While the use of NSAIDs in patients with CKD should be avoided as much as possible, their use with caution is acceptable in smaller doses and for shorter treatment durations, especially in patients with GFR 30–60 mL/min/1.73 m² [29, 31]. Patients with DM, Hypertension, heart failure or who use diuretics or angiotensin-converting enzyme (ACE) inhibitors are at greater risk for acute kidney injury (AKI) and NSAIDs should be avoided or used with extreme caution even in mild CKD with monitoring of renal function. In healthy individuals, prostaglandins play a minimal role in maintaining renal hemodynamics. Consequently, the administration of NSAIDs, potent inhibitors of prostaglandin synthesis, is unlikely to have a significant impact on renal function. Diuretics are used to good effect in patients with congestive heart failure or hypertension but lower plasma volume. The addition of ACE inhibitors and NSAIDs to diuretics, the triple whammy, lowers trans glomerular hydrostatic pressure by blocking renal autoregulation leading to AKI [32, 33]. However, in patients with GFR ≤ 30 mL/min/1.73 m², NSAIDs are contraindicated due to adverse renal effects such as acute renal failure, nephrotic syndrome, interstitial nephritis, papillary necrosis, rhabdomyolysis and electrolyte disturbances from reduced potassium and sodium excretion [34]. NSAIDs should be used with caution if at all in kidney transplant recipients treated with calcineurin inhibitors, even those with near normal GFR due to the risk of AKI [35, 36]. In patients on dialysis, especially those who are anuric, renal side effects may be of less concern, but it is still prudent to limit long-term use due to the risk of adverse cardiovascular and gastrointestinal effects.

Colchicine is a lipophilic alkaloid drug that exhibits anti-inflammatory and anti-fibrotic properties through disruption of the microtubule system and inhibition of neutrophil adhesion and recruitment [37]. Colchicine is efficacious within the first 36 hours from the onset of symptoms of acute gout, at a dose of 1.2 mg followed by 0.6 mg one hour later (Table 1). After initial dosing, colchicine can be continued once or twice daily until the resolution of symptoms in patients with normal renal function [19]. This initial dosing schedule can be safely administered in patients with advanced CKD if not repeated more than once within a 2-week interval. For patients with advanced CKD, a reduced dose of 0.3 to 0.6 mg every other day, or 0.6 mg three times a week, can be used in individuals with lingering symptoms of the acute attack. Since colchicine undergoes partial renal clearance, there is potential for increased toxicity in patients with advanced CKD including anorexia, nausea, vomiting, diarrhea, rhabdomyolysis, neuropathy, myopathy, and bone marrow suppression. Colchicine is not cleared by dialysis. It can be used for treatment of acute gout flares in dialysis patients with a single dose of 0.6 mg, not to be repeated for 14 days (Table 1). Colchicine has also been noted to interact with various drugs such as statins, non-dihydropyridine calcium channel blockers, calcineurin inhibitors (such as cyclosporine) and macrolides that typically increase the half-life of colchicine leading to increased toxicity [30, 38].

Glucocorticoids exert their anti-inflammatory effects by reducing the expression of pro-inflammatory genes by activation of glucocorticoid receptors and the concomitant inhibition of pro-inflammatory transcription factors such as nuclear factor kappa-B (NF-κβ) and activating protein-1 (AP-1) [39]. Glucocorticoids (administered either orally or via the intramuscular, intravenous, or intra-articular route) are the preferred modality of treatment for the management of acute gouty arthritis in patients with advanced CKD. There is no consensus about the most effective dosing regimen for glucocorticoids, although it may be reasonable to start with 0.5 mg/kg of body weight daily for the first few days followed by dose tapering (Table 1) [19]. A short course of glucocorticoids has been noted to have a similar efficacy as NSAIDs in patients with acute gout and CKD, making it a safe modality of treatment in these patients [40]. There have been no randomized trials comparing the efficacy of glucocorticoids and colchicine for the treatment of acute gouty arthritis in patients with CKD. Systemic glucocorticoids should be avoided in patients with brittle diabetes where even short courses may precipitate diabetic ketoacidosis. Caution should also be employed in patients with uncontrolled hypertension, congestive heart failure or untreated infections. In patients with the above-mentioned comorbidities, especially those with a monoarticular gout flare, intra-articular administration of glucocorticoids is comparatively safer and preferred given a lower incidence of adverse effects.

Interleukin-1 inhibitors target the NLRP3 inflammasomes and prevent the action of interleukin-1 beta on cells, thereby exerting an anti-inflammatory action in the affected joint [39]. Interleukin-1 inhibitors such as anakinra (recombinant interleukin-1 receptor antagonist), canakinumab (monoclonal interleukin-1 antibody) and rilonacept (soluble interleukin-1 decoy receptor) reduce inflammation and are a safe and efficacious albeit off-label treatment option in the management of acute gout in patients with advanced CKD. The usual dose of anakinra for the management of acute gout is 100 mg daily, however, some experts recommend reducing the dose of anakinra in patients with GFR < 30 mL/min/1.73 m² to 100 mg every other day due to its renal clearance, unfortunately, there is no data presently to compare various doses of anakinra in these patients and it continues to be dosed based on physician and patient preference (Table 1). It should be noted that anakinra is used intravenously in much higher doses for Macrophage Activation Syndrome and a dose reduction for gout in CKD may not be required [41]. Anakinra seems to be a safe and effective short-term therapy for acute gout in patients on dialysis and kidney transplant recipients based on small case series [42]. A dose reduction is not required for canakinumab or rilonacept for the management of acute gout in patients with advanced CKD. Despite the safety and efficacy of these drugs, lack of accessibility and high cost have limited their use, and they are currently recommended as second-line treatment in the management of acute gout, even in patients with advanced CKD [43]. The adverse effects of interleukin-1 inhibitors, although infrequent, include injection site reactions and infections [39]. Their safety profile makes them attractive options for hospitalized patients with uncontrolled DM or heart failure.

ACTH belongs to the melanocortin group of proteins that activate 5 melanocortin receptors (MC-R). ACTH is the only ligand for MC-2 R located on the adrenal glands and this binding stimulates adrenal corticosteroid release. However, ACTH is believed to possess steroid-independent anti-inflammatory properties. In the periphery, ACTH binds the MC-1 R and MC-2 R downregulating transcription factor NF-κβ, inhibiting the expression of proinflammatory cytokines and adhesion molecules [44]. ACTH, administered either subcutaneously or intramuscularly, has been used for managing acute gout off-label, especially in patients who are unable to tolerate oral medications or in patients where other agents are contraindicated due to comorbidities. A review of 181 acute gout patients, 34% with CKD stages 3−5 treated with synthetic ACTH at a dose of 1 mg demonstrated a 77% response rate. Additionally, over 80% of non-responders responded to a second dose administered the following day [45]. Synthetic ACTH is available in the European Union as Tetracosactide. Currently, no dose adjustments are recommended for advanced CKD patients. The duration of treatment with ACTH should be carefully monitored to prevent complications from long-term use such as suppression of the hypothalamic-pituitary-adrenal axis, DM, and ocular side effects such as cataracts and macular exudates [46].

For patients with normal renal function, colchicine is dosed at 0.6 mg twice daily. For those with CKD, it is reduced to once daily, and for advanced CKD, to once every 2–3 days and the dose lowered to 0.3 mg (Table 2). The recommended dose for prophylaxis in patients on dialysis is 0.3 mg twice weekly (Table 2). As mentioned above, colchicine should be used with great caution in transplant patients taking strong inhibitors of P-glycoprotein or CYP3A4 such as cyclosporine and tacrolimus respectively [38]. The risk of colchicine toxicity is markedly increased in patients with advanced CKD or on dialysis or renal transplant recipients [48, 49].

Hypertension and hyperlipidemia are common in CKD and some CYP3A4 inhibitors [diltiazem, verapamil and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] are used in the treatment of these comorbid diseases. The addition of colchicine to CYP3A4 inhibitors or vice versa may lead to toxicity manifested by vomiting, diarrhea, myopathy, neuropathy and rhabdomyolysis. Screening for colchicine toxicity with complete blood cell count and creatine kinase (CK) every 6 months was recommended for patients on prophylactic colchicine with CKD [49, 50]. However, it should be noted that an intercurrent illness, worsening of renal disease or addition of an offending medication may result in the acute onset of toxicity within days to weeks that monitoring every 6 months would not identify. Providers should remain vigilant in reviewing any medication changes, the development of an acute intercurrent illness or for early signs of toxicity (vomiting or diarrhea) in their patients with gout and CKD and should maintain a low threshold for discontinuing colchicine [48].

Low-dose prednisone (5–10 mg/day) is considered safe for prophylaxis in advanced CKD (Table 2). However, monitoring for the development or worsening of DM or hypertension should be considered. Chronic low dose glucocorticoids increase the risk for osteoporosis and appropriate treatment, or monitoring may be necessary [51].

Interleukin-1 inhibitors, such as anakinra and rilonacept can be safely used off-label for prophylaxis of gout in patients with advanced CKD. Anakinra was successfully used to prevent recurrent acute gout attacks in a report of three patients [52]. Initially used to treat the acute gout attacks in patients with chronic gout, anakinra was continued at 100 mg daily while the dose of ULT was optimized, in one patient flares were prevented even with dose reduction to every third day [52]. However, the frequent dosing of anakinra makes it cumbersome for long-term treatment, thus, longer-acting agents such as rilonacept are sometimes preferred for prophylaxis (Table 2) [53, 54].

Allopurinol is an analogue of hypoxanthine and is metabolized to oxypurinol which inhibits xanthine oxidase preventing the formation of uric acid [58]. Allopurinol is effective in reducing acute attacks and tophi if the recommended target sUA of < 6.0 mg/dL (< 0.5 mg/dL for tophaceous disease) is achieved [23, 24]. Although the United States Food and Drug Administration (FDA) approves allopurinol up to 800 mg daily, many clinical trials have used a maximum dose of 300 mg, consequently practitioners do not prescribe the higher doses required to achieve the target sUA leading to the undertreatment of gout [59]. Allopurinol is well tolerated and although skin reactions are reported in 13% of patients, severe reactions are extremely rare < 0.003 [60]. Oxypurinol, the active metabolite of allopurinol, is predominantly eliminated by the kidneys leading to safety concerns in patients with advanced CKD.

There are no randomized trials evaluating the effectiveness and safety of allopurinol in patients with gout and CKD ≥ 4, however, the STOP gout trial that compared allopurinol to febuxostat included patients with stage 3 CKD [60]. Both allopurinol and febuxostat decreased sUA and controlled flares in the stage 3 CKD patients as effectively as those with normal renal function. These results provide some reassurance for studying allopurinol in more advanced renal disease.

Although rare, AHS remains a major deterrent to its use in advanced CKD. Retrospective studies provide evidence that these reactions are more likely with higher starting doses of allopurinol > 100 mg/day and adjusting the dose to 1.5 mg per unit of eGFR maybe safe [57, 61]. Further caution should be exercised in patients with advanced age or those with the HLA-B*5801 gene, which is most common in Asians (Koreans, Han Chinese and Thai) and African Americans. These factors represent additional risks for developing AHS [62]. Patients with moderate to severe renal disease (CKD ≥ stage 3) are at greater risk for the progression of gout and development of tophi, consequently the ACR recommends initiating allopurinol after the first gout attack for this group [23, 25, 26]. It is, nevertheless, imperative to adopt the treat-to-target approach to achieve the best results from allopurinol even in the presence of advanced CKD [23, 24]. Additional evidence for the safety of allopurinol in patients with CKD stage 3 and 4 is provided by the CKD-FIX trial that was designed to examine the renal protective effect of allopurinol in patients with hyperuricemia but without gout and although it was a negative study it is reassuring that a renal safety signal was not identified [63]. However, the STOP gout study reported more episodes of AKI in the allopurinol arm compared to febuxostat [60]. It is unclear if this is related to congestive heart failure and diuretic use (there were more patients with CHF randomized to allopurinol) or if there was a role for allopurinol. Despite these concerns allopurinol remains a ULT option for patients with gout and advanced CKD. However, the starting dose should be reduced to 50 or 100 mg daily or even every other day in patients with advanced CKD (Table 3). The dose should be titrated every 4 weeks to achieve the target of < 6.0 mg/dL monitoring complete blood counts, serum creatinine and hepatic transaminases for signs of toxicity.

Febuxostat is a potent non-purine analogue inhibitor of xanthine oxidase [64]. In contrast to allopurinol, it is metabolized by glucuronidation and oxidation in the liver and its serum urate-lowering ability is not modified in renal disease [65]. Febuxostat at doses of 80 mg and 120 mg daily proved efficacious in lowering sUA, reducing flares and tophus size, however, 80 mg daily is the maximum dose approved in the US due to concerns of cardiovascular disease [56, 59]. The efficacy of febuxostat in stage 4 CKD was demonstrated in one randomized trial and evidence of efficacy for advanced renal disease was reported in a few retrospective studies [66–68]. The starting dose for febuxostat ranged from 40 to 80 mg/day however in the retrospective study by Juge et al. [66] a few patients were started at 120 mg/day. Like allopurinol, febuxostat may be used in patients with advanced CKD. However, a lower starting dose of 20 to 40 mg daily may be prudent, and the dose similarly titrated to achieve the target sUA (Table 3).

Both allopurinol and febuxostat have been shown to be safe and effective in kidney transplant recipients [69]. Oxypurinol is readily dialyzable leading to the suggestion that allopurinol should be dosed post-dialysis (Table 3) [70]. Concomitant use of allopurinol or febuxostat with azathioprine is not recommended in renal transplant recipients due to the risk of bone marrow suppression [71]. This is not an issue with mycophenolate.

Gout is associated with hypertension DM and cardiovascular disease in addition to renal disease. The results of the CARES trial raised concerns of increased cardiovascular mortality with febuxostat resulting in a black boxed warning from the FDA [56]. However, 56% of subjects in CARES did not complete the study and the results of two subsequent studies, the FAST and STOP Gout trails did not reveal a cardiovascular safety signal for febuxostat relative to allopurinol in patients with gout [60, 72].

Febuxostat and allopurinol are often discontinued or held due to concerns of worsening CKD although it is actually hyperuricemia that is associated with the progression of renal disease [73, 74]. Several recent large trials examined the ability of both allopurinol and febuxostat to slow the progression of CKD. The FEATHER trial enrolled 467 patients with asymptomatic hyperuricemia and stage 3 CKD to receive febuxostat or placebo for 108 weeks. Although there was no benefit, the stability of kidney function over the study is reassuring for patients with gout and CKD [75].

Pegloticase is a recombinant mammalian uricase linked to polyethylene glycol. It rapidly degrades uric acid to allantoin that is more soluble and easily excreted by the kidneys. Pegylation prolongs the half-life to 14 days, allowing it to break down uric acid decreasing the plasma levels to undetectable encouraging the translocation of tissue uric acid to the plasma compartment [76]. The result is a significant decrease in total body uric acid and resorption of tophi. A post hoc subgroup analysis of patients with stage 3 or 4 CKD enrolled in 2 pivotal trials was performed. Pegloticase was equally efficacious in lowering sUA regardless of stage of CKD and renal function was unchanged throughout the six-month trial and the 2.5-year open-label extension [77]. Unfortunately, only 42% of patients treated with pegloticase maintain uric acid < 6.0 mg/dL and 26% suffered infusion reactions [78]. Both events are attributable to the development of antidrug antibodies. The addition of methotrexate 15 mg weekly starting 4 weeks prior to the pegloticase improved efficacy to 78% and reduced infusion reactions to 7.1% [79]. Methotrexate is contraindicated in advanced CKD and would not be an option to improve the efficacy of pegloticase in this group. Mycophenolate mofetil (MMF) an immunosuppressant administered 2 weeks prior to pegloticase was more effective compared to placebo at 12 weeks in maintaining uric acid < 6.0 mg/dL and reducing infusion reactions [80]. In an open-label study with 10 patients co-treated with leflunomide and pegloticase 70% were able to continue on therapy with therapeutic sUA for 26.6 ± 14 infusions [81, 82]. In a small open-label phase 4 trial. Pegloticase seemed to be safe and effective in reducing urate levels in kidney transplant recipients with uncontrolled or tophaceous gout [83]. The standard pegloticase dosing of 8 mg every 2 weeks may be used in patients with advanced CKD, on dialysis or renal transplant recipients (Table 3).