comorbidities
Gout and chronic kidney disease:
An emerging risk factor
An increasing body of evidence has linked gout and hyperuricaemia to the development and
progression of chronic kidney disease, and it is suggested that urate lowering therapy might
not only reduce flares and chronic tophaceous gout but also protect kidney function and
prevent deterioration
Austin G Stack
MD MSc FRCPI
Department of
Nephrology, University
Hospital Limerick,
Limerick, Ireland
Gout is a common chronic polyarthritis that
affects between 2% and 4% of the adult
population and which causes significant pain and
disability due to its effects on joints, tendons and
bone. 1 The principal cause of gout is hyperuricaemia,
a disorder of purine metabolism, which results in
deposition of urate crystal in joints and initiates
a chronic inflammatory response that is responsible
for the phenotypic presentations. 2 A large body of
evidence now incriminates both gout and its
precursor, hyperuricaemia, in the pathogenesis
of chronic kidney disease (CKD), a major chronic
disease that contributes substantially to adverse
clinical outcomes and considerably reduced life
expectancies. 3–9 The definition of CKD, now well
established in the wider clinical community, is the
presence of pathologic abnormalities of kidney
structure or function that persist for at least three
months, usually a glomerular filtration rate (GFR)
<60ml/min/1.73m 2 , or a urinary albumin-to-
creatinine ratio (ACR) of >30mg/g. 10
For almost 60 years, it has been known that gout
and hyperuricaemia are linked to the development
of CKD and end-stage kidney disease (ESKD). Autopsy
studies by Talbot and Terplan found pathological
evidence of chronic kidney damage in almost
all gout patients. 11,12 Prospective observational
studies over the past decade have confirmed strong
independent associations of uric acid with the
development of new-onset CKD, progression of
existing CKD, and rapid development of ESKD. 3–9
Other studies have also yielded strong relationships
between gout and the risk of ESKD. 13,14 Even
more compelling evidence is now available from
clinical trials and quasi-experimental studies that
demonstrate a slowing in the rate of kidney function
decline and reduction in risk of ESKD following
treatment with urate-lowering therapies. 15–20
Together these provide compelling evidence that
uric acid and gout per se are major risk factors for
CKD. Effective treatment of hyperuricaemia and
gout treatment may afford protection and reduce
the risk of ESKD.
Pathophysiology of hyperuricaemia
Hyperuricaemia is a byproduct of purine
metabolism, and is the principal driver of gout. 2
Unlike most mammals, humans lack the enzyme
uricase, and are unable to convert uric acid to an
inactive metabolic for excretion. The degradation of
the purine nucleotides to purine bases, guanine and
hypoxanthine, and their subsequent metabolism
results in the generation of uric acid. 21 This last
step is under the enzymatic control of the oxidising
enzyme, xanthine oxidase.
20 | 2018 | hospitalpharmacyeurope.com
Under normal circumstances, the excretion
of uric acid is through the gut and the kidney in
order to maintain homeostasis. By far the greatest
contributor to the excretion of uric acid is the
kidney, which is responsible for two-thirds of the
excretion, whereas the gut eliminates a third.
These physiologic mechanisms are inadequate to
eliminate the normal daily urate production and,
consequently, serum uric acid levels have risen
in human populations over time with substantial
global variation. 22 Indeed, the average serum
concentration of uric acid in normal populations
is 400µmol/l (6.8mg/dl), which approaches the
solubility threshold of urate in blood. Uric acid
levels above this threshold precipitate out of serum
and may deposit in tissues.
The kidney is by far the most important regulator
of uric acid excretion, excreting approximately
60% of daily production. 23 Transporters, such as
URAT 1 and GLUT 9 in the proximal tubule are key
regulators of urate movement into and out of the
cell. Uric acid filters freely through the glomerulus
and approximately 90% if the filtered load is
reabsorbed through the proximal tubule. Tubular
secretion in the S2 segment of the proximal tubule
returns 50% of the filtered load back into the urinary
space for excretion.
Role of hyperuricaemia and gout in CKD
Experimental evidence
The contribution of hyperuricaemia to the
development of kidney disease has been
demonstrated in a series of elegant animal
models. 24–26 In most animals, uric acid is degraded
by uricase to allantoin and excreted. Unfortunately,
this is not the case in humans, who lost the uricase
enzyme over 15 million years ago due to mutation.
In experimental rat models, hyperuricaemia
induces the development of hypertension and
the development of a specific afferent
arteriopathy. Compared with controls, animals
with experimentally induced hyperuricaemia
experienced significant increases in afferent
arteriolar wall thickness. 25 The severity of the
arteriolar wall thickness correlated with systolic
blood pressure and the degree of hyperuricaemia.
Moreover, these models proved that hyperuricaemia
led to activation of the renin–aldosterone system
and a variety of pathological kidney abnormalities
including: arteriolarsclerosis of the afferent
arteriolar system, glomerular hypertrophy, and
interstitial fibrosis. 24
The impact of hyperuricaemia in animals
with pre-existing kidney disease was even more
striking with acceleration of kidney disease,