The world- first clinical practice guideline (CPG) for renal hypouricemia (RHUC) has developed from Japan along MINDS methodology last year. Its first goal is to clarify the criteria for diagnosing RHUC, and another goal is to work towards a consensus on clinical decision-making.

RHUC is caused by a dysfunction of renal urate reabsorption. It does not include congenital purine metabolism abnormalities or secondary hypouricemia, and is relatively common (0.3%) in Japanese populations. Genetic analyses have demonstrated its causes as dysfunctional variants in urate reabsorption transporter URAT1/SLC22A12 and/or GLUT9/SLC2A9 genes, but there should be unknown causative genes. One of the characteristics of RHUC is a low serum uric acid (SUA) level with increased renal excretion of uric acid. CPG proposed its clinical diagnostic guidance for RHUC along clinical algorithm, which enables easy diagnosis with simple tests. RHUC itself is usually asymptomatic, but exercise-induced acute kidney injury (EIAKI, also known as “ALPE”) and urolithiasis are well-known complications. EIAKI cases generally show transient and recurrent acute kidney injury (AKI), and receive common treatment for AKI. For urinary stones, urinary alkalization and citrate compounds are effective therapies and fluid intake is recommended for prevention.

We strongly recommend that individuals with an SUA of ≤ 2.0 mg/dl (120 µmol/l) be considered for differential diagnosis of hypouricemia. Some studies reports that allopurinol, a xanthine oxidoreductase (XOR) inhibiter, was administered as prevention for EIAKI, but due to low evidence, we cannot definitively state that XOR inhibitors are effective. It should be therefore decided in the light of its potential benefits and harms.

We hope that this CPG helps both healthcare providers and patients make clinical decisions, and will also promote the researches on RHUC.

Background: The serum uric acid level is considered to be a marker of metabolic disorder associated with lifestyle-related diseases. Although the relationship between the serum uric acid level and obesity, hypertriglyceridemia, and a high blood pressure is well known, relationships with the blood glucose level and their mechanisms remain unclear. Therefore, the relationships between the blood glucose level and uric acid level and uric acid excretion kinetics were analyzed.

Methods: The subjects were 630 consecutive patients who visited our hospital due to lifestyle-related diseases. Single regression analysis of the abdominal circumference, triglyceride level (TG), mean blood pressure (MBP), and blood glucose level (BS), which are factors of metabolic syndrome, and the serum uric acid level (UA) was performed. The difference in UA due to the presence or absence of diabetes was examined by analysis of variance (ANOVA). Finally, according to BS, they were divided into 4 groups: first group (normal group: lower than 100 mg / dL), second group (group corresponding to metabolic syndrome: higher than 100 but lower than 126 mg / dL), third group (diabetes group with a relatively low glucose level: higher than 126 but lower than 180 mg / dL), and fourth group (diabetes group with a high glucose level: higher than 180 mg / dL). Among these groups, differences in UA, the uric acid excretion rate (FEUA), and eGFR of each group were compared by ANCOVA with three covariates (sex, age, and BMI). The main endpoint was the difference in UA in these 4 groups. It was calculated that 80 cases per group were necessary in order to test the difference in UA (0.5 mg / dL) with a detection power of 80% and significance level of 0.05.

Results : On single regression analysis, UA was significantly correlated with the abdominal circumference, TG (log conversion value), and MBP (r = 0.293 / p < 0.0001, r = 0.217 / p < 0.0001, r = 0.157 / p < 0.0001), respectively. However, there was no significant correlation with BS (r = -0.025 / p = 0.53). In the comparison of UA (mg / dL), no significant difference was observed between the non-diabetic, respectively and diabetic groups (5.08 ± 1.39 vs. 5.20 ± 1.50, respectively (p = 0.30)). In the comparison of UA among the 4 groups divided according to BS levels, in the order of the first to fourth groups, the mean ± SD values were as follows: 5.02 ± 1.36, 5.33 ± 1.54, 5.21 ± 1.41, and 4.85 ± 1.39, respectively. Significant difference were observed between the first and fourth groups (p < 0.0001), the second and third groups (p = 0.045), the second and fourth groups (p < 0.0001), and the third and fourth groups (p = 0.007). In the comparison of eGFR among the 4 groups divided according to BS levels, in the order of the first to fourth groups, the mean ± SD values were as follows: 77.6 ± 18.5, 76.7 ± 17.2, 77.8 ± 23.1, and 86.5 ± 30.3, respectively. Significant differences were observed between the first and fourth groups (p < 0.0001), the second and fourth groups (p < 0.0001), and the third and fourth groups (p < 0.0001). In the comparison of FEUA (%) among the 4 groups divided according to BS levels, in the order of the first to fourth groups, the mean ± SD values were as follows: 7.92 ± 3.15, 8.05 ± 3.70, 7.98 ± 3.17, and 9.18 ± 5.62, respectively. Significant differences were observed between the first and fourth groups (p < 0.0001), the second and fourth groups (p = 0.003), and the third and fourth groups (p = 0.010).

Conclusion: It was suggested that BS has a different effect on serum uric acid levels during the progression of glucose metabolism disorder.

There are various lifestyle-related diseases including gout and hyperuricemia that can be improved by reducing alcohol intake. Many treatment guidelines set appropriate volumes of alcohol intake, however, specific educational methods are not mentioned. The WHO devised The Alcohol Use Disorders Identification Test (AUDIT) that consists of 10 questions to identify drinking-related problems. They proposed an educational method that aims to improve recognition of the necessity of reducing alcohol intake by utilizing AUDIT and repeated support as brief intervention to achieve this goal. In Japan, laws to control alcohol consumption were established in 2013 and basic plans have been formulated and implemented for administration. In this study, 6 patients with gout and diabetes mellitus at our facility attended a 60-minute group session utilizing AUDIT. Each patient calculated the amount of absolute alcohol they consumed based on their actual alcohol intake, and we helped them recognize the difference between their intake and appropriate alcohol (20 g). Then, they set individual goals to reduce alcohol consumption. One month later, interviews were conducted with 3 patients, revealing that all of them had achieved their goals and showed decreases in the γ GTP value. The subject group of this study was very small and support for reducing alcohol intake was limited. Daily educational methods to tackle drinking problems will be revised based on the results.

The 2^nd edition of guideline for the management of hyperuricemia and gout was published in 2011 and about 6 years have passed (The 1st edition, in 2002, the 2nd edition is issued in 2010.). During that time, several XOR inhibitors, febuxostat (launched in May, 2011) and topiroxostat (launched in September, 2013) were developed and launched.

We had no new development in Japan for about 40 years since Allopurinol was developed but, these new XOR inhibitor were developed and new choice of medicines was born besides usual uricosuric drugs. From this, we conducted a questionnaire survey for actual status of anti-hyperuricemic drugs for clinicians.

186 valid response have collected from whole 665 questionnaire distribution.

Most physicians have used several drugs appropriately as anti-hyperuricemic with Febuxostat (183 people), Allopurinol (161 people), Benzbromarone (153 people), Topiroxostat (86 people).

As the standard of uric acid level to use anti-hyperuricemic drugs was more than 8 or 9mg/dL (85.5%) in the case without complications, and more than 7 or 9mg/dL (91.4%) in the case with complications.

In addition to that, 85.5% of the whole have almost achieved the goal of uric acid level including "It was achieved by all patients mostly, (100%)" and "It was achieved by almost all patient (75%)".

As a result, it was indicated that the use of antihyperuricemic based on guideline for the management of hyperuricemia and gout was established generally.

Objective: Ingestion of yogurt containing Lactobacillus gasseri PA-3 (PA-3, Accession No: NITE BP-224) (PA-3Y) has been shown to reduce serum uric acid (SUA) levels by interfering with the intestinal absorption of food-derived purines in animal studies. To confirm this mechanism in humans, the ability of PA-3 intake to alleviate purine ingestion-induced increases in SUA levels was analyzed.

Research Methods and Procedures: In this randomized, double-blind, placebo-controlled crossover study, 16 healthy adults were randomized to groups ingesting of 112 g of PA-3Y or yogurt without PA-3 (control yogurt) in addition to standardized meals for 3 days. Purine-loading tests, in which subjects ingested 112 g of PA-3Y or control yogurt followed immediately by 498 mg of a mixture of purine nucleotides, were performed on the fourth day of each test period. Blood and urine samples were collected before and after the purine-loading tests.

Results: The increase in the SUA concentration from the baseline was significantly lower following the ingestion of PA-3Y than of control yogurt alone, especially at 30 (P=0.033) and 60 (P=0.028) minutes. In addition, the area under the curve for the increase in the SUA concentration from the baseline to 150 minutes was also significantly lower (P=0.041) in the PA-3Y than in the control yogurt group. However, urinary and fractional excretions of uric acid were not different between the two groups.

Conclusion: The ingestion of PA-3 before purine intake alleviates the increase in SUA levels, probably by reducing purine absorption in the intestine, and not by enhancing urinary excretion of uric acid.

Background: Hypertension and chronic kidney disease (CKD) are frequently accompanied by hyperuricemia because urine excretions of sodium and uric acid (UA) are reduced via stimulations of the renin-angiotensin system (RAS) and sympathetic nerve activity (SNA). Different from other calcium channel blockers (CCB), cilnidipine (CIL) has been reported to suppress excessive SNA and UA overproduction. However, few clinical studies have examined UA-lowering mechanisms induced by CIL in relation to RAS and SNA in hypertensive nephropathy.

Methods: The blood pressure (BP), pulse rate (PR), serum UA (SUA), urinary protein/creatinine (UP/Cr), urinary UA/creatinine (UUA/Cr), and estimated glomerular filtration rate (eGFR) were measured before and a year after the administration of amlodipine (AML) or CIL in 83 hyperuricemia-combined hypertensive CKD patients who received angiotensin II receptor antagonists (ARB) except for losartan and no vasodepressors. In order to assess SNA, the morning PR (MPR) and urinary norepinephrine level (UNE) were employed.

Results: In the year following CCB initiation, similar decreases in BP and UP/Cr were shown in all groups, while MPR dropped only in the group using CIL with ARB. Although a high incidence of an increase in SUA was observed in AML-using groups, declines in SUA were noted in numerous CIL-using patients. CIL+ ARB markedly reduced SUA compared with CIL alone, and also the CIL-induced decrease in SUA in patients with MPR≧70 beats/min (bpm) and UUA/Cr≧0.4 was larger than that in patients with MPR＜70 bpm and UUA/Cr＜0.4. Concerning patients with eGFR≧60 mL/min/1.73m² and UNE ≧160μg/day in the ARB+CIL group, the SUA-lowering action was most potent for the UUA/Cr＜ 0.4 type, and the UA clearance/Cr clearance ratio was significantly elevated.

Conclusion: In hypertensive nephropathy, CIL elicits a reduction in SUA independent of decreases in BP and proteinuria, usually through the disturbance of UA production and variable factors. Under the conditions of a retained renal function and sympathoexcitation, it was suggested that the SUA-lowering effect was amplified due to the promotion of UA excretion.

Gouty patients with renal dysfunction leading to an eGFR of less than 60mL/min/1.73m² before treatment were selected as the subjects from patients who visited to our clinic between February and March 2016 and were treated with febuxostat and topiroxostat. The serum uric acid level and eGFR in 34 patients treated with febuxostat were 9.1 ± 1.7 mg/dL and 50.6 ± 9.0 mL/min/1.73m² respectively. On the other hand, the serum uric acid level and eGFR in 17 patients with topiroxostat were 8.6 ± 1.1 mg/dL and 52.9 ± 5.7 mL/min/1.73m² respectively. We compared the transitional changes of the serum uric acid level and eGFR for 1 year between these groups. No clear adverse event except gouty flare appeared in either groups. More than 70% of the febxostat administered group achieved the target serum uric acid level, less than 6.0 mg/dL, although only 50~60% of topiroxostat administered group achieved the target. It was suggested that a decline in medication adherence was a cause of this result. In a half of both treatment groups, the improvement of eGFR was observed compared with pre-treatment values. The improvement in the topiroxostat group was significant, but that in the febuxostat group was non-significant. Especially, the renal function was improved in patients who achieved a serum uric acid level of less than 6.0mg/dL. The novel XO inhibitors febuxostat and topiroxostat can be safe used for patients with moderate renal dysfunction, and it was considered that they could be expected to improve the renal function.

Objective: To examine whether the supplementation of inosine augments ATP in vitro in human erythrocytes incubated in saline.

Methods: Peripheral blood was drawn from each of three subjects, i.e. one healthy male and two males with thalassemia and hemoglobinopathy. After washing the erythrocytes in saline, they were suspended in saline to which inosine was added to final concentrations of 0, 0.5 and 2.5 mM. The suspension was incubated at 37 °C for 1 or 3 hours, and 0.5 ml ice cold 8% perchloric acid was added to the 0.5 ml erythrocyte-containing solution. After removing precipitates and perchloric acid, the supernatant was submitted to HPLC for the measurement of ATP.

Results : Since the blood samples of the two subjects with thalassemia and hemoglobinopathy were transported from the clinics to the laboratory, ATP in the blood decreased considerably during the transportation. However, the reduction of ATP with time was observed in the erythrocytes in saline obtained from each of the three subjects during the incubation from 1 hour to 3 hours. In addition, dose-dependent suppression of the decrease of ATP with inosine was observed in all the three cases at both 1 hour and 3 hour incubation times.

Conclusions: Incubation of erythrocytes from a healthy subject and two thalassemia/hemoglobinopathy patients in saline at 37 °C resulted in time-dependent decreases of ATP. Supplementation of inosine to the solutions resulted in the suppression of the decreases of ATP in a dose-dependent manner.