Original Investigation

International Icodextrin Use and Association with

Peritoneal Membrane Function, Fluid Removal, Patient
and Technique Survival
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Simon Davies ,1 Junhui Zhao,2 Keith P. McCullough ,2 Yong-Lim Kim,3 Angela Yee-Moon Wang ,4
Sunil V. Badve ,5,6 Rajnish Mehrotra ,7 Talerngsak Kanjanabuch ,8 Hideki Kawanishi ,9 Bruce Robinson,2
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Ronald Pisoni,2 Jeffrey Perl10 and on behalf of PDOPPS Dialysis Prescription and Fluid Management Working Group

Key Points
 There are important national and center differences in the prescription of icodextrin, with the United States a
clear outlier; across all countries, icodextrin was more likely to be used if membrane function tests indicated
reduced ultrafiltration capacity to glucose.
 This large, international observational study was unable to show patient or hemodialysis transfer advantages to
icodextrin use.
 Where use of icodextrin was low, this was compensated for by much greater use of high glucose and overall
higher ultrafiltration volumes at each level of urine volume; this practice may confound associations between
icodextrin and survival outcomes.

Abstract
Background Icodextrin has been shown in randomized controlled trials to benefit fluid management in
peritoneal dialysis (PD). We describe international icodextrin prescription practices and their relationship to
clinical outcomes.

Methods We analyzed data from the prospective, international PDOPPS, from Australia/New Zealand, Canada,
Japan, the United Kingdom, and the United States. Membrane function and 24-hour ultrafiltration according to
icodextrin and glucose prescription was determined at baseline. Using an instrumental variable approach, Cox
regression, stratified by country, was used to determine any association of icodextrin use to death and
permanent transfer to hemodialysis (HDT), adjusted for demographics, comorbidities, serum albumin, urine
volume, transplant waitlist status, PD modality, center size, and study phase.

Results Icodextrin was prescribed in 1986 (35%) of 5617 patients, .43% of patients in all countries, except in the
United States, where it was only used in 17% and associated with a far greater use of hypertonic glucose. Patients
on icodextrin had more coronary artery disease and diabetes, longer dialysis vintage, lower residual kidney
function, faster peritoneal solute transfer rates, and lower ultrafiltration capacity. Prescriptions with or without
icodextrin achieved equivalent ultrafiltration (median 750 ml/d [interquartile range 300–1345 ml/d] versus 765
ml/d [251–1345 ml/d]). Icodextrin use was not associated with mortality (HR51.03; 95% CI, 0.72 to 1.48) or HDT
(HR 1.2; 95% CI, 0.92 to 1.57).

Conclusions There are large national and center differences in icodextrin prescription, with the United States
using significantly less. Icodextrin was associated with hypertonic glucose avoidance but equivalent
ultrafiltration, which may affect any potential survival advantage or HDT.
KIDNEY360 3: 872–882, 2022. doi: https://doi.org/10.34067/KID.0006922021

1
School of Medicine, Keele University, Keele, United Kingdom
2
Arbor Research Collaborative for Health, Ann Arbor, Michigan
3
School of Medicine, Kyungpook National University Hospital, Daegu, South Korea
4
Queen Mary Hospital, The University of Hong Kong, Hong Kong, P.R. China
5
Renal and Metabolic Division, George Institute for Global Health, UNSW Medicine, Sydney, Australia
6
Department of Renal Medicine, St. George Hospital, Sydney, Australia
7
University of Washington, Department of Medicine, Seattle, Washington
8
Division of Nephrology, Department of Medicine and Center of Excellence in Kidney Metabolic Disorders and Dialysis Policy and Practice
Program (DiP3), School of Global Health, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
9
Tsuchiya General Hospital, Hiroshima, Japan
10
St. Michael’s Hospital, Toronto, Canada

Correspondence: Prof. Simon J. Davies, David Weatherall Building, Faculty of Medicine and Health Sciences, Keele University,
Keele, United Kingdom. Email: [email protected]

872 Copyright # 2022 by the American Society of Nephrology www.kidney360.org Vol 3 May, 2022
 KIDNEY360 3: 872–882, May, 2022 Icodextrin Prescription in PD Patients, Davies et al. 873

Introduction per day, or those with implanted cardiac defibrillators

Volume overload is common in patients on peritoneal dial- were excluded. Incident patients with ,3 months on PD
ysis (PD) (1) and is linked to cardiovascular disease, the were excluded.
leading cause of death in kidney failure (2). Poor peritoneal Study baseline was defined as the initial 4-month interval
ultrafiltration contributes to volume overload and is an for each patient where information on icodextrin use or not
important reason for hemodialysis (HD) transfer (HDT) in was captured. Of those on icodextrin at baseline, 88%
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patients on PD (3,4). Icodextrin, a dialysis solution contain- remained on it throughout the study, whereas 84% of those
ing macromolecules, is able to maintain ultrafiltration for not on icodextrin at baseline continued to remain off ico-
the long dwell (8–16 hours) and has been shown in clinical dextrin throughout the study.
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trials to improve volume status (5,6), increase ultrafiltration Patient demographics and comorbidities were captured
compared with glucose, and reduce episodes of overhydra- for each patient. Laboratory measurements, blood pres-
tion in both continuous ambulatory peritoneal dialysis and sure, membrane function as determined from a peritoneal
automated peritoneal dialysis (APD) (7,8). A recent equilibration test (PET), including PSTR (dialysate/plasma
enriched meta-analysis (8) supports the theoretical predic- creatinine ratio at 4 hours) and the ultrafiltration capacity
tion that icodextrin will have its greatest effect when the (net ultrafiltration using glucose 2.5%, which was the con-
peritoneal solute transfer rate (PSTR) is above average, centration used in 94% of tests across all countries), dialy-
which is important, given the consistent finding that this sis prescription details, 24-hour urine, and ultrafiltration
aspect of membrane function has been associated with volumes were captured at baseline. Center-level practices
increased mortality on PD (9,10). Reduced net ultrafiltra- of the frequency of undertaking PETs were obtained from
tion and excess fluid reabsorption in the long exchange is a questionnaire administered to the nurse study coordina-
one of the putative mechanisms whereby a faster PSTR tor at participating facilities. Data were obtained from
leads to worse survival, and guidelines recommend icodex- manual medical chart extraction and entered into a web-
trin use under these circumstances (10). based data collection tool, with the exception of US
Randomized controlled trials of icodextrin use have not patients receiving care at large dialysis organization sites
shown a benefit in HDT and only a suggestion of a survival where data were imported from electronic health records.
benefit (7,8). This may reflect a lack of power in these trials, High glucose prescription was defined as any use of 2.27%
which were never designed to investigate these outcomes, or 3.86% solutions.
even when brought together in meta-analyses (7,8). As a
result, reliance on robust observational data is necessary.
Statistical Analyses
The Peritoneal Dialysis Outcomes and Practice Patterns
Icodextrin use at baseline was the exposure of interest.
Study (PDOPPS), one of the largest international PD cohort
Outcomes of interest included 24-hour ultrafiltration at
studies to date, is a unique opportunity to understand how
baseline, permanent HDT, and all-cause mortality. Tempo-
icodextrin prescription varies by country and by patient
rary HDT/hybrid where the patient did not return to PD
and center characteristics, and whether its use translates
within 12 weeks was also defined as HDT. Dying within
into clinical benefits, including enhanced ultrafiltration and
7 days of permanent or temporary HDT or hybrid therapy
superior patient outcomes. We sought to test the hypothe-
was considered a death (not HDT) outcome. To establish
sis that icodextrin use is associated with increased 24-hour
peritoneal ultrafiltration and improvements in patient sur- prescription practices, patient-level use of icodextrin was
vival and HDT. analyzed according to known clinical indications, including
comorbidities, level of residual kidney function, dialysis
glucose prescription, and, where available, peritoneal
membrane function (PSTR and ultrafiltration capacity). The
Materials and Methods
Study Population influence of center-level practices for the determination of
PDOPPS is an international prospective cohort study in membrane function on icodextrin use was also investigated.
collaboration with the International Society for Peritoneal Cox regression was used to analyze the association of ico-
Dialysis (11). Patients $18 years of age receiving mainte- dextrin with death, HDT, and combined outcome of either
nance PD (excluding combination HD/PD hybrid therapy) death or HDT. Follow-up started at study baseline and
were enrolled randomly from national samples of ran- ended at whichever came first: death, 7 days after modality
domly selected PD facilities treating a minimum of 20 PD switch, loss to follow-up, transplantation, or study end.
patients. Study approval was obtained by a central national To reduce confounding by indication, all models were
or institutional review board. Additional study approval adjusted for patient-level confounders, including PDOPPS
and patient consent were obtained as required by national phase, patient age, sex, time on PD (PD vintage), comorbid-
and local ethics committee regulations. Further study ities, urine volume, albumin, and transplant waiting list
details are provided at https://www.dopps.org/ status. To adjust for possible center-level confounding, we
OurStudies/PeritonealDialysisPDOPPS.aspx. also adjusted for center size and percentage APD use.
The current analysis was restricted to Australia/New
Zealand, Canada, Japan, the United Kingdom, and the Instrumental Variable Analyses
United States in PDOPPS phases 1–2 (phase 1: 2014–2018; In order to account partially for patient-level unmeas-
phase 2: 2018–2021) because icodextrin was not available in ured confounders (e.g., markers of metabolic and/or
Thailand. To avoid inclusion of patients with cardiorenal volume management challenges) that may affect the rela-
syndrome using icodextrin as an adjunct volume removal tionship between icodextrin use and outcomes, we con-
strategy, patients with a single icodextrin exchange only ducted analyses applying an instrumental variable
 874 KIDNEY360

approach that used the dialysis center as the instrument Results

(12–15). The first stage used a linear model on dialysis cen- Icodextrin Practice Patterns
ter and patient factors listed above to predict icodextrin Icodextrin was used in 1986 of the 5617 (35%) patients
use. The second stage was a Cox model for survival included in the analysis (Figure 1), although this differed
outcomes such as mortality or HDT (16). The first-stage substantially by country: 43%–56% of patients in Austra-
F statistic, used to reject the null hypothesis of weak instru- lia/New Zealand, Canada, Japan, and the United Kingdom
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ments, was 10, with the interpretation that the instrumental compared with 17% of patients in the United States. Across
variable estimates are less biased than standard regression all countries, use of icodextrin was lower among patients
(13,17,18). on PD for ,1 year (Supplemental Figure 1). Marked
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within-country center variation was observed within all

PDOPPS regions (Figure 2). For example, the bottom 25th
Subgroup Analysis and Sensitivity Analysis percentile of facilities in Canada used icodextrin for #30%
To explore if associations between icodextrin use and of their patients compared with $83% in the upper 75th
outcomes differed by patient/treatment characteristics, percentile. This center variation in practice was still appar-
models were repeated by specified subgroups (see ent when the 1328 APD dry-day patients not eligible for
Supplementary Material): age, body mass index, PSTR, icodextrin were excluded (Supplemental Figure 2).
urine volume, diabetic status, PD modality, region, dialysis Icodextrin use according to patient and treatment charac-
assistance, and use of biocompatible dialysis fluid. We cal- teristics is presented in Table 1. To clarify the country-level
culated a P value for the interaction between icodextrin use differences further, distributions of all covariates by coun-
and the subgroup variable (e.g., diabetes yes/no) using a try and icodextrin status are also presented in Table 2 and
likelihood ratio test, comparing the model with all main- Supplemental Table 1. Patients prescribed icodextrin were
effect adjustments and icodextrin use to the model with the more likely to have coronary artery disease and diabetes,
indicated interaction with icodextrin use. Because the alter- have been on PD treatment longer, have lower residual
native to an icodextrin day dwell would be a glucose day 24-hour urine volume and kidney function, use more
dwell, a sensitivity analysis excluding dry-day patients on hypertonic glucose, and have a faster PSTR. These prescrip-
APD was also performed. tion practices were similarly observed across all countries
regardless of the overall icodextrin use, with the exception
that in the United States, there was no significant increase
Treatment of Missing Data in icodextrin use with time on treatment (see Supplemental
Missing data were multiply imputed using the sequential Figure 1), and its use was not associated with a reduction
regression multiple imputation method by IVEware. in the use of hypertonic (2.27% or 3.86%) glucose, which
Results from 20 such imputed datasets were combined for overall was higher than in other countries (Table 2). At a
the final analysis using Rubin’s formula. The proportion of center level, there was considerable variation in the
missing data was ,10% for all imputed covariates, with reported approach to routine membrane function testing.
the exception of urine volume (33%) and transplant waiting In the United States, 13% of centers reported a policy of
list status (26%). Membrane function (80%) and 24-hour routine membrane function testing in prevalent patients,
ultrafiltration (60%) were not imputed or used in models whereas this proportion was 39%, 27%, 73%, and 68% for
due to the amount of missing data. Australia/New Zealand, Canada, Japan, and the United

11375 sample patients

in PDOPPS

• Exclude 2138 patients in Thailand

• Exclude 2241 patients in one of the US
LDOs that has no icodextrin data available
• Exclude 648 patients elsewhere that have
no icodextrin information

6348 patients with

icodextrin data • Exclude 88 hybrid patients
• Exclude 18 CAPD patients with only 1 daily
exchange and that exchange is icodextrin
• Exclude 36 patients with implanted cardiac
defibrillators (ICD)
• Exclude 197 patients with missing or < 3
months vintage
5617 patients in • Exclude 392 patients with no follow-up time
primary analysis

Figure 1. | Patient inclusion and exclusion criteria.

 KIDNEY360 3: 872–882, May, 2022 Icodextrin Prescription in PD Patients, Davies et al. 875

Facility % of patients Facility

Percentile
100%
95th
75th
80% 50th
25th
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5th
60%
mean
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40%

20%

0%
A/NZ Canada Japan UK US
N patients= 552 990 1124 491 2408
N facilities= 21 31 47 30 103
Facilities with at least 5 patients with icodextrin data

Figure 2. | Distribution of the center-level proportion of patients using icodextrin by country, including all patients. A/NZ, Australia/
New Zealand; UK, United Kingdom; US, United States. Note: icodextrin data are not available in one US large dialysis organization.

Kingdom, respectively (Supplemental Figure 3). Overall, of death (hazard ratio [HR]51.03; 95% confidence interval
icodextrin was prescribed in 47% of patients treated in cen- [95% CI], 0.72 to 1.48), HDT (HR51.2; 95% CI, 0.92 to 1.57),
ters that do routine PETs compared with 37% that do not. or death/HDT (HR51.12; 95% CI, 0.9 to 1.38; Figure 5,
model 5). Omitting the dry-day patients on APD did not
Outcome: Peritoneal Ultrafiltration have substantial effects on the outcomes from the instru-
The median 24-hour peritoneal ultrafiltration was 765 ml/d mental variable analyses (Supplemental Table 2). Infection
(interquartile range [IQR] 251–1345) and 750 (IQR 300–1345) was the most common cause of HDT, followed by either
for users and nonusers of icodextrin, respectively. As inadequate solute clearance or ultrafiltration and psychoso-
would be expected, the achieved 24-hour peritoneal ultra- cial/medical problems, among patients with or without
filtration was strongly affected by the residual 24-hour icodextrin use (Supplemental Figure 5).
urine volume (Figure 3). Icodextrin use was not associ-
ated with increased ultrafiltration regardless of whether Subgroup Analyses
the concomitant use of high (any glucose concentration We analyzed the association between icodextrin use and
.1.36%) or low PD glucose prescriptions were used. How- outcomes among a number of subgroups of interest. None
ever, where data were available, this demonstrated prefer- of the interactions investigated had a P value ,0.05
ential use of icodextrin in patients with faster PSTR and after accounting for multiple comparisons by using the
substantially reduced ultrafiltration capacity. This was Benjamini–Hochberg false discovery rate correction, whether
seen in all countries and translated into an equivalent dry-day patients on APD were included or excluded (Figure 6
amount of net 24-hour ultrafiltration stratified for urine Supplemental Tables 3 and 4).
volume when compared with patients not treated with ico-
dextrin (Figures 3 and 4 and Supplemental Figure 4). Ico-
dextrin use was also associated with an equivalent daily Discussion
ultrafiltration volume, despite these patients using sub- In the largest global survey of icodextrin prescription
stantially less hypertonic glucose overall, especially in practices to date, we found substantial country- and center-
those with low urine volume. The patients for whom this level variation in its use. In particular, practices in the
additional information was available did not differ from United States were different from other countries in terms
the whole group in terms of demographics, although the of both a lower frequency of icodextrin use and the lack of
data were relatively more complete for Japan and less an increase in its prescription with time on treatment
complete for the United States. (Supplemental Table 5). The explanation of this marked dif-
ference is likely to be multifactorial, but some postulations
Outcomes: Patient Survival and HDT can be made. The proportion of centers undertaking rou-
During a median follow-up of 1.14 years (IQR 0.62–1.86), tine membrane function testing in prevalent patients was
712 patients died, and 1167 patients had HDT events (the the lowest for the United States (Supplemental Figure 3),
11 patients who died within 7 days of HDT were counted which may translate into a lower likelihood of identifying
as death). When using an instrumental variable analysis, patients who might benefit from icodextrin, or conversely
icodextrin use was not significantly associated with the risk less membrane testing and icodextrin use, so as to keep
 876 KIDNEY360

down dialysis costs, reflecting the US reimbursement

Table 1. Patient characteristics by icodextrin use model. The ANZDATA registry recently reported that the
Characteristics No Icodextrin Icodextrin main center-level factor associated with icodextrin use was
the greater use of membrane function testing (19). Another
Patient/treatment N53631 N51986 likely relevant factor is the consistent finding that the
characteristics patients patients United States appears to be an outlier in the amount of
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Time on PD, yr 1.1 (0.5–2.6) 1.2 (0.5–2.9) ultrafiltration and the use of hypertonic glucose. PDOPPS
,1 48% 46% previously reported that the use of both 2.27%/2.5% and 3.
1–1.9 20% 18%
86%/4.5% glucose/dextrose is substantially higher in the
$2
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33% 37%
Age, yr 60 (15) 62 (15) United States (20); this is confirmed in the present analysis
Men, % 58% 66% in which 45% of patients used the 3.86%/4.5% concentra-
US Black, % 30% 25% tion in at least one exchange, very few (4%–6%) having pre-
Time with ESRD, yr 1.5 (0.6–3.3) 1.6 (0.6–3.5) scriptions without use of either 2.27% or 3.86%, and this is
Body mass index, kg/m2 27 (6) 28 (6) regardless of whether icodextrin is also being used. These
PD modality differences in US practices translate into higher overall
CAPD 24% 36% 24-hour ultrafiltration volumes compared with other coun-
APD 76% 64%
tries, which when combined with urine volume result in
APD with wet day, % 47% 99%
APD with dry day, % 53% 1%
equivalent total fluid removal (see Supplemental Table 1).
Caregiver(s) involved 15% 19% The reasons for these country-level differences cannot be
in PD exchanges, % determined from this study but may include dietary and
Systolic blood pressure, 138 (23) 139 (23) cultural factors, reflected here by the highest body mass
mm Hg index being observed in the US patients. Interestingly, US
,110 9% 9% patients on HD tend to have higher interdialytic weight
110–149 61% 60% gains, pointing to higher fluid intake, which may be reflect-
$150 30% 32%
ing a common underlying cause, such as salt intake (21,22).
Comorbidities
The variability in within-country facility-level prescrip-
Coronary artery disease 19% 25%
Cerebrovascular disease 7% 11% tion of icodextrin cannot be fully explained by this analysis,
Congestive heart failure 10% 13% although again frequency of routine membrane function
Peripheral vascular disease 9% 14% testing had some effect. By contrast, consistent patterns in
Other cardiovascular disease 12% 15% patient-level prescription could be seen. Generally, it was
Hypertension 82% 90% more frequently prescribed when cardiovascular or dia-
Diabetes 46% 51% betic comorbidity was present, when residual kidney func-
Gastrointestinal bleeding 2% 3% tion was lower, and when time on therapy was longer,
Lung disease 4% 6%
suggesting a reactive rather than proactive approach to
Neurologic disease 3% 5%
Psychiatric disorder 16% 12%
fluid management. Where membrane function was mea-
Cancer (nonskin) 9% 12% sured, patients on icodextrin had on average a faster PSTR
Recurrent cellulitis/gangrene 1% 2% in all countries (Table 2). This faster PSTR translated into
Transplant waitlisted, % 42% 37% an average reduction of 200-ml ultrafiltration capacity
Laboratory values (using 2.27% glucose)—enough to be clinically significant
Phosphorus, mg/dl 5.3 (1.5) 5.1 (1.3) and to necessitate the use of more hypertonic glucose if
Hemoglobin, g/L 11 (2) 11 (2) fluid reabsorption is to be avoided. Given that membrane
Albumin, g/dL 3.5 (0.5) 3.3 (0.5)
function was only measured in a small subset of patients, it
Sodium, mEq/L 139 (4) 136 (4)
cannot be assumed that this targeting of icodextrin to
Serum creatinine, mg/dl 8.8 (3.8) 8.8 (3.5)
24-h urine volume, L 0.9 (0.8) 0.8 (0.7) patients with less efficient membranes applied to all
,0.5 34% 41% patients, but this subgroup was representative of the study
0.5–0.9 24% 26% sample based on other similar characteristics. However, it
1.0–1.4 22% 18% is likely to contribute to the explanation of why patients on
$1.5 21% 16% icodextrin did not achieve overall higher levels of ultrafil-
Peritoneal solute transfer ratea 0.66 (0.13) 0.74 (0.12) tration, when stratified for residual urine volume, than
Potassium, mEq/L 4.3 (0.6) 4.2 (0.7) those treated with glucose alone. Randomized trials dem-
HbA1c in diabetic patients, % 7 (1.5) 7 (1.6)
onstrate that ultrafiltration with icodextrin is superior to
Cared for at center that 40% 51%
employs routine PET, % glucose #2.27% in the long exchange (7,8), but this benefit
would be offset by the use of higher concentrations of
Results shown as prevalence, mean (standard deviation), or glucose across remaining exchanges as appears to be the
median (interquartile range). CAPD, continuous ambulatory case in this analysis. The most reasonable conclusion to
peritoneal dialysis; APD, automated peritoneal dialysis; PD, draw from these data is that icodextrin was being used
peritoneal dialysis; PET: peritoneal equilibration test.
a selectively to maintain sufficient ultrafiltration in those
Expressed as 4-hour dialysate/plasma creatinine ratio.
with less efficient membranes and more generally to avoid
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KIDNEY360 3: 872–882, May, 2022

Table 2. Therapy characteristics by country and by icodextrin use

Australia/New Zealand Canada Japan United Kingdom United States

Characteristics Non Icodextrin Icodextrin No Icodextrin Icodextrin No Icodextrin Icodextrin No Icodextrin Icodextrin No Icodextrin Icodextrin

Number of patients 317 238 439 551 622 521 240 267 2013 409
Prescribed therapy volume, L 9.5 (3.4) 11 (4) 9.2 (3.7) 11 (4) 6 (2.4) 6.7 (2.7) 8.9 (3.6) 9.8 (4.2) 11 (4) 12 (4)
Nutrineal, % 0 0 1 2 0 0 0 5 0 0
a a
Neutral pH low GDP, % 34 32 9 6 100 99 23 30
PD solution type
Use of 2.27% but not 3.86% 73% 80% 53% 64% 27% 44% 44% 46% 53% 54%
Use of any 3.86% 10% 9% 13% 15% 0% 0% 1% 3% 42% 43%
Without any 2.27% or 3.86% use 17% 12% 34% 21% 73% 56% 55% 52% 6% 4%
Residual Kt/V urea 1 (0.9) 0.7 (0.7) 0.9 (0.8) 0.7 (0.6) 0.9 (0.7) 0.6 (0.5) 1.2 (0.7) 0.9 (0.6) 0.9 (0.8) 0.4 (0.5)
Peritoneal Kt/V urea 1.3 (0.6) 1.3 (0.5) 1.2 (0.6) 1.4 (0.5) 1 (0.4) 1.1 (0.4) 1.1 (0.5) 1.2 (0.5) 1.5 (0.5) 1.6 (0.5)

Icodextrin Prescription in PD Patients, Davies et al.

Total Kt/V urea 2.3 (0.8) 2.1 (0.8) 2.1 (0.9) 2.1 (0.7) 1.9 (0.6) 1.7 (0.4) 2.4 (0.7) 2.1 (0.6) 2.3 (0.7) 2.1 (0.5)

Results shown as prevalence or mean (standard deviation). GDP, glucose degradation product; PD, peritoneal dialysis.
a
Low GDP, neutral-pH solutions are not commercially available in the United States.

877
 878 KIDNEY360

A 24 hour peritoneal UF Urine volume, L/24 hours Percentile

5,000 <0.50 0.50–0.99 1.00–1.49 1.50+ 95th
75th
4,000 50th
25th
3,000
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5th
2,000 mean
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1,000

–1,000

–2,000

N patients= 104 77 63 55 126 124 132 105 84 77 82 71 44 51 48 76 372 214 162 123
A/NZ Canada Japan UK US

B 24 hour peritoneal UF Urine volume, L/24 hours Percentile

4,000 <0.50 0.50–0.99 1.00–1.49 1.50+ 95th
75th
3,000 50th
25th
2,000 5th
mean
1,000

–1,000

–2,000
N patients= 327 216 190 146 26 67 104 111 248 151 100 88 42 54 53 54
High glucose Low glucose High glucose Low glucose
Without lcodextrin use With lcodextrin use

Figures 3. | Twenty-four-hour peritoneal UF stratified by urine volume and country (upper panel), and by icodextrin and glucose pre-
scriptions. High-glucose prescription was defined as any 2.27% or 3.86% solution use. Low-glucose prescription was defined as no
2.27% or 3.86% solution use. As urine volume decreases UF increases, more markedly in the US. Ultrafiltration according to icodextrin
use is not different at equivalent categories of urine volume and glucose prescription. UF, ultrafiltration.

excessive use of hypertonic glucose. The exception to this may mitigate this survival disadvantage, especially as there
was prescription practice in the United States. is evidence that it was used preferentially in this half of the
This analysis did not find a beneficial association population. Unfortunately, there were insufficient meas-
between icodextrin use and patient survival or HDT. ures of membrane function for this hypothesis to be tested
Indeed, icodextrin use was associated with worse survival here, despite the size of PDOPPS.
unless this was adjusted for urine volume and plasma albu- In an attempt to account for treatment by indication bias,
min (Figure 5). This likely reflects its preferential use in we undertook an instrumental variable analysis. This tech-
patients with risk factors for worse volume status. Its fail- nique depends on the assumption that the likelihood of a
ure to improve survival may well reflect our finding that patient being prescribed icodextrin would in part be deter-
icodextrin was not associated with more overall ultrafiltra- mined by the overall propensity of their PD center to pre-
tion compared with its nonuse in contrast to randomized scribe icodextrin. In particular, this would take advantage
trials in which it is one of the proposed mechanisms by of the marked differences, especially by country, but also
which it confers clinical benefit (7,8). Given the known by facilities within countries in the proportion of patients
association between faster than average PSTR and worse receiving icodextrin. Potentially this approach would have
survival, it might be postulated that the use of icodextrin most benefited from the discrepancy in icodextrin
 KIDNEY360 3: 872–882, May, 2022 Icodextrin Prescription in PD Patients, Davies et al. 879

A B
D/P creatinine PET UF capacity
Percentile Percentile
1.0 1,200
95th 95th
75th 1,000 75th
0.8 50th 800 50th
25th 25th
5th 600 5th
0.6
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mean 400 mean

200
0.4
0
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0.2 –200
–400
0.0 –600
Without icodextrin With icodextrin Without icodextrin With icodextrin
N patients= 656 445 N patients= 659 462

Figure 4. | Peritoneal solute transfer characteristics and UF capacity at study baseline by icodextrin use. (A) D/P creatinine. (B) PET UF
capacity. D/P, dialysate to plasma creatinine ratio at 4 hours on the PET. PET, peritoneal equilibration test.

prescription observed between the United States and other This may relate to confounding based on icodextrin use
countries. Another confounding factor in this analytic and differences in peritonitis treatment practices across
approach is the other potential indications for prescribing facilities. Previous studies have shown that icodextrin
icodextrin such as improved glycemic control in diabetics reduced biofilm biomass on PD catheters, probably due to
(23,24), reduced insulin resistance (25), and avoidance of the lack of glucose as carbon source compared with bicar-
other concerns that relate to glucose exposure such as bonate/lactate buffered glucose-based solution (28,29).
weight gain and dialysate-associated membrane injury (26). However, a beneficial effect of icodextrin on HDT was not
These might explain the large country and center differ- observed in the present study.
ences in prescribing that have not been examined here. This study has limitations. As for all observational stud-
The lack of effect on overall risk of HDT was not unex- ies, especially when the proportion of prevalent subjects is
pected. In this regard, the PDOPPS cohort is in keeping high, the inferences with respect to cause and effect require
with previous randomized controlled trials (7,8). It might testing in interventional studies, and this is still true,
be anticipated that icodextrin use would have a positive despite our use of statistical adjustment and instrumental
effect on transfers to HD due to suboptimal salt and water variables approach to reduce bias. This is especially true if
removal, but this occurred in only 27% of overall HDT there are unmeasured clinical practices affecting clinical
events, ranging from 15% in the United States to 41% in outcomes that also increase the likelihood of icodextrin use.
Japan. In another PDOPPS analysis, we recently found that As already indicated, a significant limitation is the missing-
greater center use of icodextrin was associated with an ness of data relating to membrane function, the achieved
increased likelihood of cure after a peritonitis episode (27). 24-hour ultrafiltration, and residual urine volume. The rea-
son for this is that we have only included data for measure-
ment of these parameters at 4 months of the study baseline
HR(95% CI) at which the icodextrin prescription was documented. It is
Model1 Model2 Model3 Model4 Model5 also clear that many facilities do not measure these varia-
bles routinely. Given that PDOPPS is a prevalent study,
2.5
this component of the dataset was inevitably incomplete.
2.0 We compared the characteristics of patients (see Table 2)
1.5
who had these measures with those who did not, and we
1.3 found that there were no differences in the patient popula-
1.1 tions, suggesting that the data missingness reflected local
1.0 measurement practice rather than a selected patient effect.
0.8 This did affect our ability to construct a survival model
0.7 that included membrane function, known to be strongly
Death HDT Death/HDT associated with survival on peritoneal dialysis. Overall,
data missingness was affected by country, being least in
Japan and greatest in the United States. Furthermore, data
Figure 5. | Association between icodextrin and clinical outcomes were not available on icodextrin prescription from a large
by sequential adjustment. Instrumental variable models stratified dialysis organization in the United States, which was
by country and US large dialysis organization, accounting for cen-
excluded from this analysis. If anything, this may have
ter clustering. Model 1, adjusted for DOPPS phase only. Model 2,
model 11age, men, vintage. Model 3, model 21comorbidities, increased the observed differences between the United
transplant waiting list. Model 4, model 31urine volume, albumin. States and other countries. The lack of an objective
Model 5, model 41center size, center % APD. DOPPS, Dialysis measurement of volume status (e.g., bioimpedance) or
Outcomes and Practice Patterns Study; APD, automated peritoneal assessment of dietary salt and fluid intake is a further
dialysis. limitation.
 880 KIDNEY360

Sub-groups Icodextrin better Non-icodextrin better

All (n=5617)
CAPD patients (n=1594)
APD patients (n=4023)
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Without RKF (n=1175)

With RKF (n=4442)

US (n=2422)
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Japan (n=1143)
Other countries (n=2052)

Age 65+ yrs (n=2448)

Age < 65 yrs (n=3169)

PD vintage <1 yrs (n=2625)

PD vintage 1–1.9 yrs (n=1070)
PD vintage 2+ yrs (n=1922)
Non low GDP solution (n=1664)
Low GDP solution (n=1531)

BMI<25 (n=2222)
BMI 25–29 (n=1755)
BMI 30+ (n=1640)
0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0
Mortality HDT Mortality or HDT
Adjusted Hazard Ratio (95% CI)

Figure 6. | Association between icodextrin and clinical outcomes. All models stratified by country, and adjusted for PDOPPS phase, age,
sex, vintage, 13 comorbidities, transplant waiting list, center % APD, center size, albumin, urine volume, and accounting for center clus-
tering. Number of events: mortality 712, HDT 1167, mortality/HDT 1879. Patients from Japan and the United States were excluded from
the low GDP solution subgroup analysis because low-GDP solutions were not available in the US and were used exclusively in Japan.
RKF was defined as 24-hour urine volume $0.2 L. Other countries included Australia/New Zealand, Canada, and the United Kingdom.
CAPD, continuous ambulatory peritoneal dialysis; PD, peritoneal dialysis; GDP, glucose degradation product; BMI, body mass index. All
P values for interactions are .0.05.

In summary, there is variation in icodextrin use in the investigator and current recipient of the National Research Council
PDOPPS countries, with notably low use in the United of Thailand and Innovation Fund Chulalongkorn University.
States where there is much greater dependency on high received speaking honoraria from AstraZeneca and Baxter Health-
glucose concentration solutions, resulting in overall greater care. K.P. McCullough, R.L. Pisoni, B.M. Robinson, and J. Zhao are
net ultrafiltration. There is also considerable variability in employees of Arbor Research Collaborative for Health, which
icodextrin use between facilities in every country. Across funds the DOPPS. R. Mehrotra received consulting fee from Baxter
all countries, icodextrin use is more common among Healthcare. J. Perl received grants from AHRQ; consulting fee
patients who have less residual kidney function and mem- from Baxter Healthcare, Davita, Fresenius Medical Care, and
branes that are less efficient at removing fluid with glucose, Otsuka; honoraria from Baxter Healthcare, Davita Healthcare Part-
and possibly because of this, the achieved daily ultrafiltra- ners, DCI, Fresenius Medical Care, and US Renal Care; support for
tion is not different between those using versus not. There attending meetings and/or travel from Liberdi Dialysis; and stock
is, however, considerable variability in routine membrane or stock options from Liberdi dialysis. B.M. Robinson received con-
evaluation, which may be limiting the use of icodextrin. sultancy fees or travel reimbursement since 2018 from AstraZe-
Icodextrin also tends to be used in those who have been on neca, GlaxoSmithKline, and Kyowa Kirin Co., all paid directly to
dialysis for longer and have more comorbidities, suggest- his institution of employment. A.Y.-M. Wang participated on a
ing that further evaluation of a proactive approach to its Data Safety Monitoring Board or Advisory Board (DSMB
use may be necessary earlier in the course of PD therapy. ASPIRED TRIAL) and is International Society of Nephrology (ISN)
Use of icodextrin therefore appears to be targeted toward a Councilor and North and East Asia Regional Board Deputy Chair,
group expected to have worse survival chances, and this ISN Education working group Deputy Chair Council Member of
cannot be completely accounted for by survival modeling. International Society of Peritoneal Dialysis, and President of Inter-
Its use can, however, avoid the excessive use of hypertonic national Society of Renal Nutrition and Metabolism. All remaining
glucose without detriment. authors have nothing to disclose.

Disclosures Funding
S.J. Davies received consulting fees from Baxter Healthcare and This manuscript was directly supported by Baxter Healthcare.
Ellen Medical, and honoraria from Fresenius Medical Care. T. Kan- The Dialysis Outcomes and Practice Patterns Study (DOPPS) Pro-
janabuch received consultancy fees from VISTERA as a country gram is funded by a consortium of private industry, public
 KIDNEY360 3: 872–882, May, 2022 Icodextrin Prescription in PD Patients, Davies et al. 881

funders, and professional societies. More information on DOPPS Supplemental Figure 3. Percent of facilities routinely performing
funding can be found here: https://www.dopps.org/AboutUs/ peritoneal equilibration test (PET) by country.
Support.aspx. Specific grant support for UK patient involvement is Supplemental Figure 4. Twenty-four-hour peritoneal ultrafiltra-
from Kidney Research UK and the National Institutes of Health tion by urine volume, icodextrin, and glucose, excluding dry-day
Research (all payments to the employing institution, Keele Univer- patients.
sity). Funding for PDOPPS was provided by: the National Health Supplemental Figure 5. Reasons for permanent switch to hemo-
Downloaded from http://journals.lww.com/kidney360 by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw

and Medical Research Council (Australia); the National Institute dialysis/hybrid by icodextrin use at baseline.
for Health Research (United Kingdom); the National Institute of Supplemental Table 1. Patient characteristics by country and by
Diabetes and Digestive and Kidney Diseases (United States); the icodextrin use.
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 12/31/2024

Patient-Centered Outcomes Research Institute (United States); the Supplemental Table 2. Proportion of patients started icodextrin
Japanese Society of Peritoneal Dialysis; the Canadian Institute for by country and by months since start of peritoneal dialysis.
Health Research; Baxter International, Inc. (United States); the Supplemental Table 3. Icodextrin use and clinical outcomes,
National Research Council of Thailand (2558-113); Rachadaphisek- excluding automated peritoneal dialysis dry-day patients.
sompot Endorcement Fund (GCURS_59_12_30_03), Chulalongkorn Supplemental Table 4. P values for interactions by model type
University, Thailand; and the National Science and Technology and outcome, including all patients.
Development Agency (NSTDA), Thailand. Supplemental Table 5. P values for interactions by model type
and outcomes, excluding automated peritoneal dialysis dry-day
Acknowledgments patients.
We acknowledge and thank the following individuals for their
contributions: PDOPPS Dialysis Prescription and Fluid Manage- References
ment Work Group Members: Angela Wang (Hong Kong), John 1. Wang AY, Dong J, Xu X, Davies S: Volume management as a
Burkart (United States), Gillian Brunier (Canada), Hideki Kawa- key dimension of a high-quality PD prescription. Perit Dial Int
nishi (Japan), Sunil Badve (Australia), Suchai Sritippayawan 40: 282–292, 2020 https://doi.org/10.1177/
(Thailand), Sarinya Boongird (Thailand), Andreas Vychytil (Aus- 0896860819895365
2. Kim YL, Biesen WV: Fluid overload in peritoneal dialysis
tria), Wim Van Biesen (Belgium), and Thyago de Moraes (Bra-
patients. Semin Nephrol 37: 43–53, 2017 https://doi.org/10.
zil). We also thank Jennifer McCready-Maynes, an employee of 1016/j.semnephrol.2016.10.006
Arbor Research Collaborative for Health, who provided editorial 3. Mujais S, Story K: Peritoneal dialysis in the US: Evaluation of
assistance on this paper. outcomes in contemporary cohorts. Kidney Int Suppl 70:
S21–S26, 2006 https://doi.org/10.1038/sj.ki.5001912
4. Jaar BG, Plantinga LC, Crews DC, Fink NE, Hebah N, Coresh J,
Author Contributions Kliger AS, Powe NR: Timing, causes, predictors and prognosis
S.V. Badve, S.J. Davies, T. Kanjanabuch, H. Kawanishi, of switching from peritoneal dialysis to hemodialysis: A pro-
K.P. McCullough, R. Mehrotra, J. Perl, R. Pisoni, B.M. Robinson, spective study. BMC Nephrol 10: 3, 2009 https://doi.org/10.
1186/1471-2369-10-3
A.Y.-M. Wang and J. Zhao were responsible for the final approval
5. Davies SJ, Woodrow G, Donovan K, Plum J, Williams P,
of the manuscript to be published; S.J. Davies, T. Kanjanabuch, Johansson AC, Bosselmann HP, Heimbu €rger O, Simonsen O,
H. Kawanishi, Y.-L. Kim, K.P. McCullough, J. Perl, R. Pisoni, Davenport A, Tranaeus A, Divino Filho JC: Icodextrin improves
B.M. Robinson, A.Y.-M. Wang, and J. Zhao provided intellectual the fluid status of peritoneal dialysis patients: Results of a
double-blind randomized controlled trial. J Am Soc Nephrol
content of critical importance to the work described; S.J. Davies,
14: 2338–2344, 2003 https://doi.org/10.1097/01.ASN.
Y.-L. Kim, K.P. McCullough, R. Mehrotra, J. Perl, R. Pisoni, 0000083904.12234.27
B.M. Robinson, A.Y.-M. Wang, and J. Zhao were responsible for 6. Konings CJ, Kooman JP, Schonck M, Gladziwa U, Wirtz J, van
the conception or design, or analysis and interpretation of data, or den Wall Bake AW, Gerlag PG, Hoorntje SJ, Wolters J, van der
both; and S.J. Davies, Y.-L. Kim, K.P. McCullough, J. Perl, Sande FM, Leunissen KM: Effect of icodextrin on volume status,
blood pressure and echocardiographic parameters: A random-
R. Pisoni, B.M. Robinson, and J. Zhao were responsible for drafting ized study. Kidney Int 63: 1556–1563, 2003 https://doi.org/10.
the article or revising it. 1046/j.1523-1755.2003.00887.x
7. Htay H, Johnson DW, Wiggins KJ, Badve SV, Craig JC, Strippoli
GF, Cho Y: Biocompatible dialysis fluids for peritoneal dialysis.
Data Sharing Statement Cochrane Database Syst Rev 10: CD007554, 2018
The data that support the findings of this study are available 8. Goossen K, Becker M, Marshall MR, Bu €hn S, Breuing J, Firanek
from Arbor Research Collaborative for Health, but restrictions CA, Hess S, Nariai H, Sloand JA, Yao Q, Chang TI, Chen J,
Paniagua R, Takatori Y, Wada J, Pieper D: Icodextrin versus
apply to the availability of these data which were used for the cur-
glucose solutions for the once-daily long dwell in peritoneal
rent study, and so are not publicly available. Data are, however, dialysis: An enriched systematic review and meta-analysis
available from the authors upon reasonable request and with per- of randomized controlled trials. Am J Kidney Dis 75:
mission of Arbor Research Collaborative for Health. 830–846, 2020 https://doi.org/10.1053/j.ajkd.2019.
10.004
9. Mehrotra R, Ravel V, Streja E, Kuttykrishnan S, Adams SV, Katz
Supplemental Material R, Molnar MZ, Kalantar-Zadeh K: Peritoneal equilibration test
This article contains supplemental material online at http:// and patient outcomes. Clin J Am Soc Nephrol 10: 1990–2001,
2015 https://doi.org/10.2215/CJN.03470315
kidney360.asnjournals.org/lookup/suppl/doi:10.34067/KID. €
10. Morelle J, Stachowska-Pietka J, Oberg C, Gadola L, La Milia V,
0006922021/-/DCSupplemental. Yu Z, Lambie M, Mehrotra R, de Arteaga J, Davies S: ISPD rec-
Supplemental Figure 1. Icodextrin use by peritoneal dialysis vin- ommendations for the evaluation of peritoneal membrane dys-
tage and by country. function in adults: Classification, measurement, interpretation
and rationale for intervention. Perit Dial Int 41: 352–372, 2021
Supplemental Figure 2. Distribution of the center-level propor-
https://doi.org/10.1177/0896860820982218
tion of patients using icodextrin by country, excluding automated 11. Perl J, Davies SJ, Lambie M, Pisoni RL, McCullough K, Johnson
peritoneal dialysis dry-day patients. DW, Sloand JA, Prichard S, Kawanishi H, Tentori F, Robinson
 882 KIDNEY360

BM: The Peritoneal Dialysis Outcomes and Practice Patterns time and slower ultrafiltration in hemodialysis: Associations
Study (PDOPPS): Unifying efforts to inform practice and with reduced mortality in the DOPPS. Kidney Int 69:
improve global outcomes in peritoneal dialysis. Perit Dial Int 1222–1228, 2006 https://doi.org/10.1038/sj.ki.5000186
36: 297–307, 2016 https://doi.org/10.3747/pdi.2014.00288 23. Li PK, Dorval M, Johnson DW, Rutherford P, Shutov E, Story K,
12. Angrist JD, Imbens GW, Rubin DB: Identification of causal Bargman JM: The benefit of a glucose-sparing PD therapy on
effects using instrumental variables. J Am Stat Assoc 91: glycemic control measured by serum fructosamine in diabetic
444–455, 1996 https://doi.org/10.1080/01621459.1996.10476902 patients in a randomized, controlled trial (IMPENDIA).
Nephron 129: 233–240, 2015 https://doi.org/10.1159/
Downloaded from http://journals.lww.com/kidney360 by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw

13. Wooldridge J: Introductory Econometrics: A Modern Approach,

4th Ed., Nashville, NT, South-Western College Publishing, 000371554
2002, pp 506–545 24. Sniderman AD, Sloand JA, Li PK, Story K, Bargman JM:
14. Newhouse JP, McClellan M: Econometrics in outcomes Influence of low-glucose peritoneal dialysis on serum lipids
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 12/31/2024

research: The use of instrumental variables. Annu Rev Public and apolipoproteins in the IMPENDIA/EDEN trials. J Clin Lip-
Health 19: 17–34, 1998 https://doi.org/10.1146/annurev. idol 8: 441–447, 2014 https://doi.org/10.1016/j.jacl.2014.
publhealth.19.1.17 03.007
15. Greenland S: An introduction to instrumental variables for epi- 25. de Moraes TP, Andreoli MC, Canziani ME, da Silva DR, Cara-
demiologists. Int J Epidemiol 29: 722–729, 2000 https://doi.org/ mori JC, Ponce D, Cassi HV, de Andrade Bastos K, Rio DR,
10.1093/ije/29.4.722 Pinto SW, Filho SR, de Campos LG, Olandoski M, Divino-Filho
16. Pisoni RL, Arrington CJ, Albert JM, Ethier J, Kimata N, Krishnan JC, Pecoits-Filho R: Icodextrin reduces insulin resistance in
M, Rayner HC, Saito A, Sands JJ, Saran R, Gillespie B, Wolfe non-diabetic patients undergoing automated peritoneal dialysis:
RA, Port FK: Facility hemodialysis vascular access use and mor- Results of a randomized controlled trial (STARCH). Nephrol
tality in countries participating in DOPPS: An instrumental vari- Dial Transplant 30: 1905–1911, 2015 https://doi.org/10.1093/
able analysis. Am J Kidney Dis 53: 475–491, 2009 https://doi. ndt/gfv247
org/10.1053/j.ajkd.2008.10.043 26. Davies SJ, Brown EA, Frandsen NE, Rodrigues AS, Rodriguez-
17. Stock JH, Wright JH, Yogo M: A survey of weak instruments Carmona A, Vychytil A, Macnamara E, Ekstrand A, Tranaeus A,
and weak identification in generalized method of moments. Filho JC; EAPOS Group: Longitudinal membrane function in
J Bus Econ Stat 20: 518–529, 2002 https://doi.org/10.1198/ functionally anuric patients treated with APD: Data from
073500102288618658 EAPOS on the effects of glucose and icodextrin prescription.
18. Burgess S, Thompson SG; CRP CHD Genetics Collaboration: Kidney Int 67: 1609–1615, 2005 https://doi.org/10.1111/j.
Avoiding bias from weak instruments in Mendelian randomiza- 1523-1755.2005.00243.x
tion studies. Int J Epidemiol 40: 755–764, 2011 https://doi.org/ 27. Al Sahlawi M, Zhao J, McCullough K, Fuller DS, Boudville N,
10.1093/ije/dyr036 Ito Y, Kanjanabuch T, Nessim SJ, Piraino BM, Pisoni RL,
19. Rangaswamy D, Guddattu V, Webster AC, Borlace M, Boud- Teitelbaum I: Variation in peritoneal dialysis-related peritonitis
ville N, Clayton P, Badve S, Johnson DW, Sud K: Icodextrin outcomes in the Peritoneal Dialysis Outcomes and Practice
use for peritoneal dialysis in Australia: A cohort study using Patterns Study (PDOPPS). Am J Kidney Dis 79: 45–55.e1, 2022
Australia and New Zealand Dialysis and Transplant Registry. https://doi.org/10.1053/j.ajkd.2021.03.022
Perit Dial Int 40: 209–219, 2020 https://doi.org/10.1177/ 28. Vychytil A, Remo n C, Michel C, Williams P, Rodrıguez-Car-
0896860819894058 mona A, Marro n B, Vonesh E, van der Heyden S, Divino Filho
20. Wang AY, Zhao J, Bieber B, Kanjanabuch T, Wilkie M, Mar- JC; Extraneal Peritonitis Study Group: Icodextrin does not
shall MR, Kawanishi H, Perl J, Davies S; PDOPPS Dialysis Pre- impact infectious and culture-negative peritonitis rates in peri-
scription and Fluid Management Working Group: International toneal dialysis patients: A 2-year multicentre, comparative, pro-
comparison of peritoneal dialysis prescriptions from the Perito- spective cohort study. Nephrol Dial Transplant 23: 3711–3719,
neal Dialysis Outcomes and Practice Patterns Study (PDOPPS). 2008 https://doi.org/10.1093/ndt/gfn322
Perit Dial Int 40: 310–319, 2020 https://doi.org/10.1177/ 29. Sampaio J, Machado D, Gomes AM, Machado I, Santos C,
0896860819895356 Lima N, Carvalho MJ, Cabrita A, Rodrigues A, Martins M: Deci-
21. Wong MM, McCullough KP, Bieber BA, Bommer J, Hecking M, phering the contribution of biofilm to the pathogenesis of peri-
Levin NW, McClellan WM, Pisoni RL, Saran R, Tentori F, Tomo toneal dialysis infections: Characterization and microbial
T, Port FK, Robinson BM: Interdialytic weight gain: Trends, pre- behaviour on dialysis fluids. PLoS One 11: e0157870, 2016
dictors, and associated outcomes in the international Dialysis https://doi.org/10.1371/journal.pone.0157870
Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis Received: October 29, 2021 Accepted: February 22, 2022
69: 367–379, 2017 https://doi.org/10.1053/j.ajkd.2016.08.030
22. Saran R, Bragg-Gresham JL, Levin NW, Twardowski ZJ, Wize- See related editorial, “Icodextrin in Peritoneal Dialysis: Implica-
mann V, Saito A, Kimata N, Gillespie BW, Combe C, Bommer tions on Clinical Practice and Survival Outcome,” on pages
J, Akiba T, Mapes DL, Young EW, Port FK: Longer treatment 793–795.