Medico-legal Update, October-December 2020, Vol. 20, No.

4 1763

Major Adverse Cardiovascular Events in Patients Starting

Peritoneal Dialysis Based on the CKD-EPI Versus Thai eGFR
Equation: A Retrospective Cohort Study

Nathaphop Chaichaya1, Bandit Thinkhamrop2, Sajja Tatiyanupanwong3, Katharine Morley4,

Michael Morley5, Wilaiphorn Thinkhamrop6, Wongsa Laohasiriwong7
1
Doctor of Philosophy in Epidemiology and Biostatistics (International Program), Faculty of Public Health,
KhonKaen University, Thailand. 2Associate Professor, Department of Biostatistics and Demography, Faculty of
Public Health, KhonKaen University, Thailand, 3Nephrologist, Kidney Unit, Department of Internal Medicine,
Chaiyaphum Hospital, Chaiyaphum, Thailand, 4Internal Medicine Specialist, Department of Medicine,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 5Ophthalmologist, Department
of Ophthalmology, Harvard Medical School, Boston, MA, USA, 6Statistician, Data Management and Statistical
Analysis Center, Faculty of Public Health, KhonKaen University, Thailand, 7Associate Professor, Faculty of Public
Health, KhonKaen University, Thailand

Abstract
Background: Major adverse cardiovascular events (MACE) are the leading cause of deathin chronic kidney
disease (CKD) patients. The relationship between the initiation of peritoneal dialysis (PD) and MACE is
unclear.

Objective: This study compared the incidence of MACE in PD patients when the estimated- glomerular
filtration rate (eGFR) is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation with the Thai eGFR equation.

Method: The study was conducted among 684 end-stage CKD patients in a referral hospital in Thailand
between 2011-2018. The first occurrence of cardiovascular events related MACE was defined as dependent
variable. Logistic regression was used to identify the relationship.

Results: The incidence of MACE was different between CKD-EPI group (10.9%) and Thai eGFR group
(12.4%). After adjusting for other factors, the PD initiation using eGFR calculated by CKD-EPI equation
did not affect the incidence of MACE when compared to those from Thai eGFR equation (Ajd.OR: 1.11;
95%CI: 0.68-1.82, P-value = 0.685).

Conclusion: There was no effect on incidence of MACE when PD was initiated based on eGFR calculated
using the CKD-EPI equation compared with the Thai eGFR equation.

Keywords: Late stage, end stage kidney disease, PD, CVD, advanced stage, CKD.

Introduction
Corresponding Author: End-stage renal disease patients are at high risk for
Bandit Thinkhamrop major adverse cardiovascular events (MACE). It is the
Associate Professor, Department of Biostatistics and most common cause of death in this group of patients
Demography, Faculty of Public Health, KhonKaen whose illnesses frequently worsen over time as kidney
University, Thailand function declines[1-4]. Early accurate detection CKD
e-mail: bandit@kku.ac.th and monitoring of renal function can reduce MACE
1764 Medico-legal Update, October-December 2020, Vol. 20, No. 4
complications by implementing treatment and lifestyle
interventions to help slow the progression of disease,
and delay need for renal replacement therapies (RRT).
Glomerular filtration rate is the best reflection of kidney
function however it is difficult to measure with routine
clinical laboratory method. As a result, GFR is estimated
based on serum creatinine, and is the measurement
nephrologists use to decide when to initiate renal
replacement therapy (RRT) for their ESRD patients[5,6].
GFR estimates also play an important role in CVD risk
screening[7]. The Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI equation, 2009) is the most
widely used method to estimate GFR globally[8]. The
CKD-EPI equation includes variables related to race
and ethnicity. For this reason, many countries have
developed new eGFR equations that are based on data
from their population [9-13].
Peritoneal dialysis (PD) is one of the RRT options to
reduce mortality in ESRD patients. Use of life-extending
treatments like RRT should consider both physical and
spiritual benefits for patients to maximize the benefit
for individual patients and their families. In 2008, the
Thai government developed the “PD First” policy for
ESRD patients as a strategy to balance the use of clinical
resources, treatment outcomes and
medical expenditures[14]. There are several issues to
consider before initiating PD; one of the most important
ones is timing. Starting PD can provide significant
improvement in symptoms. However, it increases the risk
of dialysis related complications. PD requires significant
effort on behalf of patients and families and impact
quality of life[15]. Starting PD before it is necessary
can also result in increased costs for the patient and the
health care syst The global issue of kidney disease
reported the need for more research into the management
of CVD risk factors in CKD patients[16,17].In 2011, the
Thai eGFR equation was developed. This was followed
in 2015 by the recommendation by the Nephrology
Society of Thailand that it be used for the evaluation and
management of the adult-CKD patients in Thailand[18],
even though it uses an unconventional method compared
to the CKD-EPI equation[18, 19]. The GFR estimated by
Thai eGFR is generally higher than the CKD-EPI-eGFR,
there have not been any studies to compare the clinical
outcomes of using eGFR calculated by either method
to decide when to initiate PD. This study compared the
incidence of MACE in patients starting PD based on the
eGFR calculated using the Thai eGFR equation with
the CKD-EPI equation. MACE is a major complication
affecting on high mortality in CKD[1, 7, 20], By using
MACE as the clinical outcome of interest, rather than
mortality, this study aims to understand the cause of the
comorbidity resulting in mortality in ESRD patients.
Materials and Method
Study designand variables: A total of 684 out of
828 ESRD patients from a referral hospital in Thailand
between 2011-2018 were included in the study, 144
patients excluded due to MACE that occurred before
initiating PD. Participants were divided into two
groups based onthe results of eGFR recalculated by the
CKD-EPI equation and the Thai eGFR equation. The
data of each patient were retrieved from the hospital
information system which included: gender, age at time
PD was started and diabetes mellitus status. Physical
examination results of body mass index and blood
pressure were obtained. Laboratory results collected
were serum creatinine (SCr) during the 3-month period
before starting PD, albumin, hemoglobin, bicarbonate
and the presence or absence of hypokalemia, defined
as a serum potassium level of less than 3.5 mEq/L
(3.5 mmol/L. The first CVD-related disease (coronary
artery disease, peripheral vascular disease or stroke) that
occurred after PD initiation was a dependent variable.
The nephrologists of that hospital used the CKD-
EPI eGFR equation to make decisions regarding when to
initiate PD. In order to select the equations, a data set for
the SCr of a 60-year-old male was generated for eGFR
calculation. In the generation process, SCr was varied
while gender and age were fixed. The results showed
that the eGFR calculated by the Thai eGFR equation
was higher than that by CKD-EPI equation (Figure 1).
Two groups were then defined: the CKD-EPI equation
group which included those with eGFR ranging from 5
to 14 ml/min/1.73m2 and the Thai eGFR equation group
which included eGFR > 4 ml/min/1.73m2 and eGFR < 4
ml/min/1.73m2 obtained from CKD-EPI equation.
 Medico-legal Update, October-December 2020, Vol. 20, No. 4 1765

Y axis: eGFR in ml/min/1.73m2

Figure 1 GFR estimated by CKD-EPI and Thai eGFR equation for male 60 years old patient

The formulas used to recalculate the eGFR are eGFR equation were selected. Each participant was
displayed in Figure 2. The required parameters (age, allocated to the defined group based on their recalculated
gender, and SCr) in the CKD-EPI equation and the Thai eGFR results.

Figure 2 Glomerular filtration rate (GFR) estimating equations

Data Analysis: Data analysis was performed using
StataCorp Stata MP 16.0. We displayed the baseline
characteristics of both CKD-EPI eGFR and Thai eGFR
equations groups to demonstrate the balance of attributes
between the groups using frequency and percent for
gender, and presence or absence of diabetes mellitus
and hypokalemia. For other continuous variables, mean
and standard deviation, median and range (Minimum:
Maximum) were used.
1766 Medico-legal Update, October-December 2020, Vol. 20, No. 4
Outcome variable was the first occurrence of MACE
- coronary arterial disease (CAD), peripheral arterial
disease (PAD)or stroke - after starting PD. Univariate
analysis was employed to understand the magnitude of
the overall MACE alongside each event of CAD, PAD
and stroke. Simple logistic regression was performed
in bivariate analysis to produce results of association
between MACE and each candidate variable. All
candidate factors were included in the initial model of
multivariable analysis using multiple logistic regression.
Each variable was then eliminated from the model. No
difference between the models with and without that
variable (a result from likelihood ratio test produced
a probability of greater than 0.05). The final model
presented all factors as crude ORs and adjusted ORs
corresponding to their 95% confidence intervals (CI).
All hypothesis testing was considered as statistically
significant at p-value less than 0.05.
Results
Baseline information of participants: In the 684
end-stage renal disease patients who had not experienced
MACE prior to initiating peritoneal dialysis, there was
no significant difference between both equation groups
except the presence of DM and hypokalemia, which was
higher in CKD-EPI group (Table 1).

Table 1: Baseline information of participants with end-stage renal disease presented as number, percent or
mean (standard deviation), median (min: max)

Characteristics CKD-EPI Group (N=385) Thai eGFR Group (N=299)

Gender (no (%))
Male 209 (54.3) 127 (42.5)
Female 176 (45.7) 172 (57.5)
Age at initiated PD
Mean (SD) 55.6 (13.6) 55.5 (11.8)
Median (min: max) 57.0 (18.0:87.0) 56.0 (21.0:79.0)
Diabetes Mellitus (DM) (no (%))
No 189 (49.1) 165 (55.2)
Yes 196 (50.9) 134 (44.8)
BMI
Mean (SD) 22.5 (3.6) 23.4 (3.8)
Median (min: max) 22.1 (14.2:33.6) 23.1 (14.2:35.6)
Systolic Blood Pressure
Mean (SD) 143.1 (22.8) 143.6 (22.3)
Median (min: max) 141.0(85.0:199.0) 145.0(84.0:198.0)
Diastolic Blood Pressure
Mean (SD) 77.8 (12.5) 78.6 (11.8)
Median (min: max) 78.0 (50:.0:100.0) 80.0 (50.0:100.0)
Albumin
Mean (SD) 3.4 (0.6) 3.4 (0.6)
Median (min: max) 3.4 (1.7:5.0) 3.4 (1.6:4.9)
Hemoglobin
Mean (SD) 8.2 (1.4) 8.9 (1.4)
Median (min: max) 8.1 (3.9:13.1) 7.8 (3.9:14.5)
 Medico-legal Update, October-December 2020, Vol. 20, No. 4 1767

Characteristics CKD-EPI Group (N=385) Thai eGFR Group (N=299)

Bicarbonate (HCO3)
Mean (SD) 24.9 (4.5) 23.8 (5.4)
Median (min: max) 25.0 (10.0:40.5) 24.0 (4.0:42.5)
Hypokalemia (no (%))
No 324 (84.2) 264 (88.3)
Yes 61 (15.8) 35 (11.7)

Incidence of major adverse cardiovascular events: Incidence of MACE in the CKD-EPI group was 10.9%
compared with 12.4% in the Thai eGFR group (Table 2). Coronary artery disease was most common MACE diagnosis
followed by stroke.

Table 2 Incidence of the first major adverse cardiovascular events presented as number and percent

CKD-EPI Group Thai eGFR Group Total

Main factor
Number Percent Number Percent Number Percent
MACE (Yes/No)
No 343 89.1 262 87.6 605 88.4
Yes 42 10.9 37 12.4 79 11.6
MACE (Subgroup)
No MACE 343 89.1 262 87.6 605 88.4
CAD 29 7.5 23 7.7 52 7.6
PAD 0 0.0 1 0.3 1 0.2
Stroke 13 3.4 13 4.4 26 3.8

MACE major adverse cardiovascular event; CAD coronary arterial disease; PAD peripheral arterial disease

Relationship between different eGFR levels and occurrence. A MACE event (CAD, PAD or stroke) was
major adverse cardiovascular events: Using the 684 1.11 times more likely to occur after PD initiation in the
observations in the fitting model, the different equations Thai eGFR group than EPI-CKD group.
did not have a statistically significant effect on MACE

Table 3: Association between CKD-EPI equation compared with Thai eGFR with cardiovascular disease
among patients with end-stage renal disease

Characteristics Number % CVD Crude OR Adj. OR 95% CI P-Value

Equations/Group
CKD-EPI 385 10.9 1 1
Thai eGFR 299 12.4 1.15 1.11 0.685
Gender
Male 336 9.8 1 1
Female 348 13.2 1.40 1.29 0.79 to 2.13 0.309
Age (year) 1.01 1.01 0.99 to 1.04 0.209
1768 Medico-legal Update, October-December 2020, Vol. 20, No. 4

Characteristics Number % CVD Crude OR Adj. OR 95% CI P-Value

DM
No 354 9.9 1 1
Yes 330 13.3 1.40 1.38 0.80 to 2.37 0.241
BMI 1.03 1.03 0.96 to 1.10 0.418
SystolicBP 1.00 0.99 0.98 to 1.01 0.175
Diastolic BP 1.01 1.03 1.00 to 1.06 0.022
Albumin 0.84 0.92 0.62 to 1.37 0.690
Hemoglobin 0.93 0.91 0.77 to 1.08 0.300
Bicarbonate 1.01 1.01 0.96 to 1.06 0.768
Hypokalemia
No 588 10.5 1 1
Yes 96 17.7 1.83 1.69 0.92 to 3.09 0.091

Age refers to age at initiated PD; DM refers to diabetes mellitus; BMI refers to body mass index

Discussion disease or stroke, or both) other than kidney dysfunction

This study aims to compare the incidence of MACE
among 684 PD patients from a large provincial hospital
based on eGFR recalculated by the CKD-EPI equation
and Thai eGFR equation using serum creatinine and
other data obtained 3 months prior to initiation PD. No
significantly difference in the incidence of MACE was
found when comparing the CKD-EPI equation group
and the Thai equation in calculating eGFR (adj.OR:
1.11; 95%CI: 0.68-1.82; P-value = 0.685).
Patients in the Thai eGFR group (recalculated eGFR
> 4 ml/min/1.73m2 using the Thai eGFR and eGRF<4
ml/min/1.73m2 using the CKD-EPI) appear to be at
greater risk of MACE than those in the CKD-EPI group
(recalculated eGFR 5 to 14 ml/min/1.73m2 using CKD-
EPI equation). The percentage of patients with diabetes
and hypokalemia was higher in the Thai eGFR group.
Diabetes is a known risk factor for MACE [1, 3, 20] as
well as hypokalemia[21]. Coronary artery disease and
stroke were also found to be higher in Thai eGFR group.
However, these differences are minor and not statistically
significance (P-value = 0.685) in a multivariable analysis
that adjusted for age at PD initiation, DM, hypokalemia,
and other variables.
A study from Japan compared two equations
between the coefficient-modified CKD-EPI equation and
their own developed GFR-estimating equation (JPN-
eGFR) on CVD events, suggested that CKDEPI-eGFR
was more likely to detect some CVD event (cardiac
when compared with JPN-eGFR[7]. Stroke is one of
consequence of malfunctional kidney supported by
Kimoto et al., demonstrated that kidney dysfunction
related to elevated arterial, particularly aorta, stiffness in
type-2 DM patients[22]. In this study, the CKD-EPI and
Thai eGFR estimating equation are both based on serum
creatinine (Scr) which varies based on the ability of the
kidney to excrete waste products, muscle mass, age, and
gender. The Thai eGFR equation does not account for
all parameters related to the fluctuation of Scr compared
with the CKD-EPI equation. People are more likely to
lose muscle mass with the increasing age or ill health,
especially if they have ESRD. Therefore, they are more
likely to have a lower GFR estimation. It is noteworthy
thatCKD-EPI estimates GFR was based on specific Scr
according to male or female, this brings eGFR lower
than Thai eGFR. Hence, gaining high eGFR in the Thai
eGFR seems not have significant different effect on
MACE in Thai ESRD patients compared with CKD-EPI
calculation.
The strengths of this study include the large number
of ESRD patients on PD who have not experienced
any MACE prior to PD initiation and completeness of
the variables strongly associated with MACE. Another
strength is that the data come from a large provincial
hospital with one of the largest populations of chronic
kidney disease in Thailand, and therefore is a large sample
representative of the diversityof patients in a lower level
of health care facilities. This article also focuses on a
 Medico-legal Update, October-December 2020, Vol. 20, No. 4
major complication (MACE) which is a more practical
outcome in the evaluation and management of the adult-
CKD patients than overall mortality and can avoid “lead
time bias” in clinical care. In developing the algorithm
concerning the classification of both equations, we
allocated recalculated eGFR by covering both early and
late PD start according to the IDEAL Study definition
(Figure 1), however, decision to start PD is recommended
based on a careful discussion with the patient of the
risks and benefits of the treatment, considering patient’s
symptoms and signs of renal failure in addition to the
eGFR[23].
Conclusion
There was no effect on major adverse cardiovascular
events (MACE) either using CKD-EPI eGFR estimating
equation or the Thai eGFR equation to initiate peritoneal
dialysis. Nephrologists can consider using the Thai
eGFR as comparable as the CKD-EPI, while considering
the patient’s clinical symptoms and patient opinion as
part of the decision making.
Ethical Considerations: Ethical approval was
obtained from the Ethics Committee of KhonKaen
University (reference number HE622214) and use of the
data was approved by the administrative board of the
study hospital (EC number: 22/62).
Acknowledgement: The authors acknowledge
the support from the administrative committees of
Chaiyaphum Hospital for providing data for the analysis.
Conflict of Interest: No conflicts of interest were
disclosed.
Source of Funding: Faculty The authors declare
that no grants were involved in supporting this work.
References
1. Currie CJ, Berni ER, Berni TR, Jenkins-Jones
S, Sinsakul M, Jermutus L, et al. Major adverse
cardiovascular events in people with chronic kidney
disease in relation to disease severity and diabetes
status. PLoS One. 2019;14(8):e0221044.
2. Hundemer GL, Sood MM. Predialysis Care and
Cardiovascular Outcomes: Why the Lead Up to
Dialysis Matters. Kidney Int Rep. 2019;4(5):635-7.
3. Johnson DW, Dent H, Hawley CM, McDonald
SP, Rosman JB, Brown FG, et al. Association of
dialysis modality and cardiovascular mortality in
1769
incident dialysis patients. Clin J Am Soc Nephrol.
2009;4(10):1620-8.
4. Querido S, Quadros Branco P, Silva Sousa H,
Adragao T, Araujo Goncalves P, Gaspar MA, et al.
Peritoneal dialysis is a reasonable option in patients
with cardiovascular disease. Clin Nephrol. 2017;87
(2017)(3):111-6.
5. Stevens LA, Levey AS. Measured GFR as a
Confirmatory Test for Estimated GFR. Journal
of the American Society of Nephrology.
2009;20(11):2305-13.
6. Johnson DW, Atai E, Chan M, Phoon RK, Scott
C, Toussaint ND, et al. KHA-CARI guideline:
Early chronic kidney disease: detection, prevention
and management. Nephrology (Carlton).
2013;18(5):340-50.
7. Terawaki H, Nakayama M, Asahi K, Kakamu
T, Hayakawa T, Iseki K, et al. Comparison of
predictive value for first cardiovascular event
between Japanese GFR equation and coefficient-
modified CKD-EPI equation. Clin Exp Nephrol.
2015;19(3):387-94.
8. Levey AS, Stevens LA, Schmid CH, Zhang YL,
Castro AF, 3rd, Feldman HI, et al. A new equation
to estimate glomerular filtration rate. Ann Intern
Med. 2009;150(9):604-12.
9. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo
S. Modification of the CKD epidemiology
collaboration (CKD-EPI) equation for Japanese:
accuracy and use for population estimates. Am J
Kidney Dis. 2010;56(1):32-8.
10. Lee CS, Cha RH, Lim YH, Kim H, Song KH, Gu
N, et al. Ethnic coefficients for glomerular filtration
rate estimation by the Modification of Diet in Renal
Disease study equations in the Korean population.
J Korean Med Sci. 2010;25(11):1616-25.
11. Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y,
et al. Modified glomerular filtration rate estimating
equation for Chinese patients with chronic kidney
disease. J Am Soc Nephrol. 2006;17(10):2937-44.
12. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K,
Nitta K, et al. Revised equations for estimated GFR
from serum creatinine in Japan. Am J Kidney Dis.
2009;53(6):982-92.
13. Stevens LA, Claybon MA, Schmid CH, Chen J,
Horio M, Imai E, et al. Evaluation of the Chronic
Kidney Disease Epidemiology Collaboration
equation for estimating the glomerular filtration rate
1770 Medico-legal Update, October-December 2020, Vol. 20, No. 4
in multiple ethnicities. Kidney Int. 2011;79(5):555-
62.
14. Dhanakijcharoen P, Sirivongs D, Aruyapitipan S,
Chuengsaman P, Lumpaopong A. The “PD First”
policy in Thailand: three-years experiences (2008-
2011). J Med Assoc Thai. 2011;94 Suppl 4:S153-
61.
15. Kokubu M, Matsui M, Uemura T, Morimoto
K, Eriguchi M, Samejima K, et al. Relationship
between initial peritoneal dialysis modality and risk
of peritonitis. Sci Rep. 2020;10(1):18763.
16. Global, regional, and national burden of chronic
kidney disease, 1990-2017: a systematic analysis
for the Global Burden of Disease Study 2017.
Lancet. 2020;395(10225):709-33.
17. Said S, Hernandez GT. The link between chronic
kidney disease and cardiovascular disease. J
Nephropathol. 2014;3(3):99-104.
18. Praditpornsilpa K, Townamchai N, Chaiwatanarat
T, Tiranathanagul K, Katawatin P, Susantitaphong
P, et al. The need for robust validation for MDRD-
based glomerular filtration rate estimation in
various CKD populations. Nephrology Dialysis
Transplantation. 2011;26(9):2780-5.
19. Thailand TNSo. Clinical Practice Recommendation
for the Evaluation and Management of Chronic
Kidney Disease in Adults 20152015.
20. Currie CJ, Berni ER, Berni TR, Jenkins-Jones
S, Sinsakul M, Jermutus L, et al. Major adverse
cardiovascular events in people with chronic kidney
disease in relation to disease severity and diabetes
status. PLoS One. 2019;14(8):e0221044-e.
21. Gasparini A, Evans M, Barany P, Xu H, Jernberg
T, Ärnlöv J, et al. Plasma potassium ranges
associated with mortality across stages of chronic
kidney disease: the Stockholm CREAtinine
Measurements (SCREAM) project. Nephrology
Dialysis Transplantation. 2018;34(9):1534-41.
22. Kimoto E, Shoji T, Shinohara K, Hatsuda S, Mori
K, Fukumoto S, et al. Regional Arterial Stiffness
in Patients with Type 2 Diabetes and Chronic
Kidney Disease. Journal of the American Society
of Nephrology. 2006;17(8):2245-52.
23. Cooper BA, Branley P, Bulfone L, Collins JF, Craig
JC, Fraenkel MB, et al. A randomized, controlled
trial of early versus late initiation of dialysis. N
Engl J Med. 2010;363(7):609-19.