Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

BACKGROUND: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.

A case of multiorgan failure due to carbamazepine intoxication successfully treated with multimodal blood purification therapy.

Carbamazepine (CBZ) intoxication can occur due to various factors, including drug interactions and over-ingestion. Extracorporeal elimination, particularly through hemodialysis and hemoperfusion, is effective in treating severe carbamazepine intoxication. However, as the effectiveness of various modalities can differ, method selection may be based on a specific clinical situation. A 47-year-old woman who took CBZ for schizophrenia presented to our hospital with episodes of vomiting and consciousness disorder. As the CBZ concentration was > 20 µg/mL, she was admitted to the intensive care unit with a diagnosis of acute CBZ poisoning. She underwent one session of hemoperfusion for 2 h, and her CBZ level decreased from > 20 µg/mL to 6.4 µg/mL. However, she developed acute kidney and liver injuries 2 days after admission and underwent intermittent hemodialysis, plasma exchange, continuous hemodiafiltration (CHDF), and online HDF, depending on her condition. Her general condition improved, and she was transferred to the psychiatric department. To our knowledge, no case reports have described severe acute CBZ poisoning in a patient who developed multiorgan failure to date, which was successfully treated with multimodal blood purification therapy. When treating severe CBZ intoxication, blood purification therapy should be tailored to the changing pathophysiology of the condition.

Systemic Amyloid A Amyloidosis Secondary to Xanthogranulomatous Pyelonephritis.

The combination of systemic amyloid A (AA) amyloidosis and xanthogranulomatous pyelonephritis (XGP) resulting from a chronic urinary tract infection is extremely rare. We herein report a case of systemic AA amyloidosis secondary to XGP for which clinical remission developed after nephrectomy. To our knowledge, this is the first case report describing the clinical improvement of systemic AA amyloidosis secondary to XGP after nephrectomy in Japan. Clinicians should be aware of this uncommon combination and search for amyloid depositions in cases of XGP.

A case of a cerebellar form of progressive multifocal leukoencephalopathy in a patient undergoing peritoneal dialysis.

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system, is caused by the reactivation of the polyomavirus JC virus (JCV). It favors the cerebrum and typically occurs in patients with immunodeficiencies, with a progressive course and fatal outcome in the majority of cases. However, the cerebellar form of PML, characterized by isolated posterior fossa lesions, such as those in the cerebellum or brainstem at disease onset, is rare, and reports of its occurrence in peritoneal dialysis (PD) patients are lacking. In this paper, we describe a rare case of a cerebellar form of PML in a PD patient. A 64-year-old man undergoing PD was referred to our hospital for anorexia, nausea, and vomiting in the past month. He had finger-to-nose test abnormalities, gaze-directed nystagmus, and scanning speech. He was diagnosed with the cerebellar form of PML based on his progressive cerebellar symptoms, the typical magnetic resonance imaging findings, and the presence of JCV-DNA in the cerebrospinal fluid polymerase chain reaction test. He developed nocturnal delirium, aggravated disquiet, and died of pneumonia on the 69th day. Clinicians should consider the cerebellar form of PML as a differential diagnosis if PD patients develop progressive cerebellar symptoms.

Quantitative histological analysis of SM22α (transgelin) in an adriamycin-induced focal segmental glomerulosclerosis model.

BACKGROUND/AIMS: SM22α, transgelin, has been revealed to be specifically expressed in glomerular epithelial cells and interstitial cells, according to the nature of the renal injury. In this study, quantitative analyses of SM22α positivity were performed to investigate the pathological significance of its expression. METHODS: Kidney samples of adriamycin nephropathy underwent immunohistochemistry with a newly established anti-SM22α monoclonal antibody. The SM22α positivity was quantified by an image analyzer. The correlation of the histological values with biochemical data was investigated statistically. Microstructural localization of SM22α was studied by immunoelectron microscopy. RESULTS: SM22α was expressed along the dense basal microfilaments of degenerating podocytes, and diffusely in interstitial cells. Both the extent and intensity of SM22α expression in glomerular and tubulointerstitial area were correlated with the deterioration of renal function and the severity of proteinuria. Stepwise multiple linear regression analysis revealed that the extent of its positivity in glomerular or tubulointerstitial area was the determinant of the amount of proteinuria or the deterioration of creatinine clearance (Ccr), respectively. Inversely, the deterioration of Ccr was the most important predictor of SM22α expression. CONCLUSION: SM22α expression in podocytes and interstitial cells represented the severity of proteinuria and the deterioration of renal function. SM22α expression in renal tissues might be a hallmark of kidney diseases.

Expression of SM22α (transgelin) in glomerular and interstitial renal injury.

BACKGROUND/AIMS: SM22α, transgelin, is abundantly expressed in smooth muscle tissues and our previous work demonstrated that it is a novel marker of injured glomerular epithelial cells in rat antiglomerular basement membrane nephritis. In this study, we investigated SM22α expression in models of glomerular and interstitial renal injury. METHODS: The 5/6 nephrectomy (Nx) model, ischemia-reperfusion (I/R) model and puromycin aminonucleoside (PAN) nephrosis of rats were studied. Immunohistochemical analyses and immunoelectron microscopic studies of SM22α expression were performed. RESULTS: In the 5/6 Nx model, SM22α was first expressed in peritubular interstitial cells and was also expressed in injured glomerular epithelial cells at 8 weeks. In the I/R model, SM22α expression was induced in peritubular interstitial cells as early as 12 h after I/R with expression sustained at 7 days. However, SM22α was not detected in any glomerular cells or tubular epithelial cells. In PAN nephrosis, SM22α was only expressed in glomerular epithelial cells after 1 week, but expression was transient. CONCLUSION: SM22α was expressed in glomerular epithelial cells and interstitial cells in renal injury. SM22α is differentially upregulated in various models of renal injury and merits further study.

Injured kidney cells express SM22α (transgelin): Unique features distinct from α-smooth muscle actin (αSMA).

AIM: SM22α (transgelin) has been focused upon as a player in the process of phenotypic changes of types of cells. The SM22α expression in the rat anti-glomerular basement membrane (GBM) nephritis model and differences from an established phenotypic marker for the myofibroblast, α-smooth muscle actin (αSMA), were investigated. METHODS: The rat kidney tissues were processed for histological studies, immunohistochemical and immunoelectronmicroscopy analyses on days 0, 7, 28, 42 and 56 after injection of rabbit anti-GBM serum for the disease induction. RESULTS: Immunohistochemistry with anti-SM22α antibodies (Ab) revealed that kidneys of the nephritic rats on day 7 expressed SM22α in podocytes, crescentic cells and epithelial cells of Bowman's capsule. After 28 days, SM22α was also expressed in peritubular interstitial cells. Double immunofluorescence with anti-SM22α Ab and anti-αSMA Ab showed that SM22α was preferentially expressed in podocytes, whereas αSMA was positive in mesangial cells on day 7. After day 28, both molecules became positive in peritubular interstitial cells. CONCLUSION: SM22α was expressed in epithelial cells of inflamed glomeruli in the early phase, and then also in peritubular interstitial cells in the later phase of anti-GBM nephritis model. SM22α presented unique kinetics of expression distinct from αSMA.

LC/MS/MS method for the determination of trace amounts of cefmetazole and cefpodoxime proxetil contaminants in pharmaceutical manufacturing environments.

In this study, a selective and sensitive LC/MS/MS method for the determination of trace amounts of cefmetazole (CMZ) and cefpodoxime proxetil (CPDXPR) contaminants in manufacturing environments was developed. The necessary sensitivity of this method was estimated based on the detection limit for Penicillin G required by the FDA and the total surface area and volume of the manufacturing facility. The detection limits of this method were estimated to be 10 pg/ml for CMZ and 5 pg/ml for CPDXPR from the signal to noise ratio and as a result satisfactory sensitivity was achieved. The method was linear in a concentration range from 0.20 to 3.20 ng/ml. The accuracy and precision were verified by the determination of the amount of CMZ and CPDXPR added to the sampling materials, a glass plate and a silica fiber filter. The mean recoveries of nine replicated determinations from the glass plate were 99.1% with 5.58%R.S.D. for CMZ and 97.1% with 3.80%R.S.D. for CPDXPR, and those from the silica fiber filter were 100.7% with 4.50%R.S.D. for CMZ and 95.4% with 2.85%R.S.D. for CPDXPR. This method has been successfully applied to the determination of CMZ and CPDXPR contaminants in samples collected from an actual manufacturing environment.

Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells.

Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) have multiple physiological activities (e.g., antiviral activity). However, the potential anticancer activity of ZFE has not been fully examined. In this study, we investigated the ability of ZFE to induce autophagic cell death (ACD). ZFE caused remarkable autophagy-like cytoplasmic vacuolization, inhibited cell proliferation, and ultimately induced cell death in the human cancer cell lines DLD-1, HepG2, and Caco-2, but not in A549, MCF-7, or WiDr cells. ZFE increased the level of LC3-II protein, a marker of autophagy. Knockdown of ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, in cancer cells that could be induced to undergo cell death by ZFE, the extract increased the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 attenuated both vacuolization and cell death. Based on morphology and expression of marker proteins, ZFE-induced cell death was neither apoptosis nor necrosis. Normal intestinal cells were not affected by ZFE. Taken together, our findings show that ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.

Nephrotic syndrome and end-stage kidney disease accompanied by bicytopenia due to copper deficiency.

A 69-year-old man presented with proteinuria and hematuria. He had received total parenteral nutrition for massive small bowel resection. However, due to the iatrogenic lack of trace elements for the next four years, he developed severe copper-deficiency anemia and neutropenia. In addition, his proteinuria and kidney dysfunction worsened concurrently with the development of nephrotic syndrome and end-stage kidney disease. After receiving trace elements, the patient's anemia and neutropenia improved, and the anuria dramatically resolved. Copper-containing enzymes, including ceruloplasmin have an antioxidant activity. In patients with various types of glomerular injuries, the ceruloplasmin expression is known to be increased. Copper deficiency can worsen nephrotic syndrome by decreasing the ceruloplasmin activity, which protects the glomeruli.

A case of antiglomerular basement membrane glomerulonephritis complicated by membranous nephropathy.

The sequential or simultaneous presentation of anti-glomerular basement membrane (anti-GBM) glomerulonephritis with membranous nephropathy (MN) has been infrequently reported. Although the mechanism underlying MN superimposed on anti-GBM glomerulonephritis is unknown, the two entities are believed to be interrelated. We report the case of a 75-year-old woman diagnosed with rapidly progressive glomerulonephritis. Renal biopsy revealed crescentic glomerulonephritis with linear and granular staining of immunofluorescent IgG1 and IgG4 granular staining on the capillary loops. Electron microscopy revealed extensive subepithelial deposits. These findings suggested simultaneous development of anti-GBM glomerulonephritis and MN in this case. Serum phospholipase A2 receptor (PLA2R) antibody was negative. The patient was treated with prednisolone and plasma exchange, resulting in resolution of renal insufficiency and a decrease in urinary protein. The rapid decrease in urinary protein and absence of PLA2R antibody suggest that the mechanism of MN associated with anti-GBM glomerulonephritis differs from that of primary MN.

The importance of medical interview with CKD patient in diagnoses of a family with Fabry disease.

A 47-year-old Japanese man was admitted to our hospital for evaluation of proteinuria, which was detected when he was 37 years of age. His creatinine clearance levels had fallen to 76.3 mL/min/1.73 m2. A kidney biopsy was conducted, and the patient's low plasma α-galactosidase A levels suggested Fabry disease. After genetic counseling, GLA analysis revealed a novel mutation p.L387P. Interview with the patient revealed that both his younger brother and mother suffered from cardiomyopathy and were undergoing cardiological treatment. They also were positive for proteinuria. About 30 years ago, the patient's cousin (aged 25) was diagnosed with Fabry disease. He underwent hemodialysis for 9 years until his death at 42. At that time, the patient and his brother had not been investigated for Fabry disease so their cousin could not act as a proband for the brothers. Eventually, the patient, his mother, and his brother were put on enzyme replacement therapy with agalsidase beta. As this series of cases shows, medical interviews to collate both medical and family history were essential for the discovery of Fabry disease in these patients. In addition, being a treatable genetic disorder, Fabry disease should be listed in the standard differential diagnoses of systemic and familial diseases, including unknown cause of nephropathy or cardiomyopathy, for early detection of the disorder.

Mizoribine as a safe and effective combined maintenance therapy with prednisolone for anti-neutrophil cytoplasmic antibody-associated vasculitis in a hemodialysis patient.

A 77-year-old man developed severe renal insufficiency due to proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, and was started on hemodialysis (HD). Because his renal insufficiency appeared to be irreversible, he was maintained on oral prednisolone (PSL) at 5 mg/day. However, a disease flare-up with alveolar hemorrhage occurred. Serology revealed elevated levels of PR3-ANCA and C-reactive protein (CRP). The patient was given pulse therapy with a quarter dose of methylprednisolone (m-PSL) (250 mg, 3 days), followed by oral PSL at 15 mg/day. As a supplemental treatment, he was given 25 mg of mizoribine (MZR) immediately after each HD session. Subsequently, the levels of PR3-ANCA and CRP decreased, and the alveolar hemorrhage resolved. The dose of MZR to be given was determined by measuring the patient's serum concentrations of MZR at various time points after the HD session. The maintenance dose of MZR was finally set at 50 mg. At present, the oral PSL dosage has been tapered to 10 mg/day, and the patient has achieved a state of remission without any side effects.

HELLP syndrome, multiple liver infarctions, and intrauterine fetal death in a patient with systemic lupus erythematosus and antiphospholipid syndrome.

We report a case of HELLP syndrome, multiple liver infarctions, and intrauterine fetal death in a woman in the 17th week of pregnancy with SLE and APS who had been in remission on a regimen of low-dose prednisolone and aspirin. An increase in the dosage of corticosteroid together with intravenous heparin infusion led to improvement of the clinical symptoms, laboratory parameters, and multifocal low-density liver lesions detected by computed tomography. Early onset and signs of severe organ involvement are the characteristic features of HELLP syndrome associated with APS, and patients that are at risk should be followed up carefully.