Xanthine oxidase (XO) is an enzyme that catabolizes the transformation of hypoxanthine into xanthine and xanthine into UA. XOIs are considered the treatment of choice in patients with gout.

Allopurinol is a structural analog of hypoxanthine, which causes a competitive inhibition of XO. In addition, allopurinol is a substrate of XO that catabolizes its transformation to oxypurinol. For years, it has been established that the dose of allopurinol should be corrected for the reduction of renal function to achieve the same level of oxypurinol as would be achieved by a dose of 300 mg, in a patient with normal renal function.5 This dose adjustment was developed to reduce the occurrence of allopurinol hypersensitivity syndrome (AHS), which is characterized by rash, eosinophilia, leukocytosis, fever, hepatitis, acute renal failure and high mortality. However, with this strategy, less than 50% of subjects with CKD, achieve the target of UA. Recent studies6 have shown that the maximum peak dose of allopurinol is not associated with increased AHS. However AHS is associated with the initial dose of allopurinol and also with genetic variants (HLA B5801); furthermore, the risk is higher during the first 6 month of treatment.7,8 Thus, the latest recommendations indicate that the dose of allopurinol can be increased in patients with CKD. It should be started with a low dose of 50 mg/day in CKD patients stage 4 and 5 (GFR < 30 ml/min) and with a dose of 100 mg/day in the remaining CKD stages. Allopurinol may be used in patients on hemodialysis and peritoneal dialysis. Starting with the lowest dose, the numbers of gout attacks are reduced with less incidence of AHS and other allergic reactions. Subsequently the dose should be titrated progressively being increased by 50−100 mg/day every 2–5 weeks until the desired level of UA is achieved.

Febuxostat is a potent non-purinic XO inhibitor that inhibits both, the oxidized and reduced forms of the enzyme. Clinical studies have demonstrated a greater efficacy in the reduction of UA with the use of febuxostat than with 200−300 mg allopurinol.9 Febuxostat can be administered to CKD patients with GFR less than 30 ml/min/1.73 m2. However, data on its efficacy in these cases are scarce.10 With regard to adverse effects, severe skin reactions and even Stevens-Johnson syndrome have been reported in patients who have had in the past a reaction to allopurinol. Therefore the European and Canadian Medicines Agency have issued a warning about these adverse effects and it should not be used in patients who have had previous serious reactions.11,12 Unlike allopurinol, no association has been found with HLAB5801.13

The CARES study (Cardiovascular Safety of Febuxostat and Allopurinol in patients with gout and cardiovascular comorbidities)14 included 6,190 patients with gout who were randomized to receive allopurinol or febuxostat. Patients who received febuxostat did not have more cardiovascular events such as acute myocardial infarction, arrhythmias, unstable angina or hospitalization due to heart failure. However, cardiovascular mortality was significantly higher in the febuxostat-treated group as compared with allopurinol-treated group HR 1.34 (1.03–1.73), similar findings were obtained regarding all-cause mortality (HR 1.22 (1.01−1.47). This clinical trial included patients with mild CKD (stage 1–3) and one of its main limitations was the high dropout rate due to different reasons. These results led to the generation of a warning from the FDA (https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-death-gout-medicine-uloric-febuxostat) and from the AEMPS (https://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/seguridad/2019/NI_MUH_FV-10-2019-febuxostat.htm) warning that febuxostat increases overall and cardiovascular mortality, so it should not be recommended in patients with cardiovascular risk. However, the CARES study, published in the NEJM, has some limitations. First, as previously mentioned, there was a dropout rate of almost 50% in the treated group; secondly, there were very different findings in relation to fatal and non-fatal cardiovascular events, with no significant differences in non-fatal cardiovascular events in the febuxostat-treated group. And finally, without a placebo group, these results do not answer the question of whether treatment with febuxostat increases the risk of fatal cardiovascular events, or whether treatment with allopurinol decreases them. Furthermore, subsequent studies did not support these results. An observational study from the MEDICARE registry15 in 24,936 patients older than 65 years with gout treated with febuxostat vs allopurinol found no increased cardiovascular risk or mortality in patients treated with febuxostat as compared to those treated with allopurinol. In June/2019 it was published the clinical trial FREED (Febuxostat for Cerebral and Cadiorenovascular events Prevention Study) in which 1,070 elderly patients with hypertension and hyperuricemia were randomized to treatment with febuxostat or standard treatment. Treatment with febuxostat decreased the primary composite endpoint (HR 0.750 (0.592−0.950), p = 0.017), and did not increase cardiovascular mortality.16 In 2020, the results of the FAST study (Febuxostat vs Allopurinol Streamlined Trial) were published; the study compared the effect of febuxostat vs allopurinol in the prevention of cardiovascular events, showing no superiority of one drug over the other, and once again the study confirmed the long-term cardiovascular safety of febuxostat vs allopurinol.17 Therefore, there is insufficient data to support the contraindication of this drug, although it is recommended to be used with caution in patients with history of ischemic heart disease and heart failure.18 In Spain, both XO inhibitors are in the first line of treatment in patients with gout.

Uricosurics decrease the concentration of UA by increasing the renal excretion of UA. Uricosurics act through transporter proteins that are involved in the reabsorption and/or secretion of UA. Among these transporters are URAT1, GLUT9, and transporters of organic anions: OAT 1, OAT 3, OAT 4 and OAT10. Currently only benzbromarone has AEMPS approval. Probenecid, sulfinpyrazone and lesinurad are not approved in Spain.

Benzbromarone is a potent uricosuric that can be administered in all patients with different degrees of renal disease. This drug is not approved by the FDA and by some European countries because of its hepatotoxicity.19 Lesinurad is a URAT1 and OAT4 inhibitor that must be administered together with an XOI. The use of lesinurad has been associated with acute renal failure and it is contraindicated in subjects with GFR less than 30 and is not recommended if the GFR less than 45 ml/min/1.73 m2.20 It was marketed and approved by the AEMPS and subsequently withdrawn from the market due to high risk of acute renal failure. Uricosurics should be avoided in patients with nephrolithiasis and uricosuria greater than 800 mg/24 h.

The use of diuretics is the most frequent cause of secondary hyperuricemia. Loop diuretics and thiazides inhibit the organic anion transporters (OAT1 and OAT3) that are involved in the active uptake of UA in the renal proximal tubules. Hydrochlorothiazide also significantly increases UA uptake through the organic anion transporter OAT4. In addition, diuretics induce salt and water loss, which causes volume contraction, stimulating UA reabsorption. In contrast, many drugs currently used to treat various cardiovascular diseases have a positive secondary effect on UA metabolism and levels. Among them it should be highlighted that fenofibrate25 and atorvastatin increase the fractional excretion of UA.26

Furthermore, inhibitors of the sodium-glucose cotransporter type 2 (iSGLT2) in the post hoc analysis of clinical assays of the DAPA-HF and EMPEROR-reduce it was observed that are associated with a decrease in UA levels.27,28

Until June 2020, there were many studies published on the association between hyperuricemia, cardiovascular and renal risk. However, interventional studies were few and with limited sample size. Kanbay et al.36 demonstrate in 59 healthy subjects, that the treatment with allopurinol of patients with asymptomatic hyperuricemia results in an increase in the GFR. Talaat et al.37 in 52 patients with CKD stage 3 and 4 shows that withdrawal of allopurinol worsens hypertension and the renal function. Siu et al.,38 randomized 54 CKD stage 3 and 4 patients to receive allopurinol at doses of 100–300 mg/day for 12 months or continue with their usual therapy; the treatment with allopurinol delayed the progression of renal disease. Kao et al. treated with allopurinol (300 mg/day) 53 patients with CKD stage 3 with left ventricular hypertrophy improving endothelial function and LVH.39 Goicoechea et al. conducted a study in 113 patients with CKD40 that were randomized to continue with their usual medication or receive treatment with 100 mg/day of allopurinol for an average of 2 years. Allopurinol decreased the risk of hospitalization and it also reduced the risk of cardiovascular events by 71% and reduced the progression of renal disease at 2 years. In a post hoc analysis, after a mean follow-up period of 84 months, treatment with allopurinol reduced renal and cardiovascular events by 68% and 57% respectively.41 Subsequently, Kanbay et al.42 performed a study in 105 subjects: 72 hyperuricemic and 33 controls with normal UA levels and with normal renal function. The 72 hyperuricemic patients were randomized to receive either 300 mg allopurinol for 4 months or no treatment. The administration of allopurinol produced a decrease in uric acid level that was associated with an improvement in endothelial function (p < 0.003), in estimated glomerular filtration rate (p = 0.001) and systolic blood pressure (p = 0.001).

Shi et al.,43 in an open randomized controlled study evaluated treatment with allopurinol in 40 patients with IgA nephropathy, and they found no effect on proteinuria or in renal function, although it improved the blood pressure significantly.

In June/2020, the NEJM published two randomized clinical trials on the treatment of hyperuricemia in patients with CKD stage 3 and 4 (CKD-FIX trial)44 and in type 1 diabetic patients with albuminuria (PERL trial).45 In both populations of patients, treatment with allopurinol showed no benefit on renal function. Two considerations about these two trials: (1) the CKD-FIX included patients with rapid progression of renal disease and proteinuria whereas, in the previously published small trials, the degree of renal dysfunction and albuminuria were lower, (2) the mean UA level in the PERL clinical trial was 6.1 mg/dl, so a large percentage of patients did not have hyperuricemia and (3) in both studies the rate of dropout was high, greater than 20%. Therefore, there are still many questions to be resolved, such as what are the ideal plasma levels of UA, whether the greater reduction of UA increases the benefit or whether the beneficial effect demonstrated by xanthine oxidase inhibitors is due to their antioxidant effect or endothelial effect and which population would benefit most from a reduction of UA: early stages of CKD, interstitial or vascular and non-glomerular nephropathies, etc. Regarding a cardiovascular benefit, a randomized trial (the ALL-HEART study) found no benefit of allopurinol in patients with a history of coronary artery disease, but patients with gout were excluded and had a high dropout rate (>55%).

Therefore, some of these findings would corroborate that UA may be a modifiable factor in the progression of chronic kidney disease, without sufficient data to state whether the beneficial effect of allopurinol is due to the reduction of UA or to the antioxidant effect produced by inhibiting the xanthine oxidase enzyme, however, the two large randomized clinical trials do not offer positive results so there is insufficient evidence to recommend allopurinol treatment in patients with asymptomatic hyperuricemia.

As observed with Allopurinol, small clinical trials have shown that febuxostat, can also offer renal protection. In an experimental study performed in 5/6 nephrectomized normo- and hyperuricemic rats, febuxostat protected against renal damage, and prevented proteinuria, preserving vessel morphology and glomerular pressure, thus it prevents progression of CKD independently of its effect on UA.46 In the FOCUS47 extension study, 116 patients treated with febuxostat were followed for 5 years. Those patients with a reduction of UA to levels below 6 mg/dL had the lowest drop in glomerular filtration rate throughout follow-up. The FEATHER48 clinical trial included 467 Japanese patients with CKD stage 3 and asymptomatic hyperuricemia who were randomized to receive febuxostat or placebo. Patients were followed for 108 weeks. Treatment with febuxostat did not reduce significantly the progression renal disease, with a fall in eGFR in the placebo group of (-0.47 ± 4.48 ml/min/1.73 m2) vs 0.23 ± 5.26 ml/min/1.73 m2 in the febuxostat group. However, febuxostat was beneficial in the group of patients without proteinuria and with lower creatinine levels, suggesting that it is more effective in patients with a less renal damage. Important limitations of this study are that it was conducted only in a Japanese population, with a short follow-up time of 2 years and in a group of patients with very little progression of renal disease, since the drop of eGFR in the placebo group was less than 1 ml/min/year.

A meta-analysis has been recently published (reference?) on the effect of UA reduction with febuxostat on the renal events and CKD progression. The meta-analysis included 16 studies including patients with asymptomatic hyperuricemia and/or gout treated with febuxostat and were compared with placebo/allopurinol, demonstrating a significant reduction in renal events (doubling of serum creatinine concentration and/or entry into renal replacement therapy): HR 0.56, 95% CI 0.37–0.84, p = 0.006 and a slight decrease in the fall of glomerular filtration rate (0.90 ml/min/1.73 m2) and in albuminuria.49 Like the observed with allopurinol, there is currently insufficient evidence to suggest treatment with febuxostat for renal or cardiovascular protection in patients with asymptomatic hyperuricemia.

Table 5 summarizes the main meta-analyses published on the effect of hyperuricemia treatment on renal progression. The results are controversial, with considerable heterogeneity in the population evaluated, short follow-up times, and using eGFR and proteinuria as the final endpoints, rather than robust renal events. These data, together with the three published clinical trials with negative results, do not support treatment with uric acid-lowering drugs in patients with CKD to reduce progression of renal function deterioration. These meta-analyses did not include clinical trials of patients with gout. A post-hoc analysis of the CARES clinical trial was recently published, showing a reduction of CKD progression (a drop in GFR of 0.5 ml/min/year) in patients with gout treated with allopurinol or febuxostat who maintained a UA level of less than 6 mg/dL for a median of 2.5 years.50 These data could suggest that the deposits of monosodium urate crystals in the kidneys may be responsible for the progression of kidney disease. It is likely that the center of the causal association between hyperuricemia and kidney disease progression should not be on patients with asymptomatic hyperuricemia, but rather on the population with gout.51