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Peritoneal Dialysis in the Next Millennium
Peritoneal Dialysis in the Next Millennium Dimitrios G. Oreopoulos and Antonios H. Tzamaloukas The main thrust of research will be the prevention of renal disease and its progression to the end-stage state (ESRO); such efforts will reduce or even reverse the present epidemic of ESRO by the middle of the 21 st Century. In the meantime, the number of ESRO patients will continue to increase and, unless xenotransplantation and cloning of one's own kidneys using stem cells will provide an alternative, the various modes of dialysis will continue to be the principle treatment for an increasing numbers of ESRO patients. Peritoneal dialysis (PO) has achieved success at certain salient points and, to advance further, the next generation of nephrologists will have to build on these. They include the following: PO is the treatment of choice for children; it has low rates of peritonitis; it has similar (or in some countries, better) survival rates than hemodialysis; it has lower costs; it has adequate clearances through the introduction of automated PO; and it is an effective treatment for those awaiting a kidney transplant. This report presents the authors' views concerning the areas in which PO will improve in the future. These include (1) a reduction in technique failure rates that will allow us to maintain a larger number of patients on PO for 10 years or more; (2) prevention of long-term changes of the peritoneal membrane through the use of more "friendly" solutions; (3) prevention of malnutrition; (4) the development of better peritoneal access devices; and (5) the increased use of PO as the treatment of first choice for most ESRO patients. © 2000 by the National Kidney Foundation, Inc. Index Words: Peritonitis; peritoneal access; adequacy; ultrafiltration failure; fatigue; malnutrition; cardiovascular mortality.
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ork started in the last decade of the 20 th Century allows some predictions of what will be the practice of Nephrology in the next Century. From our viewpoint, the major developments in the field of kidney diseases will be in prevention of end-stage renal disease (ESRD) and transplantation. The current epidemic of ESRD has mobilized the renal community. A recent conference identified the important clinical elements of ESRD and developed some well thought guidelines of treatment. l,2 Basic research has made inroads into the understanding of the mechanisms of progression of chronic renal failure. Understanding of the functions of genes activated by renal damage could lead to novel means of prevention. 3 In addition, prevention and treatment of individual renal diseases is receiving great attention. That all this work, which continues at a brisk pace, will result in a major reduction From the Department of Medicine, University of Toronto, and the Peritoneal Dialysis Unit, University Health Network, the Toronto Hospital, Toronto, Ontario, Canada; and the Department of Medicine, University of New Mexico and Renal Section, New Mexico VA Health System, Albuquerque, NM. Address correspondence to Dimitrios G. Oreopoulos, MD, PhD, Chief, Peritoneal Dialysis Unit, The Toronto Hospital, Western Section, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. © 2000 by the National Kidney Foundation, Inc. 1073-4449/00/0704-0008$3.00/0 doi:10.1053/jarr.2000.18039
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in the incidence of ESRD sometime in the 21 st Century is a reasonable expectation. A second reasonable expectation is that renal transplantation will constitute the mainstay of ESRD treatment in the next century. There is strong evidence that renal transplantation constitutes the best treatment for ESRD. The superiority of renal transplantation as an ESRD treatment is global, encompassing longer patient survival} better quality of life,S and lower cost of treatment. 6 The major problem facing transplantation now is a much smaller number of expectant recipients than potential donors. We expect that 2 developments will rectify this problem in the next century. The first development will be the clinical introduction of xenotransplantation? The second development, which will come later but will provide a definitive solution, will be the" cloning" of one's own organs using stem cells. The technology for this is now in its first steps.8 The clinical application of effective means to prevent ESRD and of the new methods of transplantation will eventually reduce both hemodialysis and peritoneal dialysis (PD) to methods supporting the main treatments. However, this change will not occur until later in the 21 sl Century. The first few decades in this century will face an increase, rather than a decrease, in the number of patients needing dialysis. Millions of patients worldwide will
Advances in Renal Replacement Therapy, Vall, No 4 (October), 2000: pp 338-346
Peritoneal Dialysis in the Next Millennium
depend on dialysis during that period. Both dialysis modalities have a huge room for improvement. We see as our task for this report the identification of the areas where improvement will help substantially patient care in PD. Consequently, instead of making crystal-ball predictions for PD, as we did with the future of Nephrology practice, we will try to describe the efforts required to shape a better future for PD. In short, instead of future forecasting, we prefer to describe future shaping. We will do this by addressing the following 3 fundamental questions: (1) Where is PD now? (2) Where we would like PD (CAPD / APD) to be? and (3) How we will achieve these goals?
Where Is PD Now? PD to date has achieved certain positive points that have to be maintained or even further improved in the future. These include: (1) lower costs than hemodialysis; (2) similar survival to that on hemodialysis. Statistics from the United States Renal Data Systems (USRDS) had shown a higher mortality in PD for elderly subjects, women, and diabetics. 9 The differences in survival between the 2 dialysis modalities have narrowed or disappeared in more recent USRDS data analyses. The Canadian statistics showed better survival in patients on PD than hemodialysis for the first 2 to 3 years lO; (3) CAPD/CCPD has been the treatment of choice for young children; (4) peritonitis rates have been established between 1/24 to 1/36 patient months. However, some units still experience much higher peritonitis rates; (5) Staphylococcus aureus exit-site infections and, to a large extent, S aureus peritonitis have been decreased substantially with the use of mupirocin at the exit sitell ; (6) adequate clearance targets can now be achieved in all but the largest anuric patients with the use of enhanced dialysis. 12 In the future, the introduction in clinical practice of continuous flow peritoneal dialysis with large volumes and double lumen catheters may solve the problem of adequacy of dialysis even in the largest anuric patients; and (7) PD is effective as the treatment of those awaiting renal transplantation.13
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Points Requiring Improvement If PD is going to achieve wider acceptance,
those working in this field have to address the following 5 areas: (1) technique failure, which remains higher in PD than hemodialysis; (2) long-term changes in peritoneal structure and function, which lead to technique failure; (3) malnutrition, which is a serious concern for a percentage of patients on PD; (4) low rate of achieving long-term PD, to a large extent because of #1, 2, and 3; and (5) recent decline of PD use in certain countries.
Technique Failure and Long-Term Changes in the Peritoneal Membrane To improve technique failure, investigators must concentrate their efforts on the following areas: (1) peritonitis; (2) peritoneal access; (3) dialysis adequacy; and (4) ultrafiltration failure. Peritonitis The following are the areas that may be considered for further improvement of peritonitis rates: Patient selection. Though there have not been any studies showing that certain patient characteristics predispose to peritonitis, patients who have poor hygiene and poor environmental conditions in their home and possibly those with diverticulosis may not be good candidates for PD. Persistent peritonitis. A large number of patients fail after persistent unresolving peritonitis owing to pseudomonas, fungal, or fecal infections. We need better therapeutic regimens to improve the outcome of those infections. Because a number of patients with pseudomonas exit-site infection eventually end up with pseudomonas peritonitis, early removal and replacement of the peritoneal catheter in those who have pseudomonas exit-site infection may prevent pseudomonas peritonitis and subsequent technique failure. With regard to fungal peritonitis, prophylactic use of nystatin in patients receiving antibiotics has shown prevention of fungal peritonitis according to 1 reportI4 but not according to another. IS This issue will have to be studied further. We propose that there should be large
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prospective studies on various therapeutic regimens for the treatment of pseudomonas or fungal peritonitis. Factors associated with low incidence of peritonitis. Patient characteristics that lead to low peritonitis rates should be investigated by prospective studies. Such patients will be superior candidates for PD. In vitro studies of host defense mechanisms have not led, so far, to major improvements in the prevention and management of peritonitis. They have led, however, to better understanding of the biology of the peritoneal membrane (eg, the emergence of the mesothelial cell as a major player in both the defense against infection and the preservation of the anatomic and functional integrity of the peritoneal membrane) and of some sequelae of peritonitis (fibrosis, ultrafiltration failure). These studies should be continued. They should result, among their other benefits, in practical means to reduce both the incidence and the damage of peritonitis. Patient dropout after peritonitis. A large percent of patients who have developed persistent peritonitis and require catheter removal do not return to PD. We need to develop 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. Finally, patient and microorganism characteristics, which predispose to persistent infections, should be studied by large prospective studies. Mortality from peritonitis. Fungal peritonitis was known to be associated with significant mortality.1 6 Recent studies found an association between mortality and high rate of peritonitis,17 particularly gram-negative peritonitis. 1s Future efforts should be directed towards prevention of gastrointestinal disease and enteric contamination of the dialysate. Peritoneal Access Devices that will prevent exit-site infection should be developed and studied. The usefulness of existing devices such as the permanently bent catheter, the presternal catheter, the Moncrief catheter, and silver-coated or antibiotic coated catheters should be studied in large multicenter trials to prove their useful-
ness and safety. Recent insights in the molecular mechanisms ofbiofilm formation l9,20 should lead to means of preventing infection starting in biofilms, such as those caused by S epidermidis and Pseudomonas aeruginosa. Catheters that will improve the catheter / skin interface should be the ultimate goal in our research. Success in this area will decrease exit-site infections and peritonitis. A key point for a successful peritoneal access function is a careful peritoneal implantation. Studies in the past have indicated that surgical implantation is more effective than medical implantation. However, if surgical implantation is performed by rotating surgical residents, the results may be worse. We need to develop simple implantation techniques (surgical or medical) and manuals or videos for easy training of those who will perform the procedure. Successful peritoneal access function would also ensue from better catheter design. Research with innovative ideas is needed in this area. We need devices that prevent malpositioning of the catheter like those with the weight at the end of the catheter. An ideal catheter would be one without external parts like the one recommended by Kablitz et aFl years ago with a subcutaneous chamber. Renewed interest and research in this area may bring results. Dialysis Adequacy The Dialysis Outcome Quality Initiative (DOQI) guidelines recommended targets for small solute clearances (Kt/V urea and WCcr). The evidence supporting these targets consisted of only observational studies, which showed that total clearances lower than the DOQI targets are associated with high mortality. The critical question whether replacement of decreased renal clearance by an equal increase in peritoneal clearance, so that total clearance remains at or above the DOQI target, is associated with low mortality remains unanswered. This is the reason why these guidelines have been questioned and were not accepted worldwide. Evidence from prospective, controlled, interventional studies is required to establish the best targets. Questions where controversies exist, and prospective, controlled studies are required
Peritoneal Dialysis in the Next Millennium
include the following: (1) are renal and peritoneal clearances equivalent? A corollary of this question is the following: (2) should the clearance targets be the same in anuric patients and those with residual renal function? (3) can small solute clearance adequacy be measured by using a single solute, and if yes, which solute? A corollary to this is a search for new, more relevant to uremic toxicity, indicators of adequacy; and (4) should target clearances be the same or different for special patient groups, such as diabetic patients, children, elderly, underweight, and obese subjects? Ultrafiltration Failure Ultrafiltration failure is another cause of technique failure. Fluid retention secondary to ultrafiltration failure may cause significant cardiovascular morbidity and mortality.22,23 To eliminate this problem, we should start by developing sensitive methods to detect and study ultrafiltration failure. At present, it seems that study of ultrafiltration with 4.2S% dextrose is a much more sensitive index than the use of 2.S% dextrose solution. 24 Similarly sensitive are dialysate sodium changes in the first hour. 25 It seems that the use of hypertonic dextrose solutions is important in the development of long-term complications, including ultrafiltration failure. 26 The frequent use of hypertonic solutions should be avoided. In this respect, the use of alternative osmotic agents, such as icodextrin, may be an important determinant in the prevention of long-term ultrafiltration failure. Ultrafiltration failure is associated with peritoneal fibrosis and, in advanced cases, sclerosing encapsulating peritonitis. Some of the structural peritoneal changes are related to the prolonged use of dialysis solutions that are unphysiologic. The use of new dialysis solutions with neutral pH (with substitution of either bicarbonate or bicarbonate/lactate for lactate as the buffer) and solutions with low carbonyl stress may have important repercussions on the long-term maintenance of the peritoneal membrane. With regards to the development of progressive peritoneal fibrosis, the research that we recommend is: (1) to develop sensitive means for its early diagnosis, whether this is Ca12S,
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ultrafiltration changes, or even serial peritoneal biopsies (in selected cases); (2) to develop new solutions containing additives that 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 acids, icodextrin), use of dialysis solutions with neutral pH and low carbonyl stress, means to prevent angiogenesis in the peritoneal membrane, and use of intraperitoneal or systemic medications preventing formation and deposition of advanced glycated end products (AGEs) in the peritoneal membrane. Other research that we recommend includes: (3) to study the effects of free radical scavengers administered by mouth or intraperitoneally; (4) to study the role of chronic inflammation and its prevention; (S) to obtain insights on peritoneal biology and pathology from the surgical literature. Collaborative studies with surgeons may be quite fruitful; (6) to study prospectively simultaneous catheter removal and replacement in patients with persistent severe peritonitis and the effects of prevention of discontinuation of PD. This group of patients may be one group that could be studied prospectively with serial peritoneal biopsies; and (7) To study intensely in vitro the biology of mesothelial cells and to develop clinical protocols for peritoneal remesothelization.
Failure to Achieve Long-Term PD, Patient Fatigue, Cardiovascular Mortality and Malnutrition Today, the failure rates in patients who have been on PD for more than 8 years are extremely high. Only a small percentage of patients remain on CAPD / APD for more than 10 years. 27 Furthermore, as in hemodialysis, these patients show an increased cardiovascular mortality and can develop malnutrition. We will discuss patient fatigue, cardiovascular mortality, and malnutrition as the main reasons for failing to achieve long-term PD. Other reasons (infections, peritoneal membrane changes) were discussed in the earlier section.
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Patient Fatigue We have 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. The use of APD may be advantageous in some of these patients, when relatives are involved in the dialysis. The development of respite services once or twice a year will 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. We believe that the next generation of cyclers should have the following capacities: (1) to individualize the prescription and composition of dialysis solutions; (2) to possess software with on-line recordings of compliance and deliveries; and (3) to produce in situ large quantities of sterile PD fluid of varying composition. An important point is that the cost of these cyclers should be low. The issue of patient and family burnout is essential to prevention of technique failure and probably patient mortality. This area should receive a great deal of attention in the next decade. In general, prevention of burnout in intense, life-sustaining chronic therapies, including PD, will be a major focus of research, because the current level of knowledge is incomplete and the success rate is poor. Cardiovascular Mortality We will address this problem under 2 headings, atherogenic lipid profile of PD patients and fluid/volume overload, which was also addressed in the section on ultrafiltration failure. Atherogenic serum lipid profile. The serum of PD patients is more atherogenic than the serum of hemodialysis patients. 28 We have to find ways to improve this condition in both dialysis populations. Relevant research should include prospective, controlled studies of the effects of statins, aspirin, folic acid, and antioxidants, and strict control of serum calcium and phosphorus in the prevention of cardiovascular mortality, the effects of use of glucose-free dialysis solutions, and the role and prevention
of chronic inflammation in the production of atherosclerosis and malnutrition. Fluid/volume overload. Patients with high peritoneal solute transport characteristics have an increased risk of volume overload manifested by severe cardiovascular complications. 22 Both technique failure and mortality are high in this group.29 In this particular group, one can envision using cyclers with short exchanges during the night and icodextrin solution during the long daytime exchanges. Studies to analyze the long-term effectiveness of this regime are important.
Malnutrition Severe malnutrition is present in 8% to 10% of the PD patients, and another 30% have mild malnutrition. 3D Our goal should be to prevent this complication, which is a strong predictor of poor outcome. We recommend research in the following areas: (1) the relationship between malnutrition and small solute clearances; (2) 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. 31 Others have provided evidence that malnutrition in PD can be of 2 types. The first type is associated with other systemic conditions, among which underdialysis and uremia is notable. The second type of malnutrition is associated with chronic inflammatory state and, apparently, high transport. 32,33 Further research is needed to clarify the association between chronic inflammation, high transport, and malnutrition. Means to prevent chronic inflammation and the effects of these means on patient morbidity and mortality need to be studied by prospective studies; and (3) the relationship between malnutrition and atherosclerosis. There are reports suggesting an association between hypoalbuminemia and atherosclerosis. 34 More extensive studies are required. There is some evidence that anabolic steroids or other anabolic hormones may be useful at least for temporary control of malnutrition. This should also be studied more extensively.
Peritoneal Dialysis in the Next Millennium
Recent Trends in PD Use-New Developments There has been some concern about recent trends indicating decrease in PD use in Canada, the United States, and other countries. Reports of disparate survival between hemodialysis and PD from the large United States registry chronologically preceded this trend and generated a heated discussion. Reports from the Canadian and European registries disputed the initial report from the United States registry. More recent reports from the United States registry have shown disappearance of the survival differences in many patient groups and decreasing differences in all groups. It is possible, but will need to be proven, that these differences are minimal and that proper patient selection and performance of dialysis, not the mode of dialysis, is the critical factor in improving survival. We will discuss some possible reasons, other than the impact of the original report from the United States registry, for the recent reduction in PD use and some recent changes in initiation of dialysis which may favor the use of PD. Possible Reasons for Decreased PD Use Possible reasons for decreased PD use include unbalanced presentation of the dialysis options to the patient, physician and nurse biases, financial reasons, preferences of older patients, and a decline in committed PD leadership. Poor presentation of dialysis alternatives or no presentation of the PD option at all to patients will impact on PD use. There must be an objective and balanced presentation of all options of managing ESRD to the patient, who should then make the final choice. A good way to achieve a balanced presentation may be the production of videos explaining the dialysis options and their relative risks and benefits by a committee of experts with representatives from both the hemodialysis and PD leadership. The videos should be periodically renewed to incorporate recent research findings and should be made available to all dialysis units. Continuous education of nurses and physicians in the recent developments should also be an important part of the process. Financial reasons can influence the selec-
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tion of dialysis modality. The experience in Ontario provides an illustrative example. In this province, medical reimbursement was in excess of $9,000 a year for 1 patient on hemodialysis versus $1,500 per patient on PD before 1998. Since July 1998, this has been equalized to $6,000 per patient per year independently of the type of dialysis. It is interesting to observe whether the new fee schedule will have an impact on the utilization of PD. PD offers some advantages to the elderly ESRD patients. It will also be of interest to study whether older patients living alone or with a frail spouse will prefer PD when the simplifications discussed earlier are applied clinically or if home care nursing is used extensively as the experience in France has shown. The final potential reason for decreased PD use is a decline in committed PD leadership. This may have far going adverse effects. Whereas 15 to 20 years ago there was a large number of investigators who wanted to make dialysis in general and peritoneal dialysis in particular their career, this number has not increased and, if anything, is decreasing. This trend is more pronounced in the 2 countries, which were the cornerstones of the modem era of PD, Canada, and the United States. Table 1 shows the percents of PD abstracts submitted to 3 recent major meetings from different areas of the world. The contribution of Canada and the United States to abstracts reporting bench research or prospective clinical studies was disproportionately low. Research in PD offers a rewarding career and should be actively promoted among young investigators by academia, industry and nephrologyassociations. New Trends in Dialysis Initiation The DOQI guidelines proposed considering initiation of chronic dialysis at renal KtjV urea equal to 2.0 weekly. This level of urea clearance is substantially higher than both the average levels at which patients started dialysis in recent studies35 and the levels at which patients develop frank uremic manifestations. This last characteristic allows incremental initiation of dialysis with low initial dose, which has low cost and is less disruptive of the patient's life style. The rationale for this early
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Table 1. Percentages of PD Abstracts Submitted to Three Recent Major Meetings
Type of Abstract
Africa
Asia
Australia/ New Zealand
Europe
Latin America
Canada/ USA
Number of Abstracts
0 0 0 8% 0
3% 3% 2% 0 0
75 130 107 12 9
0 4% 2% 0 0
16% 15% 55% 82% 50%
44 104 124 22 22
0 4% 6% 0 0
9% 19% 67% 82% 50%
56 54 66 60 4
International Society for Peritoneal Dialysis (perit Dial Int 18:51-S90, 1998 [SuppI2]) Bench Prosp Retrosp QI/Cost Case Reports
0 1% 0 0 0
49% 68% 78% 67% 67%
1% 1% 0 0 0
47% 25% 20% 25% 33%
20th Annual Conference onPD (Perit Dial Int 19:51-587, 1999 [Suppl1]) Bench Prosp. Retrosp. QI/Cost Case Reports
0 0 1% 0 0
18% 26% 11% 0 6%
0 0 1% 0 0
66% 53% 30% 18% 44%
American Society of Nephrology 0 Am Soc NephrollO, Sept. 1999) Bench Prosp Retrosp QI/Cost Case Report
0 0 0 2% 0
28% 31% 15% 0 0
2% 4% 0 0 0
61% 42% 10% 23% 50%
Abbreviations: Bench, bench research; Prosp, prospective clinical studies; Retrosp, retrospective clinical studies; QA/Cost, studies on quality improvement/ cost control; case report, abstracts containing 1-4 cases. NOTE. Percentages refer to the number of abstracts in the last column of each row.
(timely may be a better term)/incremental initiation of dialysis has been presented in several publications36-39 and was discussed by Gokal in the 8th Congress of the International Society for Peritoneal Dialysis. This rationale includes the following items: (1) in CAPD, a total Kt/V urea less than 2.0 weekly is predictive of increased mortality and morbidity; (2) in chronic renal failure, a renal Kt/V urea is associated with spontaneous reduction in protein intake and malnutrition. The relationship between total Kt/V urea and dietary protein intake appears to have the same slope in pre-ESRD subjects and PD patients; (3) low serum albumin at the start of chronic dialysis predicts high mortality and morbidity on dialysis; and (4) targets for initiation of dialysis should be at or above acceptable levels for urea clearance for PD adequacy. PD has several potential advantages as the method for early /incremental dialysis initiation. These include: (1) chronic renal failure and CAPD are similar in providing continuous small solute clearance. This has led to the suggestion that renal and peritoneal clearances are equivalent in CAPD. Retrospective observational studies can not answer this ques-
tion. Prospective interventional, multicentric studies are needed. Design and conduct of such studies will be the critical step in the whole topic of PD adequacy; (2) CAPD may be associated with better preservation of renal function; (3) PD may provide smoother control of sodium and water balance earlier in chronic renal failure; (4) PD allows liberalization of diet (protein intake) to ensure nutritional rehabilitation; (5) PD allows great flexibility and ease on increasing the dose of dialysis to maintain total small solute clearances at or above the target values; (6) PD may accommodate incremental dialysis at lower cost; (7) and PD offers lifestyle benefits. The benefits of early /incremental initiation of dialysis and the potential benefits of PD in this setting should be analyzed by large, prospective controlled studies. This will be an important filed of research in the next few years.
Conclusion Dialysis techniques represent halfway technology and, as such, they are expensive, cumbersome, and have limited success. Some time in the 21't Century, they will be replaced as the
Peritoneal Dialysis in the Next Millennium
main treatment for ESRD and will be delegated to a supportive role to transplantation. However, the numbers of patients treated by dialysis will increase in the first few decades of the next century. Both techniques have major deficiencies. We do not believe that either hemodialysis or PD is fundamentally superior or that they should be considered as competing modalities. The purpose of dialysis is to provide the best and longest life possible to ESRD patients. Along these lines, we agree with Gokal and Malick40 that the 2 dialysis modalities should be considered as parts of the same treatment that can be used sequentially for the benefit of the patient. A patient should be transferred from one dialysis modality to the other when the clinical picture dictates such transfers. An important task for the nephrologic community is to make both dialysis modalities more effective and safer. This will require a lot of research and commitment from the new generation of nephrologists.
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34. Kang DH, Yoon KI, Lee 5W, et al: Impact of nutritional status on serum lipoprotein (a) concentration in patients undergoing continuous ambulatory peritoneal dialysis. Perit Dial Int 16, 5upp!. 1:5241-5245, 1996 35. Burkart JM: Clinical experience. How much earlier should patients really start renal replacement therapy? J Am Soc NephroI9:S118-5123, 1998 (suppI4) 36. Mehrotra R, Nolph KD, Gotch F: Early initiation of chronic dialysis: Role of incremental dialysis. Perit Dial Int 17:426-430, 1997 37. Golper T: Incremental dialysis. J Am Soc Nephrol 9:5107-5111,1998 (suppI4) 38. Mehrotra R, Nolph KD: Arguments for timely initiation of dialysis. J Am Soc Nephrol 9:596-599, 1998 (suppI4) 39. Tzamaloukas AH: Incremental initiation of peritoneal dialysis: Current practices. Adv Perit Dial 15:175-178, 1999 40. Gokal R, Malick NP: Peritoneal dialysis. Lancet 383:823828, 1999
W
ork started in the last decade of the 20 th Century allows some predictions of what will be the practice of Nephrology in the next Century. From our viewpoint, the major developments in the field of kidney diseases will be in prevention of end-stage renal disease (ESRD) and transplantation. The current epidemic of ESRD has mobilized the renal community. A recent conference identified the important clinical elements of ESRD and developed some well thought guidelines of treatment. l,2 Basic research has made inroads into the understanding of the mechanisms of progression of chronic renal failure. Understanding of the functions of genes activated by renal damage could lead to novel means of prevention. 3 In addition, prevention and treatment of individual renal diseases is receiving great attention. That all this work, which continues at a brisk pace, will result in a major reduction From the Department of Medicine, University of Toronto, and the Peritoneal Dialysis Unit, University Health Network, the Toronto Hospital, Toronto, Ontario, Canada; and the Department of Medicine, University of New Mexico and Renal Section, New Mexico VA Health System, Albuquerque, NM. Address correspondence to Dimitrios G. Oreopoulos, MD, PhD, Chief, Peritoneal Dialysis Unit, The Toronto Hospital, Western Section, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. © 2000 by the National Kidney Foundation, Inc. 1073-4449/00/0704-0008$3.00/0 doi:10.1053/jarr.2000.18039
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in the incidence of ESRD sometime in the 21 st Century is a reasonable expectation. A second reasonable expectation is that renal transplantation will constitute the mainstay of ESRD treatment in the next century. There is strong evidence that renal transplantation constitutes the best treatment for ESRD. The superiority of renal transplantation as an ESRD treatment is global, encompassing longer patient survival} better quality of life,S and lower cost of treatment. 6 The major problem facing transplantation now is a much smaller number of expectant recipients than potential donors. We expect that 2 developments will rectify this problem in the next century. The first development will be the clinical introduction of xenotransplantation? The second development, which will come later but will provide a definitive solution, will be the" cloning" of one's own organs using stem cells. The technology for this is now in its first steps.8 The clinical application of effective means to prevent ESRD and of the new methods of transplantation will eventually reduce both hemodialysis and peritoneal dialysis (PD) to methods supporting the main treatments. However, this change will not occur until later in the 21 sl Century. The first few decades in this century will face an increase, rather than a decrease, in the number of patients needing dialysis. Millions of patients worldwide will
Advances in Renal Replacement Therapy, Vall, No 4 (October), 2000: pp 338-346
Peritoneal Dialysis in the Next Millennium
depend on dialysis during that period. Both dialysis modalities have a huge room for improvement. We see as our task for this report the identification of the areas where improvement will help substantially patient care in PD. Consequently, instead of making crystal-ball predictions for PD, as we did with the future of Nephrology practice, we will try to describe the efforts required to shape a better future for PD. In short, instead of future forecasting, we prefer to describe future shaping. We will do this by addressing the following 3 fundamental questions: (1) Where is PD now? (2) Where we would like PD (CAPD / APD) to be? and (3) How we will achieve these goals?
Where Is PD Now? PD to date has achieved certain positive points that have to be maintained or even further improved in the future. These include: (1) lower costs than hemodialysis; (2) similar survival to that on hemodialysis. Statistics from the United States Renal Data Systems (USRDS) had shown a higher mortality in PD for elderly subjects, women, and diabetics. 9 The differences in survival between the 2 dialysis modalities have narrowed or disappeared in more recent USRDS data analyses. The Canadian statistics showed better survival in patients on PD than hemodialysis for the first 2 to 3 years lO; (3) CAPD/CCPD has been the treatment of choice for young children; (4) peritonitis rates have been established between 1/24 to 1/36 patient months. However, some units still experience much higher peritonitis rates; (5) Staphylococcus aureus exit-site infections and, to a large extent, S aureus peritonitis have been decreased substantially with the use of mupirocin at the exit sitell ; (6) adequate clearance targets can now be achieved in all but the largest anuric patients with the use of enhanced dialysis. 12 In the future, the introduction in clinical practice of continuous flow peritoneal dialysis with large volumes and double lumen catheters may solve the problem of adequacy of dialysis even in the largest anuric patients; and (7) PD is effective as the treatment of those awaiting renal transplantation.13
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Points Requiring Improvement If PD is going to achieve wider acceptance,
those working in this field have to address the following 5 areas: (1) technique failure, which remains higher in PD than hemodialysis; (2) long-term changes in peritoneal structure and function, which lead to technique failure; (3) malnutrition, which is a serious concern for a percentage of patients on PD; (4) low rate of achieving long-term PD, to a large extent because of #1, 2, and 3; and (5) recent decline of PD use in certain countries.
Technique Failure and Long-Term Changes in the Peritoneal Membrane To improve technique failure, investigators must concentrate their efforts on the following areas: (1) peritonitis; (2) peritoneal access; (3) dialysis adequacy; and (4) ultrafiltration failure. Peritonitis The following are the areas that may be considered for further improvement of peritonitis rates: Patient selection. Though there have not been any studies showing that certain patient characteristics predispose to peritonitis, patients who have poor hygiene and poor environmental conditions in their home and possibly those with diverticulosis may not be good candidates for PD. Persistent peritonitis. A large number of patients fail after persistent unresolving peritonitis owing to pseudomonas, fungal, or fecal infections. We need better therapeutic regimens to improve the outcome of those infections. Because a number of patients with pseudomonas exit-site infection eventually end up with pseudomonas peritonitis, early removal and replacement of the peritoneal catheter in those who have pseudomonas exit-site infection may prevent pseudomonas peritonitis and subsequent technique failure. With regard to fungal peritonitis, prophylactic use of nystatin in patients receiving antibiotics has shown prevention of fungal peritonitis according to 1 reportI4 but not according to another. IS This issue will have to be studied further. We propose that there should be large
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prospective studies on various therapeutic regimens for the treatment of pseudomonas or fungal peritonitis. Factors associated with low incidence of peritonitis. Patient characteristics that lead to low peritonitis rates should be investigated by prospective studies. Such patients will be superior candidates for PD. In vitro studies of host defense mechanisms have not led, so far, to major improvements in the prevention and management of peritonitis. They have led, however, to better understanding of the biology of the peritoneal membrane (eg, the emergence of the mesothelial cell as a major player in both the defense against infection and the preservation of the anatomic and functional integrity of the peritoneal membrane) and of some sequelae of peritonitis (fibrosis, ultrafiltration failure). These studies should be continued. They should result, among their other benefits, in practical means to reduce both the incidence and the damage of peritonitis. Patient dropout after peritonitis. A large percent of patients who have developed persistent peritonitis and require catheter removal do not return to PD. We need to develop 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. Finally, patient and microorganism characteristics, which predispose to persistent infections, should be studied by large prospective studies. Mortality from peritonitis. Fungal peritonitis was known to be associated with significant mortality.1 6 Recent studies found an association between mortality and high rate of peritonitis,17 particularly gram-negative peritonitis. 1s Future efforts should be directed towards prevention of gastrointestinal disease and enteric contamination of the dialysate. Peritoneal Access Devices that will prevent exit-site infection should be developed and studied. The usefulness of existing devices such as the permanently bent catheter, the presternal catheter, the Moncrief catheter, and silver-coated or antibiotic coated catheters should be studied in large multicenter trials to prove their useful-
ness and safety. Recent insights in the molecular mechanisms ofbiofilm formation l9,20 should lead to means of preventing infection starting in biofilms, such as those caused by S epidermidis and Pseudomonas aeruginosa. Catheters that will improve the catheter / skin interface should be the ultimate goal in our research. Success in this area will decrease exit-site infections and peritonitis. A key point for a successful peritoneal access function is a careful peritoneal implantation. Studies in the past have indicated that surgical implantation is more effective than medical implantation. However, if surgical implantation is performed by rotating surgical residents, the results may be worse. We need to develop simple implantation techniques (surgical or medical) and manuals or videos for easy training of those who will perform the procedure. Successful peritoneal access function would also ensue from better catheter design. Research with innovative ideas is needed in this area. We need devices that prevent malpositioning of the catheter like those with the weight at the end of the catheter. An ideal catheter would be one without external parts like the one recommended by Kablitz et aFl years ago with a subcutaneous chamber. Renewed interest and research in this area may bring results. Dialysis Adequacy The Dialysis Outcome Quality Initiative (DOQI) guidelines recommended targets for small solute clearances (Kt/V urea and WCcr). The evidence supporting these targets consisted of only observational studies, which showed that total clearances lower than the DOQI targets are associated with high mortality. The critical question whether replacement of decreased renal clearance by an equal increase in peritoneal clearance, so that total clearance remains at or above the DOQI target, is associated with low mortality remains unanswered. This is the reason why these guidelines have been questioned and were not accepted worldwide. Evidence from prospective, controlled, interventional studies is required to establish the best targets. Questions where controversies exist, and prospective, controlled studies are required
Peritoneal Dialysis in the Next Millennium
include the following: (1) are renal and peritoneal clearances equivalent? A corollary of this question is the following: (2) should the clearance targets be the same in anuric patients and those with residual renal function? (3) can small solute clearance adequacy be measured by using a single solute, and if yes, which solute? A corollary to this is a search for new, more relevant to uremic toxicity, indicators of adequacy; and (4) should target clearances be the same or different for special patient groups, such as diabetic patients, children, elderly, underweight, and obese subjects? Ultrafiltration Failure Ultrafiltration failure is another cause of technique failure. Fluid retention secondary to ultrafiltration failure may cause significant cardiovascular morbidity and mortality.22,23 To eliminate this problem, we should start by developing sensitive methods to detect and study ultrafiltration failure. At present, it seems that study of ultrafiltration with 4.2S% dextrose is a much more sensitive index than the use of 2.S% dextrose solution. 24 Similarly sensitive are dialysate sodium changes in the first hour. 25 It seems that the use of hypertonic dextrose solutions is important in the development of long-term complications, including ultrafiltration failure. 26 The frequent use of hypertonic solutions should be avoided. In this respect, the use of alternative osmotic agents, such as icodextrin, may be an important determinant in the prevention of long-term ultrafiltration failure. Ultrafiltration failure is associated with peritoneal fibrosis and, in advanced cases, sclerosing encapsulating peritonitis. Some of the structural peritoneal changes are related to the prolonged use of dialysis solutions that are unphysiologic. The use of new dialysis solutions with neutral pH (with substitution of either bicarbonate or bicarbonate/lactate for lactate as the buffer) and solutions with low carbonyl stress may have important repercussions on the long-term maintenance of the peritoneal membrane. With regards to the development of progressive peritoneal fibrosis, the research that we recommend is: (1) to develop sensitive means for its early diagnosis, whether this is Ca12S,
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ultrafiltration changes, or even serial peritoneal biopsies (in selected cases); (2) to develop new solutions containing additives that 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 acids, icodextrin), use of dialysis solutions with neutral pH and low carbonyl stress, means to prevent angiogenesis in the peritoneal membrane, and use of intraperitoneal or systemic medications preventing formation and deposition of advanced glycated end products (AGEs) in the peritoneal membrane. Other research that we recommend includes: (3) to study the effects of free radical scavengers administered by mouth or intraperitoneally; (4) to study the role of chronic inflammation and its prevention; (S) to obtain insights on peritoneal biology and pathology from the surgical literature. Collaborative studies with surgeons may be quite fruitful; (6) to study prospectively simultaneous catheter removal and replacement in patients with persistent severe peritonitis and the effects of prevention of discontinuation of PD. This group of patients may be one group that could be studied prospectively with serial peritoneal biopsies; and (7) To study intensely in vitro the biology of mesothelial cells and to develop clinical protocols for peritoneal remesothelization.
Failure to Achieve Long-Term PD, Patient Fatigue, Cardiovascular Mortality and Malnutrition Today, the failure rates in patients who have been on PD for more than 8 years are extremely high. Only a small percentage of patients remain on CAPD / APD for more than 10 years. 27 Furthermore, as in hemodialysis, these patients show an increased cardiovascular mortality and can develop malnutrition. We will discuss patient fatigue, cardiovascular mortality, and malnutrition as the main reasons for failing to achieve long-term PD. Other reasons (infections, peritoneal membrane changes) were discussed in the earlier section.
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Patient Fatigue We have 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. The use of APD may be advantageous in some of these patients, when relatives are involved in the dialysis. The development of respite services once or twice a year will 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. We believe that the next generation of cyclers should have the following capacities: (1) to individualize the prescription and composition of dialysis solutions; (2) to possess software with on-line recordings of compliance and deliveries; and (3) to produce in situ large quantities of sterile PD fluid of varying composition. An important point is that the cost of these cyclers should be low. The issue of patient and family burnout is essential to prevention of technique failure and probably patient mortality. This area should receive a great deal of attention in the next decade. In general, prevention of burnout in intense, life-sustaining chronic therapies, including PD, will be a major focus of research, because the current level of knowledge is incomplete and the success rate is poor. Cardiovascular Mortality We will address this problem under 2 headings, atherogenic lipid profile of PD patients and fluid/volume overload, which was also addressed in the section on ultrafiltration failure. Atherogenic serum lipid profile. The serum of PD patients is more atherogenic than the serum of hemodialysis patients. 28 We have to find ways to improve this condition in both dialysis populations. Relevant research should include prospective, controlled studies of the effects of statins, aspirin, folic acid, and antioxidants, and strict control of serum calcium and phosphorus in the prevention of cardiovascular mortality, the effects of use of glucose-free dialysis solutions, and the role and prevention
of chronic inflammation in the production of atherosclerosis and malnutrition. Fluid/volume overload. Patients with high peritoneal solute transport characteristics have an increased risk of volume overload manifested by severe cardiovascular complications. 22 Both technique failure and mortality are high in this group.29 In this particular group, one can envision using cyclers with short exchanges during the night and icodextrin solution during the long daytime exchanges. Studies to analyze the long-term effectiveness of this regime are important.
Malnutrition Severe malnutrition is present in 8% to 10% of the PD patients, and another 30% have mild malnutrition. 3D Our goal should be to prevent this complication, which is a strong predictor of poor outcome. We recommend research in the following areas: (1) the relationship between malnutrition and small solute clearances; (2) 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. 31 Others have provided evidence that malnutrition in PD can be of 2 types. The first type is associated with other systemic conditions, among which underdialysis and uremia is notable. The second type of malnutrition is associated with chronic inflammatory state and, apparently, high transport. 32,33 Further research is needed to clarify the association between chronic inflammation, high transport, and malnutrition. Means to prevent chronic inflammation and the effects of these means on patient morbidity and mortality need to be studied by prospective studies; and (3) the relationship between malnutrition and atherosclerosis. There are reports suggesting an association between hypoalbuminemia and atherosclerosis. 34 More extensive studies are required. There is some evidence that anabolic steroids or other anabolic hormones may be useful at least for temporary control of malnutrition. This should also be studied more extensively.
Peritoneal Dialysis in the Next Millennium
Recent Trends in PD Use-New Developments There has been some concern about recent trends indicating decrease in PD use in Canada, the United States, and other countries. Reports of disparate survival between hemodialysis and PD from the large United States registry chronologically preceded this trend and generated a heated discussion. Reports from the Canadian and European registries disputed the initial report from the United States registry. More recent reports from the United States registry have shown disappearance of the survival differences in many patient groups and decreasing differences in all groups. It is possible, but will need to be proven, that these differences are minimal and that proper patient selection and performance of dialysis, not the mode of dialysis, is the critical factor in improving survival. We will discuss some possible reasons, other than the impact of the original report from the United States registry, for the recent reduction in PD use and some recent changes in initiation of dialysis which may favor the use of PD. Possible Reasons for Decreased PD Use Possible reasons for decreased PD use include unbalanced presentation of the dialysis options to the patient, physician and nurse biases, financial reasons, preferences of older patients, and a decline in committed PD leadership. Poor presentation of dialysis alternatives or no presentation of the PD option at all to patients will impact on PD use. There must be an objective and balanced presentation of all options of managing ESRD to the patient, who should then make the final choice. A good way to achieve a balanced presentation may be the production of videos explaining the dialysis options and their relative risks and benefits by a committee of experts with representatives from both the hemodialysis and PD leadership. The videos should be periodically renewed to incorporate recent research findings and should be made available to all dialysis units. Continuous education of nurses and physicians in the recent developments should also be an important part of the process. Financial reasons can influence the selec-
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tion of dialysis modality. The experience in Ontario provides an illustrative example. In this province, medical reimbursement was in excess of $9,000 a year for 1 patient on hemodialysis versus $1,500 per patient on PD before 1998. Since July 1998, this has been equalized to $6,000 per patient per year independently of the type of dialysis. It is interesting to observe whether the new fee schedule will have an impact on the utilization of PD. PD offers some advantages to the elderly ESRD patients. It will also be of interest to study whether older patients living alone or with a frail spouse will prefer PD when the simplifications discussed earlier are applied clinically or if home care nursing is used extensively as the experience in France has shown. The final potential reason for decreased PD use is a decline in committed PD leadership. This may have far going adverse effects. Whereas 15 to 20 years ago there was a large number of investigators who wanted to make dialysis in general and peritoneal dialysis in particular their career, this number has not increased and, if anything, is decreasing. This trend is more pronounced in the 2 countries, which were the cornerstones of the modem era of PD, Canada, and the United States. Table 1 shows the percents of PD abstracts submitted to 3 recent major meetings from different areas of the world. The contribution of Canada and the United States to abstracts reporting bench research or prospective clinical studies was disproportionately low. Research in PD offers a rewarding career and should be actively promoted among young investigators by academia, industry and nephrologyassociations. New Trends in Dialysis Initiation The DOQI guidelines proposed considering initiation of chronic dialysis at renal KtjV urea equal to 2.0 weekly. This level of urea clearance is substantially higher than both the average levels at which patients started dialysis in recent studies35 and the levels at which patients develop frank uremic manifestations. This last characteristic allows incremental initiation of dialysis with low initial dose, which has low cost and is less disruptive of the patient's life style. The rationale for this early
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Table 1. Percentages of PD Abstracts Submitted to Three Recent Major Meetings
Type of Abstract
Africa
Asia
Australia/ New Zealand
Europe
Latin America
Canada/ USA
Number of Abstracts
0 0 0 8% 0
3% 3% 2% 0 0
75 130 107 12 9
0 4% 2% 0 0
16% 15% 55% 82% 50%
44 104 124 22 22
0 4% 6% 0 0
9% 19% 67% 82% 50%
56 54 66 60 4
International Society for Peritoneal Dialysis (perit Dial Int 18:51-S90, 1998 [SuppI2]) Bench Prosp Retrosp QI/Cost Case Reports
0 1% 0 0 0
49% 68% 78% 67% 67%
1% 1% 0 0 0
47% 25% 20% 25% 33%
20th Annual Conference onPD (Perit Dial Int 19:51-587, 1999 [Suppl1]) Bench Prosp. Retrosp. QI/Cost Case Reports
0 0 1% 0 0
18% 26% 11% 0 6%
0 0 1% 0 0
66% 53% 30% 18% 44%
American Society of Nephrology 0 Am Soc NephrollO, Sept. 1999) Bench Prosp Retrosp QI/Cost Case Report
0 0 0 2% 0
28% 31% 15% 0 0
2% 4% 0 0 0
61% 42% 10% 23% 50%
Abbreviations: Bench, bench research; Prosp, prospective clinical studies; Retrosp, retrospective clinical studies; QA/Cost, studies on quality improvement/ cost control; case report, abstracts containing 1-4 cases. NOTE. Percentages refer to the number of abstracts in the last column of each row.
(timely may be a better term)/incremental initiation of dialysis has been presented in several publications36-39 and was discussed by Gokal in the 8th Congress of the International Society for Peritoneal Dialysis. This rationale includes the following items: (1) in CAPD, a total Kt/V urea less than 2.0 weekly is predictive of increased mortality and morbidity; (2) in chronic renal failure, a renal Kt/V urea is associated with spontaneous reduction in protein intake and malnutrition. The relationship between total Kt/V urea and dietary protein intake appears to have the same slope in pre-ESRD subjects and PD patients; (3) low serum albumin at the start of chronic dialysis predicts high mortality and morbidity on dialysis; and (4) targets for initiation of dialysis should be at or above acceptable levels for urea clearance for PD adequacy. PD has several potential advantages as the method for early /incremental dialysis initiation. These include: (1) chronic renal failure and CAPD are similar in providing continuous small solute clearance. This has led to the suggestion that renal and peritoneal clearances are equivalent in CAPD. Retrospective observational studies can not answer this ques-
tion. Prospective interventional, multicentric studies are needed. Design and conduct of such studies will be the critical step in the whole topic of PD adequacy; (2) CAPD may be associated with better preservation of renal function; (3) PD may provide smoother control of sodium and water balance earlier in chronic renal failure; (4) PD allows liberalization of diet (protein intake) to ensure nutritional rehabilitation; (5) PD allows great flexibility and ease on increasing the dose of dialysis to maintain total small solute clearances at or above the target values; (6) PD may accommodate incremental dialysis at lower cost; (7) and PD offers lifestyle benefits. The benefits of early /incremental initiation of dialysis and the potential benefits of PD in this setting should be analyzed by large, prospective controlled studies. This will be an important filed of research in the next few years.
Conclusion Dialysis techniques represent halfway technology and, as such, they are expensive, cumbersome, and have limited success. Some time in the 21't Century, they will be replaced as the
Peritoneal Dialysis in the Next Millennium
main treatment for ESRD and will be delegated to a supportive role to transplantation. However, the numbers of patients treated by dialysis will increase in the first few decades of the next century. Both techniques have major deficiencies. We do not believe that either hemodialysis or PD is fundamentally superior or that they should be considered as competing modalities. The purpose of dialysis is to provide the best and longest life possible to ESRD patients. Along these lines, we agree with Gokal and Malick40 that the 2 dialysis modalities should be considered as parts of the same treatment that can be used sequentially for the benefit of the patient. A patient should be transferred from one dialysis modality to the other when the clinical picture dictates such transfers. An important task for the nephrologic community is to make both dialysis modalities more effective and safer. This will require a lot of research and commitment from the new generation of nephrologists.
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34. Kang DH, Yoon KI, Lee 5W, et al: Impact of nutritional status on serum lipoprotein (a) concentration in patients undergoing continuous ambulatory peritoneal dialysis. Perit Dial Int 16, 5upp!. 1:5241-5245, 1996 35. Burkart JM: Clinical experience. How much earlier should patients really start renal replacement therapy? J Am Soc NephroI9:S118-5123, 1998 (suppI4) 36. Mehrotra R, Nolph KD, Gotch F: Early initiation of chronic dialysis: Role of incremental dialysis. Perit Dial Int 17:426-430, 1997 37. Golper T: Incremental dialysis. J Am Soc Nephrol 9:5107-5111,1998 (suppI4) 38. Mehrotra R, Nolph KD: Arguments for timely initiation of dialysis. J Am Soc Nephrol 9:596-599, 1998 (suppI4) 39. Tzamaloukas AH: Incremental initiation of peritoneal dialysis: Current practices. Adv Perit Dial 15:175-178, 1999 40. Gokal R, Malick NP: Peritoneal dialysis. Lancet 383:823828, 1999