ratio 3.12; 95% CI 2.29–4.25) among 21,457 healthy
volunteers from the Vienna Health Screening Project
followed for a period of seven years. 28 The strength
of the relationship between uric acid and risk of
CKD has been demonstrated in healthy subjects,
both men and women, patients with and without
diabetes, and in kidney transplant recipients. The
results of these individual observational studies
have been pooled together in recent meta-analysis.
Sedaghat and colleagues systematically reviewed
and analysed data from 11 prospective cohort
studies. The pooled relative risk for incident CKD,
defined as occurrence of GFR <60ml/min was 1.18,
95% CI 1.15–1.22) for every 1µmol/l increase in uric
acid. 29 Some patients might be exposed to persistent
hyperuricaemia over time while others may have a
very time limited exposure. The uric acid trajectory
that an individual is exposed to may determine their
future risk of events. Tsai and colleagues analysed
data from over 5000 CKD patients who were
followed for a median of 31 months. CKD patients
with the highest trajectories of uric acid experienced
the greatest risk of kidney failure. Compared with
patients in the low uric acid trajectory (average
uric acid 5.6mg/dl), those in the highest trajectory
(average uric acid 9.8mg/dl) had a 2.8-fold higher
risk of progression to dialysis. 30 Collectively, this
body of evidence links elevations in uric acid to the
development of CKD and provides credible evidence
that individuals with the highest levels incur the
greatest risk.
proteinuria and worsening glomerulosclerosis and
tubulointerstitial disease.
The causal association between hyperuricaemia
and de novo kidney disease was further established
when these animals were treated with urate
lowering drugs, either allopurinol or febuxostat. 24–26
In these series of experiments, treatment with
either allopurinol or febuxostat resulted in a
lowering of uric acid, normalisation of systemic
blood pressure and a reduction in the severity
of the kidney damage. These series of biological
experiments prove a strong independent association
between hyperuricaemia and the development of
hypertension and kidney disease, which can be
mitigated or prevented by treatment with ULT.
Epidemiological evidence
The link between hyperuricaemia and gout and
kidney disease has been carefully explored through
several large epidemiological studies. Cross-sectional
studies conducted in the general population have
identified strong correlations between rising levels
of uric acid and the prevalence of CKD (stage 2
or higher). 27 The prevalence of CKD stage 2 or
higher was 52.5% for patients with sUA levels
of 357–410µmol/l and increased to 86% among
subjects with levels of 595µmol/l or higher. These
studies suggested that, at the very least, CKD is
very common among subjects with elevated levels
of uric acid. Several large prospective studies have
identified strong independent associations of
elevated uric acid and risk of new-onset CKD or
progression to ESKD. Obermayr et al found that
a slightly elevated uric acid level (416–529µmol/l
(7.0–8.9mg/dl)) was associated with a nearly doubled
risk for incident kidney disease (odds ratio 1.74; 95%
CI 1.45–2.09), and an elevated uric acid (>535µmol/l
or ≥9.0mg/dl) was associated with a tripled risk (odds
Novel insights to gout and risk of CKD
Gout represents the cumulative burden of
hyperuricaemia that has developed over many years.
It is speculated that gout might further increase the
risk of CKD compared with hyperuricemia alone,
potentially mediated by higher urate burden, longer
periods of exposure, repeated cycles of systemic
inflammation from acute gout flares, and indeed
greater exposure to non-steroidal anti-inflammatory
drugs (NSAIDs). 14 Dissecting out the individual
contribution of gout to the development of CKD
is difficulty as gout patients tend to have several
chronic diseases including higher prevalence
of hypertension (68%), diabetes mellitus (15%),
metabolic syndrome and cardiovascular risk factors,
which are also risk factors for kidney disease. 31
The impact of gout on risk of kidney failure
was explored in two recent large studies. Yu et al
evaluated the association of gout with risk of ESKD
using data from the National Taiwanese Insurance
Database. 13 Adjusting for demographic factors,
hypertension and diabetes, patients with gout
experienced a 57% higher risk of ESKD compared to
those without. A study by Stack et al analysed data
from the UK Clinical Practice Research Database. 14 In
this prospective cohort, adjusting for confounders,
they found that patients with gout experienced a
29% higher risk of advanced CKD, where advanced
CKD was defined as a composite of: doubling of
serum creatinine, progression to eGFR <10ml/min,
ESKD need for dialysis or kidney transplantation,
and death associated with CKD. However, the
strongest association was between gout and risk of
ESKD, where patients experienced a 213% higher
risk. These new data provide a more compelling
argument that patients with gout experience
significantly higher risks of kidney disease and
progression to kidney failure.
Does urate-lowering therapy reduce the risk
of CKD?
The benefits of lowering serum uric acid levels in
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