administered to exit sites is now advocated in published guidelines (22) and is likely to favorably affect infection rates and survival. Patient dropout after persistent peritonitis remains a problem, and those who require catheter removal for cure do not return to PD. More research needs to be done into techniques for safer catheter removal and reimplantation in the presence of persistent peritonitis to avoid interruption of PD. Prevention of adhesions, which are extensive in some patients with persistent peritonitis, is also important. Peritoneal Access Transfer of patients to HD for peritoneal access failure is now reduced to approximately 5 to 10% (Figure 1). Access-related dropout is low, and the improvement in catheter-related infections from mupirocin prophylaxis augur well for the continuing improvement in peritoneal infection. The type of catheter and method of implantation are probably less important than the meticulous care taken during implantation and subsequent care with immobilization and exit-site care; these aspects are reviewed in the catheter guidelines of the International Society of Peritoneal Dialysis (23). 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 × 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 Kidney Foundation–Dialysis Outcomes Quality Initiative (NKF-DOQI) guidelines (27). The NKF-DOQI targets are a weekly Kt/Vurea of 2.0 and a creatinine clearance of 60 L per week per 1.73 m2 for CAPD and slightly higher targets on automated PD (APD) regimens. These have been modified to lower the targets for creatinine clearance in low transporters to 50 L per week, in line with the Canadian guidelines; high transporters have a poorer outcome (28). These have been based predominantly on the Canada-USA study (29), which showed that the greater the solute clearance at start of dialysis, if maintained over the duration of the CAPD, the better the outcome. Although there is still considerable debate surrounding the evidence for such targets (30), it is generally accepted that higher target values are desirable and should be achieved if at all feasible (31). A Kt/Vurea of 1.7 and a creatinine clearance of 50 L/wk are absolute minimal targets, and all patients should be above these. In developing countries, financial constraints have not yet allowed liberalization of prescriptions to meet these targets. However, results from Hong Kong suggest that lesser total daily exchange volumes can produce good outcomes (32). The new millennium will see more studies and data from these countries to verify the needs of their patients in terms of adequacy and prescription-setting. Automated PD One way of achieving increased dialysis is by the use of APD. Use of APD is increasing rapidly—indeed, it is the fastest-growing mode of dialysis. APD is a major advantage in patients with a hyperpermeable peritoneal membrane (high transporters) because these patients are unable to ultrafilter adequately on long-dwell regimens and experience fluid overload on standard CAPD. The short-dwell exchanges on APD can overcome the loss of ultrafiltration. Clearly, achieving targets of solute and fluid clearance is likely to favorably affect outcomes. APD has also major advantages for the patient from the psychosocial point of view, and this is partly the reason for its popularity. In the West, there is a growing trend toward higher targets. These trends reflect the increasing emphasis on adequacy, and the practice of PD is bound to change with this increased emphasis on prescription setting to meet targets of adequacy; variations in the various regimens available to achieve these will considerably facilitate achievement of solute clearance targets. It would be interesting to see how these increased prescriptions are going to affect outcomes. Questions where controversies exit and where prospective controlled studies are required include the following: (1) renal versus peritoneal clearances and the equivalence; (2) small solute clearance measured via creatinine clearance and Kt/Vurea—which is better?; and (3) solute clearance targets—are they the same or different for special patient groups, such as patients with diabetes, children, the elderly, and underweight and obese subjects? Peritoneal Physiology and Changes with Long-Term PD In the last 25 yr, enormous strides have been made in the understanding of peritoneal morphology and its related physiology in terms of solute and fluid transport. This understanding has led to the development of newer PD solutions and paved the way for better treatment of patients undergoing PD with improved outcomes and longevity. The peritoneal membrane, consisting of the mesothelium and the underlying connective tissue, is a highly developed organ that provides structural support, regulates transperitoneal transport, and mediates peritoneal defense and repair. The mesothelium acts as a highly dynamic surface; it is involved in the production of peritoneal lubricants; in solute and fluid transport; in coagulation and fibrinolysis; and in the production and remodeling of the extracellular matrix and host defense (33). Solutes passing from the blood in the peritoneal capillaries to the dialysate-filled peritoneal cavity have to pass at least three structures that can offer resistance: the capillary wall (probably the most important), the interstitial tissue, and mesothelial cell layer. Diffusion and transcapillary ultrafiltration occur in two directions across these resistances. It is now recognized that there are effectively three pores that explain the capillary transport (34). This three-pore theory recognizes ultrasmall pores, small pores, and large pores. First, ultrasmall pores (3 to 5 A[Combining Ring Above]; aquaporin-1) allow the transport of water but not solutes. These have been identified in the mesothelium and the capillary endothelium (35). Glucose is effective as a crystalloid osmotic agent in spite of its small size of 2 to 3 A[Combining Ring Above], as it predominantly acts at this level. Approximately 50% of transcapillary ultrafiltration occurs through these pores. Second, colloid osmosis occurs at the level of small pores (40 to 50 A[Combining Ring Above]). Interendothelial clefts have been considered the equivalent of the small pores. Third, large pores (>150 A[Combining Ring Above]; probably less than 0.1% of total pore count) are involved in macromolecular transport. In addition, there is lymphatic absorption from the peritoneal cavity (36). Diffusion and convection are the mechanisms for solute transport, which is also bidirectional. Because of the complex structure of the various barriers to the peritoneal transport of solutes and fluid, it is simpler to regard this system as one membrane. In practical terms, the transport of low molecular weight substances across this membrane under defined conditions gives rise to dialysate/plasma ratios over the 4-h standardized dwell (peritoneal equilibration test). This defines the transporter status of the patient from high (hyperpermeability) to low (hypopermeability) and has distinct and important implications for setting the prescription (37). The permeability, combined with the surface area, gives rise to the mass transfer area coefficient, which is a measure of the diffusive permeability of the peritoneum, taking into account the surface area and the concentration gradient. Glucose is well recognized to have several deficiencies that makes it an unsuitable agent for standard, long-dwell PD for reasons of ultrafiltration, metabolic side effects, and effect on the integrity of peritoneal membrane, especially in long-term PD use. With PD, morphologic changes do take place; functional derangement is the result. These morphologic-functional relationships are therefore vitally important. The use of unphysiologic PD solutions and episodes of infection and inflammation (38–40) lead to changes in the mesothelial layer, disorganization of the interstitium (collagen fiber disruption and "fibrosis"), and duplication of the basement membrane both in the capillary endothelium and the mesothelial basement membrane (41). This tendency to fibrosis has been reported in long-term dialysis patients (42,43) and this is partly related to advanced glycation end products in the peritoneum (44) from glucose-protein reactions in the peritoneum. The end results of 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 reports a smaller incidence of 0.9 to 1.7% (47). Loss of ultrafiltration is the most common peritoneal transport abnormality in long-term PD (48–50). The major causes of ultrafiltration failure are the presence of large vascular peritoneal surface area and decrease in osmotic conductance to glucose related to decreased aquaporin function or decrease in the ultrafiltration coefficient of the peritoneum (changes in the interstitial tissues) (51,52). Long-term PD thus produces a large vascular surface area, and the fibrosis may well affect aquaporin function. Apart from the metabolic side effects (obesity, glucose intolerance, hyperinsulinemia, and reduced peripheral sensitivity to insulin, hyperlipidemia [(53,54]), there are major issues related to the bioincompatibility. There are several pathogenic factors responsible for changes in the peritoneal membrane. These appear to be the following: (1) continuous exposure to bioincompatible dialysis fluids (shown to be toxic in vitro [(55–58])—the factors that are important are a combination of low pH and lactate and glucose itself, through its metabolism via the polyol pathway (59), and molecular mechanisms such as cytokines, growth factors, and nitric oxide synthase activity (60); (2) glucose exposure leading to vascular changes of neovascularization and deposition of type IV collagen in the interstitium (61); (3) formation of advanced glycation end products in peritoneal tissue (44,62,63); and (4) the presence of glucose degradation products (GDP) generated during steam sterilization, which induces direct cytotoxicity and also accelerates the process of the formation of advanced glycation end products (55,62–64). Glucose exposure is now regarded as a significant pathogenetic factor in peritoneal membrane alteration. The goal for the clinician is to identify how to reduce patient exposure to glucose, minimize the total amount of glucose absorbed, and avoid the hyperosmolar stress and high glucose and GDP exposure to the peritoneum. Fortunately, nonglucose-based PD solutions as well as lower GDP containing solutions are now becoming available in Europe and offer a positive step forward. There is also a need to develop sensitive means for early diagnosis of membrane damage. Further research needs to be done to assess the role of CA125 (a measure of mesothelial mass), parameters of ultrafiltration changes (peritoneal equilibration test, standard permeability analysis), and serial peritoneal biopsies in assessing membrane damage and to establish whether new solutions containing additives may prevent fibrosis. Potential research in this area includes the study of addition of hyaluronic acid to the dialysate, use of glucose-free solutions (glycerol, amino acid, icodextrin), use of dialysis solutions with neutral pH and low carbonyl stress, prevention of angiogenesis in the peritoneal membrane by use of intraperitoneal or systemic medications against formation, and deposition of advanced glycation end products. Other areas of research include the study of free radical scavengers administered by mouth or intraperitoneally. Other Problem Areas Only a small percentage of patients remain on CAPD-APD for more than 8 yr (10). Furthermore, as in HD, these patients show an increased cardiovascular mortality and can develop malnutrition. These are important reasons for failing to achieve long-term PD. Patient fatigue is a significant area of concern in the long-term management on PD. Maiorca et al. (65) found that patient fatigue and psychosocial factors accounted for about half the total number that changed to HD in long-term PD patients. This may in part be related to the acceptance of elderly high-risk patients, whose comorbidity and infirmity is likely to increase with time on dialysis and will enhance the difficulties of performing the dialysis procedures on a daily basis. There is a need to develop methods to identify patients prone to fatigue. The liberal use of home care in selected patient groups, such as the elderly, and the use of PD in nursing homes could reduce the incidence of patient fatigue. Currently, some of these patients are managed in a nursing home environment (66,67); an estimated 2000 to 3000 patients with ESRD are admitted to nursing homes annually in the United States, with 13 to 15% managed on PD (68). The use of APD may be advantageous in some of these patients when relatives are involved in their dialysis. The development of respite services once or twice a year may well prevent burnout of relatives. The development of cyclers that are much simpler to operate than the current models could be of great importance in preventing burnout. It is well recognized that cardiovascular mortality is increased severalfold in these patients. The reasons are multifactorial. There are the traditional factors increasing the risk (e.g., atherogenic lipid profile, left ventricular hypertrophy, congestive cardiac failure, smoking) and several factors related to the dialysis therapy itself. For PD, the established risk relates to the development of a hyperpermeable membrane (29). Less clear is the role of an inflammatory milieu giving rise to malnutrition and atherosclerosis (MIA syndrome) (69,70) and disordered calcium-phosphate metabolism and vascular calcification (71). The serum of PD patients is more atherogenic than the serum of HD patients (72). Relevant research should include prospective, controlled studies on the effects of statins, aspirin, folic acid, antioxidants, and strict control of serum calcium and phosphorus in the prevention of cardiovascular mortality. Also needed are studies on the effects of glucose-free dialysis solutions and the role and prevention of chronic inflammation in the production of atherosclerosis and malnutrition. The identification of elevated levels of adhesion molecules expressed on the surface of vascular endothelial cells in response to proinflammatory cytokines have already been found in malnourished predialysis patients, and these are independent predictors of mortality (73). Severe malnutrition is present in 8 to 10% of the PD patients, and another 30% have mild malnutrition (74). The goal should be to prevent this complication, which is a strong predictor of poor outcome. Future research will need to concentrate on the relationship between malnutrition and small solute clearances and the role of chronic inflammation on the development of malnutrition. There is some evidence that malnutrition is associated with chronic inflammation and high peritoneal solute transport (75), but this has not found to be so by others (76). Further research is needed to clarify the association between chronic inflammation, high transport, and malnutrition, as is the reported suggestion of an association between hypoalbuminemia and atherosclerosis (77). PD patients are more prone to low-turnover bone disease (adynamic bone), which is associated with hypercalcemia and metastatic calcification from its inability to handle calcium load (78,79). A high calcium-phosphate product has been linked to increased mortality (80) and coronary vessel calcification, which is progressive in young HD patients studied with the new electron-beam computed tomography (81). These are exciting new findings, and there is a need to establish this in PD patients and assess the link between the higher prevalence of adynamic lesion on PD and cardiovascular outcomes. New Trends and Future Developments Early Start with Incremental Dialysis Even though targets have been set for solute clearance on dialysis, patients with chronic renal failure are allowed to dwindle to clearances far below these targets before dialysis is initiated (82–84). It does not seem logical to allow patients to fall below minimal targets of adequacy and then have to increase dialysis to meet these accepted levels. In addition, this practice has major drawbacks: progressive renal failure leads to nutritional decline (85,86); in addition, the worse the small solute clearance (87,88), the worse the nutritional status at the time of initiation of dialysis, which leads to a poor outcome (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 could be maintained for approximately 8 mo with a single 2.5-L exchange and from 8 to 17 mo with 2 nocturnal exchanges of 2.5 L each. The NKF-DOQI guidelines advocated starting dialytic therapy when the residual Kt/Vurea reaches 2.0; use of incremental dialysis will achieve solute clearance targets by compensating for the declining residual renal function as occurs with time. This incremental approach is possible (92,93) by performing PD only during the night or by using an exchange of icodextrin, which has prolonged ultrafiltration characteristics. Anecdotal experience of early start (sometimes called "healthy start") has been reported (94–96) and reviewed in an editorial (97). The reports show that it is possible to start early with incremental dialysis, but the experiences do not allow any firm conclusions to be drawn, and the case for early start with incremental dialysis needs to be substantiated with a large, randomized, prospective study. I suspect that as is the case with solute clearance targets, the practice will evolve to start patients earlier and earlier than is the current practice, in the hope that better outcomes will result. If this becomes the de facto practice, then better patient education and involvement in decision-making will be crucial for success of early initiation, as will the need for earlier referral. Use of PD as an Initial Therapy in an Integrated RRT Program The survival results on PD are better than on HD in the initial years of therapy (3), and technique survival on long-term PD is improving (9). It is appealing, therefore, to advocate PD as an initial therapy (98,99). If PD therapy fails for whatever reason (usually peritonitis, inadequate dialysis, or patient-related factors), then a switch from PD to HD should be considered. This approach is cost-effective and has shown better outcome results. In a Belgian study (100), this approach resulted in better survival in patients starting with PD than HD; it showed that patient outcome is not jeopardized by starting patients on PD, provided patients are transferred in a timely manner when PD-related problems arise. There are several advantages to commencing PD as an initial therapy (Table 2) pertaining to better residual renal function preservation (101), decreased incidence of hepatitis C compared with HD (102), preservation of vascular access sites (98), better initial BP control and less cardiac dysfunction (103), and better results after transplantation (104,105). The discontinuation of PD and transfer to HD at an appropriate time optimizes outcome; the failure to do so can lead to poorer outcome (9,106). Table 2: Factors favoring peritoneal dialysis as the initial dialytic therapy for patients with end-stage renal diseaseaThere are considerable obstacles to this approach that are almost entirely nonmedical (physician biases, funding and reimbursement policies) (107). The nephrology community needs to be better informed on the current outcomes and advances in PD. Other factors also affect modality selection. Time of referral is another important determinant. Patients that are referred late are more likely to go on to HD and remain on it (108,109). It is important, therefore, that there is early referral of patient with chronic renal failure to a renal center, where the patient will undergo an unbiased education program. Experience in the United States indicates that when patients were appraised of all treatment options, the percentage starting PD was higher than the national average. The USRDS in 1997 reviewed the patient-reported process of modality choice (110). Of 1174 HD patients assessed, 17% chose this dialysis modality when the decision was patient led (35% of 1049 PD patients), 53% when it was medical team led (16% for PD), and 30% when it was joint patient–medical team decision (49% for PD). In a scenario where full patient choice is available with a scheme that provides for unbiased patient education, PD would appear to be the first option if medically suitable (99) (Figure 2). This may well turn out to be an ever-increasing trend in the new millennium. Figure 2. : Schematic representation of the role of peritoneal dialysis (PD) in an integrated renal replacement therapy program where (A) patients are referred early, receive full education and therapy choice, and, on the basis of medical conditions and patient choice, are perhaps managed initially by PD. Early start may also be undertaken (B), especially in patients with diabetes; this is also feasible by using a single exchange of icodextrin overnight and by increasing the number of exchanges as the residual renal function declines (incremental dialysis).Recent and Future Innovations in PD Solutions As described in more detail above, there is now a greater appreciation