Clinical efficacy of combined therapy with peritoneal dialysis and hemodialysis

Peritoneal dialysis (PD) is recommended as a first-line renal replacement therapy
(RRT) for end-stage renal disease (ESRD) 1]. The main evidence to support this recommendation is that residual renal function
(RRF) is better preserved among patients treated with PD than in those undergoing
hemodialysis (HD) 2]. The degree of RRF affects not only adequate solute and fluid removal, but also patient
survival 3], 4]. However, standard PD is not always sufficient to avoid both the risk of uremic complications
of inadequate dialysis and fluid overload, especially once loss of RRF has occurred.
Peritoneal permeability is also widely recognized as showing gradual enhancement over
time on PD therapy. In Japanese PD patients, the 5-year technique survival rate was
estimated as 70 %, and the most common reasons for technique failure are inadequate
dialysis and/or ultrafiltration failure 5]. Treatment options for these patients include switching to HD or starting combined
therapy with PD and HD, generally in the form of 5–6 days of PD and one HD session
per week.

Combined therapy with PD and HD was introduced in Japan in the 1990s, and the first
report was written by Watanabe and Kimura [abstract: Watanabe S and Kimura Y et al.
Nihon Touseki Igakukai Zasshi. 1993;26 (suppl 1):911]. Kawanishi et al. 6] published the first report in English in 1999, describing 12 patients treated with
combined therapy. A PD + HD combination therapy study group was set up in 1996, had
met annually and discussed details of the application, mode, and indication of this
combination therapy, and issued the first clinical recommendation in 2004 7]. Since then, combined therapy has rapidly gained popularity in Japan, and as of 2012,
approximately 1800 patients (20 % of all PD patients) were estimated to be receiving
this therapy 8].

Although several reports have shown the effectiveness and impact of combined therapy
with PD and HD, most have been limited by sample size or by being single-center studies
6], 9]–20] (Table 1). In these reports, the terminology have not been standardized (i.e., combined therapy,
combination therapy, hybrid therapy, complementary dialysis, and bimodal dialysis).
We recently reported clinical outcomes for more than 100 patients treated with combination
therapy across nine centers in Japan 21]. According to that study, the PD duration prior to switching to combined therapy
was approximately 2–4 years and the reason for switching was inadequate dialysis in
25–83 % and fluid overload in 16–42 % (Table 1).

Table 1. List of previous reports regarding combined therapy with PD and HD

This review summarizes the experience with combined therapy using previous reports,
and considers the clinical efficacy of this therapy. We also propose criteria for
both initiation and discontinuation of combined therapy.

Criteria for initiation of combined therapy

For the better management of PD, adequate solute and fluid removal are essential and
targets have been defined in several guidelines, including the Kidney Disease Outcomes
Quality Initiative (KDOQI) guideline 22], the International Society for Peritoneal Dialysis (ISPD) guideline 23], and the Japanese Society for Dialysis Therapy (JSDT) guideline 24]. Weekly Kt/V is widely used to assess solute removal, and is determined using the
combined renal and peritoneal clearance of urea. The guidelines recommend maintaining
weekly Kt/V 1.7. In addition, persistent anorexia, deterioration of nutritional status,
erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia, and restless legs syndrome
could reflect inadequate dialysis even if the target for solute clearance is achieved.
Maintenance of euvolemia is also important for the better management of PD patients.
Reduction in both ultrafiltration (UF) volume and urinary volume induce volume overload.
The presence of peripheral edema, higher or drug-resistant blood pressure, and heart
enlargement or pleural effusion on chest X-rays could be signs of fluid overload.
Although definitive criteria for the initiation of combined therapy have yet to be
established, patients who cannot maintain adequate solute removal and fluid removal
are candidates for this therapy.

Table 2 summarizes the clinical and biochemical parameters at the start of combined therapy
with PD and HD. Creatinine levels were elevated (12.0–13.5 mg/dL) and urine volume
was decreased (150–250 mL/day), whereas weekly Kt/V was maintained at a target level
(1.7–2.0) at the start of combined therapy. These results suggest that small solute
removal was maintained in many cases, and fluid overload was a considerable reason
for the initiation of combined therapy. Indeed, systolic blood pressure was elevated
(140–156 mmHg) despite the high UF volume (800–1000 mL/day).

Table 2. Clinical and biochemical parameters at the start of combined therapy with PD and HD

Although the removal of urea nitrogen or creatinine was relatively maintained, ?2
microglobulin (?2m) levels were elevated (33–36 mg/L). The level of serum ?2m, as
a middle-molecule uremic toxin, is known to influence the mortality of HD patients,
and is now recognized as a potential guide to the adequacy of dialysis in this population
25]. Since a higher ?2m level represented an independent risk factor for encapsulating
peritoneal sclerosis (EPS), the most serious complication of PD 26], ?2m level is expected to be a prognostic factor for both PD alone and for combined
therapy.

Two reports showed dialysate-to-plasma ratio of creatinine (D/P Cr), obtained from
a peritoneal equilibration test (PET), at the start of combined therapy 18], 21]. Increased D/P Cr reflects deterioration in peritoneal function, and increases gradually
with duration of PD and cumulative glucose exposure 27]. In addition, D/P Cr is one of the important risk factors for EPS 28]. Since D/P Cr was not elevated, peritoneal deterioration was not clinically evident
at the start of combined therapy.

PD patients who cannot maintain adequate solute removal and fluid removal are candidates
for combined therapy as described before, and we proposed for criteria for the initiation
of combined therapy with PD and HD (Table 3). In these criteria, patients with limited peritoneal capacity and presenting with
cardiovascular instability in HD were also candidates for combined therapy even if
both solute and fluid removal were maintained 29].

Table 3. Proposed indications for combined therapy with PD and HD

Changes in clinical and biochemical parameters after initiating combined therapy

Table 4 summarizes changes in clinical and biochemical parameters after the initiation of
combined therapy. According to these comparative analyses, body weight and blood pressure
decreased and hemoglobin increased, and serum creatinine levels decreased despite
the decreased urine volume 14], 15], 18], 19], 21]. These results indicated that both the adequacy of dialysis and hydration status
were significantly improved. Several studies have demonstrated that hemoglobin levels
increased with a reduction in ESA dose, indicated that the elevation in hemoglobin
level was due to corrections of both fluid overload and ESA hyporesponsiveness one
of the uremic symptoms 15], 18], 19].

Table 4. Changes in clinical and biochemical parameters

Changes in serum ?2m varied between reports 16], 18], 21]. Dialysis clearance of ?2m with HD using a high-flux membrane is well known to be
much higher than with PD 30], 31]. Unlike in PD, serum ?2m in patients receiving HD changes dramatically over a week,
and we usually measure the highest value at the start of an HD session. Since ?2m
represents a useful risk factor in PD patients, as previously mentioned, the decline
under combined therapy is thought to be a beneficial effect 26].

In most studies, D/P Cr decreased after switching to combined therapy 16], 18], 21]. Several possible explanations for this have been suggested. Firstly, combined therapy
could limit further deterioration of the peritoneal membrane by decreasing exposure
to glucose and elimination of uremic toxins. In addition to cumulative glucose exposure
32], uremia per se 33] is also associated with structural alternations in the peritoneal membrane. Secondly,
peritoneal rest could have a positive impact on peritoneal function. In general, PD
was not carried out on the day of a HD session, and almost half of the patients did
not undergo PD on another day, defined as a “PD holiday”. Several in vivo 34] and in vitro 35] studies have shown that peritoneal rest reduces the alteration of the mesothelial
cells and improves peritoneal function. Thirdly, histological improvement of peritoneal
edema secondary to improvement of fluid status might lead to reduction in D/P Cr 36].

Assessment of efficiency of combined therapy

Although small solute removal was obviously improved after switching from PD alone
to combined therapy, no standard method has been devised to calculate solute clearances
in combined therapy. Kawanishi et al. 14], 16], 29] used equivalent renal clearance (EKR) of urea as proposed by Casino et al. 37], and both total Kt/V and total weekly creatinine clearance (Ccr) were increased in
patients after starting combined therapy. The JSDT guideline 24] recommends that the adequacy of dialysis should be determined using the concept of
body fluid clear space in combined therapy 24], 31].

Combined therapy and cardiovascular disease

Cardiovascular disease is one of the most serious complications in dialysis patients,
and is responsible for 33.5 % of deaths among Japanese dialysis patients 8]. Since both inadequate dialysis and fluid overload are risk factors, initiating combined
therapy may have a positive impact. Although no reports have clarified the effect
of combined therapy on the incidence of cardiovascular disease, changes in surrogate
markers have been reported. Tanaka et al. 19] found that left ventricular mass index (LVMI) on echocardiography, a well-known risk
factor for atherosclerosis, was significantly reduced at 9 months after switching
therapy. They also reported that systolic blood pressure was significantly decreased
despite prescription of the same dose of antihypertensive medication. Hypertension
is a risk factor for mortality, and control of blood pressure by antihypertensive
medication reduced cardiovascular morbidity and mortality rates in HD 38]. Several other reports have indicated the corrective action on blood pressure, with
a reduction in number of antihypertensive drugs 15], 18]. Interestingly, Matsuo et al. 39] recently reported that the cumulative hazard ratio for death was not lower for combined
therapy than for HD or PD alone. These results suggest that switching from PD alone
to combined therapy may have a good clinical impact on the prevention of cardiovascular
disease.

Combined therapy and quality of life

Along with reducing mortality and morbidity, maintaining high quality of life (QOL)
is also important for the management of dialysis patients. A meta-analysis by Wyld
et al. 40] reported that PD resulted in a clinically higher QOL than HD, however, but the difference
was not statistically significant. Hashimoto et al. 9] found that QOL was improved among six patients switching from PD alone to combined
therapy. They concluded that the improvements in QOL may have resulted from decreases
in uremic symptomatology and freedom from bag exchanges.

Criteria for discontinuation of combined therapy and prevention of EPS

Combined therapy with PD and HD has some concerns. Urine volume decreases during combined
therapy. Since many reports have shown an association between lower RRF and higher
mortality among PD patients 3], 4], a decline in RRF by combined therapy might require attention. Further study will
be needed to clarify the association between renal volume and outcome among patients
receiving combined therapy. Furthermore, induction of combined therapy would increase
the overall duration of PD treatment and susceptibility to peritonitis. Both prolonged
PD duration and increased number of peritonitis episodes are well known as independent
risk factors for EPS 28], and Yamamoto et al. 41] reported that the cut-off points for these parameters are 115.2 months and two times,
respectively.

In addition to the absence of criteria for initiation, criteria for discontinuation
of combined therapy have also not yet been established. For those patients receiving
combined therapy who cannot maintain adequate solute removal and fluid removal, we
have to consider discontinuation of combined therapy and switching to other mode of
RRT, especially HD thrice weekly. We also proposed criteria for discontinuation of
combined therapy PD and HD (Table 5), determined based on the criteria for conventional PD and consideration of the prevention
of EPS development as well as impaired solute and fluid removal was an important issue
24]. It is to be noted that conventional solution was used in the most of previous studies.
It is well known that neutral-pH, low-glucose degradation products solutions potentially
influence the integrity of the peritoneal membrane 42]. Indeed, Yohanna et al. found that the use of these new solutions resulted in better
preservation of RRF and greater urine volumes in systematic review 43]. In the future, the reconsideration of criteria for discontinuation will be needed.

Table 5. Proposal for discontinuation of combined therapy with PD and HD

Experience of combined therapy in Western countries

Most reports of combined therapy were from Japan, and limited experiences have been
reported from the USA 12] and UK 13]. Agarwal et al. 12] observed an improvement in the clinical symptoms for which combined therapy was initiated
in 31 patients. McIntyre et al. 13] conducted a prospective study of combined therapy, referred to as bimodal dialysis,
in eight incident patients reaching ESRD, and found that RRF was controlled and both
blood pressure and LVMI were reduced.