International Journal of

Molecular Sciences

Review
Uric Acid and Oxidative Stress—Relationship with
Cardiovascular, Metabolic, and Renal Impairment
Mihai-Emil Gherghina 1 , Ileana Peride 1, * , Mirela Tiglis 2 , Tiberiu Paul Neagu 3 , Andrei Niculae 1, *
and Ionel Alexandru Checherita 1

1 Department of Nephrology, “Carol Davila” University of Medicine and Pharmacy Bucharest,

020021 Bucharest, Romania; [email protected] (M.-E.G.); [email protected] (I.A.C.)
2 Department of Anesthesiology and Intensive Care, “Carol Davila” University of Medicine and Pharmacy
Bucharest, 020021 Bucharest, Romania; [email protected]
3 Department of Plastic Surgery and Reconstructive Microsurgery, “Carol Davila” University of Medicine and
Pharmacy Bucharest, 020021 Bucharest, Romania; [email protected]
* Correspondence: [email protected] (I.P.); [email protected] (A.N.)

Abstract: Background: The connection between uric acid (UA) and renal impairment is well known
due to the urate capacity to precipitate within the tubules or extra-renal system. Emerging stud-
ies allege a new hypothesis concerning UA and renal impairment involving a pro-inflammatory
status, endothelial dysfunction, and excessive activation of renin–angiotensin–aldosterone system
(RAAS). Additionally, hyperuricemia associated with oxidative stress is incriminated in DNA dam-
age, oxidations, inflammatory cytokine production, and even cell apoptosis. There is also increasing
evidence regarding the association of hyperuricemia with chronic kidney disease (CKD), cardiovas-
cular disease, and metabolic syndrome or diabetes mellitus. Conclusions: Important aspects need
to be clarified regarding hyperuricemia predisposition to oxidative stress and its effects in order to





 initiate the proper treatment to determine the optimal maintenance of UA level, improving patients’
Citation: Gherghina, M.-E.; Peride, I.; long-term prognosis and their quality of life.
Tiglis, M.; Neagu, T.P.; Niculae, A.;
Checherita, I.A. Uric Acid and Keywords: uric acid; cardiovascular risk; oxidative stress; chronic kidney disease; outcome
Oxidative Stress—Relationship with
Cardiovascular, Metabolic, and Renal
Impairment. Int. J. Mol. Sci. 2022, 23,
3188. https://doi.org/10.3390/ 1. Introduction
ijms23063188
Excretion of nitrogenous waste from the body can manifest in three forms: urea,
Academic Editor: Hajime Nagasu ammonia, and uric acid [1]. Uric acid (UA) is the final product of purine metabolism
(adenine and guanine degradation), mostly derived from endogenous synthesis and only
Received: 16 February 2022
a minor part from exogenous sources [2]. Neel’s hypothesis sustains that our ancestors
Accepted: 12 March 2022
Published: 16 March 2022
underwent genetic mutations that silenced the gene involved in vitamin C synthesis and
UA degradation. It seems that ascorbic acid is a competitor in tubular reabsorption with
Publisher’s Note: MDPI stays neutral UA [3]. Its role in kidney stones is well known and is the most obvious link with CKD [4],
with regard to jurisdictional claims in probably due to urate capacity to precipitate within the tubules or the extra-renal system,
published maps and institutional affil-
especially in obese subjects [5]. Emerging studies support association of high UA levels
iations.
with onset and increase progression of CKD, cardiovascular risk [6], hypertension [7,8],
diabetes mellitus, metabolic syndrome [9,10], and cognitive decline [11]. This time, the
pathogenesis is related to pro-inflammatory and pro-oxidative effects of UA. Other current
Copyright: © 2022 by the authors.
pathogenesis incriminated in the onset and progression of already mentioned diseases are
Licensee MDPI, Basel, Switzerland.
epithelial-to-mesenchymal transition in renal tubular cells, renal vasoconstriction mediated
This article is an open access article by endothelial dysfunction, and activation of renin-angiotensin system (RAAS) [12]. Some
distributed under the terms and studies reported that high levels of uric acid may exert protective effects in neurological dis-
conditions of the Creative Commons orders, such as Parkinson’s disease [13], multiple sclerosis [14,15], Alzheimer’s disease [16],
Attribution (CC BY) license (https:// and vascular-disease-related dementia [2] through its extracellular anti-oxidative role. In
creativecommons.org/licenses/by/ contrast, some researchers sustain the hypothesis that deterioration of kidney function
4.0/).

Int. J. Mol. Sci. 2022, 23, 3188. https://doi.org/10.3390/ijms23063188 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 3188 2 of 16

associated with hyperuricemia might be due to co-existing conditions, such as vascular cal-
cifications, hypertension, and obesity [17]. Serum UA has a biphasic role; therefore, many
of the studies have reported a U-shaped association with cardiovascular mortality [12].

2. Uric Acid Synthesis

As previously mentioned, UA, a ubiquitous product in different life forms [18], can
be linked to the development and progression of CKD through various pathogenesis. UA
presents a heterocyclic organic structure, C5H4N4O3, with the following characteristics [18,19]:
• White crystals or powder aspect,
• A molar weight of 168.11 g/mol,
• A heavy atom count of 12,
• A melting point >300 ◦ C,
• A water solubility of 60 mg/L (at a temperature of 20 ◦ C).
UA can be produced in/by different organs and tissues, such as liver, intestines,
muscles, kidneys, vascular endothelium, and even apoptotic cells, as it is acknowledged
that the nucleic acids, adenine, and guanine of these cells are finally degraded into UA [20].
The complex chemical reactions involved in the UA synthesis include two possible
pathways—the degradation of adenine and guanine, respectively [18,20,21]:
• Adenine pathway:
# Adenosine monophosphate (AMP) is converted by nucleotidase into adenosine,
which is further converted by purine nucleoside phosphorylase into adenine,
which, through deamination, is degraded to hypoxanthine.
# AMP can also present a deamination reaction, being converted into inosine
monophosphate (IMP), which is converted by nucleotidase into inosine, which
is further degraded by purine nucleoside phosphorylase into hypoxanthine.
# The resulting hypoxanthine, under the action of xanthine oxidase, is converted
to xanthine.
• Guanine pathway:
# Guanosine monophosphate (GMP) is converted by nucleotidase into guanosine,
which is further converted by purine nucleoside phosphorylase into guanine,
which, through deamination, is degraded to xanthine.
# GMP can also present a deamination reaction, being converted into xanthosine
monophosphate (XMP), which is converted by nucleotidase into xanthosine,
which is further degraded by purine nucleoside phosphorylase into xanthine.
• The resulting xanthine, through adenine and guanine pathway, under the action of
xanthine oxidase, is oxidized to uric acid, which in the normal human body’s physio-
logical conditions, exists as urate, with the following normal range of levels, which are
different for men and women: 2.5–7.0 mg/dL in male gender and 1.5–6.0 mg/dL in
female gender, respectively. Furthermore, the urate is easily transformed to allantoic
acid and ammonia, allowing its renal excretion (almost 200–300 mg/day).
Summarizing, there are two pathways for purine generation: (1) the novo synthesis
from non-purine compounds (i.e., bicarbonate. amino acids), regulated by phosphoribosyl-
pyrophosphate synthetase (PRPP), and (2) the purine salvage, the mechanism controlled
by hypoxanthine-guanine phosphoribosyltransferase (HPRT). Purine is then catabolized
by xanthine oxidoreductase (XOR), classified in two different isoforms: xanthine dehy-
drogenase (XDH) and xanthine oxidase (XO). Both of them catalyze the oxidation of
hypoxanthine to xanthine and subsequently form UA [3]. XO will be converted in UA
and superoxide anion, which will lead to high intracellular amounts of superoxide anions,
which may induce cell envelope damage and enhanced mutagenesis. Only mammals have
XO type [22]. XDH is the most common form of XOR and, by the conversion through
UA, will develop a reduced form of nicotinamide adenine nucleotide (NADH). In con-
ditions that cause exposure to a hypoxic environment, such as advanced cardiac failure,
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW

through UA, will develop a reduced form of nicotinamide adenine nucleotide

Int. J. Mol. Sci. 2022, 23, 3188 3 of 16
In conditions that cause exposure to a hypoxic environment, such as advance
failure, pulmonary disorders, sepsis, intoxications, and others, XDH will be conv
XO [23] (Figure
pulmonary disorders,1). XO intoxications,
sepsis, has an important roleXDH
and others, in preventing infections
will be converted by produc
into XO [23]
chondrial
(Figure 1). XOROS although
has an importantexcess formationinfections
role in preventing will imbalance the mitochondrial
by producing oxidative and anti
ROS although excess formation will imbalance the oxidative and
equilibrium and subsequently promote a pro‐inflammatory status [22]. anti-oxidative equilib-
Furtherm
rium and subsequently promote a pro-inflammatory status [22]. Furthermore, once UA is
UA is synthetized, it will be transported to the circulatory system and excreted
synthetized, it will be transported to the circulatory system and excreted through renal and
renal and gastrointestinal
gastrointestinal pathways [24]. pathways [24].

Figure
Figure 1. 1. Metabolism
Metabolism of purine
of purine through
through xanthine
xanthine oxidoreductases.
oxidoreductases. XO,
XO, xanthine xanthine
oxidase; XDH,oxidase;
thine dehydrogenase;
xanthine dehydrogenase; ROS, ROS, reactive
reactive oxygenoxygen species;
species; NADH, NADH, adenine
nicotinamide nicotinamide adenine d
dinucleotide
(Modified after: [23]).
(Modified after: [23]).
Serum UA homeostasis is determined by its production, exogenous contribution,
and theSerum
balanceUA homeostasis
between is determined
renal and intestinal by itsand
reabsorption production, exogenous contrib
secretion. Hyperuricemia
isthe balance
defined as abetween renal and
UA concentration intestinal
higher than 7 reabsorption
mg/dL in men,and secretion.
6 mg/dL Hyperurice
in women,
and 5.5 mg/dL in children and teenagers [24]. Causes of hyperuricemia
fined as a UA concentration higher than 7 mg/dL in men, 6 mg/dL in wome are rich purine
diets, congenital disorders, tumor lysis syndrome, seizures, rhabdomyolysis [25], hy-
mg/dL in children and teenagers [24]. Causes of hyperuricemia are rich purine d
percatabolic states [26], or drugs (i.e., acid acetylsalicylic, theophylline, mycophenolate,
genital
beta- disorders,
and alfa- tumor
adrenergic lysis angiotensin-converting
antagonists, syndrome, seizures,enzyme,rhabdomyolysis [25], hype
cyclosporine) [27].
states
Low [26],level
serum or drugs (i.e.,beacid
of UA may acetylsalicylic,
encountered theophylline,
in large volumes mycophenolate,
of parenteral fluids, psy- beta
chogenic polydipsia, inappropriate antidiuretic hormone (SIADH),
adrenergic antagonists, angiotensin‐converting enzyme, cyclosporine) or in some hepatic[27]. Lo
diseases (i.e., cholangiocarcinoma, viral hepatitis, primary cirrhosis), immunosuppression,
level of UA may be encountered in large volumes of parenteral fluids, psychog
or neoplasia. Hypouricemia can be defined when UA is under 2.0 mg/dL [12].
dipsia, inappropriate antidiuretic hormone (SIADH), or in some hepatic dise
3.cholangiocarcinoma,
Uric Acid Rich Diets viral hepatitis, primary cirrhosis), immunosuppression
Historically,
plasia. during thecan
Hypouricemia last be
100defined
years, there
whenis a progressive
UA is under rise 2.0
in UA serum[12].
mg/dL level,
especially in Western diets. Most likely the cause is increased consumption of fructose-
containing sugars, a product used more and more because of its high capacity of sweeten-
3. Uric
ing Acid Rich
[28]. Fructose Diets is located in the liver, has no negative feedback, and needs
metabolism
a greatHistorically,
deal of ATP (adenosine
during thetriphosphate) and intracellular
last 100 years, there is aphosphate consumption.
progressive rise in UA ser
Through phosphorylation, fructokinase converts fructose to fructose 1-phosphate (fructose
especially in Western diets. Most likely the cause is increased consumption of
1-p). Consequently, fructose 1-p aldolase (or aldolase B) converts fructose 1-p to dihy-
containing phosphate
droxyacetone sugars, a (DHAP)
productand used more and more
D-glyceraldehyde. because
Because these of its high
reactions needcapacity
ATP consumption, intracellular phosphate decreases. This will stimulate AMP deaminase feed
ening [28]. Fructose metabolism is located in the liver, has no negative
(AMPD),
needs awhich
greatwill
dealinduce AMP(adenosine
of ATP degradation to IMP (inosine monophosphate),
triphosphate) increasing
and intracellular phosphate
the rate of purine degradation and UA synthesis [3]. A meta-analysis from 2018 found
tion. Through phosphorylation, fructokinase converts fructose to fructose 1‐p
seven types of food (beer, wine, liquor, soft drinks, poultry, potatoes) and meat (i.e., beef,
(fructose
pork, lamb) 1‐p). Consequently,
that were associated withfructose
high UA 1‐p aldolase
serum level and(or aldolase
another eightB) converts
foods with fruct
dihydroxyacetone
reduced serum UA levelphosphate
but with high(DHAP) and(i.e.,
protein levels D‐glyceraldehyde.
eggs, skim milk, brownBecause
bread, these
need ATP consumption, intracellular phosphate decreases. This will stimulate
aminase (AMPD), which will induce AMP degradation to IMP (inosine monoph
increasing the rate of purine degradation and UA synthesis [3]. A meta‐analysis
found seven types of food (beer, wine, liquor, soft drinks, poultry, potatoes) and
Int. J. Mol. Sci. 2022, 23, 3188 4 of 16

non-citrus fruits, cheese, cereals, etc.) [29]. Some studies confirm that high-purine vegeta-
bles were not associated with hyperuricemia or gout involvement but should be avoided in
patients with advanced kidney disease or gout [2].

4. Possible Genetic Disorders Involved in Uric Acid Over-Synthesis

Lesch–Nyhan syndrome is an inherited disorder caused by hypoxanthine-guanine
phosphoribosyl transferase (HPRT) deficiency that can be associated with uric acid over-
production and gout. The HPRT is one of the enzymes responsible for “recycling” purine
nucleotides. Another genetic disorder associated with hyperuricemia and gout is over-
expression of phosphoribosyl pyrophosphate synthetase (PRPP). This enzyme contributes
to UA formation due to its role in purine de novo synthesis starting from ribose-5 phosphate
and ATP. Glucose high-flux metabolism can also lead to hyperuricemia by stimulating
pentose phosphate pathway and generating excessive amounts of ribose-5 phosphate [30].

5. Uric Acid Excretion

Considering that above the normal range values, especially for levels > 6 mg/dL in
both genders, UA can be precipitated into urate crystals, which can lead to the onset and
progression of various diseases (i.e., gout), it is important to underline the process of UA
elimination and regulation [18,31,32]:
• Most of the urate is excreted by the kidneys (only one-third is gastro-intestinally elimi-
nated), which involves three phases: filtration, reabsorption, and secretion; knowing
that it is not bound to the proteins, it is easily ultra-filtrated by the glomeruli. In the
proximal renal tubules, most of it is reabsorbed (~95–98%), and then, secretion occurs,
with 10% of filtered uric acid being further excreted by the kidneys [33].
• These processes of urate elimination and regulation are influenced by different pro-
teins/transporters:
# URAT1 (urate transporter 1)—it belongs to the organic anion transporter (OAT)
family and is a urate exchanger in the apical region of the proximal renal
tubules, being encoded by SLC22A12 (solute carrier family 22, organic an-
ion/urate transporter, member 12) gene. It is responsible for the urate reab-
sorption, therefore having an important key role in maintaining serum UA
normal values.
# BCRP (breast-cancer-resistance protein)—a transporter encoded by ABCG2
(adenosine triphosphate binding cassette subfamily G member 2) gene that
recently was observed to have an essential contribution in urate excretion.
In CKD, high urate levels induce a more active intestinal transporter of UA
through ABCG2 increased expression and/or functionality [34].
# GLUT9 (glucose transporter 9)—a transporter for urate, with similar roles as
URAT1, located in the basolateral region of the proximal renal tubules.
# SGLT2 (sodium-glucose transporter 2)—recent data suggested its contribution
in transporting urate and consequent involvement in its excretion.
In fact, to be accomplished, urate reabsorption (Figure 2) needs two types of apical
transporters [35]. One of them is responsible for sodium-anions cotransport (sodium-
monocarboxylate co-transporters SMCT1 and SMCT2) from tubular space into the cell, and
the other type (URAT1, OAT10, and OAT4) exchanges intracellular anions with luminal
urate. High concentration of anions, such as lactic acid [36], salicylate, nicotinate [37],
pyrazinamide [38], butyrate, and acetoacetate [39], increase urate reabsorption and induce
hyperuricemia. As already mentioned, URAT1 is the main anion–urate exchanger; therefore,
many drugs, such as Probenecid, Benzpromarone, Fenofibrat [40], or Losartan [41], that
inhibit URAT1 lead to hypouricemia. From intracellular space, urate will be transported to
circulation via GLUT9, encoded by SLC2A9 (solute carrier family 2, organic anion/urate
transporter, member 9) gene. Inherited GLUT9 deficiency prevents reabsorption with
great amounts of UA loss in urine, approximately 150% of filtered urate, with a proof for
secretion mechanism being predominant in the absence of reabsorption [42].
 diuretics inhibit NPT4, suggesting a role in reduced secretion of urate in hyperuricemia‐
associated diuretics syndrome [45].
Other control factors in the balance of serum UA can be volume status (enhances
reabsorption) [46,47], low‐salt diet (enhances reabsorption) [48,49], insulin [50–52], angio‐
tensin II [53], epinephrine, and PTH, which raises serum UA through unknown mecha‐
Int. J. Mol. Sci. 2022, 23, 3188 5 of 16
nisms [54]. In addition, an important factor in controlling serum UA is oxidative stress,
which modulates production, excretion, and reabsorption of urate [55].

Figure
Figure2.2.(A)
(A)SMCT1
SMCT1and andSMCT2
SMCT2reabsorb
reabsorbNa‐dependent
Na-dependentanions
anionsand
andraise
raiseintra‐cellular
intra-cellularconcentra‐
concen-
tion.
tration. URAT1/OAT10/OAT4 exchange intracellular anions with tubular urate, which willthe
URAT1/OAT10/OAT4 exchange intracellular anions with tubular urate, which will exit cell
exit
via GLUT9. (B) Na and alpha‐ketoglutarate will enter the cell through NADC3. Basolateral
the cell via GLUT9. (B) Na and alpha-ketoglutarate will enter the cell through NADC3. Basolateral
OAT1/OAT3 exchanges plasma urate with intracellular alpha‐ketoglutarate. Intracellular urate exit
OAT1/OAT3 exchanges plasma urate with intracellular alpha-ketoglutarate. Intracellular urate
is accomplished through voltage channels NPT1/NPT4 or ATP‐driven MRP4. SMCT1,sodium‐mon‐
exit is accomplished through voltage channels NPT1/NPT4 or ATP-driven MRP4. SMCT1,sodium-
ocarboxylate co‐transporter 1; SMCT2, sodium‐monocarboxylate co‐transporter 2; Na+, +sodium; K+,
monocarboxylate
potassium; URAT1, co-transporter 1; SMCT2,
urate transporter sodium-monocarboxylate
1; OAT10, co-transporter
organic anion transporter 10; OAT4,2; Na , sodium;
organic anion
+
K , potassium; URAT1, urateanion
transporter 1; OAT10, organic anion transporter 10; OAT4, organic
transporter 4; OAT1, organic transporter 1; OAT3, organic anion transporter 3; MRP4, multi‐
anion
drug transporter
resistance 4; OAT1,
protein organicadenosine
4; ABCG2, anion transporter 1; OAT3,
triphosphate organic
binding anionsubfamily
cassette transporterG 3; MRP4, 2;
member
multidrug
NPT1, resistance protein
Na‐phosphate 4; ABCG2,
transporter adenosine
1; NPT4, triphosphate
Na‐phosphate binding 4;
transporter cassette
GLUT9, subfamily
glucoseGtransporter
member
9;2;NADC3,
NPT1, Na-phosphate transporter
sodium‐dependent 1; NPT4, Na-phosphate
dicarboxylate cotransportertransporter 4; GLUT9,
3 (Modified glucose transporter
after [35]).
9; NADC3, sodium-dependent dicarboxylate cotransporter 3 (Modified after [35]).
6. Pathogenic Potential of Serum Uric Acid in Renal Impairment
Urate secretion (Figure 2) is made by basolateral exchanger alfa-Ketoglutarate-urate
There are several mechanisms incriminated in the association of renal impairment
named OAT1 and OAT3, through which serum urate is driven to intracellular space
and hyperuricemia.
in exchange First of all, the most
with alfa-ketoglutarate. popular mechanism
Intracellular urate will is represented
exit by monoso‐
the cell through the
dium
apicalurate
pole, (MSU)
mediatedcrystal depositions
by a cell in the joints,
negative membrane kidney,
potential and NPT1
named other and
tissues.
NPT4Studies
(Na-
showed
phosphate over 6.5 mg/dL,
thattransporter) and byserum
MRP4becomes supersaturated
channel (multidrug in MSU.
resistance Other
protein 4), pathogenic
an apical
mechanisms
ATP- driven efflux pump encoded by ABCG2 gene [35,43]. The MRP4 channel ispro‐oxidative
that correlate uric acid with kidney disease are intracellular stimulated
properties, induced endothelial
by xanthine-oxidase dysfunction,
inhibitors, such induced
as allopurinol renal
and its fibrosis,oxipurinol
metabolite and induced[44].glomer‐
Loop
ulosclerosis [25]. NPT4,
diuretics inhibit According to emerging
suggesting a role studies, UAsecretion
in reduced stimulates transcription
of urate of growing
in hyperuricemia-
factors, nuclear
associated factor
diuretics kappa‐light‐chain‐enhancer
syndrome [45]. of activated B cells (NF‐kB), and vari‐
Other controlsubstances,
ous vasoactive factors in thesuch
balance
as ofendothelin,
serum UA can be volume status
angiotensin II, or(enhances reab-
thromboxane.
sorption) [46,47], low-salt diet (enhances reabsorption) [48,49], insulin [50–52], angiotensin
II [53], epinephrine, and PTH, which raises serum UA through unknown mechanisms [54].
In addition, an important factor in controlling serum UA is oxidative stress, which modu-
lates production, excretion, and reabsorption of urate [55].

6. Pathogenic Potential of Serum Uric Acid in Renal Impairment

There are several mechanisms incriminated in the association of renal impairment and
hyperuricemia. First of all, the most popular mechanism is represented by monosodium
urate (MSU) crystal depositions in the joints, kidney, and other tissues. Studies showed that
over 6.5 mg/dL, serum becomes supersaturated in MSU. Other pathogenic mechanisms
that correlate uric acid with kidney disease are intracellular pro-oxidative properties, in-
duced endothelial dysfunction, induced renal fibrosis, and induced glomerulosclerosis [25].
According to emerging studies, UA stimulates transcription of growing factors, nuclear
Int. J. Mol. Sci. 2022, 23, 3188 6 of 16

factor kappa-light-chain-enhancer of activated B cells (NF-kB), and various vasoactive

substances, such as endothelin, angiotensin II, or thromboxane. Additionally, UA is im-
plicated in decreased oxide nitric (ON) synthesis, inhibiting endothelial cell proliferation
and migration [35]. Taken together, all these effects provide strong correlation between UA
and arterial stiffening from CKD [56]. Through RAAS, UA stimulates xanthine oxidase,
NADPH oxidase [57,58], and proliferation of smooth muscle cell [59,60]. Renal fibrosis rep-
resented by tubulointerstitial fibrosis and glomerulosclerosis was proven through a clinical
study of 1700 biopsy-confirmed patients with hyperuricemia. The incriminated pathways
are activation of epithelial- and endothelial-to-mesenchymal transition (EMT, EndoMT),
which will activate fibroblasts and myofibroblasts and subsequent renal fibrosis [25]. Other
studies associate inflammation markers, such as C-reactive protein (CRP) or TNF-alfa, as
directly proportional with serum UA concentrations [61,62]. Some researchers consider
that serum UA can be a strong predictor of acute kidney injury without correlation with
the baseline renal function [63].

7. Bimodal Role of Uric Acid in Oxidative Balance

Biologically, uric acid can have not only pro-oxidative but also anti-oxidative proper-
ties. Extracellular UA mainly acts as an anti-oxidant, also named “scavenger”, with certain
benefits in neurological diseases [64]. At the extracellular level, UA reacts with superoxides
to form allantoin, with peroxynitrite to form triuret [65], or with nitric oxide to form 6-
aminouracil, representing examples of anti-oxidative properties [66]. UA is one of the major
antioxidant products from humans, being responsible for up to 55% extracellular capacity
of free radical antioxidant scavenging [2]. Additionally, extracellular uric acid reacts with
myeloperoxidase with generation of hydroperoxide urate, a compound with pro-oxidative
properties [67]. In contrast with its extracellular double role, intracellular UA performs only
pro-oxidative actions through activating nicotinamide adenine dinucleotide phosphate
(NADPH) oxidases [68] but also through other several mechanisms, such as reducing
endothelial levels of antioxidant nitric oxide (NO), activating peroxynitrite-mediated oxida-
tion of lipids, or by stimulating pro-inflammatory biomarkers. The same authors considered
that oxidative stress (OS) from hyperuricemia may play a role in aging and apoptosis of
endothelial cells [17]. NADPH oxidases are involved in ROS production that can lead to
pro-inflammatory signaling through mitogen-activated protein kinases (MAPKs). Hype-
ruricemia associated with oxidative stress is responsible for several pathophysiological
responses, such as DNA damage, oxidations, inflammatory cytokine production, and cell
apoptosis. The main site of oxidative phosphorylation is in the mitochondria, which pro-
duce ROS by transferring electrons from electron transport chain complexes to free oxygen
radicals. Apparently, hyperuricemia is responsible of mitochondrial calcium overload,
which induces dysfunctionalities in sodium and calcium mitochondrial exchange that will
lead to ROS production [25]. The fact that hyperuricemia induces oxidative stress, which
stimulates inflammation, raises the possibility in which hyperuricemia might benefit not
only from urate-lowering agents but also from agents that target immune system aspects,
such as interleukin-1, autophagy, or other pro-inflammatory factors [66].

8. Oxidative Stress and Uric Acid

Oxidative stress is a non-traditional risk factor for all causes of mortality observed
frequently in CKD. The onset or progression of CKD, hypertension, metabolic syndrome,
and insulin resistance are closely related with a pro-oxidative state generated by chronic
inflammation. Oxidative stress is a pathological imbalance between pro-oxidative and anti-
oxidative factors in favor of pro-oxidants. The main anti-oxidative factors are superoxide
dismutase (SOD), glutathione peroxidase, catalase, and NO. According to a study from
2018, the main reactive oxygen species (ROS) generators are NADPH oxidase, xanthine
oxidase, mitochondrial enzymes, myeloperoxidase, lipoxygenase, and uncoupled NO
synthase. Xanthine oxidase enzymes are found not only in endothelial cells but also in
plasma and are considered highly generators of superoxide and hydrogen per-oxide. It
Int. J. Mol. Sci. 2022, 23, 3188 7 of 16

stimulates smooth muscle cell proliferation and LOX-1, a lectin receptor that enhances
deposition of oxidized LDL, with important roles in atheroma plaque formation. Emerging
studies consider that LOX-1 induces endothelial apoptosis, decreases NO production, and
reduces expression of scavengers’ receptors from endothelial lesions. Thereby, LOX-1 is
seen as one of the main targets in oxidative stress treatment. Oxidative stress markers
can be represented by high levels of manoldialdehyde (MDA), peroxinitrite, or advanced
glycosylation products (AGEs) and reduced SOD [69].

9. Non-Interventional Studies Focused on Uric Acid

Association between hyperuricemia and onset or progression of CKD is a well-known
topic, but it is difficult to establish if uric acid induces kidney disease progression or if it
can be an independent factor of renal impairment. Strong evidence of hyperuricemia and
progression of kidney disease is given by the protein restriction recommended in early-
stage CKD, also beneficial in decreasing UA, an end product of protein metabolism [70].
Large studies, such as National Health and Nutrition Examination Survey (NHANES) and
German Chronic Kidney Disease (GKKD), support a relationship between hyperuricemia
and renal function decline. Additionally, a meta-analysis including 18 prospective studies
and 431,000 patients supported that a high level of UA is correlated with higher incidence
of onset and accelerating progression of CKD [68]. Two meta-analyses from 2011 and
2015 conducted on 18 prospective cohorts including 55,607 patients [71], respectively, and
25 studies including 97,824 patients [72] support a moderate raise in arterial pressure
values correlated with high levels of serum UA. In addition, both of them consider that
hyperuricemia is an independent factor of hypertension. Another meta-analysis from
2013 in which were included 32,016 patients from seven studies, support serum UA as an
independent factor in onset of diabetes mellitus and onset of metabolic syndrome [73]. In
2008, Hsu et al., found that elevated serum UA was an independent factor for end-stage
renal disease in a study on 175,000 subjects after a 25-year follow up [74]. The Modification
of Diet in Renal Disease study from 2009 on 838 CKD stage 3–4 patients did not find
an association between hyperuricemia and end-stage-renal-disease; instead, the authors
sustained that hyperuricemia significantly raises the risk of all-cause and cardiovascular
mortality [75]. Luo et al., indicated in a meta-analysis from 2019 on 10 studies (26,660 sub-
jects) that every 1 mL/dL raise in levels of UA was associated with a risk of cardiovascular
mortality of 12% in CKD patients [76]. Tsai et al., in a retrospective longitudinal study
on 739 subjects, found an increased risk of progression to renal failure with 7% for each
1 mg/dL UA-level increase [77]. In 2018, Zhou et al., supported a directly proportional
association between serum UA, IL-6, TNF-alfa, MDA, and indirect proportional with SOD.
Thereby, he suggested that hyperuricemia is an independent risk factor in hypertension,
myocardial ischemia, and atherosclerosis through its pro-inflammatory and pro-oxidative
roles [78]. Additionally, several recent studies suggested an association between CRP and
hyperuricemia [79]. The classic murine model was represented by administration of oxonic
acid (an uricase inhibitor) on mice with doubling or even tripling serum UA concentration
that was associated with higher arterial pressure values through RASS stimulation, oxida-
tive stress induction, and NO reduction. Later effects were represented by hypertension
with microvascular changes independent of serum UA levels [35]. A clinical trial from
2004–2008, including 14,267 subjects with type 2 diabetes, metabolic syndrome (50% of total
cohort), hyperuricemia (14% of total cohort), and normal renal function, concluded that
14% of the patients developed CKD (eGFR < 60 mL/min), and the incidence of low eGFR
was higher in subjects with hyperuricemia and metabolic syndrome during the 4-year
follow-up [80].

10. Mendelian Randomized Studies Focused on Uric Acid

Mendelian studies and other genetic studies were used to eliminate potential con-
founders and reverse causality. For genotype, the studies used SLC2A9 gene polymorphism,
responsible for 2% of serum UA variability. Oikonen et al., found no association between
Int. J. Mol. Sci. 2022, 23, 3188 8 of 16

uric acid and intima-media thickness in 2012 [81]. In a study from 2013, Palmer et al.,
reported no association between SLC2A9 polymorphism and hypertension or ischemic
heart disease [82]. In 2014, Sedaghat et al., also found no association between hyper-
uricemia induced by 30 genetic polymorphisms and hypertension [83]. In contrast, in
2014, Mallamaci et al., associated hyperuricemia with hypertension due to SLC2A9 poly-
morphism [84]. In addition, in 2015, Kleber et al., supported the relationship between
hyperuricemia resulting from eight genetic variants and cardiovascular mortality [85].
Furthermore, Hughes et al., advanced the idea that there is an association between uric
acid genetic score and renal function improvement [86]. It appears that Mendelian random-
ization studies evidenced contradictory results regarding the relationship between uric
acid genetic risk and cardiovascular disease or renal impairment.

11. Available Treatment Option for Lowering Uric Acid

Allopurinol is a purine-like XO inhibitor and Febuxostat and Topirostat are non-
purine XO inhibitors. XO inhibitors are the first line in the treatment of hyperuricemia. In
November 2017, the U.S. Food and Drug Administrations emitted a warning alert related to
the use of Febuxostat due to its potential correlation with an increased risk of cardiovascular
mortality, and therefore, it must be used with caution [23].
The second-line therapy is attributed to uricosuric agents. Probenecid and Benzpro-
marone act through inhibition of URAT1 and GLUT9. Recently, it was shown that the use
of Benzpromarone can be associated with a lower risk of stroke in patients diagnosed with
gout [87]. It should be mentioned that Benzpromarone is considered one of the four drugs
linked to severe hepatotoxicity, and for this reason, it was withdrawn in the USA [88].
A new generation of uricosuric has been considered, such as Lesinurad (approved
by U.S. Food and Drug Administration in 2015), Arhalofenate, and Dotinurad (developed
in Japan in 2018, not yet approved by FDA), which are selective inhibitors of URAT1
and OAT4 [89]. Furthermore, a new generation of XO inhibitor, named 3,4-dihydroxy-
5-nitrobenzaldehyde (DHNB), is being studied, with similar properties as Allopurinol
but with less toxicity and with direct antioxidant capacity, reducing free radicals and
ROS productions [90].
For recombinant and pegylated uricases, other available options for lowering serum
uric acid are limited only by parenteral infusion and, presenting an addition, the possibility
of producing antidrug antibodies [91].
Inhibitors of SGLT2, a form of treatment for diabetic control through inhibition of re-
absorption of glucose, sodium, and uric acid in proximal tube, represents a promising class
drug in lowering uric acid, especially in diabetic and CKD subjects. Apparently, SGLT2
inhibitors are associated with a better control of uric acid, improvement of cardiovascular
risk, and also slowing the progression of kidney disease [81]. SGLT2-inhibition increases
intraluminal glucose, which will interact competitively with uric acid reabsorption via
GLUT9b [92]. Currently, there are three oral SGLT2 options approved by the U.S. Food and
Drug Administration and European Medicines Agency, recommended for patients with
type 2 diabetes mellitus and CKD with eGFR > 30 mL/min/1.72 m2 . Studies indicated
significant improvement in upregulation of angiotensin, reductions of UA, oxidative stress,
arterial stiffness, inflammation, and body weight [93]. Other potential advantages from
SGLT2 inhibitors may be reduction of anti-inflammatory, anti-oxidant, and anti-fibrotic
markers [94]. In addition, studies with Ipragliflozin, Dapagliflozin, and Empagliflozin
found decreased levels for oxidative stress and macrophages markers (MCP-1, NF-kB,
8-OhdG, L-fatty acid, interleukin-6, monocyte-attractive-protein-1) [95–97]. Regarding ad-
verse effects, the most commonly observed were genital infections, urinary tract infections,
bone fractures, or diabetic ketoacidosis [89,98].
Other potential beneficial therapies:
• Estradiol and Losartan are also URAT1 and GLUT9 inhibitors, whereas Fenofibrate
acts only through URAT1 inhibition [99]. Despite higher prevalence of CKD in women,
a recent study from nationwide Swedish Renal Registry—CKD evidenced that males
Int. J. Mol. Sci. 2022, 23, 3188 9 of 16

are prone to a higher eGFR decline. Apparently, more and more studies sustain that sex
hormones, especially estrogen, exerts renal and cardiovascular protective proprieties.
This may also be a reason for lower levels of uric acid in women [100].
• Vitamin E is a nutrient lipid soluble with pleiotropic benefits in protecting the in-
tegrity of cell membranes through ROS scavengers and by blocking the chain of
oxidative reactions [101].
• Vitamin C or ascorbic acid and NO are involved in a complex relationship. It has been
suggested that ascorbic acid is a potent antioxidant and reduces serum UA levels by
increasing urinary excretion, inhibiting AU synthesis, and by directly decreasing ROS-
derived cell damage. Flavonoids and other polyphenols due to their anti-oxidative
capacity act like superoxide and XO inhibitors, resulting in suppression of ROS and
UA synthesis [102].
• Ï-Arginine and N-Acetylcysteine also known as strong antioxidants and have shown
repeatedly good results in efficient anti-oxidative properties in CKD. Ï-Arginine is a
substrate for NO synthesis [17].
• An NHANES study in 14,758 subjects sustained that only tea and coffee consumption
was associated with low levels of serum UA [103].

12. Interventional Studies Focused on Uric Acid

Several studies showed that xanthine oxidase inhibitors mitigate endothelial dys-
function and reduce atherosclerosis risk in smokers [104,105]. Another study proved the
beneficial effects of xanthine oxidase inhibitors in hyperuricemia-induced endothelial le-
sions in contrast with uricosuric treatments. Kang et al., showed in their study, which
included 113 patients with CKD stage 3A, the association between oxidative stress and
kidney disease progression using xanthine oxidase inhibitors versus placebo [57]. Fur-
thermore, there are studies that supported the benefits of xanthine oxidase inhibitors in
slowing kidney disease progression and reducing arterial pressure [106]. A meta-analysis
from 2012, which included 10 studies, showed a decrease with 3.3 mmHg of systolic blood
pressure and with 1.3 mmHg of diastolic blood pressure in pre-hypertensive patients with
UA levels between 5–7.6 mg/dL, treated with xanthine oxidase inhibitors [107]. Another
study from 2010 conducted on 113 patients with CKD (estimated glomerular filtration
rate—eGFR < 60 mL/min/1.73 m2 ) treated with Allopurinol 100 mg/dL versus contin-
uum initial therapy showed a lower level of CRP (from 4.4 to 3.0 mg/dL) and a rise in
eGFR with 1.3 mL/min/1.73 m2 versus a decrease of 3.3 mL/2 years [108,109]. In 2014,
Bose et al., in a meta-analysis of eight trials on 476 subjects, reported that treatment with
Allopurinol, retarded kidney disease progression in five from eight trials [110]. Lee et al., in
144 patients with CKD stage 3 and hyperuricemia, followed from 2005 to 2018 in treatment
with Allopurinol vs. Febuxostat, found that subjects on Febuxostat had significantly lower
mean serum UA and higher mean eGFR values for 4 years [111]. In 2019, Zhang et al.,
demonstrated on a cohort of 152 CKD stage 2–3 with hyperuricemia in treatment with
Allopurinol vs. Febuxostat that mean eGFR was higher on Febuxostat group after 6 months
of follow up [112]. A meta-analysis from 2020 focused on patients diagnosed with CKD
stage 5, which included 6000 subjects, compared treatment with Allopurinol vs Febux-
ostat. The median follow up was 0.72 years, during which significantly fewer patients
on Febuxostat started renal replacement treatment [113]. Mauer et al., suggested that UA
reduction with Allopurinol slows down the progression of kidney disease in diabetics,
and more than that, they considered UA a strong predictor for diabetic nephropathy [114].
Another meta-analysis from 2018 on 12 randomized controlled trials with 832 CKD subjects
admitted that lowering UA serum level was associated with significant raise in eGFR,
with the mean difference of 3.88 mL/min/1.73 m2 between the patients who received
uric-acid-lowering therapy and those that did not [115]. In contrast, in 2017, Sampson
et al., through a meta-analysis of 12 studies on 1187 subjects, reported that urate-lowering
therapies available (Febuxostat, Allopurinol, Probenecid, Sulfinpyrazone, Benzbromarone,
Pegloticase, and Rasburicase) showed no benefits. Furthermore, one study evidenced that
Int. J. Mol. Sci. 2022, 23, 3188 10 of 16

uric-acid-lowering therapy increased CRP [116]. Su et al., compared placebo vs. acid-
lowering agents in a meta-analysis from 2017 in 16 trials that included 1211 subjects and
found that those in uric-acid-lowering therapy group presented a 55% relative reduction in
the risk of kidney failure events and 60% reduction of cardiovascular events [117]. In 2020,
Chen et al., in an overview that included 28 trials involving 6468 subjects, showed that
urate-lowering therapy did not reduce the major cardiovascular events, death, or kidney
failure [118]. An extensive review, which involved 15 systemic reviews, 144 observational
meta-analyses, 31 randomized controlled meta-analysis trials, and 107 Mendelian random-
ization studies, sustained that the only convincing evidence of a role of serum UA is in
gout and nephrolithiasis [119]. Lin et al., in a meta-analysis from 2019 on 11 trials and
1317 subjects, found a significant rise in eGFR for stage 3–4 CKD patients in treatment
with Febuxostat [120]. These substantial information regarding UA influence on renal
impairment, cardiovascular events, etc., are summarized in Table 1.

Table 1. Interventional studies focused on uric-acid-lowering treatment in CKD patients with

hyperuricemia.

Study Studied Medication Included Subjects Results

10 clinical trials with n = 738 subjects
Agarwal et al. (2012, meta-analysis) [107] Allopurinol vs. placebo 1:1 3.3 mmHg BP reduction in placebo group
with eGFR < 60 mL/min
Significant reduction of CRP level
Goicoechea et al. (2010) [108] Allopurinol vs. placebo 1:1 n = 113 with eGFR < 60 mL/min
eGFR 1.3 mL/min/24 months increment
Reduction of CKD decline with a mean
Golmohammadi et al. (2017) [109] Allopurinol vs. placebo 1:1 n = 216 with eGFR 15–60 mL/min
difference of 1 mL/min/year
8 clinical trials with n = 476 with Mean eGFR retarded by
Bose et al. (2014, meta-analysis) [110] Allopurinol vs. placebo 1:1
eGFR < 60 mL/min 3.3 mL/min/year in 5 from 8 studies
Febuxostat significant decreased UA level
Allopurinol vs. Febuxostat n = 141, mean eGFR and maintain eGFR significant higher for
Lee et al. (2019) [111]
vs placebo 12 : 12 :1 baseline = 42.1 mL/min 4 years in contrast to Allopurinol
or placebo
Febuxostat showed superiority in eGFR
Zhang et al. (2019) [112] Febuxostat vs. Allopurinol 1:1 n = 152 with CKD stage 2–3 decline but not in proteinuria or uric
acid control
Lower risk of progression to dialysis on
Hsu et al. (2020, meta-analysis) [113] Febuxostat vs. Allopurinol 1:1 n = 6057 with CKD stage 5
febuxostat group
8 trials showed a mean serum creatinine
Liu et al. (2018, meta-analysis) [115] Uric-acid-lowering therapy 12 clinical trials with 832 CKD subjects
reduction by −0.63
Conflicting evidence—no apparent
12 clinical trials with
Sampson et al. (2017, meta-analysis) [116] Uric-acid-lowering therapy benefits in eGFR, blood pressure, or
1187 CKD subjects
proteinuria control
eGFR progression retarded by
4.1 mL/min/year
Su et al. (2017, meta-analysis) [117] Uric-acid-lowering therapy 16 clinical trial with 1211 CKD subjects
55% reduced risk of AKI
60% reduced risk in cardiovascular events
No benefits in kidney failure or
Chen et al. (2020, meta-analysis) [118] Uric-acid-lowering therapy 28 trials with 6458 CKD subjects
cardiovascular events
11 trials with 1317 CKD stage Reno-protective effects with a mean
Lin et al. (2019, meta-analysis) [120] Febuxostat vs. placebo
3–4 subjects difference in eGFR of 3.6 mL/min
HU, hyperuricemia; AKI, acute kidney injury; eGFR, estimated glomerular filtration; CRP, C-reactive protein; BP,
blood pressure; UA, serum uric acid.

Current Guidelines Recommendations

• In 2020, the Guideline for Management of Gout by the American College of Rheuma-
tology (ACR) recommended initiating urate-lowering therapy for gout patients with
more than one subcutaneous tophus, evidence of radiographical damage attributable
to gout, or frequent gout flares (>2 per year) [121].
• Japanese guidelines for gout recommended to treat asymptomatic hyperuricemia
in patients with UA serum level over 8 mg/dL and complications, such as CKD,
urolithiasis, hypertension, cardiovascular disease, diabetes mellitus, and metabolic
syndrome, or in patients with UA serum level over 9 mg/dL [122].
Int. J. Mol. Sci. 2022, 23, 3188 11 of 16

• In 2017, EULAR recommendations for gout management suggested Allopurinol as

first-line treatment. If target UA level could not be managed (serum UA < 6 mg/dL),
the use of Febuxostat or other uricosuric agent was indicated. As third line, a combi-
nation of uricosuric and XO inhibitor was suggested. Pegloticase was recommended
only for refractory gout [123].
Furthermore, although in Europe, uric acid is not considered an independent risk fac-
tor, the majority of interventional studies, even though on small cohorts, prove the benefits
of xanthine oxidase inhibitors therapy in asymptomatic hyperuricemia. On the other hand,
it is important to acknowledge the risks associated with therapy administration. There were
reported rare cases of Stevens endothelial lesions Johnson syndrome, secondary vasculitis,
hepatitis, or even acute kidney injury. It is important to remember that UA takes a unique
position in uremic retention because its serum concentration can be controlled selectively
by specific medication [124]. Some researchers proposed to treat asymptomatic hyper-
uricemia under the presence of urate crystals in urine sediment and/or by asymptomatic
damage of joins identified through musculoskeletal ultrasound. Apparently, these signs
appear long term before gout is evident. Musculoskeletal ultrasound reveals asymptomatic
urate depositions by hyperechoic enhancement of the cartilage surface, cartilage with
double contour, intra-articular hyperechoic clouds, bone erosion, synovitis, or periarticular
power signal [125].

13. Conclusions
According to the meta-analyses and pilot studies presented, high levels of serum UA
are related with a prooxidative and proinflammatory state. Due to the fact that xanthine
oxidase inhibitors have more benefits regarding endothelial functions and slowing kidney
disease progression in contrast with uricosuric agents and the fact that Mendelian random-
ization studies evidence conflictual results, we are prone to establish oxidative stress as the
pathogenic factor instead of uric acid itself. However, the studies have many con-founding
factors and include a small number of patients. Therefore, to establish serum uric acid as
an independent risk factor for CKD, hypertension, cardiovascular events, or metabolic syn-
drome, more studies with larger cohorts are needed. Regardless of whether hyperuricemia
is considered or not an independent risk factor for renal impairment, cardiovascular risk,
or metabolic syndrome, we know that its formation pathway and also its intracellular
reactions contribute to oxidative stress, which is considered as a potential CKD progression
factor. Therefore, important questions need to be clarified as to whether hyperuricemia or
oxidative stress are responsible for kidney damage in order to initiate the proper treatment,
to determine the optimal maintenance of serum UA level, and improvement of patients’
outcome and quality of life.

Author Contributions: Conceptualization, M.-E.G., I.P., A.N. and I.A.C.; methodology, M.-E.G., I.P.,
M.T., T.P.N., A.N. and I.A.C.; validation, I.P., A.N. and I.A.C..; resources, M.-E.G., I.P., M.T. and
T.P.N.; data curation, A.N. and I.A.C. writing—original draft preparation, M.-E.G., I.P. and A.N.;
writing—review and editing M.-E.G., I.P., M.T., T.P.N., A.N. and I.A.C.; visualization, M.-E.G., I.P.,
M.T., T.P.N., A.N. and I.A.C.; supervision, I.A.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Mol. Sci. 2022, 23, 3188 12 of 16

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