Editorial

Serum Uric Acid and Risk of Kidney Stones

incident kidney stones were identified by ultrasono-
Related Article, p. 173
graphic examination performed yearly. After
excluding participants with self-reported gout and

K
kidney stones and ultrasound-identified kidney stones
idney stones are a common condition, associated
at baseline and adjusting for several potential con-
with high direct and indirect costs.1,2 Gout is a
founders, the authors found that the risk for devel-
well-established risk factor for stone formation: a
oping a new stone increased across increasing
history of gout has been associated with a doubling in
categories of serum uric acid concentrations among
risk for forming kidney stones.3 Patients with gout
men, with the highest category showing 70% higher
often exhibit persistently low urine pH levels, which
risk. However, there was no association among
in turn would increase the concentration of undisso-
women.
ciated uric acid relative to the more soluble urate
This study has a number of strengths, including the
anion because uric acid is a weak acid with a pKa1 of
large sample size and use of repeated ultrasono-
5.3. When the undissociated uric acid concentration
graphic assessments rather than self-reported incident
increases above the threshold of 200 mg/L at a pH of
kidney stones. However, there are also some aspects
5.3, uric acid crystals will start to form and eventually
of the study that need to be taken into account when
grow into stones. It is thus not surprising that uric acid
interpreting the findings. In general, the association
stones tend to be more frequent among patients with
reported in men is not unexpected because it is the
gout. In a matched study, pure uric acid stones were
presence of hyperuricemia (referred to in the past
found in 50% of patients with gout and 20% of those
as “gouty diathesis”) and not having had an actual
without gout.4 The reason for the persistently acidic
gout attack that is associated with abnormal renal
urine in patients with gout is thought to be a defect in
acidification mechanisms and hence with risk for
the renal production of ammonia,5 which also implies
forming a stone. In this light, both gout and kidney
a higher proportion of protonation of titratable acids,
stones could be seen as products of the deranged
including urate, with a subsequent increase in undis-
acidification mechanisms in people with hyperurice-
sociated uric acid concentrations. Although the
mia. The lack of an association in women is not
amount of urine uric acid excretion tends to be within
readily explained.
the reference range or even occasionally low among
Although the authors excluded participants with
patients with gout (serum uric acid concentration is
self-reported gout at baseline, they do not report on
high due to reduced fractional excretion of uric acid
how many participants developed gout during follow-
and not necessarily due to excessive uric acid pro-
up and how they were handled in the analysis. Given
duction), a subgroup of patients may present with
that hyperuricemia is a strong risk factor for gout,7 it
high uric acid concentrations in urine, which would
is possible that participants with high serum uric acid
further increase the risk for forming uric acid stones in
concentrations at baseline might have developed gout
an acidic urine environment. As opposed to low urine
during follow-up before forming a stone, hence the
pH, the role of isolated hyperuricemia in the devel-
definition of “isolated hyperuricemia” as the exposure
opment of kidney stones is less clear. Given the fre-
of interest might no longer apply.
quency of hyperuricemia, as well as lifestyle, dietary,
The incidence rate for kidney stones of 1.6/100
and pharmacologic approaches to reduce serum uric
person-years is almost 10-fold higher compared with
acid concentrations, this question is clinically
previous studies.8 The expected prevalence of par-
important.
ticipants with stones at baseline given such a high
In this issue of AJKD, Ryu et al6 analyze the as-
incidence rate should have been much higher than that
sociation between serum uric acid levels and risk for
reported in the article (w4%). Unfortunately, the
incident kidney stones using data from a cohort of
authors did not report a sensitivity analysis only
Korean adults undergoing a health examination dur-
looking at symptomatic stones in order to reduce the
ing the period from 2002 to 2014. In this study,
risk for misclassifying pre-existing stones too small to
be detected by ultrasound as new events. A potential
Address correspondence to Gary C. Curhan, MD, ScD, explanation for the finding is that performance of the
Channing Division of Network Medicine/Renal Division, Brigham ultrasonographic examination changed over time.
and Women’s Hospital, 181 Longwood Ave, Boston, MA 02115. As the authors acknowledge, another important
E-mail: gary.curhan@channing.harvard.edu
Ó 2017 by the National Kidney Foundation, Inc. limitation of the study is the lack of information for
0272-6386 dietary intakes. Gout and kidney stones are known to
http://dx.doi.org/10.1053/j.ajkd.2017.05.004 share dietary risk factors; thus, the analysis would

158 Am J Kidney Dis. 2017;70(2):158-159

Editorial
have been strengthened if they could have considered,
among other factors, the potential role of sugar-
sweetened beverages9,10 or dairy protein.11,12 It is
possible that results might have been affected by re-
sidual confounding due to diet.
Another potential source of residual confounding is
body mass index (BMI), a factor strongly related to
both serum uric acid concentration and kidney
stones.13 Although the authors controlled for BMI
using categories, the potential influence of BMI could
have been minimized if they had instead controlled
for BMI as a continuous variable.
Given the strong influence of urine composition,
24-hour urine composition data, particularly urine pH,
would have been useful in interpreting the findings.
The authors report on the association between
serum uric acid concentration and incident stones
separately for men and women, without clarifying
whether the analysis stratified by sex was preplanned
or performed post hoc. In addition, there was no
report of a formal test for effect modification (eg,
interaction between serum uric acid concentrations
and sex), and therefore it is difficult to say whether the
sex-specific reporting was statistically justified.
Further, the pathophysiologic basis for the observed
sex difference is not clear.
Finally, the authors cite a reference14 to support
their statement that “In patients with gout, uric acid
stones are associated with lower urinary pH, hyper-
uricemia, and normouricosuria or hypouricosuria
resulting from low fractional excretion of uric acid,
but they are not associated with 24-hour urinary uric
acid excretion.”6(p176) However, the cited study does
not support their statement because it did not have
stone composition data for all participants, and in
those with available information, most stones were
primarily calcium oxalate.
A randomized controlled trial by Ettinger et al15
found a reduction in calcium oxalate stone recur-
rence among patients with isolated hyperuricosuria
who were treated with allopurinol. Taken together
with the reported lack of association between urine
uric acid concentration and risk for stones,14 results
from the Ettinger et al study support the hypothesis
that the beneficial effect of allopurinol on reducing
risk for calcium oxalate stones might be unrelated to
its effects on lowering urine uric acid concentrations.
If this were the case, patients with gout (and poten-
tially those with hyperuricemia) would have an
additional benefit from treatment with allopurinol
beyond reducing serum uric acid concentrations,
namely reduced risk for stone formation.
In conclusion, further studies with rigorous
assessment of incident kidney stones and strict control
for residual confounding including dietary intakes are
warranted to determine whether there is an
Am J Kidney Dis. 2017;70(2):158-159
independent association between serum uric acid
concentrations and incident kidney stones. Until then,
treating hyperuricemia to reduce the risk for incident
stone formation is not justified.
Pietro Manuel Ferraro, MD, PhD 1
Gary C. Curhan, MD, ScD 2
1
Catholic University of the Sacred Heart
Rome, Italy
2
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Peer Review: Evaluated by an Associate Editor and Deputy
Editor Berns.
REFERENCES
1. Scales CD, Smith AC, Hanley JM, Saigal CS. Prevalence of
kidney stones in the United States. Eur Urol. 2012;62:160-165.
2. Pearle MS, Calhoun EA, Curhan GC. Urologic diseases in
America project: urolithiasis. J Urol. 2005;173:848-857.
3. 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):1022-1026.
4. Marchini GS, Sarkissian C, Tian D, Gebreselassie S,
Monga M. Gout, stone composition and urinary stone risk: a
matched case comparative study. J Urol. 2013;189(4):1334-1339.
5. Gutman AB, Yue TF. Urinary ammonium excretion in pri-
mary gout. J Clin Invest. 1965;44:1474-1481.
6. Kim S, Chang Y, Yun KE, et al. Development of neph-
rolithiasis in asymptomatic hyperuricemia: a cohort study. Am J
Kidney Dis. 2017;70(2):173-181.
7. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hy-
peruricemia. Risks and consequences in the Normative Aging
Study. Am J Med. 1987;82(3):421-426.
8. Tasian GE, Ross ME, Song L, et al. Annual incidence of
nephrolithiasis among children and adults in South Carolina from
1997 to 2012. Clin J Am Soc Nephrol. 2016;11(3):488-496.
9. Choi HK, Curhan G. Soft drinks, fructose consumption, and
the risk of gout in men: prospective cohort study. BMJ.
2008;336(7639):309-312.
10. Ferraro PM, Taylor EN, Gambaro G, Curhan GC. Soda and
other beverages and the risk of kidney stones. Clin J Am Soc
Nephrol. 2013;8:1389-1395.
11. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G.
Purine-rich foods, dairy and protein intake, and the risk of gout in
men. N Engl J Med. 2004;350(11):1093-1103.
12. Ferraro PM, Mandel EI, Curhan GC, Gambaro G,
Taylor EN. Dietary protein and potassium, diet-dependent net acid
load, and risk of incident kidney stones. J Am Soc Nephrol.
2016;11(10):1834-1844.
13. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight
gain, and the risk of kidney stones. JAMA. 2005;293(4):455-462.
14. Curhan GC, Taylor EN. 24-h uric acid excretion and the
risk of kidney stones. Kidney Int. 2008;73(4):489-496.
15. Ettinger B, Tang A, Citron JT, Livermore B, Williams T.
Randomized trial of allopurinol in the prevention of calcium ox-
alate calculi. N Engl J Med. 1986;315(22):1386-1389.
159