In the present single-center study of CKD patients with HUA, changes in kidney function before and after administration of dotinurad were investigated. Kidney function declined during the 3 months of observation and then increased after dotinurad administration. This result suggested two possible explanations.

(1)

HUA could contribute to the exacerbation of kidney dysfunction in patients with CKD, at least in certain settings.

(2)

Dotinurad restored kidney dysfunction caused by HUA.

The number of patients with CKD has been increasing worldwide, and the disease is estimated to affect 200 million individuals worldwide [9]. Furthermore, the number of patients with CKD is expected to increase. CKD creates a considerable burden and is recognized as an important problem for both individuals and society. CKD is a risk factor for not only end-stage kidney disease (ESKD) but also cardiovascular disease, which is the main cause of death worldwide [10, 11]. In addition, worldwide medical expenses associated with hemodialysis for ESKD are estimated to increase to US$1,000 billion within the next 10 years [12]. Therefore, establishing an effective strategy for CKD remission is an important public and national health issue.

Accumulating evidence has shown that HUA is associated with CKD progression [2,3,4]; however, most trials to clarify whether urate-lowering treatment can attenuate the decline in renal function in patients with CKD have failed to achieve these goals [13,14,15]. Although such studies adopted xanthine oxidoreductase inhibitor as a urate-lowering drug, adaptation of SURI as a urate-lowering drug might demonstrate reno-protective effects on progressive kidney damage related to HUA. Histologic findings of renal injury directly related to HUA include deposition of monosodium urate monohydrate in the renal interstitium [16,17,18], and SURI might prevent the passive inflow of urate from the internal lumen of proximal collecting tubule to the renal interstitum via URAT1 and the tubular cell matrix. This possibility is supported by the clear relationship between decreased sUA and increased eGFR observed in the present study (Fig. 4).

Of course, it is important to review diet and lifestyle in hyperuricemia, as in diabetes, which is a lifestyle-related disease such as hyperuricemia. On the other hand, as in diabetes, the nephroprotective effect of dietary and lifestyle changes in hyperuricemia is unclear. Our results suggest that SURI, which acts directly on the renal proximal tubules of the kidney, has a distinct nephroprotective effect, as do SGLT2 inhibitors, which also act directly on the renal proximal tubules.

The result of present study, however, should be interpreted with caution, for patients with CKD with apparent HUA – like present study population—may not teem in the real world, and the beneficial effect of dotinurad is supposed to be limited to patients with apparent HUA. This study had certain limitations. First, it is unclear whether the findings could be generalized to other ethnic or age groups because the subjects analyzed were all outpatients of one hospital, and the possibility of sampling bias cannot be denied. Second, the number of participants was small, preventing us from performing a stratified analysis. Third, the present study was a single-arm observational study, and we only compared post-treatment and pre-treatment phases and did not compare changes in kidney function between patients who did and did not use dotinurad. Fourth, pathological findings from renal biopsies were not examined in this study. Fifth, the reduction of deposed monosodium urate monohydrate in the renal interstitium through appropriate diagnostic images such as dual energy CT was not demonstrated in the present study. To overcome these limitations, prospective randomized studies with larger numbers of patients are required.

In conclusion, in the present study, the use of dotinurad in CKD patients with HUA appeared to be beneficial for preserving kidney function, and these results further indicate that this novel SURI might be a potential key medication for preventing kidney function decline in CKD patients with HUA.