Incremental Peritoneal Dialysis—Definition, Prescription, and Clinical Outcomes

Abstract

Incremental peritoneal dialysis (IPD) is a strategy of RRT that is based on the prescription of a lower dose rather than the standard full dose of peritoneal dialysis (PD). The clearance goals are achieved through the combination of residual kidney function (RKF) and peritoneal clearance. The dialysis prescription should be increased as the RKF declines. IPD has been associated with clinical, economic, and environmental advantages. We emphasize possible better quality of life, fewer mechanical symptoms, lower costs, slight adverse metabolic effects, and less plastic waste and water consumption. The potential benefits for RKF preservation and the lower risk of peritonitis have also been discussed. There are some concerns regarding this strategy, such as inadequate clearance of uremic toxins and/or severe electrolyte disturbances due to undetected loss of RKF, lower clearance of medium-sized molecules (such as β-2-microglobulin) which mostly depends on the total PD dwell time, and patients' reluctance to dose adjustments. Current clinical evidence is based on moderate-quality to low-quality studies and suggests that the outcomes of IPD will be at least identical to those of full dose. This review aims to define IDP, discuss strategies for prescription, and review its advantages and disadvantages according to the current evidence.

Introduction

Incremental peritoneal dialysis (IPD) was for the first time described in 1997 by the National Kidney Foundation Dialysis Outcome Quality Initiative Guideline on Peritoneal Dialysis Adequacy.¹ IPD prescription is based on a lower dose rather than the standard full dose; therefore, the combination of residual kidney function (RKF) and peritoneal clearance achieves or exceeds the clearance goals.² The prescription should be adjusted as RKF declines and/or clinical alterations appear, by increasing the number or volume of daily exchanges, as well as the dwell time.^2–5

The definition of IPD varies between different authors. IPD should be seen as a concept on the basis of the strategy rather than the prescription.² It relies on the junction of RKF and peritoneal clearance to achieve clearance goals.² In other words, the IPD prescription is lower than the standard dose and does not achieve the clearance outcomes by itself; therefore, the role of RKF is critical. The guidelines of the International Society for Peritoneal Dialysis published in 2020 exemplifies some IPD strategies: (1) continuous ambulatory peritoneal dialysis (CAPD [PD])—less than four dwells daily, <2 L dwell volumes and/or performed less than 7 days a week and (2) automated PD (APD)—performed <7 days a week, dose of total daily volume <10 L and/or without a long dwell.² This definition also emphasized that IPD prescription should be goal-directed and clearance target individualized. Although it can be used as a particular Kt/V value (such as 1.7/wk) or creatinine clearance (such as 50 L weekly), the amount of clearance necessary to keep the person well is more important.² Hence, the goals of IPD prescription should attend clearance parameters, signs and symptoms such as hypervolemia and/or uremic symptoms, quality of life, and nutritional status.³

It is crucial to distinguish IPD from other strategies that also adopt an initial dose of PD below the standard dose; however, they are not IPD because their aim is not to increase the dialysis dose as RKF declines. This type of prescription may occur in developing countries for economic reasons (low clearance PD); in some fragile older patients with multiple comorbidities, for which a less aggressive PD prescription is performed (“palliative PD”); or patients who need urgent initiation of PD to minimize abdominal complications.²

IPD incidence and prevalence is not well-known. Neri et al. published in 2017 the data related to the IPD in incident patients in all public Italian PD centers between 2005 and 2014. The authors found that the number of incident patients under IPD gradually increased over time (2005: 11.5% versus 2014: 27.5%) (4).

When and How to Start IPD?

One challenge of IPD prescription is the timing of dialysis onset. There are no studies comparing patients who start incremental dialysis with those who do not start dialysis. The Initiating Dialysis Early of Late study compared early initiation of dialysis (GFR between 10 and 14 ml/min per 1.73 m²) with late onset (GFR between 5 and 7 ml/min per 1.73 m²) and concluded that there was no superior clinical outcomes or survival with earlier onset of dialysis.⁶ However, this study did not assess patients who started incremental dialysis. So, the decision to initiate incremental dialysis should pursue clinical indications on the basis of symptoms and complications related to CKD.

IPD is a person-centered approach, and there are different strategies for prescribing it. Incremental CAPD prescription can be initiate with two or three 2-L dwells daily, four 1.5-L changes daily, or can be performed 4–6 days/wk.² There are also some authors who used satisfactorily a single daily icodextrin dwell (8–16 hours of duration) in patients with significant RFK.^7,8 Incremental APD can include APD prescription for three to five nights a week and/or without a long dwell.² It also can be prescribed through lower volumes (such as 1.5 L dwell volumes) or with lower duration (such as only 6 hours for each night).² As there are different approaches to prescribe IPD, we think that the selection of IPD prescription can be made as a result of a shared decision-making process between the patient and the PD team. The prescription decision should counterbalance among the dwell volume, the number of daily exchanges, and/or the number of dialysis-free days. It should take in count what is most appropriate for the patient according to their lifestyle, body size, peritoneal membrane type, and volume and solute clearance requirements.

Patients through an IPD approach should have a close clinical monitorization to avoid underdialysis due to an unpredicted loss of RKF. As it was previously mentioned, IPD strategy is currently an individualized approach for each person on PD.² In this regard, the adjustment of the PD prescription can be based on the measurement of the following parameters: (1) peritoneal and renal clearance to assess the trend of clearance goals (such as Kt/V of 1.7 weekly and/or a creatinine clearance of 50 L/wk); (2) clinical symptoms and signs such as uremic symptoms, reduced urine output, and/or symptoms related to hypervolemia; and (3) laboratory investigation including blood levels of creatinine, urea, phosphate and/or β-2-microglobulin.² The prescription of IPD should be reviewed at least quarterly or more frequently if the patient develops symptoms suggestive of uremia and/or related to the volume state.² If these parameters are altered, the prescribed dose should be adjusted by increasing the dwell volume, the number of daily exchanges, or the numbers of dialysis days per week.

Advantages of IPD

In the past two decades, some studies were published to assess IPD prescription, and currently, there is a resurgence interest in this modality because of the potential clinical, economic, and environmental advantages. The first publications included small populations and concluded that this prescription did not involve higher risk of complications or inadequate clearance^9,10 and it can be safely used among APD patients.¹¹

Presently, the clinical evidence regarding IPD, despite encompassing larger populations, is based on studies of low-to-moderate quality as it will be described later. These studies maintain the findings that IPD appears to be a safe strategy and with, possible, advantages in the following fields.

• Quality of life: Patients who are performing IPD may have better quality of life, lower loss of productivity, and/or lesser burden and anxiety because they had reduced procedures related to the technique.^2,3 In addition, lower intraperitoneal volumes lead to a smaller increase in intra-abdominal pressure and, consequently, less mechanical symptoms such as low back pain and/or heartburn.²
• Economical: IPD generally uses smaller volume of PD solutions, as well as fewer exchanges, which means lower costs and economic burden.^2,12
• Environmental: There is also potential environmental benefits because of fewer bags used and, consequently, lower plastic waste and lower water consumption. Nardeli et al. found that IPD prescription of 1, 2, or 3 exchanges per day leads to reduction in plastic waste of 139.2, 100.8, or 56.6 kg/patient-year and a reduction in water consume of 25.056, 18.144, or 10.196 L/patient-year, respectively.¹³
• Metabolic: Systemic glucose absorption from PD solutions can lead to adverse metabolic effects. The lower dose of IPD may be associated with a lower systemic absorption of carbohydrates.^2,12
• Infectious: IPD has a lower theoretical risk of peritonitis because of less manipulation of the PD catheter related to fewer exchanges.^2,5 There is only one randomized study that compares incremental CAPD with full-dose CAPD. The study was developed by Yan et al.; it was a prospective single-center study that included incident CAPD patients, who were randomized to prescribe three daily dwells (IPD) versus four daily dwells (full dose PD) with an intraperitoneal volume of 2 L. It included 139 patients of whom 70 started IPD. They were followed for 24 months. The amount of peritonitis per year was higher between full-dose PD patients; however, the difference was not statistically significant (26% versus 13%, P=0.06).¹⁴ Ankawi et al. published a single-center, observational study, carried out in Canada involving 124 prevalent PD patients, 54 of whom in IPD. They concluded that IPD is associated with peritonitis rates comparable with those established by the International Society of Peritoneal Dialysis.¹ Sandrini et al. compared two groups of patients regarding the development of peritonitis: (1) IPD protocol with 29 patients and (2) full-dose PD with 76 patients. The IPD protocol was associated with an incidence of peritonitis of 1/135 patients per month, while the full dose PD protocol was associated with an incidence of 1/52 patients per month. Despite the lower incidence in the IPD group, it was not statistically significant by analysis of Kaplan-Meier. It was a single-center retrospective study that included incident PD patients with at least 6 months of follow-up, initial RKF between 3 and 10 ml/min per 1.73 m², and renal indication for initiation of PD.¹⁵ The three studies showed a tendency toward a lower incidence of peritonitis in IPD patients; however, it was not significant.
• Peritoneal membrane preservation/technical survival: It is known that technique failure is associated to fibrosis, angiogenesis, and hyalinizing vasculopathy in the peritoneal membrane. Some factors have been associated with these changes because of peritonitis and long-term exposure to PD solutions containing high concentrations of glucose and glucose degradation products (because they promote peritoneal chronic inflammation).¹⁶ An extremely rare but serious complication that can be part of inflammatory continuum affecting the peritoneal membrane is encapsulating peritoneal sclerosis (EPS). It was associated with high mortality and morbidity, which led to a decrease in adoption of PD in some countries. Currently, some studies have suggested a decrease in the incidence of EPS, and the Dutch EPS registry found a six-fold decrease in the yearly incidence of EPS between 2009 and 2015.¹⁷

Strategies and interventions that may prevent functional and structural alterations in membrane peritoneal are essential to its preservation. In this regard, IPD uses a smaller volume of PD solutions, so there is a lower exposure of the peritoneal membrane to solutions with glucose and glucose degradation products.^2,12 In addition, IPD prescription can be based on a single icodextrine daily exchange,^7,8 and it has been linked to a lower risk of peritonitis (as discussed previously). Consequently, it has been hypothesized a potential benefit of IPD for technical survival. As can be seen in Table 1, studies that compare IPD with full-dose PD concluded that there is no superiority of one strategy over the other.^14,18,19

• RKF preservation: RKF loss has been identified as a cardiovascular risk factor, with higher global and cardiovascular mortality.² RKF may be associated with best survival outcomes because of different mechanisms, as superior water and salt remove, more efficient phosphorus excretion, higher clearance of medium-sized molecules, and/or superior endogenous production of vitamin D and erythropoietin.²⁰

Table 1 - Summary of studies on incremental peritoneal dialysis

Author, Year	Interval of Time	Type of Study	Total/IPD Patients	IPD Prescription	GFR Baseline	Outcomes
Yan et al., 2015 14	2004–2010	Randomized and controlled Unicentric	139/70	3 dwells/d	5.7 ml/min	After 24 mo: GFR (1.6±2 versus 1.7±1.9 ml/min; P = 0.8) Urinary output (505±522 versus 474±422 ml/d; P = 0.8) Time to anuria (log-rank test statistic=0.055; P = 0.8) Survival (log-rank test statistic=0.987; P = 0.3) Technique survival (log-rank test statistic=0.347; P = 0.6)
Garofalo et al., 2018 24	Until June 30, 2018	Systematic review with meta-analysis	75,292/115	CAPD<3 dwells/d APD<5 times/wk Incremental HD<3 times/wk	7.14 ml/min	Mortality risk of 1.14 [95% CI, 0.85 to 1.52] Average RKF loss (−0.58 ml/min per mo, 95% CI, 0.16 to 1.01; P = 0.007) Average time to full dose of 12.1 mo (95% CI, 9.8 to 14.3)
Ankawi et al., 2016 1	June–July 2013	Retrospective Unicentric	124/58	Peritoneal Kt/V<1.7/wk and total Kt/V>1.7/wk and any one of the following: (1) CAPD<8L PD solution daily; (2) CAPD<7 days a week; (3) APD without any day dwell; (4) APD<7 days a week	6.2 ml/min	Average time to full dose of 15 mo Survival comparable with other PD centers in Canada
Sandrini et al., 2016 15	2002–2007	Retrospective Unicentric	105/29	<3 dwells/d	5.74 ml/min	Average time to full dose of 17 mo (10–27) Lower incidence of hospitalizations (1/23 patients per month versus 1/9 patients per month) No statistical difference in terms of mortality Higher urine output was associated with improved survival (HR, 0.387; 95% CI, 0.181 to 0.826; P = 0.014)
Lee et al., 2019 18	2007–2015	Retrospective Unicentric	347/176	<3 dwells/d	6.9 ml/min	Average time to full dose of 2.6 yr (1.6–4.5 yr) Lower risk of anuria (HR, 0.61, 95% CI, 0.43 to 0.88) Survival (10.9 events per 1000 person-years versus 7.6 events per 1000 person-years; P = 0.449) Technique survival (2.7 versus 2.9 yr; P = 0.332)
Lee et al., 2021 19	January 2007–December 2018	Retrospective Unicentric	117/39	2 or 3 dwells/d	8.3 ml/min	Survival (log-rank test, P = 0.067) Survival among the patients with DM (log-rank test, P = 0.009) Technical survival (log-rank test, P = 0.409) Average duration of IPD of 24.1 mo (15.4–36.8)
Huang et al., 2022 29	January 2015–December 2019	Retrospective Unicentric	96/54	CAPD<8 L/d of exchange volume APD—without a last fill	10 ml/min	Survival (log-rank test, P = 0.325) Peritonitis rate (episode/patient-years) (0.12 versus 0.23, P = 0.112) Hospitalizations (episode/patient-years) (0.16 versus 0.23, P = 0.232)
Borràs Sans et al., 2015 30	2003–2012	Retrospective Unicentric	46	<4 dwells/d	8 ml/min	Average time to full dose of 24 mo Lower loss of RKF compared with predialysis period (−7.06 versus −1.58 mL/min per yr; P = 0.0001)

IPD, incremental peritoneal dialysis; APD, automated peritoneal dialysis; CI, confidence interval; RKF, residual kidney function; HR, hazard ratio.

IPD has been identified as a factor for the preservation of RKF. According to the intact nephron hypothesis by Bricker et al., there are mechanisms of glomerular hyperfiltration and increased tubular secretion when the functioning nephrons decrease.^21,22 The prescription of a higher dialysis dose may remove the stimulus for the hyperfunction of residual nephrons.²⁰ In this regard, incremental dialysis may be associated with a more gradual reduction in RKF because it removes water and salt without a significant hemodynamic fluctuation which may prevent the ischemia of the remaining nephrons.^3,20

Several studies have been developed to assess the role of IPD in the preservation of RKF. The abovementioned study carried out by Yan et al. concluded that both prescriptions (IPD versus full-dose PD) seem to have a similar effect in terms of the preservation of RKF (1.6±2 versus 1.7±1.9 ml/min, P=0.8), urinary output (505±522 versus 474±442 ml/d, P=0.8), and time of evolution to anuria (log-rank test statistic 0.055, P=0.8).¹⁴ These results can be seen in Table 1.

There are other observational studies that compare the outcomes of IPD with the strategy in full dose regarding the preservation of RKF; however, these are small studies and without randomization. Domenici et al. analyzed the role of IPD as a bridge to renal transplantation. They compared IPD with hemodialysis (HD). The authors found a superior preservation of RKF in IPD group during the dialysis period (loss rate of RKF: −0.27±0.4 versus −0.77±0.5, P<0.0001). At the time of kidney transplantation, six of the 17 patients on IPD and 19 of the 24 patients on HD were anuric (P=0.0086, relative risk=0.44, 95% confidence interval, 0.22 to 0.87, P=0.019). The authors include CKD stage 5 patients with at least 1 year of predialysis follow-up, who started IPD or HD and, subsequently, were kidney transplanted. This study has some limitations because of the small sample size (17 patients in IPD prescription and 24 patients in HD prescription).²³

Garofalo et al. analyzed published studies up to June 2018 that included IPD or incremental HD patients through a systematic review and meta-analysis. A total of 75.292 patients were analyzed (22 studies, of which seven was IPD prescription). It was found that patients under incremental dialysis (PD and HD) showed a mean reduction of RKF lower than patients under full-dose dialysis (−0.58 ml/min per mo, 95% confidence interval, 0.16 to 1.01, P=0.007). It should be noted that despite the general sample size, there was only 115 patients under IPD prescription.²⁴

In conclusion, for RKF preservation, the only randomized study demonstrated similar effects between IPD and full-dose PD. The remaining studies showed a slight advantage of IPD.

Barriers to IPD

First, the patient and/or helper may be reluctant to increase PD prescription because of higher number of associated procedures.³ It is also necessary for a close clinical surveillance of the RKF to detect insidious or unpredictable losses, and, therefore, it may involve a greater workload for the nephrologist and the nursing team.²⁵ An undetected loss of RKF may lead to an inadequate clearance of uremic toxins, a state of hypervolemia and/or potentially serious electrolyte changes.^3,25 In this sense, it is important a shared decision-making, with a patient who is informed about the principle of the technique from the beginning, including potential advantages and disadvantages. This may lead to the patient being more resilient in dose adjustments and better adherence to diet restrictions.

The loss of RKF can also affect the nutritional status, and in this setting, Caravaca et al. found that the loss of RKF was associated with a lower dietary and protein intake among IPD patients, and the protein intake reduction was significantly correlated with the higher energy delivered by peritoneal dextrose solutions.²⁶

Another concern corresponds to the clearance of medium-sized molecules, and IPD prescription should regard this aspect. The peritoneal clearance of middle molecules (such β-2-microglobulin) is mainly dependent of the total PD dwell time, in opposition to clearance of small molecules (as creatinine), which depends on the number of exchanges. Comparing the prescription of two exchanges over 12 hours/d with the same two exchanges over 24 hours, the last prescription has almost doubled peritoneal clearance of β-2-microglobulin.²⁷

Finally, shortage of PD solutions had been a concern of Food and Drug Administration in the United States, and in 2014, it was the most critical shortage. At this time, there were a higher number of patients requiring PD, and the companies were not able to increase the PD solutions production (its production takes several weeks because of the complex process of sterility). This situation may limit new patients requiring dialysis from opting for PD, as well as may lead PD patients to switch to HD. Food and Drug Administration adopted strategies to prevent and mitigate PD fluid shortages, such as temporary importation.²⁸ The scarcity of PD solutions may be a limitation for patients to start this modality; however, IPD may be a more viable option because of the lower dose and, consequently, smaller volume of PD solution used.

Other Outcomes of IPD

There are others concerns regarding IPD modality because of its prescription in the different types of peritoneal transport. In this regard, Guest et al. evaluated different incremental CAPD prescriptions (between 1 and 3 dwells/d with intraperitoneal volume of 2 L/dwell), using the modified three-pore model of peritoneal transport and two types of solutions, icodextrin and glucose. The authors concluded that the prescription of 2 dwells/d, in patients with GFR of at least 6 mL/min per 1.73 m², is sufficient to achieve clearance goals in the four types of peritoneal transport.¹²

A major concern is related to clinical outcomes. For mortality, the studies presented in Table 1, demonstrated similar mortality (Yan et al., Ankawi et al. and Lee et al.) or the absence of a significant increased risk (Garofalo et al.) between the two modalities of PD.^{1,14,18,19,24,29} Lee et al. achieved a survival benefit among the subpopulation of IPD diabetic patients comparing with full dose (log-rank test, P=0.009).¹⁹ Sandrini et al. demonstrated that urine output positively affects patient survival, and that the rate of hospitalizations is significantly lower in IPD patients compared with full-dose PD patients.¹⁵

Some authors evaluated the time until reaching the standard dose of PD, which varied from 1 year to a maximum of 2.6 years.^1,18,24,30

In conclusion, although IPD was first described about two decades ago, the current scientific evidence is based on studies of low-to-moderate quality, and large randomized studies are still scarce. The previously presented studies suggest that IPD will be as safe as PD full dose and that this modality can be maintained for at least 1 year. In addition, some of the studies suggested a superiority of IPD in preserving RKF. There are others potential benefits as a better quality of life and lower economic and environmental burden. The nephrologist should be aware of the need for close supervision to avoid potential complications related to inertia in dose adjustment.

There are some important questions that should be addressed in the future because the best way of dialysis dose adjustment is regarding the choice between volume, dwell time, or number of daily exchanges and the clinical impact of IPD between kidney transplant candidates.

It is difficult to create an ideal profile of IPD prescription or candidate. A personalized approach (patient-centered) would be a suitable option in patients who maintain significant RKF (GFR>5 ml/min).