Study protocol
Study title:
Prevalence of peripheral vascular disease and abdominal aortic calcification in
peritoneal dialysis patients,
and
the predictive value of vascular disease and metabolic syndrome
for cardiovascular disease and mortality
Heikki Saha and Markku Asola (principal investigators)
and
members of Nordic PD Council
BACKGROUND:
Compared to coronary or cerebrovascular diseases there are few reports on peripheral vascular disease
(PVD) in a dialysis population and the data on PVD among peritoneal dialysis (PD) patients is
particularly scarce. Therefore, due to the lack of evidence, the recommendations for screening and the
treatment options for PVD lag behind those for other forms of cardiovascular disease. (1)
Both medical history (claudication) and clinical examination have very low sensitivity for detecting
large-vessel disease. An ABI using the Doppler technique is a simple, non-invasive and inexpensive
method to confirm PVD for epidemiological or clinical purposes.
In a recent exceptionally large Japanese study on a total of 1,010 hemodialysis patients, an ABI below
0.90 was observed in 16.9% of the subjects (2). In a Finnish study, using both ABI and toe brachial
index (TBI) the prevalence of PVD was 30.6% in dialysis patients, one third of whom were on PD (3).
In hemodialysis populations, low ABI (<0.9) has been shown to be a powerful, independent predictor
of mortality (1). Additionally, even those with modest reductions in the ABI (0.90 – 1.10) or
abnormally high ABI (> 1.30) had increased all-cause and cardiovascular mortality (2). An ABI value
greater than 1.3 suggests the presence of medial arterial calcification.
Abdominal aortic calcification (AAC) score described by Kauppila et al is a simple method to screen
cardiovascular calcification (4). Only one lateral lumbar radiography (L1-L4) is needed, and
calcification of the aorta can be graded using a previously validated system (4). In hemodialysis
patients the presence is associated with both all-cause and cardiovascular mortality (5).
The prevalence of metabolic syndrome (MS) in general population is around 10 - 45% and in stage 4-5
CKD 20 - 47% (6). The prevalence is highest in PD patients. The prognostic significance of MS in PD
population is unclear. A “reverse epidemiology” of obesity is seen in HD, whereas the results are
mixed in PD (7,8)
There are different definitions of MS, such as those of WHO, IDF and NCEP. Important parameters
include blood pressure, waist circumference, blood lipid levels, blood glucose levels and
microalbuminuria. No definition as such may be directly applied to the PD patient population without
controversy.
1. Saha HHT, Leskinen YKJ, Salenius JP, Lahtela JT. Peripheral vascular disease in diabetic peritoneal dialysis patients.
Perit Dial Int 2007; 27 (Suppl 2): 210-214
2. Ono K, Tsuchida A, Kawai H, Matsuo H, Wakamatsu R, Maezawa A, et al. Ankle-brachial blood pressure index predicts
all-cause and cardiovascular mortality in hemodialysis patients. J Am Soc Nephrol 2003;14(6):1591-8.
3. Leskinen Y, Salenius JP, Lehtimaki T, Huhtala H, Saha H. The prevalence of peripheral arterial disease and medial
arterial calcification in patients with chronic renal failure: requirements for diagnostics. Am J Kidney Dis 2002;40(3):472-9.
4. Kauppila L, Polak JF, Cupples LA, et al. New indices to classify location, severity and progression of calcific lesions in
the abdominal aorta: a 25-years follow-up study. Atherosclerosis 1997; 132: 245-250
5. Okuno S, Ishimura E, Kitani K, et al. Presence of abdominal aortic calcification is significantly associated with all-cause
and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2007; 49: 417-425
6. Johnson DW, Armstrong K, Campbell SP et al. Metabolic syndrome in severe chronic kidney disease: Prevalence,
predictors, prognostic significance and effects of risk factor modification. Nephrology (Carlton). 2007 Aug;12(4):391-8.
7. Kalantar-Zadeh K, Bolck G, Humphreys NH et al. Reverse epidemiology of cardiovascular risk factors in maintenance
dialysis patients. Kidney Int. 2003 Mar;63(3):793-808
8. Johnson DW. What is the optimal fat mass in peritoneal dialysis patients? Perit Dial Int. 2007 Jun;27 Suppl 2:S250-4.
STUDY RATIONALE
PVD and its consequences are very common in PD. Clinicians should be aware of PVD and aim for the
early detection (with ABI) and prophylactic therapy of asymptomatic PVD among high-risk group such
as PD patients. Patient education, lifestyle modification, and other therapies should be initiated at an
early stage when surgical interventions are not yet required.
Early detection of vascular calcification by AAC score may help to start more focused investigations
and more intensified treatment in those patients with progressive or advanced vascular disease.
In general population, metabolic syndrome is associated with an increased risk for type 2 diabetes and
cardiovascular disease. Given the high risk of cardiovascular events in the dialysis population and the
glucose load due to PD treatment, an evaluation of the presence of MS in PD patient population is of
interest.
METHODS
Study design:
Part one: A multi-center, cross-sectional analysis of the prevalence of vascular disease in PD patients;
Part two: secondly prospective, non-interventional, observational cohort study
Objectives
1. To evaluate the prevalence of vascular disease in PD patients assessing ankle brachial blood pressure
index (ABI) and abdominal aortic calcification (AAC) score, and the prevalence of MS according to
commonly accepted criteria (WHO, EGIR, NCEP) ;
and
2. To evaluate the predictive value of vascular disease and metabolic syndrome for all-cause and
cardiovascular morbidity and mortality in PD patients
End points:
Part one (see study design): Detection of a) subclinical PVD with ABI measurement, b) vascular
calcification by AAC score and c) metabolic syndrome.
Part two (see study design): All-cause and cardiovascular morbidity and mortality during 2 years
follow-up
PATIENTS:
Inclusion criteria:
All prevalent and incident PD patients
A goal is to get up to 600-1000 PD patients included (in 10-15 dialysis units in Finland, Sweden,
Denmark, Norway, Estonia and Latvia)
The analyses will be performed on an intention to treat principle.
METHODS:
An ABI measurement:
An ABI measurement is performed by PD nurse or physician to all PD patients on normal out patient
clinic visit.
Systolic blood pressure is measured by a Doppler probe from the brachial artery as well as the posterior
tibial or dorsal pedal artery from each ankle. ABI is determined by dividing the blood pressure in the
ankle by that measured from the brachial artery. An ABI ≤0.90 indicates PVD, normal range being
0.91-1.30, and ABI >1.30 or noncompressible ankle artery suggest a calcified vessel. ABI less than
0.90 has 95 % sensitivity and almost 100 % specificity in detecting angiogram-positive PVD in
apparently healthy individuals.
TBI (toe brachial index) - OPTIONAL extra methods for evaluation of PVD
ABI using the Doppler technique is a simple, non-invasive and inexpensive method to confirm PVD for
epidemiological or clinical purposes . Yet, it is not an optimal method of diagnosing PVD in diabetes
and CKD patients due to high prevalence of medial arterial calcification (MAC). In the case of MAC
the use of TBI is superior to ABI. However, TBI measurement is technically more demanding and
requires additional equipments, and is more expensive. It may not be available in all hospitals.
In the present study a TBI measurement together with ABI can be optionally performed in those
hospitals where the resources are available.
Abdominal aortic calcification (AAC) score
Lateral lumbar radiography is performed using standard radiographic equipment. A minimum of 5 cm
anterior to the lumbar spine had to be visible. The abdominal aorta is divided into 4 segments in front
of the 1. through 4. lumbar vertebra. Calcific deposits are assessed separately for the posterior and
anterior wall of each segment and scored according to Kauppila et al. (see ref. 4). A radiograph may be
used if it has been taken less than 3 months before the entry to the study.
Waist circumference measurement:
The position for measuring waist circumference is midpoint between the lowest rib and the iliac crest.
Measurements should be made without PD solution in the abdomen, after the patient exhales while
standing without shoes, both feet touching, and arms hanging freely. The tape should be placed
perpendicular to the long axis of the body and horizontal to the floor, and applied with sufficient
tension to conform to the measurement surface.
Data collection:
Baseline data is collected:
Age, gender, smoking history (current, past, ever), weight, height (BMI); waist circumference,
diagnosis of ESRD, comorbid conditions (Stoke Davies comorbidity score), functional performance
(Karnofsky score), blood pressure, medication (ESA, antihypertensives, statins, phosphate binders,
vitamin D)
Diagnosis of PVD (claudication, arterial pulses; history of ischemic ulcers, gangrene or amputations,
history of angiography)
Baseline laboratory parameters: Hemoglobin, CRP, albumin, creatinine, lipids, calcium, phosphate,
PTH, HBA1c, P-insulin (optional), adequacy of dialysis
Abdominal aortic calcification (AAC) score
Ankle brachial index (ABI)
Toe brachial index (TBI) /OPTIONAL
The follow-up period for all patients is 2 years (data collection at 1 and 2 years).
Outcome data collection
Death (cardiovascular or non-cardiovascular)
Cardiovascular events: cerebrovascular (infarctation, bleeding), coronary artery disease (myocardial
infarctation, by pass surgery or angioplasty), heart failure
Peripheral vascular disease (ischemic ulcers or gangrene of the foot, vascular surgery or amputation)
Duration of the study:
Enrollment period until the end of May 2010 with a follow-up of 2 years.
BASELINE DATA
Patients (unit-no + patient-no)
Date
Age
years
Sex
(F / M)
PD modality: CAPD
APD
Icodextrin solution_____
Amino acid solution______
Smoking:
Past
Current
Weight
kg
Height
Blood pressure
Dialysis duration
months
Never
m
Waist circumference
mmHg
Diagnosis of CKD
Diabetes
yes
type 1
or 2________
no
Ischemic nephropathy
Glomerulonephritis
PKD
Interstitial
Other
Comorbidity score ( S.Davies NDT 2002; 17: 1085-1092)
1. malignancy
(active, non-cutaneous)
2. Ischemic heart disease
(post-AMI, angina pectoris, positive angiography
or other diagnostic test)
3. peripheral vascular disease
(aortic, renovascular, lower limb, cerebrovasculat disease
Symptomatic disease or sign. Stenosis>50% on vascular
Imagining or Doppler Ultrasound)
4. Left ventrucular dysfunction
(pulmonary oedema not attributable to errors in fluid balance
Or moderate to severe LVH on echocardiography)
5. Diabetes
(type 1 or 2)
6. Systemic collagen vascular disease
(vasculitis, rheumatoid arthritis, systemic sclerosis)
7. Other significant pathology
(Impact on survival, e.g. COPD, cirrhosis etc.)
/7
cm
BASELINE DATA
Patients (unit-no + patient-no)
Date
Karnofsky score











____________%
100% - normal, no complaints, no signs of disease
90% - capable of normal activity, few symptoms or signs of disease
80% - normal activity with some difficulty, some symptoms or signs
70% - caring for self, not capable of normal activity or work
60% - requiring some help, can take care of most personal requirements
50% - requires help often, requires frequent medical care
40% - disabled, requires special care and help
30% - severely disabled, hospital admission indicated but no risk of death
20% - very ill, urgently requiring admission, requires supportive measures or
treatment
10% - moribund, rapidly progressive fatal disease processes
0% - death.
Diagnosis of PVD:
Claudication
yes
History of ulcers
yes
Gangrene/surgery
yes
Positive angiography
yes
Arterial pulses palpable, yes/no:
Arteria dorsalis pedis (ADP) yes_______
Arteria tibialis posterior (ATP) yes_______
no
no
no
no
no________
no________
Medication:
ESA
yes
no
Statins:
yes
no
Antihypertensives:
Angiotensin converting enzyme inhibitor (ACEi)
Angiotensin II receptor blocker (ARB)
Calcium channel blocker (CCB)
Beta-blocker
Diuretic
Other
______
______
______
______
______
______
not done___
Phosphate binder: Calcium salt
Vitamin D:
Non-activated
Activated:
yes
yes
Alphacalcidol
Paricalcitol
Other
Non-calcium-containing
no
no
______
______
______
BASELINE DATA
Patients (unit-no + patient-no)
Date
Baseline Laboratory Data
Hemoglobin
g/l
CRP
mg/l
Albumin
g/l
Creatinine
µmol/l
Total calcium
mmol/l
Ionised calcium
mmol/l
Phosphate
mmol/l
PTH
pmol/l
Lipids (mmol/l)
Total chol_____
mmol/l
pg/ml
HDL-chol_____
HBA1c
%
LDL-chol_____
Triglycerides_____
P-insulin (optional)
mU/l
Adequacy of dialysis
Kt/V_______/wk
Creatinine clearance
l/week/1.73 m2
RRF (mean of renal creatinine and urea clearances)
Urine volume
ml/min
/24h
Membrane type: H______
D/P creatinine at 4 h_______
HA______
LA______
L______
BASELINE DATA
Patients (unit-no + patient-no)
Date
Ankle-brachial index
ABI
Blood pressure - brachial:
mmHg
Blood pressure – ankle:
Dorsal pedal artery:
right
mmHg
left
mmHg
Posterior tibial artery: right
mmHg
left
mmHg
Ankle blood pressure > 300 mmHg = non-compressible (non-C)
Aortic abdominal calcification score (to be filled by Dr. Leena Kauppila)
AAC score
Total score
Level
Affected
segments
Composite score
(AAC)
Posterior wall (range 0-3)
L1
L2
L3
L4
Total
Maximum
Toe-Brachial index
TBI (OPTIONAL)
ABI
TBI
4
12
Anterior wall (range 0-3)
12
24
OUTCOMEDATA
Patients (unit-no + patient-no)
Date
Outcome Data Collection at 1 year
PD treatment
Continuing
Discontinued, date _____________
… due to 


death
transplantation
hemodialysis
Death
No
Yes, date
Cardiovascular
Non-cardiovascular
Definition:__________________________________________
Cardiovascular events
No
Yes
Date: Cardiovascular (infarctation, by-pass or angioplasty)
Cerebrovascular (infarctation, bleeding)
Hospitalisation for heart failure
Peripheral vascular disease
____________
____________
__________
(ulcer, gangrene, vascular surgery, amputation)
Definition:__________________________________________
OUTCOMEDATA
Patients (unit-no + patient-no)
Date
Outcome Data Collection at 2 years
PD treatment
Continuing
Discontinued, date _____________
… due to 


death
transplantation
hemodialysis
Death
No
Yes, date
Cardiovascular
Non-cardiovascular
Definition:__________________________________________
Cardiovascular events
No
Yes
Date: Cardiovascular (infarctation, by-pass or angioplasty)
Cerebrovascular (infarctation, bleeding)
Hospitalisation for heart failure
Peripheral vascular disease
____________
____________
__________
(ulcer, gangrene, vascular surgery, amputation)
Definition:__________________________________________