A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility

Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, gout patients can be divided into those with renal overload (ROL) gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 (MCT9/SLC16A9) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL gout (p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all gout cases (p = 0.10), non-ROL gout cases (p = 0.83), and RUE gout cases (p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of gout as well as the physiological roles of MCT9.     

Acid-base equilibrium of blood in chicken with gout

It is shown that visceral gout in chicken is accompanied by acute metabolic acidosis. The mentioned change in the acid-base equilibrium is supposed to aggravate the course of the disease.     

Risk of end-stage renal disease associated with gout: a nationwide population study

Introduction

We explored the risk of end-stage renal disease (ESRD) among gout patients in a representative cohort in Taiwan.

Methods

The primary database used was the Taiwan National Health Insurance Research Database. Subjects older than 20 years without ESRD, coronary heart disease, or stroke were included in the study. The case definition of gout in the present study was gout diagnosis and medical treatment for gout. An ESRD case was defined by the presence of chronic renal failure necessitating long-term renal replacement therapy. Multivariate Cox proportional hazards models were used to evaluate the risk of ESRD among gout patients.

Results

The analysis included data of 656,108 patients who were followed up for a mean of 8.0 years. Among them, 19,963 (3.0%) patients had gout. At the end of 2008, 2,377 individuals (gout, n = 276; non-gout, n = 2,101) had ESRD, and 861 individuals (gout, n = 77, 27.9%; non-gout, n = 521, 24.8%) died due to ESRD. The rates of incidence of ESRD were 1.73 and 0.41 cases per 1,000 patient-years in the gout and non-gout groups. After adjustment for age, sex, and history of diabetes mellitus and/or hypertension, gout was associated with a hazard ratio (HR) of 1.57 for ESRD (95% confidence interval [CI], 1.38-1.79; P < 0.001). In patients with ESRD, the adjusted HR for death in patients with gout was 0.95 (0.74-1.23, P = 0.71), which was similar to the HR obtained in patients without gout.

Conclusions

Gout is associated with an increased hazard for development of ESRD.     

Comorbidities in patients with gout

Gout is one of the most important diseases associated with hyperuricemia. Gout is characterized by acute monoarthritis with frequent flares. Some patients with gout have gouty tophi that are composed of monosodium urate crystals and inflammatory cells. In addition to tophi, gout is associated with various comorbidities such as obesity, hypertension, abnormal lipid metabolism, renal dysfunction, and urolithiasis. We examined the associations of the presence of tophi and comorbidities with demographic and disease characteristic data of gout patients. Subjects were 422 male patients with gout who visited our outpatient clinic. The patients' background data and laboratory data at the first visit were collected from patient records. We investigated the relationship between comorbidities and characteristics of patients using multiple regression models. The age of gout onset was 44 ± 13 years. The duration of gout at the first visit was 6 ± 8 years. Five percent of subjects had tophi. The presence of tophi was significantly associated with the duration of gout and maximum serum uric acid (SUA), indicating a close association of tophi with urate deposition. Reduced estimated glomerular filtration rate was associated with older age of onset, longer duration of gout, and higher levels of maximum SUA, indicating that sustained hyperuricemia relates with renal impairment of gout. Urolithiasis did not associate with gout duration and maximum SUA. The increased frequency of hypertension was associated with the duration of gout, suggesting that poor control of gout is one of the causes of hypertension. This study provides useful information for gout management and patient education.     

Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics

Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.     

非布司他治疗原发性痛风合并轻中度肾功能不全的临床疗效

目的:探讨非布司他治疗原发性痛风合并轻中度肾功能不全的患者的临床疗效及安全性。方法:选取2015年1月至2016年8月于南京中医药大学附属中西医结合医院收治的原发性痛风合并轻中度肾功能不全的男性患者60例,随机分为两组,每组30例。对照组接受别嘌呤醇治疗,观察组接受非布司他治疗。比较两组患者治疗期间血尿酸(BUA)以及肝肾功能的变化,同时记录两组患者治疗期间的不良反应以及痛风再发作次数。结果:治疗后第1月、第2月及第3月,观察组患者的血尿酸水平均显著低于对照组(P0.05)。两组患者治疗后肾功能均较治疗前显著改善(P0.05),但两组之间比较差异无统计学意义(P0.05);治疗3个月内,两组均有痛风再发作,其发生率比较差异无统计学意义(P0.05);对照组患者有四肢不适、嗜睡、恶心、腹胀、腹泻、皮肤瘙痒等不良反应的发生,观察组有四肢不适、嗜睡、腹胀等不良反应的出现,其中对照组有1例出现过敏性皮疹停用别嘌醇。观察组的总发生率显著低于对照组(P0.05)。结论:非布司他治疗原发性痛风合并轻中度肾功能不全患者可安全、有效地降低血尿酸水平,并改善患者肾功能。     

Adherence to the 2012 American College of Rheumatology (ACR) Guidelines for Management of Gout: A Survey of Brazilian Rheumatologists

Objective

To describe the current pharmacological approach to gout treatment reported by rheumatologists in Brazil.

Methods

We performed a cross-sectional survey study using an online questionnaire e-mailed to 395 rheumatologists, randomly selected, from among the members of the Brazilian Society of Rheumatology.

Results

Three hundred and nine rheumatologists (78.2%) responded to the survey. For acute gout attacks, combination therapy (NSAIDs or steroid + colchicine) was often used, even in monoarticular involvement, and colchicine was commonly started as monotherapy after 36 hours or more from onset of attack. During an acute attack, urate-lowering therapy (ULT) was withdrawn by approximately a third of rheumatologists. Anti-inflammatory prophylaxis (98% colchicine) was initiated when ULT was started in most cases (92.4%), but its duration was varied. Most (70%) respondents considered the target serum uric acid level to be less than 6 mg/dl. Approximately 50% of rheumatologists reported starting allopurinol at doses of 100 mg daily or less and 42% reported the initial dose to be 300 mg daily in patients with normal renal function. ULT was maintained indefinitely in 76% of gout patients with tophi whereas in gout patients without tophi its use was kept indefinitely in 39.6%.

Conclusion

This is the first study evaluating gout treatment in a representative, random sample of Brazilian rheumatologists describing common treatment practices among these specialists. We identified several gaps in reported gout management, mainly concerning the use of colchicine and ULT and the duration of anti-inflammatory prophylaxis and ULT. Since rheumatologists are considered as opinion leaders in this disease, a program for improving quality of care for gout patients should focus on increasing their knowledge in this common disease.     

高尿酸血症和痛风的流行病学及其危险因素的研究进展

高尿酸血症和痛风是由于长期嘌呤代谢紊乱所引起的一种代谢性疾病,随着各国经济的发展,其患病率在全球范围呈逐年升高的趋势,因此相关研究也日益增多.本文就近年来有关高尿酸血症与痛风的流行病学及其危险因素的研究作一综述,并着重阐述高尿酸血症与糖尿病关系的相关研究进展.     

Late Failure in Cadaveric Renal Allografts

Sixteen patients with renal cadaveric allografts who have survived for one year or longer are reported. The patients were analyzed from the standpoint of incidence, quantity and course of proteinuria in relation to renal function and the nature of the original disease.This analysis shows that proteinuria is progressive and is accompanied by a decline in renal function when the original disease is of an immune nature. This was not so in patients with non-immune original disease. These findings suggest that recurrence of original disease plays an important role in late failure of cadaveric renal allografts.     

Familial juvenile hyperuricaemic nephropathy is not such a rare genetic metabolic purine disease in Britain

Renal disease is rare today in classic adult gout, and gout is rare in renal disease--especially in the young. Here we summarise studies in 158 patients from 31 kindreds diagnosed with familial juvenile hyperuricaemic nephropathy FJHN from a total of 230 kindred members studied in Great Britain. Some patients have been followed for up to 30 years, and allopurinol has ameliorated the progression of the renal disease in all 113 surviving members provided: They have been diagnosed and treated sufficiently early. Compliance with allopurinol treatment and diet has been as important as early recognition. Hypertension has been rigorously controlled. The use of oral contraceptives has been avoided, as has pregnancy in any female with a Glomelar Filtration Rate GFR <70 ml/min. The question arising is: Why is FJHN the most prevalent genetic purine disorder diagnosed in Britain? Is it a lack of awareness which needs to be improved Europe-wide?     

Reduced Glomerular Function and Prevalence of Gout: NHANES 2009–10

Background

The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population.

Study Design

Cross-sectional, survey-weighted analyses of data on adults (age>20 years) in the 2009–10 cycle of the US National Health and Nutrition Examination Surveys (n = 5,589). Associations between self-reported physician diagnosis of gout and degrees of renal impairment were the primary focus of the present analyses.

Results

In the 2009–2010 period, there was an estimated 7.5 million people with gout in the US. There were 1.25 million men and 0.78 million women with moderate or severe renal impairment and gout. The age standardized prevalence of gout was 2.9% among those with normal GFR compared to 24% among those with GFR<60 ml/min/1.73 m².In multivariable logistic regression analyses that adjusted for age, gender, body mass index, hypertension, diabetes, hypertension medications, including diuretics, blood lead levels, and hyperlipidemia, the odds ratios of gout and hyperuricemia were 5.9 (2.2, 15.7) and 9.58 (4.3, 22.0) respectively among those with severe renal impairment compared to those with no renal impairment. Approximately 2–3 fold increase in prevalence of gout was observed for each 30 ml/min/1.73 m² decrease in GFR, after accounting for the above factors.

Conclusions

Renal glomerular function is an important risk factor for gout. The prevalence of hyperuricemia and gout increases with decreasing glomerular function independent of other factors. This association is non-linear and an eGFR of 60 ml/min/1.73 m² appears to be a threshold for the dramatic increase in the prevalence of gout.     

SLC2A9rs1014290位点基因多态性与北方汉族地区男性痛风发病的相关性研究

目的:探讨可溶性载体2家族成员9基因(SLC2A9)rs1014290位点的单核苷酸多态性与北方汉族地区男性原发性痛风的发病的相关性。方法:选取404例原发性痛风男性患者和412名健康体检者,分别检测其血清尿酸、血脂、肾功等生化指标,同时提取外周血DNA,应用连接酶检测反应(LDR)法分析其SLC2A9基因rs1014290位点基因型和等位基因频率。结果:痛风组空腹血糖、尿酸(UA)、甘油三酯(TG)、胆固醇(TC)、收缩压、BMI、肌酐(Cr)水平均显著高于对照组,差异有统计学意义(P0.05)。痛风组SLC2A9基因rs1014290位点各基因型频率(CC:12.8%;CT:53.5%;TT:38.7%)与对照组(CC:16.2%;CT:50.9%;TT:32.9%)相比差异有统计学意义(X2=3.978,P=0.041);两组的等位基因频率相比差异无统计学意义(X2=0.314,P=0.496)。结论:SLC2A9基因rs1014290位点多态性可能与我国北方汉族男性原发性痛风的易感性相关,携带TT基因型的个体更易患痛风。     

Relationship between insulin resistance and low urinary pH in patients with gout, and effects of PPARalpha agonists on urine pH.

Patients with gout frequently have low urinary pH, though the underlying mechanism has not been identified. Recently, nephrolithiasis has been reported to be involved with renal manifestation of metabolic syndrome. The present study was conducted to clarify the mechanism of low urinary pH in gout patients. The relationships between urine pH and factors contributing to metabolic syndrome were investigated. In addition, the effects of PPAR alpha agonists on urine pH were examined. Patients with 24-hour urine samples below a level of pH 5.5 showed higher values for factors constituting metabolic syndrome, compared with those with 24-hour urine pH equal to or greater than 5.5. Multiple regression analysis demonstrated that HOMA index was the only contributing factor to low urinary pH in gout patients, except for serum uric acid. Administrations of PPAR alpha agonists significantly raised 24-hour urine pH levels in gout patients in accordance with a reduction in serum triglyceride concentration, probably through their activities to improve insulin resistance. Our results suggest that insulin resistance plays an important role in the development of low urinary pH in patients with gout and that PPAR alpha agonist is preferable for raising urinary pH of the gout patients with hypertriglyceridemia.     

Familial nephropathy associated with hyperuricemia in Spain: our experience with 3 families harbouring a UMOD mutation

Since 1993 we have studied 5 Spanish families with familial nephropathy associated with hyperuricemia (FJHN). Among these families, 24 patients have been identified. All patients had some combination of hyperuricemia, gout, renal insufficiency, arterial hypertension, and reduced kidney size. The clinical presentation in the different families and in the members of the same family was heterogeneous. Allopurinol treatment did not appear to influence renal disease. From a clinical perspective, this syndrome is a distinctive interstitial nephropathy, inherited as an autosomal dominant trait, that progresses to renal failure and is not halted nor prevented by allopurinol therapy. In 2003, genetic linkage analysis in 3 of the 5 families showed linkage of FJHN to 16p 11.2. One family was not analyzed and one family did not show linkage to this region confirming the genetic heterogeneity of this syndrome. A mutation in UMOD gene was found in these 3 families as the cause of the FJHN. The mutations cluster in exon 4 and exon 5 and were point mutation that results in an amino acid change in the uromodulin or Tamm Horsfall protein. This fact allowed in 2004, the presymptomatic genetic diagnosis of an 8-years-old boy belonging to one of these 3 Spanish families. We conclude that in families with a history of renal failure and/or gout in which FJHN is suspected, UMOD mutation screening may enable a definite diagnosis. When a mutation is found, family members can be tested for a UMOD mutation and pre-symptomatic diagnosis may allow counseling to prevent or halt the progression to renal insufficiency.     

Familial Nephropathy Associated with Hyperuricemia in Spain: Our Experience with 3 Families Harbouring a UMOD Mutation

Since 1993 we have studied 5 Spanish families with familial nephropathy associated with hyperuricemia (FJHN). Among these families, 24 patients have been identified. All patients had some combination of hyperuricemia, gout, renal insufficiency, arterial hypertension, and reduced kidney size. The clinical presentation in the different families and in the members of the same family was heterogeneous. Allopurinol treatment did not appear to influence renal disease. From a clinical perspective, this syndrome is a distinctive interstitial nephropathy, inherited as an autosomal dominant trait, that progresses to renal failure and is not halted nor prevented by allopurinol therapy. In 2003, genetic linkage analysis in 3 of the 5 families showed linkage of FJHN to 16p 11.2. One family was not analyzed and one family did not show linkage to this region confirming the genetic heterogeneity of this syndrome. A mutation in UMOD gene was found in these 3 families as the cause of the FJHN. The mutations cluster in exon 4 and exon 5 and were point mutation that results in an amino acid change in the uromodulin or Tamm Horsfall protein. This fact allowed in 2004, the presymptomatic genetic diagnosis of an 8-years-old boy belonging to one of these 3 Spanish families. We conclude that in families with a history of renal failure and/or gout in which FJHN is suspected, UMOD mutation screening may enable a definite diagnosis. When a mutation is found, family members can be tested for a UMOD mutation and pre-symptomatic diagnosis may allow counseling to prevent or halt the progression to renal insufficiency.     

Fractional clearance of urate: validation of measurement in spot-urine samples in healthy subjects and gouty patients

Introduction

Hyperuricemia is the greatest risk factor for gout and is caused by an overproduction and/or inefficient renal clearance of urate. The fractional renal clearance of urate (FCU, renal clearance of urate/renal clearance of creatinine) has been proposed as a tool to identify subjects who manifest inefficient clearance of urate. The aim of the present studies was to validate the measurement of FCU by using spot-urine samples as a reliable indicator of the efficiency of the kidney to remove urate and to explore its distribution in healthy subjects and gouty patients.

Methods

Timed (spot, 2-hour, 4-hour, 6-hour, 12-hour, and 24-hour) urine collections were used to derive FCU in 12 healthy subjects. FCUs from spot-urine samples were then determined in 13 healthy subjects twice a day, repeated on 3 nonconsecutive days. The effect of allopurinol, probenecid, and the combination on FCU was explored in 11 healthy subjects. FCU was determined in 36 patients with gout being treated with allopurinol. The distribution of FCU was examined in 118 healthy subjects and compared with that from the 36 patients with gout.

Results

No substantive or statistically significant differences were observed between the FCUs derived from spot and 24-hour urine collections. Coefficients of variation (CVs) were both 28%. No significant variation in the spot FCU was obtained either within or between days, with mean intrasubject CV of 16.4%. FCU increased with probenecid (P < 0.05), whereas allopurinol did not change the FCU in healthy or gouty subjects. FCUs of patients with gout were lower than the FCUs of healthy subjects (4.8% versus 6.9%; P < 0.0001).

Conclusions

The present studies indicate that the spot-FCU is a convenient, valid, and reliable indicator of the efficiency of the kidney in removing urate from the blood and thus from tissues. Spot-FCU determinations may provide useful correlates in studies investigating molecular mechanisms underpinning the observed range of efficiencies of the kidneys in clearing urate from the blood.

Trial Registration

ACTRN12611000743965     

High prevalence of hyperuricaemia and gout in an urbanised Micronesian population.

The prevalence of hyperuricaemia and gout was investigated in the Micronesian inhabitants of the highly urbanised central Pacific island of Nauru. Sixty-four per cent of men and 60% of women aged 20 years and over had hyperuricaemia--the highest prevalence rates yet reported for a population. The hyperuricaemia in men was accompanied by a high prevalence of clinical gout (6.9%). While the hyperuricaemia is probably genetic, the high prevalence of gout may be related to the environmental change from the traditional island style of living to one of almost complete Westernisation.     

高尿酸血症和痛风的遗传学研究进展

痛风是由高尿酸血症引发的一种常见炎性关节炎,受遗传因素和环境因素共同作用。早期研究表明,PRPS1和HPRT1等单基因稀有突变会引起嘌呤合成代谢紊乱,从而引发高尿酸血症和痛风。近年来,全基因组关联分析(Genome-wide association studies,GWAS)已检出多个导致高尿酸血症和痛风的易感位点及相关候选基因。其中SLC2A9、SLC22A11和SLC22A12基因功能缺失性突变可引起遗传性低尿酸血症,而过表达则会加强尿酸的重吸收。ABCG2、SLC17A1和SLC17A3基因功能缺陷型变异会降低肾脏和肠道对尿酸的排泄量。因此,诱发尿酸排泄障碍(高重吸收和低排泄)的基因变异是影响高尿酸血症和痛风的主要遗传因素。另外,抑制-激活生长因子系统、转录因子、细胞骨架以及基因和环境的互作等因素也一定程度影响血液尿酸水平。在中国汉族人群中,两个新发现的易感基因RFX3和KCNQ1可能造成免疫应答受损和胰岛B细胞功能缺陷,从而直接或间接引起高尿酸酸血症和痛风。本文系统综述了高尿酸血症和痛风的遗传学研究,以促进人们对高尿酸血症和痛风发病机理的理解。     

Determination of plasma levels of apolipoprotein E and of HDL-cholesterol in gouty patients

The authors have examined the levels of the plasma cholesterol and triglycerides, of the plasma lipoprotein (HDL, LDL, VLDL) and of their main apolipoproteins (apo-A and apo-B) in a group of 34 patients affected by gout and in a population of healthy subjects considered as a contrast group, trying to establish a plausible dislipidemic factor which could justify the major occurrence of coronary heart disease in patients suffering from gout. Statistical analysis was done with the t-test. The group of patients affected by gout had significantly higher levels of triglycerides and VLDL-C and lower levels of HDL-C than the population of healthy subjects. The change of the lipoprotein pattern observed in the patients suffering from gout may be linked to reduction of the catabolism of the triglycerides rich lipoprotein. This reduction is probably linked to a inhibition of lipoprotein lipase.