Thalidomide Prevents the Progression of Peritoneal Fibrosis in Mice

Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-β was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-β-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis

SAHA Suppresses Peritoneal Fibrosis in Mice

Objective: Long-term peritoneal dialysis causes peritoneal fibrosis in submesothelial areas. However, the mechanism of peritoneal fibrosis is unclear. Epigenetics is the mechanism to induce heritable changes without any changes in DNA sequences. Among epigenetic modifications, histone acetylation leads to the transcriptional activation of genes. Recent studies indicate that histone acetylation is involved in the progression of fibrosis. Therefore, we examined the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on the progression of peritoneal fibrosis in mice. Methods: Peritoneal fibrosis was induced by the injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. SAHA, or a dimethylsulfoxide and saline vehicle, was administered subcutaneously every day from the start of the CG injections for 3 weeks. Morphologic peritoneal changes were assessed by Masson’s trichrome staining, and fibrosis-associated factors were assessed by immunohistochemistry. Results: In CG-injected mice, a marked thickening of the submesothelial compact zone was observed. In contrast, the administration of SAHA suppressed the progression of submesothelial thickening and type III collagen accumulation in CG-injected mice. The numbers of fibroblast-specific protein-1?positive cells and α-smooth muscle actin α?positive cells were significantly decreased in the CG + SAHA group compared to that of the CG group. The level of histone acetylation was reduced in the peritoneum of the CG group, whereas it was increased in the CG +SAHA group. Conclusions: Our results indicate that SAHA can suppress peritoneal thickening and fibrosis in mice through up-regulation of histone acetylation. These results suggest that SAHA may have therapeutic potential for treating peritoneal fibrosis

A case of reversible posterior leukoencephalopathy syndrome in a patient on peritoneal dialysis.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a recently identified clinical and radiologic entity. The characteristic radiologic findings are bilateral gray and white matter edema in the posterior regions of the cerebral hemispheres. The typical clinical syndrome includes headache, confusion, visual symptoms, and seizures. RPLS most often occurs in the setting of hypertensive crisis, preeclampsia, or with cytotoxic immunosuppressive therapy, but many other clinical settings are described, such as cryoglobulinemia, hemolytic uremic syndrome, systemic lupus erythematosus, and use of erythropoietin. A 24-year-old man, diagnosed as having anaphylactoid purpura nephritis at 12 years of age and who started peritoneal dialysis (PD) at 23 years of age, was admitted to our hospital with a seizure and consciousness disturbance. His blood pressure (BP) and body fluid volume had not been controlled well because of poor compliance with medication and PD. T2-weighted magnetic resonance imaging (MRI) revealed high signal intensity changes restricted to the cortex and subcortical white matter of the cerebellum. On the other hand, diffusion-weighted imaging showed an isointense signal. From these findings, he was diagnosed as having RPLS. With appropriate control of BP and volume control by PD and hemodialysis, his symptoms improved, and a follow-up cranial MRI 1 month later was almost normal. To the best of our knowledge, this is the first report of RPLS in an adult PD patient

Significance of subepithelial deposits in patients diagnosed with IgA nephropathy

Subepithelial deposits are observed in rare adult IgA nephropathy (IgAN) cases and are a key diagnostic finding in IgA-dominant infection-related glomerulonephritis (IgA-IRGN). Sometimes, it is difficult to distinguish IgA-IRGN from IgAN without a precise clinical history. We hypothesized that some IgA-IRGN cases might be diagnosed as IgAN with subepithelial deposits (IgAN-SD) and aimed to clarify the significance of subepithelial deposits in patients diagnosed with IgAN. We examined 464 patients diagnosed with IgAN at Nagasaki University Hospital and affiliated hospitals between 1996 and 2013. The differences in clinicopathological findings between IgAN-SD and IgAN with no subepithelial deposits (IgAN-NSD) were investigated.In addition to clinical data and typical IgAN pathological features, we analyzed complement levels, immunoglobulin localization, light chain staining patterns, and intramembranous deposits. There were 214 men and 250 women with a mean age of 38.8 ± 18.3 years. Subepithelial deposition was observed in 51 patients (11%). Compared to patients with IgAN-NSD, those with IgAN-SD had significantly lower mean serum protein (6.4 g/dL vs. 6.7 g/dL; p = 0.02), albumin (3.7 g/dL vs. 3.9 g/dL; p = 0.02), and complement (C3) (94 mg/dL vs. 103 mg/dL; p = 0.02) levels.Diffuse mesangial hypercellularity (M) (65% vs. 45%; p<0.01), endocapillary hypercellularity: (E) (43% vs. 28%; p = 0.03),and IgA staining in the glomerular capillary wall (22% vs. 8%; p<0.01) were more common in patients with IgAN-SD. The incidence of light chain lambda predominance was lower in patients with IgAN-SD (47% vs. 63%; p = 0.03). Hump-shaped subepithelial deposits and intramembranous deposits were observed in nine and 17 patients with IgAN-SD, respectively. Patients with IgAN-SD tended to have the characteristics of IgA-IRGN rather than IgAN-NSD.Since the therapeutic strategies for IgA-IRGN differ from those for IgAN, we should review the clinical history and pay careful attention to the clinical course in cases with atypical findings, such as subepithelial deposits

Juvenile Idiopathic Nonspecific Interstitial Pneumonia. and Review of Literature

We describe a case of juvenile idiopathic nonspecific interstitial pneumonia (NSIP). This is the first report of a Japanese patient with idiopathic NSIP aged 27 years. A computed tomographic scan of the chest showed groundglass opacities and reticular opacities in subpleural distribution. Bronchoalveolar lavage fluid revealed no specific finding except for decreased CD4/CD8 ratio of lymphocyte subset. Histopathological features on examination of thoracoscopic lung biopsy specimens were consistent with those of NSIP group III. The patient was treated with corticosteroids and immunosuppressants, but no clinical improvement was noted and the general condition has gradually worsened. Although the prognosis is generally considered to be good in patients with NSIP, some patients die as a result of progression of the disease. The prediction of prognosis based on histopathological, radiologic, and bronchoalveolar lavage cell findings in NSIP seems to be difficult at present

Involvement of Leptin in the Progression of Experimentally Induced Peritoneal Fibrosis in Mice

013LeptinThe isJapana hormoneSociety mainlyof Histochemistryproduced byandwhite adipose cells, and regulates body fat and food intake by acting on hypothalamus. Leptin receptor is expressed not only in the hypothalamus but in a variety of peripheral tissues, suggesting that leptin has pleiotropic functions. In this study, we investigated the effect of leptin on the progression of peritoneal fibrosis induced by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 2 or 3 weeks in mice. This study was conducted in male C57BL/6 mice and leptin-deficient ob/ob mice. Peritoneal fluid, blood, and peritoneal tissues were collected 15 or 22 days after CG injection. CG injection increased the level of leptin in serum and peritoneal fluid with thickening of submesothelial compact zone in wild type mice, but CG-injected ob/ob mice attenuate peritoneal fibrosis, and markedly reduced the number of myofibroblasts, infiltrating macrophages, and blood vessels in the thickened submesothelial area. The 2-week leptin administration induced a more thickened peritoneum in the CG-injected C57BL/6 mice than in the PBS group. Our results indicate that an upregulation of leptin appears to play a role in fibrosis and inflammation during peritoneal injury, and reducing leptin may be a therapeutically potential for peritoneal fibrosis

Association between potassium supplementation and the occurrence of acute kidney injury in patients with hypokalemia administered liposomal amphotericin B: a nationwide observational study

Background: Hypokalemia and acute kidney injury (AKI) occur in patients administered liposomal amphotericin B (L-AMB), a wide-spectrum anti-fungicidal drug. However, the association between potassium supplementation and the occurrence of AKI in patients with hypokalemia who were administered L-AMB is not well understood.Methods: Using nationwide claims data and laboratory data, the occurrence of AKI during L-AMB treatment was retrospectively compared between patients with hypokalemia who were or were not supplemented with potassium and between those adequately or inadequately supplemented with potassium (serum potassium levels corrected to ≥3.5 mEq/L or remained < 3.5 mEq/L, respectively) before or after L-AMB treatment initiation.Results: We identified 118 patients who developed hypokalemia before L-AMB treatment initiation (43 received potassium supplementation [25 adequate and 18 inadequate supplementation] and 75 did not receive potassium supplementation), and 117 patients who developed hypokalemia after L-AMB initiation (79 received potassium supplementation [including 23 adequate and 15 inadequate supplementation] and 38 did not receive potassium supplementation). The occurrence of any stage of AKI was similar between patients with hypokalemia, regardless of potassium supplementation (i.e., before L-AMB treatment initiation [supplementation, 51%; non-supplementation, 45%; P = 0.570] or after L-AMB initiation [supplementation, 28%; non-supplementation, 32%; P = 0.671]). After adjusting for confounding factors, we found that the occurrence of any stage of AKI was not associated with potassium supplementation before L-AMB initiation (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 0.584–2.852, P = 0.528) or after L-AMB initiation (OR: 0.954, 95% CI: 0.400–2.275, P = 0.915). The occurrence of any stage of AKI tended to decline in patients with hypokalemia who were adequately supplemented with potassium (44%) before, but not after, L-AMB initiation relative to that in patients inadequately supplemented with potassium (61%), however this result was not significant (P = 0.358).Conclusion: Potassium supplementation was not associated with any stage of AKI in patients with hypokalemia who were administered L-AMB

Efficacy of early administration of liposomal amphotericin B in patients with septic shock: A nationwide observational study

Introduction: Liposomal amphotericin B (L-AMB), a broad spectrum anti-fungicidal drug, is often administered to treat invasive fungal infections (IFIs). However, the most suitable time to initiate treatment in septic shock patients with IFI is unknown.Methods: Patients with septic shock treated with L-AMB were identified from the Japanese Diagnosis Procedure Combination national database and were stratified according to L-AMB treatment initiation either at septic shock onset (early L-AMB group) or after the onset (delayed L-AMB group) to determine their survival rates following septic shock onset and the shock cessation period.Results: We identified 141 patients administered L-AMB on the day of or after septic shock onset: 60 patients received early treatment, whereas 81 patients received delayed treatment. Survival rates after septic shock onset were higher in the early L-AMB group than in the delayed L-AMB group (4 weeks: 68.4% vs 57.9%, P = 0.197; 6 weeks: 62.2% vs 44.5%, P = 0.061; 12 weeks: 43.4% vs 35.0%, P = 0.168, respectively). The septic shock cessation period was shorter in the early L-AMB group than in the delayed L-AMB group (7.0 ± 7.0 days vs 16.5 ± 15.4 days, P < 0.001), with a significant difference confirmed after adjusting for confounding factors with propensity score matching (7.1 ± 7.2 days vs 16.7 ± 14.0 days, P = 0.001).Conclusion: Early L-AMB administration at septic shock onset may be associated with early shock cessation

Effect of switching from sevelamer hydrochloride to lanthanum carbonate on metabolic acidosis in dialysis patients

Treatments for hyperphosphatemia in dialysis patients include dietary therapy and oral administration of phosphate binders; however, it has recently been suggested that oral administration of sevelamer hydrochloride, a phosphate binder, may cause metabolic acidosis. Owing to the decreased supply of sevelamer hydrochloride after the Eastern Japan Great Earthquake Disaster on March 11, 2011, hyperphosphatemia patients switched to another phosphate binder, lanthanum carbonate. Here, we retrospectively evaluated the effect of this medication substitution on metabolic acidosis in patients on maintenance hemodialysis. 32 patients, who underwent maintenance hemodialysis at Nagasaki Kidney Center in Japan, were enrolled in our study and followed to evaluate the effect of switching medication on metabolic acidosis at 3 months after switching from sevelamer hydrochloride to lanthanum carbonate. The mean dose of sevelamer hydrochloride prior to the earthquake disaster was 3 g/day, and the mean dose of lanthanum carbonate thereafter was 0.9 g/day. Three months after the medication was changed, the concentration of bicarbonate ion did not increase significantly (p = 0.186), whereas pH and base excess increased significantly (p = 0.007 and p = 0.036, respectively). In this study, although the HCO3 - level was not significantly changed, the pH and base excess were significantly increased. Our findings indicate that lanthanum carbonate ameliorates metabolic acidosis

Tubulointerstitial Nephritis Complicated by Fanconi Syndrome and Renal Tubular Acidosis Associated with three autoimmune diseases

A 45-year-old woman experiencing back pain showed signs of metabolic acidosis and electrolyte imbalances. The results of blood and urine tests indicated Fanconi syndrome and renal tubular acidosis. An x-ray showed vertebral fractures, which were thought to responsible for the back pain. In addition, the patient had proteinuria and renal dysfunction; therefore, renal biopsy was performed, and tubulointerstitial nephritis (TIN) was diagnosed. While investigating TIN, primary biliary cirrhosis and Sjögren’s syndrome were also detected. She had been previously diagnosed with chronic thyroiditis. We report a rare case of TIN and 3 autoimmune disorders with review of literature