a I JN

JNEPHROL 2013; 26 ( 4) : 624- 628
REVIEW
DOI: 10.5301/jn.5000204
Managing new-onset gout in pediatric
renal transplant recipients: when, how,
to what extent?
Farahnak Assadi
Section of Nephrology, Department of Pediatrics, Rush
University Medical Center, Chicago, Illinois - USA
Abstract
Introduction
Hyperuricemia and gout are common among adult renal transplant recipients, but it is rarely reported following pediatric renal transplantations. Treating gout in
pediatric kidney transplant recipients presents clinical
challenges to the management of both immunosuppressive regimen and hyperuricemia for their effects on
serum uric acid levels, renal function and drug interactions. Most renal transplant recipients have a relative
impairment of renal clearance of urate due to abnormalities in renal transport, explaining the association
of hyperuricemia and decreased glomerular filtration
rate. Risk factors for the development of gout include
impaired renal function, hypertension, heart failure and
diabetes mellitus. Calcineurin inhibitors, particularly
cyclosporine, are the most important risk factor for
gout in transplant recipients and should not be used
in pediatric renal transplant recipients. Diuretic therapy increases the risk of gout by causing extracellular
volume contraction with consequent enhancement
of proximal tubular reabsorption. Corticosteroids are
increasingly replacing nonsteroidal antiinflammatory
drugs and colchicine for the treatment of acute gout
flares because they have little effect on kidney function.
Proper management is aimed at lowering serum uric
acid level below 6.0 mg/dL with xanthine oxidase inhibitors such as allopurinol or febuxostat. Allopurinol and
mycophenolate mofetil are safer to use in combination
than are allopurinol and azathioprine. Febuxostat is an
alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity. Pegloticase is indicated
for patients with severe gout in whom allopurinol and
febuxostat have not been effective or tolerated.
Key words: Azathioprine, Calcineurin inhibitors, Gout,
Pediatric kidney transplant recipients, Pegloticase, Uric
acid–lowering agents
624
Hyperuricemia and gout are common among adult renal
transplant recipients with the highest incidence in those
treated with calcineurin inhibitors (CNIs) (1-4). The relatively
high incidence of gout among renal transplant recipients is
attributable to abnormal renal urate transport mechanisms
due to the use of immunosuppressive agents, especially cyclosporine (CSA) and/or intrinsic renal tubular defects following renal transplantation (5-7).
New-onset gout may occur in as many as 13% of renal
transplant recipients, with a cumulative incidence of 7.6%
at 3 years posttransplant (3). The improved quality of life
gained through renal transplantation may be offset by gout
that becomes severe and debilitating (4). Gout has been observed to be more aggressive in renal transplant recipients
than in the general population, with early onset and fast progression (8).
Although medications that are used to treat gout in transplant patients are generally similar in children and adults,
dosages should be lowered based on weight and renal
impairment, and adjusted very carefully for children. While
reports in the literature have been accumulated on hyperuricemia and gout among adult renal transplant patients (1-7),
there have been only infrequent reports in pediatrics (9-11)
and rarely in the adult literature.
This article will review the pathogenesis of gout in renal
transplant recipients. The new strategy available for treating
gout will be examined with particular emphasis on drug interactions following pediatric renal transplantations.
Pathophysiology
Uric acid is the end product of purine metabolism. The pKa
of uric acid is approximately 5.3. At the normal blood pH of
7.40, most uric acid in the extracellular fluid is in the form of
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 4) : 624- 628
monosodium urate. A serum uric acid level greater than 7.0
mg/dL favors the formation of monosodium urate crystals.
Acute symptoms are due to deposition of monosodium
urate crystals in joints and tissues. The deposition of monosodium urate crystals in joints can damage cartilage, bone
and periarticular soft tissue through the release of several
proinflammatory cytokines, of which interleukin-1β plays a
central role (12). The presence of monosodium urate crystals in synovial fluid is required for a definite diagnosis of
gout (7, 12).
Approximately 95% of the uric acid produced by purine
metabolism is freely secreted through the glomerulus (4, 7).
The filtered urate is absorbed extensively in the proximal
tubule via the organic anion transporter, and then further
reabsorbed by the kidney with the sodium-dependent reabsorption of anions, resulting in renal clearance of only 7% to
10% of the filtered load (4, 7, 10).
Several risk factors may contribute to the relatively high incidence of gout among renal transplant patients (13-15). Most
renal transplant recipients are prone to hypertension and
edema, and diuretics are commonly used in their management. Renal uric acid excretion may be impaired due to poor
graft function. There is a linear relationship between hyperuricemia and impaired renal function, hypertension and cardiovascular disease (13). Both loop and thiazide diuretics
reduce uric acid excretion by causing extracellular volume
contraction with consequent enhancement of proximal tubular reabsorption. Loop diuretics may also reduce uric acid
secretion by competing with uric acid secretion via organic
acid transporter at the proximal tubule (13-15).
Immunosuppressive therapy with CSA poses more potential
risk factors for developing gout (5, 16). CSA decreases the
renal clearance of urate by both reducing glomerular filtration rate (GFR) and impairing the handling of urate in the
proximal tubules (16, 17).
Treatment of acute gout attack
There are several considerations for treating gout, with regard to drug interactions and specific needs of the transplant patient.
Corticosteroid, an antiinflammatory agent, is highly effective
for acute gout symptoms in renal transplant recipients with
acute gouty attack. Corticosteroids are increasingly replacing nonsteroidal antiinflammatory drugs (NSAIDs) and colchicine for the treatment of acute gout flares because they
have little effect on kidney function.
Oral corticosteroids can provide complete relief from acute
attacks and are typically given as prednisone, 0.5 mg/kg per
day in 2 divided doses for 3-7 days and then tapered to
the maintenance steroid dose within a 14-day period (7, 15).
Intra-articular injections of a long-acting corticosteroid are
useful when gout is limited to a single joint (4).
Colchicine is not a preferred agent for acute gout flares in
renal transplant patients. Normal kidney excretes up to 20%
of a dose of colchicine. Thus, the renal clearance of colchicine is further reduced in patients with renal impairment and
may accumulate in serum and cause gastrointestinal toxicity and neutropenia (18). Myopathy and neuropathy may also
occur after long-term treatment (4, 7). In addition, patients
receiving CSA may be further predisposed to colchicine
toxicity, and dose reduction is necessary in patients with
GFR <50 ml/min per 1.73 m2 (13, 16).
NSAIDs are an effective alternative to colchicines but are associated with an increase in blood pressure and when used
in patients with impaired kidney function can potentiate
acute kidney injury (19). The new cyclooxygenase-2 (COX-2)
inhibitors, such as celecoxib, have not been well studied in
renal transplant patients and are generally thought to offer
no advantage over traditional NSAIDs in term of renal complications (20). One of the more renal-sparing NSAID such as
sulindac or a nonacetylated salicylate is not always effective
against acute gout attack.
CNIs, particularly CSA, are the most important risk factor for
gout in transplant recipients (7, 16). Recently, Abbott et al
reported that the prevalence of new-onset gout was significantly lower in renal transplant patients treated with tacrolimus (TAC) than in those treated with CSA (6.1% vs. 7.9%,
p<0.05) within 3 years of transplantation (3). Furthermore,
independent correlations with new-onset gout were found
for use of CSA compared with use of TAC after discharge
(3). A few studies in small patient populations have reported
a decrease in serum uric acid level after switching from CSA
to TAC (4); others have found no advantage to TAC over
CSA (5).
Patient education plays an important role in preventing the
development of gout, particularly regarding dietary precautions for renal transplant recipients (15). Increased serum
uric acid levels are associated with red meat, fructosesweetened beverages, dairy products, coffee, vitamin C and
alcohol (15). However, dietary regimen, even if successfully
followed, may result in a reduction in serum urate concentrations of only 1.0 mg/dL.
Uric acid–lowering agents to prevent
gout
A serum urate goal of <6.0 mg/dL is associated with a
marked reduction in acute gout flares (13, 15). This can be
achieved in either of 2 ways: by increasing uric acid ex-
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
625
Assadi: Gout in pediatric renal transplantations
cretion through the use of uricosuric agents such as probenecid or by attenuating the production of uric acid with
allopurinol or febuxostat (4, 7) (Tab. I).
Allopurinol is effective in both overproduction (10%) and
underexcretion (90%) of urate and is considered a first-line
therapy for lowering the serum uric acid level (Tab. I). In a
controlled clinical trial, allopurinol 300 mg/day lowered serum uric acid by about 33% in a population in which 30%
had detectable tophi (13).
The drug reduces the metabolism of uric acid by inhibiting
the activity of xanthine oxidase. This action of allopurinol
also blocks the breakdown of the purine antimetabolite
azathioprine (AZA) (1, 15, 21). For this reason, allopurinol
should not be given with AZA or 6-mercaptopurine, because both drugs are metabolized by xanthine oxidase,
and inhibition of xanthine oxidase increases circulating
levels of mercaptopurine and potentiates AZA toxicity (21).
Unlike AZA, mycophenolate mofetil (MMF) metabolism is
not affected by allopurinol, a significant advantage in patients with gout (22).
TABLE I
DRUGS FOR TREATING HYPERURICEMIA AND GOUT IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS
Class and agent
Indications, adverse effects and drug interactions
Treatment of acute gout attack
Antiinflammatory agents
NSAID
• Relatively contraindicated in transplant patients with CKD, CVD or GI bleeding
• Drug interaction with warfarin
Colchicine
• Relatively contraindicated; risk of myopathy and neuropathy
• Dose adjustment needed for renal impairment
• Can cause serious GI adverse effects
• Drug interactions with CSA, statins and macrolides
Corticosteroids
• Generally well tolerated
• Use with caution in patients with infection and/or diabetes
• Dose should be tapered to avoid rebound flare
Uric acid–lowering agents
to prevent gout
Xanthine oxidase inhibitors
Allopurinol
• Effective in patients who underexcrete or overproduce uric acid
• Dose adjustment needed for impaired renal function (GFR <50 ml/min per 1.73 m2)
• Contraindicated for use with AZA or 6-mercaptopurine
• Potentially fatal hypersensitivity syndrome
Febuxostat
• Option for allopurinol hypersensitivity or intolerance
• No dose adjustment needed for patients with renal insufficiency
• Contraindicated for use with AZA or 6-mercaptopurine, and theophylline
Uricosuric agents
Probenecid
• Ineffective if GFR is <50 ml/min per 1.73 m2
• Risk for nephrolithiasis in patients with high uric acid production
Recombinant uricase
pegloticase
• No dose adjustment needed for patients with kidney impairment
• Administered by intravenous infusion every 2 weeks
Contraindicated in patients with G6PD deficiency
• May cause allergy reactions (hives, itching, shortness of breath, chest pain)
AZA = azathioprine; CKD = chronic kidney disease; CSA = cyclosporine; CVD = cardiovascular disease; GFR = glomerular filtration rate; GI = gastrointestinal; G6PD = glucose-6-phosphate dehydrogenase; NSAID = nonsteroidal antiinflammatory drug.
626
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 4) : 624- 628
Febuxostat, a non-purine selective xanthine oxidase inhibitor, is an appropriate alternative for patients with allopurinol
hypersensitivity or intolerance (23, 24). Clinical trials have
demonstrated improved efficacy of febuxostat over allopurinol in patients with impaired renal function (23, 24). In a
recent clinical trial, febuxostat 40 or 80 mg/day was more
effective than allopurinol 300 mg/day in achieving a serum
urate levels of 5.0 mg/dL after 3 months in patients with
or without renal insufficiency (24). Unlike allopurinol, febuxostat is metabolized primarily in the liver with little renal
elimination, so there is no dose adjustment in patients with
chronic kidney disease. However, febuxostat is contraindicated for use with azathioprine and 6-mercaptopurine
because it prolongs the half-life of these purine analogues
(7, 23, 24).
Recent studies report the intravenous use of recombinant
uricase pegloticase for the treatment of chronic gout in patients refractory to conventional treatment (25, 26) (Tab. I).
Pegloticase is administered by intravenous infusion 8.0 mg
every 2 weeks for 3 months and requires no dose adjustment for patients with kidney impairment (25). A key difference between the xanthine oxidase inhibitor febuxostat
and pegloticase is that therapeutic effectiveness may be reduced by the development of antibodies to pegloticase but
not to febuxostat (23-26).
Patients allergic to allopurinol may be given a uricosuric
agent such as probenecid. However, probenecid is not recommended in patients who are overproducers of uric acid
and whose urinary uric acid levels are >800 mg/day (7, 27).
Probenecid blocks reabsorption of the uric acid in the proximal tubules and increases urinary uric acid excretion.
At a urine pH <5.5, most of the urate in the urine is uric
acid, which is less soluble than monosodium urate (4, 7).
Uric acid excretion should be measured periodically in
transplant patients receiving probenecid, and they should
be monitored sonographically at regular intervals. Patients
should increase their fluid intake, and consideration should
be given to alkalinization of the urine with acetazolamide to
prevent the development of renal calculi. Probenecid becomes less effective in patients with renal impairment, and
there are potential interactions with AZA and NSAID, and
CSA (13).
prevalence of gout in renal transplant recipient is clearly attributable to CSA use and the individual patient’s existing
risk factors.
The risks and benefits of the pharmacological agents that
are used to treat acute gout attack and chronic hyperuricemia should be evaluated carefully for their side effects
on serum uric acid levels, renal function and drug-induced
interactions. Corticosteroids are increasingly replacing
NSAIDs and colchicine for the treatment of acute gout flares
because they have little effect on kidney function. Proper
management is aimed at lowering serum uric acid levels
over the long term. Uric acid levels less than 6.0 mg/dL are
associated with decreased gout frequency. The choice of
serum uric acid–lowering agent and dosage may need to
be tailored according to the patient’s comorbidities such as
renal impairment, hypertension and cardiovascular disease.
Febuxostat is an alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity. Pegloticase is indicated for patients with severe gout in whom allopurinol and
febuxostat have not been effective or tolerated. Allopurinol
and MMF are safer to use in combination than are allopurinol and AZA.
Institutional review board/ethics committee approval was not
required for this review article.
This study is in adherence with the Declaration of Helsinki.
Financial support: The author acknowledges that there has been
no financial support to report for this review.
Conflict of interest statement: The author has no conflict of interest
to report.
Conclusions
New-onset gout can occur in the pediatric renal transplant
recipient and presents challenges to the management of
both immunosuppressants and hyperuricemia. Decreased
renal excretion of uric acid is the primary problem leading
to gout in patients after kidney transplantation. The high
Address for correspondence:
Farahnak Assadi
18 Scarlet Oak
Haverford, PA 19041, USA
fassadi@rush.edu
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
627
Assadi: Gout in pediatric renal transplantations
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
628
Stamp L, Ha L, Searle M, O’Donnell J, Frampton C, Chapman
P. Gout in renal transplant recipients. Nephrology (Carlton).
2006;11(4):367-371.
Hernández-Molina G, Cachafeiro-Vilar A, Villa AR, Alberú J,
Rull-Gabayet M. Gout in renal allograft recipients according
to the pretransplant hyperuricemic status. Transplantation.
2008;86(11):1543-1547.
Abbott KC, Kimmel PL, Dharnidharka V, Oglesby RJ, Agodoa
LY, Caillard S. New-onset gout after kidney transplantation:
incidence, risk factors and implications. Transplantation.
2005;80(10):1383-1391.
Stamp L, Searle M, O’Donnell J, Chapman P. Gout in solid
organ transplantation: a challenging clinical problem. Drugs.
2005;65(18):2593-2611.
Kanbay M, Akcay A, Huddam B, et al. Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney
transplant recipients. Transplant Proc. 2005;37(7):3119-3120.
Fuldeore MJ, Riedel AA, Zarotsky V, Pandya BJ, Dabbous
O, Krishnan E. Chronic kidney disease in gout in a managed
care setting. BMC Nephrol. 2011;12(1):36.
Clive DM. Renal transplant-associated hyperuricemia and
gout. J Am Soc Nephrol. 2000;11(5):974-979.
Pascual E. Gout update: from lab to the clinic and back. Curr
Opin Rheumatol. 2000;12(3):213-218.
Spartà G, Kemper MJ, Neuhaus TJ. Hyperuricemia and gout
following pediatric renal transplantation. Pediatr Nephrol.
2006;21(12):1884-1888.
Trück J, Laube GF, von Vigier RO, Goetschel P. Gout in pediatric renal transplant recipients. Pediatr Nephrol. 2010;25(12):
2535-2538.
Laine J, Holmberg C. Mechanisms of hyperuricemia in
cyclosporine-treated renal transplanted children. Nephron.
1996;74(2):318-323.
Choi HK, Mount DB, Reginato AM. American College of Physicians; American Physiological Society. Pathogenesis of
gout. Ann Intern Med. 2005;143(7):499-516.
Terkeltaub R. Gout. Novel therapies for treatment of gout and
hyperuricemia. Arthritis Res Ther. 2009;11(4):236.
Johnson RJ, Kivlighn SD, Kim Y-G, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal
disease. Am J Kidney Dis. 1999;33(2):225-234.
15. Baroletti S, Bencivenga GA, Gabardi S. Treating gout in kidney
transplant recipients. Prog Transplant. 2004;14(2):143-147.
16. Ben Hmida M, Hachicha J, Bahloul Z, et al. Cyclosporineinduced hyperuricemia and gout in renal transplants. Transplant Proc. 1995;27(5):2722-2724.
17. Marcén R, Gallego N, Orofino L, et al. Impairment of tubular
secretion of urate in renal transplant patients on cyclosporine. Nephron. 1995;70(3):307-313.
18. Jonsson J, Gelpi JR, Light JA, Aquino A, Maszaros S.
Colchicine-induced myoneuropathy in a renal transplant
patient. Transplantation. 1992;53(6):1369-1371.
19. Palmer BF. Renal complications associated with use of nonsteroidal anti-inflammatory agents. J Investig Med. 1995;
43(6):516-533.
20. Schneider A, Stahl RA. Cyclooxygenase-2 (COX-2) and the
kidney: current status and potential perspectives. Nephrol
Dial Transplant. 1998;13(1):10-12.
21. Venkat Raman G, Sharman VL, Lee HA. Azathioprine and
allopurinol: a potentially dangerous combination. J Intern
Med. 1990;228(1):69-71.
22. Jacobs F, Mamzer-Bruneel MF, Skhiri H, Thervet E, Legendre
C, Kreis H. Safety of the mycophenolate mofetil-allopurinol
combination in kidney transplant recipients with gout. Transplantation. 1997;64(7):1087-1088.
23. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia
and gout. N Engl J Med. 2005;353(23):2450-2461.
24. Dubchak N, Falasca GF. New and improved strategies for
the treatment of gout. Int J Nephrol Renovasc Dis. 2010;3:
145-166.
25. Reinders MK, Jansen TL. New advances in the treatment of gout: review of pegloticase. Ther Clin Risk Manag.
2010;6:543-550.
26. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability
of pegloticase for the treatment of chronic gout in patients
refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720.
27. Bieber JD, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum.
2004;50(8):2400-2414.
Accepted: June 13, 2012
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428