Effect of a concomitant elemental diet with maintenance anti-tumor necrosis factor-α antibody therapy in patients with Crohn's disease: A multicenter, prospective cohort study.

BACKGROUND AND AIM: The aim of this study was to clarify the additional effect of a concomitant elemental diet (ED) for patients with Crohn's disease on maintenance anti-tumor necrosis factor-α antibody (anti-TNF). METHODS: Crohn's disease patients who received anti-TNF induction therapy were enrolled. Patients who achieved clinical response (defined as delta Crohn's disease activity index [CDAI] > 70 and CDAI < 200) at 10-14 weeks after the start of infliximab or adalimumab were included. Eligible patients took a tolerability test of ED (900 kcal/day) for 3 days. Then, patients who preferred concomitant ED and whose ED tolerance was confirmed were allocated to the ED group and given Elental 900 kcal/day or more. Other patients were allocated to the non-ED group. The primary endpoint was the cumulative remission rate at 2 years after baseline. Clinical relapse was defined as CDAI > 200 and/or need for additional treatment. Adherence to the ED was confirmed at each visit. RESULTS: Seventy-two patients were included. Thirty-seven were allocated to the ED group, and 35 were allocated to the non-ED group. The cumulative remission rate at 2 years was not significantly different between the two groups (60.9% vs 56.7%, P = 0.98). Adherence to the ED in the ED group was relatively low, and only 11 patients were maintained on an ED of 900 kcal/day. CONCLUSIONS: The addition of ED for Crohn's disease patients who responded to initial anti-TNF induction therapy was not found to improve outcomes. The efficacy of concomitant ED in other clinical settings, such as loss of response, needs to be clarified in the future (UMIN000009789).

Efficacy of Endoscopic Balloon Dilation for Small Bowel Strictures in Patients With Crohn's Disease: A Nationwide, Multi-centre, Open-label, Prospective Cohort Study.

BACKGROUND AND AIMS: Endoscopic balloon dilation [EBD] is an alternative to surgery for Crohn's strictures. However, there have been no prospective studies of EBD for small bowel strictures in patients with Crohn's disease [CD]. The aim of this study was to clarify the efficacy and safety of EBD using balloon-assisted enteroscopy for small bowel strictures in CD. METHODS: This was a nationwide, multi-centre, open-label, prospective cohort study. The subjects were CD patients with at least one symptom [abdominal pain, abdominal bloating, nausea] attributable to small bowel stricture. The primary endpoint related to short-term outcomes was the level of improvement of symptoms evaluated using a 10-cm visual analogue scale [VAS]. Cases in which VAS scores for all symptoms improved 4 weeks after EBD compared with baseline were considered to have short-term symptomatic improvement. Factors related to short-term treatment outcomes and safety were investigated as secondary endpoints. RESULTS: A total of 112 patients were enrolled. Seventeen were later excluded because they did not meet the criteria, and the analysis was conducted with the remaining 95 patients. Of these 95 patients, procedure failure occurred in six [6.3%], and short-term symptomatic improvement was achieved in 66 patients [69.5%]. Adverse events were seen in five patients [5%] and all of these improved with conservative treatment. A large dilation diameter of the balloon was a factor contributing to the success of EBD. CONCLUSIONS: EBD using balloon-assisted enteroscopy for small bowel strictures in CD patients was shown to be an effective and safe procedure. CLINICAL TRIAL REGISTRY: UMIN000005946.

2.4 g Mesalamine (Asacol 400 mg tablet) Once Daily is as Effective as Three Times Daily in Maintenance of Remission in Ulcerative Colitis: A Randomized, Noninferiority, Multi-center Trial.

BACKGROUND: The noninferiority of pH-dependent release mesalamine (Asacol) once daily (QD) to 3 times daily (TID) administration was investigated. METHODS: This was a phase 3, multicenter, randomized, double-blind, parallel-group, active-control study, with dynamic and stochastic allocation using central registration. Patients with ulcerative colitis in remission (a bloody stool score of 0, and an ulcerative colitis disease activity index of ≤2), received the study drug (Asacol 2.4 g/d) for 48 weeks. The primary efficacy endpoint of the nonrecurrence rate was assessed on the full analysis set. The noninferiority margin was 10%. RESULTS: Six hundred and four subjects were eligible and were allocated; 603 subjects received the study drug. The full analysis set comprised 602 subjects (QD: 301, TID: 301). Nonrecurrence rates were 88.4% in the QD and 89.6% in the TID. The difference between nonrecurrence rates was -1.3% (95% confidence interval: -6.2, 3.7), confirming noninferiority. No differences in the safety profile were observed between the two treatment groups. On post hoc analysis by integrating the QD and the TID, nonrecurrence rate with a mucosal appearance score of 0 at determination of eligibility was significantly higher than the score of 1. The mean compliance rates were 97.7% in the QD and 98.1% in the TID. CONCLUSIONS: QD dosing with Asacol is as effective and safe as TID for maintenance of remission in patients with ulcerative colitis. Additionally, this study indicated that maintaining a good mucosal state is the key for longer maintenance of remission.

A case of Turner syndrome (46XXp-/45X) complicated with Crohn's disease after hormone therapy.

A 19-year-old woman, who had been receiving hormone replacement therapy for 13 months before the diagnosis of mosaic Turner syndrome (46XXp-/45X), developed Crohn's colitis and erythema nodosum of the lower legs. Colonoscopy revealed an anal fistula and the presence of deep longitudinal ulcers with cobblestoning in the colorectum. Therapy with prednisolone and adalimumab was effective for the intestinal and skin lesions. To date, all seven case reports of Turner syndrome in Japan have also developed Crohn's disease after hormone therapy, suggesting a possible association of sex hormones in the pathogenesis.

[Clinical features and pathophysiology of acute esophageal mucosal lesion].

Acute esophageal mucosal lesions (AEMLs) are categorized into black esophagitis (type B) and non-black esophagitis (type NB) on endoscopy. To clarify the distinct pathophysiology, we compared the clinical features and hematological findings at onset among 17 patients with type B esophagitis and 6 patients with type NB esophagitis. In type B esophagitis, time to endoscopy after onset was significantly shorter, and blood levels of lactate, urea nitrogen, creatinine, and glucose were higher than in type NB esophagitis. However, there were no significant intergroup differences in the incidences of other predisposing factors, such as diabetic ketoacidosis or esophageal hernias. These findings suggest that AEMLs are caused by acid reflux and peripheral vascular insufficiency, the latter being more associated with type B esophagitis by its etiology. In addition, blood lactate may indicate the severity of AEML, leading to black esophagitis.

Efficacy and safety of two pH-dependent-release mesalamine doses in moderately active ulcerative colitis: a multicenter, randomized, double-blind, parallel-group study.

BACKGROUND/AIMS: The therapeutic effect of mesalamine is considered to be dose-dependent; however, no consensus has been reached regarding the optimal doses for individual patients. This study aimed to provide new insight for dose optimization using two doses of pH-dependent release mesalamine for induction of remission of moderately active ulcerative colitis (UC). METHODS: In a multicenter, double-blind, randomized study, 110 patients with moderately active UC were assigned to two groups after treatment with a constant dose of mesalamine. Fifty-five patients were treated with a pH-dependent release formulation of 3.6 or 4.8 g/day for 8 weeks. The primary endpoint was a decrease in the UC disease activity index (UCDAI) adjusted by covariates. RESULTS: In the full analysis set (n=110), the mean decrease in UCDAI was 3.1 in the 3.6 g/day group and 3.4 in the 4.8 g/day group (P>0.05). In a subgroup analysis, the effectiveness of the 4.8 g/day dose was greater in particular populations, such as those who had been previously treated with a lower dose of mesalamine and those with more severe disease. The safety was comparable between the two groups. CONCLUSIONS: The results suggest that treatment with pH-dependent release mesalamine at either 3.6 or 4.8 g/day was effective and safe for the induction of remission in patients with moderately active UC. However, the patients receiving mesalamine at 2.4 g/day but in whom the therapeutic effect is not sufficient and having more severe symptoms (UCDAI 9-10), benefit from higher doses of mesalamine compared to others.

Investigation of a High-Dose pH-Dependent-Release Mesalazine on the Induction of Remission in Active Crohn's Disease.

INTRODUCTION: The effect of mesalazine in treating active Crohn's disease (CD) remains controversial, possibly due to the various formulae of mesalazine used to treat inflammation located in different regions of the digestive tract. METHODS: This exploratory, multicenter, uncontrolled, open-label study included 17 patients with active CD. The inclusion criteria were patients with a CD activity index (CDAI) of ≥ 200 and <350, and in whom mucosal lesions were observed in the area from the terminal ileum to the rectum using colonoscopy (CS). Each patient was treated with pH-dependent-release mesalazine at 4.8 g/day. The drug was administered three times daily for 12 weeks. Efficacy was evaluated by the change in CDAI at the time of final observation (at week 12 or at discontinuation), and safety was evaluated by the incidence of adverse events (AEs) and adverse drug reactions (ADRs). RESULTS: In the full analysis set (n = 17), the change in CDAI at the time of final observation was -67.4, and the mean change in CDAI from baseline was -49.3 at week 2, -61.8 at week 4, -78.3 at week 8, and -101.1 at week 12. A statistically significant improvement was observed from week 2 to week 12 compared with baseline, and the incidences of AEs and ADRs were 94.1 and 58.8%, respectively. All events were known events, as the results suggested, which is in line with the known safety profile of pH-dependent-release mesalazine. CONCLUSIONS: The results suggest that the administration of pH-dependent-release mesalazine 4.8 g/day for 12 weeks could be an effective and highly safe treatment option for patients with mild to moderately active CD in whom mucosal lesions were observed in the area from the terminal ileum to the rectum. TRIAL REGISTRATION NUMBER: JapicCTI-111460.

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn's disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of "chronic enteropathy associated with SLCO2A1 gene" (CEAS).

Double-balloon endoscopy is safe and effective for the diagnosis and treatment of small-bowel disorders: prospective multicenter study carried out by expert and non-expert endoscopists in Japan.

BACKGROUND AND AIM: Double-balloon endoscopy (DBE) has enabled direct, detailed examination of the entire small bowel with interventional capabilities. Although its usefulness is recognized, efficacy and safety have not been extensively evaluated by prospective multicenter studies. To evaluate the efficacy and safety of DBE carried out by expert and non-expert endoscopists, a prospective, multicenter study was conducted in five university hospitals and a general hospital in Japan. METHODS: A total of 120 patients who underwent 179 procedures were enrolled in the study. Experts carried out 129 procedures and non-experts carried out 50 procedures. Primary and secondary end points were evaluation of safety, the rate of achievement of procedural objectives, namely, identification of a new lesion, detailed examination to establish a therapeutic strategy, or exclusion of significant lesions by total enteroscopy, and rate of successful examination of the entire small bowel and evaluation of safety. RESULTS: Overall rate of achievement of procedural objectives was 82.5% (99/120). Overall success rate for examination of the entire small bowel was 70.8% (34/48). Incidence of adverse events was 1.1% (a mucosal injury and an episode of pyrexia in two of 179 examinations). No severe adverse events were encountered. There were no significant differences in any of the outcome measures comparing expert and non-expert operators. CONCLUSIONS: DBE is effective and safe for patients with suspected small bowel diseases, and can be safely carried out even by a non-expert under the supervision of an expert, following a simple training program.

Risk of cancer in the rectal remnant after ileorectal anastomosis in patients with familial adenomatous polyposis: single center experience.

BACKGROUND AND AIM: We aimed to evaluate the long-term risk of cancer in the rectal remnant in patients with familial adenomatous polyposis after ileorectal anastomosis. METHODS: Cumulative incidence and clinicopathological characteristics of cancer in the rectal remnant were retrospectively investigated in 27 patients with familial adenomatous polyposis who had undergone ileorectal anastomosis. RESULTS: During the follow-up period ranging from 3.0 to 35.0 years (median, 21.1 years), cancer in the rectal remnant developed in 10 patients. Cumulative risk of cancer in the rectal remnant 30 years after surgery was 57%. Five patients had metastases and three patients died of cancer in the rectal remnant after proctectomy. There was a trend towards a higher incidence of cancer in the rectal remnant in patients with small-intestinal adenoma and congenital hypertrophy of the retinal pigment epithelium. Multivariate analysis revealed that the ocular lesion was an independent risk factor associated with cancer in the rectal remnant. CONCLUSION: Subtotal colectomy with ileorectal anastomosis does not seem to be an appropriate prophylactic surgery in patients with familial adenomatous polyposis.

Association of systolic blood pressure and pulse pressure with carotid intima thickness in elderly Japanese patients.

Many studies have demonstrated that increased carotid intima-media thickness (IMT) is related to future cardiovascular events and is influenced by cardiovascular risk factors such as sex, hypertension, diabetes, and hypercholesterolemia. Although aging is a well-known risk factor for an increase in carotid IMT, few studies have investigated which factors influence carotid IMT in the very elderly. In the present study, we investigated the relationship of pulse pressure (PP), blood pressure (BP), and its variability (six consecutive visits) with carotid IMT among 240 high-risk elderly in whom risk factors were managed clinically (average age was 79 ± 5 years). In the simple correlation, mean systolic BP (SBP) had a positive correlation with IMT and max IMT (P = .012 and P = .045), as did PP (P = .018 and P = .004), but did not diastolic BP or standard deviation of BP and coefficient of variation of BP. In multiple regression analyses, mean SBP and mean PP were each determinants of both IMT and max IMT, when each parameter was added separately to the regression model. We concluded that high SBP and wide PP still have an influence on increased carotid IMT in the very elderly Japanese patients.

[An autopsy case of ulcerative colitis with disseminated aspergillosis, complicated by brain hemorrhage].

An 80-year-old Japanese woman suffered multiple brain infarctions of unknown etiology during maintenance therapy of prednisolone and azathioprine for ulcerative colitis. Although a small cavity in the left lung spontaneously regressed, the patient suddenly died of massive brain hemorrhage due to disseminated aspergillosis, which was not identified until autopsy.

A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population.

BACKGROUND & AIMS: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population. METHODS: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS: We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27). CONCLUSIONS: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease.

Profiles of circulating cytokines in patients with Crohn's disease under maintenance therapy with infliximab.

BACKGROUND AND AIMS: The effects of maintenance infliximab for Crohn's disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab. METHODS: Cytokine profiles of 35 Crohn's disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6 weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6 weeks after infliximab infusion. RESULTS: At baseline, serum levels of IL-23 (p<0.05), IL-17A (p<0.01), IFN-γ (p<0.05), and IL-6 (p<0.01) were significantly higher in active Crohn's disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p<0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter. CONCLUSION: Higher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy.

Optimal cutoff value of the serum pepsinogen level for prediction of gastric cancer incidence: the Hisayama Study.

BACKGROUND: Serum pepsinogen (sPG) levels have been established as a good marker of chronic atrophic gastritis and the sequential occurrence of gastric cancer. However, there have been few prospective investigations which investigated the predictive performance of sPG for future gastric cancer incidence. SUBJECTS AND METHODS: We prospectively followed-up a total of 2446 community-dwelling Japanese aged ≥ 40 years for 10 years and used the Youden's index to determine the cutoff values of the pepsinogen I level and pepsinogen I/II ratio to accurately discriminate gastric cancer events. Predictive performance of sPG was assessed by ROC curve. RESULTS: During the follow-up, 69 subjects developed gastric cancer. The most predictive sPG test criteria were determined to be a pepsinogen I level ≤ 59 ng/ml and pepsinogen I/II ratio ≤ 3.9. The sensitivity and specificity of these criteria to discriminate the actual occurrence of gastric cancer were 71.0% and 69.2%, respectively. The area under the ROC curve for gastric cancer occurrence increased significantly by adding the sPG test to the model that included the status of Helicobater pylori infection and other potential risk factors (from 0.742 to 0.809; p for difference in the area < 0.001). CONCLUSIONS: This study determined the optimal sPG test criteria for predicting gastric cancer occurrence over 10 years in a general Japanese population. These criteria would be effective to screen for individuals at high risk of this disease.

White blood cell count and risk of gastric cancer incidence in a general Japanese population: the Hisayama study.

The authors examined the association between white blood cell (WBC) count and the development of gastric cancer in a 19-year follow-up study of 2,558 Japanese subjects aged ≥40 years (1988-2007). The subjects were stratified into 4 groups according to baseline WBC quartile (≤4.4, 4.5-5.2, 5.3-6.3, or ≥6.4 × 10(3) cells/µL). During follow-up, 128 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer increased linearly with higher WBC level: 1.7, 2.6, 3.9, and 5.4 per 1,000 person-years, respectively, for the 4 quartile groups (P for trend < 0.01). The risk of gastric cancer was 2.22-fold (95% confidence interval: 1.19, 4.14) higher in the highest WBC quartile group than in the lowest group after adjustment for confounding factors. With respect to Helicobacter pylori infection status, H. pylori-seropositive subjects in the highest WBC quartile group showed a significantly greater risk of gastric cancer than those in the lower 3 quartile groups, whereas such an association was not observed in H. pylori-seronegative subjects. There was no evidence of heterogeneity in the association (P for heterogeneity = 0.65). The study findings suggest that higher WBC levels are a risk factor for gastric cancer, especially in subjects with H. pylori infection.

Lower levels of high-density lipoprotein cholesterol on admission and a recurrence of ischemic stroke: a 12-month follow-up of the Fukuoka Stroke Registry.

BACKGROUND: Despite recent progress in treatments for secondary prevention, ischemic stroke recurs in 8% to 12% of stroke survivors. We investigated the predisposing factors associated with recurrence within the first 12 months after an ischemic event to explore more effective preventive strategies. METHODS: Between June 2007 and April 2008, acute (within 7 days of onset) ischemic stroke patients were registered in the Fukuoka Stroke Registry (FSR), a multicenter, prospective, observational database. The clinical characteristics on admission were analyzed, and the patients were followed for 12 months. RESULTS: Two hundred sixty patients (151 males and 109 females, 71 ± 11 years of age) were registered; 25 (9.6%) had recurrence of ischemic stroke during the follow-up period. Kaplan-Meier curve analysis revealed a significant difference in recurrence-free survival between patients with high-density lipoprotein (HDL) cholesterol <40 mg/dL on admission and those with HDL cholesterol ≥ 40 mg/dL (P = .042). Adjusted multivariate logistic regression analysis showed that age (odds ratio 1.06; 95% CI, 1.00-1.11; P = .035) and HDL cholesterol <40 mg/dL (odds ratio 2.73; 95% CI, 1.01-7.38; P = .048) on admission were independently associated with a recurrence of ischemic stroke within 12 months of the initial onset. CONCLUSIONS: Aging and low HDL cholesterol levels are considered independent risk factors for a recurrence of ischemic stroke.

Dietary vitamin A intake and incidence of gastric cancer in a general Japanese population: the Hisayama Study.

BACKGROUND: The results of prospective studies examining the association between dietary vitamin A intake and the risk of gastric cancer have often been conflicting. The objective of this study was to investigate this issue in a general Japanese population. METHODS: A total of 2,467 community-dwelling Japanese subjects aged 40 years or older were followed up prospectively for 14 years. Dietary vitamin A intake was estimated using a semiquantitative food frequency method. RESULTS: During the follow-up period, gastric cancer developed in 93 subjects. The age- and sex-adjusted incidence of gastric cancer rose progressively with increasing levels of dietary vitamin A intake: at 2.2, 3.0, 3.8, and 4.5 per 1,000 person-years for quartile groups defined by dietary vitamin A intake levels of <639, 639-837, 838-1,061, and >1,061 µg retinol equivalents (RE)/day, respectively (P for trend <0.01). The risk of gastric cancer was significantly higher in the fourth quartile than in the first one even after multivariate adjustment [hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 0.70-3.09, P = 0.30 for the second quartile; HR = 1.85, 95% CI = 0.82-4.18, P = 0.14 for the third quartile; HR = 2.96, 95% CI = 1.12-7.80, P = 0.03 for the fourth quartile]. Comparable effects of vitamin A intake were observed irrespective of the location or histological type of gastric cancer. The HR for gastric cancer increased significantly only in subjects with a combination of high vitamin A intake (>1,061 µg RE/day) and Helicobacter pylori infection. CONCLUSIONS: Our findings suggest that dietary vitamin A intake is clearly associated with the risk of gastric cancer in the general Japanese population.

The antioxidant tempol ameliorates arterial medial calcification in uremic rats: important role of oxidative stress in the pathogenesis of vascular calcification in chronic kidney disease.

Vascular calcification is closely related to cardiovascular morbidity and mortality. Accumulating data indicate that oxidative stress is associated with dysfunction of various organs, including cardiovascular diseases in chronic kidney disease (CKD). However, it remains undetermined if oxidative stress induced by uremia promotes arterial medial calcification. The present study investigated the role of oxidative stress in the pathogenesis of arterial medial calcification in uremic rats. Rats with uremia induced by adenine-rich diet progressively developed arterial medial calcification, which was accompanied by time-dependent increases in both aortic and systemic oxidative stress. Immunohistochemical and biochemical analyses showed that the arterial medial calcification progressed in a time-dependent manner that is parallel to the osteogenic transdifferentiation of vascular smooth muscle cells. Accumulation of oxidative stress was also identified in the calcified regions. Time-course studies indicated that both oxidative stress and hyperphosphatemia correlated with arterial medial calcification. Tempol, an antioxidant, ameliorated osteogenic transdifferentiation of vascular smooth muscle cells and arterial medial calcification in uremic rats, together with reduction in aortic and systemic oxidative stress levels, without affecting serum biochemical parameters. Our data suggest that oxidative stress induced by uremia can play a role in the pathogenesis of vascular calcification in CKD, and that antioxidants such as tempol are potentially useful in preventing the progression of vascular calcification in CKD.