Advances in Peritoneal Dialysis, Vol. 30, 2014
Katarzyna Janda,1 Marcin Krzanowski,1 Paulina Dumnicka,2
Beata Kuśnierz–Cabala,3 Przemysław Miarka,1 Władysław
Sułowicz1
The aim of the present study was to assess the influence of peritoneal permeability expressed as the
dialysate-to-plasma ratio of creatinine (D/P Cr) on
total and cardiovascular (CV) mortality in a population of peritoneal dialysis (PD) patients during a
6-year observation period.
The study recruited 55 patients (mean age: 53
years) treated with PD for a median of 24 months.
Hematology parameters and serum albumin were
determined using routine methods. Tumor necrosis
factor α (TNF-α) and transforming growth factor β1
(TGF-β1) were determined by high-sensitivity ELISA.
Peritoneal transport characteristics were identified
using D/P Cr reference values after a peritoneal
equilibration test.
During the 6-year observation period, 22 patients
(40%) died, mostly from CV complications (77% of
deaths). In multiple Cox regression, D/P Cr and dialysate volume at PD initiation predicted total [hazard
ratio (HR): 1.57; p = 0.02; and HR: 1.20; p = 0.04
respectively] and CV mortality (HR: 1.65; p = 0.02;
and HR: 1.23; p = 0.05 respectively) independent
of age, dialysis therapy duration, serum albumin
concentration, dialysis adequacy measures, TGF-β1,
and TNF-α. Additionally, TNF-α was independently
associated with all-cause and CV mortality, and
albumin, with all-cause mortality.
Baseline D/P Cr was a strong independent marker
of survival in PD patients. Baseline D/P Cr and
From: 1Chair and Department of Nephrology, 2Department of Medical Diagnostics, and 3Chair of Clinical Biochemistry, Jagiellonian University, Collegium Medicum,
Cracow, Poland.
Peritoneal Solute Transport
Rate as an Independent
Risk Factor for Total and
Cardiovascular Mortality in
a Population of Peritoneal
Dialysis Patients
dialysate volume were independent risk factors for
total and CV mortality in the PD population and could
be significant for assessing CV risk in this population.
Key words
Cardiovascular mortality, peritoneal solute transport
rate, total mortality
Introduction
Cardiovascular (CV) diseases are the most frequent
cause of comorbidity and mortality in patients with
end-stage renal disease. Traditional risk factors for
CV disease such as advanced age, diabetes mellitus,
fluid volume overload, hypertension, and hyperlipidemia frequently coexist in patients with chronic
kidney disease. The various dialysis modalities,
such as continuous ambulatory peritoneal dialysis
(CAPD), automated peritoneal dialysis (APD), and
hemodialysis have different effects on fluid volume
control. Automated peritoneal dialysis (PD) shares
some characteristics with CAPD, and with the shorter
dwell times used in APD, higher ultrafiltration volumes can be obtained (1).
Peritoneal transport characteristics play an important role in determining morbidity, mortality, and
management in PD patients. Small-solute peritoneal
transport is assessed by the peritoneal equilibration
test (2). Peritoneal transport varies from one patient
to another and can change over time in the same
patient. Patients with high small-solute peritoneal
transport have an increased risk of morbidity and
mortality despite their more rapid diffusive clearance
of urea and creatinine. In patients with high peritoneal small-solute transport, the increased risk of
mortality can potentially be mitigated by combining
16
optimization of the short dwell times of APD with
icodextrin use, rather than by using CAPD (3). Increases in the peritoneal solute transport rate (PSTR)
are associated with an increased risk of mortality
and a tendency to increased technique failure (4–7).
Development of a high PSTR has been attributed to
numerous factors, including hypoalbuminemia, comorbid disease, duration of PD (with exposure to
high glucose), number and severity of peritonitis
episodes, loss of residual renal function (RRF), and
bioincompatible dialysis fluid (8–10).
The aim of the present study was to assess the influence of peritoneal permeability—expressed as the
dialysate-to-plasma ratio of creatinine (D/P Cr)—on
total and CV mortality in a population of PD patients
during a 6-year observation period.
Methods
The study group consisted of 55 patients (25
women, 30 men; mean age: 53 ± 13 years) being
treated with PD (27 on APD, 28 on CAPD). Median duration of dialysis treatment was 24 months
(range: 4 – 100 months).
On the day of blood collection, serum albumin
was measured using an automated clinical chemistry
analyzer (Modular P: Roche Diagnostics, Mannheim,
Germany), and hematology parameters were assessed
using an automated hematology analyzer (Sysmex
XE 2100: Sysmex Corporation, Kobe, Japan). Sera
samples for other laboratory tests were aliquoted and
stored at more than –70°C. Measurements of tumor
necrosis factor α (TNF-α) and transforming growth
factor β1 (TGF-β1) were performed using highsensitivity ELISA kits (R&D Systems, Minneapolis,
MN, U.S.A.). References ranges for the tests (Table I)
represent the values set by the manufacturers.
Peritoneal transport characteristics were identified using D/P Cr reference values after a peritoneal
equilibration test (2,11). In addition, the PD dose
was assessed using weekly Kt/V, weekly creatinine
clearance (CCr), RRF, and dialysate volume. Body
mass index was calculated using the Quetelet index. Data on mortality were collected over a 6-year
(72-month) period. All deaths occurred in hospital,
and the causes of death were determined according
to disease history.
The study was approved by the Bioethics Committee of Jagiellonian University, and all patients
provided informed consent for their participation.
PSTR as a Predictor for Mortality in PD Patients
Statistical analysis
Number and proportion of patients in a group are reported for categorical variables, and mean ± standard
deviation or median with lower and upper quartiles
are reported for continuous variables, according to
distribution. The Shapiro–Wilks test was used to
assess normality. Spearman coefficients were used
to assess simple correlations (at least 1 variable being non-normally distributed). Survival curves were
computed by the Kaplan–Meier method. Unadjusted
and adjusted hazard ratios (HRs) for all-cause and
cardiovascular mortality were estimated by Cox proportional regression and are reported with 95% confidence intervals (CIs). All tests were two-sided, and
results at p ≤ 0.05 were considered significant. The
Statistica 9.0 statistical software application (StatSoft,
Tulsa, OK, U.S.A.) was used for all computations.
Results
Table I presents clinical and biochemical characteristics and dialysis adequacy parameters for the
study group.
During the 6-year observation period, 22 patients
died (17 from CV causes, 3 from encapsulating peritoneal sclerosis, and 2 from infections), 19 patients
(35%) were transferred to hemodialysis, and 11 (20%)
underwent renal transplantation. Median overall
survival was 37 months.
In univariate analysis, the D/P Cr was significantly positively associated with all-cause mortality
(HR per 0.1 increase: 1.49; 95% CI: 1.08 to 2.04;
p = 0.01) and approached statistical significance for
mortality from CV causes (HR per 0.1 increase: 1.43;
95% CI: 0.99 to 2.04; p = 0.054). Figure 1 presents
cumulative survival for patients having high-average
and high (HA/H) peritoneal permeability (D/P Cr ≥
0.65) compared with those having low-average and
low (LA/L) peritoneal permeability (D/P Cr < 0.65).
Significant correlations with mortality were also
shown for dialysate volume (HR for all-cause mortality: 1.21; 95% CI: 1.04 to 1.41; p = 0.02; HR for
CV mortality: 1.21; 95% CI: 1.02 to 1.45; p = 0.03).
Another significant predictor of all-cause and CV
mortality was TNF-α (HR: 1.57; 95% CI: 1.14 to 2.18;
p = 0.006; HR: 1.70; 95% CI: 1.19 to 2.44; p = 0.004
respectively). Albumin was associated with overall
survival (HR: 0.89; 95% CI: 0.81 to 0.99; p = 0.03).
Using multivariable analysis, we studied associations with survival in the context of dialysis adequacy
Janda et al.
table i
17
Characteristics of the study group
Characteristic
Value
[n (%)]
Patients
Age (years)
Sex
Men
Women
Dialysis duration (months)
Hypertension
Ischemic heart disease
Observation period (months)
All-cause mortality
Cardiovascular mortality
Body mass index (kg/m2)
Hemoglobin (g/dL)
White blood cells (×103/μL)
Albumin (g/L)
TNF-α (pg/mL)
TGF-β1 (ng/mL)
Weekly Kt/V
Weekly CCr (L/1.73 m2)
RRF (mL/min/1.73 m2)
D/P creatinine
Dialysate volume (dL/24 h)
Mean or
median
IQR
Min
Max
Reference
19
75
—
—
55
53±13
30 (55)
25 (45)
24
15–51
4
100
20
6–45
1
72
25.3±4.1
11.9±1.6
17.2
7.7
34.2
15.3
7.48±2.43
37.9±4.9
2.89
4.22
2.22
68.0
1.72
0.63±0.13
8.0
2.77
20.0
1.37
1.92
1.34
43.2
0
0.38
6.0
14.33
47.0
7.91
20.06
5.26
213.8
11.33
0.91
15.5
47 (85)
21 (38)
22 (40)
17 (31)
2.26–3.54
3.22–5.63
1.93–2.63
58.8–95.7
0.04–4.62
8.0–10.0
—
—
—
—
—
—
—
—
20–25
Women: 11.0–15.0
Men: 12.0–17.0
4.0–10.0
35–50
0–4.71
0.903–1.654
>1.7
>45
—
0.34–1.03
—
IQR = interquartile range; Min = minimum; Max = maximum; TNF-α = tumor necrosis factor α; TGF-β1 = transforming growth
factor β1; CCr = creatinine clearance; RRF = residual renal function.
(weekly Kt/V and CCr), RRF, TGF-β1, age, and
dialysis duration. However, the correlation of D/P
Cr with dialysate volume was so highly significant
(R = 0.45, p = 0.0005) that, to avoid redundancy, we
constructed separate multiple Cox regression models
including either D/P Cr or dialysate volume.
In multivariable Cox regression, D/P Cr was
an independent predictor of total and CV mortality
(Table II). Similarly, dialysate volume was shown to
predict mortality independently of the other studied
variables (Table III). Additionally, proinflammatory
TNF-α was independently associated with total and
CV mortality (Tables II and III).
1 Kaplan–Meier survival curves for all-cause mortality
in patients with a dialysate-to-plasma creatinine ratio of 0.65 or
more (solid line) and less than 0.65 (dashed line), log-rank p = 0.08.
figure
Discussion
In PD, the PSTR is a major determinant of patient
survival. Our study shows that in the population
of PD patients, D/P Cr and dialysate volume both
18
table ii
PSTR as a Predictor for Mortality in PD Patients
Cox regression models including dialysate-to-plasma (D/P) creatinine
Independent variable
D/P creatinine
Albumin
TNF-α
TGF-β1
Weekly Kt/V
Weekly CCr
RRF
Dialysis duration
Age
Change of 0.1
Grams per liter
Picograms per milliliter
Nanograms per milliliter
Liters per 1.73 m2
Milliliters per minute per 1.73 m2
Months
Years
All-cause mortality
Cardiovascular mortality
HR
95% CI
p Value
HR
95% CI
p Value
1.57
0.89
1.83
0.98
1.39
0.98
1.10
1.00
1.00
1.08 to 2.28
0.80 to 0.98
1.16 to 2.88
0.84 to 1.14
0.38 to 5.13
0.95 to 1.02
0.77 to 1.56
0.97 to 1.02
0.96 to 1.05
0.02
0.02
0.009
0.8
0.6
0.4
0.6
0.7
0.9
1.65
0.93
1.87
0.96
1.51
0.99
1.01
0.99
1.01
1.07 to 2.53
0.81 to 1.06
1.14 to 3.07
0.81 to 1.16
0.33 to 6.91
0.96 to 1.03
0.70 to 1.45
0.96 to 1.01
0.96 to 1.07
0.02
0.3
0.01
0.7
0.6
0.6
0.9
0.3
0.6
HR = hazard ratio; CI = confidence interval; TNF-α = tumor necrosis factor α; TGF-β1 = transforming growth factor β1; CCr = creatinine
clearance; RRF = residual renal function.
table iii
Cox regression models including dialysate volume
Independent variable
Dialysate volume
Albumin
TNF-α
TGF-β1
Weekly Kt/V
Weekly CCr
RRF
Dialysis duration
Age
Deciliters in 24 hours
Grams per liter
Picograms per milliliter
Nanograms per milliliter
Liters per 1.73 m2
Milliliters per minute per 1.73 m2
Months
Years
All-cause mortality
Cardiovascular mortality
HR
95% CI
p Value
HR
95% CI
p Value
1.20
0.86
1.72
0.99
1.04
0.99
1.09
1.00
1.01
1.003 to 1.44
0.78 to 0.95
1.07 to 2.74
0.83 to 1.19
0.27 to 3.96
0.96 to 1.03
0.78 to 1.54
0.98 to 1.02
0.96 to 1.06
0.04
0.004
0.02
0.9
0.9
0.7
0.6
0.7
0.7
1.23
0.89
1.80
0.98
1.21
1.00
0.98
1.00
1.02
1.001 to 1.52
0.78 to 1.02
1.08 to 3.00
0.80 to 1.21
0.25 to 5.65
0.97 to 1.03
0.69 to 1.39
0.97 to 1.02
0.97 to 1.08
0.05
0.08
0.02
0.8
0.8
0.8
0.9
0.7
0.4
HR = hazard ratio; CI = confidence interval; TNF-α = tumor necrosis factor α; TGF-β1 = transforming growth factor β1; CCr = creatinine
clearance; RRF = residual renal function.
predicted CV and all-cause mortality independently
of inflammatory cytokines, albumin level, dialysis
adequacy (weekly Kt/V and CCr), RRF, age, and
dialysis therapy duration.
Authors from the Karolinska Institutet indicated
that intraperitoneal and systemic inflammation increase in PD patients during the first year of therapy.
Intraperitoneal and systemic inflammation might
be interrelated, and the interleukin 6 (IL-6) system
might be a link. Particularly in the early phase of PD
treatment, IL-6 is associated with PSTR, and smalland large-solute transport are linked. Inflammation
might be responsible for the development of a high
PSTR, which could potentially be a reason for the high
mortality in patients with a high PSTR (12). Higher
solute transport at the start of PD might be associated
with the risk of peritonitis.
Gołembiewska et al. (13) showed that solute
transport measured as D/P Cr during the peritoneal
equilibration test was significantly higher in the group
of patients who had experienced a peritonitis episode
than in the group of peritonitis-free patients.
Matsuo et al. (14) evaluated risk factors and mortality in PD patients. In their group of 98 patients,
the leading causes of death were CV and infectious
disease. Patients who died were significantly older
and more frequently had a history of CV disease.
Their serum albumin was significantly lower, and
their D/P Cr was higher. The authors postulated
that diabetic nephropathy, a history of CV disease,
Janda et al.
and higher peritoneal permeability at PD initiation
are independent risk factors for death in patients
starting PD.
In another study, Rodrigues et al. (15) revealed
that fast peritoneal transport at baseline was not
associated with markers of systemic inflammation,
nor was it predictive of worse patient survival in
incident PD patients. In a population with preserved
RRF and an absence of serious baseline comorbidity, it was not predictive of a worse prognosis. Fast
transporters did not present higher levels of C-reactive
protein (CRP) or serum IL-6. Patients with more than
2 comorbidities had lower levels of plasma albumin,
significantly higher median levels of serum IL-6,
and a greater intima media thickness. Multivariate
analysis confirmed that baseline peritoneal transport
was not a significant determinant of patient survival,
but comorbidity score remained significant.
In our multivariable Cox regression (adjusted for
all studied variables and for age and dialysis therapy
duration), D/P Cr at PD initiation was an independent
predictor of total and CV mortality.
In dialyzed patients (CAPD or hemodialysis), the
concentrations of inflammatory factors, especially
high-sensitivity CRP and TNF-α, are increased. In a
study by Kir et al. (16), the highest increases in TNF-α
were observed in patients on CAPD. In our multivariable analysis, an increased TNF-α concentration at
baseline was independently associated with increased
all-cause and CV mortality.
Peritoneal transport status is one of the main
determinants of dialysis adequacy and of dialysisrelated complications in chronic kidney disease
patients who undergo PD (17). Zhe et al. (18) showed
that carotid–femoral pulse wave velocity, established
as a CV risk factor, was positively associated with
patient age, time on PD, diabetes status, D/P Cr, pulse
pressure, and the ratio of extracellular water to total
body water. In multivariate regression analysis, pulse
wave velocity was independently determined by the
ratio of extracellular water to total body water, pulse
pressure, age, and D/P Cr, suggesting that greater
aortic stiffness and an increased rate of peritoneal
small-solute transport might be linked.
In another study, Sezer et al. (19) investigated the
relationship between peritoneal transport characteristics and known promoters of atherosclerosis in PD
patients. After 36 months, those authors observed
that, compared with LA/L transport, HA/H transport
19
was associated with lower albumin, higher CRP, and
a higher need for recombinant human erythropoietin. During follow-up, 28 of 84 patients showed an
atherosclerosis-related event (myocardial infarction,
coronary artery disease diagnosis by angiography or
myocardial scintigraphy, cerebrovascular accident, or
development of clinically evident peripheral arterial
disease). Of those 28 patients, 22 were in the HA/H
group (constituting 43.1% of that group), and only 6
were in the LA/L group (constituting 18.1% of the
group, p < 0.01). Re-analysis of the 18 patients with
atherosclerosis-related events and high CRP levels
(>10 mg/L) showed that 15 were in the HA/H group,
and 3 were in the LA/L group. Of patients with an
atherosclerotic event, 68% belonging to the HA/H
group and 50% belonging to the LA/L group also
had chronic inflammation (p < 0.001). A Pearson correlation analysis showed that D/P Cr was positively
correlated with 36-month mean CRP concentration
and negatively correlated with 36-month mean serum
albumin. A high-transport peritoneal membrane
characteristic was thus shown to be a risk factor for
an inflammatory state in patients with end-stage renal
disease. Compared with their low-transport counterparts, high-transport patients were at an increased risk
of atherosclerosis through chronic inflammation (19).
Sawai et al. (20) investigated the relationships
of local peritoneal inflammation, angiogenesis, and
systemic inflammation with baseline permeability.
Peritoneal biopsy specimens from 42 pre-dialysis
uremic patients and 11 control subjects were investigated. Compared with control peritoneum, predialysis uremic peritoneum showed infiltration by
CD68+ macrophages and mast cells. Baseline D/P Cr
correlated with the density of CD68+ macrophages,
IL-6–positive cells, CD31-positive blood vessels,
and serum albumin. On multiple linear regression
analysis, the number of CD68+ macrophages in
peritoneum was an independent predictor of baseline
peritoneal permeability.
Our study shows that PSTR is an important determinant of survival in PD patients. Additionally, high
PSTR at PD initiation is associated with an increased
risk for total and CV mortality.
Conclusions
Baseline D/P Cr represents a strong independent
marker of survival of PD patients. Baseline D/P Cr
and dialysate volume are independent risk factors for
20
PSTR as a Predictor for Mortality in PD Patients
total mortality and for CV mortality in the PD population and can be significant markers in the assessment
of CV risk in that population.
relationship to other predictors of survival. Nephrol
Dial Transplant 2002;17:1085–92.
Oh KH, Moon JY, Oh J, et al. Baseline peritoneal solute
transport rate is not associated with markers of systemic inflammation or comorbidity in incident Korean
peritoneal dialysis patients. Nephrol Dial Transplant
2008;23:2356–64.
Krediet RT, Struijk DG. Peritoneal dialysis membrane evaluation in clinical practice. Contrib Nephrol
2012;178:232–7.
Pecoits–Filho R, Carvalho MJ, Stenvinkel P, Lindholm B, Heimbürger O. Systemic and intraperitoneal
interleukin-6 system during the first year of peritoneal
dialysis. Perit Dial Int 2006;26:53–63.
Gołembiewska E, Safranow K, Kabat–Koperska J,
Ciechanowski K, Romanowski M. Solute transport at
the start of peritoneal dialysis and the risk of peritonitis.
Adv Clin Exp Med 2013;22:77–83.
Matsuo N, Maruyama Y, Terawaki H, et al. Risk factors for death in patients starting PD for their first renal
replacement therapy [Japanese]. Nihon Jinzo Gakkai
Shi 2009;51:38–43.
Rodrigues AS, Almeida M, Fonseca I, et al. Peritoneal
fast transport in incident peritoneal dialysis patients is
not consistently associated with systemic inflammation. Nephrol Dial Transplant 2006;21:763–9.
Kir HM, Eraldemir C, Dervisoglu E, Caglayan C,
Kalender B. Effects of chronic kidney disease and
type of dialysis on serum levels of adiponectin, TNFalpha and high sensitive C-reactive protein. Clin Lab
2012;58:495–500.
Kim YL. Update on mechanisms of ultrafiltration
failure. Perit Dial Int 2009;29(suppl 2):123–7.
Zhe XW, Tian XK, Chen W, et al. Association between
arterial stiffness and peritoneal small solute transport
rate. Artif Organs 2008;32:416–19.
Sezer S, Tutal E, Arat Z, et al. Peritoneal transport
status influence on atherosclerosis/inflammation in
CAPD patients. J Ren Nutr 2005;15:427–34.
Sawai A, Ito Y, Mizuno M, et al. Peritoneal macrophage
infiltration is correlated with baseline peritoneal solute
transport rate in peritoneal dialysis patients. Nephrol
Dial Transplant 2011;26:2322–32.
Acknowledgments
This work was supported by a department grant (no.
K/ZDS/000597) and was previously presented as a
poster during the 49th ERA-EDTA Congress; Paris,
France; May 24–27, 2012.
Disclosures
The authors have no financial conflicts of interest
to declare.
10
11
12
13
References
1 Paniagua R, Ventura MD, Avila–Díaz M, et al. NTproBNP, fluid volume overload and dialysis modality
are independent predictors of mortality in ESRD patients. Nephrol Dial Transplant 2010;25:551–7.
2 Twardowski ZJ. Clinical value of standardized
equilibration tests in CAPD patients. Blood Purif
1989;7:95–108.
3 La Milia V, Limardo M, Cavalli A, Crepaldi M, Locatelli F. Transport of peritoneal membrane assessed
before and after the start of peritoneal dialysis. Nephrol
Dial Transplant 2009;24:2894–8.
4 Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR,
Oreopoulos DG, Pagé D. Increased peritoneal membrane transport is associated with decreased patient and
technique survival for continuous peritoneal dialysis
patients. The Canada–USA (CANUSA) Peritoneal Dialysis Study Group. J Am Soc Nephrol 1998;9:1285–92.
5 Brimble KS, Walker M, Margetts PJ, Kundhal KK,
Rabbat CG. Meta-analysis: peritoneal membrane
transport, mortality, and technique failure in peritoneal
dialysis. J Am Soc Nephrol 2006;17:2591–8.
6 Rumpsfeld M, McDonald SP, Johnson DW. Higher
peritoneal transport status is associated with higher
mortality and technique failure in the Australian and
New Zealand peritoneal dialysis patient populations.
J Am Soc Nephrol 2006;17:271–8.
7 Cueto–Manzano AM. Rapid solute transport in the
peritoneum: physiologic and clinical consequences.
Perit Dial Int 2009;29(suppl 2):S90–5.
8 Margetts PJ, McMullin JP, Rabbat CG, Churchill DN.
Peritoneal membrane transport and hypoalbuminemia:
cause or effect? Perit Dial Int 2000;20:14–18.
9 Davies SJ, Phillips L, Naish PF, Russell GI. Quantifying comorbidity in peritoneal dialysis patients and its
14
15
16
17
18
19
20
Corresponding author:
Katarzyna Janda, md phd, Department of Nephrology, Jagiellonian University, Collegium Medicum,
Kopernika 15C Street, Cracow 31-501 Poland.
E-mail:
[email protected]