Background

Peritoneal dialysis (PD) is a common kidney replacement therapy for patients with end-stage kidney disease. The benefits of PD treatment include preservation of the residual kidney function (RKF) and high quality of life [1]. However, adequate solute and fluid removal are difficult to achieve with PD alone, particularly after extensive periods of PD treatment. Therefore, switching to hemodialysis (HD), followed by kidney transplantation or initiating combined therapy with PD and HD (combPDHD), is an option for patients who cannot continue PD alone, or for those who require an increased dosage of PD.

CombPDHD was first introduced in Japan [2, 3] and has subsequently been adopted widely. CombPDHD has been covered by the National Health Care Insurance System in Japan since April 2010. The percentage of patients receiving combPDHD therapy has increased slightly in recent years. In 2018, approximately 1800 patients (~ 20% of all PD patients) were receiving this therapy in Japan [4]. CombPDHD therapy is indicated as an alternative for increasing the number of dialysis sessions owing to loss of RKF, peritoneal fibrosis, and functional failure induced by a bioincompatible peritoneal dialysate [5]. Generally, the treatment regimen is 5–6 days of PD combined with one session of HD per week. According to some reports [6, 7], the potential benefits of combPDHD include peritoneal rest expecting improved peritoneal function, delay in membrane deterioration, and minimization of HD-related cardiovascular complications. However, Moriishi et al. [8] reported that improvement in peritoneal function with combPDHD cannot be expected in patients with deteriorated peritoneal function. It is well known that long-term PD causes encapsulating peritoneal sclerosis (EPS), a few cases of which have been observed even after PD cessation [9]. Recently, prospective studies on long-term peritoneal function [10], survival [11], and hospitalization [12] in patients treated with combPDHD have been reported. However, multicenter and prospective studies evaluating the long-term effects of combPDHD are lacking (Table 1). Therefore, we aim to review the studies that have reported the outcomes of combPDHD.

Table 1 Previous reports of combined therapy with peritoneal dialysis and hemodialysis
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Reports on combined PDHD in previous studies

It is well known that long-term PD is a cause of EPS, with some EPS cases observed even after PD cessation [9]. Improved fluid overload and peritoneal function were clinical status characteristics during short-term combPDHD. Body weight, systolic blood pressure, and left ventricular mass index (LVMI) decreased significantly, and the level of hemoglobin (Hb) increased significantly after combination therapy, suggesting that fluid overload was the primary cause. Previous studies also reported that hydration status significantly improved both in PD therapy [13] and in combPDHD [14]. This therapy could be maintained for over 1 year to improve Hb level and cardiac function by adjusting the body fluid status. CombPDHD should be used in PD patients with fluid overload attributable to ultrafiltration failure, poor self-management of fluid balance, and severe heart failure. The dialysate-to-plasma ratio of creatinine (D/PCr) decreased significantly after short-term combination therapy, which corroborated previous studies [6, 7]. A decline in exposure to the advanced glycosylated end-products, glucose degradation products in the PD fluid, and uremic toxins by combination therapy could prevent the deterioration of the peritoneal membrane [15]. Peritoneal rest could lead to improved peritoneal function and delay in membrane deterioration. However, it is well known that long-term PD therapy is a risk factor for EPS. Previous studies reported that PD could be continued successfully with an acceptably low risk of EPS for at least 8 years; however, greater caution is required for patients receiving PD for long term [9]. According to these reports, the duration of PD might be prolonged by the peritoneal rest provided by combPDHD. However, short-term and long-term combPDHD did not significantly alter the plasma β2-microglobulin (MG) level (Table 2). CombPDHD should be used in PD patients with sufficient clearance of solutes such as urea, and β2-MG, which are indexes for small-solute and middle-molecule clearance, respectively. The level of plasma β2-MG in patients undergoing PD alone should be < 30 mg/L. The level of plasma β2-MG is associated with increased mortality among HD patients [16] and is a risk factor for EPS [17]. A decline in RKF is another factor. EPS, a rare and serious complication, occurs in patients undergoing long-term PD. Therefore, a high level of plasma β2-MG and a decline in RKF may lead to a poor outcome. Urine volume was reported in several studies (Table 3). The clinical evidence supporting combPDHD has been steadily accumulating, with several observational studies published to date (Table 1). Notably, most reports were from Japan, and most of them were retrospective single-center studies with small cohorts. Furthermore, all these studies involved before-and-after comparisons but lacked control groups. Recently, multicenter research has been conducted (see Table1). Surprisingly, the total weekly Kt/V ratio [K = clearance dialysis coefficient, t = dialysis duration, and V = body fluid volume] was relatively stable (Table 4). Adequate solute removal is essential in the management of PD, and treatment targets have been defined in several guidelines, including those published by the International Society for Peritoneal Dialysis (ISPD) [18] and the Japanese Society for Dialysis Therapy (JSDT) [19]. The total weekly Kt/V ratio indicates the efficacy of small-molecule uremic toxins removal and is calculated as the sum of renal and peritoneal clearance of urea. The recommend weekly Kt/V ratio is > 1.7 [18, 19]. In contrast, circulating β2-MG, a marker of middle-molecule uremic toxins, is elevated when combPDHD is initiated. The ISPD or JSDT guidelines do not state an optimal range for β2-MG; however, higher values are believed to be associated with poorer outcomes. Yokoyama et al. [20] reported that a higher β2-MG level was an independent risk factor for EPS, which is the most serious complication of PD. Several studies have reported about the D/PCr status at the beginning of combPDHD, which is obtained using the peritoneal equilibration test (Table 5). Increased D/PCr indicates a deterioration in peritoneal function and is an independent risk factor for EPS. Therefore, the JSDT guidelines [19] recommend monitoring of D/PCr and considering cessation of PD if D/PCr is elevated. There was no clinical evidence regarding the deterioration of peritoneal function at the beginning of combPDHD. The observation period ranged from 3 to 72 months; however, the changes in the clinical parameters were similar for all these studies. The patients’ body weight (Table 6) and blood pressure (BP) (Table 7) decreased, suggesting an improvement in the fluid overload status. There was also a decrease in creatinine levels (Table 8), indicating an improvement in the adequacy of dialysis. Hb levels increased after initiating combPDHD (Table 9), for which there are two possible explanations. First, dilutional anemia may have improved because of the reduction in excess body fluid, as reflected by the decreased body weight and BP. Second, the improved removal of solutes may have enhanced the response to an erythropoiesis-stimulating agent (ESA). The JSDT guidelines [19] state that a poor response to an ESA for anemia could reflect inadequate dialysis, even if the target solute clearance is achieved. The details of the mechanism involved are unclear; however, the removal of uremic toxins, resolution of peritoneal edema, and peritoneal rest, including the HD treatment time, may improve the function of the peritoneal membrane. Correction of both inadequate dialysis and fluid overload by switching to combPDHD could help prevent cardiovascular disease (CVD) and lower the mortality risk in PD patients. LVMI levels were reported in several studies (Table 10). High BP is a strong risk factor for CVD and is observed to decline after switching to combPDHD.

Table 2 Plasma β2-microglobulin (MG) levels before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 3 Urine volume before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 4 Total weekly Kt/V ratio before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 5 Peritoneal equilibration test before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 6 Body weight before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 7 Systolic blood pressure before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 8 Creatinine levels before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 9 Hemoglobin levels before and after combined therapy with peritoneal dialysis and hemodialysis
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Table 10 Left ventricular mass index levels before and after combined therapy with peritoneal dialysis and hemodialysis
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Recent reports on combined PDHD

The management of PD becomes more challenging as RKF declines and peritoneal function deteriorates. Subsequently, inadequate dialysis and/or fluid overload becomes clinically evident. Several guidelines recommend that optimal small-solute clearance, indicated as a Kt/V ratio of > 1.7, and euvolemia should be maintained by monitoring both urine volume and the amount of ultrafiltration achieved [18, 19]. Several reports have demonstrated the clinical utility of combPDHD for the correction of inadequate dialysis and/or fluid overload. However, previous studies assessing patients starting combPDHD compared several clinical parameters before and after switching to combPDHD. The primary objective of our prospective multicenter observational cohort study was to compare patient hospitalization, mortality, and various clinical parameters between patients who switched from PD monotherapy to combined therapy and those who switched directly to HD (see Table 1).

In a single-center prospective study, Kanda et al. [10] reported that the levels of LVMI (measured using echocardiography) and human atrial natriuretic peptide at 6 months after therapy initiation were significantly lower than those at the start of combPDHD. Moreover, D/PCr levels at 6 months after combined therapy were significantly lower than those at the initiation of combPDHD. Additionally, D/PCr levels at 12 or 18 months after combPDHD were not elevated.

Tanaka et al. [12] reported that the risk of hospitalization was not significantly different between combPDHD and HD alone, although combPDHD patients had a higher risk of dialysis access-related complications than patients receiving HD alone. Because combPDHD requires both a PD catheter and vascular access (VA), combPDHD patients potentially have an increased risk of dialysis access-related complications. Indeed, the hospitalization rate for the sum of PD-related infections and VA complications in combPDHD was threefold than in HD patients.

In a large, multicenter, and retrospective study from Taiwan, Chung et al. [21] reported that combPDHD (two HD sessions per month) is not redundant but a rational and cost-effective treatment, particularly for patients without recent peritonitis. Dialysis staff should therefore be familiar with the advantages and disadvantages of combPDHD, and consider it an essential part of integrated dialysis care. The Taiwanese National Health Insurance (TNHI) system provides services for HD and PD, including the use of icodextrin, nutrineal, and automated PD. The TNHI system has also expanded coverage to combPDHD, but only if the symptoms of uremia and fluid overload cannot be ameliorated by maximizing PD prescription. Patients undergoing PD can decide whether to switch to HD directly or receive combPDHD. Murashima et al. [22] reported that combPDHD was associated with lower all-cause, cardiovascular, and heart failure-related mortalities, but an earlier transition to HD than PD alone might have improved fluid removal. This study aimed to compare the outcomes of combPDHD and PD alone using the Japanese Renal Data Registry database, which is a nationwide cohort of dialysis patients in Japan.

In a multicenter, prospective study, Maruyama et al. [11] first reported the clinical outcomes for patients on PD alone transferred to combPDHD with those for patients directly transferred to HD. No significant differences were observed in the survival outcomes between the two groups. Comparison of patient survival was difficult because of the small number of deaths; however, PD patients with inadequate dialysis and/or volume overload could continue PD therapy safely by switching to combPDHD.

The main limitation of the studies [11, 12, 21, 22] included in this review must be considered. These studies did not evaluate the efficacy of dialysis. The JSDT guidelines [19] recommend that the adequacy of dialysis should be determined using the concept of body fluid clear space in combined therapy [19, 22]; however, established methods to assess the efficacy of combPDHD are lacking. Kt/V ratio was used for the assessment of dialysis adequacy in both PD and HD patients; however, the definitions of these two treatments are completely different [23].

How long can we continue with combPDHD in the future?

It was previously reported that the mean duration of PD was 120.5 ± 42.8 months, and the mean observation period was 211.5 ± 70.1 months in patients with EPS [24]. No significant differences in PD duration, utilization of acidic peritoneal dialysis solution, combPDHD status, combPDHD duration, observation period, and age at death were observed between the EPS and non-EPS groups [24]. Recently, a laparoscopic examination has been used to help diagnose peritoneal degeneration because it facilitates easy observation of the characteristic gross thickening of the peritoneum and increased vascularity of the visceral peritoneal surface [25]. Furthermore, previous studies involving patients with combPDHD have reported on laparoscopic procedures for evaluating angiogenesis, color changes, and plaques in the peritoneum [26]. In each case, there was a difference in abdominal wall degeneration depending on the intra-abdominal cavity. Particularly in the lower abdomen, there was a tendency for stronger degeneration to be more pronounced. Furthermore, there were cases in which no change in the abdominal wall degeneration occurred. Therefore, the timing of PD withdrawal needs to be examined on an individual basis; thus far, there is no clear determining marker. The limitations of the studies included in this review must also be considered. Some degree of selection bias could not be avoided because of the timing of changing modality, and the selection of a new modality type; particularly regarding combPDHD or HD alone selections were at the discretion of the treating physicians.

Conclusions

CombPDHD should be used in PD patients with the fluid overload that is attributable to ultrafiltration failure, poor self-management of fluid balance, and severe heart failure. A previous study revealed that combPDHD might be useful for the long-term maintenance of the peritoneal membrane and cardiac function. However, a high level of plasma β2-MG with long-term combPDHD can impact patient prognosis. Therefore, we conclude that in cases of declining RKF or when self-management of fluid balance is poor, combPDHD should be initiated to adjust the body fluid status, with a sufficient dialysis dose and peritoneal rest. Further studies are required to evaluate the peritoneal function and determine when PD therapy should be discontinued. Conclusively, combPDHD is useful from a lifestyle perspective for patients during the transition from PD to HD; however, at present, it should not be continued indefinitely.