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.

Acquired aplastic anemia complicated with anti-glomerular basement membrane disease successfully treated with immunosuppressive therapy: a case report.

BACKGROUND: Aplastic anemia (AA) is a rare but fatal disorder characterized by pancytopenia due to bone marrow hypoplasia. Anti-glomerular basement membrane disease (anti-GBM disease) is an immune complex small-vessel vasculitis that presents as rapidly progressive glomerulonephritis and/or pulmonary hemorrhage. Although both involve autoreactive T cells that are partially triggered by human leukocyte antigen (HLA)-DR15, there have been no reports of their co-existence and the treatment strategy is not well understood. CASE PRESENTATION: A 67-year-old woman presented with fever, malaise, and acute kidney injury with proteinuria and hematuria requiring hemodialysis. She was diagnosed with anti-GBM antibody disease based on high serum anti-GBM antibody titer and crescentic glomerulonephritis on a renal biopsy. Pulse administration of methylprednisolone (MP), oral prednisolone (PSL), and plasmapheresis were performed. Only 2 weeks after the diagnosis of anti-GBM disease, the patient developed pancytopenia requiring frequent blood transfusions. The blood cell count did not recover even 1 month after discontinuing the drugs that could cause pancytopenia. Bone marrow examination showed hypocellularity without abnormal infiltrates or fibrosis, which led to the diagnosis of severe acquired AA. Further HLA phenotyping revealed that she had HLA-DR15. Increased dose of PSL with the secondary MP pulse and the addition of cyclosporine improved pancytopenia. Although she remained dialysis-dependent, anti-GBM disease and pancytopenia did not recur for more than 2 years. CONCLUSIONS: We report the first case of acquired AA complicated with anti-GBM disease in an elderly woman with HLA-DR15, which was successfully treated with immunosuppressive therapy (IST). This report is valuable not only because it shows they may co-occur, but also because it provides a therapeutic option for this complex condition. It was also suggested that pancytopenia in patients with anti-GBM disease recalls serious hematologic diseases including AA that require immediate treatment based on bone marrow examination.

Characterization of Endothelial Progenitor Cell: Past, Present, and Future.

Endothelial progenitor cells (EPCs) are currently being studied as candidate cell sources for revascularization strategies. Despite these promising results, widespread clinical acceptance of EPCs for clinical therapies remains hampered by several challenges. The challenges and issues surrounding the use of EPCs and the current paradigm being developed to improve the harvest efficiency and functionality of EPCs for application in regenerative medicine are discussed. It has been observed that controversies have emerged regarding the isolation techniques and classification and origin of EPCs. This manuscript attempts to highlight the concept of EPCs in a sequential manner, from the initial discovery to the present (origin, sources of EPCs, isolation, and identification techniques). Human and murine EPC marker diversity is also discussed. Additionally, this manuscript is aimed at summarizing our current and future prospects regarding the crosstalk of EPCs with the biology of hematopoietic cells and culture techniques in the context of regeneration-associated cells (RACs).

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.

Renal hemosiderosis presenting with acute kidney Injury and macroscopic hematuria in Immunoglobulin A nephropathy: a case report.

BACKGROUND: Macroscopic hematuria-associated acute kidney injury (AKI) is a well-known complication of immunoglobulin A (IgA) nephropathy. In such cases, intratubular obstruction by red blood cell (RBC) casts and acute tubular necrosis are mainly observed pathologically. Herein, we report the case of a patient with IgA nephropathy presenting with AKI following an episode of macrohematuria. The patient presented with severe renal tubular hemosiderosis and acute tubular necrosis and without any obvious obstructive RBC casts. CASE PRESENTATION: A 68-year-old woman, who was diagnosed with IgA nephropathy on renal biopsy 6 years ago, was admitted to our hospital after an episode of macroscopic glomerular hematuria and AKI following upper respiratory tract infection. Renal biopsy showed mesangial proliferation of the glomeruli, including crescent formation in 17 % of the glomeruli, and acute tubular necrosis without obvious hemorrhage or obstructive RBC casts. The application of Perls' Prussian blue stain showed hemosiderin deposition in the renal proximal tubular cells. Immunofluorescence showed granular mesangial deposits of IgA and C3. Based on these findings, she was diagnosed with acute tubular necrosis with a concurrent IgA nephropathy flare-up. Moreover, direct tubular injury by heme and iron was considered to be the cause of AKI. She was treated with intravenous pulse methylprednisolone followed by oral prednisolone. Thereafter, the gross hematuria gradually faded, and her serum creatinine levels decreased. CONCLUSIONS: IgA nephropathy presenting with acute kidney injury accompanied by macrohematuria may cause renal hemosiderosis and acute tubular necrosis without obstructive RBC casts. Hemosiderosis may be a useful indicator for determining the pathophysiology of macroscopic hematuria-associated AKI. However, renal hemosiderosis may remain undiagnosed. Thus, Perls' Prussian blue iron staining should be more widely used in patients presenting with hematuria.

Efficacy of repeat-dose rituximab maintenance therapy for minimal change disease in adults.

BACKGROUND: Rituximab (RTX) has been reported to effectively treat minimal change disease (MCD) in adults. However, the efficacy of RTX as maintenance therapy, especially in older patients, remains unclear. This study aimed to evaluate the efficacy of repeat-dose RTX maintenance therapy regardless of age. METHODS: We retrospectively reviewed the clinical courses of 13 biopsy-proven adult MCD patients receiving RTX and evaluated the relapse rate, concomitant steroid and immunosuppressant use, relationship between B-cell depletion time and relapse, and adverse events. RESULTS: Mean patient age at start of RTX therapy was 51.5 ± 20.1 years. Each RTX induction consisted of a single 375 mg/m2 dose. One patient received two RTX doses with a 1-year interval. The remaining 12 patients received RTX at 6-month intervals up to four times after RTX introduction. The median observation period was 28 (16-60) months after RTX induction, median relapse frequency was significantly decreased from 0.83 (0.18-1.92) to 0 (0-0.71) times/year (P < 0.001), and median prednisolone dose was reduced from 25 (5-40) mg to 2.5 (0-10) mg (P < 0.001). CD19-positive B cells remained depleted during RTX administration in 6-month intervals. No serious adverse events were observed after RTX administration. CONCLUSIONS: Repeat-dose RTX as maintenance therapy efficiently prevented recurrence and was well tolerated in adult MCD patients including older. This regimen has the potential to maintain prolonged remission. Future studies in larger cohorts are needed to identify the optimal dose and frequency and evaluate the long-term effectiveness and safety of this regimen.

Association between eosinophilia and renal prognosis in patients with pathologically proven cholesterol crystal embolism.

BACKGROUND: Approximately, 20-70% of patients with cholesterol crystal embolism (CCE) have eosinophilia. However, it remains unknown how eosinophilia influences renal prognosis in patients with CCE. In this study, we investigated the association between eosinophil count (Eo) and renal prognosis in CCE patients on steroid therapy. METHODS: The present study is a single-centered retrospective cohort study in patients with renal dysfunction and CCE from April 2007 to May 2018. This study included the patients who were treated with neither maintenance dialysis nor steroid before CCE diagnosis, and followed-up for kidney function until November 2019. We assessed whether eosinophilia at the time of CCE diagnosis was related to renal death after treating with steroid therapy. RESULTS: Thirty patients with pathologically diagnosed CCE were enrolled and followed-up for 11.0 (5.2-43.4) months. There were significant differences in the white blood cell count (p = 0.01), hemoglobin (p = 0.009), serum creatinine levels (p = 0.008), phosphate (p = 0.049), and Eo (p = 0.008) between the renal survival and renal death groups. Using the receiver operating characteristic curve analysis with Youden index, Eo of 810/µL showed 100% sensitivity and 69.6% specificity for detecting renal death (area under the curve: 0.839). Comparing the outcomes in patients having Eo ≥ and < 810/µL using the log-rank test, there is a significantly higher renal death rate in CCE patients with Eo ≥ 810/µL (p = 0.0016). CONCLUSION: Higher eosinophilia was a prognostic risk factor for renal death in the patients with CCE.

Efficacy and Tolerability of Ombitasvir/Paritaprevir/Ritonavir in HCV Genotype 1-infected Elderly Japanese Patients.

INTRODUCTION AND AIM: We assessed the characteristics of virological response to a combination treatment of ombitasvir, paritaprevir, and ritonavir in hepatitis C virus genotype 1-infected elderly Japanese patients. MATERIAL AND METHODS: This multicenter prospective study was conducted at six locations in Japan. Seventy patients with chronic hepatitis C virus genotype 1b infection were orally administered ombitasvir/paritaprevir/ritonavir once daily for 12 weeks. The primary endpoint was the proportion of elderly patients with sustained virological response (SVR) 12 weeks after the completion of treatment. Adverse events were also recorded to evaluate drug safety and tolerability during the trial period. SVR in elderly patients (age > 65; 94% [47 / 50]) was lower than that in younger patients (100% [20 / 20]). RESULTS: No significant differences in SVR 12 weeks after the completion of treatment were observed between the age groups (P = 0.153). Adverse events were observed in 16 patients (23.3%). Multivariate analysis confirmed that the change or discontinuation of concomitant drugs owing to drug interactions was independent of risk factors for adverse events associated with this drug combination (P = 0.015; odds ratio, 15.9; 95% confidence interval, 1.79 - 148). Ombitasvir/paritaprevir/ritonavir combination treatment was highly effective in elderly patients. CONCLUSION: Tolerability should be monitored in older patients for whom concomitant medications are discontinued or changed because of drug interactions.

Intradialytic hypotension is an important risk factor for critical limb ischemia in patients on hemodialysis.

BACKGROUND: Critical limb ischemia (CLI) and intradialytic hypotension (IDH) are common complications in patients on hemodialysis (HD). However, limited data are available on whether IDH is related to CLI in these patients. The aim of this retrospective study was to evaluate whether IDH is a risk factor for CLI in HD patients. METHODS: We examined the frequency of IDH in 147 patients who received HD between January 1 and June 30, 2012. Blood pressure was measured during HD every 30 min and IDH was defined as a ≥ 20 mmHg fall in systolic blood pressure compared to 30 min before and a nadir intradialytic systolic blood pressure < 90 mmHg. The primary study outcome was newly developed CLI requiring revascularization treatment or CLI-related death. We assessed the association of IDH with outcome using a multivariable subdistribution hazard model with adjustment for male, age, smoking and history of cardiovascular disease. RESULTS: The median follow-up period was 24.5 months. Fifty patients (34%) had episodes of IDH in the study entry period. During follow-up, 14 patients received endovascular treatment and CLI-related death occurred in 1 patient. Factors associated with incident CLI in univariate analysis were age, smoking, diabetes mellitus, peripheral arterial disease, history of cardiovascular disease, and IDH. IDH was significantly associated with the outcome with the subdistribution hazard ratio of 3.13 [95% confidence interval, 1.05-9.37]. CONCLUSIONS: IDH was an independent risk factor for incident CLI in patients on HD.

Seasonality of acute kidney injury incidence and mortality among hospitalized patients.

Background: Understanding disease seasonality is important for improving clinical practice, hospital resource utilization and community-based preventive care. However, no studies have investigated the seasonality of acute kidney injury (AKI). Methods: In the Tokushukai Medical Database, which includes 38 Japanese community hospitals, we identified hospitalized patients with AKI based on the Kidney Disease: Improving Global Outcomes serum creatinine criteria from January 2012 to December 2014. We plotted the number and proportion of patients with AKI among hospitalized patients by month of hospital admission. Subgroup analyses were conducted by the admission diagnosis category, timing of AKI diagnosis and age. We also examined the association between month of hospital admission and AKI, adjusting for patient characteristics and AKI risk factors. Finally, we assessed seasonal variations in disease severity and 30-day mortality of patients with AKI. Results: We identified 81 279 (14.6%) patients with AKI among 555 940 hospitalized patients. The proportion of patients with AKI was highest in January (16.7%) and lowest in June (13.4%). Subgroup analyses suggested that the seasonality of AKI incidence was driven by community-acquired AKI associated with the admission diagnosis of cardiovascular and pulmonary diseases among older patients. The adjusted odds ratio for AKI (January versus June) was 1.24 (95% confidence interval, 1.17-1.31). Patients with AKI showed a larger number of failing organs in winter, and their 30-day mortality was 16.4% in spring, 14.5% in summer, 15.6% in autumn and 18.4% in winter. Conclusion: AKI is more common among hospitalized patients and patients with AKI are more severely ill in winter.

Outcome From a Randomized Controlled Clinical Trial　- Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating Factor-Mobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation (IMPACT).

BACKGROUND: The clinical usefulness of peripheral blood (PB) mononuclear cell (MNC) transplantation in patients with peripheral arterial disease (PAD), especially in those with mild-to-moderate severity, has not been fully clarified.Methods and Results:A randomized clinical trial was conducted to evaluate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMNC transplantation in patients with PAD (Fontaine stage II-IV and Rutherford category 1-5) caused by arteriosclerosis obliterans or Buerger's disease. The primary endpoint was progression-free survival (PFS). In total, 107 subjects were enrolled. At baseline, Fontaine stage was II/III in 82 patients and IV in 21, and 54 patients were on hemodialysis. A total of 50 patients had intramuscular transplantation of PBMNC combined with standard of care (SOC) (cell therapy group), and 53 received SOC only (control group). PFS tended to be improved in the cell therapy group than in the control group (P=0.07). PFS in Fontaine stage II/III subgroup was significantly better in the cell therapy group than in the control group. Cell therapy-related adverse events were transient and not serious. CONCLUSIONS: In this first randomized, large-scale clinical trial of G-CSF-mobilized PBMNC transplantation, the cell therapy was tolerated by a variety of PAD patients. The PBMNC therapy was significantly effective for inhibiting disease progression in mild-to-moderate PAD.

Nephritis-associated plasmin receptor (NAPlr) positive glomerulonephritis caused by Aggregatibacter actinomycetemcomitans bacteremia: A case report.

Infection-related glomerulonephritis (IRGN) develops after various infections. It was previously thought to be caused by Streptococcus species alone but can also be caused by other pathogens. Nephritis-associated plasmin receptor (NAPlr) was discovered as a candidate nephritis-inducing factor in acute post-streptococcal glomerulonephritis. More recently, renal lesions caused by other pathogens were found to be positive for the same molecular marker. We report the case of a 64-year-old man who experienced repeated fever for several months and presented with progressively-deteriorating renal function. He had previously undergone aortic valve replacement. Aggregatibacter actinomycetemcomitans, a component of the oral flora, was detected in a blood culture. Renal biopsy showed diffuse proliferative glomerulonephritis. Immunofluorescence staining of the kidney specimen was positive for immunoglobulins, complements, and NAPlr. The patient was diagnosed with infectious endocarditis and IRGN. Six weeks of intravenous antibiotic therapy improved the patient's clinical condition and kidney function. In this case, IRGN was caused by a rare pathogen. This is the first published case to show NAPlr positivity in the glomeruli after systemic infection with the periodontal bacteria, Aggregatibacter actinomycetemcomitans. This case and subsequent research might expand the concept of IRGN, anchored by NAPlr as a key diagnostic biomarker.
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Rationale and study design of a clinical trial to assess the effects of LDL apheresis on proteinuria in diabetic patients with severe proteinuria and dyslipidemia.

BACKGROUND: Diabetic nephropathy is a leading cause of end-stage kidney disease in the world. Although various types of treatment for diabetes, hypertension and dyslipidemia have improved prognosis and quality of life in patients with diabetic nephropathy, there still exist some diabetic patients with severe proteinuria showing poor prognosis. This clinical trial, LICENSE, aims to confirm the impact of LDL apheresis on proteinuria exhibiting hyporesponsiveness to treatment. METHODS: This ongoing trial is a multicenter, prospective study of diabetic patients with severe proteinuria. The objective is to examine the impact of LDL apheresis on proteinuria in patients with diabetic nephropathy. The other subject is to investigate safety of LDL apheresis in these patients. RESULTS: The subjects consist of diabetic patients with serum creatinine (Cr) levels below 2 mg/dL who present severe proteinuria above 3 g/g Cr or 3 g/day and LDL cholesterol above 120 mg/dL. The target number of registered patients will be 35 patients. Urinary protein excretion and renal function will be observed for 24 weeks after the treatment of LDL apheresis. CONCLUSION: This study will determine the effectiveness and safety of LDL apheresis for diabetic nephropathy patients with severe proteinuria and dyslipidemia.

Intravascular lymphoma forming massive aortic tumors complicated with sarcoidosis and focal segmental glomerulosclerosis: a case report and literature review.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by proliferation of B cells within small vessels. Herein, we report a case of a 77-year-old man who presented with IVLBCL and massive tumor formation on the aortic wall who was previously diagnosed with sarcoidosis and focal segmental glomerulosclerosis (FSGS). To our knowledge, this is the first reported case of an IVLBCL with aortic tumor formation. CASE PRESENTATION: A 77-year-old ambulatory man with sarcoidosis and FSGS had neurological symptoms for nine months. The patient presented to the emergency department with sudden left leg pain, and was diagnosed with acute femoral artery occlusion. Emergency thrombectomy was performed subsequently. Pathological evaluation of the thrombi revealed that its surface was filled with large atypical B cells. Bone marrow biopsy showed infiltration of large atypical B cells within the small vessels. IVLBCL was suspected and further examination was planned, but the patient died due to sudden respiratory and cardiac arrest on hospital day twelve. Autopsy revealed intravascular tumors adherent to the aortic arch, left ventricle, and the abdominal aorta. All enlarged lymph nodes and the ventricular septum of the heart showed hyalinized lesions with granular formation consistent with sarcoidosis. The patient was diagnosed with IVLBCL with aortic tumor formation complicated with sarcoidosis and FSGS. CONCLUSIONS: IVLBCL may present with tumor formation on the aortic wall. Although the cause of its affinity to the aortic wall is yet unknown, autopsy findings imply that arteriosclerosis may have contributed to the tumor formation. The literature suggests that T-cell abnormalities could possibly be the common etiology of intravascular lymphoma, sarcoidosis, and FSGS.

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.

Plasma neutrophil gelatinase-associated lipocalin (NGAL) is an indicator of interstitial damage and a predictor of kidney function worsening of chronic kidney disease in the early stage: a pilot study.

BACKGROUND: The aim of this study was to examine whether plasma neutrophil gelatinase-associated lipocalin (NGAL) levels predict the outcome of kidney function and correlate with the severity of tubulointerstitial damages in patients with chronic kidney disease (CKD). METHODS: In this prospective 18-month cohort study of 112 patients with CKD between 2010 and 2011, associations between plasma NGAL levels and estimated glomerular filtration ratio (eGFR), further worsening of kidney function and histological lesion on kidney biopsy were investigated. RESULTS: Serum levels of creatinine and eGFR before the study were 1.48 ± 0.65 mg/dl and 42.6 ± 22.0 ml/min/1.73 m2. Median plasma NGAL level was 148.5 (83.75-248.25) ng/ml and showed no correlation with eGFR or age. 87 out of 112 patients were able to follow up for 18 months. Patients with higher levels of NGAL (>107.8 ng/ml) showed significantly more decrease in eGFR in CKD stage 1 or 2 than those with lower levels of NGAL (≦107.8 ng/ml), while there was no difference in change in eGFR in CKD stage 3-5 between patients with higher and lower levels of NGAL. In the kidney biopsy of 27 patients out of enrolled patients, plasma NGAL levels correlated significantly with the degree of interstitial cell infiltration and fibrosis, but did not correlate with that of glomerular sclerosis. In ROC analysis, plasma NGAL levels predicted tubulointerstitial cell infiltrations more accurately [AUC = 0.8300 than eGFR (AUC = 0.716)]. CONCLUSION: Plasma NGAL is a useful marker of interstitial lesions in patients with CKD and a predictor of further kidney worsening in the early CKD stage.

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney.

Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genome-wide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy.

LDL-apheresis dramatically improves generalized calciphylaxis in a patient undergoing hemodialysis.

We present the first documented case of generalized calciphylaxis that dramatically improved after low-density lipoprotein-apheresis (LA) in a patient undergoing long-term hemodialysis. Calciphylaxis was diagnosed by skin biopsy and was manifest as painful ulcers on the right leg, left buttock, and glans penis. Skin perfusion pressure (SPP), which has recently been used as an indicator of impaired capillary perfusion in distal lesions of the lower extremities, was markedly reduced. The ulcers continued to worsen despite general wound care, correction of levels of calcium × phosphate product, hyperbaric oxygen therapy, and use of bisphosphonate, antiplatelet therapy, and vasodilators. Because LA is known to exert favorable effects on peripheral arterial disease through improved hemorheology, anti-inflammatory action, vasodilation, and angiogenesis, we introduced LA to produce the same effects on calciphylaxis. LA dramatically increased SPP and promoted ulcer healing, demonstrating that LA can be a useful treatment option for calciphylaxis.

Angiotensin receptor blocker (ARB)-diuretic versus ARB-calcium channel blocker combination therapy for hypertension uncontrolled by ARB monotherapy.

Diuretics or calcium channel blockers (CCBs) are used concomitantly with an angiotensin II receptor blocker (ARB). However, it is not established which ARB-based combination therapy is the most effective and safe. This prospective randomized open-label study compared the efficacy and safety of a fixed-dose tablet of losartan (LST)-hydrochlorothiazide (HCTZ) (n = 99) and LST-amlodipine (AML) (n = 77) in Japanese patients whose hypertension was uncontrolled by ARB monotherapy. Blood pressure changed similarly over the 12-month study period. Only LST-HCTZ significantly increased serum uric acid (SUA) in patients with low baseline SUA (<5.6 mg/dL) but not in patients with high baseline SUA.

Morphologic features of humeral head and glenoid version in the normal glenohumeral joint.

BACKGROUND: The morphologic features and clinical significance of version of the humeral head and glenoid remain unclear. The purpose of this study was to evaluate the normal values of humeral head version and glenoid version on computed tomography scans and to clarify their features in the normal glenohumeral joint. METHODS: Images for analysis were computed tomography scans of 410 normal shoulders from healthy volunteers. Values of humeral head and glenoid version were measured. In glenoid version measurement, 3-dimensionally corrected slices were reconstructed to eliminate scapular inclination. Differences in humeral head version and glenoid version were assessed between dominant and nondominant shoulders and between men and women. Correlation analyses were also performed in the values of version between dominant and nondominant shoulders and between humeral head version and glenoid version. RESULTS: The values of humeral head retroversion were widely distributed from -2° to 60°, with an average of 26° ± 11°. Average glenoid retroversion was 1° ± 3°, ranging from -9° to 13°. Both humeral head retroversion and glenoid retroversion were significantly higher on the dominant side than on the nondominant side and significantly higher in men than in women. Humeral head version and glenoid version values were well correlated with those of the contralateral shoulder. No correlation was found between humeral head version and glenoid version. CONCLUSIONS: This study found differences in humeral head version and glenoid version by sex and shoulder dominance in a large sample. Both the humeral head and glenoid are thought to be more retroverted in high-demand shoulders.