The Future of Peritoneal Dialysis

Abstract

New and emerging technologies are being developed to combat some of the most pressing issues regarding peritoneal dialysis training, delivery, and complication identification. Currently used peritoneal dialysis solutions are high-dextrose concentrated acidic solutions that can cause increased glucose absorption and peritoneal membrane degradation via a combination of pseudohypoxia and inflammation. Supply storage, the portability of the currently available devices, and the reactive approach to peritonitis identification and treatment are amongst the challenges facing peritoneal dialysis providers and patients. Technologic advancement to combat these issues are underway, and it is important that we study them comprehensively prior to widespread implementation. In this work, I discuss some of these advancements and technologies.

1. Introduction

While peritoneal dialysis delivery varies across regions depending on capabilities, supplies, public policy, and automated versus continuous, there are overarching issues with its delivery that unify these differences.

The peritoneal dialysis (PD) solutions currently in use for patients’ daily exchanges are high-dextrose concentrated acidic solutions with resultant glucose absorption and peritoneal membrane degradation via a combination of pseudohypoxia and inflammation. Despite these concentrated solutions, approximately 50% of PD patients and their providers worldwide encounter the issue of inadequate ultrafiltration after 6 years of PD treatment [1], sometimes necessitating a modality change to hemodialysis.

While on treatment, the overall peritonitis rate targets are relatively low at 0.4 episodes per patient-year [2]. However, our approach to identifying and diagnosing peritonitis is reactive. Patients reporting abdominal pain, cloudy effluent, nausea, vomiting, and fever, amongst other symptoms, trigger a clinical investigation whereby the timely treatment of the suspected peritonitis is encouraged to reduce the risk of PD failure and/or death [3].

Finally, while peritoneal dialysis providers pride themselves on the portability of PD cyclers, the ability to have PD solutions delivered around the world, and the flexibility of converting to continuous ambulatory PD on their travels, it is still an arduous process to travel while bringing along all the supplies needed.

In this piece, I will explore the most recent advancements in PD delivery, highlight how they help combat some of the aforementioned solutions, and provide a summary of how these technologies can help shape the future of peritoneal dialysis.

2. Peritoneal Dialysis Solution Generation System

Whether undertaking continuous or automated PD, space is needed for the storage of PD solutions and treatment consumables. I mentioned earlier the large amount of waste generated through the delivery of peritoneal dialysis. Moreover, due to space restrictions in some households, some patients may opt not to pursue PD or other home modalities and instead elect to go a dialysis center to receive their treatments.

A potential solution to these issues is the automated PD (APD) solution generation system (SGS), developed by Baxter International Inc (Deerfield, IL, USA). This, for the first time, brings forth the concept of home generation of solutions bypassing the PD solution storage issues and potentially reducing the carbon footprint associated with glucose-based PD fluid—estimated at around 656 kg CO₂ [4]—and the delivery of these heavy solutions to patients’ homes, similarly to what the NxStage PureFlow system achieves for home hemodialysis patients. The system is compromised of (1) Amia APD cycler, (2) dextrose and electrolyte concentrates, (3) a disposable set (consisting of a cassette, water line, holding bag, two sterilizing grade filters, heater bag, patient line, last fill solution line, electrolyte, and concentrate lines and a drain line), (4) bag tray, (5) water softener, and (6) water treatment device [4].

In a multicenter study of 14 prevalent PD patients in the United States, all the APD SGS samples that underwent microbiological and chemical testing met the International Organization for Standardization (ISO) standards [5]. Analysis of the chemical composition of the solutions generated matched those of Baxter’s prepackaged Dianeal low-calcium PD solutions (1.5%, 2.5%, and 4.25% dextrose). This provided clear evidence that we had arrived at a stage where not only do we have the capability to generate PD solutions in the comfort of patients’ homes, but that they were safe and equivalent to those that would have needed to be delivered and stored. One thing to note, however, is that the study sample size is small and further studies are needed to validate the study findings.

3. Portable Peritoneal Dialysis Devices

One of the drawbacks of dialysis care is that no matter how small and “portable” conventional devices are, they are still burdensome to carry and transport and require the delivery of prepackaged PD solutions. An automated wearable artificial dialysis system would solve this issue. Enter the AWAK device, a portable and lightweight PD system which generates fresh dialysate at a rate of 2 L/h [6]. It delivers PD in a tidal fashion with sessions lasting up to 7 h, all while being monitored and controlled through a mobile application installed on patients’ cellular phones.

The system works through the instillation of up to 2 L of peritoneal dialysate into the peritoneum followed by connecting the AWAK device. Initial priming occurs with 125 mL of the instilled fluid, followed by the incremental recycling of 250 mL increments of the dialysate. The dialysate increments are pumped into the adsorber system where the sorbent comprises urease, zirconium phosphate, hydrous zirconium oxide, and activated carbon. It then courses through the bacteria filter and into the infusion reservoir where it is exposed to a calcium, magnesium, and glucose bath before being pumped back into the peritoneal cavity. The resultant recycled dialysate composition is as follows: pH 6.8, Ca 1.19 mmol/L, Mg 0.24 mmol/L, and Glucose 1.21% [6]. To test this out, 14 participants underwent three 7 h exchanges per day for a three-day period and compared uremic toxin clearance and serum electrolyte levels pre- and post-AWAK use [6]. Uremic toxin removal was superior in the post-AWAK samples. Although serum chloride, bicarbonate, and magnesium levels were statistically significantly lower in the post-AWAK samples, this was not clinically significant (for example: serum bicarbonate 25.2 vs. 24.1). The AWAK portable PD device represents a merger of two concepts in PD delivery: continuous flow PD and tidal PD.

The system’s use, however, was not without complications. Among these complications, nine participants reported abdominal pain or discomfort, seven reported abdominal distension or bloating, and four were found to have increases in their blood pressure readings [6]. The abdominal pain and distension were attributed to the likely incomplete mixing of concentrated hypertonic infusate, the acidic pH of the regenerated dialysate, and the production of carbon dioxide in the sorbent system. The elevation in blood pressures seen in patients was attributed to a likely combination of the aforementioned abdominal pain and discomfort as well as a relative reduction in ultrafiltration, given that the glucose concentration of the regenerated dialysate was lower than the lowest commercially available dextrose solutions (1.21% vs. 1.5%). While the AWAK system represents a significant step forward in the delivery of portable PD, much work remains to be carried out to determine if these adverse events were related to inherent technological issues and can be mitigated through design enhancement. This remains a step into the potential future of portable peritoneal dialysis.

4. Virtual Reality Peritoneal Dialysis Training

Peritoneal dialysis training is an essential part of a successful transition to home dialysis care. This foundational step of PD care takes an average of 6 to 15 days, with patients coming to the home dialysis unit for 4–6 h per training session. These sessions involve hands-on training with the PD nurse, reading materials, educational videos, and practicing on mannequins. PD training normally starts with training patients on continuous ambulatory PD (CAPD), and for those going home on a cycler, this is then followed by automated PD (APD) cycler training. While these all sound like reasonable expectations for the implementation of PD education, this involves patients taking time off from work and arranging transportation to the home dialysis unit, and they are unable to take these hands-on training experiences home with them. Scheduling training days is not only subject to patients’ availability but also nursing staff availability and bandwidth.

A potential solution to this is virtual reality PD training. The stay.safe MyTraining VR [7] training provides patients with the opportunity to learn the CAPD portion of their training in a 3D environment with visual and auditory prompts anywhere. The training sessions have interactive steps whereby patients have to execute a step in order to be able to move on to the next step in the training process. Moreover, the virtual reality training is available in different languages, making it accessible to patients of different backgrounds around the world. While it is not intended to replace hands-on training, it gives patients a chance to practice and learn in a virtual environment in the comfort of their own homes, while potentially shortening PD training periods. The effect of the implementation of virtual reality PD training on training time and patient outcomes, however, remains to be seen and future studies are needed to determine this.

5. Alternatives to Current Dextrose Solutions

5.1. Steady Glucose Concentration PD

A commonly cited issue in the current dextrose-based solutions is the exposure to hypertonic, acidic solutions that not only cause peritoneal membrane degradation via a combination of pseudohypoxia and inflammation [8], but also through glucose absorption, with resultant hyperglycemia. Another issue facing patients on PD is inadequate ultrafiltration, with resultant treatment termination.

In an effort to combat these issues, Heimbürger et al. [9] set out to determine the clinical applicability of a device that delivers a steady glucose concentration PD solution that is lower than the marketed dextrose solution concentrations. The Carry Life UF device connects to the PD catheter extension set during a patient’s routine treatment. A small amount of the intraperitoneal fluid is transferred to the device and mixed with 50% glucose solution (Fresenius Kabi 500 mg/mL). They set out to compare glucose absorption and ultrafiltration achieved between a 4 h dwell of 2 L of 2.5% dextrose, and 5 h dwells using 1.5 L of 1.5% dextrose with the Carry Life UF device connected mixing 11, 14, and 20 g of glucose/hour [9].

Compared to the 2.5% dextrose dwell, the 14 g/h and 20 g/h Carry Life UF dwells resulted in statistically significantly greater glucose absorption and ultrafiltration achieved. However, when considering glucose ultrafiltration efficiency (ultrafiltration achieved per gram of glucose absorbed), the 11 g/h was the most efficient. This meant that the Carry Life UF 11 g/h setting provided glucose absorption equivalent to a 2.5% dextrose dwell, but was more efficient compared to all the other groups in terms of the ultrafiltration achieved. This provides an alternative path whereby patients can be exposed to lower glucose concentrations, while achieving superior ultrafiltration volumes.

5.2. Zero-Sodium PD Solutions

Another potential solution to ultrafiltration issue, particularly in patients with volume overload, is a reduction in the sodium load in the dialysate through the delivery of zero-sodium PD solutions. In order to be able to achieve similar ultrafiltration to the traditional dextrose-based solutions, a sodium-free PD equivalent can achieve this through higher dextrose concentrations. In this case, Rao et al. [10] used a 10% dextrose solution to create a sodium-free equivalent to the 4.25% dextrose solution.

While the glucose absorption was expectedly higher in the zero-sodium PD solution, the relative glucose absorption percentage was similar when compared to a 4.25% dextrose solution. Serum sodium levels, systolic blood pressure, and heart rate were all not statistically different between the two groups at the end of a 2 h dwell [10]. All 10 patients who trialed both solutions achieved statistically significantly higher ultrafiltration volumes using the zero-sodium PD solution [9]. This provides a potential future avenue to adequately treat patients with acute, symptomatic volume overload with peritoneal dialysis.

5.3. Non-Dextrose Based PD Solutions

Contrary to the zero-sodium PD solution approach, which necessitated increasing the dextrose content to maintain equivalent osmolarity to the traditional PD solutions, the use of a combination of xylitol and L-carnitine offers an alternative option.

Xylitol is an efficiently metabolized sugar alcohol that does not cause hyperglycemia and triggers less insulin secretion than glucose [11]. L-carnitine is an essential compound for fatty acid oxidation, an effective osmotic agent and has been shown to reduce apoptosis of endothelial cells when compared to glucose [12]. This innovative combination PD solution (Xylocore^® - Iperboreal Pharma, Pescara, Italy) is currently being tested as part of the ELIXIR trial [10], a phase III, open-label randomized controlled trial with the primary objective of demonstrating the non-inferiority of Xylocore^® when compared to glucose-based PD solutions in terms of PD Kt/Vurea.

If successful, this would be the first step towards a future where patients have an alternative to the commercially available glucose-based PD solutions, lowering hyperglycemic episodes, reducing PD membrane glucose exposure, and therefore potentially increasing the longevity of the membrane’s functionality.

Both the steady glucose concentration and non-dextrose-based PD solutions offer a future with lower usage of dextrose-based solutions. The deleterious effects of high glucose exposure to the peritoneal membrane have been examined. Some of these effects include the upregulation of adaptive immunity and fibrogenesis genes, perivascular infiltrates, as well as pseudohypoxia physiology with resultant peritoneal fibrosis and its contribution to the developments of encapsulating peritoneal fibrosis [8]. This is aside from reducing the occurrence of other long-term metabolic complications of peritoneal dialysis exposure, such as the development of abnormalities across the glucose control spectrum: new-onset diabetes (8%), impaired glucose tolerance (15%), and impaired fasting glucose levels (32%) [13].

6. Identifying Peritonitis Prior to Symptom Onset

The current standard of care in identifying peritonitis is set by the International Society for Peritoneal Dialysis (ISPD) as the presence of at least two of the following [2]:

(1)

Abdominal pain and/or cloudy effluent;

(2)

Effluent white blood cell count >100/mm³, with at least 50% polymorphonuclear leukocytes;

(3)

Positive PD effluent culture.

It has been previously shown that the timely identification and treatment of peritonitis is integral to PD patient, catheter, and modality survival [3,14]. Not every patient with peritonitis develops abdominal pain, and thresholds of pain differ from one patient to another. The identification of cloudy effluent is also subjective and is something that patients may not be alert to. Given that PD treatments are conducted at home, the identification of diagnostic criteria 2 and 3, listed above, is not possible for a patient to do without the identification of the first criterion.

A switch from a reactive, delayed approach to peritonitis identification to a more proactive and early approach is crucial. Enter CloudCath, a system that collects samples of PD effluent over the course of a patient’s treatment and measures the turbidity of the effluent. An increase in turbidity during a predetermined number of cycles triggers a notification. To demonstrate its effectiveness, an open-label multicenter study was undertaken where 243 PD patients used the CloudCath system over a period of 12–18 months [15]. Notifications were turned off to ensure that the system did not affect clinical outcomes. During the study period, a total of 71 potential peritonitis events were reported by patients and clinicians, of which 51 met the ISPD criteria for peritonitis. Of these 51 events (45 met the ISPD white blood cell count criteria for peritonitis), 41 (80.4%) had also been detected by Cloudcath. The Cloudcath system identified these episodes a median of 2.6 days prior to notification events through the traditional peritonitis reporting methods [15].

Once the system identifies a potential peritonitis case, the clinical team is notified. This provides patients and providers an opportunity to identify peritonitis sooner and initiate the work-up and peritonitis prophylaxis. This has the potential to allow patients to avoid invasive procedures such as PD catheter removal/replacement, spend more time on their dialysis modality of choice, and live longer.

7. Conclusions

The future of peritoneal dialysis is bright. New and emerging technologies are being developed to combat some of the most pressing issues regarding PD training, delivery, and complication identification. A future where large deliveries of PD solution bags and storage, relatively immobile PD cyclers, non-biocompatible high dextrose solutions, and delayed peritonitis identification are no longer the norm is one that we can all aspire to and hope for (

Table 1. Summary of some of the current issues facing peritoneal dialysis patients and providers along with potential future solutions currently being studied.

Issue	Potential Solution
Large amount of consumables, boxes, and space needed for peritoneal dialysis solutions	Peritoneal Dialysis Solution Generation System
Lack of portability of automated peritoneal dialysis cyclers	Wearable artificial peritoneal dialysis system
Longer training times and labor-intensive sessions	Virtual reality peritoneal dialysis training
Non-biocompatible high dextrose concentration peritoneal dialysis solutions and ultrafiltration failure	(1) Steady glucose concentration peritoneal dialysis (2) Zero-sodium peritoneal dialysis solutions (3) Non-dextrose based peritoneal dialysis solutions
Reactive assessment and treatment of peritonitis	Online assessment and notification of effluent turbidity

). Pushing forward technologies in the privileged, developed parts of the world while assisting and identifying gaps in PD delivery worldwide is key to the betterment of dialysis care for everyone.

While innovation is important, the widescale adoption of these solutions is dependent on a number of both clinical and non-clinical factors. Large-scale efficacy and safety studies are needed, while adoption into societal guidelines and prescription instructions, manufacturing, and overall costs to the healthcare system and payors are amongst the barriers to widespread implementation.