A case of effective intravenous methylprednisolone pulse therapy against severe COVID-19 infection after arteriovenous graft surgery.

Perioperative COVID-19 infections in patients suffering from end-stage renal disease (ESRD) are more likely to become severe, with a high mortality rate, than those in other patients. For such patients, corticosteroid therapy is one of the limited number of treatment options. We experienced a case of ESRD in which COVID-19 infection immediately followed arteriovenous graft surgery. Although the respiratory condition deteriorated following dexamethasone administration, requiring invasive mechanical ventilation, intravenous methylprednisolone pulse therapy (pulse therapy) improved it dramatically, suggesting that pulse therapy may be effective against severe COVID-19 infection in patients suffering from ESRD.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Silent Cerebral Microbleeds and Longitudinal Risk of Renal and Cardiovascular Events in Patients with CKD.

BACKGROUND AND OBJECTIVES: In the general population, the presence of cerebral microbleeds on T2*-weighted magnetic resonance imaging has been reported to be a predictor of future stroke. Patients with CKD have a high prevalence of microbleeds and are at higher risk of ESRD as well as cardiovascular disease, including stroke. Because endothelial dysfunction is the common pathophysiology among microbleeds, CKD, and cardiovascular disease, we hypothesized that the presence of microbleeds would be an important predictor of composite outcome, including both cardiovascular disease and renal events, in those with CKD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: This was a prospective cohort study of 404 patients with CKD who underwent T2*-weighted magnetic resonance imaging for this study between January of 2008 and January of 2011. The primary outcome was composite of cardiovascular and renal outcomes. Cardiovascular outcomes included cardiovascular death, the new onset of myocardial infarction, coronary revascularization, stroke, and amputation/revascularization because of peripheral artery disease. Renal outcomes included doubling of the serum creatinine level and development of ESRD requiring dialysis or transplantation. RESULTS: At baseline, microbleeds were present in 83 (20.5%) patients. During the follow-up median period of 2.3 years, 124 of the 404 patients experienced the composite outcome. The presence of microbleeds was associated with higher risk for the composite outcome in an unadjusted Cox model, and it remained significant after adjustment for age, sex, diabetes, and systolic BP (hazard ratio [HR], 2.58; 95% confidence interval [95% CI], 1.68 to 3.46 for composite outcome; hazard ratio, 2.41; 95% CI, 1.55 to 3.77 for renal outcome; hazard ratio, 3.46; 95% CI, 1.62 to 7.43 for cardiovascular disease outcome). CONCLUSIONS: In patients with CKD, the presence of microbleeds is a novel and independent predictor of both renal and cardiovascular disease end points.

Cerebral Microbleeds Predict Intracerebral Hemorrhage in Hemodialysis Patients.

BACKGROUND AND PURPOSE: In hemodialysis patients, previous reports have described a high prevalence of cerebral microbleeds (CMBs), but no longitudinal studies have been performed to determine the clinical significance of CMBs in these patients. In this study, we investigated whether the presence of CMBs was a predictor of future strokes in hemodialysis patients. METHODS: Cranial MRI, including T2*-weighted magnetic resonance imaging, was performed on 179 hemodialysis patients with no past history of cerebrovascular events. The patients were followed prospectively until death or renal transplantation. We used the Cox proportional hazards model with inverse probability of treatment weighting using the propensity score to compare the event-free survivals of patients with/without CMBs. For sensitivity analyses, stratification by propensity score quintile and regression adjustment were used. RESULTS: CMBs were detected in 45 of the 179 patients. During a median follow-up period of 5.0 years, stroke occurred in 24 patients, including 12 with intracerebral hemorrhage and 12 with cerebral infarctions. Cox proportional hazards analysis with inverse probability of treatment weighting using the propensity score revealed that the presence of CMBs was a strong and significant predictor of intracerebral hemorrhage (hazard ratio, 26.53; 95% confidence interval, 2.88-244.90) but not cerebral infarction (hazard ratio, 0.91; 95% confidence interval, 0.25-3.34). Sensitivity analyses yielded similar results. CONCLUSIONS: This study showed that the presence of CMBs was an independent and strong predictor of intracerebral hemorrhage in stroke-free hemodialysis patients, indicating that hemodialysis patients with CMBs should be carefully monitored for future onset of intracerebral hemorrhage.

Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Fatigue is a predictor of cardiovascular events in patients with end-stage renal disease (ESRD) undergoing hemodialysis treatment. We hypothesized that multinutritional support would improve quality of life, fatigue symptoms, and potential quantitative measures including endocrine, immune and autonomic functions in patients with ESRD undergoing hemodialysis. METHODS: Two hundred and two hemodialysis patients were randomly assigned to receive active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naïve galacto-oligosaccharide, and zinc) or placebo after each dialysis session for 12 weeks. The patients and attending physicians were blinded to the treatment, and 172 patients (86 in each group) completed the study. Fatigue was evaluated via fatigue questionnaire at 0, 4, and 12 weeks. To assess human herpes virus (HHV) 6 and 7 reactivation, numbers of viral DNA copies were determined in saliva by polymerase chain reaction at weeks 0 and 12. Autonomic function was determined via measurement of beat-to-beat variation by using acceleration plethysmography. RESULTS: Clinical characteristics, changes in fatigue, quality of life score, endocrine functions, and laboratory data did not differ significantly between the two groups. Several parameters of heart rate variability significantly increased after nutritional treatment compared to placebo. Nutritional drink for 12 weeks significantly suppressed HHV7 DNA copy numbers. Similarly, HHV6 DNA copy numbers tended to be decreased by treatment but without reaching statistical significance. CONCLUSIONS: Nutritional supplementation may modulate immune and autonomic dysfunction in ESRD patients undergoing hemodialysis.

Clinical experiences of bixalomer usage at our hospital.

In 2012, bixalomer was launched as new non-calcium (Ca) containing phosphorus (P) binder, increasing the choices available for the treatment of hyperphosphatemia. In this study, among the maintenance dialysis patients at our hospital, we newly administered bixalomer to 21 patients who were not receiving any P binders, and switched to bixalomer for 13 patients who had been receiving sevelamer hydrochloride and 23 patients who had been receiving lanthanum carbonate. The initial dosage of bixalomer was set as 1500 mg/day for new administration patients and dosage equivalent to that of the previously-used P binder for patients who were switched to bixalomer. The dosage of bixalomer was increased if the effects were insufficient. The serum P, Ca and intact parathyroid hormone concentrations as well as serum pH, HCO3 concentration and base excess were evaluated prior to administering bixalomer, 3 months and 6 months after administering bixalomer. For the group who were newly administered bixalomer, significant reductions in serum P concentrations were seen (P<0.01) and no significant changes were seen in clinical test items that serve as indices for acidosis. For the group who were switched from sevelamer hydrochloride to bixalomer, significant reductions in serum P concentrations were seen (P<0.01) together with significant improvements in acidosis (P<0.01). For the group who were switched from lanthanum carbonate to bixalomer, by increasing the dosage of bixalomer to approximately three times the dosage of lanthanum carbonate, it was possible to maintain post-switch serum P concentrations at almost the same levels as before the switch. Furthermore, there were minor, yet significant improvements in acidosis (P<0.01). From these results, it was shown that bixalomer can be useful treatment alternative in dialysis patients for whom it is necessary to change the P binder due to insufficient management of serum P concentrations or development of acidosis.

Cerebral white matter hyperintensity predicts cardiovascular events in haemodialysis patients.

AIM: Cerebral white matter hyperintensities (WMHs), comprised of periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH), have been presumed to be predictors for future stroke, cognitive impairment and dementia in the general population. However, no longitudinal studies have been performed to determine the clinical significance of WMHs in haemodialysis (HD) patients. In the present study, we investigated the influence of WMHs as a predictor of future cardiovascular disease in HD patients. METHODS: Cranial magnetic resonance imaging was performed on 179 HD patients with no past history of stroke from April 2006 to October 2009, and the prevalence of WMHs was investigated. The patients were followed prospectively until March 2012 or death or renal transplantation. The influence of WMHs on cardiovascular events was investigated using the Kaplan-Meier method and Cox proportional hazards analysis. RESULTS: The patients with advanced PVH and DSWMH had a significantly higher incidence of cardiovascular morbidity than those without advanced PVH and DSWMH by Kaplan-Meier analysis. By multivariate Cox proportional hazards analysis, the presence of advanced PVH and DSWMH increased the risk of cardiovascular events, independent of other cardiovascular risk factors. In addition, the present study revealed that of the subtypes of WMHs, PVH was a stronger predictor of cardiovascular events compared to DSWMH. CONCLUSIONS: The present study indicates that the presence of WMHs is a novel predictor of cardiovascular events in HD patients, and that PVH is more closely associated with incident cardiovascular disease.

Chronic kidney disease in patients with ileal conduit urinary diversion.

While renal dysfunction is often observed in patients following urinary diversion due to bladder cancer, there have been few studies on this subject. A cross-sectional study was performed on the renal function of ileal conduit urinary diversion patients and the prevalence and risk factors for chronic kidney disease (CKD) were examined. Patients with ileal conduit urinary diversion (n=102), who were being followed-up as outpatients and who were in stable condition, as well as age- and gender-matched healthy control subjects (n=63) were selected for this study. The prevalence of CKD was compared between the patients and healthy subjects. Next, the clinical factors associated with the presence of CKD were investigated in the patients with ileal conduit diversion using logistic regression analysis. The prevalence of CKD was significantly higher in the patients with ileal conduit diversion compared with the healthy subjects [60 patients (58.8%) vs. 11 healthy subjects (17.5%), P<0.0001]. The mean decrease in the estimated glomerular filtration rate per year of the patients with urinary diversion was 0.95±2.0 ml/min/1.73 m(2). Multiple logistic regression analysis revealed that the independent and significant factors associated with the presence of CKD were older age and the presence of hypertension, urolithiasis and a past history of hydronephrosis. In conclusion, an increased prevalence of CKD was revealed in the patients with ileal conduit urinary diversion, suggesting the need for better management of hypertension, urolithiasis and hydronephrosis following surgery.

A case of warfarin-induced eosinophilia.

Warfarin is widely used in clinical practice all over the world. We report a man in whom prominent eosinophilia appeared after the initiation of warfarin administration following aortic valve replacement. Laboratory data following the administration and discontinuation of warfarin suggested that this drug was responsible for the eosinophilia. It is important to recognize the possibility of warfarin-induced hypereosinophilia as a latent adverse effect even when there are no clinical signs or symptoms.

Factors associated with cerebral white matter hyperintensities in haemodialysis patients.

AIM: Cerebral white matter hyperintensities (WMHs), comprising periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH) on magnetic resonance imaging (MRI), have been reported to be markers of ischaemic cerebral small-vessel disease and risk factors for future stroke, cognitive impairment and dementia in the general population. However, there have been only a few reports describing WMHs in haemodialysis (HD) patients and these previous studies have been relatively small population studies with little investigation on prevalence and risk factors according to the regional subtypes of WMHs. METHODS: Cranial MRI was performed on 179 HD patients and 58 healthy control subjects and we investigated the prevalence of WMHs (PVH and/or DSWMH) and the clinical factors associated with the presence of WMHs. RESULTS: The prevalence of WMHs was significantly higher in the HD patients than in the healthy subjects. In the HD patients, multiple logistic regression analysis showed that independent and significant factors associated with the presence of PVH were age, female gender and systolic blood pressure and those associated with the presence of DSWMH were age, female gender, systolic blood pressure and body mass index. CONCLUSIONS: These findings indicated a high prevalence of WMHs in HD patients. Older age, female gender and high blood pressure were strong factors associated with the presence of both PVH and DSWMH. Moreover, excess body weight was a significant factor associated with the presence of DSWMH only, indicating that there may be differences in risk factors according to the subtype of WMHs.

Chronic kidney disease in urolithiasis patients following successful extracorporeal shockwave lithotripsy.

Recently, it has been reported that kidney stones are a significant and independent risk factor for chronic kidney disease (CKD) in the general population. However, the prevalence of CKD in patients following successful extracorporeal shockwave lithotripsy (ESWL) has yet to be elucidated. In the present study, the prevalence of CKD and the clinical factors associated with the presence of CKD in patients following successful ESWL were investigated. A cross­sectional study was performed in 114 patients who had undergone ESWL for upper urinary tract stones and 96 age- and gender-matched healthy control subjects. We initially determined the stage of CKD and compared the prevalence of CKD between healthy subjects and patients who underwent successful ESWL. We then investigated the clinical factors associated with the presence of CKD by logistic regression analysis. The prevalence of CKD was significantly higher in patients following successful ESWL than in the healthy subjects [40 patients (35.1%) vs. 9 healthy controls (9.4%), P<0.0001]. Logistic regression analysis showed that the significant factors associated with the presence of CKD were increased body mass index (BMI) and the presence of a ureteric stone (pre­ESWL stone position). The findings indicated that there was a high prevalence of CKD among patients following successful ESWL, and that an increased BMI and a ureteric stone were factors associated with the presence of CKD.

Fatigue is a predictor for cardiovascular outcomes in patients undergoing hemodialysis.

BACKGROUND AND OBJECTIVES: Despite potential significance of fatigue and its underlying components in the occurrence of cardiovascular diseases, epidemiologic data showing the link are virtually limited. This study was designed to examine whether fatigue symptoms or fatigue's underlying components are a predictor for cardiovascular diseases in high-risk subjects with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 788 volunteer patients under hemodialysis therapy (506 male, 282 female) completed the survey between October and November 2005, with the follow-up period up to 26 months to monitor occurrence of fatal or nonfatal cardiovascular events. The questionnaire consisted of 64 questions, and promax rotation analysis of the principal component method conceptualized eight fatigue-related factors: fatigue itself, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection. RESULTS: 14.7% of the patients showed fatigue scores higher than twice the SD of the mean for healthy volunteers. These highly fatigued patients exhibited a significantly higher risk for cardiovascular events (hazard ratio: 2.17; P < 0.01), with the relationship independent of the well-known risk factors, including age, diabetes, cardiovascular disease history, and inflammation and malnutrition markers. Moreover, comparisons of the risk in key subgroups showed that the risk of high fatigue score for cardiovascular events was more prominent in well-nourished patients, including lower age, absence of past cardiovascular diseases, higher serum albumin, and high non-HDL cholesterol. CONCLUSIONS: Fatigue can be an important predictor for cardiovascular events in patients with ESRD, with the relationship independent of the nutritional or inflammatory status.

Cerebral microbleeds in predialysis patients with chronic kidney disease.

BACKGROUND: Gradient-echo T2*-weighted magnetic resonance imaging (T2*-weighted MRI) is highly sensitive for detecting cerebral microbleeds (CMBs). CMBs have been reported to be a risk factor for future cerebrovascular events and a marker of cerebral small vessel disease in the general population. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. The relationship between CKD and CMBs, which has not been clarified to date, is examined. METHODS: In this cross-sectional study, T2*-weighted MRI of brain was performed with a 1.5-T MRI system in 162 CKD patients (CKD stages 1-5, excluding CKD stage 5(D)) and 24 normal subjects. RESULTS: CMBs were found in 35 CKD patients (25.6%), but not in control subjects. CMBs were more prevalent in male patients, in those with higher blood pressure, advanced age and poor kidney function. There was a significant association between the prevalence of CMBs and the CKD stage, with higher prevalence of CMBs as the CKD stages advanced (P < 0.01). Estimated glomerular filtration rate was a significant factor associated with the prevalence of CMBs, independent of age, gender and hypertension. There was no significant relationship between CMBs and the presence of diabetes mellitus and dyslipidemia. CONCLUSIONS: Decreased renal function is a significant risk factor for CMBs, independent of the presence of hypertension. Poor kidney function could be associated with future cerebrovascular events.

[A patient in whom oral UFT/Leucovorin therapy proved markedly effective for lung metastasis after surgery for colon cancer].

A 78-year-old male with sigmoid colon cancer underwent sigmoidectomy. The lesion was se, p1(+), n1, and Stage IV. Oral UFT therapy was performed, but was replaced with oral S-1 therapy 1 year and 6 months after surgery. Three months later, lung metastases 2.0 x 1.5 cm and 0.6 x 0.6 cm were found by chest CT in right S10a and S5b, respectively. Since the patient did not wish surgery, the treatment was changed to oral UFT/Leucovorin(LV)therapy(UFT 300 mg/ LV 75 mg, 4-week administration and 1-week no-administration periods). After 2 courses, chest CT showed disappearance of both lung metastases, indicating complete remission. Oral UFT/LV therapy is convenient because of the oral route. Adverse reactions are few, and the therapeutic effect has been reported to be comparable to that of intravenous 5-FU/LV therapy. Also, in this patient, no adverse reaction was noted, and complete remission was maintained until the patient died of another disease 31 months after the beginning of oral UFT/LV therapy.

Significant correlation of glycated albumin, but not glycated haemoglobin, with arterial stiffening in haemodialysis patients with type 2 diabetes.

OBJECTIVE: We recently reported that glycated albumin (GA) is a better indicator of glycaemic control compared with glycated haemoglobin (HbA1c) in haemodialysis (HD) patients with type 2 diabetes. As poor glycaemic control is considered an independent risk factor for atherosclerosis in diabetes, the relationship between GA, HbA1c and arterial stiffening was examined in HD patients with type 2 diabetes. PATIENTS AND METHODS: The present study comprised 134 HD patients with type 2 diabetes, and 158 patients without diabetes. Brachial-ankle pulse wave velocity (baPWV) was measured in all patients using a waveform analyser. RESULTS: The mean plasma glucose (PG), GA and HbA1c levels were 7.49 +/- 2.28 mmol/l, 20.8 +/- 5.57% and 5.62 +/- 1.26%, respectively, in HD patients with diabetes (n = 134), which were significantly greater than the respective values of 5.77 +/- 1.89 mmol/l, 15.6 +/- 2.34% and 4.98 +/- 0.80% in those without diabetes (n = 158) (P < 0.0001). BaPWV was 21.69 +/- 6.90 m/s in HD patients with diabetes, which was significantly greater than the value of 18.74 +/- 4.89 m/s in those without diabetes (P < 0.0001). When the analysis was performed in a combined population of those patients with and without diabetes, the mean PG (r = 0.155, P < 0.05) and GA (r = 0.117, P < 0.05), but not HbA1c (r = 0.092, P = 0.125), exhibited significant correlations with baPWV. Multivariate regression analysis, which included age, gender, mean blood pressure, and serum levels of albumin, creatinine and LDL cholesterol, to evaluate the independent association of each marker for glycaemic control with baPWV values in HD patients demonstrated that GA, but not HbA1c or PG, was an independent factor that was significantly associated in a positive manner with baPWV in HD patients. CONCLUSION: It was suggested that poor glycaemic control, as reflected by increased GA values, might be associated with increased arterial stiffening in HD patients.

Microarray analysis of glomerular gene expression in murine lupus nephritis.

To elucidate the molecular mechanism of glomerular events in lupus nephritis, we performed genome-wide mRNA expression analysis of glomeruli microdissected from lupus mice. MRL/lpr mice (12-week-old) were orally given vehicle or prednisolone (10 mg/kg per day) for 4 weeks. Renal histology of MRL/lpr mice revealed mesangial proliferative glomerulonephritis with cellular infiltration of macrophages, T cells, and neutrophils. We identified 567 up-regulated genes in MRL/lpr glomeruli compared to control congenic mice. Those included complement components, adhesion molecules, chemokines and their receptors, and molecules related to antigen presentation. Over 130 genes were considered preferentially or exclusively expressed in hematopoietic cell lineages possibly reflecting leukocytes accumulation. Of note is the finding that chemokines and chemokine receptors (CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11, CXCL16, CCR5, CXCR3, and CXCR6) that are related to T helper 1 (Th1) cells accumulation were up-regulated concomitantly with increased expression of Ebi3, a subunit of IL-27 that plays a role in Th1 predominance. These changes were accompanied by increased mRNA expression of many genes that were inducible by Th1 cytokine interferon-gamma. Prednisolone markedly attenuated glomerular lesion and leukocyte influx parallel with the reduction of enhanced gene expression. The present study shows additional evidence supporting glomerular Th1 cells accumulation and their role. Our data also provide an important resource in seeking new therapeutic targets to lupus nephritis. Supplemental table: available only at http://dx.doi.org/10.1254/jphs.FP0071337.

Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection.

The significance of glycated albumin (GA), compared with casual plasma glucose (PG) and glycated hemoglobin (HbA(1c)), was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. The mean PG, GA, and HbA(1c) levels were 164.5 +/- 55.7 mg/dl, 22.5 +/- 7.5%, and 5.85 +/- 1.26%, respectively, in HD patients with diabetes (n = 538), which were increased by 51.5, 31.6, and 17.7%, respectively, compared with HD patients without diabetes (n = 828). HbA(1c) levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the relationship among the three parameters in patients who had diabetes without renal dysfunction (n = 365), as reflected by the significantly more shallow slope of regression line between HbA(1c) and PG or GA. A significant negative correlation was found between GA and serum albumin (r = -0.131, P = 0.002) in HD patients with diabetes, whereas HbA(1c) correlated positively and negatively with hemoglobin (r = 0.090, P = 0.036) and weekly dose of erythropoietin injection (r = -0.159, P < 0.001), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA(1c) levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartile by HbA(1c) level led to better glycemic control in a significantly higher proportions of HD patients with diabetes than those assessed by GA. Multiple regression analysis demonstrated that the weekly dose of erythropoietin, in addition to PG, emerged as an independent factor associated with HbA(1c) in HD patients with diabetes, although PG but not albumin was an independent factor associated with GA. In summary, it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA(1c) in these patients might lead to underestimation likely as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Possible involvement of nuclear factor-kappaB inhibition in the renal protective effect of oral adsorbent AST-120 in a rat model of chronic renal failure.

Oral adsorbent, AST-120 removes uremic toxins (such as indoxyl sulfate) and retards the progression of chronic renal failure (CRF). However, its mechanism of action has not been precisely clarified. Since indoxyl sulfate elicits renal tubular nuclear factor-kappaB (NF-kappaB) activation in vitro, the present experiments were conducted to elucidate the involvement of NF-kappaB in the beneficial effects of AST-120 using rats with 3/4 nephrectomy, a model of early-stage CRF. Daily administration of AST-120 was started at 6 weeks after 3/4 nephrectomy and continued for 18 weeks. Sham-operated rats, untreated CRF rats and AST-120-treated CRF rats were compared for NF-kappaB DNA-binding activity, gene expression and renal histology. Systolic blood pressure was increased in CRF rats, and this increase was not affected by AST-120. Blood urea nitrogen, serum creatinine and urinary protein were increased in CRF rats. Although AST-120 attenuated these increases, it did not do so to a statistically significant extent. Indoxyl sulfate, which was accumulated in serum of CRF rats, was significantly eliminated by AST-120. Renal cortical NF-kappaB DNA-binding activity was increased in CRF rats. AST-120 significantly inhibited this increase. Monocyte/macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) mRNA observed in CRF rats were attenuated by AST-120. Furthermore, AST-120 significantly blocked renal fibrosis with concomitant inhibition of transforming growth factor beta1 (TGF-beta1) gene expression. It appeared that AST-120 reduced NF-kappaB activation and possibly the activity of NF-kappaB-dependent pathways of interstitial inflammation including MCP-1 expression and macrophage infiltration. The anti-inflammatory effect of AST-120 mediated via inhibition of NF-kappaB is a possible mechanism by which AST-120 retards the progression of renal fibrosis in CRF.

Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation.

BACKGROUND: It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors. METHODS: CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay. RESULTS: DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28. CONCLUSIONS: Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.