Abstract
Background: The association between uric acid and kidney disease has been extensively investigated. Numerous studies have reported the association between circulating levels of uric acid and renal function. Objectives: To test, by the Mendelian randomization method, whether there is a causal association between circulating levels of uric acid and renal function. Methods: In 989 participants, estimated glomerular filtration rate (eGFR) was calculated, the circulating level of uric acid was tested, and the uric acid polymorphism (rs11722228) was genotyped. Results: After adjusting for age, gender, smoking history, alcohol intake, antihypertensive medication, body mass index, waist-to-hip ratio, and levels of urea nitrogen and creatinine, a significant allelic difference was found in uric acid levels for each genotype (p < 0.0001). Furthermore, the circulating levels of uric acid were negatively associated with eGFR after adjusting for cardiovascular risk factors and other potential confounders (p < 0.0001). Meanwhile, eGFR was significantly associated with the genotypes of rs11722228 (β = –0.07; p = 0.02). Conclusions: Evidence from the Mendelian randomization approach implied a causal relationship between uric acid and renal function in an apparently healthy population.
References
1.
Capuano
V
, Marchese
F
, Capuano
R
, Torre
S
, Iannone
AG
, Capuano
E
, et al. Hyperuricemia as an independent risk factor for major cardiovascular events: a 10-year cohort study from Southern Italy
. J Cardiovasc Med (Hagerstown)
. 2017
Mar
;18
(3
):159
–64
.
[PubMed]
1558-20272.
Gudiño Gomezjurado
Á
. Hyperuricemia as a risk factor for cardiovascular disease: clinical review
. Medwave
. 2016
Nov
;16
(10
):e6606
.
[PubMed]
0717-63843.
Go
AS
, Chertow
GM
, Fan
D
, McCulloch
CE
, Hsu
CY
. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization
. N Engl J Med
. 2004
Sep
;351
(13
):1296
–305
.
[PubMed]
0028-47934.
Mende
C
. Management of Chronic Kidney Disease: The Relationship Between Serum Uric Acid and Development of Nephropathy
. Adv Ther
. 2015
Dec
;32
(12
):1177
–91
.
[PubMed]
0741-238X5.
Mun
KH
, Yu
GI
, Choi
BY
, Kim
MK
, Shin
MH
, Shin
DH
. Effect of Uric Acid on the Development of Chronic Kidney Disease: The Korean Multi-Rural Communities Cohort Study
. J Prev Med Public Health
. 2018
Sep
;51
(5
):248
–56
.
[PubMed]
1975-83756.
Ye
M
, Hu
K
, Jin
J
, Wu
D
, Hu
P
, He
Q
. The association between time-mean serum uric acid levels and the incidence of chronic kidney disease in the general population: a retrospective study
. BMC Nephrol
. 2018
Jul
;19
(1
):190
.
[PubMed]
1471-23697.
Rincon-Choles
H
, Jolly
SE
, Arrigain
S
, Konig
V
, Schold
JD
, Nakhoul
G
, et al.; RRincon-Choles H
. Impact of Uric Acid Levels on Kidney Disease Progression
. Am J Nephrol
. 2017
;46
(4
):315
–22
.
[PubMed]
0250-80958.
Mwasongwe
SE
, Fülöp
T
, Katz
R
, Musani
SK
, Sims
M
, Correa
A
, et al. Relation of uric acid level to rapid kidney function decline and development of kidney disease: The Jackson Heart Study
. J Clin Hypertens (Greenwich)
. 2018
Apr
;20
(4
):775
–83
.
[PubMed]
1524-61759.
Chang
WX
, Xu
N
, Kumagai
T
, Iijima
R
, Waki
K
, Yamanaka
M
, et al. Uric Acid in the Follow-Up Determines 30% Decline in Estimated GFR Over 2 Years: a Propensity Score Analysis
. Kidney Blood Press Res
. 2017
;42
(6
):1053
–67
.
[PubMed]
1420-409610.
Tsai
CW
, Lin
SY
, Kuo
CC
, Huang
CC
. Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review
. PLoS One
. 2017
Jan
;12
(1
):e0170393
.
[PubMed]
1932-620311.
Kamei
K
, Konta
T
, Hirayama
A
, Suzuki
K
, Ichikawa
K
, Fujimoto
S
, et al. A slight increase within the normal range of serum uric acid and the decline in renal function: associations in a community-based population
. Nephrol Dial Transplant
. 2014
Dec
;29
(12
):2286
–92
.
[PubMed]
0931-050912.
Chini
LS
, Assis
LI
, Lugon
JR
. Relationship between uric acid levels and risk of chronic kidney disease in a retrospective cohort of Brazilian workers
. Braz J Med Biol Res
. 2017
Aug
;50
(9
):e6048
.
[PubMed]
0100-879X13.
Kuriyama
S
, Maruyama
Y
, Nishio
S
, Takahashi
Y
, Kidoguchi
S
, Kobayashi
C
, et al. Serum uric acid and the incidence of CKD and hypertension
. Clin Exp Nephrol
. 2015
Dec
;19
(6
):1127
–34
.
[PubMed]
1342-175114.
Nacak
H
, van Diepen
M
, de Goeij
MC
, Rotmans
JI
, Dekker
FW
; PREPARE-2 study group
. Uric acid: association with rate of renal function decline and time until start of dialysis in incident pre-dialysis patients
. BMC Nephrol
. 2014
Jun
;15
(1
):91
.
[PubMed]
1471-236915.
Kanji
T
, Gandhi
M
, Clase
CM
, Yang
R
. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis
. BMC Nephrol
. 2015
Apr
;16
(1
):58
.
[PubMed]
1471-236916.
Lawlor
DA
, Harbord
RM
, Sterne
JA
, Timpson
N
, Davey Smith
G
. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology
. Stat Med
. 2008
Apr
;27
(8
):1133
–63
.
[PubMed]
0277-671517.
Smith
GD
, Ebrahim
S
. Mendelian randomization: prospects, potentials, and limitations
. Int J Epidemiol
. 2004
Feb
;33
(1
):30
–42
.
[PubMed]
0300-577118.
Bobulescu
IA
, Moe
OW
. Renal transport of uric acid: evolving concepts and uncertainties
. Adv Chronic Kidney Dis
. 2012
Nov
;19
(6
):358
–71
.
[PubMed]
1548-559519.
Matsuo
H
, Chiba
T
, Nagamori
S
, Nakayama
A
, Domoto
H
, Phetdee
K
, et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia
. Am J Hum Genet
. 2008
Dec
;83
(6
):744
–51
.
[PubMed]
0002-929720.
Hamajima
N
, Okada
R
, Kawai
S
, Hishida
A
, Morita
E
, Yin
G
, et al. Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population
. Mol Genet Metab
. 2011
Aug
;103
(4
):378
–82
.
[PubMed]
1096-719221.
Guan
M
, Zhou
D
, Ma
W
, Chen
Y
, Zhang
J
, Zou
H
. Association of an intronic SNP of SLC2A9 gene with serum uric acid levels in the Chinese male Han population by high-resolution melting method
. Clin Rheumatol
. 2011
Jan
;30
(1
):29
–35
.
[PubMed]
0770-319822.
Friedewald
WT
, Levy
RI
, Fredrickson
DS
. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge
. Clin Chem
. 1972
Jun
;18
(6
):499
–502
.
[PubMed]
0009-914723.
Levey
AS
, Bosch
JP
, Lewis
JB
, Greene
T
, Rogers
N
, Roth
D
; Modification of Diet in Renal Disease Study Group
. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation
. Ann Intern Med
. 1999
Mar
;130
(6
):461
–70
.
[PubMed]
0003-481924.
Livak
KJ
. Allelic discrimination using fluorogenic probes and the 5′ nuclease assay
. Genet Anal
. 1999
Feb
;14
(5-6
):143
–9
.
[PubMed]
25.
Zhang
X
, Yang
X
, Wang
M
, Li
X
, Xia
Q
, Xu
S
, et al. Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis
. Rheumatol Int
. 2016
Aug
;36
(8
):1157
–65
.
[PubMed]
0172-817226.
Döring
A
, Gieger
C
, Mehta
D
, Gohlke
H
, Prokisch
H
, Coassin
S
, et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects
. Nat Genet
. 2008
Apr
;40
(4
):430
–6
.
[PubMed]
1061-403627.
Vitart
V
, Rudan
I
, Hayward
C
, Gray
NK
, Floyd
J
, Palmer
CN
, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout
. Nat Genet
. 2008
Apr
;40
(4
):437
–42
.
[PubMed]
1061-403628.
Dehghan
A
, Köttgen
A
, Yang
Q
, Hwang
SJ
, Kao
WL
, Rivadeneira
F
, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study
. Lancet
. 2008
Dec
;372
(9654
):1953
–61
.
[PubMed]
0140-673629.
Smith
GD
, Ebrahim
S
. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?
Int J Epidemiol
. 2003
Feb
;32
(1
):1
–22
.
[PubMed]
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