Vascular stiffness in incident peritoneal dialysis patients over time
1
2
3*
Mila Tang, BSc Alexandra Romann, MSc Giusy Chiarelli, MD , Ognjenka Djurdjev,
2
1,2
1
1
MSc , Monica Beaulieu, MD , Mhairi Sigrist, PhD , Paul Taylor, MD , Suneet Singh,
1
1,2
MD .,Adeera Levin, MD
1
2
Division of Nephrology, University of British Columbia, Vancouver, Canada; BC
3
Provincial Renal Agency, Vancouver, Canada; Nephrology and Dialysis Unite, Ospedale
di Circolo di Melegnano, Milano, Italy.
*Current affliation: Renal Unit, Azienda Ospedaliera della Provincia di Lodi, Lodi, Italy
Acknowledgements
Supported by an unrestricted grant from Genzyme Inc
Disclosures: The conception, execution, data analysis and writing of the manuscript were
done entirely by the authors. We gratefully acknowledge the financial assistance from
Genzyme to conduct and fund the study procedures, assays and analysis. Gabriela
Espino-Hernandez and Genevieve Brin assisted in statistical analysis.
Disclaimer
The results presented in this paper have not been published previously in whole or part,
except in abstract form.
Correspondence to
Mila Tang
Monica Beaulieu
St. Paul’s Hospital
St. Paul’s Hospital
1081 Burrard Street
1081 Burrard Street
Comox Rm. 302
Comox Rm. 307
Vancouver, B.C. V6Z 1Y6
Vancouver, B.C. V6Z 1Y6
Email : mxtang@providencehealth.bc.ca
Tel : 604-806-9376
Mhairi Sigrist
Fax : 604-806-8856
570 West 7th Ave - Suite 100
Vancouver, BC
Alexandra Romann
V5Z 4S6
St. Paul’s Hospital
1081 Burrard Street
Paul Taylor
Comox Rm. 504
St. Paul’s Hospital
Vancouver, B.C. V6Z 1Y6
1081 Burrard Street
Vancouver, B.C. V6Z 1Y6
Giusy Chiarelli
Renal Unit
Suneet Singh
Azienda Ospedaliera Della Provincia di
Gordon and Leslie Diamond Health
Lodi
Care Centre
Piazza Ospitale, 10
5th floor – 2775 Laurel Street
26900 Lodi – Italy
Vancouver, B.C. V5Z1M9
Ognjenka Djurdjev
BC Provincial Renal Agency
700-1380 Burrard Street
Vancouver, BC V6Z 2H3 Canada
Adeera Levin
St. Paul’s Hospital
1081 Burrard Street
Providence Building Rm. 6010
Vancouver, B.C. V6Z 1Y6
Running Title
Vascular Stiffness in PD
Vascular Stiffness in PD
1
Abstract
OBJECTIVE: Vascular stiffness is prevalent in end stage renal disease patients and
predicts adverse events. This study describes the prevalence of vascular stiffness and its
associated factors in a cohort of incident peritoneal dialysis (PD) patients. METHODS: In a
prospective observational study of 50 patients, carotid-femoral pulse wave velocity (PWV)
were conducted at baseline, 3, 6 and 12 months after initiation of PD. Aortic calcification
scores (ACS) were derived using plain lateral abdominal films. We examined the
association of significant changes in PWV (defined as 1 m/s or 15% change from baseline)
over 6 months in conjunction with demographic and clinical data. RESULTS: The mean
age was 58 years, 67% were male, and 48% were Caucasian. One third was diabetic, and
23% had pre-existing cardiovascular disease. Median eGFR was 8.7mL/min. ACS was
strongly correlated with PWV (r=0.62,p<0.0001). Over 6 months, 42% demonstrated
significant increases, while 23% demonstrated decreases in their PWV. Factors shown to
be associated with increasing PWV were Caucasian race (OR=4.50;CI:0.97-20.83), higher
phosphate (OR=8.36;CI:1.10-63.51) and a lower baseline PWV (OR=0.67;CI:0.45-0.99).
Decrease in PWV was associated with the absence of calcium based phosphate binder
usage (OR=0.11;CI:0.02-0.73). Changes in weight and PWV at 12 months were
significantly correlated (p=0.007,r= 0.57). CONCLUSION: In this group of incident PD
patients, we demonstrate a lower prevalence of vascular calcification than in hemodialysis
patients, a correlation of calcification with PWV, and an important finding that PWV can
change in either direction over a short period of time, which are associated with modifiable
risk factors.
Keywords:
incident PD-stiffness-pulse wave velocity-phosphate binders-fluid
Vascular Stiffness in PD
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Introduction
Vascular calcification and mineral metabolism abnormalities are highly prevalent in dialysis
patients and are associated with poor outcomes [1, 2]. Further, higher vascular stiffness
has been shown to have substantial impact on predicting patient mortality, as assessed by
surrogate measures such as pulse pressure and pulse wave velocity (PWV) [3, 4]. Data
regarding end stage renal disease (ESRD) patients at the time of dialysis initiation are
relatively limited. While it has been described by Block et al that 85% of patients at
hemodialysis (HD) initiation have calcification [5] and various prevalent peritoneal dialysis
(PD) vascular studies have been published in literature [6-11], descriptions of incident PD
are few.
In this study, we describe the distribution and association of mineral metabolism
parameters, vascular calcification and vascular stiffness in a cohort of patients at the start
of PD and the changes in these parameters at 6 and 12 months.
Methods
Patient Selection: Fifty consecutive incidence patients were enrolled into the study,
accrued from a cohort of those starting PD at 2 tertiary centres in Vancouver BC: St Paul’s
Hospital and Vancouver General Hospital. The study protocol was approved by
Providence Health Care/University of British Columbia ethics board and written informed
consent was obtained from all participants.
Patients over the age of 19 starting PD were eligible, except for those patients with
congestive heart failure starting PD for fluid management and not because of uremia. Two
patients were not able to continue in the study due to technically difficult PWV
measurements and hence we report results on 48 patients studied in the first week of PD
training between Dec 1st 2007 and Aug 31st 2009.
Vascular Stiffness in PD
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Vascular calcification and vascular stiffness assessment: Semi-quantitative aortic
calcification scores (ACS) were calculated using plain lateral abdominal X-rays as
described by Kauppila et al [12]. A single reader, blinded to clinical information read all the
films. Vascular stiffness was assessed through noninvasive pulse wave estimation by
means of applanation tonometry. Carotid-femoral PWV and augmentation index with
normalized heart rate (AIx%) were measured by SphygmoCor technology.
The ACS and PWV were collected in the first week of PD training. Subsequent PWV
measurements were done at 3, 6 and 12 month thereafter.
Demographics and other parameters: Demographics, co-morbidities, medications and
physical examination data were collected using the Provincial Renal data system: Patient
Registration and Outcome Management Information System (PROMIS). Peritoneal
equilibration testing (PET) and initial dialysis adequacy measures were performed on the
same day 4 weeks after starting PD. Laboratory results were accrued at dialysis
commencement.
Novel Biomarkers of vascular health and inflammation: Asymmetric dimethylarginine
(ADMA), C-reactive protein (CRP), interleukin-10 (IL10) and fetuin-A levels were
measured in baseline serum. All testing was performed in an accredited laboratory
(iCAPTURE, Providence Healthcare), on batched samples in duplicate, using approved
standardized laboratory kits.
Outcome measures: Clinical outcomes were tabulated which included: death, intermittent
or permanent switch to HD, major adverse cardiovascular events (MACE), infections and
gastrointestinal bleeds. We define “progressors” with respect to PWV, based on chnages
Vascular Stiffness in PD
4
of PWV greater than 1m/s or 15% between baseline to 6 months.
Regressors were
defined as those with decreases of greater than 1m/s or 15% within the same time frame.
All definitions were determined a priori and in accordance with current literature.
Statistical methods:
Continuous variables are described as mean ± standard deviation for normally distributed
data, and median (interquartile range) for data where the underlying distribution is not
normal.
Comparisons are made using the t-test or Wilcoxon test depending on the
underlying distribution. Normality of the underlying distribution of the continuous variables
was assessed using the Shapiro-Wilk test for normality.
Categorical variables are
represented as frequency (percentage) and comparisons are made via the χ2 test or
Fisher’s exact test (cell count <5). Logistic regression analysis was used to find which
variables are associated with signficant PWV increase in progressors and significant
decreases in regressors.
Statistical software used were SAS, version 9.1 (SAS Institute, Cary, NC, USA) and S-plus
7.0.
Results
Table 1a describes the demographics and clinical characteristics of the cohort in total.
Note that 48% are Caucasian, 67% male, mean age 58±16 years, 33% were diabetic and
23% had known cardiovascular disease at dialysis initiation.
Mineral metabolism parameters were quite well controlled with mean serum phosphate of
1.8 ± 0.5 mmol/L, median calcium of 2.24 mmol/L (2.14-2.36) and median intact
parathyroid hormone (PTH) of 25 pmol/L. Over half (56%) of all patients demonstrated
some degree of aortic calcification at the start of dialysis. We stratified the cohort into 3
Vascular Stiffness in PD
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groups based on tertiles of PWV as follows: low PWV (5.7-9.15 m/s), moderate PWV (9.212.2 m/s) and high PWV (12.25-24.2 m/s). The demographics and laboratory variables of
these 3 groups are presented in table 1b. Factors such as age, diabetes, pulse pressure,
history of cardiovascular disease, previous HD, estimated GFR (eGFR), serum creatinine,
PTH levels and AIx% were significantly different depending on PWV group (table 1b).
Figure 1 describes the relationship between higher vascular stiffness (PWV) and higher
calcification scores (p <0.0001). The correlation between ACS and baseline PWV was
highly significant (r=0.68, p<0.0001).
Changes in PWV over time
Figure 2 describes the changes in PWV over time for each group. In the lowest tertile,
there is no significant difference over time, those in the middle tertile display variable
change over time with some tendency to increase, while interestingly, those in the highest
tertile demonstrate an overall decrease over time.
Figure 3 presents the PWV measurements at baseline, 6 and 12 month for subjects with
repeated measurements. ‘Progressors’ are shown in purple and ‘non-progressors’ are
shown in green. Out of the 31 subjects who had a follow-up PWV measurement at 6
months, 13 (42%) had an increase and 7 (23%) had a decrease in PWV by 1m/s or 15%
from baseline. Note that those who regressed tend to have higher PWV at baseline than
those who did not have a significant change in PWV. Due to small numbers, statistical
significance of this trend was not demonstrated at 12 months, though the trend is in the
same direction.
Univariate logistic regression analysis of variables associated progressors are shown in
table 2 which includes Caucasian race,
(OR=4.50; CI: 0.97-20.83), higher phosphate
(OR= 8.36; CI: 1.10-63.51) and low PWV (OR=0.67; CI: 0.45-0.99). Compared to the
Vascular Stiffness in PD
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lowest PWV tertile, the middle and highest tertile were less likely to progress, OR=0.10; CI:
0.01-0.69 and OR=0.04; CI: 0-0.69 respectively.
Figure 4 describes the correlation between PWV and weight change over 12 months. Note
that those with greatest weight change had the greatest change in PWV and vice versa:
this correlation is highly statistically significant at p=0.007, r= 0.57.
Outcomes
Overall, there were 3 deaths within the 1 year follow-up, all of non-cardiovascular causes.
Eight patients switched modalities to HD permanently and 5 patients received temporary
HD during the study duration ranging from 4 to 54 days.
Adverse outcomes include events that occurred during the 12 month period (MACE,
infection, HD and death), presented in table 3 compared among the PWV tertiles. Note
that there is a bimodal distribution of events: those in highest and lowest PWV tertiles had
more events than those in the middle tertile.
Discussion
This is one of a few studies that describe PWV, aortic calcification, mineral metabolism,
and changes over time in an incident PD cohort treated in the current era. Larger studies
have shown association of vascular calcification with adverse clinical outcomes in the PD
population [1, 13],. We explore here the associated factors and mechanisms related to
PWV in incident PD patients, with complete baseline data.
Note that 56% of patients have calcification, which compares favorably to incident HD
patients, in whom 85% are calcified at dialysis start [5]. We describe the strong correlation
of aortic calcification with PWV, which is consistent with other studies [14]. Within the 3
Vascular Stiffness in PD
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tertiles of PWV, those who were older, diabetic, had higher pulse pressure and had
comorbid cardiovascular disease had higher PWV at the time of dialysis start. This too is
consistent with the HD literature [14]. Those with the lowest creatinine values at the time of
dialysis start had the highest PWV, as did those with lowest PTH values. These findings
may suggest that this group was composed of relatively ‘sicker’ patients: those with low
bone turnover and lower muscle mass. Given that individuals commence dialysis for
different reasons which include increasing specific symptomatology attributable to ESRD,
and the other being general clinical malaise (with or without volume overload) in the
context of worsening kidney function, it is possible that our data reflect the real world
practice that those who are sicker, commence dialysis; the higher PWV at dialysis
commencement is reflective of their burden of illness [15]. The lower serum phosphate in
this group would also corroborate this ‘unwellness’ hypothesis. Of note,
fetuin-A, a
calcium-regulatory glycoprotein that inhibits vascular calcification, was not associated with
PWV at baseline nor was it predictive of PWV change after 1 year, similar to the findings of
Jung et al [16].
We have also confirmed that low PTH is associated with vascular
calcification [16, 17], which is consistent with the hypothesis that bone turnover and
vascular calcification are linked. It further may corroborate current tenets that it may be
important to maintain higher serum PTH values as people progress towards ESRD.
We were able to demonstrate characteristics of high-risk patients likely to have a change
in PWV: being of Caucasian decent, having higher serum phosphate levels and lower
baseline PWV, were all associated with the likelihood of increasing PWV or stiffness.
Higher serum phosphate was associated with worse outcomes, which is consistent with
other studies [5, 18]. Note that comparatively, the lowest PWV tertile was more likely to
have an increase in PWV,
Vascular Stiffness in PD
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Most interestingly, we observed that a portion of the patients demonstrated a decrease in
their PWV score significantly after only 6 months of PD treatment. Note that the majority
of this group had higher baseline PWV, so that the phenomenon of ‘regression to the
mean’ must be entertained. However, it could be explained within our current
understanding of the mechanisms behind vascular stiffening. It is important to note that it
is the additive effect of intima calcification and medial stiffening that result in a high PWV
measurement. Changes in structure and function may be transient or fixed, and there is a
need to ascertain which component is potentially modifiable, or ‘transient’,.Structural
damage cannot be reversed; however, other aspects such as water and salt infiltration of
the media may be reversible. Thus a possible explanation for the change in PWV
observed here, after treatment with PD treatment may be that the removal of fluid in the
initial dialysis phase is of benefit for vascular health. In the hemodialysis population, the
use of calcium-containing phosphate binders pertained to vascular calcification and higher
risk of mortality [5]. Interestingly, we demonstrated in this cohort that the non–use of
calcium-containing phosphate binders was associate with improved vascular outcomes.
While weight gain is often seen in PD due to high caloric content of the glucose based
dialysis solution, we observed a weight loss and an association between that and a
reduction in PWV. It is highly probably that the weight loss seen in this cohort reflects fluid
removal. In as much as stiffness may be affected by interstitial water accumulation, the
change in stiffness may well represent this phenomenon. This finding is of importance in
the light of new understandings of regarding the significance of fluid management in all
ESRD and CKD patients.
Small differences in phosphate serum levels are associated with worse vascular
parameters and outcomes [19]; we demonstrate the importance of this parameter in
Vascular Stiffness in PD
9
predicting worsening PWV values over time. Other publications have called for attention to
the phosphate binders and adequate management in fluid status,in order to lower the
mortality risk in this group of patients [5, 20].
Conclusion
We describe the clinical and biochemical profiles of patients at the time of PD initiation,
and document their vascular health, measured by both aortic calcification and PWV, at
baseline and over time. Half of the patients have aortic calcification at dialysis start. While
ACS was strongly associated with the degree of vascular stiffness as measured by PWV,
we demonstrated that PWV is a dynamic measure in these patients, and does change in
both directions over time. Caucasians, higher phosphate and lower PWV at PD start are
factors associated with increases in PWV. Non-use of calcium-containing phosphate
binders was associated with reduction in PWV. Note that after 1 year of PD, in those that
had increase or decrease in body weight, there was a concomitant increase or decrease in
PWV.
Further large studies are required to better understand the relationship between volume
status, PD and vascular stiffness. Comparing dialysis modalities and investigating factors
associated with adverse outcomes may allow insight into improving future care for ESRD
patients.
Vascular Stiffness in PD
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Legend of Tables and Figures
Table 1a.
Table 1b.
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Table 2.
Table 3.
Characteristics of the study population at baseline.
Baseline statistics by PWV categories.
PWV boxplot depending on aortic calcification score.
PWV boxplot for baseline, 6 months and 12 months for the whole cohort and
in the low, moderate and high PWV tertiles.
Progression plot of actual PWV for patients with repeated PWV at baseline, 6
months and 12 months.
Correlation of delta PWV with delta weight at 12 months
Univariate logistic regression of variables associated with progressors.
Comparison of adverse outcomes during study period by PWV tertiles.
.
Vascular Stiffness in PD
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