Comparison of Recommendations Made by Committee Members with and without Financial Conflict of Interest on Japanese Guideline of Treatment of Hyperuricemia and Gout, Third Edition.

Clinical practice guidelines (CPGs) consist of clinical questions (CQs) and corresponding recommendations. Considering the estimation of body of evidence, patients' opinions, and medical economics, recommendations can vary depending on the votes of the committee members of CPGs. Taking this into consideration, concerns have already been raised on how financial conflict of interest (COI) potentially influences recommendations. In this study, we developed the third edition of guideline for the management of hyperuricemia and gout. This CPG was composed of seven CQs and recommendations. The direction and strength of the recommendations were determined by votes. There are three CQs. Individual questions asked whether uric acid-lowering-agents (ULAs) could be applied to hyperuricemic patients with chronic kidney disease (CKD) (CQ A), hypertension (CQ B), or heart failure (CQ C) to prevent organ damage. We examined whether the absence (18 members) or presence (8 members) of COIs of committee members could influence the votes. In total, 26 committee members with and without COI have equally determined the direction and strength of recommendations. In CQ A, members without financial COIs and those with financial COI selected conditional recommendation for the use of ULAs in patients with CKD (without COI, 17/18; with COI, 7/8). In CQ B, members without financial COIs and those with financial COI selected conditional recommendation against the use of ULAs in hypertensive patients (without COI, 14/18; with COI, 5/8). In CQ C, members without financial COIs and those with financial COIs have selected conditional recommendation against the use of ULAs in patients suffering from heart failure (without COI, 15/18; with COI, 4/8). We found that members with financial COIs have determined their recommendations in the same direction and strength as those without financial COIs.

Xanthinuria Type 1 with a Novel Mutation in Xanthine Dehydrogenase and a Normal Endothelial Function.

Whether or not extremely low levels of serum uric acid (SUA) in xanthinuria are associated with impairment of the endothelial function and exercise-induced acute kidney injury (EIAKI) is unclear. A 59-year-old woman without EIAKI or urolithiasis had undetectable levels of UA in serum and urine and elevated levels of hypoxanthine and xanthine in urine. A genetic analysis revealed homozygous mutations in the XDH gene [c.1585 C>T (p. Gln529*)]. Flow-mediated dilation was within the normal range. This is the first report of a case with extremely low levels of SUA, xanthinuria with novel mutations of xanthine dehydrogenase (XDH) and a normal endothelial function.

Evaluation of Treatment Success Rate Among Antihyperuricemic Using Real-World Data.

In this study, treatment and the serum uric acid (UA) level were compared using medication history generated by prescription order records of antihyperuricemic to examine the treatment success rate. We examined the treatment success rate among these patients based on the serum UA level during 120-180 days after the initiation of treatment, which was set as the endpoint. The number of patients whose UA level before the start of treatment was > 8.0 mg/dL but decreased to < 6.0 mg/dL after the treatment, which is the target treatment success, was 92 (success rate of 14.2%), 50 (53.2%), 76 (41.5%), 35 (31.9%), and 45 (37.8%) in the allopurinol 100 mg/day (A1) and 200 mg/day (A2), febuxostat 10 mg/day (F1) and 20 mg/day (F2), and benzbromarone 50 mg/day (B), respectively. Compared with that of the other drugs, the treatment success rate was high with A2 and low with A1. From the generated medication history, the treatment success rate with antihyperuricemic can be extracted mechanically.

Clinical practice guideline for renal hypouricemia (1st edition).

Renal hypouricemia (RHUC) is a disease caused by dysfunction of renal urate reabsorption transporters; however, diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC. This review describes a world-first clinical practice guideline (CPG) and its first version in English for this condition. It was developed following the "MINDS Manual for Guideline Development" methodology, which prioritizes evidence-based medicine. It was published in Japanese in 2017 and later translated into English. The primary goal of this CPG is to clarify the criteria for diagnosing RHUC; another aim is to work towards a consensus on clinical decision-making. One of the CPG's unique points is that it contains textbook descriptions at the expert consensus level, in addition to two clinical questions and recommendations derived from a systematic review of the literature. The guidance shown in this CPG makes it easy to diagnose RHUC from simple blood and urine tests. This CPG contains almost all of the clinical foci of RHUC: epidemiology, pathophysiology, diagnostic guidance, clinical examinations, differential diagnosis, and complications, including exercise-induced acute kidney injury and urolithiasis. A CPG summary as well as a clinical algorithm to assist healthcare providers with a quick reference and notes from an athlete for both physicians and patients are included. We hope that this CPG will help healthcare providers and patients to make clinical decisions, and that it will promote further research on RHUC.

Increased double product on Monday morning during work.

It has been reported that cardiovascular events often occur on Monday morning, especially in the young working population. Because hypertension is a major cardiovascular risk, we examined whether blood pressure was elevated on Monday, especially in the morning during work. However, there were no weekly rhythms in blood pressure itself. Instead, we found significant interactions between the double product (systolic blood pressure × heart rate) and weekly (high on Monday) and circadian (high in the morning) rhythms. Further studies are required to determine whether Monday morning preference in cardiovascular events is caused by increased double product.

Prevalence and complications of hypouricemia in a general population: A large-scale cross-sectional study in Japan.

BACKGROUNDS: Hypouricemia was reported as a risk factor for exercise-induced acute renal injury (EIAKI) and urinary stones. However, the prevalence of kidney diseases among hypouricemic subjects has not been evaluated. This study was conducted to clarify the prevalence of hypouricemia and the association of hypouricemia with kidney diseases by using a large-scale Japanese population data. METHODS: This study is a retrospective cross-sectional study at the Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, and Sanin Rousai Hospital, Yonago, Japan. We analyzed the medical records of 90,143 Japanese subjects at the center in St. Luke's International Hospital, Tokyo, and 4,837 subjects in Sanin Rousai Hospital, Yonago, who underwent annual regular health check-up between January 2004 and June 2010. We defined hypouricemia as serum uric acid level of ≤2.0 mg/dL. We checked the medical history of all the study subjects and compared the rates of complications including urinary stones and kidney diseases among those with or without hypouricemia. RESULTS: The prevalence of hypouricemia was 0.19% in St. Luke's International Hospital, Tokyo, and 0.58% in Sanin Rousai Hospital, Yonago. The prevalence of hypouricemia in women was larger than that in men both in Tokyo (0.31% vs 0.068%, p<0.001) and in Yonago (1.237% vs 0.318%, p<0.001). Among 172 hypouricemic subjects (30 men), the rates of previous urinary stones and kidney diseases (including nephritis/nephrosis) were 1.2% (3.3% men, 0.7% women) and 2.3% (10% men, 0.7% women), respectively. Hypouricemic men had a 9-fold higher rate of previously having kidney diseases compared to non-hypouricemic men (p<0.001). However, the rates of other diseases including urinary stones were not significantly different between the two groups. CONCLUSIONS: Hypouricemia was associated with a history of kidney disease especially in men.

Effects of azelnidipine on uric acid metabolism in patients with essential hypertension.

PURPOSE: To examine effects of a long-acting calcium channel blocker (CCB) azelnidipine on uric acid metabolism in hypertensive patients. METHODS: Azelnidipine was administered to 72 patients at a daily dose of 8 mg or 16 mg. In 22 cases out of the 72 patients, a different CCB was switched to azelnidipine. Blood pressure was measured and biochemical parameters of blood and urine were evaluated before and 2-3 months after the administration. RESULTS: Azelnidipine significantly decreased both systolic and diastolic blood pressure and the heart rate. It decreased both serum urate levels and the urinary uric acid to creatinine ratio (Uur/Ucr), but did not affect the uric acid clearance to creatinine clearance ratio (Cur/Ccr). Azelnidipine decreased both Uur/Ucr and Cur/Ccr in patients with Uur/Ucr ≥ 0.5 or ≥ 0.34, although it did not change these clearance parameters in patients with Uur/Ucr <0.5 or <0.34. Azelnidipine decreased the serum urate levels and Uur/Ucr in hyperuricemic patients with uric acid levels ≥ 7.0 mg/dL in males and ≥ 6.0 mg/dL in females. It did not change these parameters in normouricemic patients with serum urate levels <7.0 mg/dL in males and <6.0 mg/dL in females. Azelnidipine decreased Uur/Ucr and Cur/Ccr in hyperuricemic patients with normal or over excretion of uric acid, although it did not change these clearance parameters in hyperuricemic patients with uric acid hypoexcretion. CONCLUSIONS: Azelnidipine decreased the serum urate acid levels and Uur/Ucr, and this response was most prominent in hyperuricemic patients or patients with normal and over excretion of uric acid.

A comparative study on the effectiveness of losartan/hydrochlorothiazide and telmisartan/hydrochlorothiazide in patients with hypertension.

PURPOSE: Long-term effects of a low-dose hydrochlorothiazide (HCTZ) with losartan (LOS) on uric acid (UA) metabolism as well as glucose metabolism have been studied in hypertensive patients in comparison with those of a low-dose HCTZ with telmisartan (TEL). METHOD: Fifty-nine hypertensive patients were allocated to a combination therapy with either losartan (50 mg/day)/HCTZ (12.5 mg/day) (LOS + HCTZ group: n = 37) or telmisartan (40 mg/day)/HCTZ (12.5 mg/day) (TEL + HCTZ group: n = 22), respectively. Before and 1 year after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. RESULTS: Both systolic and diastolic blood pressures significantly decreased in two groups, without any statistical differences among them. LOS + HCTZ caused no changes in the serum UA level or the ratio of UA clearance to creatinine clearance (CUA/Ccr), whereas TEL + HCTZ significantly increased the serum UA level and reduced CUA/Ccr. LOS + HCTZ did not influence CUA/Ccr in patients with their serum UA below 5.4 mg/dl, while LOS + HCTZ significantly increased CUA/Ccr in patients with their serum UA above 5.5 mg/dl. TEL + HCTZ significantly reduced CUA/Ccr in patients with their serum UA below and above 5.4 mg/dl to increase serum UA level significantly. Neither combination therapies caused any changes in fasting plasma glucose, HbA1c and HOMA-R. In patients with their serum UA level above 5.4 mg/dl, TEL + HCTZ increased HOMA-R, whereas LOS + HCTZ did not. CONCLUSIONS: LOS + HCTZ did not influence UA metabolism as well as glucose metabolism, likely because of inhibitory action of losartan on URAT1, although TEL + HCTZ were accompanied with impairment of the UA metabolism and glucose metabolism.

Effects of cilnidipine on serum uric acid level and urinary nitrogen monoxide excretion in patients with hypertension.

The effects of cilnidipine on the serum uric acid level and urinary NO excretion in hypertensive patients were investigated. Blood and urine samples of 16 hypertensive outpatients were collected before and 2 months after cilnidipine therapy (10 mg). The serum uric acid level decreased significantly after cilnidipine treatment, while the uric acid-creatinine clearance ratio was unaffected. The cilnidipine medication produced a significant increase in urinary NO excretion, although amlodipine did not change it significantly. Therefore, cilnidipine has a profound antihypertensive effect and may reduce the serum uric acid level and increase NO production in the kidney.

Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients.

BACKGROUND: The angiotensin receptor blocker losartan inhibited urate transporter 1 (URAT1) according to in vitro experiments. However, it is still unknown whether the inhibitory effect of losartan on URAT1 contributes to its uricosuric action in humans. METHODS: Thirty-two patients with hypertension and nine patients with idiopathic renal hypouricemia (five with and four without hypertension) were enrolled for this study. Hypertensive patients were prescribed oral losartan (50 mg/day, n = 16) or candesartan (8 mg/day, n = 16). Before and after 1-month treatment, the serum concentration of urate (Sur) and creatinine (Scr), and the clearance value of urate (Cur) and creatinine (Ccr) were determined. Clearance studies using the URAT1 inhibitor benzbromarone (100 mg/day) or losartan (50 mg/day) loading test were also performed in these patients. RESULTS: Blood pressure (BP) significantly decreased in the patients treated with either losartan or candesartan. Losartan significantly reduced Sur, which was associated with a concomitant increase in the Cur/Ccr ratio, whereas candesartan did not alter these parameters. In hypertensive patients with loss-of-function mutation of URAT1, losartan did not alter either Sur or Cur/Ccr, nor did benzbromarone. The lack of effect of URAT1 inhibitors on renal excretion of urate was independent of the renal function of hypouricemic patients. On the other hand, both losartan and benzbromarone increased Cur/Ccr ratio in hypertensive patients harboring the wild URAT1 gene, regardless of the presence of hypouricemia. CONCLUSIONS: These findings suggested that losartan inhibited URAT1 and thereby it lowered Sur levels in hypertensive patients.

Plasma levels of uridine correlate with blood pressure and indicators of myogenic purine degradation and insulin resistance in hypertensive patients.

BACKGROUND: The relationship between plasma uridine levels and blood pressure (BP), and indicators of muscular purine degradation and insulin resistance (IR) has been evaluated in hypertensive (HT) patients. METHODS AND RESULTS: In 36 HT patients and 10 normotensive subjects, seated BP was measured, and blood samples were drawn after overnight fast. In 18 of the HT patients, the semi-ischemic forearm test was performed to examine the release of hypoxanthine, ammonium and lactate. Plasma uridine levels were significantly higher than in the normotensive subjects. Fasting plasma insulin levels and homeostasis model assessment of IR correlated with plasma uridine levels in the HT patients. Plasma uridine levels showed a significant correlation with hypoxanthine, ammonia and lactate released from the semi-ischemic exercising muscles of the HT patients. CONCLUSIONS: Taken together with the positive correlation with indicators of IR, it is suggested that plasma uridine levels in HT are responsible for purine degradation and IR in skeletal muscles.

[Clinical features of coronary artery ectasia].

OBJECTIVES: To investigate the clinical significance of coronary artery ectasia in Japanese patients. METHODS: Coronary artery ectasia was found in 54 of 3,778 (1.4%) consecutive patients who underwent coronary angiography. The clinical characteristics and the coronary angiographic findings of these patients were studied. Follow-up data were obtained for 49 patients, who were separated into two groups: Group A subsequently suffered a follow-up major cardiac event, and Group B did not develop such an event. RESULTS: Among the coronary artery ectasia patients, 65% had myocardial infarction, 91% had coronary artery disease, and 48% had single-vessel disease. Seventy-six percent had single-vessel involvement with coronary artery ectasia. Eighteen patients (37%) suffered 22 follow-up major events. Seventy-two percent of the first follow-up event cases occurred within 4 years after the first cardiac event. The follow-up event in 78% of cases was acute coronary syndrome. There were no significant differences in age and prevalence of each coronary artery risk factor between Groups A and B. There were no significant differences in the incidence of follow-up event between the patients with single-vessel disease and the patients with multi-vessel disease, nor between the patients with single-vessel involvement with coronary artery ectasia and the patients with multi-vessel involvement with coronary artery ectasia. There was no significant difference in the percentage of patients in whom the culprit vessel of the cardiac event was the same as the ectatic vessel between the first cardiac event and follow-up cardiac events (41% vs 62%). CONCLUSIONS: Coronary artery ectasia is not benign and must be carefully monitored. Coronary atherosclerosis may contribute to the occurrence of subsequent cardiac events.

Acute secondary gastrointestinal amyloidosis in a patient with rheumatoid arthritis.

Secondary amyloidosis is well recognized as a severe complication in the late stages of rheumatoid arthritis (RA). However, there have been few reported cases of secondary amyloidosis developing early during the course of RA. We here report the case of a 35-year-old woman, in whom RA who had been diagnosed 1 year before, with intractable watery diarrhea as a symptom of RA-induced secondary intestinal amyloidosis. Combination treatment with intravenous hyperalimentation, corticosteroids, and methotrexate (MTX) resulted in a dramatic improvement of her symptoms and objective findings of serological abnormalities. Subsequent administration of corticosteroids and MTX resulted in long-term survival without recurrence. This case indicates that we should be alert for the development of secondary amyloidosis, even in patients with a short history of RA, when the disease is active. Furthermore, combination therapy with intravenous hyperalimentation and strong immunosuppressive agents seems to be very efficacious in the treatment of RA-associated secondary intestinal amyloidosis.

Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects.

OBJECTIVE: The acute effects of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism were evaluated. METHODS: Losartan (50 mg) was administered orally to 6 healthy males. Blood and urine samples for uric acid and oxypurine were collected before and up to 6 hours after losartan administration. The same examinations were performed later using enalapril (5 mg). RESULTS: Losartan decreased the serum uric acid concentration (from 5.9 +/- 0.9 to 5.2 +/- 1.0 mg/dl) and increased its fractional clearance, which reached a maximum after 2 hours, while enalapril did not. Losartan also induced an increase in the plasma concentration of hypoxanthine, peaking in the fourth hour, and a decrease in its urinary clearance, while the plasma xanthine concentration and its urinary clearance were unchanged. The extent of uric acid excretion was much greater than that of the oxypurines. CONCLUSIONS: Losartan, which has a high affinity for the urate/anion exchanger, has a transient uricosuric effect. Our data indicate that losartan induces a significant decrease in the urinary excretion of hypoxanthine without changes in xanthine.

Isolated autonomic cardiovascular neuropathy in a patient with primary Sjögren syndrome: a case of successful treatment with glucocorticoid.

Autonomic failure is rare in patients with Sjögren syndrome (SS). We report the case of a 46-year-old woman with severe autonomic cardiovascular failure, manifested by incapacitating postural hypotension, as the first symptom of primary SS. Treatment with glucocorticoid resulted in a dramatic improvement of her symptoms and objective findings of autonomic cardiovascular dysfunction. We suggest that SS should be considered in patients with idiopathic autonomic cardiovascular neuropathy, especially in those with idiopathic orthostatic hypotension. Furthermore, glucocorticoid therapy seems to be very efficacious in the treatment of SS-associated autonomic cardiovascular neuropathy.

Characteristics of cardiac myxoma with constitutional signs: a multicenter study in Japan.

BACKGROUND: A relationship between constitutional signs in patients with cardiac myxoma and interleukin-6 has been noted. However, there is little information about characteristics of cardiac myxomas associated with constitutional signs. HYPOTHESIS: The objective of this study was to clarify the characteristics of myxoma patients who had constitutional signs. METHODS: Questionnaires were sent to cardiology or cardiovascular surgery divisions at university hospitals throughout Japan. Constitutional signs were considered present when a patient had fever, weight loss, or elevations of C-reactive protein or gammaglobulin. In addition, interleukin-6 concentrations were evaluated in some patients. RESULTS: Data were obtained in 249 patients with primary cardiac tumors (204 myxomas, 15 other primary benign tumors, and 30 primary malignant tumors), confirmed histologically between 1993 and 1996. Fever and weight loss were observed in 15 and 6% of patients with myxoma, respectively, while C-reactive protein and gammaglobulin were increased in 39 and 21%, respectively. This amounted to a prevalence of constitutional signs in 49%. All constitutional signs disappeared after tumor resection. Age, gender, tumor site, and frequency of thrombosis did not differ between patients with and without constitutional signs. Tumors associated with constitutional signs were significantly more likely to be large, multiple, or recurrent than those unassociated with constitutional signs. CONCLUSIONS: Constitutional signs are present in about half of patients with myxoma. Large or multicentric tumors are likely to induce constitutional signs, which are reversible upon resection. These might suggest that constitutional signs result when interleukin-6 concentrations exceed a certain threshold.