Kepada YTH:

dr.Henny Tannady Tan

Journal Reading

Serum Uric Acid and Cardiovascular Mortality in

Chronic Kidney Disease : A Meta-analysis

Nama : dr. Elsy Pramitha Sari

NIM : 2150302202
Tanggal Presentasi : 12 Januari 2022

Program Studi Pendidikan Dokter Spesialis I

Bagian Penyakit Dalam RSUP Dr. M. Djamil Padang
Fakultas Kedokteran Universitas Andalas
2022
Luo et al. BMCNephrology (2019) 20:18
https://doi.org/10.1186/s12882-018-1143-7

Serum uric acid and cardiovascular

mortality in chronic kidney disease: a
meta- analysis
Qimei Luo1,2†, Xi Xia1,2†, Bin Li1,2, Zhenchuan Lin1,2, Xueqing Yu1,2 and Fengxian Huang1,2*

independent risk factor for cardiovascular mortality in patients with chronic kidney disease (CKD).

studies reporting on the association between SUA levels and cardiovascular mortality in patients with

CKD. intervals (CI).

with CKD.

Background
Chronic kidney disease (CKD) has become a major glo-
bal health burden. The age-standardized global preva-
lence of CKD stages 1–5 among adults in 2010 was
10.4% in men and 11.8% in women [1]. CKD was ranked
as the 19th highest global cause of life years lost, with an
age-standardized death rate of 15.8 per 100,000 [2]. Pa-
tients with CKD have an increased risk of cardiovascular
mortality compared with those with normal kidney func-
tion [3]. Cardiovascular disease (CVD) causes most of
* Correspondence: hfxyl@163.net
†
Qimei Luo and Xi Xia contributed equally to this work.
1
Department of Nephrology, The First Affiliated Hospital of Sun Yat-
sen University Guangzhou 510080, People’s Republic of China
2
Key Laboratory of Nephrology, Ministry of Health and Guangdong
Province, Guangzhou 510080, People’s Republic of China
the deaths in individuals with CKD [3, 4]. Many risk fac-
tors have been identified for cardiovascular mortality in
patients with CKD, such as smoking, diabetes, systolic
hypertension, high levels of C-reactive protein, and left
ventricular hypertrophy [5–7]. Several studies have sug-
gested that hyperuricemia may be another potential risk
factor for cardiovascular mortality in individuals with
CKD [8–10]. Elevated serum uric acid (SUA) is related to
the development and progression of hypertension [11],
stroke [12], and cardiovascular disease [13]. In the general
population, SUA level is an independent pre- dictor for
future cardiovascular mortality [14].
Many [8, 9, 15–18] but not all [19, 20] studies have de-
tected a significant association between SUA levels and car-
diovascular mortality in individuals with CKD. Furthermore,
there is still some debate whether SUA levels can be an

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons
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in this article, unless otherwise stated.

independent risk factor for cardiovascular mortality in pa-
tients with CKD. Several studies [8, 9, 16] indicated that
higher SUA is a predictor of increased risk of death from
cardiovascular disease in patients with CKD, while other
studies [15, 17, 18] reported that higher SUA levels are as-
sociated with lower risk of cardiovascular mortality. We
hypothesized that SUA levels could be a predictor for car-
diovascular mortality in individual with CKD. In this
study, we conduct a meta-analysis of all relevant studies to
evaluate the association of SUA levels with cardiovascular
mortality in patients with CKD.
Methods
Study design and search strategy
The meta-analysis was designed and conducted according
to the consensus guidelines in “Meta-Analysis of Observa-
tional Studies in Epidemiology” [21]. A systematic litera-
ture search was performed using the PubMed and Web of
Science databases from the time of their inception to May
8, 2017. No restrictions were imposed on the search. The
following search terms and search strings were used:
(“uric acid” OR hyperuricemia OR urate) AND (renal or
kidney or dialysis) AND (mortality or death or survival or
cardio- vascular or stroke). The key words and abstract
were searched. In addition, we performed a manual survey
of cited references in the retrieved reviews and articles to
capture all relevant studies. Two of the authors independ-
ently conducted the literature searches.
Study selection
The following inclusion criteria were used to select studies for
this meta-analysis: (1) studies had baseline information about
SUA concentration; (2) studies exploring cardiovascular mor-
tality as a study outcome; (3) studies recruiting adult patients
with CKD and CKD defined according to the Kidney Disease
Outcomes Quality Initiative (KDOQI) guideline [22]; and (4)
studies that compared the highest SUA levels with the lowest
SUA levels, or performed controlled comparison of 1 mg/dl
increase in SUA levels, and provided statistical data on hazard
ratio (HR) and 95% confidence interval (CI), or included suffi-
cient data to enable the calculation of HR and 95% CI. In the
case of multiple studies based on the same population or sub-
population, only the most informative report or the most re-
cent publication was included. Two authors independently
reviewed the retrieved articles and determined whether the
article satisfied the inclusion criteria. Disagreement was re-
solved by discussion with the senior author. We requested
additional data from corresponding authors for two articles (n
= 2) to enable statistical calculation of HR and 95% CI. How-
ever, the corresponding authors in both cases did not respond
to our requests. A total of 44 articles were selected by the in-
clusion criteria, and these were then subjected to the exclusion
criteria listed in Additional file 1: Table S1. Finally, a total of
11 articles were selected for this meta-analysis.
Page 2 of 12
Data extraction and quality assessment
Two authors independently extracted data from full-text arti-
cles. The data included author, publication year, study design,
population, number of participants, mean age of participants,
percentage of men, diabetes, mean SUA levels, median dur-
ation of follow-up, number of deaths due to cardiovascular
events, definition of cardiovascular mortality, and adjusted
factors. The most fully adjusted HR and 95% CI were ex-
tracted from all included studies. The quality of observa-
tional cohort studies was evaluated according to the
Newcastle-Ottawa quality assessment scale [23]. Study qual-
ity was categorized as poor (score 1–3), fair (score 4–6), or
good (score 7–9) depending on the quality of study partici-
pant selection, comparability, and outcome. The quality of
randomized controlled trials was evaluated using the Jadad
scale; a high-quality trial should have a Jadad score ≥ 3 [24].
Statistical analysis
HRs were adjusted for the maximum number of con-
founding variables. Every HR was transformed into the
natural logarithm (log HR), and the standard error ob-
tained from its corresponding 95% CI. Since multivari-
able Cox proportional hazards regression analyses were
used to obtain the adjusted HRs of SUA levels for car-
diovascular mortality, random-effects analyses were per-
formed to calculate the pooled log HR values. Then, we
obtained the overall HR and its corresponding 95% CI
through exponentiation of the pooled log HR [25].
We analyzed SUA as a continuous variable to test the
possibility of a nonlinear dose-response relationship be-
tween SUA levels and cardiovascular mortality [26]. For
this analysis, we used the restricted cubic splines method
with three knots at the 25th, 50th, and 75th percentiles
of serum uric levels. In some cases, SUA was analyzed
as a categorical variable to evaluate the trends between
SUA levels and cardiovascular mortality using two differ-
ent methods. Generalized least-squares regression ana-
lysis was used when data for the cases and person-years
or participants and HRs were available for each category.
Variance-weighted least-squares regression analysis was
used when information for the cases or participants was
not available for each category [27, 28].
The I2 index, Q statistic, and P value were used to describe
the heterogeneity of effect size estimates across studies. We
performed meta-regression analyses to evaluate the influence
of prespecified covariates on between-study heterogeneity.
Funnel plots were computed and Egger’s tests were per-
formed to assess the potential publication bias [29]. Sensitiv-
ity analyses were performed to evaluate the influence of a
single study on the overall risk estimate by removing one
study at a time. All analyses were performed with STATA
statistical software version 12.0 (Stata Corp, College Station,
TX, USA). A P value < 0.05 was regarded as statistically
significant.

Results
Study selection and study characteristics
Our systematic literature search was inclusive from the data-
base inception up to May 8, 2017. We retrieved 2.092 ab-
stracts in PubMed and 5004 abstracts in Web of Science. A
total of 5359 non-duplicate studies were identified. After the
first selection procedure, we evaluated 44 full-text articles
further. Finally, 11 articles representing 27,081 study partici-
pants fulfilled all eligibility criteria [8–10, 16–20, 30–32]. A
detailed description of our study selection is presented in
Fig. 1. The characteristics and quality of the individual stud-
ies are presented in Table 1. The articles included four pro-
spective cohort studies, six retrospective cohort studies, and
one randomized controlled trial. The number of participants
in individual studies ranged from 261 [30] to 13,059 [16].
The percentage of study participants with diabetes varied
from 5% [8] to 59% [30]. The median duration of follow-up
ranged from 23 months to 10 years. All 11 studies provided
adjusted risk estimates, nine studies adjusted for kidney func-
tion [8–10, 16, 18–20, 30, 31], and five studies adjusted for
drugs to lower uric acid levels [8, 10, 17, 18, 31].
The definition of cardiovascular mortality events varied
among the included studies: two studies used the Inter-
national Classification of Diseases Codes (ICD) [8, 16]; five
studies reported the mortality from cardiovascular disease,
cerebrovascular disease, and peripheral vascular disease [9,
10, 19, 30, 31]; one study reported the mortality from
Page 3 of 12
cardiovascular disease and cerebrovascular disease [17]; two
studies only reported the mortality from cardiovascular dis-
ease [18, 20]; and one study did not provide information re-
garding the definition of cardiovascular mortality [32]. None
of the included studies reported the risk for cardiovascular
mortality associated with the lowest and median SUA levels.
All cohort studies had fair to good quality according to the
Newcastle-Ottawa Scale. The randomized control trial had
high quality with a Jadad score of 3.
Association of SUA with cardiovascular mortality
1sSeven studies [8, 10, 17–20, 32] reported the association
of SUA as a categorical variable with cardiovascular mor-
tality. A total of 11,050 participants were included in this
meta-analysis. Patients in the group with the highest SUA
levels were associated with an increased risk of cardiovas-
cular mortality compared with patients with the lowest
levels (HR 1.47, 95% CI 1.11–1.96; Fig. 2). There was
mod- erate heterogeneity among these included studies (I2
= 40.4%, P = 0.109). One study also reported the
estimated association between SUA as the categorical
variable and cardiovascular mortality [16]. Those authors
reported that the adjusted HR for cardiovascular mortality
was 1.42 (95% CI 1.11–1.81) and 1.65 (95% CI 1.22–
2.24) for pa-
tients with the second-highest SUA levels (9.0–10.9 mg/
dl) and those with the highest levels (≥11.0 mg/dl) com-
pared with those with medium levels (5.0–6.9 mg/dl) [16].
Table 1 Characteristics of 11 studies included in the meta-analysis
Author,
Study Population Patients Men Diabetes Age Uric acid Follow-up Cardiovascular Comparison Adjust Adjustments Quality
year design (n) (%) (%) (years) (mg/dl) mortality HR score
events and (95%CI)
definition (n)
Madero, RCT United States, 838 39 5 52 ± 12 7.63 ± 1.66 Median 127 Per 1 mg/dl 1.16 (1.01–1.33) Age, gender, blood 3
2009 [8] 10 years CV mortality was increase pressure, protein
defined as death Tertile3 vs. 1.47 (0.90–2.39) diet randomization
MDRD, resulting from CVD tertile 1 assignments, history
CKD3–4 (International 8.4–15.6mg/dl of CVD, DM, BMI,
classification of vs. 1.7–6.9 systolic blood
diseases, ninth mg/dl pressure, HDL-C, log-
revision [ICD-9] codes transformed C-
390 to 459) reactive protein, GFR,
albumin, diuretic,
allopurinol.
Latif, PCS DOPPS, HD 4637 58.2 24.5 Mean Mean 6.97 Median NA Per 1 mg/dl 0.92 (0.86,0.99) Age, black race, 5
2011 [17] 58–64 23 months CV mortality was Increase gender, BMI, years
defined as death < 8.2 mg/dl 1.54 (1.15–2.07) with ESRD, albumin-
resulting from vs. corrected calcium, al-
acute myocardial > 8.2 mg/dl bumin, ferritin, creatin-
infarction, ine, phosphorus,
atherosclerotic heart allopurinol, 14 comor-
disease, bid conditions, study
cardiomyopathy, phase and facility
cardiac arrhythmia,
cardiac arrest,
congestive heart
failure,
cerebrovascular
accident including
intracranial
hemorrhage,
ischemic brain
damage and
anoxic
encephalopathy
Kanbay, RCS Turkey, 303 49.8 23.4 Mean NA Median 33 Per 1 mg/dl 2.819 (1.783–4.458) Age, gender, eGFR, 6
2012 [9] CKD 3–5 47–53 39 months CV mortality was Increase DM, smoking,
defined as death hypertension, LDL,
resulting from systolic blood
coronary heart pressure, hsCRP,
disease, sudden HOMA-IR index,
death, stroke FMD, NMD
and complicated
peripheral vascular
disease
Kuo, 2013 RCS Taiwan, 13,059 NA NA NA NA Median NA 9.0–10.9mg/dl vs. 1.42 (1.11–1.81) Age, gender, eGFR, 6
[16] CKD 4.6 years CV mortality was 5.0–6.9 mg/dl fasting glucose, total

12
Page 4 of
defined as death < 11.0 mg/dl 1.65 (1.22–2.24) cholesterol and
resulting from vs. 5.0–6.9 history of
cardiovascular mg/dl hypertension, DM,
disease (ICD-9 codes: CHD, stroke, heart
Table 1 Characteristics of 11 studies included in the meta-analysis (Continued)
Author,
Study Population Patients Men Diabetes Age Uric acid Follow-up Cardiovascular Comparison Adjust Adjustments Quality
year
design (n) (%) (%) (years) (mg/dl) mortality HR score
events and (95%CI)
definition (n)
390.x-459.x) failure.
Yin, 2013 RCS China, CKD 1132 71.7 33.6 67.7 ± 7.8 ± 1.9 Median 50 Quartile 4 vs. 0.84 (0.37–1.89) Age, gender, DM, 7
[20] undergoing 7.8 38.5 months CV mortality was quartile 1 eGFR, left ventricular
DES defined as death > 8.98 mg/dl vs. ejection, proteinuria,
resulting from < 6.46 mg/dl AMI, incomplete
coronary artery revascularization
disease, cardiac
arrhythmia,
congestive heart
failure, sudden
death
Dong, 2014 RCS China, SSOP, 2193 49 37.7 58.1 ± 6.41 ± 1.87 Median 231 Per 1 mg/dl 1.04 (0.89,1.20) Age, residual renal 7
[19] PD 15.5 26.5 months CV mortality was increase function, albumin,
defined as death Gender-specific 1.35 (0.74,2.46) hemoglobin,
resulting from Tertile 3 vs. phosphate, C-
myocardial tertile 1 reactive protein, his-
infarction, Men: 7.39–16.7 tory of CVD, DM,
congestive heart mg/dl women: BMI, mean arterial
failure, cerebral 6.66–8.08 mg/dl pressure, LDL-C, cen-
bleeding, cerebral vs. Men: 2.09– ter size, gender-
infarction, 5.79 mg/dl adjusted only SUA as
arrhythmia, women: 1.74– continuous variable
peripheral arterial 5.37 mg/dl
disease and
sudden death
Miyaoka,
RCS Japan, 551 59.3 10 58.5 6.57 ± 1.35 6 years 19 Tertile 3 vs. 1.042 (0.139–7.831) Gender, smoking 8
2014 [18]
CKD2–4 CV mortality was tertile 1 status, history of
defined as death 7.2–12.4 mg/dl CVD, systolic blood
resulting from vs. 3.0–5.8 pressure, HDL-C,
myocardial mg/dl triglyceride,
infarction, hemoglobin, C-
congestive heart reactive protein
failure. (log), eGFR,
protein- uria (log),
etiology of kidney
disease, di- uretics,
allopurinol

Hyperuricemia vs. 0.274 (0.103–0.731) Gender, smoking

normouricemia status, CVD, HDL-
Hyperuricemia C, triglyceride,
(> 7.0 mg/dl or hemoglobin, C-
with allopurinol) reactive protein
(log), eGFR, protein-

12
Page 5 of
uria (log), etiology
of kidney disease,
di- uretics,
allopurinol
Table 1 Characteristics of 11 studies included in the meta-analysis (Continued)
Author, Study Population Patients Men Diabetes Age Uric acid Follow-up Cardiovascular Comparison Adjust HR Adjustments Quality
year design (n) (%) (%) (years) (mg/dl) mortality (95%CI) score
events and
definition (n)
Beberashvili, PCS Isreael, 261 61.3 59 68.6 ± 5.76 ± 2 years 31 Per 1 mg/dl 0.53 (0.33–0.86) Age, gender, 7
1.16
2015 [30] MHD 13.6 CV mortality was Increase vintage, Kt/v, DM,
defined as death comorbidity index,
resulting from smoking, systolic
coronary heart blood pressure, waist
disease, sudden hip rate, phosphorus,
death, stroke, or creatinine, residual
complicated renal function,
peripheral vascular malnutrition
disease. inflammation score,
interleukin-6
Hsieh, 2015 RCS Taiwan 2408 56.9 38.3 65.7 ± 7.73 ± Median 143 Per 1 mg/dl 1.16 (0.92–1.32) Age, gender, BMI, 7
1.78
[31] CKD 3–5 12.6 3.03 years CV mortality was Increase DM, hypertension,
defined as death cardiovascular
resulting from disease, gout,
coronary artery glycated
disease, hemoglobin,
cerebrovascular or cholesterol,
peripheral vascular triglyceride, BUN,
disease eGFR, GPT, albumin,
Ca × P, white blood
cell count,
hemoglobin,
proteinuria, diuretics,
hypouricemic
agents,
erythropoiesis
stimulating agents,
ACE inhibitor and
angiotensin II
receptor blocker
Xia, 2016 PCS China, PD 1278 58.8 25.7 47.6 ± 7.2 ± 1.4 Median 30.7 126 Per 1 mg/dl 1.42 (1.13–1.79) Age, BMI, 8
[10] 15.0 months CV mortality was increase DM Men hypertension, CVD,
defined as death 1.12 (0.78–1.61) hemoglobin,
resulting from acute DM Women albumin,
myocardial infarction, 1.41 (1.09–1.82) phosphorus, serum
cardiac arrhythmia, NDM Men creatinine, HDL-C,
cardiac arrest, 1.24 (0.85–1.82) re- sidual renal
congestive heart NDM Women function, log-
failure, transformed high-
cerebrovascular sensitive C-

12
Page 6 of
accident, and reactive protein,
peripheral vascular gly- cated
disease. hemoglobin, use of
allopurinol, and use
Table 1 Characteristics of 11 studies included in the meta-analysis (Continued)
Author, Study Population Patients Men Diabetes Age Uric acid Follow-up Cardiovascular Comparison Adjust Adjustments Quality
year design (n) (%) (%) (years) (mg/dl) mortality HR Score
events and (95%CI)
definition (n)
Gender-adjusted
Gender-specific only SUA as continu-
Tertile 3 vs. 2.26 (1.14–4.48)
tertile 1 DM ous variable. Gly-
DM Men: cated hemoglobin-
7.1–13.8 mg/dl, adjusted on in
women: 6.9–12.6 DM.
mg/dl vs.
Men: 1.5–5.6 mg/
dl, women: 1.2–
5.4 mg/dl.

NDM Men:
7.1–13.8 mg/dl,
women: 6.9–12.6 3.07 (1.54–6.08)
mg/dl vs. NDM
Men: 1.5–5.6
mg/dl,
women: 1.2–5.4
mgj/dl
Li, 2016 [32] PCS China,
421 NA NA NA NA Median 3.9 NA Tertile 4 vs. tertile 0.72 (0.28,1.81) Age, gender, leisure- 6
CKD
3–5 years 1 time physical activ-
7.29–18.88 mg/dl ity, smoking, alcohol
vs ≤ 5.08 mg/dl drinking, occupation,
BMI, SBP, DBP, LDL-
C, duration of
CAD, type of CAD,
history of diabetes,
history of heart
failure, cor- onary
artery stenosis
degree on
coronary
angiography, use
of antidiabetic,
cholesterol-lowering
or antiplatelet drugs,
use of diuretics, β-
blockers and antihy-
Conversion factors for units: serum uric acid in mg/dl to umol/l, ×59.48 pertensive drugs
Abbreviations: AMI acute myocardial infarction, BMI body mass index, CAD coronary artery disease, CV cardiovascular, CVD cardiovascular disease, CHD coronary heart disease, CKD chronic kidney disease, DBP
diastolic blood pressure, DM diabetes mellitus, DOPPS The Dialysis Outcome and Practice Patterns Study, DES drug-eluting stent, eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, FMD flow-
mediated dilatation, HD hemodialysis, HDL-C high density lipoprotein cholesterol, HOMA-IR homeostasis model assessment-insulin resistance, hsCRP high sensitivity C reactive protein, LDL-C low density lipoprotein
cholesterol, MHD maintenance hemodialysis, MDRD Modification of Diet In Renal Disease, NDM nondiabetes, NMD nitroglycerine-mediated dilatation, NA not available, PD peritoneal dialysis, SBP systolic
blood pressure, SSOP Socioeconomic Status on the Outcome of Peritoneal Dialysis, SUA serum uric acid, RCT randomized controlled trial, PCS prospective cohort study, RCS retrospective cohort study

12
Page 7 of

Seven of the included studies [8–10, 17, 19, 30, 31] re-
ported the association of increasing SUA levels (per 1 mg/dl)
with cardiovascular mortality. Three studies only reported
the association of SUA as a categorical variable with cardio-
vascular mortality [16, 18, 20]; these results were evaluated
using variance-weighted least-squares regression analyses to
obtain the dose-response relationship between SUA levels
and cardiovascular mortality. A total of 26,660 participants
were included in this meta-analysis. Higher SUA levels (per
1 mg/dl increment) were associated with significantly higher
hazard ratios for cardiovascular mortality (HR 1.12, 95% CI
1.02–1.24; Fig. 3). A significant heterogeneity among these
studies was observed (I2 = 79.2%; P < 0.001). The nonlinear
relationship test result suggested that SUA levels had no
nonlinear association with cardiovascular mortality (p for
nonlinearity = 0.109).
Subgroup analyses
Subgroup analyses were performed on the association of
SUA (per 1 mg/dl increase) with cardiovascular mortality
(Fig. 4). A significant and positive association between
SUA levels and increased risk of cardiovascular mortality
was observed in the Asian group, high quality scoregroup,
sample size > 1000 participants group, median follow-up
duration > 3 years group, and adjusted for allopurinol
treatment group. Six studies analyzed CKD populations
that were not undergoing dialysis; each 1 mg/dl increase
in SUA was independently associated with a 16% increase
in cardiovascular mortality risk (HR 1.16, 95% CI 1.02–
1.33). By contrast, for CKD populations that were under-
going dialysis, each 1 mg/dl increase in SUA was not
asso- ciated with increased cardiovascular mortality risk
(HR 1.08, 95% CI 0.90–1.29). Nine studies analyzed the
associ- ation adjusted for kidney function, each 1 mg/dl
increase in SUA was independently associated with a 16%
increase
withchronickidneydisease. Abbreviations: CI, confidenceinterval; DM, diabetesmellitus; HR, hazardratio; NDM, non-diabetes
mellitus
Page 8 of 12
in cardiovascular mortality risk (HR 1.16, 95% CI 1.04–
1.28). Two cohort studies focused on patients receiving peri-
toneal dialysis (PD), and reported a significant association be-
tween higher SUA levels and increased cardiovascular
mortality (HR 1.22, 95% CI 1.05–1.43). By contrast, two co-
hort studies focused on patients receiving hemodialysis (HD)
did not observe any association between higher SUA levels
and cardiovascular mortality (HR 0.74, 95% CI 0.43–1.25).
Sensitivity analyses and publication bias
Sensitivity analyses and Egger’s tests for publication bias
were performed using SUA as both categorical and
continuous variables. The sensitivity analysis of SUA as a
categorical variable indicated that there was moderate
influence on the pooled HR and 95% CI when the study of
Latif et al. [17] was excluded from the analysis. The
sensitivity analysis of SUA as a continuous variable suggested
that the results did not change significantly when one study
was omitted at a time (Additional file 2: Figure S1). There
was no statistical evidence of publication bias among studies
of the association of SUA as a categorical variable and
cardiovascular mortality (p = 0.680) or among studies of the
association of SUA (per 1 mg/dl increase) with
cardiovascular mortality (p = 0.430). The funnel plots
representing these analyses are presented in Additional file 3:
Figure S2.
Discussion
Our meta-analysis of 11 cohort studies indicates that el-
evated SUA levels in patients with CKD are associated
with significantly increased risk of cardiovascular mor-
tality. This is the first meta-analysis that analyzed the as-
sociation of SUA with cardiovascular mortality in patients
with CKD. Our previous meta-analysis showed that higher
SUA levels were associated with higher mor- tality risk in
patients with CKD [33]. These results are
 Page 9 of 12

Fig. 3 Forest plot and summary hazard ratio for the association of serum uric acid as a continuous variable (per 1 mg/dl increment) and

NDM, non-diabetes mellitus

Fig. 4 Forest plot and summary hazard ratio of subgroup analysis for the association of serum uric acid as a continuous variable
(per 1 mg/dl

RCS, retrospective cohort study


consistent with the trends reported in three previous
systematic reviews [12, 14, 34]. A meta-analysis of nine
prospective observational studies with 165,922 partici-
pants reported that elevated SUA was associated with a
37% greater risk for cardiovascular mortality in the gen-
eral population [14]. Two other meta-analyses focused on
the association between hyperuricemia and mortality from
stroke, and reported that hyperuricemia might increase the
risk of stroke mortality [12, 34]. Previous meta-analysis re-
ported that hyperuricemia increased the risk of cardiovascu-
lar events such as heart failure [35] and coronary heart
disease [36]. Only one study reported this association separ-
ately in men and women [10], so we did not perform sub-
group analysis for gender in our meta-analysis.
Two studies captured during our literature search were
not included in this meta-analysis because they did not con-
tain sufficient data to estimate the HR. A study with a cohort
of 2645 patients with systolic heart failure analyzed the asso-
ciation of hyperuricemia with all-cause mortality, cardiovas-
cular mortality, and heart failure hospitalization among all
heart failure patients and those with and without CKD [37],
and suggested that hyperuricemia was not significantly asso-
ciated with cardiovascular mortality in heart failure patients
with CKD. However, the study did not present detailed data
for the HR of hyperuricemia with cardiovascular mortality.
A single-center prospective study assessed whether SUA and
superoxide dismutase could be predictive factors for cardio-
vascular mortality in patients undergoing hemodialysis [15],
and found that lower SUA levels could predict cardiovascular
mortality in hemodialysis patients (HR 0.937, 95% CI
0.883– 0.994). However, this study analyzed the association
of per 1 μmol/l increase in SUA levels with cardiovascular
mortal- ity, and did not provide sufficient data to calculate
HR.
Several potential mechanisms support the pathogenic as-
sociation between higher SUA levels and higher risk of car-
diovascular mortality. Hyperuricemia could disturb
mitochondrial function and reduce ATP content, which
would induce oxidative stress [38]. Experimental studies have
shown that uric acid could enhance NALP3 expression,
caspase-1 activation, and IL-1β and ICAM-1 production,
suggesting that uric acid could stimulate inflammatory re-
sponses [39, 40]. Uric acid itself also may increase
inflamma- tion in patients with CKD [41]. Higher uric acid
levels are related with diminished endothelial function [42–
44], and endothelial dysfunction may contribute to
hypertension and cardiovascular morbidity [45]. Chronically
elevated uric acid levels could cause structural changes in
vessel walls [46].
The core aspects of hyperuricemia management were
patient education, lifestyle advice, and pharmacological
therapies such as allopurinol [47]. A prospective, random-
ized trial found that allopurinol treatment reduced risk of
cardiovascular events in patients with CKD [48]. The re-
sults from an observational study suggested that allopur-
inol lowered cardiovascular-related mortality in Japanese
Page 10 of 12
patients receiving hemodialysis who had no history of car-
diovascular disease [49]. A prospective study reported that
treatment of hyperuricemia with allopurinol could im-
prove endothelial function in patients with CKD [50].
Heterogeneity was significantly high among the 10 studies
that analyzed the association of increasing SUA (per 1 mg/
dl) with cardiovascular mortality. However, the results of
meta-regression analyses indicated that region, study design,
population, study quality, sample size, follow-up time, treat-
ment modality, and adjustment for allopurinol treatment
could not account for the heterogeneity. The high heterogen-
eity might be related to age and/or other participant charac-
teristics across the analyzed studies. The definitions of
cardiovascular mortality were not exactly the same among
these 10 studies, which may partly explain the heterogeneity.
The included studies all have different definitions of car-
diovascular mortality, different entry stages of CKD,
differ- ent definitions of high versus low uric acid, it
seems pointless quoting HR for increased cardiovascular
mortal- ity given that the single number cannot be applied
to any particular situation, but the results of our meta-
analysis showed trend of higher uric acid and
cardiovascular mor- tality in patients with CKD.
Subgroup analysis of the predictive role of SUA on cardio-
vascular mortality differed with respect to the treatment mo-
dality, which may be due to differences in the clearance of
uric acid between hemodialysis and PD. Malnutrition in dia-
lysis patients may lead to low uric acid levels. Higher uric
acid in hemodialysis patients is an indicator of better nutri-
tional status [17, 51], which may partly explain the associ-
ation of lower uric acid levels with higher cardiovascular
mortality. Few of the included studies explored the associ-
ation between SUA and cardiovascular mortality with respect
to different CKD stages. Therefore, there was not enough
data to perform the subgroup analysis for CKD stage. Instead
we performed the subgroup analysis for the population of
non- dialysis or dialysis. A near-significantly larger effect (p
= 0.054) of treatment modality was observed in subgroup
ana- lysis of pooled risk estimates. The heterogeneity among
stud- ies that analyzed the association of SUA as a categorical
variable with cardiovascular mortality was quite low. Although
there was no evidence of publication bias, it cannot be com-
pletely ruled out due to the unpublished null findings.
Several limitations of our study should be acknowledged.
First, most of the included studies were observational studies
that could not prove a causal relationship, and some poten-
tial confounders including declining kidney function, nutri-
tional status, and urate-lowering therapy during follow-up
were difficult to fully adjust. Second, high heterogeneity was
observed among the included studies that analyzed the asso-
ciation of SUA as a continuous variable with cardiovascular
mortality. Individual studies did not adjust for the same po-
tential risk factors. Each study had different cut-off values for
the SUA groups, which might lead to misclassification of

individuals in each group. Third, although the nonlinear rela-
tionship test suggested an approximately linear relationship
between SUA and cardiovascular mortality in patients with
CKD, only three of the included studies provided sufficient
data to perform the nonlinear relationship test. Therefore,
more data is needed to support the exact relationship be-
tween SUA and cardiovascular mortality. Fourth, the sensi-
tivity analysis of SUA as a categorical variable indicated that
the results were not significant when the Latif [17] study was
omitted. Fifth, only few of the included studies reported data
for cardiovascular mortality with respect to gender; therefore,
we could not evaluate whether SUA level affected the
cardio- vascular mortality risk of men and women.
Our study has several strengths. This study is the first sys-
tematic review and meta-analysis of the association of base-
line SUA levels with cardiovascular mortality in patients with
CKD. The included studies had relatively high quality and
adjusted for other risk factors. Furthermore, we considered
uric acid not only as a categorical variable but also as a con-
tinuous variable.
Conclusions
In conclusion, the results of our meta-analysis suggest that
elevated levels of SUA increase the risk of cardiovascular
mortality in patients with CKD. Future studies, preferably
randomized controlled studies, should explore whether hy-
peruricemia is a potentially modifiable risk factor for cardio-
vascular mortality in patients with CKD.
Additional files
Additional file 1: Table S1. The reasons of excluded articles at the
(DOCX 86 kb)
Additional file 2: Figure S1. Sensitivity analysis. Sensitivity analyses
wereperformedtoevaluatetheinfluenceofasignalstudyontheoverall risk
estimate by removing one study at a time. (DOCX 13200 kb)
Additional file 3: Figure S2. Publication bias. Funnel plots and Egger’s
kb)
Abbreviations
CKD: Chronic kidney disease; CVD: Cardiovascular disease; HD: Hemodialysis;
PD: Peritoneal dialysis; SUA: Serum uric acid
Acknowledgements
Not applicable
Funding
This study was supported by grants from National Key Basic Research
Program of China (Grant No. 2011CB504005, support study design), National
Key Technology Research and Development Program of the Ministryof
Science and Technology of China (Grant No. 2011BAI10B05, support
study design), National Natural Science Foundation of China (Grant No.
81170765, 81370908, 81570750, 81870575, support collection and analysis of
data and support writing manuscript), National Natural Science Foundation
for Young Scholars of China (Grant No. 81700718, support collection and
analysis of data), Natural Science Foundation of Guangdong Province
(Grant No. 2017A030310044, support interpretation of data) and
Science and
Page 11 of 12
Technology Project of Guangdong Province (Grant NO. 2013B022200003,
support interpretation of data).
Availability of data and materials
The datasets generated and analyzed during the current study are
available from the corresponding author on reasonable request.
Authors’ contributions
QML originated the study, acquired data, analyzed statistics, interpreted
data, drafted the manuscript, and critically revised the manuscript. XX
originated the study, acquired data, analyzed statistics, interpreted
data, drafted the manuscript, and critically revised the manuscript. BL
analyzed statistics, interpreted data, and critically revised the
manuscript. ZCL analyzed and interpreted data, and critically revised the
manuscript. XQY interpreted data and critically revised the manuscript for
important intellectual content. FXH designed the study, interpreted data
and critically revised the manuscript. All authors read and approved the
final manuscript.
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 7 November 2017 Accepted: 20 November 2018
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 Asam Urat Serum dan Mortalitas Kardiovaskular pada Penyakit Ginjal
Kronis: Meta-analisis

Abstrak

Latar Belakang: Hasil yang bertentangan telah dilaporkan dari penelitian yang
mengevaluasi kadar serum uric acid (SUA) sebagai faktor risiko independen
untuk kematian kardiovaskular pada pasien dengan chronic kidney disease
(CKD).

Metode: Kami secara sistematis mencari di Medline, Web of Science, dan

artikel bibliografi yang diambil untuk mengidentifikasi studi yang melaporkan
hubungan antara kadar SUA dan mortalitas kardiovaskular pada pasien dengan
CKD. Model efek acak digunakan untuk menghitung hazard ratios (HR) dan
confidence intervals 95% (CI) yang sesuai.

Hasil: Kami memasukkan 11 studi dengan sampel keseluruhan 27.081 pasien

dengan CKD dalam meta-analisis ini. Dengan meta-analisis, terbatas pada 7
penelitian (n = 11.050), pasien dengan SUA tertinggi dikaitkan dengan
peningkatan risiko kematian kardiovaskular (HR 1,47, 95% CI 1,11-1,96)
dibandingkan dengan pasien dengan SUA terendah. Tidak ada indikasi bias
publikasi atau heterogenitas yang signifikan (I2 = 40,4%; P = 0,109). Meta-
analisis dari 10 studi (n = 26.660) menunjukkan bahwa setiap 1 mg/dl
peningkatan kadar SUA meningkatkan 12% risiko kematian kardiovaskular (HR
1,12, 95% CI 1,02-1,24), dengan heterogenitas yang signifikan (I2 = 79,2% , P
< 0,001).

Kesimpulan: Kadar SUA yang lebih tinggi berhubungan dengan peningkatan

risiko kematian kardiovaskular yang signifikan pada pasien dengan CKD. Studi
yang lebih dirancang, terutama uji coba terkontrol secara acak, harus dilakukan
untuk menentukan apakah kadar SUA yang tinggi merupakan faktor risiko yang
berpotensi dimodifikasi untuk kematian kardiovaskular pada pasien dengan
CKD.

1. Pendahuluan

Chronic kidney disease (CKD) telah menjadi beban kesehatan global yang
1
utama. Prevalensi global standar usia CKD stage I-V di antara orang dewasa pada

2
tahun 2010 adalah 10,4% pada pria dan 11,8% pada wanita [1]. CKD
menduduki peringkat sebagai penyebab global tertinggi ke-19 dari tahun
kehidupan yang hilang, dengan tingkat kematian standar usia 15,8 per 100.000
[2]. Pasien dengan CKD memiliki peningkatan risiko kematian kardiovaskular
dibandingkan dengan mereka yang memiliki fungsi ginjal normal [3].
Cardiovascular disease (CVD) menyebabkan sebagian besar kematian pada
individu dengan CKD [3, 4]. Banyak faktor risiko telah diidentifikasi untuk
kematian kardiovaskular pada pasien dengan CKD, seperti merokok, diabetes,
hipertensi sistolik, kadar protein C-reaktif yang tinggi, dan hipertrofi ventrikel
kiri [5-7]. Beberapa penelitian telah menyarankan bahwa hiperurisemia mungkin
menjadi faktor risiko potensial lain untuk kematian kardiovaskular pada
individu dengan CKD [8-10]. Peningkatan asam urat serum (SUA) berhubungan
dengan perkembangan dan progresivitas hipertensi [11], stroke [12], dan
penyakit kardiovaskular [13]. Pada populasi umum, kadar SUA merupakan
prediktor independen untuk kematian kardiovaskular di masa depan [14].

Banyak [8,9,15-18] tetapi tidak semua [19,20] penelitian telah mendeteksi

hubungan yang signifikan antara kadar SUA dan kematian kardiovaskular pada
individu dengan CKD. Selanjutnya, masih ada beberapa perdebatan [8,9,16]
apakah kadar SUA dapat menjadi faktor risiko independen untuk kematian
kardiovaskular pada pasien dengan CKD. Beberapa penelitian [15,17,18]
menunjukkan bahwa SUA yang lebih tinggi adalah prediktor peningkatan risiko
kematian akibat penyakit kardiovaskular pada pasien dengan CKD, sementara
penelitian lain melaporkan bahwa kadar SUA yang lebih tinggi dikaitkan
dengan risiko kematian kardiovaskular yang lebih rendah. Kami berhipotesis
bahwa kadar SUA bisa menjadi prediktor kematian kardiovaskular pada
individu dengan CKD. Dalam penelitian ini, kami melakukan meta-analisis dari
semua penelitian yang relevan untuk mengevaluasi hubungan kadar SUA
dengan mortalitas kardiovaskular pada pasien dengan CKD.

2. Metode

2.1 Desain studi dan strategi pencarian

3
 Meta-analisis dirancang dan dilakukan sesuai dengan pedoman konsensus
dalam "Meta-Analysis of Observational Studies in Epidemiology" [21].
Pencarian literatur yang sistematis dilakukan dengan menggunakan database
PubMed dan Web of Science sejak awal hingga 8 Mei 2017. Tidak ada batasan
yang dikenakan pada pencarian. Istilah pencarian dan string pencarian berikut
digunakan: ("asam urat" atau hiperurisemia atau urat) dan (ginjal atau ginjal atau
dialisis) dan (kematian atau kematian atau kelangsungan hidup atau
kardiovaskular atau stroke). Kata kunci dan abstrak dicari. Selain itu, kami
melakukan survei manual dari referensi yang dikutip dalam ulasan dan artikel
yang diambil untuk menangkap semua studi yang relevan. Dua dari penulis
secara independen melakukan pencarian literatur.

2.2 Pilihan studi

Kriteria inklusi berikut digunakan untuk memilih studi untuk meta-analisis ini:
(1) studi memiliki informasi dasar tentang konsentrasi SUA; (2) studi
mengeksplorasi kematian kardiovaskular sebagai hasil studi; (3) studi yang
merekrut pasien dewasa dengan CKD dan CKD yang ditentukan menurut
pedoman Inisiatif Kualitas Hasil Penyakit Ginjal (KDOQI) [22] dan (4) studi
yang membandingkan kadar SUA tertinggi dengan kadar SUA terendah, atau
melakukan perbandingan terkontrol peningkatan kadar SUA 1 mg/dl, dan
memberikan data statistik tentang rasio hazard (HR) dan interval kepercayaan
95% (CI), atau menyertakan data yang cukup untuk memungkinkan
penghitungan HR dan 95% CI. Dalam kasus beberapa studi berdasarkan
populasi atau subpopulasi yang sama, hanya laporan yang paling informatif atau
publikasi terbaru yang disertakan. Dua penulis secara independen meninjau
artikel yang diambil dan menentukan apakah artikel tersebut memenuhi kriteria
inklusi. Ketidaksepakatan diselesaikan dengan diskusi dengan penulis senior.
Kami meminta data tambahan dari penulis yang sesuai untuk dua artikel (n = 2)
untuk memungkinkan perhitungan statistik HR dan 95% CI. Namun, penulis
terkait dalam kedua kasus tidak menanggapi permintaan kami. Sebanyak 44
artikel dipilih dengan kriteria inklusi, dan ini kemudian menjadi sasaran kriteria
eksklusi yang tercantum dalam file tambahan 1: Tabel S1. Akhirnya, total 11
artikel dipilih untuk meta-analisis ini.

4
2.3 Ekstraksi data dan penilaian kualitas

Dua penulis secara independen mengekstrak data dari artikel teks lengkap.
Data termasuk penulis, tahun publikasi, desain penelitian, populasi, jumlah
peserta, usia rata-rata peserta, persentase pria, diabetes, kadar SUA rata-rata,
median durasi tindak lanjut, jumlah kematian akibat kejadian kardiovaskular,
definisi kematian kardiovaskular, dan faktor yang disesuaikan. HR yang paling
sepenuhnya disesuaikan dan 95% CI diekstraksi dari semua studi yang
disertakan. Kualitas studi kohort observasional dievaluasi menurut skala
penilaian kualitas Newcastle-Ottawa [23]. Kualitas studi dikategorikan sebagai
buruk (skor 1-3), cukup (skor 4-6), atau baik (skor 7-9) tergantung pada kualitas
seleksi peserta studi, komparabilitas, dan hasil. Kualitas uji coba terkontrol
secara acak dievaluasi menggunakan skala Jadad; uji coba berkualitas tinggi
harus memiliki skor Jadad 3 [24].

2.4 Analisis statistik

HR disesuaikan untuk jumlah maksimum variabel pengganggu. Setiap HR

ditransformasikan ke dalam logaritma natural (log HR), dan kesalahan standar
diperoleh dari CI 95% yang sesuai. Karena analisis regresi proporsional hazard
Cox multivariabel digunakan untuk mendapatkan HR yang disesuaikan dari
kadar SUA untuk mortalitas kardiovaskular, analisis efek acak dilakukan untuk
menghitung nilai log HR yang dikumpulkan. Kemudian, kami memperoleh HR
keseluruhan dan CI 95% yang sesuai melalui eksponensial dari HR log yang
dikumpulkan [25].

Kami menganalisis SUA sebagai variabel kontinu untuk menguji

kemungkinan hubungan dosis-respons nonlinier antara kadar SUA dan
mortalitas kardiovaskular [26]. Untuk analisis ini, kami menggunakan metode
splines kubik terbatas dengan tiga knot pada persentil ke-25, ke-50, dan ke-75
dari kadar urat serum. Dalam beberapa kasus, SUA dianalisis sebagai variabel
kategori untuk mengevaluasi tren antara kadar SUA dan mortalitas
kardiovaskular menggunakan dua metode yang berbeda. Analisis regresi kuadrat
terkecil umum digunakan ketika data untuk kasus dan orang-tahun atau peserta
dan SDM tersedia untuk setiap kategori. Analisis regresi kuadrat terkecil

5
varians-tertimbang digunakan ketika informasi untuk kasus

6
atau peserta tidak tersedia untuk setiap kategori [27, 28].

Indeks I2, statistik Q, dan nilai P digunakan untuk menggambarkan

heterogenitas perkiraan ukuran efek di seluruh studi. Kami melakukan analisis
meta-regresi untuk mengevaluasi pengaruh kovariat yang telah ditentukan
sebelumnya pada heterogenitas antar-studi. Plot corong dihitung dan tes Egger
dilakukan untuk menilai potensi bias publikasi [29]. Analisis sensitivitas
dilakukan untuk mengevaluasi pengaruh satu studi pada perkiraan risiko
keseluruhan dengan menghapus satu studi pada satu waktu. Semua analisis
dilakukan dengan perangkat lunak statistik STATA versi 12.0 (Stata Corp,
College Station, TX, USA). Nilai P
<0,05 dianggap signifikan secara statistik.

3. Hasil

3.1 Pemilihan studi dan karakteristik studi

Pencarian literatur sistematis kami termasuk dari awal basis data hingga 8
Mei 2017. Kami mengambil 2.092 abstrak di PubMed dan 5004 abstrak di Web
of Science. Sebanyak 5359 studi non-duplikat diidentifikasi. Setelah prosedur
seleksi pertama, kami mengevaluasi 44 artikel teks lengkap lebih lanjut.
Akhirnya, 11 artikel yang mewakili 27.081 peserta studi memenuhi semua
kriteria kelayakan [8-10, 16-20, 30-32]. Penjelasan rinci tentang pemilihan studi
kami disajikan pada Gambar 1. Karakteristik dan kualitas studi individu
disajikan pada Tabel 1. Artikel termasuk empat studi kohort prospektif, enam
studi kohort retrospektif, dan satu uji coba terkontrol secara acak. Jumlah
peserta dalam studi individu berkisar antara
261 [30] hingga 13.059 [16]. Persentase peserta penelitian dengan diabetes
bervariasi dari 5% [8] hingga 59% [30]. Durasi rata-rata follow-up berkisar dari
23 bulan sampai 10 tahun. Semua 11 studi memberikan perkiraan risiko yang
disesuaikan, 9 studi yang disesuaikan dengan fungsi ginjal [8-10, 16, 18-20, 30,
31], dan 5 studi yang disesuaikan dengan obat-obatan untuk menurunkan kadar
asam urat [8, 10, 17, 18, 31].

7
Gambar 1. Diagram alir pemilihan studi dari studi yang disertakan. Singkatan:
CKD, Cronic Kidney Disease

Definisi kejadian mortalitas kardiovaskular bervariasi di antara studi yang

disertakan: dua studi menggunakan Kode International Classification of
Diseases (ICD) [8, 16]; lima penelitian melaporkan kematian akibat penyakit
kardiovaskular, penyakit serebrovaskular, dan penyakit pembuluh darah perifer
[9, 10, 19, 30, 31]; satu studi melaporkan kematian akibat penyakit
kardiovaskular dan penyakit serebrovaskular [17]; dua penelitian hanya
melaporkan kematian akibat penyakit kardiovaskular [18, 20]; dan satu
penelitian tidak memberikan informasi mengenai definisi kematian
kardiovaskular [32]. Tak satu pun dari studi yang disertakan melaporkan risiko
kematian kardiovaskular terkait dengan kadar SUA terendah dan median. Semua
studi kohort memiliki kualitas yang adil hingga baik menurut Skala Newcastle-
Ottawa. Uji coba kontrol secara acak memiliki kualitas tinggi dengan skor Jadad
3.

8
Tabel 1 Karakteristik dari 11 studi yang termasuk dalam meta-analisis
Penulis, Ranc Populasi Pasien( Laki Diabetes Usia Asam urat Follow-up Kejadian mortalitas Perbandingan Penyesu
tahun angan n) -laki (%) (tahun) (mg/dl) Kardiovaskular dan (95%CI)
Studi (%) definisi (n)

Madero, RCT Amerika 838 39 5 52 ± 12 7.63 ± Median 127 Peningkatan Per 1.16 (1.0
2009 Serikat, 1.66 10 tahun Mortalitas CV didefinisikan 1 mg/dl
MDRD, sebagai kematian akibat Tertile 3 vs. 1.47 (0.9
CKD3–4 CVD (Klasifikasi penyakit tertile 1 8.4–
internasional, revisi 15.6mg/dl vs.
kesembilan [ICD-9] kode 1.7–6.9 mg/dl
390 hingga 459)

Latif, PCS DOPPS, HD 4637 58.2 24.5 Mean Mean 6.97 Median NA Peningkatan Per 0.92 (0.8
2011 58–64 23 bulan Mortalitas CV didefinisikan 1 mg/dl
sebagai kematian akibat < 8.2 mg/dl vs. 1.54 (1.1
infark miokard akut, > 8.2 mg/dl
penyakit jantung
aterosklerotik,
kardiomiopati, aritmia
jantung, henti jantung,
gagal jantung kongestif,
kecelakaan
serebrovaskular termasuk
perdarahan intrakranial,
kerusakan otak iskemik dan
ensefalopati anoksik.
Kanbay, RCS Turki, 303 49.8 23.4 Mean NA Median 33 Peningkatan Per 2.819
2012 CKD 3–5 47–53 39 bulan Mortalitas CV didefinisikan 1 mg/dl (1.
sebagai kematian akibat
penyakit jantung koroner,
kematian mendadak, stroke
dan penyakit pembuluh
darah perifer yang rumit

7
Kuo, 2013 RCS Taiwan, 13,059 NA NA NA NA Median NA 9.0–10.9mg/dl vs. 1.42 (1.11–1.81) Usia, jenis kelamin, 6
CKD 4.6 tahun Mortalitas CV didefinisikan 5.0–6.9 mg/dl eGFR, glukosa puasa,
sebagai kematian akibat < 11.0 mg/dl 1.65 (1.22–2.24) kolesterol total dan
penyakit kardiovaskular (kode vs. 5.0– riwayat hipertensi, DM,
ICD-9: 390.x-459.x) 6.9mg/dl PJK, stroke, gagal
jantung
Yin, 2013 RCS China, 1132 71.7 33.6 67.7 ± 7.8 ± 1.9 Median 50 Quartile 4 vs. 0.84 (0.37–1.89) Usia, jenis kelamin, 7
CKD 7.8 38.5 bulan Mortalitas CV didefinisikan quartile 1 DM, eGFR, ejeksi
undergoing sebagai kematian akibat > 8.98 mg/dl vs. ventrikel kiri,
penyakit arteri koroner, aritmia < 6.46 mg/dl proteinuria, AMI,
DES
jantung, gagal jantung revaskularisasi tidak
kongestif, kematian mendadak lengkap
Dong, 2014 RCS China, SSOP, 2193 49 37.7 58.1 ± 6.41 ± Median 231 Peningkatan 1.04 (0.89,1.20) Usia, fungsi ginjal 7
PD 15.5 1.87 26.5 bulan Mortalitas CV didefinisikan Per 1 mg/dl residual, albumin,
sebagai kematian akibat Spesifik-jenis 1.35 (0.74,2.46) hemoglobin, fosfat,
infark miokard, gagal kelamin protein C-reaktif, riwayat
jantung kongestif, Tertile 3 vs. CVD, DM, BMI,
perdarahan otak, infark tertile 1 tekanan arteri rata-
serebral, aritmia, penyakit Laki-laki: rata, LDL-C, ukuran
arteri perifer dan kematian 7.39–16.7 pusat, hanya SUA
mg/dl yang disesuaikan
mendadak.
Perempuan: gender sebagai variabel
6.66–8.08 mg/dl kontinu
vs. Laki-laki: 2.09–
5.79 mg/dl
perempuan: 1.74–
5.37 mg/dl
Miyaoka, RCS Japan, 551 59.3 10 58.5 6.57 ± 6 tahun 19 Tertile 3 vs. 1.042 (0.139–7.831) Jenis kelamin, status 8
2014 CKD2–4 1.35 Mortalitas CV didefinisikan tertile 1 merokok, riwayat CVD,
sebagai kematian akibat 7.2–12.4 mg/dl tekanan darah sistolik,
infark miokard, gagal vs. 3.0–5.8 HDL-C, trigliserida,
jantung kongestif. mg/dl hemoglobin, C-reactive
protein (log), eGFR,
proteinuria (log), etiologi
penyakit ginjal, diuretik,
allopurinol
Hyperuricemia vs. 0.274 (0.103–0.731) Jenis kelamin, status
normouricemia merokok, CVD,
Hyperuricemia HDL-C, trigliserida,
hemoglobin, protein
(> 7.0 mg/dl C-reaktif (log), eGFR,
atau tanpa proteinuria (log),
allopurinol) etiologi penyakit ginjal,

8
 diuretik, allopurinol
Beberashvili, PCS Israel, MHD 261 613 59 68,6 ± 5,76 ± 2 tahun 31 Peningkatan per 0,53 (0,33 – 0,86) Usia, jenis kelamin, 7
2015 13,6 1,16 Mortalitas Kardiovaskular 1mg/dl model tahun, Kt/v, DM,
didefinisikan sebagai indeks komorbiditas,
kematian akibat penyakit merokok, tekanan
jantung koroner, kematian darah sistolik, lingkar
mendadak, stroke, atau pinggang, fosfor,
penyakit pembuluh darah kreatinin, sisa fungsi
perifer berkomplikasi ginjal, skor inflamasi
malnutrisi, interleukin-6
Hsieh, 2015 RCS Taiwan 2408 56,9 38,3 65,7 ± 7,73 ± Median 143 Peningkatan per 1,16 (0,92 – 1,32) Usia, jenis kelamin, 7
CKD 3-5 12,6 1,78 3,03 tahun Mortalitas kardiovaskular 1mg/dl BMI, DM, hipertensi,
didefiniskan sebagai penyakit kardiovaskular,
kematian akibat penyakit asam urat, hemoglobin
jantung coroner, penyakit terglikasi, kolesterol,
cerebrovascular dan trigliserida, BUN, eGFR,
vascular perifer GPT, albumin, Ca × P,
jumlah sel darah putih,
hemoglobin, proteinuria,
diuretik, agen
hipourisemia,
perangsang eritropoiesis
agen, ACE inhibitor dan
angiotensin II receptor
blocker
Xia, 2016 PCS China, PD 1278 58,8 25,7 47,6 ± 7,2 ± 1,5 Median 126 Peningkatan per 1.42 (1.13–1.79) Usia, BMI, hipertensi, 8
15,0 30,7 bulan Mortalitas kardiovaskular 1mg/dl Laki-laki DM penyakit kardiovaskular,
1.12 (0.78–1.61) hemoglobin, albumin,
didefinsikan sebagai
Wanita DM fosfor, kreatinin serum,
kematian akibat infark
1.41 (1.09–1.82) HDL-C, fungsi ginjal
miokard akut, aritmia
Laki-laki NDM residual, protein Creactive
cardiac, cardiac arrest,
1.24 (0.85–1.82) sensitif tinggi yang
gagal jantung kongestif,
Wanita NDM ditransformasi log,
cedera serebrovaskular,
hemoglobin terglikasi,
penyakit vascular perifer
penggunaan allopurinol, dan
penggunaan ACE
inhibitor atau angiotensin
receptor
blocker.

9
 Spesifik-jenis 2,26 (1,14 – 4,48) Hanya SUA yang
kelamin DM disesuaikan jenis kelamin
Tertile 3 vs tertile sebagai variabel
1 kontinu. Hemoglobin
terglikasi yang
DM Pria: 7,1–13,8 disesuaikan pada DM
mg/dl, wanita:
6,9–12,6 mg/dl vs.
Pria: 1,5–5,6
mg/dl, wanita:
1,2–5,4 mg/dl.
NDM Pria: 3,07 (1,54 – 6,08)
7,1–13,8 mg/dl, NDM
wanita: 6,9–12,6
mg/dl vs. Pria:
1,5–5,6 mg/dl,
wanita: 1,2–5,4
mg/dl.
Li, 2016 PCS China, CKD 421 NA NA NA NA Median, 39 NA Tertile 4 vs tertile 0,72 (0,28 – Usia, jenis kelamin, 6
3-5 tahun 1 1,81) aktivitas fisik waktu
7,29 -18,88 mg/dl senggang, merokok,
vs ≤ 5,08 mg/dl minum alkohol,
pekerjaan, BMI, SBP,
DBP, LDLC, durasi
CAD, jenis CAD,
riwayat diabetes,
riwayat gagal jantung,
derajat stenosis arteri
koroner pada angiografi
koroner, penggunaan
obat antidiabetes,
penurun kolesterol atau
antiplatelet, penggunaan
diuretik, β-blocker dan
obat antihipertensi
Faktor konversi untuk unit: asam urat serum dalam mg/dl ke umol/l, ×59,48
Singkatan: AMI infark miokard akut, indeks massa tubuh BMI, penyakit arteri koroner CAD, kardiovaskular CV, penyakit kardiovaskular CVD, penyakit jantung koroner PJK, penyakit ginjal
kronis CKD, tekanan darah diastolik DBP, diabetes mellitus DM, DOPPS Hasil Dialisis dan Pola Praktek Studi, DES drug-eluting stent, eGFR perkiraan laju filtrasi glomerulus, penyakit ginjal
stadium akhir ESRD, dilatasi yang dimediasi aliran FMD, hemodialisis HD, high density lipoprotein cholesterol HDL-C, penilaian model homeostasis HOMA-IR-resistensi insulin, hsCRP tinggi
sensitivitas C protein reaktif, LDL-C low density lipoprotein cholesterol, tekanan darah sistolik SBP, SSOP Status Sosial Ekonomi pada Hasil Dialisis Peritoneum, asam urat serum SUA,
Randomized Controlled Trial RCT, studi kohort prospektif PCS, RCS retro studi kohort prospektif

10
3.2 Hubungan SUA dengan mortalitas kardiovaskular

Tujuh studi [8, 10, 17-20, 32] melaporkan hubungan asam urat serum
sebagai variabel kategori dengan mortalitas kardiovaskular. Sebanyak 11.050
peserta dilibatkan dalam meta-analisis ini. Pasien dalam kelompok dengan kadar
SUA tertinggi dikaitkan dengan peningkatan risiko kematian kardiovaskular
dibandingkan dengan pasien dengan kadar terendah (HR 1,47, 95% CI 1,11-
1,96; Gambar 2). Ada heterogenitas sedang di antara studi yang disertakan (I2 =
40,4%, P
= 0,109). Satu studi juga melaporkan perkiraan hubungan antara SUA sebagai
variabel kategori dan mortalitas kardiovaskular. Para penulis tersebut
melaporkan bahwa HR yang disesuaikan untuk kematian kardiovaskular adalah
1,42 (95% CI 1,11-1,81) dan 1,65 (95% CI 1,22-2,24) untuk pasien dengan
kadar SUA tertinggi kedua (9,0-10,9 mg/dl) dan mereka dengan tingkat tertinggi
(≥11.0 mg/dl) dibandingkan dengan tingkat sedang (5.0-6.9 mg/dl) [16].

Gambar 2. Forest plot dan ringkasan hazard ratio untuk hubungan asam urat
serum sebagai variabel kategori dan mortalitas kardiovaskular pada pasien
dengan penyakit ginjal kronis. Singkatan: CI, confidence interval; DM, diabetes
melitus; HR, hazard ratio; NDM, non-diabetes mellitus

Tujuh dari studi [8-10, 17, 19, 30, 31] yang disertakan melaporkan
hubungan peningkatan kadar asam urat serum (per 1 mg/dl) terhadap mortalitas
kardiovaskular. Tiga penelitian hanya melaporkan hubungan asam urat serum
11
sebagai variabel kategori terhadap mortalitas kardiovaskular [16, 18, 20]; hasil
ini dievaluasi menggunakan analisis regresi kuadrat terkecil tertimbang varians
untuk mendapatkan hubungan dosis-respons antara kadar asam urat serum dan
mortalitas kardiovaskular. Sebanyak 26.660 peserta dilibatkan dalam meta-
analisis ini. Kadar asam urat serum yang lebih tinggi (per kenaikan 1 mg/dl)
dikaitkan dengan hazard ratio yang lebih tinggi secara signifikan terhadap
mortalitas kardiovaskular (HR 1,12, 95% CI 1,02-1,24; Gambar 3).
Heterogenitas yang signifikan antara studi ini diamati (I2 = 79,2%; P <0,001).
Hasil uji hubungan nonlinier menunjukkan bahwa kadar SUA tidak memiliki
hubungan nonlinier dengan mortalitas kardiovaskular (p untuk nonlinier =
0,109).

Gambar 3. Forest plot dan ringkasan hazard ratio untuk hubungan asam urat
serum sebagai variabel kontinu (per kenaikan 1 mg/dl) dan mortalitas
kardiovaskular pada pasien dengan penyakit ginjal kronis. Singkatan: CI,
confidence interval; DM, diabetes melitus; HR, hazard ratio; NDM, non-
diabetes mellitus

3.3 Analisis subkelompok

Analisis subkelompok dilakukan pada hubungan SUA (per kenaikan 1

mg/dl) dengan mortalitas kardiovaskular (Gambar 4). Hubungan yang signifikan
dan positif antara kadar SUA dan peningkatan risiko kematian kardiovaskular

12
diamati

13
pada kelompok Asia, kelompok skor kualitas tinggi, ukuran sampel kelompok >
1000 peserta, durasi follow-up, rata-rata > 3 tahun kelompok, dan disesuaikan
untuk kelompok pengobatan allopurinol. Enam studi menganalisis populasi
CKD yang tidak menjalani dialisis; setiap 1 mg/dl peningkatan SUA secara
independen terkait dengan 16% peningkatan risiko kematian kardiovaskular
(HR 1,16, 95% CI 1,02-1,33). Sebaliknya, untuk populasi CKD yang menjalani
dialisis, setiap peningkatan SUA 1 mg/dl tidak terkait dengan peningkatan risiko
kematian kardiovaskular (HR 1,08, 95% CI 0,90-1,29). Sembilan studi
menganalisis hubungan yang disesuaikan dengan fungsi ginjal, setiap 1 mg/dl
peningkatan SUA secara independen terkait dengan 16% peningkatan risiko
kematian kardiovaskular (HR 1,16, 95% CI 1,04-1,28). Dua studi kohort
berfokus pada pasien yang menerima dialisis peritoneal (PD), dan melaporkan
hubungan yang signifikan antara kadar SUA yang lebih tinggi dan peningkatan
mortalitas kardiovaskular (HR 1,22, 95% CI 1,05-1,43). Sebaliknya, dua studi
kohort yang berfokus pada pasien yang menerima hemodialisis (HD) tidak
menemukan hubungan antara kadar SUA yang lebih tinggi dan mortalitas
kardiovaskular (HR 0,74, 95% CI 0,43-1,25).

3.4 Analisis sensitivitas dan bias publikasi

Analisis sensitivitas dan tes Egger untuk bias publikasi dilakukan

menggunakan SUA sebagai variabel kategoris dan kontinu. Analisis sensitivitas
SUA sebagai variabel kategori menunjukkan bahwa terdapat pengaruh moderat
pada pooled HR dan 95% CI ketika penelitian Latif et al [17] dikeluarkan dari
analisis. Analisis sensitivitas SUA sebagai variabel kontinu menunjukkan bahwa
hasil tidak berubah secara signifikan ketika satu studi dihilangkan pada suatu
waktu (File tambahan 2: Gambar S1). Tidak ada bukti statistik bias publikasi
antara studi tentang hubungan SUA sebagai variabel kategoris dan mortalitas
kardiovaskular (p
= 0,680) atau di antara studi tentang hubungan SUA (per kenaikan 1 mg/dl)
dengan mortalitas kardiovaskular (p = 0,430 ). Plot corong yang mewakili
analisis ini disajikan dalam file tambahan 3: Gambar S2.

4. Diskusi

14
Meta-analisis kami dari 11 studi kohort menunjukkan bahwa peningkatan

15
kadar SUA pada pasien dengan CKD dikaitkan dengan peningkatan risiko
kematian kardiovaskular secara signifikan. Ini merupakan meta-analisis pertama
yang menganalisis hubungan SUA dengan mortalitas kardiovaskular pada
pasien dengan CKD. Meta-analisis kami sebelumnya menunjukkan bahwa kadar
SUA yang lebih tinggi dikaitkan dengan risiko kematian yang lebih tinggi pada
pasien dengan CKD [33]. Hasil ini konsisten dengan tren yang dilaporkan dalam
tiga tinjauan sistematis sebelumnya [12, 14, 34]. Sebuah meta-analisis dari
sembilan studi observasional prospektif dengan 165.922 peserta melaporkan
bahwa peningkatan SUA dikaitkan dengan risiko 37% lebih besar terhadap
kematian kardiovaskular pada populasi umum [14]. Dua meta-analisis lainnya
berfokus pada hubungan antara hiperurisemia dan kematian akibat stroke, dan
melaporkan bahwa hiperurisemia dapat meningkatkan risiko kematian akibat
stroke [12, 34]. Meta-analisis sebelumnya melaporkan bahwa hiperurisemia
meningkatkan risiko kejadian kardiovaskular seperti gagal jantung [35] dan
penyakit jantung coroner [36]. Hanya satu penelitian yang melaporkan
hubungan ini secara terpisah pada pria dan wanita [10], jadi kami tidak
melakukan analisis subkelompok untuk jenis kelamin dalam meta-analisis kami.

Dua studi yang diambil selama pencarian literatur kami tidak dimasukkan
dalam meta-analisis ini karena tidak mengandung data yang cukup untuk
memperkirakan HR. Sebuah penelitian dengan kohort 2645 pasien dengan gagal
jantung sistolik menganalisis hubungan hiperurisemia dengan semua penyebab
kematian, kematian kardiovaskular, dan rawat inap gagal jantung di antara
semua pasien gagal jantung dan mereka dengan dan tanpa CKD [37], dan
menyarankan bahwa hiperurisemia tidak terkait secara signifikan dengan
kematian kardiovaskular pada pasien gagal jantung dengan CKD. Namun,
penelitian ini tidak menyajikan data rinci untuk HR hiperurisemia dengan
kematian kardiovaskular. Sebuah studi prospektif pusat tunggal menilai apakah
SUA dan superoksida dismutase dapat menjadi faktor prediktif mortalitas
kardiovaskular pada pasien yang menjalani hemodialysis 15], dan menemukan
bahwa kadar SUA yang lebih rendah dapat memprediksi mortalitas
kardiovaskular pada pasien hemodialisis (HR 0,937, 95% CI 0,883-0,994).
Namun, penelitian ini menganalisis hubungan per 1 mol/l peningkatan kadar
SUA dengan mortalitas kardiovaskular, dan tidak

16
memberikan data yang cukup untuk menghitung HR.

Beberapa mekanisme potensial mendukung hubungan patogen antara kadar

SUA yang lebih tinggi dan risiko kematian kardiovaskular yang lebih tinggi.
Hiperurisemia dapat mengganggu fungsi mitokondria dan menurunkan
kandungan ATP, yang akan memicu terjadinya stres oksidatif [38]. Studi
eksperimental telah menunjukkan bahwa asam urat dapat meningkatkan ekspresi
NALP3, aktivasi caspase-1, dan produksi IL-1β dan ICAM-1, menunjukkan
bahwa asam urat dapat merangsang respons inflamasi [39, 40]. Asam urat
sendiri juga dapat meningkatkan peradangan pada penderita CKD [41]. Kadar
asam urat yang lebih tinggi berhubungan dengan penurunan fungsi endotel [42 -
44], dan disfungsi endotel dapat menyebabkan hipertensi dan morbiditas
kardiovaskular [45]. Peningkatan kadar asam urat secara kronis dapat
menyebabkan perubahan struktural pada dinding pembuluh darah [46].

Aspek inti dari manajemen hiperurisemia adalah pendidikan pasien, saran

gaya hidup, dan terapi farmakologis seperti allopurinol [47]. Sebuah percobaan
prospektif acak menemukan bahwa pengobatan allopurinol mengurangi risiko
kejadian kardiovaskular pada pasien dengan CKD [48]. Hasil dari studi
observasional menunjukkan bahwa allopurinol menurunkan mortalitas terkait
kardiovaskular pada pasien Jepang yang menerima hemodialisis dan tidak
memiliki riwayat penyakit kardiovaskular [49]. Sebuah studi prospektif
melaporkan bahwa pengobatan hiperurisemia dengan allopurinol dapat
meningkatkan fungsi endotel pada pasien dengan CKD [50].

Heterogenitas secara signifikan tinggi di antara 10 studi yang menganalisis

hubungan peningkatan SUA (per 1 mg/dl) dengan mortalitas kardiovaskular.
Namun, hasil analisis meta-regresi menunjukkan bahwa wilayah, desain
penelitian, populasi, kualitas penelitian, ukuran sampel, waktu tindak lanjut,
modalitas pengobatan, dan penyesuaian pengobatan allopurinol tidak dapat
menjelaskan heterogenitas. Heterogenitas tinggi mungkin terkait dengan usia
dan / atau karakteristik peserta lainnya di seluruh studi yang dianalisis. Definisi
kematian kardiovaskular tidak persis sama di antara 10 studi ini, yang sebagian
dapat menjelaskan heterogenitas. Semua studi yang disertakan memiliki definisi

17
mortalitas kardiovaskular yang berbeda, staging CKD yang berbeda, definisi
asam urat tinggi dan rendah yang berbeda, tampaknya tidak ada gunanya
mengutip HR untuk peningkatan mortalitas kardiovaskular mengingat bahwa
angka tunggal tidak dapat diterapkan pada situasi tertentu, tetapi hasil meta-
analisis kami menunjukkan trend asam urat yang lebih tinggi dan mortalitas
kardiovaskular pada pasien dengan CKD.

Analisis subkelompok peran prediktif SUA pada mortalitas kardiovaskular

berbeda sehubungan dengan modalitas pengobatan, yang mungkin disebabkan
oleh perbedaan pembersihan asam urat antara hemodialisis dan peritonel
dialisis. Malnutrisi pada pasien yang dialisis dapat menyebabkan rendahnya
kadar asam urat. Asam urat yang lebih tinggi pada pasien hemodialisis
merupakan indikator status gizi yang lebih baik [17, 51], yang sebagian dapat
menjelaskan hubungan kadar asam urat yang lebih rendah dengan mortalitas
kardiovaskular yang lebih tinggi. Beberapa studi yang disertakan menelaah
hubungan antara SUA dan mortalitas kardiovaskular sehubungan dengan
tahap/staging CKD yang berbeda. Oleh karena itu, tidak ada cukup data untuk
melakukan analisis subkelompok terhadap tahap CKD. Sebaliknya kami
melakukan analisis subkelompok untuk populasi non-dialisis atau dialisis. Efek
yang hampir secara signifikan lebih besar (p = 0,054) dari modalitas pengobatan
diamati dalam analisis subkelompok dari perkiraan risiko yang dikumpulkan.
Heterogenitas antara studi yang menganalisis hubungan SUA sebagai variabel
kategori dengan mortalitas kardiovaskular cukup rendah. Meskipun tidak ada
bukti bias publikasi, itu tidak dapat sepenuhnya dikesampingkan karena temuan
nol yang tidak dipublikasikan.

Beberapa keterbatasan penelitian kami harus diakui. Pertama, sebagian

besar studi yang disertakan adalah studi observasional yang tidak dapat
membuktikan hubungan sebab akibat, dan beberapa cofounder/penghambat
potensial termasuk penurunan fungsi ginjal, status gizi, dan terapi penurun urat
selama masa tindak lanjut sulit untuk sepenuhnya disesuaikan. Kedua,
heterogenitas tinggi diamati di antara studi termasuk yang menganalisis
hubungan SUA sebagai variabel kontinu dengan mortalitas kardiovaskular.
Studi individu tidak menyesuaikan faktor risiko potensial yang sama. Setiap
studi memiliki nilai cut-off yang berbeda untuk
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kelompok SUA, yang mungkin menyebabkan kesalahan klasifikasi individu
dalam setiap kelompok. Ketiga, meskipun uji hubungan nonlinier menunjukkan
hubungan yang mendekati linier antara SUA dan mortalitas kardiovaskular pada
pasien dengan CKD, hanya tiga dari studi yang disertakan memberikan data
yang cukup untuk melakukan uji hubungan nonlinier. Oleh karena itu,
diperlukan lebih banyak data untuk mendukung hubungan yang tepat antara
SUA dan mortalitas kardiovaskular. Keempat, analisis sensitivitas SUA sebagai
variabel kategoris menunjukkan bahwa hasilnya tidak signifikan ketika studi
Latif dihilangkan [17]. Kelima, hanya sedikit dari studi yang disertakan
melaporkan data kematian kardiovaskular sehubungan dengan jenis kelamin;
oleh karena itu, kami tidak dapat mengevaluasi apakah kadar SUA
mempengaruhi risiko kematian kardiovaskular pria dan wanita.

Studi kami memiliki beberapa kekuatan. Studi ini adalah tinjauan sistematis
dan meta-analisis pertama dari hubungan kadar SUA awal dengan mortalitas
kardiovaskular pada pasien dengan CKD. Studi yang disertakan memiliki
kualitas yang relatif tinggi dan disesuaikan dengan faktor risiko lainnya.
Selanjutnya, kami menganggap asam urat tidak hanya sebagai variabel kategoris
tetapi juga sebagai variabel kontinue.

5. Kesimpulan

Hasil meta-analisis kami menunjukkan bahwa peningkatan kadar SUA

meningkatkan risiko kematian kardiovaskular pada pasien dengan CKD. Studi
di masa depan, sebaiknya studi terkontrol secara acak/RCT, harus menelaah
apakah hiperurisemia merupakan faktor risiko yang berpotensi dimodifikasi
untuk kematian kardiovaskular pada pasien dengan CKD.

19
 PICO

Population Research articles that evaluate Chronic Kidney Disease

Intervention No intervention have been carried out

Comparison
Lower and higher serum urat acid level for
cardiovascular mortality in individual with
CKD
Outcomes Hypothesized that SUA levels could be a predictor
for cardiovascular mortality in individual with CKD

CRITICAL APRAISAL
DOES THIS REVIEW ADDRESS A CLEAR QUESTION?

1. Did the review address a clearly focussed Yes Can’t No

issue?
tell

Was there enough information on: ꞏ

√
- The population studied
√
- The intervention given
√
- The outcomes considered
2. Did the authors look for the appropriate sort
ofpapers?
The ‘best sort of studies’ would?

- Address the review’s question √

- Have an appropriate study design √

20
 ARE THE RESULTS OF THIS REVIEW VALID?

3. Do you think the important, Yes Can’ttell No

relevant studieswere included?
Look for

- Which bibliographic databases were used √

- Follow up from reference lists √

- Personal contact with experts √

- Search for unpublished as well

√
as publishedstudies
- Search for non-English language studies √
4. Did the review’s authors do enough to
assess thequality of the included studies?
The authors need to consider the rigour of √
the studies they have identified. Lack of
rigour
may affect the studies results
5. If the results of the review have been
combined,was it reasonable to do so?
Consider whether

- The results were similar from study to

√
study

- The results of all the included studies are √

clearlydisplayed
- The results of the different studies are √
similar

- The reasons for any variations are √

discussed

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 WHAT ARE THE RESULTS ?

6. What is the overall result of Higher SUA levels are associated with
the review? significantly increased risk of
cardiovascular mortality in patients
with
CKD.
7. How precise are the results ? YES

Are the results presented with
confidence intervals?
Patients with the highest SUA were
associated with an increased risk of
cardiovascular mortality (HR 1.47, 95%
CI 1.11–1.96) compared with patients
with the lowest SUA. Every 1 mg/dl
increase in SUA levels increased a 12%
risk in cardiovascular mortality (HR 1.12,
95% CI
1.02–1.24)

WILL THE RESULTS HELP LOCALLY?

8. Can the results be applied to the local Yes Can’t No

population? Tell
Consider whether

- The patients covered by the review could √

be sufficiently
- Your local setting is likely to differ much √
from that of of the review

9. Were all important outcomes considered? √

10. Are the benefits worth the harms and √
costs?
Even if this is not addressed by the review,
what do you think?

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