The CARI Guidelines – Caring for Australasians with Renal Impairment

Uric acid
Date written: July 2004
Final submission: July 2004
Author: David Johnson

GUIDELINES

No recommendations possible based on Level I or II evidence.

SUGGESTIONS FOR CLINICAL CARE

(Suggestions are based on Level III and IV sources)

• Treating hyperuricaemia does not retard the progression of renal failure and
cannot be recommended for this indication. (Level IV evidence; limited case
series; clinically relevant outcomes; consistent effects)

• Physicians should be aware that the use of protein-restricted diets in

chronic renal patients treated with allopurinol may require further reduction
of the dose of allopurinol due to inhibition of urinary excretion of
oxypurinol. (Level II evidence; single randomised cross-over study;
surrogate outcome; Moderate effect)

Background

Hyperuricaemia is an almost invariable feature of renal failure (Ifudu et al 1994). Long-

standing hyperuricaemia has occasionally been associated with the development of
Chronic Kidney Disease (CKD) (Foreman and Yudkoff 1990, Yu and Berger 1975,
Coombs et al 1940, Gutman and Yu 1957, Talbott and Terplan 1960, Barlow and Beilin
1968, Duncan and Dixon 1960, Rosenbloom et al 1967, Van Goor et al 1971, Massari
et al 1980), although it has been difficult to establish whether the elevated plasma urate
levels in these patients reflect a cause, consequence or accelerant of renal dysfunction.
The aim of this guideline is to evaluate the available clinical evidence that treatment of
hyperuricaemia retards the progression of CKD.

Search strategy

Databases searched: Medline (1999 to November Week 2, 2003). MeSH terms for
kidney diseases were combined with MeSH terms and text words for allopurinol and
hyperuricaemia. The results were then combined with the Cochrane highly sensitive
search strategy for randomised controlled trials and MeSH terms and text words for
identifying meta-analyses and systematic reviews. The Cochrane Renal Group
Specialised Register of Randomised Controlled Trials was also searched for relevant
trials not indexed by Medline.

Prevention of Progression of Kidney Disease

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 The CARI Guidelines – Caring for Australasians with Renal Impairment

Date of search: 16 December 2003.

What is the evidence?

There are no randomised or prospective controlled trials addressing the effect of

treatment of hyperuricaemia on progression of renal failure.

Occasional renal patients with hyperuricaemia and CKD have demonstrated histologic
findings of urate crystals in the renal cortical, medullary or papillary interstitium with
surrounding giant cell reaction (Talbott and Terplan 1960, Sokoloff 1957, Brown et al
1950). It is uncertain whether this contributes to renal dysfunction, is a consequence of
renal injury or is merely an epiphenomenon.

A case-control study by Fessel (1979) demonstrated that azotaemia occurred in only 2

of 113 patients with asymptomatic hyperuricaemia compared with 4 of 193
normouricaemic controls over a mean follow-up period of 8 years. Similarly, long-term
follow-up studies of 524 gouty patients failed to demonstrate any adverse effect of
hyper-uricaemia on renal function (Berger and Yu 1979).

Therapy directed at lowering plasma urate levels (uricosurics or allopurinol) in patients

with familial hyperuricaemia has not been successful in preventing the development of
renal insufficiency (Van Goor et al 1971, Massari et al 1980).

Case series reports (Emmerson 1999) have generally not observed an alteration in the
rate of progression of renal disease after correction of hyperuricaemia by allopurinol.

In a retrospective case series, Fairbanks et al (2002) examined the effects of allopurinol

commencement in 32 patients with familial juvenile hyperuricaemic nephropathy.
Twenty-seven patients started immediately on allopurinol (serum creatinine < 0.2
mmol/L) experienced mild deterioration of renal function compared with five patients
who commenced allopurinol with a serum creatinine concentration > 0.2 mmol/L, all of
whom progressed to end-stage kidney disease (ESKD) with an average period of 6
years. The study’s results were significantly limited by the absence of a control group
and lead-time bias.

The unproven benefit of allopurinol in preventing renal failure progression in the setting
of asymptomatic hyperuricaemia must be balanced against the documented small
incidence of serious adverse reactions to allopurinol, including drug hypersensitivity
syndromes. For example, a review of allopurinol hypersensitivity reactions by Lupton
and Odom (1979) reported that 97% of such reactions occurred in the setting of pre-
existing renal failure and that in over 60% of cases, allopurinol was prescribed for the
treatment of asymptomatic hyperuricaemia; 10% of the reported patients died from
allopurinol hypersensitivity.

The use of protein-restricted diets has been shown in a randomised crossover trial
(Berlinger et al 1985) to significantly diminish the excretion of allopurinol and its active
metabolite oxypurinol by 28% and 64%, respectively. This results in a 3-fold increase in
the half-life of oxypurinol.
Prevention of Progression of Kidney Disease
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 The CARI Guidelines – Caring for Australasians with Renal Impairment

Summary of the evidence

There are no randomised or prospective controlled trials addressing the effect of

treatment of hyperuricaemia on progression of renal failure. The majority of the small
numbers of published case series and anecdotal reports suggest that treatment of
hyperuricaemia per se does not appreciably influence renal failure progression.

What do the other guidelines say?

Kidney Diseases Outcome Quality Initiative: No recommendation.

UK Renal Association: No recommendation.

Canadian Society of Nephrology: No recommendation.

European Best Practice Guidelines: No recommendation.

International Guidelines: No recommendation.

Implementation and audit

No recommendation.

Suggestions for future research

A multicentre, prospective, randomised controlled trial of allopurinol therapy on the

progression of renal failure would help to clarify the issue, although such a study would
not be a very high priority. The study would need to be stratified for sex, diabetes and
severity of renal dysfunction.

Prevention of Progression of Kidney Disease

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 The CARI Guidelines – Caring for Australasians with Renal Impairment

References

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Berger L, Yu TF. Renal function in gout IV. An analysis of 524 gouty subjects including
long-term follow-up studies. Am J Med 1979; 59: 605–613.

Berlinger WG, Park GD, Spector R. The effect of dietary protein on the clearance of
allopurinol and oxypurinol. N Engl J Med 1985; 313: 771–76.

Brown J, Mallory GK. Renal changes in gout. N Engl J Med 1950; 243: 325–329.

Coombs FS, Pecora LJ, Thorogood E. Renal function in patients with gout. J Clin
Invest 1940; 19: 525–535.

Duncan H, Dixon ST. Gout, familial hyperuricaemia and renal failure. Q J Med 1960 29:
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Emmerson BT. Gout and renal disease. In. Gout, hyperuricaemia and other
crystal-associated arthropathies, 1st ed., edited by Smyth CJ, Holers VM, New York,
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Fairbanks LD, Cameron JS, Venkat-Raman G et al. Early treatment with allopurinol in
familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term
progression of renal disease. QJM 2002; 95: 597–607.

Fessel WJ. Renal outcomes of gout and hyperuricemia. Am J Med 1979; 67: 74–82.

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Ifudu O, Tan CC, Dulin AL et al. Gouty arthritis in end-stage renal disease: clinical
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Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol
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Massari PU, Hsu CH, Barnes RV et al. Familial hyperuricemia and renal disease. Arch
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Rosenbloom FM, Kelley WN, Carr AA. Familial nephropathy and gout in a kindred. Clin
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Sokoloff L. The pathology of gout. Metabolism 1957; 6: 230–43.

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 The CARI Guidelines – Caring for Australasians with Renal Impairment

Talbott JH, Terplan KL. The kidney in gout. Medicine 1960; 39: 405–467.

Van Goor W, Koorker CJ, Mees CJD. An unusual form of renal disease associated
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Prevention of Progression of Kidney Disease

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