Curr Rheumatol Rep (2022) 24:132–138

https://doi.org/10.1007/s11926-022-01069-3

CRYSTAL ARTHRITIS (M PILLINGER, SECTION EDITOR)

Update on Uric Acid and the Kidney

Giana Kristy Ramos1,2 · David S. Goldfarb1,2

Accepted: 21 February 2022 / Published online: 14 April 2022

This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022

Abstract
Purpose of Review  In this review, we report on new findings regarding associations of uric acid with kidney health. We
discuss kidney stones, effects of uric acid in chronic kidney disease (CKD), and management of gout in CKD. Recent studies
on neuroprotective effects of raising uric acid provide interesting data regarding nephrolithiasis.
Recent Findings  Elevated urate levels have been implicated in the progression of chronic kidney disease (CKD), but the
results from PERL and CKD-FIX studies did not demonstrate that allopurinol slowed CKD progression. The SURE-PD3
sought to determine if increasing uric acid would slow the progression of Parkinson’s disease. Results ultimately did not
support this hypothesis, but high urinary uric acid levels caused uric acid stones, not calcium stones. Low urinary pH remains
the key to the formation of uric acid stones. Thiazolidinediones improve insulin resistance, which is associated with an
increase in urine pH.
Summary  The most recent research has not supported the hypothesis that lowering serum uric acid levels will slow the
progression of CKD or provide neuroprotection in Parkinson’s disease. It is still unclear as to why uric acid stone formers
have a high net acid excretion. The STOP-GOUT trial demonstrates that there was a lack of significant adverse events with
higher urate-lowering dosages of allopurinol and febuxostat, despite patients’ kidney function. This may push other studies
to administer higher dosages per ACR guidelines. Future studies could then demonstrate decreased progression of CKD.

Keywords  Allopurinol · Chronic kidney disease · Febuxostat · Kidney stones · Urolithiasis

Introduction that uric acid might confer benefits of being neuroprotective

The end product of metabolism by which nitrogen sources
are excreted is dependent on the animal species and can be
in the form of ammonia, urea, or uric acid. Purine mononu-
cleotides are broken down into hypoxanthine and guanine
bases. These are further broken down from xanthine to urea
via xanthine oxidase (also known as xanthine oxidoreductase
or xanthine dehydrogenase) [1]. For most mammals, urea is
the final end product to excrete their nitrogen, but humans
and certain primates still have relatively high uric acid lev-
els due to the loss of uricase [2]. It has been hypothesized
and hold antioxidant properties. In addition, high levels have
other implications for human clinical health. In this review,
we report on new findings regarding associations of uric acid
with kidney health. We will discuss kidney stones, effects
of uric acid in chronic kidney disease (CKD), and manage-
ment of gout in CKD. Recent studies on neuroprotective
effects of raising uric acid provide interesting data regarding
nephrolithiasis.
Potential Benefits of Uric Acid

Most clinicians’ experiences entail lowering serum uric acid

This article is part of the Topical Collection on Crystal Arthritis in order to prevent gout, hyperuricemia, and perhaps higher
uricosuria. However, the progressive loss of uricase over
* David S. Goldfarb many eons implies that its deletion confers an evolution-
david.goldfarb@nyulangone.org
ary advantage [3]. It has been hypothesized that if higher
1
Nephrology Division, NYU Langone Health, New York, NY, serum uric acid levels had an evolutionary advantage, uric
USA acid must hold benefits besides being the means of excreting
2
New York Harbor VA Healthcare System, New York, NY, nitrogen waste. Uric acid contributes more than 50% of the
USA

13
 Curr Rheumatol Rep (2022) 24:132–138
antioxidant capacity of blood. However, oxidative stress is
linked with aging and cancer, yet there is no evidence that
patients with high uric acid live longer [2]. It is also believed
that uric acid played a role in maintaining blood pressure
during times of low salt availability and ingestion, allowing
hominids to maintain a vertical position. Some studies have
demonstrated an association of hyperuricemia with hyper-
tension. However, a recent attempt to lower blood pressure
by urate-lowering therapy was not successful in a study in
which 82 adults, age 18–40 years (mean 28.0 ± 7.0 years,
62.6% men, 40.4% African American), were given 300 mg
of allopurinol for 1 month and then crossed-over to pla-
cebo [4]. Serum uric acid in the two groups before treat-
ment was 5.8 ± 1.0 mg/dl in the active treatment arm and
5.9 ± 1.3 mg/dl in the placebo arm; the mean ± SD serum
urate level decreased by 1.33 ± 1.21 mg/dl during the allopu-
rinol phase and did not change during the placebo period.
In the primary intent-to-treat analysis, systolic blood pres-
sure did not change during either the allopurinol or pla-
cebo treatment phases (mean ± SEM − 1.39 ± 1.16  mm
Hg; − 1.06 ± 1.08 mm Hg, respectively). The lack of change
in blood pressure was noted despite an increase in flow-
mediated dilation during the allopurinol treatment period.
This result contrasts with an earlier study which demon-
strated a blood pressure lowering effect of the drug in ado-
lescents, aged 11–17 years, with newly diagnosed hyper-
tension [5]. The mean change in systolic blood pressure
for allopurinol was − 6.9 mm Hg vs − 2.0 mm Hg for pla-
cebo, while the mean change in diastolic BP for allopurinol
was − 5.1 mm Hg vs − 2.4 for placebo. Twenty of the 30
participants achieved normal blood pressure while taking
allopurinol and only 1 participant while taking placebo
(p < 0.001). Although other subsequent studies have failed
to reproduce that oft-cited finding, improvement in BP was
also seen in a recent post hoc analysis of randomized con-
trolled trials of pegloticase (a recombinant uricase conju-
gated to polyethylene glycol) [6]. In chronic refractory gout
patients, participants who were given this medication every
2 weeks had a change (± SD) in mean arterial pressure from
the beginning to the end of the trial of − 10.2 (9.5) mm Hg.
With its antioxidant properties, it has also been hypoth-
esized that uric acid offers some neuroprotective benefit.
In a prospective study, investigators found that low serum
urate levels were associated with worsening motor function
in early Parkinson disease (PD) [7]. However, a recent ran-
domized trial did not support this possibility. The Effect of
Urate-Elevating Inosine on Early Parkinson Disease Pro-
gression (SURE-PD3) study was a randomized, double-
blind, placebo-controlled trial which aimed to determine
whether sustained urate-elevating treatment with urate pre-
cursor inosine slowed early PD progression [8]. Inosine dos-
ages were titrated to reach a targeted trough concentration of
uric acid of 7.1 to 8 mg/dl. Eighty-one percent of this group
133
achieved a measured trough serum urate of at least 7.1 mg/
dl (vs 4.7% in the placebo group). The study was termi-
nated early due to a lack of efficacy, as clinical progression
rates of PD were not significantly different between groups.
Although the study was negative from the point of view of
diminishing progression of Parkinson disease, it had some
interesting implications for kidney stone pathophysiology,
which we detail below.
Whether high uric acid levels also provided neuroprotec-
tive properties was also examined in patients with amyo-
trophic lateral sclerosis (ALS). The relationship of urate
levels with ALS progression in those who participated in
the EMPOWER study, a trial of pharmacologic therapy for
ALS, was determined [9]. Only a modest inverse relation-
ship between the two variables was noted: participants with
serum urate levels equal to or above the median (5.1 mg/
dl) had a survival advantage compared to those below (haz-
ard ratio adjusted for BMI: 0.67; 95% confidence interval:
0.47 to 0.95). However, more significant results were noted
in another observational study. Higher serum uric acid
levels were associated with a decrease risk of death in the
male, but not female, population. In males, serum urate lev-
els ≤ 292 μmol/l (4.9 mg/dl) were associated with a shorter
survival (HR: 1.936; 95% CI: 1.334–2.810) [10].
Uric Acid and Kidney Stones
The perfect storm for uric acid stone formation involves
low urinary pH, low urinary volume, and higher uricosuria.
However, the latter condition is not necessary for uric acid
stones. Obesity, type 2 diabetes, and metabolic syndrome
are associated with more acidic urine, which leads to crys-
tallization of uric acid. During times of hyperinsulinemia,
non-uric acid-stone forming participants, who demonstrate
greater insulin sensitivity by glucose disposal rates, have a
higher urine pH [11]. Uric acid stone formers on the other
hand, had insulin resistance, which was associated with
lower urinary pH. They also had higher titratable acid and
net acid excretion which contributed to their “unduly acid
urine.” It is now clear that insulin is capable of stimulat-
ing ammoniagenesis; insulin resistance, a characteristic of
metabolic syndrome, even short of diabetes, is associated
with impaired ammoniagenesis, resulting in acidic urine pH
[12]. The resulting question was whether improved insulin
sensitivity would cause a reversal of the effect and lead to a
higher urine pH. In a recent study, 36 patients with a history
of uric acid stones were given pioglitazone 30 mg/day or
placebo (10 patients in the pioglitazone group and 5 patients
in the placebo group were previously diagnosed with type
2 diabetes) [13]. Those in the pioglitazone group signifi-
cantly increased their urine pH (5.37 to 5.59, p = 0.007) and
the fraction of net acid excretion carried by ammonium. In
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134
addition, titratable acid and net acid excretion were also
decreased. These results confirmed that insulin resistance is
an important cause of the reduced urinary pH nearly always
seen in uric acid stone formers [14].
Still unclear however is why uric acid stone formers
demonstrate greater net acid excretion, even when diet is
carefully controlled, compared to non-uric acid stone form-
ers. A recent comprehensive study made several important,
and not entirely understood, observations [15]. First, body
mass index (BMI) was only weakly correlated with urine
pH, net acid excretion, and N ­ H4+/net acid excretion among
uric acid stone formers, suggesting that factors other than
obesity contribute to uric acid stones, particularly in patients
who have lower BMI. In addition, a metabolomic analysis of
urine attempted to determine the organic anions responsible
for the increased net acid excretion in the uric acid stone
formers. Those anions identified only accounted quantita-
tively for a small portion of the excess titratable acid, leav-
ing unresolved the identities and sources of the excess acid.
One hypothesis suggested by these data is that the intestinal
microbiome has a potential effect on the net acid load pre-
sented to the kidneys.
Observational studies have found an association between
hyperuricemia and uric acid stones. For example, elevated
serum uric acid levels were associated with increased
risk for nephrolithiasis in a dose–response manner (p for
trend < 0.001) in men, not women [16]. In men, multivar-
iable-adjusted HRs for incident kidney stones, comparing
uric acid levels of 6.0 to 6.9, 7.0 to 7.9, 8.0 to 8.9, 9.0 to 9.9,
and ≥ 10.0 mg/dl with uric acid levels less than 6.0 mg/dl,
were 1.06 (95% CI, 1.02–1.11), 1.11 (95% CI, 1.05–1.16),
1.21 (95% CI, 1.13–1.29), 1.31 (95% CI, 1.17–1.46), and
1.72 (95% CI, 1.44–2.06), respectively. Utilizing Mende-
lian randomization, however, investigators can reduce effects
of confounding variables. In a recent analysis of the UK
Biobank, which excluded patients with gout or prior stones,
no causal effect of high serum urate levels on the incidence
of urolithiasis was found in unadjusted (OR 0.93, 95% CI
0.81–1.08) or adjusted (OR 0.94, 95% CI 0.80–1.09) models
[17]. Again the more consistent key to uric acid stone forma-
tion is low urine pH. While hyperuricemia may not be a risk
factor for stones, gout does increase the risk, probably for
both calcium stones and uric acid stones [18, 19]. Patients
with gout are often overweight and have lower urine pH,
leading to a risk for uric acid stones. But overweight is also
a risk for calcium stones, with less clear pathophysiology.
Such shared risk factors may account for a risk for both cal-
cium and uric acid stones in patients with gout.
Higher uricosuria has also been thought to increase the
risk of calcium stones. This effect was seen in several obser-
vational studies. However, it is worth noting that rather than
over-production of uric acid and high uric acid excretion,
the more frequent cause of hyperuricemia is reduced renal
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Curr Rheumatol Rep (2022) 24:132–138
fractional excretion of uric acid [20]. Through the phenom-
enon of “salting out,” uric acid reduces the solubility of
calcium oxalate [21]. This potential pathophysiology was
given credence by a randomized controlled trial: calcium
stone formers, with a history of higher uricosuria and nor-
mal urinary calcium excretion, were randomly assigned to
allopurinol or placebo. After 2 years, participants in the
allopurinol group had 82% fewer calculi [22]. However,
this hypothesized relationship was not confirmed by pro-
spective, observational studies of stone formation: higher
uric acid excretion was not associated with greater incidence
of stones [23]. That finding may suggest that a benefit of
allopurinol in preventing uric acid stones could be the result
of some mechanism other than reduction of urinary uric
acid excretion [24]. Interestingly, in the SURE-PD3 trial, in
which patients with Parkinson disease who received inosine
supplementation in order to increase serum uric acid, 21
patients developed nephrolithiasis. Only 5 had stone com-
position determined: they were found to have uric acid, not
calcium, stones [8].
The treatment of uric acid stones involves increasing fluid
intake and alkalinization of the urine. Increasing one’s fluid
intake may reduce uric acid supersaturation. Uric acid lev-
els are affected by diet and a diet low in animal protein and
high in fruits and vegetables can help alkalinize the urine.
In a study of diet effects, young healthy women were given
either a more acidic diet (high in animal protein and low in
fruits and vegetables) or a more alkaline diet (less protein
and high fruits and vegetables) [25]. As expected, those on
the acid diet had urine pH of 5.92 ± 0.28 and those on the
alkaline diet had a urine pH of 6.51 ± 0.34. When urine pH
increased, despite lower dietary purine intake, uric acid
excretion increased significantly. More often, patients are
more willing to take medications such as potassium citrate
and bicarbonate to achieve a urine pH greater than 6, rather
than modifying diet [26].
The American College of Rheumatology recommends
starting urate-lowering therapy (ULT) in patients with CKD
stage 3 or more, serum uric acid level of greater than 9 mg/
dl, or with urolithiasis [27]. As noted above, there is little
consistent research that suggests hyperuricemia leads to uric
acid stones and a low urinary pH is key. Therefore, alkalin-
izing the urine would be a preferable treatment.
However, in a recent, non-randomized, retrospective
study, febuxostat significantly decreased serum uric acid
compared to allopurinol, promoted dissolution of radio-
lucent nephrolithiasis, and reduced the total stone num-
ber [28]. Ninety-six patients with radiolucent stones on a
plain radiograph, and hyperuricemia of at least 8.0 mg/dl,
were given allopurinol 300 mg/day, febuxostat 40 mg/day,
or febuxostat 80 mg/day in addition to potassium citrate.
The baseline median (range) serum uric acids were 9.7
(8.1–13.6), 9.8 (8.1–13.8), and 9.9 (8.1–14.2), respectively.
 Curr Rheumatol Rep (2022) 24:132–138
At the end of 6 months, 83.3% of the febuxostat 80 mg
group, 58.1% of the allopurinol 300 mg group, and 58.6%
of the febuxostat 40 mg group had a serum uric acid less
than 6.0 mg/dl. Successful treatment was considered as a
50% or greater decrease in stone diameter or reduction in
the number of stones with diameter more than 5 mm. These
favorable outcomes occurred in 80% of the febuxostat 80 mg
group versus 58.1% of the allopurinol group and 65.5% of
the febuxostat 40 mg group. The basis for the difference is
not clear, since the superiority of febuxostat to allopurinol
is not established. The authors stated that urine pH was the
same in the groups, suggesting that differences in ULT and
not the dose of potassium citrate was responsible. As is true
in other studies, allopurinol may be as effective if its dose
is titrated upwards.
Hyperuricemia and CKD
An association between hyperuricemia and CKD has been
consistently observed, but which comes first: the chicken or
the egg, remains up for debate [29]. Various mechanisms
for the strong suggestion that uric acid is associated with
adverse kidney outcomes have been proposed [30]. Most
often, the effect was attributed to crystallopathy, the pre-
cipitation of uric acid in the kidney interstitium. Other
underlying pathophysiologic effects may involve the small
population of immune cells residing in the kidney. When the
kidney is injured, an inflammatory response occurs which
involves these cells and endothelial, mesangial, and tubular
epithelial cells leading to the recruitment of more circulating
immune cells. Uric acid can induce the expression or release
of inflammatory cytokines and chemokines and stimulate
fibrosis. In micropuncture studies, kidneys in a hyperurice-
mic environment were found to have increased resistance
of both afferent and efferent arterioles [31]. This observa-
tion was attributed to decreased cellular proliferation and
reduced nitric oxide release.
A meta-analysis including 17 studies found that the
prevalence of CKD stage 3 or worse and nephrolithiasis, in
patients with gout, were 24% and 14%, respectively [32].
Although CKD can result in decreased uric acid excretion
(and hence hyperuricemia), those with gout eventually
develop impaired kidney function, though again, the direc-
tion of this causality is debated [29]. A recent study sought
to determine if there were any renal ultrasound findings seen
in Vietnamese patients with untreated gout [33]. A diffuse
hyperechoic renal medulla was seen in 26% of 502 partic-
ipants. This was not seen in the non-gout control group.
The experimental group tended to have tophaceous gout,
received very little treatment with urate-lowering drugs, and
had renal function and non-specific urinary features con-
sistent with tubulointerstitial nephritis. Participants did not
135
have kidney biopsies performed to confirm these imaging
findings. Although autopsy studies have found urate crystals
deposited in the tubules and interstitium, finding uric acid
deposition in kidney biopsies is quite limited because they
disintegrate during processing.
Given that background, it was plausible that allopurinol
did slow CKD progression in a smaller study [34]. One
hundred and thirteen patients with eGFR < 60 ml/min were
treated with allopurinol 100 mg/day or continued on their
usual therapy. The mean uric acid level was 7.3 ± 1.6 mg/dl
in the control group and 7.9 ± 2.1 mg/dl in the allopurinol
group. In the control group, eGFR decreased 3.3 ± 1.2 ml/
min/1.73 ­m2, and in allopurinol group, eGFR increased
1.3 ± 1.3 ml/min/1.73 ­m2 after 24 months (p = 0.018). In
addition, allopurinol treatment, which lowered serum uric
acid to 6.0 ± 1.2 mg/dl, reduced the risk of cardiovascular
events by about 50% compared with standard therapy.
Those very positive results of the effect of uric acid on
glomerular filtration rate (GFR) and progression of CKD
have not been confirmed recently in two larger studies
of ULT. The Serum Urate Lowering with Allopurinol
and Kidney Function in Type 1 Diabetes study (PERL)
investigated if allopurinol would slow the progression
of CKD in type 1 diabetics [35]. Two hundred and sixty-
seven patients with type 1 diabetes received allopurinol
with dose-adjustment based on estimated GFR. The mean
decrease in the iohexol-based GFR was − 3.0 ml/min/1.73
­m 2 /year with allopurinol and − 2.5  ml/min/1.73 ­m 2 /
year with placebo (between-group difference, − 0.6 ml/
min/1.73 ­m 2/year; 95% CI, − 1.5 to 0.4). The reduction
in urate level did not alter the progression of CKD. Per-
haps the reason that there was no difference seen was
due to the fact patients did not receive a high enough
dose of allopurinol, with sufficient lowering of serum
urate levels.
A second study, the Controlled Trial of Slowing of Kid-
ney Disease Progression from the Inhibition of Xanthine
Oxidase (CKD-FIX), also failed to show a benefit of ULT
on CKD [36]. The study was a randomized, controlled trial
of adults with stage 3 or 4 CKD and no history of gout who
had a urinary albumin:creatinine ratio of at least 265 mg/g
creatinine, or an eGFR decrease of at least 3.0 ml/min/1.73
­m2 in the previous year. They received either allopurinol
(100 to 300 mg daily) or placebo. The primary outcome
was the change in eGFR from randomization to week 104.
Among 363 patients (mean eGFR, 31.7 ml/min/1.73 ­m2;
median urine albumin:creatinine ratio, 716.9 mg/g; mean
serum urate level, 8.2 mg/dl), the change in eGFR did
not differ between the allopurinol group and the placebo
group. The two studies are summarized in Table 1.
Limitations of PERL and CKD-FIX studies include
high drop-out rates, exclusion of patients with gout,
and the inclusion of patients who did not have marked
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136 Curr Rheumatol Rep (2022) 24:132–138

Table 1  Summary of PERL and CKD-FIX studies

Study information PERL CKD-FIX

Population • Type 1 diabetes for more than 8 years • CKD stage 3 or 4 (eGFR 15 to 59 ml/min/1.73 ­m2)
• 18–70 years of age • UACR 265 mg/g
• Estimated GFR 40–99 ml/min/1.73 ­m2 BSA
• Evidence of diabetic kidney disease:
• UACR 20–3333 µg/min or
• Treatment with RAS blockers
• Serum urate level of 4.5 mg/dl (268 µmol/l)
Intervention • Oral placebo or • Oral placebo or
• Allopurinol: minimum of 100 mg/day for • Allopurinol: minimum of 100 mg/day
4 weeks and increased to: - Increased every 4 weeks to a maximum of 3 tablets daily
- 400 mg /day if eGFR was ≥ 50 ml/min/1.73
­m2
- 300 mg/day if eGFR was 25–49 ml/min/1.73
­m2
- 200 mg day if eGFR was 15–24 ml/min/1.73
­m2
Mean baseline urate level 6.1 mg/dl (360 µmol/l) 8.2 ± 1.8 mg/dl (490 ± 110 µmol/l)
Serum urate level post-allopurinol 3.7 mg/dl (220 µmol/l) 5.1 mg/dl (300 µmol/l)
Change in GFR • Placebo*: − 2.5 ml/min/1.73 ­m2/year • Placebo¥: − 3.23 ml/min/1.73 ­m2/year
• Allopurinol*: − 3.0 ml/min/1.73 ­m2/year • Allopurinol¥: − 3.33 ml/min/1.73 ­m2/year

*Iohexol-based GFR
¥Estimated GFR

hyperuricemia. Many unanswered questions have been Management of Gout with CKD

raised, so that perhaps the possibility that uric acid has
an adverse effect may still be worth studying in other
patient sub-groups [29]. Can these studies be extrapo-
lated to non-diabetics and patients with gout? The studies
did not include patients with gout, or tophi. Serum uric
acid levels were not as high as in the earlier Goicoechea
study in which allopurinol did have a bigger effect on CKD
progression. There may be additional groups of patients
with more marked hyperuricemia, with greater uric acid
production, or with normal kidney function who would be
appropriate subjects in further studies of urate-lowering on
kidney function. For example, a systematic review study
found that febuxostat provided a significant improvement
in renal function in CKD patients with hyperuricemia
compared to other ULT (mean difference [95% CI]: 0.85
[0.02; 1.67], p = 0.045) [37].
Though not reissued since 2013, it does not appear
that guideline 3.1.20 of the Kidney Disease: Improving
Global Outcomes (KDIGO) guidelines on CKD needs to
be revised: “There is insufficient evidence to support or
refute the use of agents to lower serum uric acid concen-
trations in people with CKD and either symptomatic or
asymptomatic hyperuricemia in order to delay progression
of CKD” [38]. The ACR guideline, cited above, recom-
mending ULT for patients with CKD stage 3 or more and
serum uric acid level of greater than 9 mg/dl, may need
revision [27].
It is well known that the management of gout in patients
with CKD is troubling to practitioners with a relative lack
of adequate trials to guide evidence-based practice. At least
25% of American gout patients have CKD stage 3b or 4,
with at least 20% not at serum uric acid levels less than
6.5 mg/dl [39]. The topic is reviewed thoroughly in a recent
consensus statement issued by the Gout, Hyperuricemia and
Crystal-Associated Disease Network (G-CAN) [40]. Clinical
trials have often excluded participants with CKD. Dosing
of colchicine, allopurinol, and febuxostat all are associ-
ated with questions relating to adjustment based on eGFR.
Allopurinol’s dose-dependent risk of hypersensitivity, and
dependence on kidney function for excretion, are thought
to be the reasons that many practitioners do not increase its
doses to target reduced serum uric acid levels. Prescription
of febuxostat, which is largely metabolized by the liver and
not excreted by the kidney, is used infrequently because of
the black-box warning attending to its use because of the
increased cardiovascular endpoints seen in the CARES trial;
such risks might be particularly relevant in the CKD popula-
tion, already suffering from a greater number of cardiovas-
cular events [41]. Repeated use of pegloticase may require
chronic use of immunosuppressives [42].
A recent Department of Veterans Affairs Cooperative
Study Program trial (STOP-GOUT) addresses many of
these issues [39, 43]. The trial examined whether allopuri-
nol was non-inferior to febuxostat in the treatment of gout.

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 Curr Rheumatol Rep (2022) 24:132–138
Importantly, a portion of its participants had CKD stage
3. Dosages were adjusted as per the American College of
Rheumatology guidelines. Allopurinol could be maximally
titrated to 800 mg and febuxostat to 120 mg (reduced to
80 mg in 2019 per FDA’s request). Ultimately they found
that allopurinol was non-inferior to febuxostat: 78.4% of
febuxostat-treated patients and 81.1% of allopurinol-treated
patients achieved serum urate levels less than 6.0 mg/dl.
Both groups had mean serum urate values of 5.2 mg/dl. Par-
ticipants with CKD were also successful in achieving target
serum urate, 80.0%, with both drugs. The median doses of
drugs used to achieve the target goal were 400 mg of allopu-
rinol and 40 mg for febuxostat. There were no significant
differences in serious adverse events or major cardiovascular
events in those with or without CKD, with one exception.
Among participants with CKD, there were more serious
adverse events for superimposed acute kidney injury in the
allopurinol group than the febuxostat group; none was felt
to be related to study drug by site investigators.
The STOP-GOUT trial result, particularly for the par-
ticipants with CKD, is likely to influence further trials and
future therapy of gout. Its lack of significant adverse events
with higher urate-lowering dosages, and despite patients’
kidney function, may push other studies to administer
higher, and appropriate, dosages per ACR guidelines. Per-
haps CKD progression in some patients could be slowed
with higher allopurinol dosing than used thus far. In addition
to decreasing gout flares, ULT may improve vascular and
cardiovascular disease. Besides urate crystals depositing in
the kidneys, one study found they can also be found in blood
vessels and the spine [44]. As in the kidneys, these crystals
can act as a nidus for calcification leading to vascular calci-
fication. However, based on the negative trials cited above,
it is also possible that uric acid plays only a minor role in the
progression of CKD with genotypes, diabetes, and microvas-
cular disease being more significant variables.
Conclusion
Despite earlier reports that high serum uric acid led to
high blood pressure or was neuroprotective in PD patients,
recent trials have not confirmed these effects. Higher uri-
nary uric acid excretion rates may be associated with kid-
ney stones, and both calcium and uric acid stones appear
more frequently in patients with gout and diabetes. Impaired
ammoniagenesis, attributed to insulin resistance, appears
to be responsible for the lower urine pH that is most often
the cause of uric acid stones. Urinary alkalinization, rather
than urate-lowering therapy, remains the major therapeutic
intervention required for treatment and prevention of uric
acid stones. While uric acid nephropathy remains a pos-
sible cause of CKD, trials of urate-lowering therapy have
137
thus far failed to show benefits for delaying progression of
CKD. However, additional studies that would include patient
groups not represented in the major trials recently published
will still be of interest.
Declarations 
Conflict of Interest  Ramos: none; Goldfarb: owner: Moonstone Inc;
consultant: Allena, Alnylam, AstraZeneca, Cymabay, Dicerna, Syn-
logic; research: Travere.
Human and Animal Rights and Informed Consent  This article does not
contain any studies with human or animal subjects performed by any
of the authors.
References
1. Mehta TH, Goldfarb DS. Uric acid stones and hyperuricosuria.
Adv Chronic Kidney Dis. 2012;19(6):413–8.
2. Alvarez-Lario B, Macarron-Vicente J. Uric acid and evolution.
Rheumatology (Oxford). 2010;49(11):2010–5.
3. Moe OW. Uric acid nephrolithiasis: proton titration of an essential
molecule? Curr Opin Nephrol Hypertens. 2006;15(4):366–73.
4. Gaffo AL, Calhoun DA, Rahn EJ, Oparil S, Li P, Dudenbostel T,
et al. Effect of serum urate lowering with allopurinol on blood
pressure in young adults: a randomized, controlled, crossover trial.
Arthritis Rheumatol. 2021;73(8):1514–22.
5. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood
pressure of adolescents with newly diagnosed essential hyperten-
sion: a randomized trial. JAMA. 2008;300(8):924–32.
6. Johnson RJ, Choi HK, Yeo AE, Lipsky PE. Pegloticase treatment
significantly decreases blood pressure in patients with chronic
gout. Hypertension. 2019;74(1):95–101.
7. Sleeman I, Lawson RA, Yarnall AJ, Duncan GW, Johnston F,
Khoo TK, et al. Urate and homocysteine: predicting motor and
cognitive changes in newly diagnosed Parkinson’s disease. J Par-
kinsons Dis. 2019;9(2):351–9.
8. Parkinson Study Group S-PDI, Schwarzschild MA, Ascherio A,
Casaceli C, Curhan GC, Fitzgerald R, et al. Effect of urate-ele-
vating inosine on early Parkinson disease progression: the SURE-
PD3 randomized clinical trial. JAMA. 2021;326(10):926–39.
9. O’Reilly EJ, Liu D, Johns DR, Cudkowicz ME, Paganoni S,
Schwarzschild MA, et al. Serum urate at trial entry and ALS pro-
gression in EMPOWER. Amyotroph Lateral Scler Frontotemporal
Degener. 2017;18(1–2):120–5.
10. Xu LQ, Hu W, Guo QF, Xu GR, Wang N, Zhang QJ. Serum uric
acid levels predict mortality risk in male amyotrophic lateral scle-
rosis patients. Front Neurol. 2021;12:602663.
11. Abate N, Chandalia M, Cabo-Chan AV Jr, Moe OW, Sakhaee
K. The metabolic syndrome and uric acid nephrolithiasis: novel
features of renal manifestation of insulin resistance. Kidney Int.
2004;65(2):386–92.
12. Maalouf NM, Cameron MA, Moe OW, Sakhaee K. Metabolic
basis for low urine pH in type 2 diabetes. Clin J Am Soc Nephrol.
2010;5(7):1277–81.
13. Maalouf NM, Poindexter JR, Adams-Huet B, Moe OW, Sakhaee
K. Increased production and reduced urinary buffering of acid in
uric acid stone formers is ameliorated by pioglitazone. Kidney Int.
2019;95(5):1262–8.
13
138
14. Asplin JR, Goldfarb DS. Effect of thiazolidinedione therapy on
the risk of uric acid stones. Kidney Int. 2019;95(5):1022–4.
15. Bobulescu IA, Park SK, Xu LHR, Blanco F, Poindexter J, Adams-
Huet B, et al. Net acid excretion and urinary organic anions in
idiopathic uric acid nephrolithiasis. Clin J Am Soc Nephrol.
2019;14(3):411–20.
16. Kim S, Chang Y, Yun KE, Jung HS, Lee SJ, Shin H, et al. Devel-
opment of nephrolithiasis in asymptomatic hyperuricemia: a
cohort study. Am J Kidney Dis. 2017;70(2):173–81.
17. Narang RK, Gamble GG, Topless R, Cadzow M, Stamp LK, Mer-
riman TR, et al. Assessing the relationship between serum urate
and urolithiasis using Mendelian randomization: an analysis of
the UK Biobank. Am J Kidney Dis. 2021;78(2):210–8.
18. Kramer HJ, Choi HK, Atkinson K, Stampfer M, Curhan GC. The
association between gout and nephrolithiasis in men: the health
professionals’ follow-up study. Kidney Int. 2003;64(3):1022–6.
19. Daudon M, Traxer O, Conort P, Lacour B, Jungers P. Type 2 dia-
betes increases the risk for uric acid stones. J Am Soc Nephrol.
2006;17(7):2026–33.
20. Goldfarb DS, MacDonald PA, Hunt B, Gunawardhana L. Febux-
ostat in gout: serum urate response in uric acid overproducers and
underexcretors. J Rheumatol. 2011;38(7):1385–9.
21. Grover PK, Marshall VR, Ryall RL. Dissolved urate salts out cal-
cium oxalate in undiluted human urine in vitro: implications for
calcium oxalate stone genesis. Chem Biol. 2003;10(3):271–8.
22. Ettinger B, Tang A, Citron JT, Livermore B, Williams T. Rand-
omized trial of allopurinol in the prevention of calcium oxalate
calculi. N Engl J Med. 1986;315(22):1386–9.
23. Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of
kidney stones. Kidney Int. 2008;73(4):489–96.
24. Ferraro PM, Curhan GC. Serum uric acid and risk of kidney
stones. Am J Kidney Dis. 2017;70(2):158–9.
25. Kanbara A, Hakoda M, Seyama I. Urine alkalization facilitates
uric acid excretion. Nutr J. 2010;9:45.
26. Kenny JE, Goldfarb DS. Update on the pathophysiology and
management of uric acid renal stones. Curr Rheumatol Rep.
2010;12(2):125–9.
27. FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R,
Guyatt G, et al. American College of Rheumatology Guideline
for the Management of Gout. Arthritis Care Res (Hoboken).
2020;72(6):744–60.
28. Yunhua M, Hao Z, Ke L, Wentao H, Xiaokang L, Jie S. Febuxostat
promoted dissolution of radiolucent nephrolithiasis in patients
with hyperuricemia. Urol J. 2020;18(1):34–9.
29. Goldberg A, Garcia-Arroyo F, Sasai F, Rodriguez-Iturbe B,
Sanchez-Lozada LG, Lanaspa MA, et  al. Mini review: reap-
praisal of uric acid in chronic kidney disease. Am J Nephrol.
2021;52(10–11):837–44.
30. Su HY, Yang C, Liang D, Liu HF. Research advances in the mech-
anisms of hyperuricemia-induced renal injury. Biomed Res Int.
2020;2020:5817348.
31. Jung SW, Kim SM, Kim YG, Lee SH, Moon JY. Uric acid and
inflammation in kidney disease. Am J Physiol Renal Physiol.
2020;318(6):F1327–40.
32. Roughley MJ, Belcher J, Mallen CD, Roddy E. Gout and risk
of chronic kidney disease and nephrolithiasis: meta-analysis of
observational studies. Arthritis Res Ther. 2015;17:90.
13
Curr Rheumatol Rep (2022) 24:132–138
33. Bardin T, Nguyen QD, Tran KM, Le NH, Do MD, Richette P,
et al. A cross-sectional study of 502 patients found a diffuse hyper-
echoic kidney medulla pattern in patients with severe gout. Kidney
Int. 2021;99(1):218–26.
34. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampu-
ero J, Rincon A, et al. Effect of allopurinol in chronic kidney dis-
ease progression and cardiovascular risk. Clin J Am Soc Nephrol.
2010;5(8):1388–93.
35. Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay
I, et al. Serum urate lowering with allopurinol and kidney function
in type 1 diabetes. N Engl J Med. 2020;382(26):2493–503.
36. Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A,
et al. Effects of allopurinol on the progression of chronic kidney
disease. N Engl J Med. 2020;382(26):2504–13.
37. Tsukamoto S, Okami N, Yamada T, Azushima K, Yamaji T,
Kinguchi S, et al. Prevention of kidney function decline using
uric acid-lowering therapy in chronic kidney disease patients: a
systematic review and network meta-analysis. Clin Rheumatol.
2021;41(3):911–9.
38. Kidney Disease: Improving Global Outcomes (KDIGO) CKD
Work Group. KDIGO clinical practice guideline for the evalua-
tion and management of chronic kidney disease. Kidney Int Suppl.
2013;(3):1–150.
39. Timilsina S, Brittan K, O’Dell JR, Brophy M, Davis-Karim A,
Henrie AM, et al. Design and rationale for the Veterans Affairs
“Cooperative Study Program 594 Comparative Effectiveness in
Gout: Allopurinol vs. Febuxostat” trial. Contemp Clin Trials.
2018;68:102–8.
40. Stamp LK, Farquhar H, Pisaniello HL, Vargas-Santos AB, Fisher
M, Mount DB, et al. Management of gout in chronic kidney dis-
ease: a G-CAN consensus statement on the research priorities. Nat
Rev Rheumatol. 2021;17(10):633–41.
41. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whel-
ton A, et al. Cardiovascular safety of febuxostat or allopurinol in
patients with gout. N Engl J Med. 2018;378(13):1200–10.
42. Keenan RT, Botson JK, Masri KR, Padnick-Silver L, LaMoreaux
B, Albert JA, et al. The effect of immunomodulators on the effi-
cacy and tolerability of pegloticase: a systematic review. Semin
Arthritis Rheum. 2021;51(2):347–52.
43. O’Dell JR, Brophy MT, Pillinger MH, Neogi T, Palevsky PM, Wu
H, et al. Comparative effectiveness of allopurinol and febuxostat
in gout management. NEJM Evid 2022;1(3). https://​doi.​org/​10.​
1056/​EVIDo​a2100​028
44. Khanna P, Johnson RJ, Marder B, LaMoreaux B, Kumar A. Sys-
temic urate deposition: an unrecognized complication of gout? J
Clin Med. 2020;9(10):3204.
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