Colchicine has been shown to be efficacious when used for the treatment of gout flares as well as for flare prophylaxis. The AGREE study reported that low dose colchicine (1.2 mg followed by 0.6 mg 1 hour later), had similar efficacy compared to a high dose strategy (1.2 mg followed by 0.6 mg every hour for 6 hours) for the treatment of gout flares, with less adverse effects. This study excluded individuals with creatinine clearance (CrCL) < 60 mls/min according to the Cockroft-Gault formula [19]. A recent prospective study of 62 prescriptions for colchicine for crystal-induced arthritis (58 gout flares, one case of calcium pyrophosphate deposition disease, and three cases of combined gout and calcium pyrophosphate deposition disease) in 54 individuals with CKD (stage G4, eGFR 15–30 mls/min/1.73 m², stage G5, eGFR < 15 mls/min/1.73 m², or dialysis) reported that low dose colchicine (≤ 1 mg daily) was effective and no serious adverse effects were observed [20]. Colchicine has also been demonstrated to be of benefit for flare prophylaxis when initiating urate-lowering therapy in individuals with gout and an eGFR ≥ 30 mls/min/1.73 m² [21]. Whether colchicine can reduce the progression of CKD has been the subject of recent study. Colchicine was associated with a lower risk of progression of kidney disease in a nested case control study including individuals with eGFR 15–59 mls/min/1.73 m², and gout or hyperuricemia, who received treatments that included allopurinol, febuxostat, and colchicine. Whether colchicine itself leads to better renal outcomes cannot be definitively established from this study, and additional studies for example randomized controlled trials are needed to further evaluate this question [22].

Colchicine has a narrow therapeutic index and its clearance is influenced by renal and hepatic function as well as drug interactions. Overall systemic exposure following a single dose of 0.6 mg of colchicine is doubled in individuals with severe renal impairment (eGFR 15–29 mls/min/1.73 m²) compared to those with normal renal function [23]. Cytochrome P450 3A4 and p-glycoprotein are involved in the metabolism and elimination of colchicine, and medications that inhibit these increase colchicine exposure [24]. Therefore, dose reduction is recommended in individuals with impaired renal function or receiving concomitant cytochrome P450 3A4, and p-glycoprotein inhibitors (Table 1).

NSAIDs have shown benefit over placebo for management of gout flares, and similar efficacy has been demonstrated for non-selective NSAIDs vs. selective coxibs, and NSAIDs vs. steroids [26]. Naproxen demonstrated similar efficacy to colchicine for the treatment of gout flares in an open label randomized trial [27].

Although NSAIDs are effective for managing gout flares, their potential to adversely affect renal function is well established. Of particular concern, reduced renal function increases the risk of NSAID-induced acute kidney injury [28]. There is also often a concern in clinical practice that NSAIDs may lead to the progression of underlying CKD. A systematic review of seven observational studies found that while overall NSAIDs use did not increase the risk of accelerated CKD progression, high dose NSAIDs did, although there was no clear definition for what constitutes high [29]. A prospective cohort study including 4,101 people with rheumatoid arthritis registered in the Swiss clinical quality management database evaluated long-term decline in renal function associated with NSAIDs. No deterioration in renal function in NSAID users compared to NSAID naive, among those with eGFR > 30 mls/min/1.73 m² was identified. However, in people with an eGFR < 30 mls/min/1.73 m², the decline in renal function was faster in those who used NSAIDs [30].

It is also important to note that the risk of adverse renal outcomes associated with NSAID use in people with pre-existing renal impairment is influenced by a number of factors including comorbidities and other medications, and cautious use of NSAIDs may be considered in selected patients with appropriate monitoring [31]. Specialist societies recommend avoidance of NSAIDs in individuals with severe CKD (eGFR < 30 mls/min/1.73 m²), or those with moderate CKD (eGFR 30–59 mls/min/1.73 m²) taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or diuretics [32]. There is a lack of evidence to guide clinicians regarding the safety of NSAIDs in people with end stage renal disease (ESRD), especially those receiving dialysis however some experts also suggest cautious use of NSAIDs in some people may be appropriate [33].

Oral corticosteroids have been shown to have similar efficacy to NSAIDs for the management of gout flares [34, 35]. Intra-articular, intravenous, and intramuscular corticosteroids have also been shown to be effective [36–38]. Parenteral glucocorticoids are typically recommended over ACTH or IL-1 inhibitors in those unable to take oral medications [16]. Glucocorticoids don’t adversely affect kidney function directly but may lead to adverse effects such as hypertension and hyperglycemia which are risk factors for kidney disease [39, 40]. Glucocorticoids are therefore a useful option when colchicine and NSAIDs are contraindicated and other treatments are not available.

The beneficial effect of ACTH for the treatment of gout flares has been demonstrated in clinical trials, case-series, and case reports; however large randomized controlled trials are necessary to fully determine efficacy and safety [41, 42]. A retrospective study of 181 individuals with gout which included 63 individuals with CKD stages 3, 4, or 5, reported that 77.9% responded to 1 mg synthetic ACTH given intramuscularly. The majority of those who didn’t respond did respond to a second dose. Neither efficacy nor adverse effects were reported according to renal function. Among diabetics an increase in fasting glucose 24 hours post-treatment was observed. Other adverse events included a small number of local skin reactions, a case of flushing, oedema, headache, dizziness, and tachycardia/palpitations [43].

IL-1 inhibitors include canakinumab, rilonacept, and anakinra. There is insufficient evidence regarding these treatments in the context of renal impairment for conclusions about efficacy and safety to be made. Major trials of canakinumab and rilonacept excluded individuals with more severe degrees of renal impairment [18]. Anakinra is predominantly eliminated via renal excretion, and plasma clearance is reduced 50% in people with moderate renal impairment (CrCL 30–49 mls/min), 70% in severe renal impairment (CrCL < 30 mls/min), and 75% in people with ESRD. A reduced dosing frequency to 100 mg every second day rather than daily may therefore be appropriate in people with severe renal impairment or ESRD [44]. A retrospective study including 25 people with CKD stage 4 or 5, and six people with renal transplant, reported that anakinra was effective in all individuals, and did not cause significant changes in renal function. One infection occurred three months following treatment. Most individuals received 100 mg daily. Five individuals received anakinra every 48 or 72 hours and four of these were on haemodialysis and received anakinra on days when dialysis did not occur [45].

The use of allopurinol in people with gout and CKD sadly remains controversial due to concerns over the increased risk of the rare but serious allopurinol hypersensitivity syndrome (AHS) or other serious cutaneous adverse reactions (SCARs) including Steven’s Johnson Syndrome and toxic epidermal necrolysis. These concerns were initially based on a small case series and literature review which highlighted that “the development of this syndrome was associated with the use of standard (200 to 400 mg per day) doses of allopurinol in patients with renal insufficiency” [47]. The authors went on to recommend “Avoidance of allopurinol or use of reduced doses in patients with renal insufficiency according to proposed (dosing) guidelines should be adequate to inhibit uric acid production in most patients and may reduce the incidence of life-threatening allopurinol toxicity”. However, it is important to note that two of the six cases in this series were receiving allopurinol for asymptomatic hyperuricaemia and all but one started on doses above 100 mg daily.

When considering the risk of AHS, it is important to note that it is the starting dose of allopurinol in relation to renal function, not the maintenance dose i.e., the dose required to achieve target SU, that has been associated with AHS [48, 49]. Based on these data a maximum allopurinol starting dose of 100 mg daily is recommended with a lower dose in those with CKD [16, 17]. There is little doubt that the restrictive doses proposed by Hande et al. [47] (Table 2) result in failure to achieve target SU in the majority [50]. However, in those who tolerate allopurinol, monthly dose escalation to achieve target SU has been shown to be safe and effective [51, 52]. In a post hoc analysis, of this dose escalation trial there was no difference in the percentage of participants achieving target SU based on renal function: CrCL < 30 mls/min 64.3%, CrCL ≥ 30 to < 60 mls/min 76.4%, and CrCL ≥ 60 mls/min 75.0% (p = 0.65) [53]. Interestingly the mean allopurinol dose was significantly lower in those with CrCL < 30 mls/min as compared to those with CrCL ≥ 30 to < 60 mls/min or CrCL ≥ 60 mls/min [mean (standard deviation (SD))]: 250 (43), 365 (22), and 460 (19) mg/day, respectively (p < 0.001)]. Finally, the majority of those who do not achieve target SU on CrCL-adjusted doses of allopurinol require an increase of ≤ 200 mg daily to achieve target SU [54]. It is also important to note that a large population-based cohort study reported that neither allopurinol initiation, nor achieving target SU with allopurinol, nor allopurinol dose escalation was associated with increased mortality in people with gout and concurrent CKD [55].

In individuals with ESRD receiving dialysis about 25% will have gout [56]. While haemodialysis can clear urate, it may not be sufficient to reduce SU to below the treatment target [57]. In a series of six individuals with gout on hemodialysis the median [interquartile range (IQR)] SU immediately prior to dialysis was 5.9 mg/dL (4.7–8.9 mg/dL). Serum urate dropped precipitously during dialysis and was back to baseline or within 80% of baseline by 42 hours after dialysis [58] suggesting SU should be measured pre-dialysis. However, in another study SU dropped below the point of saturation with hemodialysis and remained low; however, in this study, not all individuals were hyperuricaemic or had gout [59]. Oxypurinol, the active metabolite of allopurinol, is also efficiently removed by dialysis and allopurinol dosing pre-dialysis results in about a 25–35 % reduction in exposure compared to post-dialysis [60]. Thus, for individuals on haemodialysis, allopurinol should be administered post-dialysis and if low doses do not lead to achievement of target SU the dose should be gradually increased.

Sulphinpyrazone, an alternative uricosuric, may be effective in gout [79] but there is virtually no data on its use in people with CKD and gout. Sulphinpyrazone has been associated with acute kidney injury typically acute tubular necrosis in individuals with volume depletion [80].

Pegloticase, a recombinant uricase, rapidly metabolizes urate to the more water soluble allantoin which can be readily excreted through the kidneys. Pegloticase was FDA-approved for gout in 2010 and is currently considered last line therapy for those who do not achieve target urate or do not tolerate other urate-lowering therapies.

There is limited data on the use of pegloticase 8 mg every two weeks in people with gout and CKD. In a post-hoc analysis of two replicate phase III clinical trials using pegloticase 8 mg every two weeks, which included 103 (49%) people with CKD stage 3 (n = 80) or 4 (n = 23) there was no difference in the percentage of participants who had plasma UA < 6.0 mg/dL for 80% of the time during months 3 and 6 combined by CKD stage (32% CKD 1; 23% CKD 2; 35% CKD 3, and 39% CKD 4) [81]. Importantly there were no differences in adverse effect profiles when stratified by CKD stage [81].

Infusion reactions and loss of efficacy have been limiting factors with pegloticase. Both of these are thought to occur secondary to the development of anti-drug antibodies which accelerate pegloticase clearance [82, 83]. Recently attention has focused on co-administration of immunosuppressive agents in order to prevent the development of anti-drug antibodies thereby prolonging the efficacy of pegloticase therapy. Methotrexate [84, 85], mycophenolate mofetil [86], leflunomide [87], and azathioprine may all improve responder rates and/or persistence with therapy. Clinicians will need to consider the implications of CKD when co-administering with pegloticase.

An open-label phase I study examined the pharmacokinetics and pharmacodynamics of a single intravenous dose of pegloticase 8 mg 3 hours prior to hemodialysis in 12 participants with gout. No significant effect of hemodialysis on the stability of serum pegloticase concentrations, urate-lowering effect or adverse event profile was observed [88]. These data are reassuring but there are no data on people with gout receiving longer term pegloticase.