Biocompatible dialysis fluids for peritoneal dialysis

Htay Htay; David W Johnson; Kathryn J Wiggins; Sunil V Badve; Jonathan C Craig; Giovanni FM Strippoli; Yeoungjee Cho

doi:10.1002/14651858.CD007554.pub3

. 2018 Oct 26;2018(10):CD007554. doi: 10.1002/14651858.CD007554.pub3

Biocompatible dialysis fluids for peritoneal dialysis

Htay Htay ¹, David W Johnson ^2,³, Kathryn J Wiggins ⁴, Sunil V Badve ⁵, Jonathan C Craig ^6,⁷, Giovanni FM Strippoli ^6,^8,^9,¹⁰, Yeoungjee Cho ^2,^3,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6517187 PMID: 30362116

Abstract

Background

Biocompatible peritoneal dialysis (PD) solutions, including neutral pH, low glucose degradation product (GDP) solutions and icodextrin, have previously been shown to favourably influence some patient‐level outcomes, albeit based on generally sub‐optimal quality studies. Several additional randomised controlled trials (RCT) evaluating biocompatible solutions in PD patients have been published recently. This is an update of a review first published in 2014.

Objectives

This review aimed to look at the benefits and harms of biocompatible PD solutions in comparison to standard PD solutions in patients receiving PD.

Search methods

The Cochrane Kidney and Transplant Specialised Register was searched up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal and ClinicalTrials.gov.

Selection criteria

All RCTs and quasi‐RCTs in adults and children comparing the effects of biocompatible PD solutions (neutral pH, lactate‐buffered, low GDP; neutral pH, bicarbonate(± lactate)‐buffered, low GDP; glucose polymer (icodextrin)) in PD were included. Studies of amino acid‐based solutions were excluded.

Data collection and analysis

Two authors extracted data on study quality and outcomes. Summary effect estimates were obtained using a random‐effects model, and results were expressed as risk ratios and 95% confidence intervals (CI) for categorical variables, and mean differences (MD) or standardised mean differences (SMD) and 95% CI for continuous variables.

Main results

This review update included 42 eligible studies (3262 participants), including six new studies (543 participants). Overall, 29 studies (1971 participants) compared neutral pH, low GDP PD solution with conventional PD solution, and 13 studies (1291 participants) compared icodextrin with conventional PD solution. Risk of bias was assessed as high for sequence generation in three studies, allocation concealment in three studies, attrition bias in 21 studies, and selective outcome reporting bias in 16 studies.

Neutral pH, low GDP versus conventional glucose PD solution

Use of neutral pH, low GDP PD solutions improved residual renal function (RRF) preservation (15 studies, 835 participants: SMD 0.19, 95% CI 0.05 to 0.33; high certainty evidence). This approximated to a mean difference in glomerular filtration rate of 0.54 mL/min/1.73 m² (95% CI 0.14 to 0.93). Better preservation of RRF was evident at all follow‐up durations with progressively greater preservation observed with increasing follow up duration. Neutral pH, low GDP PD solution use also improved residual urine volume preservation (11 studies, 791 participants: MD 114.37 mL/day, 95% CI 47.09 to 181.65; high certainty evidence). In low certainty evidence, neutral pH, low GDP solutions may make little or no difference to 4‐hour peritoneal ultrafiltration (9 studies, 414 participants: SMD ‐0.42, 95% CI ‐0.74 to ‐0.10) which approximated to a mean difference in peritoneal ultrafiltration of 69.72 mL (16.60 to 122.00 mL) lower, and may increase dialysate:plasma creatinine ratio (10 studies, 746 participants: MD 0.01, 95% CI 0.00 to 0.03), technique failure or death compared with conventional PD solutions. It is uncertain whether neutral pH, low GDP PD solution use led to any differences in peritonitis occurrence, hospitalisation, adverse events (6 studies, 519 participants) or inflow pain (1 study, 58 participants: RR 0.51, 95% CI 0.24 to 1.08).

Glucose polymer (icodextrin) versus conventional glucose PD solution

In moderate certainty evidence, icodextrin probably reduced episodes of uncontrolled fluid overload (2 studies, 100 participants: RR 0.30, 95% CI 0.15 to 0.59) and augmented peritoneal ultrafiltration (4 studies, 102 participants: MD 448.54 mL/d, 95% CI 289.28 to 607.80) without compromising RRF (4 studies, 114 participants: SMD 0.12, 95% CI ‐0.26 to 0.49; low certainty evidence) which approximated to a mean creatinine clearance of 0.30 mL/min/1.73m² higher (0.65 lower to 1.23 higher) or urine output (3 studies, 69 participants: MD ‐88.88 mL/d, 95% CI ‐356.88 to 179.12; low certainty evidence). It is uncertain whether icodextrin use led to any differences in adverse events (5 studies, 816 participants) technique failure or death.

Authors' conclusions

This updated review strengthens evidence that neutral pH, low GDP PD solution improves RRF and urine volume preservation with high certainty. These effects may be related to increased peritoneal solute transport and reduced peritoneal ultrafiltration, although the evidence for these outcomes is of low certainty due to significant heterogeneity and suboptimal methodological quality. Icodextrin prescription increased peritoneal ultrafiltration and mitigated uncontrolled fluid overload with moderate certainty. The effects of either neutral pH, low GDP solution or icodextrin on peritonitis, technique survival and patient survival remain uncertain and require further high quality, adequately powered RCTs.

Plain language summary

Biocompatible dialysis fluids for peritoneal dialysis

What is the issue?

Peritoneal dialysis is a form of dialysis therapy for people with kidney failure delivered at home. Patients are required to use peritoneal dialysis solutions to perform the dialysis by putting solution in their abdomen. Peritoneal dialysis uses the lining of the abdomen called the “peritoneal membrane” as a filter, across which toxins and fluids are removed from the body. The longevity of peritoneal dialysis can be limited by peritoneal membrane injury, which is partly as a result of biologically 'unfriendly' peritoneal dialysis solutions, which are acidic and consist of high levels of glucose and toxic glucose breakdown products. To overcome these hurdles, biocompatible peritoneal dialysis solutions (i.e. with a neutral pH and low levels of glucose breakdown products or with a glucose‐alternative like icodextrin) have been manufactured with the aim of providing patient benefit.

What did we do?

We conducted a review of the literature to examine the benefits and harms from the use of biocompatible peritoneal dialysis solutions.

What did we find?

We identified 42 studies (3262 participants) examining the effects of these solutions on patient outcomes. When compared to conventional peritoneal dialysis solutions, we found that neutral pH, low glucose breakdown product peritoneal dialysis solutions resulted in better preservation of a patient's own kidney function including urine output. Patients who received non‐glucose based (icodextrin) peritoneal dialysis solutions achieved greater fluid removal with their dialysis and were 70% less likely to experience uncontrolled episodes of fluid overload. No significant harms were identified with any of the biocompatible peritoneal dialysis solutions. Many of the studies were limited by small size, short follow‐up duration, suboptimal methodological quality, and inconsistent reporting of outcomes. Consequently, the effects of biocompatible peritoneal dialysis solutions on the length of time that a patient is able to either remain on peritoneal dialysis or stay alive are uncertain.

Conclusions  Compared with peritoneal dialysis patients treated with conventional peritoneal dialysis solutions, those treated with biocompatible solutions experience important benefits including better preservation of their own kidney function and urine volume with neutral pH, low glucose breakdown product peritoneal dialysis solutions and more effective prevention of fluid overload due to increased dialysis‐related fluid removal with icodextrin. Whether these benefits help patients to stay on peritoneal dialysis longer or live longer are uncertain and require further study.

Summary of findings

Background

Description of the condition

Peritoneal dialysis (PD) is a widely utilised and highly cost‐effective method of renal replacement therapy that is practised by approximately 11% of the world’s population (Li 2017). Its annual global growth rate of 8% per annum exceeds that of haemodialysis (HD) (6% to 7% per annum) (Li 2017) and public policy changes in some parts of the world (e.g. Thailand and USA) have triggered unprecedented expansion of the therapy (Mehrotra 2016). Compared with HD, PD offers a number of advantages including better preservation of residual renal function (RRF), improved quality of life, greater treatment satisfaction, improved ability to provide incremental dialysis, deferred need for vascular access creation, reduced bacteraemia risk, reduced hepatitis transmission, less restricted diet and lifestyle, greater ability to travel, and possibly superior survival in the first few years after dialysis (Nadeau‐Fredette 2015). Additional advantages in lower income countries include reduced requirements for technical support and electricity, treatment simplicity, lesser need for trained clinical staff and lower propensity to be adversely affected by natural disasters (Li 2017). Improvements in PD patient survival have outstripped those of HD patients and progressive technical innovations have allowed patients to remain on PD for longer periods of time (Li 2017). However, the majority of PD patients ultimately transfer to HD after a few years, primarily because of infection, membrane failure, mechanical complications or patient burnout (Lan 2016).

A significant factor underpinning PD technique failure is the development of structural and functional changes of the peritoneal membrane with increasing PD duration (Williams 2003). These changes include thickening of the submesothelial compact collagenous zone and subendothelial hyalinisation of post‐capillary venules, with obliteration or narrowing of the vascular lumen (Williams 2003). The risk of encapsulating peritoneal sclerosis also increases with longer duration of PD (Brown 2009; Brown 2017; Johnson 2010; Rigby 1998). Progressive damage to the peritoneal membrane contributes to inadequate solute clearance, ultrafiltration (UF) failure, and change in peritoneal membrane transport properties, thereby affecting the ability of the membrane to function adequately. Loss of RRF also contributes to both UF failure and reduced solute clearance and is a predictor of increased death (Bargman 2001).

Both peritoneal membrane changes and loss of RRF in PD patients may be at least partly related to the use of PD solutions. Conventional PD solutions have an acidic pH and rely on hyperosmolar dextrose solutions to achieve an adequate gradient for UF across the peritoneal membrane (Szeto 2017). Their low pH and hyperosomolarity have been implicated in acute toxicity, such as inflow pain (Cho 2012; Nataatmadja 2017; Szeto 2017). Furthermore, heat sterilisation of PD solutions results in generation of glucose degradation products (GDP) (Nilsson‐Thorell 1993; Wieslander 1996),which in turn leads to formation of advanced glycation end products (AGE) (Lamb 1995; Nakayama 1997) and possibly to chronic peritoneal membrane toxicity, such as increased peritoneal solute transport rate, membrane fibrosis and neovascularisation, membrane failure and encapsulating peritoneal sclerosis (Mateijsen 1999; Pollock 2005; Szeto 2017).Damage to the peritoneal membrane may also impair host defences and predispose patients to peritonitis (Jorres 1992; Topley 1997). Finally, systemic absorption of GDPs may lead to direct nephrotoxicity and loss of RRF (Justo 2005).

Description of the intervention

Newer, biocompatible, dialysis solutions have been designed to minimise perturbation of the physiological milieu in the peritoneal cavity. The main approaches to creation of biocompatible solutions have been generation of solutions with a neutral pH and low GDP content, use of bicarbonate (± lactate) buffer, substitution of dextrose with glucose polymers (resulting in low GDP content albeit with an acidic pH), and use of amino acids as the osmotic agent.

How the intervention might work

Results of in vitro studies and small studies using surrogate end points suggest that biocompatible PD fluids may cause less damage to the peritoneal membrane than conventional fluids, and hence may improve patient outcomes (Mortier 2004; Mortier 2005). Improvement in peritoneal morphology with use of biocompatible PD solution has also been reported (Ayuzawa 2012). Furthermore, use of glucose polymer PD solution has been shown to augment peritoneal UF (Johnson 2003). Reduced exposure to GDP in biocompatible PD solutions may also lead to reduced systemic GDP absorption and ensuing nephrotoxicity (Justo 2005).

Why it is important to do this review

In comparison to conventional PD solutions, biocompatible solutions are more costly in some countries and the effect of these solutions on 'hard' (patient‐level clinical outcomes) endpoints are unclear. Furthermore, their role in clinical practice has not been established

Objectives

This review aimed to look at the benefits and harms of biocompatible PD solutions in comparison to standard PD solutions in patients receiving PD.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the effects of biocompatible dialysis solutions on patient outcomes in PD. The first period of randomised cross‐over studies was also included. When it was not possible to establish which data from cross‐over studies was from the first arm of the study, studies were excluded from the meta‐analysis.

Types of participants

Adults and children receiving any type of home‐based PD (continuous ambulatory PD (CAPD) or automated PD (APD)).

Types of interventions

Studies comparing the treatment of biocompatible PD solution to conventional PD solution were included. Groups of biocompatible PD solutions considered were:

Neutral pH, lactate‐buffered, low GDP
Neutral pH, bicarbonate (± lactate) buffered low GDP
Glucose polymer (icodextrin)
Combination regimens (e.g. PPEN)

The following types of studies were included:

Studies of neutral pH, low GDP PD solutions (lactate and bicarbonate ± lactate buffered) against conventional PD solutions
Studies of icodextrin against conventional PD solution

Studies of amino acid‐based dialysis fluids were excluded.

Types of outcome measures

Primary outcomes

Decline in RRF (changes in residual creatinine clearance (CrCl), urea clearance, Kt/V, glomerular filtration rate (GFR), and urine output)
Peritoneal UF (during peritoneal equilibration test and daily UF)
Peritonitis rate (episodes/y, episode/total patient‐months on PD) and incidence (number of events/follow‐up period)
Technique survival (number of participants remaining on PD at study completion)
Patient survival (number of participants alive at study completion)
Toxicity/adverse events (e.g. rash, uncontrolled fluid overload)

Secondary outcomes

Inflow pain
Changes in peritoneal membrane transport (four‐hour dialysate:plasma creatinine)
Dialysis adequacy (CrCl, Kt/V)
Hospitalisation (number of hospitalisation days during study follow‐up period)

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Specialised Register up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. The Specialised Register contains studies identified from:

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Handsearching of kidney‐related journals and the proceedings of major kidney conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Reference lists of review articles, relevant studies and clinical practice guidelines.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The review was undertaken by six authors. The search strategy described was used to obtain titles and abstracts of studies that have been relevant to the review. The titles and abstracts were screened independently by two authors. Studies that were not applicable were discarded. Two authors independently assessed retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by the same authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the most recent or most complete data set were used. Any discrepancy between published versions was highlighted. Disagreements were resolved by consultation.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
Were incomplete outcome data adequately addressed (attrition bias)?
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias?

If a sufficient number of studies (greater than 10) measured the same outcome, thereby assessed to have enough power to detect asymmetry, a funnel plot was performed to evaluate for possible publication bias.

Measures of treatment effect

For dichotomous outcomes (e.g. death, inflow pain, peritonitis) results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (e.g. decline in RRF, urine volume), the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales were used. When data were not presented in a format suitable for inclusion in meta‐analysis (e.g. median, interquartile range (IQR)), they were presented in tabulated form.

Unit of analysis issues

For cross‐over studies where data were available, only data from the first phase of studies were included.

Dealing with missing data

Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

Two authors independently assessed the risk of reporting biases in studies using the risk of bias assessment tool (Higgins 2011).

Data synthesis

Data were summarised using the random‐effects model although the fixed‐effect model was also analysed to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was performed where feasible to explore possible sources of heterogeneity (e.g. study duration, participants, interventions and study quality). Heterogeneity among participants may have been related to age and renal pathology. Heterogeneity in treatments may have been related to prior agents used and the agent, dose and duration of therapy (Table 3).

1. Summary of analyses.

Outcome	Subgroup analyses performed	‘Other data’ tables
Neutral pH, low GDP PD solutions versus conventional PD solutions
Residual renal function	Study duration Incident versus prevalent patients Single versus multicentre study Parallel versus cross‐over design PD fluid types Presence of selection bias Presence of other significant bias Weekly residual GFR in patients with baseline GFR > 2 mL/ min/ 1.73 m²	‐‐
Urine volume	Study duration Standard versus hypertonic PET Single versus multicentre study Parallel versus cross‐over design Presence of selection bias Presence of other significant bias	‐‐
Anuria	‐‐	‐‐
4‐hour peritoneal ultrafiltration	Study duration Standard versus hypertonic PET Single versus multicentre study Parallel versus cross‐over design Presence of selection bias Presence of other significant bias	‐‐
Daily peritoneal ultrafiltration	Study duration Incident versus prevalent patients Single versus multicentre study Parallel versus cross‐over design Presence of selection bias Presence of other significant bias	‐‐
Peritoneal solute transport rate (4‐hour dialysate:plasma creatinine)	Study duration Presence of selection bias Presence of other significant bias	‐‐
Dialysis adequacy (CrCl/ Kt/V urea)	‐‐	Dialysis adequacy and peritoneal transport in anuric patients (median (IQR))
Inflow pain	‐‐	‐‐
Peritonitis	Presence of selection bias Presence of attrition bias Presence of other significant bias	‐‐
Technique failure	‐‐	‐‐
Hospitalisation	‐‐	‐‐
Death (all causes)	‐‐	‐‐
Glucose polymer (icodextrin) versus conventional PD solution
Uncontrolled fluid overload	‐‐	‐‐
Rash	‐‐	‐‐
Residual renal function	‐‐	‐‐
Urine volume	‐‐	Change in urine volume (mL)
Daily peritoneal ultrafiltration	Change in ultrafiltration volume/membrane transport characteristics	‐‐
Peritoneal solute transport rate (4‐hour dialysate:plasma creatinine)	‐‐	‐‐
Dialysis adequacy (CrCl)	Change in peritoneal CrCl/membrane transport characteristics	‐‐
Peritonitis	‐‐	‐‐
Technique failure	‐‐	‐‐
Death (all causes)	‐‐	‐‐

Neutral pH, low GDP PD solutions versus standard glucose PD solutions
Patient or population: PD patients  Setting: community  Intervention: neutral, low GDP dialysate (all buffer types)  Comparison: standard glucose dialysate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with standard glucose dialysate	Risk with low GDP dialysate (all buffer types)	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Residual renal function (GFR; follow‐up 3 months to more than 3 years)	The mean residual renal function (GFR) was 0.54 mL/min/1.73 m² higher with low GDP dialysate (0.14 to 0.93 higher) compared to standard glucose dialysate		‐	835 (15)	⊕⊕⊕⊕  HIGH ^a	SMD 0.19 higher  (0.05 to 0.33 higher)
Urine volume (follow‐up to more than 3 years)	The mean urine volume was 114.37 mL/d higher with low GDP dialysate (47.09 to 181.65 higher) compared to standard glucose dialysate		‐	791 (11)	⊕⊕⊕⊕  HIGH ^b	‐
Peritoneal ultrafiltration: 4 hours (follow‐up to 24 months)	The estimated mean peritoneal ultrafiltration 69.72 mL/4 hours lower with low GDP dialysate (16.60 to 122.84 lower) compared to standard glucose dialysate		‐	414 (9)	⊕⊕⊝⊝  LOW ¹	‐
Peritoneal solute transport rate (4‐hour dialysis:plasma creatinine) (follow‐up to more than 3 years)	The mean peritoneal solute transport rate was 0.01 higher with low GDP dialysate (0 to 0.03 higher) compared to standard glucose dialysate		‐	746 (10)	⊕⊕⊝⊝  LOW ²	SMD 0.42 lower  (0.74 to 0.10 lower)
Peritonitis rate (episodes/total patient‐months) (up to 24 months)	31 per 1,000	36 per 1,000  (26 to 51)	RR 1.18  (0.84 to 1.64)	18,184 (10)	⊕⊕⊝⊝  LOW ³	‐
Technique failure (death‐censored) (follow‐up to more than 3 years)	74 per 1,000	81 per 1,000  (55 to 120)	RR 1.10  (0.75 to 1.63)	1275 (15)	⊕⊕⊝⊝  LOW ⁴	‐
Death (all causes) (follow‐up to more than 3 years)	77 per 1,000	21 fewer per 1,000  (41 fewer to 11 more)	RR 0.73  (0.47 to 1.14)	1229  (15 )	⊕⊕⊝⊝  LOW ⁴	‐
In very low certainty evidence, it is uncertain whether neutral pH, low GDP solution use led to any differences in inflow pain compared with standard PD solution (1 studies, 58 participants)
In very low certainty evidence, it is uncertain whether neutral pH, low GDP solution use led to adverse events including exit site/tunnel infection, non‐PD related infection/general infection, inadequate dialysis, fluid overload/hypervolaemia, hypertension, hypotension, hernia, peritoneal leak, catheter blockage, malposition, gastrointestinal disorder, abdominal pain, pancreatitis, enteritis, vomiting, newly diagnosed cancer, arthritis, angina, apoplexy, hypercalcaemia, hypocalcaemia, hyperphosphataemia, and hyperglycaemia (6 studies, 519 participants).
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio GFR: glomerular filtration rate
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Glucose polymer (icodextrin) compared to standard glucose dialysate for PD
Patient or population: PD patients  Setting: community  Intervention: glucose polymer (icodextrin)  Comparison: standard glucose dialysate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with standard glucose dialysate	Risk with glucose polymer (icodextrin)	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Uncontrolled fluid overload (follow‐up to 24 months)	531 per 1,000	159 per 1,000  (80 to 313)	RR 0.30  (0.15 to 0.59)	100 (2)	⊕⊕⊕⊝  MODERATE ¹	‐
Rash (follow‐up to 12 months)	43 per 1,000	109 per 1,000  (26 to 466)	RR 2.51  (0.59 to 10.72)	755 (3)	⊕⊕⊝⊝  LOW ²	‐
Residual renal function (renal CrCl) (follow‐up to 24 months)	The mean residual renal function (renal CrCl) was 0.30 mL/min higher with icodextrin (0.65 lower to 1.23 higher) than standard glucose dialysate		‐	114 (4)	⊕⊕⊝⊝  LOW ³	SMD 0.12 higher (0.26 lower to 0.49 higher)
Urine volume (follow‐up to 24 months)	The mean urine volume was 88.88 mL/d lower with icodextrin (356.88 lower to 179.12 higher) than standard glucose dialysate		‐	69 (3)	⊕⊕⊝⊝  LOW ³	‐
Daily ultrafiltration (follow‐up to 24 months)	The mean daily ultrafiltration was 448.54 mL/d higher with icodextrin (289.28 to 607.8 higher) than standard glucose dialysate		‐	102 (4)	⊕⊕⊕⊝  MODERATE ¹	‐
Peritonitis (follow‐up to 24 months)	236 per 1,000	12 fewer per 1,000  (54 fewer to 42 more)	RR 0.95  (0.77 to 1.18)	667  (6)	⊕⊕⊝⊝  LOW ⁴	‐
Technique failure (death‐censored) (up to 24 months)	107 per 1,000	64 per 1,000  (34 to 120)	RR 0.60  (0.32 to 1.12)	350 (4)	⊕⊝⊝⊝  VERY LOW ⁵	‐
In very low certainty evidence, it is uncertain whether icodextrin use led to any difference in death (all causes) compared to standard glucose solution (6 studies, 816 participants).
In very low certainty evidence, it is uncertain whether icodextrin use led to any difference in adverse events including abdominal discomfort, anaemia, arterial emboli, cardiac failure, cerebrovascular accident, diabetic foot, dizzy, electrolyte disturbances, exit site infection, fatigue, fluid overload, headache, stroke, hyperglycaemia, hypotension, myocardial infarction, pain, pleural effusion, pneumonia, pulmonary embolism, thirsty, uncontrolled hypertension, congestion, upper respiratory tract infection, and vomiting (5 studies, 816 participants).
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio CrCl: creatinine clearance; GFR: glomerular filtration rate
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Adverse events	Standard glucose solution		Low GDP solution		Studies reporting outcome
Adverse events	No. events	No. at risk	No. events	No. at risk	Studies reporting outcome
Neutral pH, low GDP PD solution (excluding peritonitis, death)
Exit site infection	6 0 1	91 19 36	4 5 3	91 40 37	balANZ 2010 Coles 1997 Feriani 1998
Tunnel infection	2	91	1	91	balANZ 2010
Non‐PD related infection/general infection	20 0	91 19	4 6	91 40	balANZ 2010 Coles 1997
Inadequate dialysis	1	91	1	91	balANZ 2010
Fluid overload/hypervolaemia	3 1 2	91 19 36	1 4 0	91 40 37	balANZ 2010 Coles 1997 Feriani 1998
Hypertension	2 1	19 36	3 0	40 37	Coles 1997 Feriani 1998
Hypotension	0	36	1	37	Feriani 1998
Hernia	11 1	91 36	10 0	91 37	balANZ 2010 Feriani 1998
Peritoneal leak	3	91	1	91	balANZ 2010
Catheter blockage	4	91	5	91	balANZ 2010
Malposition	2	91	1	91	balANZ 2010
Gastrointestinal disorder	6	91	14	91	balANZ 2010
Abdominal pain	0	19	3	40	Coles 1997
Pancreatitis	1	36	0	37	Feriani 1998
Enteritis	0	36	2	37	Feriani 1998
Vomiting	0	36	1	37	Feriani 1998
Newly diagnosed cancer	3	91	4	91	balANZ 2010
Arthritis	1	36	0	37	Feriani 1998
Angina	0	36	1	37	Feriani 1998
Apoplexy	1	36	1	37	Feriani 1998
Hypercalcaemia	0 3	19 36	3 2	40 37	Coles 1997 Feriani 1998
Hypocalcaemia	0	19	3	40	Coles 1997
Hyperphosphataemia	3	19	4	40	Coles 1997
Hyperglycaemia	1	36	0	37	Feriani 1998
Glucose polymer (icodextrin) (excluding rash, peritonitis, death)
Abdominal discomfort	1	103	0	98	Lin 2009a
Anaemia	24 26	29 112	6 39	30 175	Paniagua 2008 Wolfson 2002
Arterial emboli	1	103	0	106	MIDAS 1994
Cardiac failure	1	103	1	106	MIDAS 1994
Cerebrovascular accident	0	103	2	106	MIDAS 1994
Diabetic foot	5	29	1	30	Paniagua 2008
Dizzy	0	103	1	98	Lin 2009a
Electrolyte disturbances	4	29	1	30	Paniagua 2008
Exit site infection	3 24	27 112	4 28	33 175	STARCH 2015 Wolfson 2002
Fatigue	0	103	2	98	Lin 2009a
Fluid overload	17 17	132 29	6 5	136 30	Lin 2009a Paniagua 2008
Headache	9	112	25	175	Wolfson 2002
Stroke	1	27	0	33	STARCH 2015
Hyperglycaemia	27	29	8	30	Paniagua 2008
Hypotension	28	215	25	273	Lin 2009a Wolfson 2002
Myocardial infarction	4 3	103 29	2 0	106 30	MIDAS 1994 Paniagua 2008
Pain	18	112	30	175	Wolfson 2002
Pleural effusion	6	29	1	30	Paniagua 2008
Pneumonia	0	103	1	106	MIDAS 1994
Pulmonary embolism	0	103	1	106	MIDAS 1994
Thirsty	0	103	1	98	Lin 2009a
Uncontrolled hypertension	0 21	103 112	1 40	106 175	MIDAS 1994 Wolfson 2002
Hypotension	1	27	3	33	STARCH 2015
Hypertension	0	27	1	33	STARCH 2015
Congestion	1	27	0	33	STARCH 2015
Upper respiratory tract infection	25	112	41	175	Wolfson 2002
Vomiting	1	103	0	98	Lin 2009a

Change in urine volume (mL)
Study	Time point	Glucose polymer	Standard glucose solution
Davies 2003	1 month	‐44.3	‐44.1
Davies 2003	3 months	‐34.6	‐56.6
Davies 2003	6 months	‐10.7	‐126.6

Date	Event	Description
27 August 2018	New citation required and conclusions have changed	New data added
27 August 2018	New search has been performed	Search strategies updated; new studies incorporated

Date	Event	Description
18 August 2016	Amended	Correction of table 2 results
2 May 2014	Amended	Minor edits to study names to match Renal Group's Specialised Register

Database	Search terms
CENTRAL	peritoneal dialysis:ti,ab,kw (CAPD or CCPD or APD or PD):ti,ab,kw (#1 OR #2) biocompatib:ti,ab,kw dialysis solution.ti,ab,kw bicarbonate:ti,ab,kw (lactate or lactic next acid):ti,ab,kw buffer:ti,ab,kw (ph next neutral):ti,ab,kw icodextrin:ti,ab,kw (glucose degradation product")) and (fluid or solution* or dialysate)):ti,ab,kw (gdp) and (fluid or solution* or dialysate*)):ti,ab,kw (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 or #12) (#3 AND #13)
MEDLINE	exp Peritoneal Dialysis/ peritoneal dialysis.tw. (CAPD or CCPD or APD or PD).tw. or/1‐3 Biocompatible Materials/ Dialysis Solutions/ Bicarbonates/ Lactates/ Lactic Acid/ Buffers/ biocompatib$.tw. bicarbonate$.tw. (lactate$ or lactic acid).tw. buffer$.tw. neutral pH.tw. icodextrin.tw. (glucose degradation product$ and (fluid$ or solution$ or dialysate$)).tw. (GDP and (fluid$ or solution$ or dialysate$)).tw. or/5‐18 and/4,19
EMBASE	Peritoneal Dialysis/ Continuous Ambulatory Peritoneal Dialysis/ peritoneal dialysis.tw. (CAPD or CCPD or APD or PD).tw. or/1‐4 Biocompatibility/ dialysis fluid/ Bicarbonate/ Lactic Acid/ Buffer/ biocompatib$.tw. bicarbonate$.tw. (lactate$ or lactic acid).tw. buffer$.tw. neutral pH.tw. icodextrin.tw. (glucose degradation product$ and (fluid$ or solution$ or dialysate$)).tw. (GDP and (fluid$ or solution$ or dialysate$)).tw. or/6‐18 and/5,19

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Residual renal function	15	835	Std. Mean Difference (IV, Random, 95% CI)	0.19 [0.05, 0.33]
1.1 3 months	3	143	Std. Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.37, 0.29]
1.2 12 months	6	349	Std. Mean Difference (IV, Random, 95% CI)	0.18 [‐0.04, 0.39]
1.3 24 months	5	218	Std. Mean Difference (IV, Random, 95% CI)	0.33 [0.06, 0.60]
1.4 3 years +	1	125	Std. Mean Difference (IV, Random, 95% CI)	0.24 [‐0.11, 0.59]
2 Residual renal function: up to 12 months	12	860	Std. Mean Difference (IV, Random, 95% CI)	0.18 [0.05, 0.32]
2.1 4 weeks	1	48	Std. Mean Difference (IV, Random, 95% CI)	0.11 [‐0.46, 0.67]
2.2 3 months	3	143	Std. Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.37, 0.29]
2.3 6 months	6	440	Std. Mean Difference (IV, Random, 95% CI)	0.32 [0.10, 0.54]
2.4 8 months	1	91	Std. Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.44, 0.38]
2.5 9 months	1	138	Std. Mean Difference (IV, Random, 95% CI)	0.21 [‐0.12, 0.55]
3 Residual renal function: 12 months up to 24 months	10	641	Std. Mean Difference (IV, Random, 95% CI)	0.25 [0.10, 0.41]
3.1 12 months	8	545	Std. Mean Difference (IV, Random, 95% CI)	0.26 [0.09, 0.43]
3.2 18 months	2	96	Std. Mean Difference (IV, Random, 95% CI)	0.23 [‐0.17, 0.64]
4 Residual renal function: 24 months and beyond	6	343	Std. Mean Difference (IV, Random, 95% CI)	0.30 [0.08, 0.51]
4.1 24 months	5	218	Std. Mean Difference (IV, Random, 95% CI)	0.33 [0.06, 0.60]
4.2 3 years +	1	125	Std. Mean Difference (IV, Random, 95% CI)	0.24 [‐0.11, 0.59]
5 Residual renal function: PD fluid types	15	835	Std. Mean Difference (IV, Random, 95% CI)	0.19 [0.05, 0.33]
5.1 Balance	9	495	Std. Mean Difference (IV, Random, 95% CI)	0.20 [0.02, 0.37]
5.2 Purely bicarbonate buffered	3	58	Std. Mean Difference (IV, Random, 95% CI)	0.07 [‐0.46, 0.59]
5.3 Multiple fluid types in treatment group	2	218	Std. Mean Difference (IV, Random, 95% CI)	0.10 [‐0.20, 0.41]
5.4 Gambrosol trio	1	64	Std. Mean Difference (IV, Random, 95% CI)	0.52 [0.02, 1.02]
6 Urine volume	11	791	Mean Difference (IV, Random, 95% CI)	114.37 [47.09, 181.65]
6.1 3 months	2	120	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐515.46, 514.38]
6.2 12 months	6	392	Mean Difference (IV, Random, 95% CI)	120.94 [45.49, 196.39]
6.3 24 months	2	154	Mean Difference (IV, Random, 95% CI)	123.27 [‐51.83, 298.36]
6.4 3 years +	1	125	Mean Difference (IV, Random, 95% CI)	270.6 [10.53, 530.67]
7 Urine volume: up to 12 months	10	819	Mean Difference (IV, Random, 95% CI)	69.72 [‐55.95, 195.40]
7.1 1 month	1	50	Mean Difference (IV, Random, 95% CI)	‐30.0 [‐399.49, 339.49]
7.2 3 months	2	120	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐515.46, 514.38]
7.3 6 months	6	558	Mean Difference (IV, Random, 95% CI)	157.25 [58.48, 256.01]
7.4 8 months	1	91	Mean Difference (IV, Random, 95% CI)	‐147.2 [‐262.68, ‐31.72]
8 Urine volume: 12 months up to 24 months	8	579	Mean Difference (IV, Random, 95% CI)	110.57 [40.81, 180.34]
8.1 12 months	6	392	Mean Difference (IV, Random, 95% CI)	120.94 [45.49, 196.39]
8.2 18 months	2	187	Mean Difference (IV, Random, 95% CI)	60.94 [‐186.22, 308.10]
9 Urine volume: 24 months and beyond	3	279	Mean Difference (IV, Random, 95% CI)	169.22 [23.98, 314.46]
9.1 24 months	2	154	Mean Difference (IV, Random, 95% CI)	123.27 [‐51.83, 298.36]
9.2 3 years +	1	125	Mean Difference (IV, Random, 95% CI)	270.6 [10.53, 530.67]
10 Urine volume: PD fluid types	11	791	Mean Difference (IV, Random, 95% CI)	114.37 [47.09, 181.65]
10.1 Balance	7	482	Mean Difference (IV, Random, 95% CI)	120.48 [47.99, 192.97]
10.2 Purely bicarbonate buffered	1	27	Mean Difference (IV, Random, 95% CI)	345.50 [‐274.17, 965.17]
10.3 Multiple fluid types in the treatment group	2	218	Mean Difference (IV, Random, 95% CI)	37.84 [‐423.31, 498.99]
10.4 Gambrosol trio	1	64	Mean Difference (IV, Random, 95% CI)	130.0 [‐105.87, 365.87]
11 Anuria	2	246	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.18, 1.75]
12 Peritoneal ultrafiltration: 4 hours	9	414	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.74, ‐0.10]
12.1 2.26%/2.5% glucose	4	218	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.76, 0.07]
12.2 3.86%/4.25% glucose	5	196	Std. Mean Difference (IV, Random, 95% CI)	‐0.49 [‐1.08, 0.11]
13 4‐hour dialysate:plasma creatinine (2.27%, 2.4%, or 2.5% glucose)	10	746	Mean Difference (IV, Random, 95% CI)	0.01 [0.00, 0.03]
13.1 3 months	1	24	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.11, 0.09]
13.2 12 months	6	448	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.01, 0.03]
13.3 24 months	2	149	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.01, 0.04]
13.4 3 years +	1	125	Mean Difference (IV, Random, 95% CI)	0.06 [0.02, 0.10]
14 4‐hour dialysis:plasma creatinine (patient characteristics)	10	746	Mean Difference (IV, Random, 95% CI)	0.01 [0.00, 0.03]
14.1 Incident patients	7	554	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.00, 0.04]
14.2 Prevalent patients	3	192	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.03, 0.04]
15 4‐hour dialysis:plasma creatinine (PD fluid types)	10	746	Mean Difference (IV, Random, 95% CI)	0.01 [0.00, 0.03]
15.1 Balance	6	470	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.01, 0.03]
15.2 Purely bicarbonate buffered	1	24	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.11, 0.09]
15.3 multiple fluid type in the treatment group	2	187	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.04, 0.10]
15.4 Gambrosol trio	1	65	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.01, 0.05]
16 4‐hour dialysis:plasma creatinine (study design)	10	746	Mean Difference (IV, Random, 95% CI)	0.01 [0.00, 0.03]
16.1 Single centre	4	277	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.01, 0.04]
16.2 Multicentre	6	469	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.00, 0.04]
17 Peritoneal creatinine clearance [L/wk/1.73 m²]	7	510	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐2.03, 1.15]
17.1 3 months	1	24	Mean Difference (IV, Random, 95% CI)	‐7.46 [‐20.65, 5.73]
17.2 12 months	4	273	Mean Difference (IV, Random, 95% CI)	‐0.31 [‐2.28, 1.66]
17.3 24 months	1	88	Mean Difference (IV, Random, 95% CI)	‐2.60 [‐6.80, 1.60]
17.4 3 years +	1	125	Mean Difference (IV, Random, 95% CI)	1.30 [‐2.37, 4.97]
18 Peritoneal Kt/V urea	6	422	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.12, 0.09]
18.1 3 months	1	24	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.78, 0.76]
18.2 12 months	4	273	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.18, 0.16]
18.3 3 years +	1	125	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.18, 0.10]
19 Incidence of peritonitis	12	1055	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.92, 1.72]
19.1 8 weeks follow‐up	1	59	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.49, 5.10]
19.2 24 weeks	1	73	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.58, 2.36]
19.3 12 months follow‐up	5	507	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.93, 1.73]
19.4 18 months follow‐up	1	69	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.56, 2.07]
19.5 24 months follow‐up	4	347	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.62, 2.84]
20 Peritonitis rate (episodes/total patient‐months)	10	18184	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.84, 1.64]
21 Incidence of peritonitis: attrition bias risk	12	1055	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.92, 1.72]
21.1 Low risk	3	359	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.47, 0.90]
21.2 High risk	9	696	Risk Ratio (M‐H, Random, 95% CI)	1.58 [1.28, 1.96]
22 Inflow pain	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
22.1 6 months	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.24, 1.08]
23 Hospitalisation	2	230	Mean Difference (IV, Random, 95% CI)	3.02 [‐7.08, 13.12]
23.1 12 months	1	48	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐6.71, 5.91]
23.2 24 months	1	182	Mean Difference (IV, Random, 95% CI)	10.79 [‐4.28, 25.86]
24 Technique failure (death‐censored)	15	1275	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.75, 1.63]
24.1 3 months	2	52	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
24.2 6 months	2	179	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.04, 2.97]
24.3 12 months	5	478	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.31, 2.21]
24.4 24 months	5	441	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.70, 1.90]
24.5 3 years +	1	125	Risk Ratio (M‐H, Random, 95% CI)	2.89 [0.58, 14.33]
25 Death (all causes)	15	1229	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.47, 1.14]
25.1 3 months	2	52	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 3.09]
25.2 12 months follow‐up	7	633	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.29, 1.19]
25.3 18 months follow‐up	1	69	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.02, 1.84]
25.4 24 months follow‐up	4	350	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.56, 2.51]
25.5 3 years +	1	125	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.29, 2.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Daily ultrafiltration	4	102	Mean Difference (IV, Random, 95% CI)	448.54 [289.28, 607.80]
1.1 3 months	1	33	Mean Difference (IV, Random, 95% CI)	416.0 [236.26, 595.74]
1.2 4 months	1	32	Mean Difference (IV, Random, 95% CI)	607.0 [‐2164.12, 3378.12]
1.3 24 months	2	37	Mean Difference (IV, Random, 95% CI)	510.55 [10.10, 1011.00]
2 Uncontrolled fluid overload	2	100	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.15, 0.59]
2.1 24 months	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.10, 1.01]
2.2 12 months	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.12, 0.67]
3 Residual renal function	4	114	Std. Mean Difference (IV, Random, 95% CI)	0.12 [‐0.26, 0.49]
3.1 Residual GFR (mL/min)	1	32	Std. Mean Difference (IV, Random, 95% CI)	‐0.05 [‐0.75, 0.66]
3.2 Renal CrCl (mL/min/1.73 m²)	1	25	Std. Mean Difference (IV, Random, 95% CI)	0.28 [‐0.51, 1.07]
3.3 Renal CrCl (mL/min)	1	24	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐1.05, 0.58]
3.4 Residual renal function (mL/min/1.73 m²)	1	33	Std. Mean Difference (IV, Random, 95% CI)	0.40 [‐0.29, 1.09]
4 Urine volume	3	69	Mean Difference (IV, Random, 95% CI)	‐88.88 [‐356.88, 179.12]
4.1 4 months	1	32	Mean Difference (IV, Random, 95% CI)	‐35.0 [‐2561.49, 2491.49]
4.2 2 years	2	37	Mean Difference (IV, Random, 95% CI)	‐89.49 [‐359.01, 180.03]
5 Change in urine volume (mL)			Other data	No numeric data
6 Peritoneal creatinine clearance	3	237	Std. Mean Difference (IV, Random, 95% CI)	0.36 [‐0.24, 0.96]
6.1 4 weeks	1	183	Std. Mean Difference (IV, Random, 95% CI)	0.07 [‐0.22, 0.36]
6.2 3 months	1	33	Std. Mean Difference (IV, Random, 95% CI)	1.03 [0.30, 1.77]
6.3 12 months	1	21	Std. Mean Difference (IV, Random, 95% CI)	0.11 [‐0.74, 0.97]
7 Episodes of peritonitis	6	667	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.18]
7.1 4 weeks	1	201	Risk Ratio (M‐H, Random, 95% CI)	5.25 [0.26, 108.05]
7.2 6 weeks follow‐up	1	22	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.3 3 months	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.12, 5.43]
7.4 12 months follow‐up	2	346	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.69, 1.58]
7.5 2 years follow‐up	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.63, 1.22]
8 Rash	3	755	Risk Ratio (M‐H, Random, 95% CI)	2.51 [0.59, 10.72]
9 Technique failure (death‐censored)	4	350	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.32, 1.12]
10 Death (all causes)	6	816	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.32, 2.13]
10.1 4 weeks follow‐up	1	201	Risk Ratio (M‐H, Random, 95% CI)	3.15 [0.13, 76.45]
10.2 6 months follow‐up	2	249	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.01, 4.00]
10.3 12 months	1	287	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.34, 3.74]
10.4 2 years follow‐up	2	79	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 3.00]

Methods	Study design: parallel RCT Study duration: 4 years Follow‐up period: 24 months
Participants	Country: Spain Setting: multicentre (2 sites), university hospital Incident adult CAPD patients Number: treatment group (13); control group (20) Mean age ± SD (years): treatment group (62 ± 11); control group (59 ± 15) Sex (M/F): treatment group (10/3); control group (9/11) Exclusion criteria: none
Interventions	Treatment group Balance (Fresenius Medical Care) Control group Standard PD fluid (Stay Safe)
Outcomes	Peritonitis rate Peritoneal UF (4 hours, 4.25% glucose solution) RRF Patient survival
Notes	Supported by grants from RETICS from Instituto de Salud Carlos III and unrestricted grant from Fresenius Medical Care
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "patients were alternately assigned to either 'balance' or standard PD fluid depending on the time point of inclusion"
Allocation concealment (selection bias)	High risk	Quote: "patients were alternately assigned to either 'balance' or standard PD fluid depending on the time point of inclusion"
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	High drop‐out rate: 21/33 (63.6%)
Selective reporting (reporting bias)	Low risk	All relevant outcomes reported
Other bias	High risk	Outcome parameters significantly different at baseline (e.g. urine volume, RRF)

Methods	Study design: parallel RCT Study duration: not reported Follow‐up period: 3 months
Participants	Country: Spain Setting: multicentre (4 sites) Prevalent adult CAPD patients Number: treatment group (20); control group (11) Age, range (years): treatment group (58.8, 23 to 76); control group (56.7, 34 to 79) Sex (M/F): treatment group (9/11); control group (5/6) Exclusion criteria: antibiotics during the previous 30 days; serious illnesses (e.g. requiring hospitalisation during the previous 30 days); HIV positive; pregnancy or lactating; bicarbonate supplementation into PD fluids or orally
Interventions	Treatment group 25 mmol/L bicarbonate/15 mmol/L lactate PD solution Control group Standard 35 mmol/L lactate PD solution
Outcomes	Venous plasma bicarbonate concentrations Vital signs
Notes	This was a study primarily examining the ability of the new bicarbonate/lactate PD solutions on improving acidosis in PD patients Author contacted, awaiting response Funding received from Baxter Healthcare Ltd
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation (3 patients/block)
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Open label, however, unlikely to have affected measured outcomes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No drop‐outs
Selective reporting (reporting bias)	High risk	Limited reporting of clinical outcomes
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel RCT Study duration: April 2001 to December 2003 Follow‐up period: 12 months
Participants	Country: Republic of Korea Setting: multicentre (2 sites) Incident adult CAPD patients Exclusion criteria: Severe systemic disease including liver cirrhosis, SLE, rheumatoid arthritis, inflammatory bowel disease, vasculitis and malignancy
Interventions	Treatment group Low‐GDP solution (Balance solution, Fresenius Medical Care) Control group Conventional solution (StaySafe, Fresenius Medical Care)
Outcomes	UF volume RRF 24‐hour peritoneal UF Urine volume solute clearance glucose absorption inflammatory markers nutritional status
Notes	Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	open‐label, unlikely to affect the outcomes of study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	24% dropout
Selective reporting (reporting bias)	High risk	limited outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open, parallel RCT Study duration: 1999 to 2005 Follow‐up period: 18 months
Participants	Country: Germany, France, Austria Setting: multicentre (23 sites) Adult patients on CAPD or APD aged 18 to 80 years; ESKD, GFR ≥ 3 mL/min (arithmetic mean of renal urea and CrCl) or ≥ 6 mL/min (CrCl) as measured by 24‐hour urine collection Number: treatment group (44); control group (36) Mean age ± SD (years): treatment group (52 ± 12); control group (53.8 ± 14.6) Sex (M/F): treatment group (36/18); control group (14/12) Exclusion criteria: pregnant or breastfeeding; severe peritonitis episodes; cancer; positive for hepatitis B, hepatitis C and HIV
Interventions	Treatment group Received either Gambosol trio, a multi‐compartment bag with minimal amounts of GDPs (3, 4‐DGE < 1 µM) Control group Standard PD fluids from different manufacturers in single compartment bags, all containing 3,4‐DGE (13‐20 µM)
Outcomes	RRF (arithmetic mean of renal creatinine and urea clearance) Assessment of fluid balance (body weight, 24‐hour urine volume) Serum parameters (CRP, total protein, albumin, electrolytes and phosphate) CA125 in PD effluent Assessment of peritoneal membrane transport characteristics Medications (e.g. BP medications, diuretics and phosphate binders)
Notes	Sponsored by Gambro
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from Methods section of paper: "Randomization was performed by means of a centrally managed list based on a table of random numbers in blocks of four and stratified for the presence of diabetes"
Allocation concealment (selection bias)	Low risk	Quote from Methods section of paper: "Randomization was performed by means of a centrally managed list based on a table of random numbers in blocks of four and stratified for the presence of diabetes"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote from Methods section of paper: "... open, parallel study". As fluid balance is one of the main outcomes assessed, risks influencing co‐intervention
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	High drop‐out rate (41/80 (51.3%)), imbalance between the number of dropouts from each arm. Per protocol analysis
Selective reporting (reporting bias)	Low risk	All relevant clinical outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open‐label, parallel RCT Study duration: November 2004 to September 2010 Follow‐up period: 24 months
Participants	Countries: Australia, New Zealand, Singapore Setting: multicentre (16 sites) Adult PD patients ≥ 18 and < 81 years (either CAPD or APD); diagnosis of ESKD; first treatment for ESKD by any dialysis modality within 90 days prior to or following enrolment (patients may be enrolled prior to commencing first treatment if there is clear indication that the treatment modality is CAPD or APD and they consent in advance to enter the study); selected to be treated by CAPD or APD; residual GFR at enrolment ≥ 5 mL/min/1.73 m², urine volume/d ≥ 400 mL at enrolment; written informed consent before any study related activities; ability to understand the nature and requirements of the study Number: treatment group (91); control group (91) Mean age ± SD (years): treatment group (59.3 ± 14.2); control group (57.9 ± 14.7) Sex (M/F): treatment group (52/39); control group (48/43) Exclusion criteria: prognosis for survival < 12 months; pregnancy or lactation period; history of malignancy other than a successfully and completely treated cutaneous squamous cell or basal cell carcinoma or carcinoma in‐situ of the cervix within the last 5 years; any acute infections at the time of enrolment; any disease of the abdominal wall, such as injury or surgery, burns, hernia, dermatitis, that in the opinion of the Investigator would preclude the patient from being able to have PD; any inflammatory bowel diseases (Crohn's disease, ulcerative colitis or diverticulitis) that in the opinion of the Investigator would preclude the patient from being able to have PD; any intra‐abdominal tumours or intestinal obstruction; active serositis; any condition (mental or physical) that would interfere with the patient's ability to comply with the study protocol; known or suspected allergy to study product or related products; participation in any other clinical study where an intervention is designed to moderate rate of change of RRF
Interventions	Treatment group Neutral pH, low GDP dialysis solution (Balance) Control group Conventional dialysis solution (StaySafe) for a period of 2 years
Outcomes	Primary outcome Slope of RRF decline measured as GFR (mean of renal urea and CrCl) over time (follow‐up 24 months) Secondary outcomes Time from initiation of PD to anuria (daily urine volume < 100 mL) Peritoneal small solute clearance (Kt/V, CrCl) Peritoneal transport status (PET D/P creatinine and D/Do glucose) Peritoneal UF capacity (mL/d) and UF (mL/day/m²) Technical survival Patient survival Peritonitis rates Adverse events
Notes	Study funded by Fresenius Medical Care
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "To ensure adequate concealment of allocation, randomization was performed using a central computer and web‐based link to the central database, with stratification according to centre and the presence or absence of diabetic nephropathy"
Allocation concealment (selection bias)	Low risk	Quote: "To ensure adequate concealment of allocation, randomization was performed using a central computer and web‐based link to the central database, with stratification according to centre and the presence or absence of diabetic nephropathy"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "An open‐label study", but unlikely to have influenced the objective outcomes measured
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Drop‐out rate 3/185 (1.6%), balanced between groups
Selective reporting (reporting bias)	Low risk	All relevant clinical parameters reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: cross‐over RCT Study duration: not reported Follow‐up period: 6 weeks during each arm (overall 3 months)
Participants	Country: Netherlands Setting: single centre, university hospital Prevalent adult patients on CAPD; established on CAPD for at least 3 months, using 3 to 4 standard exchanges/24 h; free of peritonitis and mechanical drainage complications for at least 3 months prior to their inclusion Number: 21 Mean age ± SD: 50.3 ± 11.8 years Sex (M/F):15/6 Exclusion criteria: not reported
Interventions	Treatment group 7.5% icodextrin in place of glucose‐containing fluid for the overnight dwell Control group Standard glucose‐containing PD fluid (1.36%, 2.27%, 3.86%) for the overnight dwell Patients performed CAPD with both control and treatment fluids for a period of 6 weeks each
Outcomes	Peritonitis
Notes	Funding received from Rijnstate Hospital Arnhem and Baxter Healthcare Company, Benelux
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Drop‐out rate: 1/22 (5%)
Selective reporting (reporting bias)	High risk	Limited clinical outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open parallel RCT Study duration: not reported Follow‐up period: 12 months
Participants	Country: Korea Setting/ study design: single centre, university hospital PrevaIent adult patients on CAPD; maintained on CAPD for at least 6 months prior to study enrolment using standard PD fluids, and considered to be adequately dialysed; patients used three or four 1.5 to 2.5 L exchanges/d Number: treatment group (51); control group (53) Mean age ± SD (years): treatment group (52.6 ± 12.4); control group (55.4 ± 11.9) Sex (M/F): treatment group (20/31); control group (27/26) Exclusion criteria: dialysis‐related complications (e.g. CAPD peritonitis, exit‐site infection, tunnel infection) within the previous 8 weeks; more than 2 episodes of peritonitis within the previous 6 months
Interventions	Treatment group Neutral pH, low GDP solution (Balance; Fresenius Medical Care) Control group Standard PD solution
Outcomes	Urine volume Death (due to causes unrelated to PD) 4‐hour dialysate:plasma creatinine Change in D:P Cr over the study period Peritoneal UF Change in peritoneal UF Kt/V urea (renal, peritoneal and total) CrCl (renal, peritoneal and total)
Notes	Funding received from Yonsei University College of Medicine, the Korean Society of Nephrology and Fresenius Medical Care
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Open‐label design thus no blinding of investigators or participants. However, unlikely to have impacted on objective clinical outcomes (e.g. urine volume)
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	Large number of patients voluntarily changed to the low GDP PD solution (36/104 (35%)). Per protocol analysis
Selective reporting (reporting bias)	Low risk	All appropriate outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open, cross‐over design and parallel arms Study duration: not reported Follow‐up: 12 weeks
Participants	Country: 11 European countries Setting: multicentre (22 sites) Prevalent adult patients on PD Number: treatment group (36); control group (35) Median age, IQR (years): treatment group (61, 46‐68); control group (57, 51‐71) Sex (M/F): treatment group (19/7); control group (23/12) Exclusion criteria: not reported
Interventions	Treatment group Neutral pH, low GDP dialysate (Balance) Control group Conventional dialysate Patients received 12 weeks of treatment with both solutions
Outcomes	4‐four dialysate:plasma creatinine Kt/V CrCl UF Urine volume Peritonitis rate Adverse events (including inflow pain)
Notes	Study funded by Fresenius Medical Care
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Specific randomisation technique not reported. Quote: "After the run‐in phase, patients were randomized (1:1) to either ..."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study with subjective outcome measure such as inflow pain was one of the assessed parameters
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Dropout rate: 15/86 (17%). Although per protocol analysis performed, the reasons for dropout from initial study group is balanced after excluding the reasons that are unlikely to be dialysis related (e.g. transplantation, flare‐up of vasculitis)
Selective reporting (reporting bias)	Low risk	All relevant outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel, open label RCT Study duration: not reported Follow‐up period: 24 weeks
Participants	Countries: Germany Setting: multicentre (14 sites) Adult patients on CAPD (prevalent) who were free of peritonitis for at least 4 weeks preceding the study commencement. Phase II study (24 weeks) Number: treatment group (37); control group (36) Median age, range (years): treatment group (54.5, 18.6‐78); control group (55, 21.27‐79.4) Sex (M/F): treatment group (17/20); control group (20/16) Exclusion criteria: not reported
Interventions	Treatment group 34 mmol/L bicarbonate‐buffered solution Control group 35 mmol/L lactate‐buffered PD solution
Outcomes	RRF UF Subjective assessment ‐ symptoms Adverse events
Notes	Grant from Fresenius Phase I study data only available from conference abstract 36 patients left at the end of phase I of study ‐ no explanation provided
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised centrally and separately for each study centre and block randomisation in steps of four used
Allocation concealment (selection bias)	Low risk	No specific information provided. However central randomisation with probable low risk of selection bias
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open label, may have affected symptom assessment
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	Large number of participants missing between two phases of study that are not accounted for in the paper: 18/123 (14.6%) for 12 weeks; 4/73 (5.5%) for 24 week study
Selective reporting (reporting bias)	Low risk	All relevant clinical outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: prospective RCT, presumed open‐label (not disclosed) Study duration: not reported Follow‐up period: 24 months
Participants	Countries: Spain Setting: multicentre (2 university hospitals) Incident patients who are able and willing to perform CAPD with no expressed indication for APD Number: treatment group (11); control group (20) Mean age ± SD (years): treatment group (68.22 ± 8.8); control group (59 ± 15) Sex (M/F): treatment group (8/3); control group (9/11) Diabetic: treatment group (38%); control group (15%) Exclusion criteria: none
Interventions	Treatment group BicaVera (1.5, 2.3%, 4.25% glucose) Control group Conventional PD fluid (Stay‐safe; 1.5%, 2.3% and 4.25%)
Outcomes	Peritonitis rate Death Technique survival UF capacity RRF
Notes	Study supported by grants from REDinREN, MLC and unrestricted grant from Fresenius Medical Care. Note: significant difference in outcome re: UF capacity and RRF reported, but these differences were present from the baseline
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "patients were randomly assigned to either BicaVera or the standard PD fluid by the doctors"
Allocation concealment (selection bias)	High risk	Quote: "patients were randomly assigned to either BicaVera or the standard PD fluid by the doctors"
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	High dropout rate (23 /31 (74.2%)). Imbalance in missing data between the two groups
Selective reporting (reporting bias)	Low risk	All relevant clinical outcomes reported
Other bias	High risk	Outcome parameters significantly different at baseline (e.g. urine volume, RRF)

Methods	Study design: open, cross‐over RCT Study duration: not reported Follow‐up period: 12 months (6 months in each phase)
Participants	Country: Germany Setting: single centre, university Adult patients on APD Number: 14 Mean age ± SD: 40.0 ± 10.7 years Sex (M/F): 4/10 Exclusion criteria: not reported
Interventions	Treatment group Neutral pH bicarbonate/ lactate buffered PD solution (Physioneal; Baxter Healthcare) Control group Conventional PD solution (Dianeal; Baxter Healthcare) Patients completed 6 months of APD using either control or treatment PD solution, followed by a further 6 months of APD using the alternative PD solution
Outcomes	Inflow pain
Notes	Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not blinded. This is particularly relevant as 'inflow pain' was reported as one of the outcomes in unblinded state
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Dropout rate: 2/14 (14%)
Selective reporting (reporting bias)	High risk	Primary outcome of interest of this study related to peritoneal macrophages and inflammatory markers. No other clinical parameter was reported ‐ including peritonitis, survival, RRF
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open label, cross‐over RCT Study duration: not reported Follow‐up period: 6 months
Participants	Country: Slovenia Setting: single‐centre, University hospital Prevalent CAPD patients (adult), treated with Dianeal solution for at least 3 months and > 18 years Number: 21 Mean age ± SD: 54.3 ± 12.4 years Sex (M/F): 13/8 Exclusion criteria: peritonitis episode in the last 3 months; a history of or current systemic inflammatory disease or immunomodulatory therapy; HIV, HBV or HCV positivity or other chronic infectious disease; malignant disease; acute exacerbation of heart failure in the last 3 months prior to inclusion in the study
Interventions	After 1‐month run‐in phase with the Dianeal solution (D solution), patients were randomised (1:1) to either 3 months of treatment with the D solution (group D‐P) or to 3 months of treatment with Physioneal 40 (P solution; group P‐D) After 3 months, patients switched therapies to receive a further 3 months of treatment
Outcomes	Primary endpoint Daily UF Secondary endpoints Overnight UF of a timed 10‐hour dwell 4‐hour UF with 2.27% solution on PET Low‐molecular‐weight solute peritoneal transport rates expressed as a D/P for creatinine ratio and D/D1 for glucose ratio Peritoneal urea and CrCl Residual GFR
Notes	Study partly supported by a grant from the Slovenian Research Agency and partly by a grant from Baxter Healthcare, Ljubljana, Slovenia. One of the authors is employed by Baxter Healthcare
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement other than, quote: "patients were randomized (1:1)"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "open‐label, randomized". However, unlikely to have influenced the measured objective outcomes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Dropout rate ‐ 5/26 (19.2%). Per protocol analysis
Selective reporting (reporting bias)	Low risk	All relevant outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open label, parallel RCT Study recruitment: October 2004 to January 2005 Follow‐up period: 12 months
Participants	Country: Mexico Setting: multicentre (4 sites) Adult prevalent CAPD patients; diabetes mellitus; high and high average peritoneal transport status Number: treatment group (30); control group (29) Mean age ± SD (years): treatment group (58.9 ± 7.9); control group (60.5 ± 9.3) Sex (M/F): treatment group (12/18); control group (16/13) Exclusion criteria: seropositive for hepatitis B or HIV; malignancies; receiving immunosuppressive medications; peritonitis episode within 1 month of screening period
Interventions	Treatment group 7.5% icodextrin in the long dwell Control group At least 1 bag with 2.5% glucose in the long dwell Liberal use of 2.5% or 4.25% glucose was allowed in both groups in order to reach treatment goals. Dietary sodium intake prescription was 50 mmol/d for both groups
Outcomes	Primary outcomes Improvement in peritoneal UF Reduction in extracellular fluid volume Improvement in metabolic control Secondary outcomes Hospitalisations Therapy‐related complications
Notes	Financial support from Baxter, SA de RL, Mexico
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: Assignment was in a 1:1 ratio through a central randomisation centre
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Open‐label study. However, unlikely to have influenced the objective outcomes measured
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	23 participants dropped out. It is also unclear if 23 were out of 59, or the 82 participants to start with. Per protocol analysis
Selective reporting (reporting bias)	High risk	Limited reporting of clinical outcomes
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open cross‐over RCT Study duration: not reported Follow‐up period: 12 weeks
Participants	Countries: Austria, France, Germany Setting: multicentre (6 specialised paediatric dialysis units) Prevalent paediatric patients < 18 years on APD with an average peritoneal fill volume close to 1000‐1100 mL/m² BSA Number: 28 Median age (range): 6.0 years (range 0.6 to 15.7) Sex (M/F): 19/9 Exclusion criteria: severe chronic pulmonary, cardiac, hepatic or malignant disease; history of peritonitis in the previous 3 weeks; clinical evidence of major peritoneal adhesions
Interventions	Treatment group Neutral pH PD fluid (34 mM bicarbonate, BicaVera 170/180/190; Fresenius Medical Care) Control group Conventional PD fluid (35 mL lactate, pH 5.5, CAPD 17/18/19; Fresenius Medical Care) Patients performed their usual APD regimen with either the control or treatment fluid for 12 weeks. After a 4 week washout period they completed 12 weeks of APD using the alternative fluid
Outcomes	Peritonitis rate, relapsing peritonitis rate Other adverse events (acute fluid overload, aggravated hypertension, severe hyperparathyroidism) Residual GFR 24‐hour UF Peritoneal transport (4‐hour dialysate:plasma creatinine)
Notes	Funding received from Fresenius Medical Care (Bad Homburg, Germany)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Open‐label, however, unlikely to have influenced the objective outcome measures reported
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	High dropout rate (12/28, 43%), unclear during which phase of treatment the dropouts occurred. Per protocol analysis
Selective reporting (reporting bias)	Low risk	All relevant clinical outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

PERMALINK

Biocompatible dialysis fluids for peritoneal dialysis

Htay Htay

David W Johnson

Kathryn J Wiggins

Sunil V Badve

Jonathan C Craig

Giovanni FM Strippoli

Yeoungjee Cho

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

1. Summary of analyses.

Sensitivity analysis

'Summary of findings' tables

Summary of findings (Table 1)

Summary of findings (Table 2)

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Low GDP (all buffer types) compared to standard glucose dialysate for peritoneal dialysis (PD).

Summary of findings 2. Glucose polymer (icodextrin) compared to standard glucose dialysate for peritoneal dialysis (PD).

Neutral pH, low GDP versus conventional glucose PD solution

Residual renal function

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

4.

Urine volume

Methods	Study design: RCT Study duration: August 2005 to July 2010 Follow‐up period: 24 months
Participants	Countries: Canada and Hong Kong Setting: multicentre Incident adults CAPD or APD patients Number: treatment group (51); control group (50) Mean age ± SD (years): treatment group ( 59.9 ± 11); control group (59.0 ± 11) Sec (M/F): treatment group (29/22); control group (31/19) Exclusion criteria: unlikely to continue PD for at least 6 months
Interventions	Treatment group Neutral pH, low GDP PD solution (Gambrosol Trio solution) Control group Conventional PD solution (Dianeal solution)
Outcomes	RRF Urine output 4‐hour dialysate:plasma creatinine Peritoneal small solute clearance Peritoneal UF peritonitis rate
Notes	"The Trio Trial was partially funded by an unrestricted grant from Gambro Lundia AB, Lund, Sweden. TS, GW, MT, DO, and PT conceived, designed, and supervised the Trio Trial. TS, SM, AS, and MA conducted the statistical analysis"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Standard computerized algorithm
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Open‐label, unlikely to have major impact on outcomes of study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Unlikely to effect the outcomes of study
Incomplete outcome data (attrition bias)   All outcomes	High risk	33% dropout rate
Selective reporting (reporting bias)	Low risk	All outcomes of study were reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: RCT Study duration: not reported Follow‐up period: 12 months
Participants	Country: Republic of Korea Setting: single centre Prevalent CAPD patients Number: treatment group (75); control group (39) Mean age ± SD (years): treatment group (50.9 ± 11.5); control group (50.7 ± 13.2) Sex (M/F): treatment group (34/41); control group (16/23) Exclusion criteria: not reported
Interventions	Treatment group Neutral pH, low GDP PD solution (Physioneal solution) Control group Conventional PD solution (Dianeal solution)
Outcomes	Biochemical maker ( CA‐125, IL‐6) Peritoneal UF 4‐hour dialysate:plasma creatinine Solute clearance Peritonitis rate
Notes	Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random number
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Open‐label, unlikely to affect outcomes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	15.5% dropout
Selective reporting (reporting bias)	High risk	Limited outcomes are reported
Other bias	Unclear risk	Insufficient information to permit judgement

Study	Reason for exclusion
BIOKID 2004	Wrong intervention: comparing two types of biocompatible PD solutions
Braide 2009	Wrong intervention: citrate supplementation rather than use of biocompatible PD fluids
Chang 2016	Wrong intervention: icodextrin versus non‐icodextrin in the background of using low GDP biocompatible solutions
Chow 2014	Wrong intervention: icodextrin as part of treatment of peritonitis
Coester 2006	Wrong intervention: effect of glucose sparing therapy (NEP)
Dallas 2004	Wrong intervention: icodextrin versus Icodextrin/glucose combination novel fluid
de Fijter 1993	Study conducted over a short period with a view to assessing macrophage function hence study duration too short to evaluate pre‐specified outcomes
EDEN 2013	Wrong intervention: glucose sparing therapy (NEP)
Fang 2008	Wrong intervention: neutral pH, low GDP PD solution as peritoneal equilibration test solution
Feriani 1993	Wrong intervention: two solutions with differences in buffers (bicarbonate against lactate)
Fischbach 2004	Study conducted over two days to examine the effect of PD solutions on intraperitoneal pressure. Duration of study was too short to evaluate pre‐specified patient level clinical outcomes
Hiss 2013	Wrong intervention: normal versus reduced glucose content in the dialysis solution
Hwang 2006	Wrong intervention: icodextrin as peritoneal equilibration test solution
IMPENDIA 2013	Wrong intervention: glucose sparing therapy (NEP)
Jenkins 2003	Wrong intervention: icodextrin versus novel combination solution composed of icodextrin and dextrose
John 2008	Study conducted over one day to examine the effect of biocompatible PD solutions on baroreflex sensitivity. Duration of study was too short to evaluate pre‐specified patient level clinical outcomes
le Poole 2004	Wrong intervention: amino acid‐based dialysis solution
Liberek 2002	Study conducted following 2 overnight dwells (one week apart) of biocompatible and conventional PD solutions to measure inflammatory markers in the PD effluent. Duration of study was too short to evaluate pre‐specified patient level clinical outcomes
Lui 2012	Wrong intervention: amino acid‐containing dialysis solution
Martikainen 2005	Wrong intervention: amino acid‐containing dialysis solution
Parikova 2007	Wrong intervention: neutral pH, low GDP PD solution as a peritoneal equilibration test solution
Pedersen 1985	Wrong intervention: comparing buffers in PD solution
Peers 1997	Wrong intervention: novel icodextrin/glucose combination fluid
Plum 1997	Wrong intervention: amino acid‐containing dialysis solution
Rodriguez‐Carmona 2007	Wrong intervention: amino acid‐based dialysis solution
Sav 2009	Wrong intervention: twice‐daily icodextrin versus daily icodextrin
Sav 2010	Wrong intervention: twice‐daily icodextrin versus daily icodextrin
Selby 2005	Study conducted over two days to examine the effect of PD solutions on haemodynamic parameters. Duration of study was too short to evaluate pre‐specified patient level clinical outcomes
Selby 2007a	Wrong intervention: amino acid fluid
Smit 2000	Wrong intervention: glycerol‐based fluid
Smit 2001	Wrong intervention: different strengths of glucose solutions
Ueda 2000	Wrong intervention: amino acid fluid study
Van Biesen 2004	Wrong intervention: amino acid fluid study
Yehia 2014	Wrong intervention: icodextrin versus exchange‐free dialysis regimen in the setting of peritonitis
Yoon 2014	Wrong intervention: icodextrin versus non ‐icodextrin in the background of using biocompatible solution (physioneal)

Methods	Study design: parallel RCT Randomisation method: not reported Blinding: not reported Intention to treat: unclear Follow‐up period: 12 months
Participants	Country: Republic of Korea Setting: single centre Incident adult CAPD patients
Interventions	Group 1 55 participants Neutral pH, low GDP PD solution (Balance, Fresenius Medical Care, Germany) Group 2 23 participants Conventional PD solution (StaySafe, Fresenius Medical Care, Germany) Group 3 22 participants Neutral pH, low GDP PD solution (Physioneal, Baxter Healthcare, USA) Group 4 26 participants Conventional PD solution (Dianeal, Baxter Healthcare, USA)
Outcomes	UF volume Glucose absorption 24‐hour peritoneal UF Urine volume Body weight Bioimpedance analysis for fluid status assessment
Notes	Abstract format only. Unable to obtain additional information from authors

Methods	Study design: cross‐over RCT Randomisation method: not reported Blinding: open label Intention to treat: yes Follow‐up period: 16 weeks
Participants	Country: Spain Setting: multicentre Prevalent adult APD patients
Interventions	neutral pH, low GDP dextrosed based solution (balance)
Outcomes	peritonitis peritoneal UF urine volume
Notes	Unable to obtain data from the first phase of the cross‐over study

Methods	Study design: RCT Randomisation method: not reported Blinding: not reported Intention to treat: not reported Follow‐up period: uncertain
Participants	Country: Republic of Korea Setting: single centre Incident CAPD patients who survived more than 3 months
Interventions	Treatment group StaySafe Balance (Fresenius Medical Care, Germany) or Physioneal (Baxter, USA) Control group StaySafe (Fresenius Medical Care, Germany) or Dianeal (Baxter, USA)
Outcomes	high sensitive CRP CA‐125 of dialysate peritoneal equilibrium test patients survival
Notes	Information available only in abstract form; unable to obtain further data

Methods	Study design: cross‐over design Randomisation method: not reported Blinding: open label Intention to treat: unclear Follow‐up period: 10 weeks
Participants	Country: Spain Setting: single centre Prevalent PD patients Exclusion criteria: age < 18 or > 85 years; PD for < 2 months; significant clinical events (including peritonitis) during the previous 3 months; unwillingness or inability to cooperate
Interventions	Treatment group Neutral pH, low GDP PD solution (Physioneal Clear Flex, Baxter) Control group Conventional PD solution (Dianeal, Baxter) 5 weeks in each arm then cross‐over
Outcomes	Body weight Urine output RRF Peritoneal small solute clearance Peritoneal UF 4‐hour dialysate:plasma creatinine
Notes	Unable to obtain data from the first phase of cross‐over study

Trial name or title	Sympathetic Activity in Patients With End‐stage Renal Disease on Peritoneal Dialysis (SAPD)
Methods	Study design: parallel Randomisation method: not reported Blinding: open label, single blind (outcome assessor) Intention to treat: unclear Follow‐up period: 18 weeks
Participants	Countries: Canada Setting: single centre Incident CAPD and CCPD patients
Interventions	Icodextrin for the night‐time exchange for a period of 12 weeks ( 7 to 18 week of study)
Outcomes	muscle sympathetic nerve activity change in extracellular volume BP RRF
Starting date	July 2017
Contact information	Marcel Ruzicka, MD, mruzicka@ottawahospital.on.ca
Notes