[Comparison of benefits to non-dialysis CKD patients between darbepoetin alpha and epoetin beta pegol].

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients. METHODS: This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated. RESULTS: No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA. CONCLUSIONS: It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Challenges of caring for an advanced chronic kidney disease patient with severe thrombocytopenia.

An autogenous arteriovenous fistula has been considered to be the optimal form of vascular access for hemodialysis (HD) in the field of nephrology. Nevertheless, the decision regarding the type of access, whether it be an arteriovenous fistula, an arteriovenous graft, or a central venous catheter, must still be individualized. In the present report, we describe the case of a female patient with advanced chronic kidney disease (CKD) associated with a hemostatic disorder. Despite the exhausted peripheral vasculature, she required recurrent platelet transfusions for severe thrombocytopenia due to aplastic anemia. The goal of care for this patient was to optimize the dialysis treatment without increasing the bleeding risk. Various concerns regarding the therapeutic conundrums encountered in the case are also discussed.

Cetuximab-induced nephrotic syndrome in a case of metastatic rectal cancer.

Proteinuria is common adverse effect that occurs after the use of bevacizumab, but it occurs rarely during administration of cetuximab. We report the first case of nephrotic syndrome induced by cetuximab after completing mFOLFOX6 with bevacizumab followed by sLV5FU2 with bevacizumab for metastatic rectal cancer. Prior to the administration of cetuximab, the patient had never presented proteinuria. After the completion of the loading (400 mg/m(2)) and two subsequent maintenance (250 mg/m(2)) infusions of cetuximab, edema of the lower extremities occurred concomitantly with facial acneiform rash. Based on the laboratory data, diagnosis of nephrotic syndrome was made and secondary diseases of nephrotic syndrome were excluded. Oral administration of prednisolone (0.6 mg/kg/day) was initiated, resulting in no response. The trigger of nephrotic syndrome other than cetuximab was not suggested and attention on occurrence of proteinuria must be devoted to this medicine.

A case of diffuse endocapillary proliferative glomerulonephritis associated with polymyalgia rheumatica.

A 70-year-old man complained of muscle pain in his neck, shoulders and pelvic girdle. Proteinuria and hematuria subsequently developed. Blood analysis showed increased acute phase reactants. The histology of renal biopsy showed diffuse endocapillary proliferative glomerulonephritis. There were no signs of autoimmune diseases, malignancies and bacterial or viral infections. His extrarenal symptoms and the results of blood analysis fulfilled three different criteria of polymyalgia rheumatica (PMR). Therefore, diffuse endocapillary proliferative glomerulonephritis associated with PMR was diagnosed. After low-dose prednisolone (10 mg/day) treatment, the muscle pain disappeared, acute phase reactants decreased and hematuria and proteinuria improved. The renal complication of PMR is rare but important to be considered early in the right clinical context.

Development and prevention of morphologic and ultrastructural changes in uremia-induced hyperplastic parathyroid gland.

The detailed ultrastructural changes of uremia-induced hyperplastic parathyroid gland and the effects of current medical treatments for secondary hyperparathyroidism were investigated. Marked enlargement of parathyroid cell with accumulation of mitochondria and lipids and a significant increase in the thickness of the pericapillary area with increased fibrosis and appearance of fibroblast like cells were noted in the hyperplastic gland caused by uremia and phosphate retention. These ultrastructural changes and biochemical findings indicating hyperparathyroidism were significantly suppressed by all of the treatment using phosphate restriction, calcitriol, and cinacalcet. The characteristic ultrastructural changes, including the morphologic evidence of nodule formation, were indicated.

Central venous stenosis among hemodialysis patients is often not associated with previous central venous catheters.

It is widely assumed that central venous stenosis (CVS) is most commonly associated with previous central venous catheterization among the chronic hemodialysis (HD) patients. We evaluated the validity of this assumption in this retrospective study. The clinical records from 2,856 consecutive HD patients with vascular access failure during a 5-year period were reviewed, and a total of 26 patients with symptomatic CVS were identified. Combined with radiological findings, their clinical characteristics were examined. Only seven patients had a history of internal jugular dialysis catheterization. Diagnostic multidetector row computed tomography angiography showed that 7 of the 19 patients with no history of catheterization had left innominate vein stenosis due to extrinsic compression between the sternum and arch vessels. These patients had a shorter period from the time of creation of the vascular access to the initial referral (9.2 ± 7.6 months) than the rest of the patients (35.5 ± 18.6 months, p = 0.0017). Our findings suggest that cases without a history of central venous catheterization may not be rare among the HD patients with symptomatic CVS. However, those still need to be confirm by larger prospective studies of overall chronic HD patients with symptomatic CVS.

Reduced hydration status characterized by disproportionate elevation of blood urea nitrogen to serum creatinine among the patients with cerebral infarction.

The significance of fluid metabolism among the patients with cerebral infarction has barely mentioned in the literature despite the several reports suggesting the potential risk of reduced hydration status for the development of cerebral infarction. The aim of the this study is to explore the validity of the presumable relationship between hydration status and cerebral infarction. Ninety-seven patients with cerebral infarction from April 1, 2008 to March 31, 2009 were retrospectively investigated, and their hydration status were evaluated by using several clinical parameters such as a blood urea nitrogen to serum creatinine (BUN/Cr) ratio of >25 and plasma osmolality. Subjects with active infection, congestive heart failure, hepatic failure, gastrointestinal bleeding, or a malignancy were excluded since these conditions should modulate the absolute value of BUN/Cr ratio without a change in hydration status. Twenty-eight patients (29%) were considered as having reduced hydration status. The BUN/Cr ratio decreased significantly after the initiation of medical support (median 21.3; IR: 18.1-24.6), including oral or parenteral fluid supplementation, in comparison to the values at the time of patient admission (median 30.0; IR: 26.8-40.7; p<0.0001). Similar decreases were also observed in the hematocrit, hemoglobin, and plasma osmolality. The group considered to have reduced hydration status had a significantly higher prevalence of cardioembolic stroke than the other subjects. The hydration status may be a contributing factor to subtypes of cerebral infarction. Whether our findings are also the case with overall patients with cerebral infarction should be evaluated in greater detail.

Sleep-disordered breathing predicts cardiovascular events and mortality in hemodialysis patients.

BACKGROUND: Sleep-disordered breathing (SDB), characterized by repetitive apnea and hypopnea during sleep, is a risk factor for cardiovascular disease. However, the links between SDB and cardiovascular events in hemodialysis (HD) patients have not been clearly evaluated. METHODS: We followed the clinical outcome of 94 HD patients, who underwent overnight pulse oximetry on dialysis day. The SDB group was defined as 3% oxygen desaturation index (ODI) over five events per hour, and the others were the normal group. The primary outcome was cardiovascular events and death. We used Kaplan-Meier curve and Cox proportional hazard model for survival analyses. RESULTS: Forty-four patients (46.8%) were classified into the SDB group. Body mass index, diabetes mellitus, 3% ODI and Epworth sleepiness scale were significantly higher, and duration of dialysis, Kt/V, normalized protein catabolism rate and hemoglobin were lower in the SDB group than in the normal group. During a median 55 months of follow-up, Kaplan-Meier analysis revealed that the SDB group had a significantly higher rate of cardiovascular events and all-cause mortality than the normal group. Age, cardiothoracic ratio, serum albumin and 3% ODI were predictors of cardiovascular events and all-cause mortality at univariate Cox regression analysis. In the adjusted analysis, SDB is an independent predictor of increased cardiovascular events (hazard ratio 3.10; 95% confidence interval (CI), 1.35-7.12; P = 0.008) and all-cause mortality (hazard ratio 2.81; 95% CI, 1.07-7.41; P = 0.037). CONCLUSIONS: SDB is an independent risk factor for cardiovascular events and mortality in HD patients. Effective and earlier treatment for these patients is needed to improve clinical outcome.

[A case report: multiple air embolism after the laryngopharyngoesophagectomy occurred by the cervical infection from postoperative fistula].

Systemic air embolism, a very rare clinical condition, has many causes. We report a case of multiple air embolisms following laryngopharyngoesophagectomy salvage surgery for hypopharyngeal residual cancer after concurrent chemoradiotherapy. Cervical infection arose from a fistula caused by postoperative suture failure in which the 56-year-old man suddenly lost consciousness and went into shock. A few days post operation, an air embolism happened and caused in the brain, pulmonary, myocardiac and cerebral infarction. The man died two months after initial occurrence. We suspect that air entered through the ruptured left internal jugular vein via infection due to aspiration at the injury site. Air embolisms are associated with different medical maneuvers, and it is necessary to recognize that they may become a serious perioperative complication.

Vesnarinone represses the fibrotic changes in murine lung injury induced by bleomycin.

We investigated the potential usefulness of vesnarinone, a novel cytokine inhibitor, for the treatment of lung fibrosis using a murine model of bleomycin (BLM)-induced pulmonary fibrosis. Mice were fed a control diet (n=42), or a diet containing low (n=42) or high (n=42) dose of vesnarinone. Dietary intake of vesnarinone minimized the BLM toxicity as reflected by significant decreases in numbers of inflammatory cells, KC, and soluble TNF receptors in the bronchoalveolar lavage fluid. A quantitative evaluation of histology demonstrated significantly mild lung parenchymal lesions in BLM-treated mice fed with diet containing high dose of vesnarinone than in the control diet group. Consistent with the histopathology, hydroxyproline levels in lung tissue from BLM-treated mice fed with diet containing vesnarinone were significantly lower than that from mice fed with control diet. We concluded that vesnarinone inhibits BLM-induced pulmonary fibrosis, at least in part, by the inhibition of acute lung injuries in the early phase.

Molecular and morphological approach of uremia-induced hyperplastic parathyroid gland following direct maxacalcitol injection.

The mechanisms explaining the clinical effects of direct maxacalcitol (OCT) injection into the hyperplastic parathyroid gland (PTG) in uremic patients with advanced secondary hyperparathyroidism (SHPT) were investigated by molecular and morphological examination. PTG of uremia-induced SHPT model rats were treated by a direct injection of OCT (DI-OCT) or vehicle (DI-vehicle). The changes in serum intact parathyroid hormone (intact-PTH) level, vitamin D and Ca-sensing receptor (VDR and CaSR, respectively) expression levels in PTG, and the calcium (Ca)-PTH response curve were examined; the induction of apoptosis in parathyroid cells (PTC) was also analyzed by the TUNEL method, DNA electrophoresis, and electron microscopic examination. Serum intact-PTH level following DI-OCT significantly decreased. Upregulation of both VDR and CaSR, a clear shift to the left downward in the Ca-PTH curve, and many apoptotic PTCs were observed in the DI-OCT-treated PTGs. However, these findings were not observed in the DI-vehicle-treated PTGs. Moreover, these effects were confirmed by the DI-OCT into one PTG and DI-vehicle alone into another PTG in the same rat. DI-OCT may introduce simultaneous VDR and CaSR upregulation and the regression of hyperplastic PTG, and these effects may provide a strategy for strongly suppressing PTH level in uremia-induced advanced SHPT.

Platelet-activating factor (PAF) induced cytokine production and otitis media with effusion (OME) in the rat middle ear.

OBJECTIVES: We examined the effect of platelet-activating factor (PAF) on IL-8 production in cultured rat middle ear epithelial cells (RMECs), and the concentrations of cytokine, PAF, and PAF-acetylhydrolase (PAF-AH) were also examined in the PAF-induced experimental OME (otitis media with effusion) of rats. METHODS: Using an enzyme-linked immunospecific assay, we measured the levels of cytokines in the cultured RMECs and the PAF-induced OME of rats. The PAF was quantitated by the platelet-aggregating activity and the PAF-AH was measured by radioimmunoassay. RESULTS: Both PAF and C-PAF, which is a stable analogue of PAF, significantly induced production of IL-8 in the RMECs in a dose-dependent manner. The PAF-induced IL-8 production was abolished by co-incubation with WEB2170, a specific PAF receptor antagonist. The concentrations of the cytokines and PAF in the PAF-induced OME of rats were higher on day 1 and the PAF and cytokine levels seemed to correspond well with the persistence of OME. CONCLUSION: PAF may stimulate the local production of cytokines and may induce OME in the middle ear.

Kimura disease: diagnosis and prognostic factors.

OBJECTIVES: To establish a preoperative diagnostic system and examine prognostic factors for Kimura disease. STUDY DESIGN: Retrospective study. SETTING: Hospital records were reviewed for nine cases of Kimura disease treated in our department. Preoperative eosinophil counts for 74 cases with untreated malignancy in the parotid gland were also examined. RESULTS: Parotid swelling with inhomogeneities and subcutaneous invasion on magnetic resonance imaging and eosinophils > 10.5 percent in Asian patients clearly indicates Kimura disease. Eosinophils > 50 percent, serum IgE levels > 10,000 IU/mL, and multifocal lesions outside salivary glands are prognostic factors suggesting disease recurrence. CONCLUSIONS: A preoperative decision based on our diagnostic criteria and prognostic factors should lead to better therapeutic outcomes for Kimura disease, for which a definitive treatment policy has never been determined.

[Clinical phase I trial of concurrent chemo-radiotherapy with S-1 for T2NO glottic carcinoma].

We conducted a phase I study to determine a recommended dose (RD) of S-1 for chemo-radiotherapy consisting of S-1+ radiotherapy for T 2 N 0 larynx cancer. The method of administration used to assess the RD was irradiation with 2 Gy/day for 5 days a week until a total dose of 60 Gy, and concomitant administration of S-1 once a day for 2 weeks beginning on the day therapy was started followed by 2 weeks off the drug and 2 weeks on the drug with the dose escalating from S-1 60 mg/body/day (level 1) to 80 mg/body/day (level 2), and then to 100 mg/body/day (level 3). 18 patients were enrolled. 4 patients developed an adverse event of grade 3 radiation dermatitis which became a dose-limiting toxicity (DLT) at level 3. We then concluded that 100 mg/body/day was the maximum tolerated dose (MTD) of S-1 and decided that the RD of S-1 was 80 mg/body/day.

Unilateral adrenalectomy improves insulin resistance and diabetes mellitus in a patient with ACTH-independent macronodular adrenal hyperplasia.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing's syndrome. Bilateral adrenalectomy is considered to be a standard therapy for AIMAH, although lifetime replacement of glucocorticoids is necessary after the procedure. This paper describes a subject with AIMAH who underwent unilateral adrenalectomy of the predominantly enlarged gland and subsequently displayed an improvement in insulin resistance and diabetes mellitus, the cardinal symptoms before the operation, concomitant with alleviation of abnormal cortisol secretion. The patient was a 61-year-old man with a body mass index of 25.6 kg/m2. He was diagnosed as having diabetes mellitus, hypertension, and hyperlipidemia at 50 years of age. Eight years after diagnosis, bilateral enlargement of the adrenal glands was revealed by chance upon computed tomography of the abdomen. Typical manifestations of Cushing's syndrome were not demonstrated. Basal levels of serum and urinary cortisol had not increased, although the serum cortisol level displayed no circadian rhythm and no response to the administration of dexamethasone. Despite sulfonylurea treatment, the patient's HbA1C level was as high as 7.6% (normal range 4.3-5.8%). Fasting insulin concentration was increased to 42.6 microU/ml, and the homeostasis model insulin resistance index (HOMA-R) was calculated to be 15.5 (with a normal range of less than 2.5), indicating severe insulin resistance. Unilateral adrenalectomy of the predominantly enlarged gland revealed that the resected gland consisted of multiple nodules of various sizes. Based on endocrinological, radiological, and pathological findings, a diagnosis of AIMAH was made. Ten months after the unilateral adrenalectomy, cortisol circadian rhythms were restored, and serum cortisol concentration was suppressed in response to the administration of low doses of dexamethasone, suggesting an improvement in the cortisol secretory pattern. Levels of HbA1C, fasting insulin, and HOMA-R decreased to 5.7%, 12.7 microU/ml, and 2.2, respectively. An improvement in hyperlipidemia was also observed. Insulin resistance and glucose intolerance are recognized as features of mild hypercortisolism. In the present case, unilateral adrenalectomy was effective in ameliorating insulin resistance and improving glycemic control. Unilateral adrenalectomy might be an alternative therapy for improvement of glucose and lipid metabolism in subjects with AIMAH.

Experimental otitis media with effusion induced by leukotriene D4.

OBJECTIVE: inflammatory mediators such as prostaglandins (PGs), leukotrienes (LTs), and platelet-activating factor (PAF) have been identified in human middle ear effusions (MEEs), as well as in the experimentally induced MEEs of animals. However, the exact function of LTs in the middle ear cavity is still unknown. In this study, the role of LTs was investigated using an experimental model in which OME was induced by LTD4. METHODS: to examine whether leukotrienes (LTs) induce otitis media with effusion (OME), 2x10(-6), 2x10(-5), 1x10(-4) and 2x10(-4) M of LTD4 was injected into the rat ear. The severity of OME was assessed based on the histological findings. The concentrations of IL1-beta, TNF-alpha, and GRO/CINC-1 in MEE were also measured. Additionally the therapeutic efficacy of a specific LTs antagonist, pranlukast on experimental OME was investigated. RESULTS: all ears developed middle ear effusion (MEE) within 24 h and about 50% of the animals continued to demonstrate MEE for 14 days in the 1x10(-4) and 2x10(-4) M groups. The cytokine levels seemed to correspond well with the persistence of OME. The oral administration of a specific LTs antagonist, pranlukast, was found to alleviate the experimental OME. CONCLUSION: these findings suggest that LTs appear to plays an important role in the pathogenesis of OME.

Presence of platelet-activating factor in nasal polyps and eosinophils.

Platelet-activating factor (PAF) has been reported to play a role in allergy and inflammatory reactions but its role in the pathogenesis of nasal polyps remains unclear. In this study, we examined both PAF and peptide leukotrienes (peptLTs) in individual preparations from nasal polyps. The amounts of PAF were much greater than those of peptLTs in all preparations. Nasal polyps were divided into two groups according to the severity of eosinophil infiltration: a severe group (eosinophil count > or = 50/mm2) and a mild group (eosinophil count < 50/mm2). The amounts of PAF in the nasal polyps were significantly higher in the severe group than in the mild group (p < 0.01). PAF activity correlated with tissue eosinophilia and polyps obtained from patients with aspirin-sensitive asthma contained relatively large amounts of PAF, with enriched infiltration of eosinophils.