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Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients

Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients
Literature review current through: May 2024.
This topic last updated: Oct 19, 2022.

INTRODUCTION — Reduced uric acid excretion can occur after kidney transplantation, leading to hyperuricemia and, in some cases, gout [1-4]. This problem is more common among patients treated with calcineurin inhibitors (especially cyclosporine) to prevent graft rejection. Other comorbidities that are common among kidney transplant recipients, such as impaired kidney function, hypertension, diabetes mellitus, and cardiovascular disease, may also contribute to the increased risk of gout. The pharmacologic management of these comorbidities after transplantation may lead to the potential for drug interactions that can compromise the safety and efficacy of pharmacologic therapies used for gout management. Thus, the use of antiinflammatory drugs and glucocorticoids to treat and/or prevent gout flares and urate-lowering therapies for the long-term management of gout are not without risk in kidney transplant recipients. For this reason, gout in these patients should ideally be managed by clinicians experienced in addressing these clinical problems.

This topic reviews the treatment and prevention of gout among kidney transplant recipients. The pathogenesis, clinical manifestations, diagnosis, treatment, and prevention of gout in nontransplant patients and issues related to asymptomatic hyperuricemia are discussed separately:

(See "Pathophysiology of gout".)

(See "Clinical manifestations and diagnosis of gout".)

(See "Treatment of gout flares".)

(See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)

(See "Nonpharmacologic strategies for the prevention and treatment of gout".)

(See "Asymptomatic hyperuricemia".)

EPIDEMIOLOGY AND RISK FACTORS — Hyperuricemia and gout are common in kidney transplant recipients, particularly in those receiving the calcineurin inhibitor cyclosporine to prevent graft rejection [1,2,5-15]. The majority of studies evaluating hyperuricemia and gout in the kidney transplant population were performed in an era when most immunosuppression regimens consisted of prednisone plus either cyclosporine or azathioprine:

In one study of kidney transplant recipients, the incidence of hyperuricemia was 84 percent in those treated with cyclosporine and prednisone versus 30 percent in those treated with azathioprine and prednisone [1]. Gout developed in nine patients (7 percent) in the cyclosporine group and in none of the patients in the azathioprine group.

In a retrospective cohort study of 29,597 United States Medicare kidney transplant patients, the cumulative incidence of new-onset gout was 7.6 percent at three years posttransplant [11]. There was an increased relative risk of new-onset gout with cyclosporine compared with tacrolimus (adjusted hazard ratio [HR] 1.25, 95% CI 1.07-1.47). No other immunosuppressive agent was clearly associated with new-onset gout. The development of new-onset gout after transplantation was independently associated with reductions in patient survival (HR 1.26, 95% CI 1.08-1.47) and death-censored graft survival. New-onset gout has also been associated with an increased risk of returning to dialysis posttransplant [16].

Fewer studies have examined the risk of hyperuricemia and gout in patients receiving tacrolimus and/or mycophenolate mofetil, which have largely replaced the use of cyclosporine and azathioprine, respectively. In one study of 121 kidney transplant recipients treated with a tacrolimus- and mycophenolate-based regimen, the incidence of hyperuricemia at one year posttransplant was 38 percent [9]. Some [17,18], but not all [19], studies have reported a decrease in serum urate levels with switching from cyclosporine to tacrolimus. In the retrospective study of Medicare recipients cited above, the incidence of new-onset gout at three years posttransplant was lower with tacrolimus compared with cyclosporine (6.1 versus 7.9 percent) [11].

The lower glomerular filtration rate (GFR) induced by cyclosporine (and tacrolimus) probably contributes to urate retention [1], but tubular damage may also be important by impairing urate secretion [2]. Concurrent diuretic use, kidney function impairment due to rejection, higher body mass index, older age, and male sex are other risk factors for hyperuricemia and gout [2,11]. (See "Diuretic-induced hyperuricemia and gout".)

While hyperuricemia has been associated with higher rates of cardiovascular morbidity and mortality in the general population, such an association has not been demonstrated in kidney transplant recipients. In a post hoc analysis of kidney transplant recipients enrolled in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial, serum urate levels were not independently associated with cardiovascular events, mortality, or transplant failure [20] (see "Overview of possible risk factors for cardiovascular disease", section on 'Urate'). Another retrospective study found that gout was not associated with a higher risk of all-cause mortality after adjustment for baseline confounders such as age, time from transplantation, and kidney function [21].

CLINICAL FEATURES — Gout may emerge de novo in patients after organ transplantation or recur in transplant recipients in whom a diagnosis of gout was established. In most kidney transplant recipients, the clinical features of gout are similar to those seen in nontransplant gout patients (see "Clinical manifestations and diagnosis of gout", section on 'Clinical manifestations'). However, gout may be more severe in transplant recipients with more frequent gout flares and tophi [22].

DIAGNOSIS OF GOUT IN TRANSPLANT PATIENTS — The diagnosis of gout in kidney transplant recipients is established using an approach similar to that used in nontransplant patients. (See "Clinical manifestations and diagnosis of gout", section on 'Diagnosis' and "Clinical manifestations and diagnosis of gout", section on 'Differential diagnosis'.)

In kidney transplant recipients who present with new-onset symptoms and signs suggestive of a first gout flare (see "Clinical manifestations and diagnosis of gout", section on 'Gout flares'), arthrocentesis and synovial fluid analysis (including red-compensated polarized light microscopy for monosodium urate crystal identification) and culture should be performed to establish the diagnosis of gout and exclude alternative diagnoses. Ruling out septic arthritis is especially important in transplant patients who are receiving immunosuppressive therapy to prevent graft rejection and are at higher risk for infection. However, the feasibility of arthrocentesis may be limited by clinician inexperience with this procedure, inaccessibility to needle aspiration of the affected joint, or patient location. In transplant recipients with a first presentation of inflammatory arthritis and for whom there is difficulty undertaking arthrocentesis, consideration should be given to radiologically guided joint aspiration or patient transfer to a site where arthrocentesis can be performed. In the latter situation, we avoid initiating antiinflammatory therapy with glucocorticoids (either by oral or parenteral routes) or an interleukin (IL) 1 inhibitor, but we will initiate treatment with a nonsteroidal antiinflammatory drug (NSAID) or colchicine if the patient is a candidate for one of these agents. (See "Joint aspiration and injection in adults: Indications and technique" and "Joint aspiration or injection in adults: Complications" and "Septic arthritis in adults" and 'Patients with new-onset gout' below.)

In kidney transplant recipients with a documented history of gout flares who are experiencing a recurrence of acute joint inflammation, we often initiate flare treatment without a preceding arthrocentesis if the patient's symptoms and signs are the same as those encountered in prior gout flares and do not include fever, chills, or other symptoms/signs of local or regional infection. In such patients, arthrocentesis and synovial fluid analysis and culture may unnecessarily delay treatment, and arthrocentesis is not without risk of iatrogenic infection, albeit small. However, in patients with fever, chills, and/or symptoms/signs of an ongoing infection, despite antiinflammatory therapy for gout flare, arthrocentesis and synovial fluid analysis and culture should be performed, as gout and septic arthritis can coexist in the same joint [23]. (See 'Patients with a prior history of gout' below.)

TREATMENT OF GOUT FLARES — Gout flares are painful and disabling but self-limiting. Early treatment can reduce pain and shorten flare duration. The principles of gout flare treatment in the general population also apply to treatment of gout flares in transplant recipients. These include treatment with antiinflammatory drugs at full antiinflammatory (as opposed to analgesic) doses as soon as possible after the onset of the flare, the use of adjunctive measures such as icing of the affected joint [24], and joint protection/immobilization. Most of these adjunctive measures are of unproven efficacy. (See "Treatment of gout flares", section on 'Pretreatment considerations'.)

Special considerations in the treatment of gout flares in kidney transplant recipients include the following:

Patient comorbidities and their treatment may impact the safety and/or efficacy of antiinflammatory agents in transplant recipients; careful consideration of these comorbidities is critical in selecting appropriate treatment for gout flares. The following are of particular importance:

Kidney allograft function/kidney function impairment

Cardiovascular disease and hypertension

Gastrointestinal disease (eg, hepatic impairment, peptic ulcer disease)

Concomitant medication use

Diabetes mellitus (especially if poorly controlled)

Composition of the maintenance immunosuppression regimen

Drug allergies or intolerances

Because kidney transplant recipients receive immunosuppressive therapies to prevent allograft rejection, the likelihood of joint infection as an alternative or concomitant diagnosis should be considered in all transplant patients presenting with symptoms of a gout flare. (See 'Diagnosis of gout in transplant patients' above and "Joint aspiration and injection in adults: Indications and technique" and "Joint aspiration or injection in adults: Complications" and "Septic arthritis in adults".)

Patients receiving urate-lowering therapy for long-term management of gout should not discontinue this therapy if a gout flare occurs, as there is no benefit in temporary discontinuation, and later reinitiation predisposes the patient to another flare. A flare provides the opportunity to ensure urate-lowering therapy is adequately dosed to achieve target serum urate levels. (See 'Prevention of gout flares and progression to joint damage and tophi' below.)

Selection of initial antiinflammatory therapy — Several classes of antiinflammatory agents have been shown to be effective in the treatment of gout flares [25-27]. These include systemic and intraarticular glucocorticoids, oral nonsteroidal antiinflammatory drugs (NSAIDs), oral colchicine, and, where available, interleukin (IL) 1 beta antagonists [28,29]. Although there is no single best agent for all patients, the availability of multiple agents and approaches enables the clinician to choose, on the basis of individual patient characteristics and the gout flare history, which therapy is most likely to achieve benefit and minimize the risk of an adverse drug reaction or drug interactions. This is particularly important in the treatment of a gout flare in organ transplant recipients. (See "Treatment of gout flares", section on 'Selection of agent'.)

There is no high-quality evidence specifically directed to kidney transplant recipients to guide the optimal treatment of gout flares. Our overall approach is based primarily upon our clinical experience and studies of gout flare treatment in nontransplant patients. This evidence is presented in more detail elsewhere and, in general, conforms to the gout recommendations/guidelines published by the American College of Rheumatology (ACR), the American College of Physicians, and the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [25-27]. (See "Treatment of gout flares", section on 'Glucocorticoids' and "Treatment of gout flares", section on 'Nonsteroidal antiinflammatory drugs (NSAIDs)'.)

Patients with new-onset gout — In kidney transplant recipients with new-onset gout (ie, no history of gout prior to transplantation) and who do not have evidence of joint infection (as determined by arthrocentesis and synovial fluid analysis and culture) (see 'Diagnosis of gout in transplant patients' above), our approach to the treatment of a gout flare is as follows:

In patients with a first gout flare who have one or two actively inflamed joints, we suggest arthrocentesis with joint fluid aspiration followed by intraarticular injection of glucocorticoids. As long as the aspirated fluid is not obviously purulent, the joint fluid should be sent for microscopy, gram stain, and culture, and any evidence of bacteria on gram stain or culture should prompt treatment of septic arthritis. Use of this approach is contingent upon the ready availability of a clinician with expertise in such procedures and the accessibility of the inflamed joint(s) to injection. We use triamcinolone acetonide (40 mg for a large joint [eg, knee], 30 mg for a medium joint [wrist, elbow, or ankle], and 10 mg for a small joint) or equivalent doses of methylprednisolone acetate. (See "Joint aspiration and injection in adults: Indications and technique" and "Joint aspiration or injection in adults: Complications" and "Treatment of gout flares", section on 'Intraarticular glucocorticoids'.)

In patients who have more than two actively inflamed joints or who have one or two actively inflamed joints but are unable to receive intraarticular glucocorticoids, we treat with oral antiinflammatory agents:

We suggest oral glucocorticoids (eg, prednisone or prednisolone) as first-line therapy in most kidney transplant recipients with a gout flare, given their safety in patients with moderate to severe kidney function impairment. We use prednisone (or an equivalent glucocorticoid) 30 to 40 mg once daily for five days, followed by a gradual dose tapering over a week to either the dose previously used for maintenance immunosuppression or full withdrawal in individuals not receiving maintenance prednisone. (See "Treatment of gout flares", section on 'Oral glucocorticoids'.)

Glucocorticoids should be used with caution and with close monitoring in patients who have coexisting heart failure, poorly controlled hypertension, or glucose intolerance. Diabetes is not a contraindication to the use of glucocorticoids, but patients must be warned of the effects of glucocorticoids on blood glucose levels and undertake appropriate monitoring.

In patients with glucocorticoid intolerance or with a contraindication to glucocorticoid use, low-dose colchicine and NSAIDs are alternative options. We treat with low-dose oral colchicine in patients initiating antiinflammatory treatment within 24 hours of symptom onset. An effective response to colchicine is less likely if treatment is initiated between 24 and 36 hours after symptom onset. Colchicine should not be given to kidney transplant recipients with the following:

-Concomitant use of cyclosporine or another medication that strongly inhibits the cytochrome P450 system component CYP3A4 (table 1) or the membrane P-glycoprotein (P-gp) multidrug resistance transporter (table 2) [30,31]

-Severe kidney function impairment (ie, estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2)

-Moderate to severe hepatic impairment

-Concomitant kidney and hepatic function impairment of any degree

In transplant recipients who are receiving tacrolimus (rather than cyclosporine), our approach to dosing colchicine is similar to that used for nontransplant patients with kidney function impairment. This is discussed in more detail elsewhere.

In patients who cannot receive colchicine, we treat with a potent oral NSAID, such as naproxen (500 mg twice daily) or indomethacin (50 mg three-times daily). A short course of NSAIDs (five to seven days) can usually be administered in kidney transplant recipients without significant adverse consequences as long as kidney allograft function and patient well-being are closely monitored. NSAIDs are most effective when treatment is initiated within 48 hours of symptom onset. The dose can be reduced in a stepwise fashion after a significant decrease in symptoms occurs, but the frequency of dosing should be maintained for several more days for optimal antiinflammatory effect. The NSAID can be discontinued within two days after complete resolution of the flare. The use of NSAIDs should be avoided in older patients (>60 years old) and those with active peptic ulcer disease, kidney function impairment (eGFR <50 mL/min per 1.73 m2), active cardiovascular disease, or NSAID allergy. NSAIDs should not be used for gout flare prophylaxis in kidney transplant recipients. (See 'Antiinflammatory prophylaxis during initiation of urate-lowering therapy' below and "Treatment of gout flares", section on 'Nonsteroidal antiinflammatory drugs (NSAIDs)'.)

In patients who are unable to take oral medications and are not candidates for intraarticular glucocorticoids, we treat with parenteral (intravenous or intramuscular) glucocorticoids. The dosing and duration of parenteral glucocorticoids for a gout flare in kidney transplant patients are the same as that in nontransplant patients and are discussed separately (see "Treatment of gout flares", section on 'Parenteral glucocorticoids'). Intravenous colchicine should not be used because of the risk of serious adverse effects, including death, that are associated with the intravenous administration of this drug.

An alternative therapeutic approach in this setting is the off-label use of anakinra, a short-acting IL-1 receptor antagonist, given as three (or more, as required by clinical response) daily subcutaneous injections of 100 mg each [32]. Canakinumab, an IL-1 beta monoclonal antibody [29], has been approved by European Union regulatory authorities for use only in gout patients with three or more annual flares refractory to other antiinflammatory agents. However, we do not recommend use of canakinumab in organ transplant recipients because of concern about the prolonged inhibition of IL-1 beta action in these already immunosuppressed individuals.

Patients with a prior history of gout — In kidney transplant recipients with an established history of gout, the therapeutic approach to the gout flare is similar to that in patients with new-onset gout (see 'Patients with new-onset gout' above). However, certain features of the patient's prior gout history, including the total flare number, recent rate of flare occurrence, and prior flare experience with specific therapies, may also impact the selection of an antiinflammatory agent as well as the duration of treatment:

If the patient has been experiencing an acceleration in flare rate (ie, shortening of the symptom-free period between flares), the use of oral glucocorticoids should be accompanied by a more prolonged taper over 10 to 21 days; alternatively, a different antiinflammatory agent can be used.

In patients with prior intolerance or lack of an effective response to a particular antiinflammatory agent, an alternative antiinflammatory agent should be initiated. Those who are unable to take any available antiinflammatory agents should be referred to a rheumatologist for further management. (See "Treatment of gout flares", section on 'Resistant or refractory disease'.)

If the gout flare occurs in a patient who is receiving colchicine as antiinflammatory flare prophylaxis (see 'Antiinflammatory prophylaxis during initiation of urate-lowering therapy' below) or who has been treated with colchicine for a gout flare within the past 14 days, we add oral or intraarticular glucocorticoids. Alternatively, in patients who are not receiving oral prednisone as part of their maintenance immunosuppression regimen, we switch from colchicine to low-dose prednisone (2.5 to 7.5 mg daily) for gout flare prophylaxis if repeated flares indicate failure of colchicine prophylaxis at an acceptable colchicine dose.

In patients already receiving urate-lowering therapy at the time of a gout flare (eg, allopurinol, febuxostat, probenecid, benzbromarone, or pegloticase), the urate-lowering medication should be continued without interruption. There is no benefit to temporary discontinuation, and subsequent reintroduction may predispose to another gout flare. (See 'Prevention of gout flares and progression to joint damage and tophi' below.)

Special populations

Patients with a persistent gout flare that has not responded to standard antiinflammatory therapy — Gout flares are generally self-limited and do not typically last more than two weeks. In the event of gout flare persistence despite the ongoing use of individual antiinflammatory agents and adjunctive measures, we review the diagnosis to ensure that there is no other cause for the acute inflammatory arthritis. In particular, gout needs to be confirmed by the presence of monosodium urate crystals in synovial fluid, and septic arthritis must be excluded by arthrocentesis. If gout is confirmed, options for treatment include combining antiinflammatory agents (eg, adding a glucocorticoid [oral or parenteral] to a patient already receiving colchicine or an NSAID) or off-label use of a short-acting IL-1 beta inhibitor, such as anakinra. (See "Treatment of gout flares", section on 'Interleukin 1 blockade'.)

Patients with a concomitant infection — In transplant recipients with a gout flare and a concurrent systemic infection not involving an inflamed joint, we generally avoid the use of glucocorticoids (by any route of administration) and IL-1 beta inhibitors. In such patients, we prefer to administer colchicine or an NSAID, unless there are contraindications to these agents. (See 'Patients with new-onset gout' above.)

PREVENTION OF GOUT FLARES AND PROGRESSION TO JOINT DAMAGE AND TOPHI

Overview of prevention — In individuals with gout, the disease can be successfully managed over time by achieving and maintaining a target serum urate level with pharmacologic therapy. Pharmacologic urate-lowering measures are indicated in patients with frequent gout flares (≥2 flares per year) or those who have tophi or joint damage attributable to gout [27]. While urate-lowering therapy is often indicated in kidney transplant recipients, it is generally perceived as more challenging. As for the general population, the recommended target serum urate level in kidney transplant recipients with gout is <6 mg/dL (<357 micromol/L) [26,27]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Serum urate goals and targeted therapy'.)

In kidney transplant recipients, the asymptomatic ("intercritical") periods following a gout flare present an opportune time to evaluate longer-term treatment options to prevent further flares and development or progression of tophi and/or joint damage. Issues that should be addressed during such periods include:

The need for pharmacologic urate-lowering therapy. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Indications' and 'Pharmacologic urate-lowering therapy' below.)

Pharmacologic management of comorbid diseases common in kidney transplant recipients with gout, such as hypertension, diabetes, and cardiovascular disease, is important. The need for pharmacologic therapies that increase serum urate levels, such as thiazide and loop diuretics, commonly prescribed for the treatment of hypertension and fluid overload, should be reviewed and, if required, replaced with agents that either have no effect on or lower serum urate. As an example, loop or thiazide diuretics might be replaced with losartan (unique among angiotensin II receptor blockers [ARBs], which has uricosuric as well as antihypertensive properties [33,34]) and/or potassium-sparing diuretics, which may successfully avert kidney uric acid retention as well as achieve effective blood pressure control. (See "Nonpharmacologic strategies for the prevention and treatment of gout", section on 'Treating comorbid conditions' and "Diuretic-induced hyperuricemia and gout", section on 'Benefits of angiotensin inhibition and losartan' and "Nonpharmacologic strategies for the prevention and treatment of gout", section on 'Hypertension'.)

Identification of reversible causes of hyperuricemia, if present, may have a small effect in risk reduction, such as weight loss, reduction/avoidance of excessive alcohol and sugar-sweetened beverage intake, and substitution for medications (eg, cyclosporine, diuretics) that may promote hyperuricemia. These interventions will rarely lead to normalization of the serum urate, particularly in the setting of established gout. (See "Nonpharmacologic strategies for the prevention and treatment of gout".)

Pharmacologic urate-lowering therapy — There are several classes of urate-lowering medications, including:

Xanthine oxidase inhibitors (XOIs), including allopurinol and febuxostat (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Xanthine oxidase inhibitors')

Uricosuric agents, including probenecid, benzbromarone, and losartan (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Uricosuric drugs')

Uricase, available as pegloticase and rasburicase (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Uricase')

While urate-lowering therapies, alone or sometimes in combination, can establish and maintain target serum urate levels and ultimately decrease or abolish gout flares and prevent or resolve tophi, their use is not without risk in kidney transplant recipient. Thus, asymptomatic hyperuricemia is not an indication for urate-lowering therapy in kidney transplant recipients. (See "Asymptomatic hyperuricemia", section on 'Management'.)

Because of the risk for complex and potentially serious drug interactions, urate-lowering therapy and concomitant gout flare prophylaxis in kidney transplant recipients should ideally be managed by clinicians experienced in dealing with these problems. In contrast to the management of gout flares, initiation of urate-lowering therapy and flare prophylaxis rarely demands urgent decisions. Clinicians who are managing gout in a transplant recipient but who are not part of the patient's transplant team are encouraged to establish or maintain contact with the patient's transplant team in order to maximize the likelihood of a safe and effective urate-lowering therapy outcome.

A more detailed discussion of the different urate-lowering therapies and the evidence supporting their use is presented elsewhere. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Urate-lowering medications'.)

Initiation and duration of urate-lowering therapy — In kidney transplant recipients, urate-lowering therapy should be initiated at a low dose. (See 'Selection of urate-lowering therapy' below and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Initiation and duration of urate-lowering pharmacotherapy'.)

In patients who are initiating urate-lowering therapy, we also administer low-dose antiinflammatory agents, when feasible, to reduce the risk of gout flares during the early phases of urate lowering. (See 'Antiinflammatory prophylaxis during initiation of urate-lowering therapy' below and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-lowering therapy'.)

Once the decision is made to begin urate-lowering therapy, the duration of therapy is indefinite and should be continuous to remain effective. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Initiation and duration of urate-lowering pharmacotherapy'.)

Selection of urate-lowering therapy — There is no high-quality evidence to guide the optimal pharmacologic urate-lowering management of transplant recipients with gout. Our approach to the selection of initial urate-lowering therapy in kidney transplant recipients is based primarily upon studies in the nontransplant population, reports of treatment in cohorts of transplant recipients, and our clinical experience.

First-line therapy (allopurinol monotherapy) — In most kidney transplant recipients, we suggest the XOI allopurinol as first-line urate-lowering therapy. We prefer allopurinol over the alternative XOI febuxostat given the higher cost of febuxostat and concerns about a greater frequency of adverse cardiovascular events (particularly cardiovascular death) with febuxostat compared with allopurinol in patients at high risk for cardiovascular events [35]. We prefer allopurinol over uricosuric agents because of the ease of allopurinol use and the reduced effectiveness of some readily available and established uricosuric agents in individuals with impaired kidney function. (See 'Second-line therapy (febuxostat monotherapy)' below and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Choosing the urate-lowering drug' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Adverse effects'.)

Transplant patients of Chinese, Thai, or Korean ethnicity who are under consideration for allopurinol therapy should be tested before allopurinol initiation for the human leukocyte antigen HLA-B*58:01 allele, which is associated with severe allopurinol hypersensitivity reactions; patients testing positive for this allele should not receive allopurinol. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Adverse effects'.)

In patients with an estimated glomerular filtration rate (eGFR) of >60 mL/min per 1.73 m2, we usually initiate allopurinol treatment at 100 mg daily and titrate the dose upward by 100 mg every two to four weeks to the dose required to achieve and maintain a target serum urate of <6 mg/dL (<357 micromol/L) [27]. An initial dose of 100 mg or less of allopurinol is associated with reduced risks for developing rare but severe cutaneous adverse reactions (SCAR) or allopurinol hypersensitivity syndrome [36,37] as well as gout flares, which are otherwise common during initiation of urate-lowering therapy. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Allopurinol'.)

In patients with an eGFR of 30 to <60 mL/min per 1.73 m2, we initiate allopurinol at a dose of 50 mg once daily and titrate the dose upward in 50 mg increments every three to four weeks to the minimum dose needed to achieve and maintain a target serum urate of <6 mg/dL (<357 micromol/L).

In patients with an eGFR of <30 mL/min per 1.73 m2, we initiate allopurinol at a dose equivalent to ≤1.5 mg/day per mL/min eGFR (eg, for a patient with an eGFR of 17 mL/min per 1.73 m2, the daily allopurinol dose would be 25 mg, which can be given more conveniently as 50 mg of allopurinol every two days). We then titrate the dose of allopurinol upward in 50 mg increments every three to four weeks to the minimum dose needed to achieve and maintain a target serum urate of <6 mg/dL (<357 micromol/L).

We do not limit the maximum dose of allopurinol administered to patients with impaired kidney function (within respective regulatory agency-approved dosing limits) [27,36]. Although impaired kidney function does impart an increased risk for severe and often life-threatening but rare serious adverse events with allopurinol, there is no evidence that the incidence of these uncommon but potentially life-threatening events has been reduced following recommended allopurinol maintenance dose-reduction schemes [38]. Additional studies have found that goal serum urate levels can be safely achieved with stepwise serum urate-monitored titration of allopurinol dosing in patients with kidney function ranging from normal to severely impaired [36,38,39]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Urate-lowering therapy in chronic kidney disease'.)

Allopurinol (and febuxostat) should be avoided in patients treated with azathioprine as the metabolism of 6-mercaptopurine, the active metabolite of azathioprine, involves conversion of 6-mercaptopurine to 6-thiouric acid, a reaction that is catalyzed by xanthine oxidase [40]. Thus, 6-mercaptopurine accumulation and severe bone marrow toxicity may result from coadministration of azathioprine and an XOI [41]. However, if the patient taking azathioprine has severe gout and an XOI must be used, we reduce the azathioprine dose (by at least 50 percent) and carefully monitor the white blood cell count. Despite this monitoring, discontinuation of azathioprine is frequently required in many such patients. An alternative option is to switch the patient from azathioprine to mycophenolate mofetil, if possible, since mycophenolate does not interact with allopurinol or febuxostat. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Mycophenolate'.)

Second-line therapy (febuxostat monotherapy) — For patients who are unable to tolerate or who do not reach target serum urate levels with allopurinol, urate-lowering therapy with the XOI febuxostat is an alternative option, provided that the patient is not receiving azathioprine and does not have established high cardiovascular risk. Febuxostat has been found to effectively treat hyperuricemia in kidney transplant patients [42-45]; however, the results of one large trial comparing febuxostat with allopurinol raised concerns about the cardiovascular safety of febuxostat among patients at high risk for cardiovascular events [35]. A subsequent trial in nontransplant patients with gout found no increased risk of all-cause or cardiovascular death or cardiovascular events with long-term use of febuxostat compared with allopurinol, although only one-third of patients in this trial had established cardiovascular disease at baseline [46]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Urate-lowering medications' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Febuxostat' and 'Selection of initial antiinflammatory therapy' above.)

We start febuxostat at a dose of 40 mg once daily and measure the serum urate level after two to four weeks of treatment. If target serum urate has not been achieved, we increase the dose in 40 mg increments and monitor serum urate levels two to four weeks after each dose increase. Regulatory agency-approved dosing limits vary by country (eg, 80 mg daily in the United States and Canada, 120 mg daily in the European Union). Febuxostat dose reduction in kidney function impairment is not required in patients with an eGFR >30 mL/min per 1.73 m2; however, in patients with an eGFR between 15 and 29 mL/min per m2, the febuxostat dose should not exceed 40 mg daily.

Third-line therapy (combination of XOI and uricosuric agent) — In the infrequent patient who fails to achieve target serum urate levels with the available XOIs at the highest doses indicated (ie, the maximum approved dose, dose to achieve target urate levels, or the maximum tolerated dose), combination therapy with both an XOI and a uricosuric agent (benzbromarone or probenecid) may be of benefit. (See 'First-line therapy (allopurinol monotherapy)' above and 'Other therapeutic options' below.)

Uricosuric agents should be avoided in patients at risk for the development of nephrolithiasis or uric acid nephropathy, such as those with uric acid overproduction. In addition, benzbromarone therapy should not be initiated in patients with impaired liver function, and probenecid should not be used in hyperuricemic patients with cystinuria or receiving D-penicillamine. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Uricosuric drugs'.)

Benzbromarone – Benzbromarone is an effective uricosuric agent that can be administered in a single daily dose [47-49] and has been studied in kidney and cardiac transplant recipients [49,50]. This agent, which is not widely available due to concerns about hepatotoxicity and should not be initiated in patients with impaired liver function, has been successful as monotherapy as well as in combination with allopurinol in patients in whom allopurinol titration has been ineffective in establishing target serum urate levels [47,49]. The uricosuric effect of benzbromarone has been reported to be retained during treatment of kidney [49] and cardiac [50] transplant recipients with residual kidney function as low as an eGFR of 20 to <60 mL/min per 1.73 m2. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Choosing the urate-lowering drug' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Agents and dosing'.)

In kidney transplant recipients, benzbromarone is initiated at a starting dose of 25 mg daily, and the dose is titrated in 25 to 50 mg increments up to a maximum daily dose of 100 mg to achieve and maintain the goal serum urate level. Hepatic function as well as serum urate levels should be routinely monitored. (See 'Monitoring the response to urate-lowering therapy' below.)

ProbenecidProbenecid is an effective urate-lowering agent in most gout patients but is likely to be ineffective when the eGFR is <50 mL/min per 1.73 m2 [27]. Probenecid is started at a dose of 250 mg twice daily and titrated in 250 mg increments every three to four weeks according to serum urate levels. Usual maintenance doses necessary to reach the target serum urate level are 500 to 1000 mg twice or three times per day. The maximal effective dose is 3 g per day.

Support for combination therapy with an XOI and uricosuric agent was suggested at the time allopurinol was approved in the United States in 1966 and was included in the 2012 American College of Rheumatology (ACR) guidelines for the management of the hyperuricemia of gout [27]. In our experience, however, this approach has rarely been necessary, because we have had success in achieving goal serum urate levels by titrating doses of allopurinol in the majority of patients.

For a variety of reasons, however, there is continued reluctance to titrate allopurinol to doses higher than 300 mg per day, despite substantial evidence that only a minority of people with gout achieve goal serum urate levels with this restricted dosing. While we strongly prefer monotherapy, we acknowledge the potential for combination therapy with allopurinol and a uricosuric agent to improve the overall outcome of urate-lowering efforts in gout.

Other therapeutic options — In transplant recipients who cannot tolerate allopurinol or febuxostat, or are known to be at high risk of adverse reactions to allopurinol (eg, patients who possess the HLA-B*58:01 allele) [51], we administer uricosuric drug monotherapy with benzbromarone [47,48], if available, or probenecid if the baseline eGFR is ≥50 mL/min per 1.73 m2. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Uricosuric drugs'.)

We do not routinely use uricases (pegloticase, rasburicase) as initial urate-lowering therapy in kidney transplant recipients. In general, we reserve the use of uricases for patients with progressively severe gout who do not have any other treatment options. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Uricase'.)

Antiinflammatory prophylaxis during initiation of urate-lowering therapy — Gout flares are common early in the course of urate-lowering therapy. Thus, in individuals commencing urate-lowering therapy, low-dose antiinflammatory therapy (either colchicine or oral glucocorticoids) for gout flare prophylaxis is recommended [27].

The duration of flare prophylaxis is usually three to six months after the target serum urate level is achieved and confirmed in patients without tophi and for the same duration after the resolution of tophi in patients with more advanced gout [27]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-lowering therapy'.)

In kidney transplant recipients who are initiating urate-lowering therapy, we take the following approach to gout flare prophylaxis:

In most kidney transplant patients, we prefer reduced doses of oral colchicine for gout flare prophylaxis, similar to those used in nontransplant patients with kidney function impairment (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylactic therapy'). Although there is no high-quality evidence in transplant patients, oral colchicine has been shown in nontransplant patients to reduce the frequency of recurrent gout flares early in the course of urate-lowering therapy with an XOI [52] or a uricosuric [53] agent. Due to concerns about increased toxicity and drug interactions, colchicine prophylaxis should generally not be given to patients with severe kidney function impairment (ie, creatinine clearance <30 mL/min), with moderate to severe hepatic impairment, with any degree of both kidney and hepatic function impairment, or treated with cyclosporine or another medication that strongly inhibits the cytochrome P450 system component CYP3A4 (table 1) or the membrane P-glycoprotein (P-gp) multidrug resistance transporter (table 2). (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Colchicine prophylaxis'.)

Patients should be closely monitored for the development of neuromyopathy (eg, paresthesias, numbness, and/or weakness) and/or gastrointestinal symptoms (eg, abdominal pain, diarrhea, and nausea). The nature and severity of such symptoms of colchicine excess should prompt either reduced dose or dosing frequency or discontinuation of colchicine prophylaxis. In addition, laboratory assessment of kidney and hepatic function as well as blood counts should be performed in the course of routine clinical laboratory monitoring of transplant recipients during colchicine treatment or when changes in medications for graft retention or comorbidities are made.

In patients who are unable to receive colchicine, low-dose oral glucocorticoids may be prescribed for flare prophylaxis, although there is no high-quality evidence to support the benefit of prophylactic glucocorticoids for this purpose. We typically give prednisone 2.5 to 7.5 mg once daily. Similar doses of prednisone may also be given to transplant patients already receiving prednisone as part of a maintenance immunosuppression regimen.

We do not use nonsteroidal antiinflammatory drugs (NSAIDs) for gout flare prophylaxis in kidney transplant recipients. Although NSAIDs can usually be used for the short-term treatment of a gout flare without significant adverse consequences, longer-term prophylaxis with NSAIDs is a potential concern in kidney transplant patients since inhibition of kidney prostaglandin synthesis may result in a further reduction in glomerular filtration rate (GFR) and worsening calcineurin inhibitor nephrotoxicity.

Monitoring the response to urate-lowering therapy — Monitoring serum urate levels in response to urate-lowering therapy is critical to ensure that the target serum urate level is achieved and sustained. In kidney transplant recipients who are initiated on urate-lowering therapy, we monitor the following:

In all kidney transplant recipients who are initiated on urate-lowering therapy, we monitor serum urate levels monthly while titrating therapy and after the introduction of drugs that could potentially raise serum urate levels. Once the serum urate target is achieved, we monitor serum urate levels every three months for the first year and every six months thereafter. In addition, most transplant centers monitor a complete blood count, serum creatinine, and electrolytes on a monthly basis in patients receiving urate-lowering therapy.

In kidney transplant recipients receiving allopurinol or febuxostat, we monitor liver function tests (serum aminotransaminases and serum bilirubin) three months after initiation and then every 6 to 12 months. In kidney transplant recipients receiving benzbromarone, we monitor liver function tests monthly.

In kidney transplant recipients receiving colchicine as antiinflammatory prophylaxis during initiation of urate-lowering therapy, we monitor serum creatine kinase levels once or twice yearly, especially in patients receiving interacting drugs, such as statins.

The clinical benefits of urate-lowering pharmacotherapy are not immediately apparent even though a reduction in serum urate at a given dose of oral urate-lowering agent is usually demonstrable within two to three weeks of initiation or dose titration. Reductions in flare frequency or severity are often not apparent until after 6 to 18 months of urate-lowering therapy (even longer in the case of tophus resolution [54] ) and appear to depend upon the extent of baseline urate crystal burden and magnitude of serum urate reduction achieved. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Urate-lowering medications' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Colchicine prophylaxis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

Overview – Reduced uric acid excretion can occur after kidney transplantation, leading to hyperuricemia and, in some cases, gout. This problem is more common among patients treated with calcineurin inhibitors (especially cyclosporine) to prevent graft rejection. (See 'Introduction' above and 'Epidemiology and risk factors' above.)

Clinical features – Gout may emerge de novo in patients after kidney transplantation or in transplant recipients with gout prior to transplantation. In most organ transplant recipients with gout, clinical features of the disease are similar to but may be more severe than those seen in nontransplant gout patients. (See 'Clinical features' above.)

Diagnosis – In kidney transplant recipients who present with new-onset symptoms and signs suggestive of a first gout flare, arthrocentesis and synovial fluid analysis and culture should be performed to establish the diagnosis of gout and to exclude alternative diagnoses, particularly septic arthritis.

In kidney transplant recipients with prior documented gout flares who are experiencing a recurrence of acute joint inflammation, we often initiate flare treatment without a preceding arthrocentesis if the patient's symptoms and signs are the same as those encountered in prior gout flares and do not include fever, chills, or other symptoms/signs of local or regional infection. (See 'Diagnosis of gout in transplant patients' above.)

Treatment of gout flares

New-onset gout – In kidney transplant patients with new-onset gout (ie, without an established history of gout prior to transplantation) and no evidence of joint infection, our approach to the treatment of a gout flare is as follows:

-For patients with a first gout flare who have one or two actively inflamed joints, we suggest arthrocentesis with joint fluid aspiration followed by intraarticular injection of glucocorticoids rather than systemic therapies (Grade 2C). This approach and the rationale are discussed elsewhere. (See "Treatment of gout flares", section on 'Intraarticular glucocorticoids'.)

-For patients who have more than two actively inflamed joints or who have one or two actively inflamed joints but are unable to receive intraarticular glucocorticoids, we suggest oral glucocorticoids rather than colchicine or nonsteroidal antiinflammatory drugs (NSAIDs) (Grade 2C). In patients with glucocorticoid intolerance or with a contraindication to glucocorticoid use, low-dose colchicine and NSAIDs are alternative options.

-For patients who are unable to take oral medications and are not candidates for intraarticular glucocorticoids, we treat with parenteral (intravenous or intramuscular) glucocorticoids. An alternative approach in this setting is the off-label use of anakinra, a short-acting interleukin (IL) 1 receptor antagonist. (See 'Patients with new-onset gout' above.)

Prior history of gout – In kidney transplant recipients with an established prior history of gout, the therapeutic approach to the gout flare is similar to that in patients with new-onset gout. However, certain features of the patient's prior gout history, including the total flare number, recent rate of flare occurrence, and prior flare experience with specific therapies, may also impact the selection of an antiinflammatory agent as well as the duration of treatment. In patients already receiving urate-lowering pharmacotherapy at the time of a gout flare, the urate-lowering medication should be continued without interruption. (See 'Patients with a prior history of gout' above.)

Prevention of gout flares – Pharmacologic urate-lowering measures are indicated in patients with frequently recurrent flares or those who develop tophi or have radiologic evidence of joint damage. In kidney transplant recipients with gout, we titrate the urate-lowering medication to achieve a serum urate level <6 mg/dL (<357 micromol/L). (See 'Overview of prevention' above.)

Initiation of urate-lowering therapy – In kidney transplant recipients who are starting urate-lowering therapy, we initiate urate-lowering therapy at a low dose. Once the decision is made to begin therapy to lower serum urate, the duration of therapy is indefinite and should be continuous to remain effective. (See 'Initiation and duration of urate-lowering therapy' above.)

Selection of urate-lowering therapy – Our approach to the selection of urate-lowering therapy in kidney transplant recipients is as follows:

-For most kidney transplant recipients who plan to initiate urate-lowering therapy, we suggest the xanthine oxidase inhibitor (XOI) allopurinol as first-line urate-lowering therapy, rather than febuxostat or uricosuric agents (Grade 2C). Transplant patients of Chinese, Thai, or Korean ethnicity should be tested for the human leukocyte antigen HLA-B*58:01 allele before allopurinol initiation as it is associated with severe allopurinol hypersensitivity reactions; patients testing positive for this allele should not receive allopurinol. (See 'First-line therapy (allopurinol monotherapy)' above.)

-For transplant recipients who are unable to tolerate or who do not reach goal urate levels with allopurinol, the XOI febuxostat is an alternative option, provided the patient is not receiving azathioprine and is not at high cardiovascular risk. (See 'Second-line therapy (febuxostat monotherapy)' above.)

-For transplant recipients who fail to achieve the target serum urate level with the available XOIs at the highest doses medically indicated, we administer combination therapy with both an XOI and a uricosuric agent (benzbromarone or probenecid). (See 'Third-line therapy (combination of XOI and uricosuric agent)' above.)

-For transplant recipients who cannot tolerate allopurinol or febuxostat or who are known to be at high risk of adverse reactions to allopurinol (eg, patients who possess the human leukocyte antigen HLA-B*58:01 allele), we administer uricosuric drug monotherapy with benzbromarone, if available, or probenecid if the baseline estimated glomerular filtration rate (eGFR) is ≥50 mL/min per 1.73 m2. (See 'Other therapeutic options' above.)

Antiinflammatory prophylaxis – In most kidney transplant recipients, we administer prophylactic therapy with oral colchicine to prevent flares during the initiation of urate-lowering therapy. This approach is similar to that used in nontransplant patients (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-lowering therapy'). In patients who are unable to receive colchicine, low-dose oral glucocorticoids may be prescribed for flare prophylaxis, although there is no high-quality evidence to support the benefit of prophylactic glucocorticoids for this purpose. We do not use NSAIDs for gout flare prophylaxis in kidney transplant recipients. (See 'Antiinflammatory prophylaxis during initiation of urate-lowering therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael A Becker, MD, who contributed to earlier versions of this topic review.

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References

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