Radiocontrast-induced nephropathy is attenuated by autophagy through regulation of apoptosis and inflammation.

Radiocontrast-induced nephropathy (RCN) is the third most common cause of acute renal failure among inpatients. Although the number of patients undergoing exams using radiocontrast is increasing, little progress has been made for RCN treatment. The pathophysiology of RCN is known as tubular injury due to oxidative stress. As autophagy regulates cellular damage under stressful conditions, we investigated the role of autophagy in RCN. RCN was induced in male C57BL/6 J mice by intraperitoneal injection of iohexol, and 3-methyladenine (3-MA) was used as an autophagy inhibitor. Tubular injury caused by iohexol was also examined in vitro using rat tubular cells (NRK-52E). Increased autophagy after iohexol administration was demonstrated by the increase of light chain 3-II in the damaged kidney tubules both in vivo and in vitro. Serum creatinine and tubular injury were significantly increased at 24 h after iohexol treatment, as compared to control group. Further they worsened with autophagy inhibition by 3-MA. In vitro studies also demonstrated that decreased cell viability by iohexol was aggravated with 3-MA pretreatment. Malondialdehyde measured for oxidative stress was increased by iohexol, and it was accentuated by autophagy inhibition, which resulted in increase of cytochrome c Apoptosis, increased by iohexol treatment, was augmented with autophagy inhibition. Macrophage infiltration and increase of monocyte chemotactic protein-1 in kidneys were induced by iohexol, and it was aggravated with autophagy inhibition. This study showed that autophagy was involved with the pathophysiology of RCN, and the role of autophagy in modulation of apoptosis, oxidative stress, and inflammatory cell infiltration was supposed as mechanisms mitigating RCN.

Predicting postoperative total calcium requirements after parathyroidectomy in secondary hyperparathyroidism.

BACKGROUND/AIMS: To prevent hypocalcemia after parathyroidectomy (PTX), parenteral calcium is required in addition to oral calcitriol and calcium. After switching to oral calcium, patients can be discharged from the hospital. The aim of this study was to analyze the clinical characteristics and outcomes of PTX performed at a single Korean center and to investigate the associated laboratory factors used to analyze the total amount of postoperative calcium required. METHODS: We enrolled 91 hemodialysis patients undergoing PTX from November 2003 to December 2011. We collected clinical and laboratory data preoperatively, 12 and 48 hours postoperatively, at discharge, and 3 and 6 months postoperatively. RESULTS: In total, 59 patients underwent PTX with autotransplantation (AT), 6 underwent total PTX without AT, 11 underwent subtotal PTX, and 15 underwent limited PTX. Total PTX without AT showed the lowest recurrence rate. At all postoperative time points, the mean levels of serum calcium, phosphorus, and intact parathyroid hormone (iPTH) decreased significantly, compared with preoperative levels; however, alkaline phosphatase (ALP) increased significantly from 48 hours postoperatively to discharge (p < 0.001). On multiple linear regression analysis, the total amount of injected calcium during hospitalization showed a significant correlation with preoperative ALP (p < 0.001), preoperative iPTH (p = 0.037), and Δphosphorus at 48 hours (p < 0.001). We developed an equation for estimating the total calcium requirement after PTX. CONCLUSIONS: Preoperative ALP, preoperative iPTH, and Δphosphorus at 48 hours may be significant factors in estimating the postoperative calcium requirement. The formula for postoperative calcium requirement after PTX may help to predict the duration of postoperative hospitalization.

Optimal hemoglobin level for anemia treatment in a cohort of hemodialysis patients.

BACKGROUND: Anemia is a major risk factor that contributes to mortality in patients with chronic kidney disease. There is controversy over the optimal hemoglobin (Hb) target in these patients. This study investigated the association between Hb level and mortality in a cohort of hemodialysis (HD) patients in Korea. METHODS: This study was a multicenter prospective observational study of maintenance HD patients that was performed for 5 years in western Seoul, Korea. Three hundred and sixty-two participants were enrolled. Laboratory values and mortality were accessed every 6 months. Repeated measures of laboratory values in each interval were averaged to obtain one semiannual mean value. The Hb values were divided into six groups: (1) Hb<9 g/dL; (2) 9 g/dL≤Hb<10 g/dL; (3) 10 g/dL≤Hb<11 g/dL; (4) 11 g/dL≤Hb<12 g/dL; (5) 12 g/dL≤Hb<13 g/dL; and (6) Hb≥13 g/dL. We analyzed the odds ratio for all-cause mortality, based on the Hb group, and adjusted for demographics and various laboratory values. Statistics were performed with SAS, version 9.1 software (SAS Institute Inc., Cary, NC, USA). RESULTS: Mortality odds ratios relative to the reference group (10-11 g/dL) in the fully adjusted model were 3.61 for<9 g/dL; 3.17 for 9-10 g/dL(⁎); 4.65 for 11-12 g/dL(⁎); 5.50 for 12-13 g/dL(⁎); and 2.05 for≥13 g/dL ((⁎) indicates P<0.05). CONCLUSION: In this study, a Hb level of 10-11 g/dL was associated with the lowest mortality among the groups with Hb level<13 g/dL. Larger interventional trials are warranted to determine the optimal Hb target for Korean HD patients.

Diameter of parathyroid glands measured by computed tomography as a predictive indicator for response to cinacalcet in dialysis patients with secondary hyperparathyroidism.

BACKGROUND/AIMS: Cinacalcet is one of the important treatments of secondary hyperparathyroidism (SHPT). We evaluated the role of computed tomography (CT) for parathyroid glands (PTGs) to determine the response to cinacalcet therapy in dialysis patients. METHODS: In study 1, we compared the predictive cutoff values of the largest volume or diameter of PTGs on ultrasonography or CT for achievement of target intact parathyroid hormone (iPTH) level according to K/DOQI guideline after cinacalcet treatment in a single dialysis center. In study 2, the role of the cutoff diameter of PTGs on CT in predicting responsive to cinacalcet therapy was reevaluated in dialysis patients with SHPT in multiple centers. RESULTS: In study 1, among the total population of 26 patients, the number of patients with baseline iPTH over 600 pg/mL was 16 (61%). In study 2, it was 45 (54%), among 82 patients. In study 1, the number of PTGs equal to or larger than the cutoff value (≥ 11.2 mm) on CT, not ultrasonography, was significantly higher in non-responders than in responders (p=0.038). In study 2, the proportion of patients with PTGs ≥ 11.2 mm on CT was significantly higher in non-responders than responders (p=0.003). Multivariate analysis showed that pretreatment iPTH (odds ratio [OR] 1.498, p=0.003) and the existence of enlarged PTGs on CT (OR 8.940, p=0.015) were significant clinical factors affecting the response to cinacalcet. CONCLUSIONS: The diameter of PTGs on CT could predict the response to cinacalcet in dialysis patients with SHPT.

Raoultella planticola peritonitis in a patient on continuous ambulatory peritoneal dialysis.

A 65-year-old man on continuous ambulatory peritoneal dialysis was admitted with peritonitis. Empirical antibiotic therapy was initiated, and Raoultella planticola was identified in the peritoneal fluid culture. We treated the patient with intraperitoneally administered ciprofloxacin and ceftazidime according to the antibiotic susceptibility. His condition improved, and he was well treated with a 2-week antibiotic course.

A case of late onset-acute tubulointerstitial nephritis with infliximab and mesalazine treatment in a patient with Crohn's disease.

Infliximab is a chimeric anti-tumor necrosis factor-alpha monoclonal antibody. Infusion related reactions and infection are well known side effects of infliximab; however, renal complications have not been well recognized. We report on a patient with late onset-acute tubulointerstitial nephritis (ATIN) after treatment with infliximab and mesalazine for Crohn's disease. A 25-year-old woman was admitted with a purpuric rash on both lower extremities and arthralgia. She had been diagnosed with Crohn's disease 5.6 years previously and had been treated with mesalazine and infliximab. Serum creatinine level, last measured one year ago, was elevated from 0.6 mg/dL to 1.9 mg/dL. Results of urinalysis, ultrasound, and serologic examinations were normal. With a tentative diagnosis of Henoch-Schonlein purpura, oral prednisolone was given, and serum creatinine decreased to 1.46 mg/dL, but was elevated to 2.6 mg/dL again at two months after discontinuation of prednisolone. Renal biopsy indicated that ATIN was probably induced by drug, considering significant infiltration of eosinophils. Concomitant use of infliximab with mesalazine was supposed to trigger ATIN. Oral prednisolone was administered, and serum creatinine level showed partial recovery. Thus, ATIN should be suspected as a cause of renal impairment in Crohn's disease even after a long period of maintenance treatment with infliximab and mesalazine.

The association of Klotho gene polymorphism with the mortality of patients on maintenance dialysis.

Despite medical progress, high morbidity and mortality rates have persisted in patients with end-stage renal disease (ESRD). The role in atherosclerosis and cardiovascular disease of klotho, an aging process-related gene, has been highlighted. Genetic variation in klotho has been reported to be a risk factor for coronary artery disease and ischemic stroke. Regarding the significance of cardiovascular disease for the outcome of ESRD patients, we investigated whether genetic variation of klotho was associated with mortality in ESRD patients on hemodialysis. 478 patients on maintenance hemodialysis for more than 3 months at dialysis facilities affiliated with the Western Dialysis Physician Association were enrolled in September 2004. Patient survival was checked annually until September 2007. Genotypings of klotho in terms of G395A in the promoter region, C1818T in exon 4, and KL-VS was performed. 45 deaths (11.2%) occurred over 3 years. Mortality was higher in the GA+AA group than in the GG group (18.9% vs. 6.7%, respectively, p < 0.001). Kaplan-Meier analysis also revealed that the survival of the GA+AA group was worse than that of GG group (p = 0.002). Cox's proportional hazards regression analysis showed that age, A allele carrier status in G395A of klotho, hemoglobin, albumin and HDL cholesterol levels were the significant factors affecting survival of hemodialysis patients. The A allele of the G395A polymorphism of klotho may be associated with the risk of mortality in Korean hemodialysis patients. Age, hemoglobin, albumin and HDLC were also significant prognostic factors for survival in the present study.

The association of Klotho polymorphism with disease progression and mortality in IgA nephropathy.

BACKGROUNDS: IgA nephropathy (IgAN) is the most common primary glomerulonephritis causing end stage renal disease (ESRD), and vasculopathy is known to involve disease progression. Klotho, a gene related to aging, has been reported to play a role in atherosclerosis and endothelial dysfunction. We investigated whether klotho gene polymorphism affect clinical course of IgAN. METHODS: The data registered for PREMIER study which enrolled the patients with biopsy proven IgAN were analyzed. Two single nucleotide polymorphisms for klotho gene, G395A of promoter region and C1818T of exon 4, were examined, and investigated the association klotho genotypes with the progression of IgAN and patient survival. RESULTS: Clinical data from 973 patients confirmed about survival were analyzed. The allele frequency was 0.830 and 0.170 for allele G and A, and 0.816 and 0.184 for allele C and T, which were complied with Hardy-Weinberg equilibrium (p=0.996 and 0.531 respectively). Death was observed more frequently in A-allele carriers of G395A polymorphism (0.7 vs. 2.6 %, GG vs. GA+AA, p=0.022). Renal survival in Kaplan-Meier survival curve was also worse in same group (p=0.04). CONCLUSION: Klotho gene polymorphism was associated with patient survival and disease progression of IgAN.

Healthcare-associated risk factors of vancomycin-resistant Enterococci colonization among outpatients undergoing hemodialysis.

Stool specimens and data were obtained from 399 outpatients undergoing hemodialysis (HD) in order to estimate the colonization rate of vancomycin-resistant enterococci (VRE) and to determine risk factors for VRE acquisition. The prevalence of VRE colonization in outpatients ranged from 0%-22.2%. Risk factors associated with VRE colonization were high hierarchy of hospital, short duration of HD, recent hospitalization, prior use of antimicrobial products, high platelet count, and low hemoglobin/albumin/blood urea nitrogen/creatinine levels, showing that VRE colonization was more common in patients with prior infections and poor nutritional status. Although pulsed-field gel electrophoresis (PFGE) analysis showed that most VRE isolates had diverse patterns, 2 paired cases from separate hospitals presented identical PFGE types.

Orthorexia nervosa with hyponatremia, subcutaneous emphysema, pneumomediastimum, pneumothorax, and pancytopenia.

30-year-old male was admitted with general weakness and drowsy mental status. He had eaten only 3-4 spoons of brown rice and fresh vegetable without salt for 3 months to treat his tic disorder, and he had been in bed-ridden state. He has had weight loss of 14 kg in the last 3 months. We report a patient with orthorexia nervosa who developed hyponatremia, metabolic acidosis, subcutaneous emphysema, mediastinal emphysema, pneumothorax, and pancytopenia and we will review the literature. Also, we mention to prevent refeeding syndrome, and to start and maintain feeding in malnourished patients.

Serum globotriaosylceramide assay as a screening test for fabry disease in patients with ESRD on maintenance dialysis in Korea.

BACKGROUND/AIMS: Fabry disease is an X-linked recessive and progressive disease caused by α-galactosidase A (α-GaL A) deficiency. We sought to assess the prevalence of unrecognized Fabry disease in dialysis-dependent patients and the efficacy of serum globotriaosylceramide (GL3) screening. METHODS: A total of 480 patients of 1,230 patients among 17 clinics were enrolled. Serum GL3 levels were measured by tandem mass spectrometry. Additionally, we studied the association between increased GL3 levels and cardiovascular disease, cerebrovascular disease, or left ventricular hypertrophy. RESULTS: Twenty-nine patients had elevated serum GL3 levels. The α-GaL A activity was determined for the 26 patients with high GL3 levels. The mean α-GaL A activity was 64.6 nmol/hr/mg (reference range, 45 to 85), and no patient was identified with decreased α-GaL A activity. Among the group with high GL3 levels, 15 women had a α-GaL A genetics analysis. No point mutations were discovered among the women with high GL3 levels. No correlation was observed between serum GL3 levels and α-GaL A activity; the Pearson correlation coefficient was 0.01352 (p = 0.9478). No significant correlation was observed between increased GL3 levels and the frequency of cardiovascular disease or cerebrovascular disease. CONCLUSIONS: Fabry disease is very rare disease in patients with end-stage renal disease. Serum GL3 measurements as a screening method for Fabry disease showed a high false-positive rate. Thus, serum GL3 levels determined by tandem mass spectrometry may not be useful as a screening method for Fabry disease in patients with end stage renal disease.

Alpha-lipoic acid attenuates cisplatin-induced tubulointerstitial injuries through inhibition of mitochondrial bax translocation in rats.

BACKGROUND: Renal tubule cell apoptosis plays a pivotal role in cisplatin-induced nephrotoxicity. alpha-Lipoic acid (LA), a thiol antioxidant, is well known to be cytoprotective in various cell death models through its involvement in the death receptor apoptosis pathway. However, we hypothesized that LA would attenuate cisplatin-induced nephrotoxicity through inhibition of mitochondrial bax translocation in rats. METHODS AND MATERIALS: Sprague-Dawley rats were treated with cisplatin (7 mg/kg) with or without pretreatment with LA (100 mg/kg x 3 times). Renal function was evaluated based on blood urea nitrogen (BUN), serum creatinine, and fractional excretion of sodium. Tubular necrosis scores were assessed by light microscopy findings and apoptotic cell deaths by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Cytosolic bax, mitochondrial bax, cytochrome c, caspase-9 and caspase-3 were investigated using Western blot in each group. RESULTS: LA pretreatment significantly decreased both BUN and serum creatinine. Morphologically, both tubular necrosis and apoptosis of tubular cells were decreased significantly with LA pretreatment. LA attenuated the translocation of mitochondrial bax, reduced the release of cytochrome c, and decreased the expression of caspase-3 and caspase-9 serially in cisplatin nephrotoxicity. CONCLUSION: We demonstrated that LA attenuates cisplatin-induced renal tubular damages by inhibition of mitochondrial bax translocation in vivo.

Aldosterone Synthase Gene (CYP11B2) Polymorphism in Korean End-Stage Renal Disease Patients on Hemodialysis.

Aldosterone synthase gene (CYP11B2) -344C/T polymorphism has been reported to be associated with serum aldosterone level, urinary aldosterone excretion, blood pressure, and left ventricular size and mass. The aim of this study was to evaluate the relation between CYP11B2 polymorphism and end-stage renal disease (ESRD) in the Korean population and the association with CYP11B2 polymorphism and cardiovascular morbidity in ESRD patients on hemodialysis. Genotyping was performed in 134 control subjects and 271 ESRD patients for CYP11B2 polymorphism using polymerase chain reaction through subsequent cleavage with restriction enzyme. Also current blood pressure, demographic, anthropometric and biochemical variables were investigated. The genotype distribution did not differ between ESRD patients and controls and there were no significant differences in blood pressure, use of antihypertensive medication, left ventricular hypertrophy and cardiovascular disease among the three genotypes in ESRD patients on hemodialysis. Our findings do not support the hypothesis that CYP11B2 polymorphism may be associated with prevalence of ESRD and suggest that CYP11B2 polymorphism may not be a genetic marker for cardiovascular morbidity in Korean ESRD patients.

Insomnia in diabetic hemodialysis patients. Prevalence and risk factors by a multicenter study.

BACKGROUND: Insomnia is one of the most common problems in dialysis patients, and likely to contribute impairment in quality of life, which has a positive correlation with patients' survival. In diabetic patients, morbidity and mortality are substantially higher than in the nondiabetic counterparts, and also the incidence of sleep disturbances. However, there is no means to predict sleep disturbance in the dialysis patients especially in diabetics. To define the prevalence and risk factors for insomnia in diabetic patients on hemodialysis, we undertook a cross-sectional multicenter study. METHODS: Eighty-two diabetic patients (50 men/32 women, aged 58.7 +/- 9.23 years) on maintenance hemodialysis for more than 6 months from 12 different hospitals were enrolled. The demographic data, subjective symptoms, depression scale, and insomnia were assessed by questionnaires, and lean body mass, BMI, Kt/V, subjective global assessment, nursing assessment score (NAS), and biochemical parameters were examined. RESULTS: The number of patients with and without insomnia were 56 and 26, respectively, which amounted to 68.2% for insomnia. NAS (28.1 +/- 3.81 vs. 30.8 +/- 2.88, p = 0.002), serum albumin concentration (3.82 +/- 0.44 vs. 4.09 +/- 0.36 g/dl, p = 0.008), and depression scale (25.2 +/- 12.1 vs. 18.9 +/- 10.3, p = 0.025) were significantly different between them. Patients with insomnia were older (60.5 +/- 9.0 vs. 56. 1 +/- 9.60 years, p = 0.053) and felt pain (38.5 vs. 15.3%, p = 0.06) more frequently than those without insomnia. The scale of depression was correlated with NAS (r = -0.455, p < 0.001) and the serum albumin concentration was correlated with NAS (r = 0.337, p = 0.002). NAS, age, and serum albumin concentration were the major risk factors for insomnia in logistic regression analysis. CONCLUSION: The prevalence of insomnia in diabetic hemodialysis patients was 68.2%. Age, nutritional status, and depression were the major risk factors for sleep disturbance in diabetic patients.