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26, 27 There are other mechanisms also being targeted, though none are advanced enough in their development for approval or clinical use. Table 1 Urate-lowering agents with recommendations for urate-lowering management in patients with normal and reduced kidney function. Optimally, ULT should be initiated when the patient is free of a gout flare, although the 2012 ACR gout treatment guidelines propose that ULT could be started during a gout flare as long as effective anti-inflammatory therapy has been established. Thus, XOIs decrease the production of UA from endogenous and dietary purine sources and are considered first-line therapy, though uricosurics are an acceptable alternate first-line option. 18 Allopurinol Allopurinol, a purine base analogue available since the 1960’s, is the most widely used ULT. Although it is effective, its appropriate use has been hampered by certain misconceptions. This is partly related to the need for multiple tablets and twice daily dosing of probenecid, which, until recently, was the only uricosuric agent available in the US. Lesinurad, a uricosuric URAT-1 and OAT-4 inhibitor approved by the FDA in 2015, must be co-prescribed with a XOI, because, in randomized trials, lesinurad monotherapy was associated with acute kidney failure more commonly than the comparator arms; thus an indication for monotherapy was not pursued. Creatinine rises noted during these trials were generally reversible. Patients on a uricosuric agent must assure adequate fluid intake due to risk of nephrolithiasis. Because uricosurics lose efficacy as kidney function declines, probenecid is not recommended for those with CrCl While not developed as drugs that reduce urate, two commonly used drugs have uricosuric properties: losartan and fenofibrate. Losartan, an angiotensin receptor blocker, is commonly used in all stages of CKD. The safety of fenofibrate is uncertain in advanced kidney disease, particularly in combination with statins due to increased risk of rhabdomyolysis. Uricase Pegloticase is a pegylated recombinant porcine uricase, the enzyme responsible for converting UA to allantoin, which is more soluble than uric acid and therefore more easily eliminated. Its approved use is for gout that is refractory to oral ULT. Pegloticase is administered intravenously every two weeks, with the current label supporting 6 months of therapy, though longer term therapy has been successfully reported. Following completion of that regimen, patients are transitioned back to oral ULT. Because pegloticase is derived from porcine uricase and is pegylated, there is a risk for immunogenicity, with infusion reactions and anaphylaxis.