Managing Hyperuricemia and Gout in Chronic Kidney Disease

A Clinical Conundrum

Kulanka H. Premachandra; Richard O. Day; Darren M. Roberts

Disclosures

Curr Opin Nephrol Hypertens. 2021;30(2):245-251. 

In This Article

Treatment of Chronic Gout

Reflecting the prevalence of gout, multiple societies from across the world have produced management guidelines, Table 1. The EULAR, ACR and the British Society of Rheumatology guidelines recommend a 'treat-to-target' approach with early commencement of ULT that is dose-adjusted to SUA targets. The recommended target is SUA less than 6 mg/dl (360 μmol/l) in recurrent, polyarticular gout, or less than 5 mg/dl (300 μmol/l) in tophaceous gout.[8] However, there is a lack of consensus regarding commencement and maximum doses of ULT in the context of CKD.

Urate-lowering Therapy

The three main groups of drugs for serum ULT (Table 3) are as follows:

  1. Xanthine oxidase inhibitors (XOIs), including allopurinol and febuxostat.

  2. Uricosuric agents, including probenecid, benzbromarone and lesinurad.

  3. Recombinant uricase agents, such as pegloticase.

When commencing these agents, guidelines recommend the concomitant administration of an anti-inflammatory medicine such as colchicine, NSAIDs or prednisolone to reduce the occurrence of flares. Such prophylaxis should be continued for 3–6 months as shorter durations have been associated with flares upon cessation of prophylaxis.[24,25] Prophylaxis with low-dosage colchicine, adjusted for kidney function, has been stated to be a safer option than low-dose NSAIDs.[12,26,27] However, colchicine treatment can be challenging in advanced CKD due to complications of neutropenia. Shorter acting NSAIDs may be used on a case-by-case basis with careful monitoring when estimated GFR (eGFR) is more than 15 ml/min/1.73 m2, particularly when used for a short duration (e.g. less than 5 days).[22]

XOIs: Xanthine oxidase converts purine metabolites to uric acid. Inhibiting this enzyme reduces the production of uric acid from endogenous and dietary purine sources. Allopurinol and febuxostat are examples of XOIs and allopurinol remains the first-line agent for serum ULT globally given ease of access, familiarity and cost, Table 3.

Allopurinol dosing in CKD has been controversial. Until recently, its maximum daily dose was adjusted according to the patient's creatinine clearance due to concerns surrounding adverse effects, notably allopurinol hypersensitivity.

For example, previous guidance had recommended the allopurinol maintenance dose was 100 mg/day for creatinine clearance 20 ml/min, and less frequent dosing was recommended for more advanced CKD.[28] The EULAR guidelines still recommend that the allopurinol maximum dosage is adjusted to creatinine clearance (specifics not provided) and if the SUA target cannot be achieved at this dose, then a change in treatment is required.[8] However, it is now apparent that this dosing strategy does not achieve target serum urate levels in many patients.

It is now accepted by ACR and British Society of Rheumatology guidelines that higher doses are needed and safe when treating patients with CKD. For example, allopurinol doses of 800–900 mg/day are permitted by ACR and British Society of Rheumatology, Table 1. Recent studies have proven that in patients with both normal and impaired kidney function, slow upward titration of allopurinol dose will not only achieve target serum urate concentrations but is also safe.[29] Changing prescribers' dosing habits remains a challenging undertaking, however.

Allopurinol hypersensitivity, notably severe cutaneous adverse reactions, has been related to a number of risk factors including ethnicity, genetics, allopurinol starting dose, kidney function and concomitant diuretic use. Screening for HLA-B*5801 in Han Chinese and other ethnic East Asian patients, commencing allopurinol at low dose (Table 3) and warning patients of the signs and symptoms of a cutaneous adverse event has been shown to be effective in minimizing this risk.[30–34]

A recent large (n = 6057 participants) Taiwanese observational study concluded that in patients with predialysis CKD stage 5 with concurrent gout or hyperuricemia, there was a lower risk of progression to dialysis with febuxostat use (43% of participants) compared with allopurinol (57% of participants): 42.01 vs. 69.57%; P less than 0.0001.[35]

Uricosuric agents: These agents increase uric acid excretion by inhibiting renal transporters such as urate acid transporter 1 (URAT1), glucose transporter 9 and organic anion transporters (OAT1–3 and OAT10) in the proximal convoluted tubule.

Probenecid, benzbromarone and lesinurad are primarily indicated for gout. Fenofibrate, losartan, SGLT2 inhibitors such as dapagliflozin and high-dose aspirin also have uricosuric effects in addition to their primary indications for dyslipidemia, hypertension, hyperglycemia and inflammation, respectively.

The role of uricosuric agents in the treatment of gout is either in combination with a XOI in patients who do not achieve target SUA levels with XOIs alone or, in those in whom XOIs are contraindicated or not tolerated, Table 3. Recent evidence has shown that benzbromarone, probenecid, lesinurad and verinurad (a more recent URAT1 inhibitor), in combination with XOI is more effective than XOI monotherapy.[36] Examples of these data are discussed below for individual drugs. All patients treated with uricosuric agents should maintain good oral hydration and uricosuric agents should be used with caution in those with a history of nephrolithiasis.

Lesinurad. Three randomized double-blind studies (CLEAR, CLEAR 2, CRYSTAL) have shown lesinurad 200 mg/day in combination with a XOI, is effective and safe in lowering serum urate levels in those who fail to achieve target levels with a XOI alone.[37–39] However, it was noted that some patients developed kidney-related adverse events including a reversible elevation in serum creatinine requiring ongoing monitoring of kidney function. On the contrary, there is a paucity in research looking at dosing lesinurad in CKD. At present, dosing is guided by expert opinion and the product information which recommends against the use of lesinurad in creatinine clearance less than 30–45 ml/min.[40,41]

Probenecid. Probenecid is the most widely available uricosuric agent. The therapeutic effects of probenecid are limited when GFR is less than 50 ml/min due to a reduced ability to block resorption of filtered urate. It is also important to note that probenecid has potential drug–drug interactions with penicillins, methotrexate, naproxen, paracetamol and indomethacin by reducing their clearance.[42]

Benzbromarone. Benzbromarone is a potent URAT1 inhibitor that outperforms probenecid in lowering SUA and tolerability in those who did not achieve SUA targets with allopurinol.[43] A recent prospective, cohort study found when compared with allopurinol, benzbromarone may be more effective at lowering SUA levels and reducing the risk of progression to dialysis among patients with CKD.[44] Its efficacy is also less affected by CKD in comparison with other uricosuric agents, still being effective in GFRs as low as 20 ml/min. Benzbromarone was withdrawn by the FDA due to concerns regarding hepatotoxicity. Some feel this was not in the best interest of patients as the risk of benzbromarone-induced hepatotoxicity is very low and can be safely managed with appropriate patient selection and close monitoring of liver function.[45] Benzbromarone continues to be recommended and used in Europe.

Recombinant uricase: Uricase (urate oxidase), the enzyme that catalyzes conversion of urate to the more soluble purine degradation product allantoin, is absent in humans and Dalmatian dogs. Pegloticase and rasburicase, both recombinant uricase molecules have potent urate lowering effects by supplying the enzyme activity absent in humans. Rasburicase is generally not used for chronic gout due to its immunogenicity and short half-life. Two randomized controlled trials have demonstrated profound serum lowering effects, resolution of tophi and a reduction in both tender joint count and swollen joint count with improvement in quality of life.[46] Phase 3 trial data indicate that pegloticase does not reduce eGFR in CKD and that pegloticase therapeutics are independent of CKD stages 1–4. The major limitation with pegloticase, apart from its expense and limited access, is the propensity to develop antidrug antibodies that lead to infusion reactions, loss of efficacy and increased drug clearance. Gout flares are also particularly more frequent in the first 3 months of therapy compared with other ULT. More potent flare prophylaxis may be needed in patients receiving pegloticase. An open-label phase 1 trial showed no significant effect of hemodialysis on either the stability of serum pegloticase concentrations after a single dose or the capacity of pegloticase to lower SUA without an increase in the incidence, type or severity of adverse events.[47]

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