A Potential Role of Peritoneal Dialysis as ‘a Bridging Therapy’ to Other Renal Replacement Therapies

According to the most recent survey conducted by the Japanese Society for Dialysis Therapy, there were approximately 186,000 patients undergoing dialysis in Japan at the end of 1998. Among them, 95% of these patients were maintained on hemodialysis (HD), and the remainder were receiving peritoneal dialysis (PD) [1], indicating that the acceptance of PD in Japan is low compared to that in other countries [2]. The low utilization of PD in Japan raises questions concerning the reason for this disparity in the acceptance of these two renal replacement modalities.More than 30 years after becoming a clinical reality, HD has provided for excellent long-term survival of end-stage renal disease patients in Japan. With the exception of diabetic patients, survival over 20 years has been reported in many Japanese dialysis patients on HD with many patients having a substantially well-rehabilitated state and with well-maintained QOL [1]. PD has been accepted as one of the useful renal replacement therapies (RRT) over the last decade. Yet, because of less clinical outcomes originating from a relatively small number of patients on long-term PD, the place of PD as an accepted modality of RRT still remains unidentified.Unlike other countries, kidney transplantation is very uncommon in Japan. Only 658 renal transplants (77% living related; 23% cadaver donors) were performed in 1998. The transplantation rate in the US is currently 47 transplants per million population compared to only 2 transplants per million population in Japan. Because of the minimal opportunity to receive a renal transplant in Japan and in view of the decreasing trend in the number of renal transplants performed in the last decade, dialysis therapy has been viewed by many Japanese patients and physicians as permanent RRT for almost all patients with end-stage renal failure.Focusing on the integration of RRT in patients with chronic renal failure who want to know which sequence of RRT will increase their total survival as long as possible, the present communication addresses how to select and integrate RRT under currently available dialysis modalities in Japan. Special attention is paid to the potential role of PD as ‘a bridging therapy’ to other RRT, especially in consideration of residual renal function (RRF).A true comparison of survival between HD and PD is not possible because randomized control study would be almost impossible to perform. As a result, comparison of survival between the two forms of dialysis over the last decade has produced controversial results. There have been significant discrepancies regarding survival on HD and PD, with some authors reporting no difference between the two therapies [3], others reporting better outcomes in HD [4, 5, 6]and yet others documenting improved survival with PD [7, 8, 9]. This controversy also holds true in the comparison of hospitalization between these two therapies, with some authors reporting increased hospitalization in patients on PD [10, 11, 12, 13]; however, this has not been confirmed by others [14, 15]. Thus, the current literature would not support the notion that PD as an RRT is inferior to HD. Improvements in both of these therapies during the 1990s and recent initiatives focusing on improving PD adequacy would also suggest that historical comparisons between these two therapies may not be valid based on current practices. Actually, there have been significant changes in the practice of PD globally, which include increased utilization of automated PD (APD) therapy and strategies to increase dwell volumes, especially focusing on the US [16, 17]. A number of investigators have recently compared PD to HD and have suggested potential clinical benefits of PD, including better cardiovascular morbidity [18], a lower incidence of delayed graft function following renal transplantation [19], better preservation of RRF [20], significantly higher hematocrit [21, 22], a lower incidence of amyloidosis [23], a lower risk of hepatitis C [24]and QOL advantages resulting from the less constrictive nature of this therapy [4, 5, 25, 26, 27, 28, 29, 30].These advantages of PD would suggest that this therapy has a potential role for a number of patients with end-stage renal disease. Yet, the lower retention rate in PD as compared to HD is related to the inherent problems of this dialysis modality. Factors such as the need for strict self-care, the limited availability of medical staff trained in the clinical practice of PD in Japan, and the fear of peritonitis and sclerosing encapsulating peritonitis (SEP) all may contribute to its low retention. Another factor which also should be considered is the possible lack of awareness of PD therapy among patients beginning RRT in Japan. We believe that many Japanese predialysis patients and patients on HD are not always correctly informed about the availability of PD as an option for RRT. In the selection of dialysis, the patients with end-stage renal failure must be correctly informed and educated throughout the period of the progression of his/her renal disease on the differences and characteristics of available RRT.Preservation of RRF is important not only in optimizing volume homeostasis and solute clearances, but also in maintaining and replacing endocrine functions and eliminating β2-microglobulin [23, 31, 32]. Data from large-scale clinical studies have documented that mortality increases as RRF declines [33], and others have also reported that higher levels of RRF at the initiation of RRT (either HD or PD) and maintenance of RRF throughout the course of RRT have been associated with improved outcome and reduced patient mortality [34, 35]. These reports would suggest that there are numerous physiologic benefits associated with RRF in dialysis patients which may have significant clinical implications.A number of studies have shown that RRF is better preserved in PD patients than HD patients [20, 35]. In a retrospective analysis of patients receiving PD or HD, Lysaght et al. [20]reported that the decline in RRF is significantly faster in the HD group compared to patients receiving CAPD. The rate of the decline was approximately twofold faster in HD than in CAPD (30% reduction/year in HD and 15%/year in CAPD). Based on the report, it is suggested that most HD patients are anuric in 4 years after initiating HD therapy. Alternatively, CAPD patients maintained a level of RRF greater than 2 ml/min of Ccr even 4 years after the start of dialysis. This suggests that some patients may not be anuric until 7–8 years following the initiation of PD therapy. While the reasons for the better preservation of RRF seen in PD patients have not been fully explained, it has been suggested that these observations are due to the greater hemodynamic stability afforded by PD as a result of less abrupt fluctuations in volume and osmotic load during the dialysis procedure. On the other hand, abrupt removal of solutes and volume in HD produces greater perturbation in renal hemodynamics, thereby accelerating the decline in RRF.Over the clinical course of PD, RRF makes a significant contribution to total clearance [35, 36]. The preservation of RRF may have important implications for the adequacy of dialysis prescription regimen. Heimburger [31]found that RRF accounted for 25% of total dialysis clearance of patients on CAPD. Kasai et al. [37]similarly demonstrated that the renal/peritoneal ratio of weekly Ccr and KT/V was 3:7 and 2:8, respectively, indicating that RRF contributes approximately 20–30% to total solute clearance in PD patients. The Canada-USA (CANUSA) study similarly showed that 30–40% of total solute clearance over time was the result of a decline in RRF [33]. In addition, the presence of RRF has been shown to provide survival advantages in patients on PD. A report by Maiorca et al. [38]showed that PD patients who survived over a 3-year period of study had significantly greater RRF than those who died during the same observation period. In the CANUSA study, total solute clearance and RRF were strongly correlated with decreased mortality [33, 39]. Additionally, reduction in total clearance over time in PD patients was due to the decline in RRF rather than to a decrease in peritoneal membrane function [34].The above would suggest that appropriate clinical strategies should be pursued to preserve RRF as long as possible after the initiation of chronic dialysis. Since RRF is well preserved in patients on PD compared to HD, it might be favorable for uremic patients to start on PD, and to transfer to HD when RRF declines or when other serious PD-related complications arise.Facing the commencement of chronic dialysis, most nephrologists in Japan have followed the initiation criteria of dialysis recommended by the Japanese Society of Nephrology [40]. Based on the criteria, the majority of patients start dialysis with a serum creatinine concentration over 8 mg/dl or a Ccr less than 10 ml/min, and a large majority of patients experience nausea/vomiting at the time of dialysis initiation. Thus, the risk of malnutrition can be substantial in this patient population [41]. There is no doubt that delays in initiating dialysis result in unnecessary morbidity and potentially high costs. In response to this issue, guidelines developed by the National Kidney Foundation’s (NKF)’s Dialysis Outcomes Quality Initiative (DOQI) suggest that unless certain conditions are met, patients should be advised to initiate some form of dialysis when the weekly renal KT/V falls below 2.0 (equivalent to a GFR of 10.5 or a Ccr of 9–14 ml/min/1.73 m2) [42]. The conditions that may indicate dialysis is not yet necessary even though the KT/V is less than 2.0 include complete absence of clinical signs or symptoms. Others have also suggested the potential benefit of earlier initiation of chronic dialysis and have proposed initiating therapy utilizing an incremental dialysis approach when levels of RRF are high [43]. Since earlier initiation of chronic dialysis at higher levels of RRF would result in the need to maintain RRF for a longer period of time, the better ability of PD to preserve RRF may play a role in the determination of which dialysis therapy should be utilized as initial RRT when this approach is chosen.The length of time a patient can remain on PD is usually determined by one of several clinical factors. One of the primary factors, which affect duration of PD therapy is the presence of RRF. It is probably the main factor to limit long-term CAPD in Japan. Based on the CANUSA study concerning adequacy of PD, a weekly Ccr of 60– 70 liters/week/1.73 m2 is proposed to be the recommended target [33]. Under the special consideration of RRF, targeted dialysis adequacy of PD has also been proposed by Blake et al. [44]who similarly showed the acceptable goal to be a total Ccr of 60–69 liters/week/ 1.73 m2, and a total KT/V of 1.9–2.0. The NKF-DOQI peritoneal dialysis adequacy guidelines currently recommended a weekly KT/V of 2.0 or a weekly Ccr of 60 liters/week/1.73 m2 [42]. According to the report of Blake et al. [44]and Kasai et al. [37], the minimal requirement of urine volume to achieve the ideal dialysis adequacy is estimated to be over 400–500 ml/day [44]. Meanwhile, according to the report of Lysaght et al. [20]indicating that Ccr of PD patients declines by 15% per year [20], it is estimated that residual urine volume is reduced by less than 400–500 ml/day within 4–5 years. This would suggest that reduction in UF or under-dialysis will result from the loss of the contribution of RRF to total solute clearance in patients on long-term PD therapy. Under these circumstances, the continuation of PD may become problematic unless alteration of PD prescriptions or the utilization of different PD approaches are successful towards achieving adequate solute clearance and volume control in patients with little or no RRF.The second factor which may affect the duration of PD therapy is UF failure due to the change in peritoneal permeability (determined as a PET) as a result of changes in its morphology. Krediet et al. [45]reported that UF failure usually occurs in patients on long-term CAPD. Changes in peritoneal membrane morphology in association with increase in peritoneal membrane permeability during PD have been reported by several investigators [46, 47, 48]. These results imply that the longer the PD continues, the higher the peritoneal permeability would become. This would suggest that most patients on PD are at risk of developing UF loss after a certain period of time. In practice, progressive fall in RRF leads to anuria, an absolute absence of renal clearance of fluid and solutes, which leads to a further need for removal. Yet, long-term observation regarding morphological changes in the peritoneal membrane is lacking except for the one reported by Hirano [49]. He reported that morphology of the peritoneum remains almost intact for over 5 years in the absence of peritonitis. However, even in the absence of peritonitis, sclerotic change and thickening of the peritoneum occurred in 7–8 years, leading to peritoneal sclerosis. He commented that long-term PD might be associated with peritoneal sclerosis and future development of sclerosing encapsulating peritonitis. Biesen et al. [50]observed that the outcomes of the patients who remained on their initial therapy for more than 4 years and who were not transferred were worse for PD patients compared to HD patients. In addition, Fenton et al. [51]reported that outcome after 5 years was worse in PD than in HD patients. These results could be explained by the deterioration of the quality of the peritoneal membrane and by the progressive loss of RRF. It is natural that both factors lead to a progressive decline in total adequacy and fluid balance problems which will result in a decreased survival.The third factor, which affects duration of PD therapy in Japan, is concern about the development of SEP. SEP is a serious complication of PD, characterized by a recurrent and persistent ileus. The incidence varies from 1 to 3% in Japan, creating a fear of PD in PD community [52]. Unfortunately, the etiology of SEP is still largely unknown and must be urgently investigated. Of note is that the majority of the patients with SEP exhibit UF failure as a result of a peritoneal membrane with high transport characteristic. The duration of PD in patients developing SEP is estimated to be 7–8 years (average 60 months). The clinical evidence could support a notion that PD should be discontinued and transfer to either HD or transplantation should be considered when the peritoneum becomes highly permeable and UF failure becomes symptomatic as PD continues. Although the etiology of SEP is unknown, this idea may help to prevent and minimize further occurrence of this serious complication.The question of how long we should continue PD must be addressed based on the above-mentioned clinical issues. As we discussed above, RRF is preserved approximately for 6–7 years; additionally, peritoneal permeability becomes high within 6–7 years. Furthermore, peritoneal fibrosis is observed in about 8 years even in the absence of peritonitis. Most of the cases developing SEP have 7–8 years history of being on PD. Considering these clinical evidences, it seems rational and safe to set the duration of PD to be within 6–7 years. After this given duration of time, PD should be withdrawn, and patients should be transferred to other RRT. This discontinuation criterion for PD is not different from the one recommended by the Working Group on SEP of the Japanese Ministry of Health and Welfare [52]. There are patients whose peritoneal permeability remains unchanged for a long time, successfully maintaining UF and dialysis adequacy; the discontinuation criteria cannot be applied to such patients. Moreover, they may be suitable candidates for long-term PD and could go on for much longer than indicated by these criteria.In order to achieve effective UF volume in the face of declining RRF, alterations in PD prescription must be pursued. These attempts include increased dwell volume and an appropriate use of APD based upon changes in transport status. In order to help optimize patient prescription, there are kinetic modeling software programs such as PD Adequest (Baxter Healthware Corporation), PDC (Gambro AB, Sweden) and PACK PD (Fresenius USA, Walnut, USA) which clinicians can use to tailor PD prescription to the needs of the individual patient, especially anuric patients. However, such attempts are not always successful, and if further deterioration of UF failure develops, the only clinical recourse currently available for PD patients is the increased utilization of higher glucose concentration dialysate. This potentiates the negative effects and further increases peritoneal permeability.For many patients, the loss of fluid control provided by RRF the utilization of higher glucose concentration in the PD to achieve adequate fluid removal. The higher concentration of glucose produces a which potentially peritoneal membrane permeability This can lead to the development of a highly permeable which is associated with greater in achieving adequate UF or UF clinical recently to for PD have from about high concentration of glucose as a potential risk factor a on peritoneal Among are and the not peritoneal the occurrence of UF failure and the development of SEP will PD will be of for end-stage renal failure has been a of in the US and can the of the integration of PD in the of be The of RRT is to patients to as a level of as possible and to and However, of the available therapies a complete and has its RRT is as the in which HD, PD and transplantation can be on the of the that renal replacement therapy should be to its The integration should be and the patient from one to Of is that renal replacement is the effective integration of PD, and a number of concerning RRT and suggested that over the 5 years of RRT, PD is as effective as HD and may even certain We that PD is a of ‘a renal replacement or bridging between predialysis and other RRT, HD or In other PD can be as an and of the patients at the predialysis As discussed RRF is well preserved with PD compared to HD. Thus, PD may be a RRT. It is well that for many patients in many countries, the goal is renal Yet, the present of renal transplantation in Japan is different from that in other countries and the US in that transplantation is very in practice, there are only two to the kidney HD and PD. Thus, the of currently available RRT in Japan is by which initiating with HD and maintaining with HD (HD), initiating with PD and maintaining with PD initiating with PD and transfer to HD initiating with HD and transfer to PD and PD with HD. it should be that the main of the integration is the that PD, HD and transplantation are with the of to all of and a among PD is to we had ‘a for PD. it is different from selection by The difference between the two is that PD is to PD within its limited In PD patients are on PD as an RRT of the predialysis After a given period on PD, the patients must be transferred to the other RRT. PD was as a modality in Japan. However, because of the inherent problems of PD, that an change in peritoneal function and PD must not be as a RRT. In other the of PD is as a bridging therapy between predialysis and HD or One however, be to the that long-term PD may be possible if peritoneal permeability remained unchanged and UF failure not One factor that or not a patient will be with PD is the time of in their disease to a renal are more to PD. who are usually to on HD [43]. and initiation of dialysis are associated with patient less of uremic of with ability to dialysis and for PD is ideal for maintenance of of progression of complications and the ability to the use of for future HD, time on dialysis compared to a HD patient In most PD patients, the need for transfer can be and a of can be improving the quality of It is also to UF loss or development of SEP compared to a PD problems and to to be suitable for PD and for may not be suitable but still for PD This is ‘a negative selection for in which of HD is PD clinical advantages including less and better One must be to the that patients who transfer from HD to PD usually RRF. In such patients, the successful of long-term PD may not be PD last still may be a better dialysis modality than HD for the last of that to in which from dialysis might be therapy of PD with HD was for patients with UF loss or for PD patients with Data concerning this therapy are Yet, the idea seems to be of and A of such a prescription is 5 PD with a HD a A opportunity to the peritoneum to may and peritoneal and the of a HD UF loss and a dialysis however, may be to receive the because of the need for both and of peritoneal Furthermore, at this there is no that the is fully by the currently available in Japan. The medical and of PD with HD must be further in the of the small number of kidney dialysis is viewed as a permanent renal replacement modality in Japan. PD should be as a of an renal replacement in which different are with the of to to a better preservation of RRF than in HD, the of PD could be as a of RRT, being in between the predialysis period and HD or potentially bridging between the two different of chronic renal attention must be paid to the that the peritoneum is a PD should be discontinued if peritoneal permeability increases and UF failure becomes the safe for PD to be is estimated to be 6–7 years.

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