One afternoon during my year as Chief Resident, I was asked to cover the resident Clinic at our Veteran’s Affairs (VA) hospital. One of the senior residents presented a patient who had stage 4 CKD. Several weeks prior, he had been treated through the walk-in clinic for his second flare of monoarticular gout and was started on allopurinol 50 mg daily after the flare resolved, but he still had an elevated serum urate. He concluded with, and I’m paraphrasing, that there was nothing else [we] could do because of his CKD. Not the first time I’d heard it, and not the last, but that encounter stuck with me and left me asking the question, “Is he right?”
Gout is the most common form of inflammatory arthritis, and with rising numbers of CKD patients, as well as the complex interplay of the two diseases, the overlap is obvious. This topic was reviewed in a recent review article published in AJKD by Vargas-Santos and Neogi. They illustrate the complexities of these patients but emphasize that with appropriate attention and follow-up, we can safely manage both their acute gout attacks as well as their hyperuricemia. The authors also review the existing evidence for the treatment of asymptomatic hyperuricemia as it relates to CKD progression, concluding that urate lowering therapy (ULT) has not definitively demonstrated improvement in CKD outcomes.
We have all seen patients with CKD who flutter from flare to flare, without ever achieving adequate control of their hyperuricemia. Given that this is likely driven by provider practice, which is in turn driven by uncertainty around the use of urate lowering agents in this population, those patients exist as “urate time bombs,” waiting to explode into their next episode of articular disease. The authors emphasize that this does not need to be the case, and that the treatment paradigm among patients with and without CKD is the same. They note that management is driven by four principles: (1) lower serum urate levels – with regular monitoring of urate levels, (2) provide prophylaxis while correcting hyperuricemia, (3) treat flares that occur, and (4) recommend urate-lowering lifestyle/dietary changes.
The most commonly prescribed agents for urate lowering are the xanthine oxidase inhibitors, namely allopurinol and febuxostat. Because of cost considerations, allopurinol is certainly more commonly prescribed in my practice. Table 1 reviews these and the other available options very nicely – and it highlights the limited utility of the alternate options in more advanced CKD and ESRD.
There is often angst among treating physicians around dose escalation of xanthine oxidase inhibitors in CKD patients, especially allopurinol, due to the risk of hypersensitivity reactions. Indeed, the increased risk for allopurinol hypersensitivity syndrome (AHS) in CKD patients was first described over three decades ago by faculty at the very VA hospital where I was supervising that clinic. That article in 1984 by Hande et al suggested that urate levels may be controlled in CKD patients with lower doses of allopurinol than those needed among the general population and that use of “standard” dose may associate with increased risk of AHS. That line of inquiry led to changes to the package insert – and to changes in the practice patterns of physicians – that continue to contribute to the undertreatment of hyperuricemia. That recommended dosing strategy has never been shown to reduce the risk of adverse events, and as Vargas-Santos and Neogi point out, leads to chronic undertreatment of hyperuricemia. Like so much else in medicine, so long as we counsel well and “start low, and go slow,” the most worrisome adverse events can be minimized and caught early. The authors further emphasize the importance of urate monitoring and continued dose adjustment to achieve the desired urate.
Another principle of management that trainees often struggle with is the use of agents concurrent with ULT initiation to mitigate the risk of an acute gout flare. The American College of Rheumatology (ACR) recommends treating patients beginning ULT with anti-inflammatory agents for at least 6 months after initiation of therapy or 3 months after urate goal is achieved or tophi resolve, whichever comes first. Given that non-steroidal anti-inflammatory drugs are relatively contraindicated in people with advanced CKD, the available armamentarium is more limited. The classic alternative, colchicine, also gives us pause when we consider its chronic use in the setting of CKD because of the risk of neuromyotoxicity and marrow suppression. The authors highlight that it can still be used in our patient population – just remember to dose-reduce and monitor closely for signs and symptoms of toxicity.
Vargas-Santos and Neogi also discuss the management of acute gout flares, with a nice discussion of lesser-used therapies, including ACTH and IL-1 inhibitors (Table 3). They note that patients with advanced CKD who are suffering from a gout flare should generally avoid NSAIDs, and if they are already receiving colchicine for prophylaxis, it should not be dose-escalated as a treatment. Glucocorticoids are the safest anti-inflammatory with respect to renal function, but bring their own unique set of obstacles around long-term use. The less commonly prescribed agents, ACTH and IL-1 inhibitors, are presented as options in patients for whom the classical alternatives are not suitable, though the authors note that these agents come with a paucity of trial data around their use in this setting.
The review closes with the oft-asked question of hyperuricemia treatment for asymptomatic patients as a modifier of CKD progression. Indeed, they lay out the argument using several observational and randomized trials as the available evidence, but conclude that such data remains insufficient to recommend for or against the treatment of asymptomatic hyperuricemia. For now, patients suffering from gout should be treated aggressively, but treat asymptomatic hyperuricemia with an eye on the balance between uncertain benefit and the risk of hypersensitivity and pill burden. The jury is still out on its effect on CKD progression.
All AJKD In Practice articles are available in this collection.