Hyperuricemia Resistant to a Xanthine Oxidase Inhibitor, Topiroxostat: a Case Report

Hyperuricemia is a common complication of chronic kidney disease. Gout is a clinical symptom of hyperuricemia, and lowering serum uric acid concentration (sUA) is recommended to prevent its recurrence. Febuxostat and topiroxostat are sUA-lowering agents, which are presumed to act on the same site of xanthine oxidase (XO), the rate-limiting enzyme for urate production. We present a case of gout where febuxostat but not topiroxostat lowered sUA. The different efficacy between them indicates that XO inhibitors are not interchangeable even among those acting on the same site of XO.


Introduction
Hyperuricemia is a common complication of chronic kidney disease (CKD), because the kidney normally excretes around two-thirds of urate load [1,2]. Gout is a clinical symptom of hyperuricemia, which typically presents acute onset monoarthritis at the first metatarsophalangeal joint in the foot [3]. Lowering serum uric acid concentration (sUA) has been recommended to prevent the recurrence of gout, and pharmacological sUA-lowering therapy is generally required, because dietary and lifestyle optimization can reduce sUA only slightly [2,3]. Because of renal impairment, which weakens the efficacy of uricosuric agents, the agents that inhibit xanthine oxidase (XO), the rate-limiting enzyme for urate production, are generally used to lower sUA in hyperuricemic CKD patients [1,2]. In this report, we present a case of gout where 2 XO inhibitors (febuxostat and topiroxostat), which have been presumed to act on the same site of XO, showed different sUA-lowering efficacy.

Case Report
An 80-year-old man with chronic kidney disease (CKD) stage G4 had a gout attack, when his serum uric acid concentration (sUA) and creatinine concentration were 12.2 and 3.2 mg/dL, respectively (Table 1). After the symptom of gouty arthritis was improved by glucocorticoid therapy, sUA-lowering therapy by oral administration of topiroxostat was started. However, even 2 months after the dose of topiroxostat had been increased to 60 mg/day, sUA did not decrease (Fig. 1); it was 10.8 mg/dL while it had been around 10.5 mg/dL before the gout attack. Then, febuxostat 40 mg/day was substituted for topiroxostat 60 mg/day. The substitution lowered sUA to 7.0 mg/dL by 1 month and further to 6.2 mg/dL by 2 months. During the treatment, his serum creatinine concentration increased to 4.4 mg/dL, but renal replacement therapy was not started.

Discussion
This report presented a case of hyperuricemia, which was resistant to an XO inhibitor, topiroxostat, but not another inhibitor, febuxostat. The different efficacy between them indicates that XO inhibitors are not interchangeable even among those acting on the same site of XO and that it is worth to try other inhibitors when one inhibitor is ineffective.
Topiroxostat is presumed to inhibit XO by forming a tight complex with molybdenum at the enzymatic center [4,5].
Febuxostat is also presumed to inhibit the same enzymatic center [6]. It was reported that topiroxostat 60 mg/day provided sUA-lowering efficacy as well as febuxostat 40 mg/day in hyperuricemic CKD patients [7]. It was also reported that topiroxostat 20 mg/day lowered sUA in most of the patients even with advanced CKD [8]. Thus, irrespective the stage of CKD, topiroxostat 60 mg/day is expected to lower sUA. However, in the present case, while febuxostat 40 mg/day lowered sUA, topiroxostat 60 mg/day did not lower sUA; the level of sUA 2 months after the therapy by topiroxostat 60 mg/day did not differ from that before the gout attack.
It might be possible that sUA began to decrease at the timing when febuxostat was substituted for topiroxostat, while topiroxostat inhibited XO. However, if topiroxostat had inhibited XO, decrease in urate production by the inhibition should have lowered sUA during the topiroxostat therapy. Since the renal and gastrointestinal excretion of urate depends on sUA [9] , decrease in urate production, which reduces a demand for the urate excretion, lowers sUA.
Thus, the clinical course that febuxostat but not topiroxostat lowered sUA indicated that topiroxostat did not inhibit the XO of the present case while febuxostat did. However, we could not confirm it, since we did not measure XO activity in the case. We did not measure the blood concentration of topiroxostat either and could not clarify whether topiroxostat was delivered to the XO. The topiroxostat resistance, however, could be attributable to either (i) topiroxostat was not delivered to the XO or (ii) the delivered topiroxostat did not inhibit the XO. Some genetic mutation in either the topiroxostat transporters or the XO of the present case would have made the XO not inhibitable by topiroxostat.

Conclusion
Even among the inhibitors blocking the same site of XO, XO inhibitors are not interchangeable. Their efficacy will differ between individuals depending on the individual delivery system and XO affinity of them. Thus, it is worth to try other inhibitors when one inhibitor is ineffective.
Author Contribution T.K.: data acquisition and manuscript writing. S.Y.: data acquisition. M.T.: concept and manuscript writing.

Declarations
Consent for Publication Written informed consent was obtained from the patient reported.

Conflict of Interest
The authors declare no competing interests.