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Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca 2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca 2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP 3 R2), which is an intracellular Ca 2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP 3 R2 -/- mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP 3 R2 -/- murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca 2+ entry (SOCE) was significantly enhanced in IP 3 R2 -/- PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca 2+ imaging. Furthermore, the enhancement of SOCE in IP 3 R2 -/- PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)-Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP 3 R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM-Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP 3 R in the development of PAH and may contribute to the development of targeted therapies.

Introduction: Previously, we reported the caveolae-mediated intracellular trafficking pathway of albumin through glomerular endothelial cells (GEnCs) as a new etiological hypothesis of urinary albumin excretion. The selective serotonin reuptake inhibitor, sertraline (Ser), inhibits dynamin, which plays a pivotal role in the fission of caveolae from the cell membrane during caveolae endocytosis., Objective: In this study, we evaluated whether Ser reduces albuminuria levels by interfering with albumin endocytosis through caveolae into GEnCs and podocytes as a novel treatment for glomerulonephritis., Methods: After treating the cells with Ser, albumin and caveolin-1 (Cav-1) expression levels were evaluated by immunofluorescence (IF) and western blot (WB) analyses. The albuminuria level was determined by histology in a puromycin aminonucleoside (PAN)-induced nephrotic syndrome mouse model (PAN mice) treated with or without Ser., Results: IF and WB analyses showed that the albumin expression level was significantly decreased by Ser treatment; however, Cav-1 expression was not decreased in GEnCs or podocytes based on the IF results. In PAN mice treated with or without Ser, Cav-1 expression increased, and the foot process effacement of podocytes and swelling of GEnCs were observed. However, proteinuria levels were not increased in PAN mice treated with Ser relative to that in normal control mice (p = 0.17), and a significant increase was observed in PAN mice without Ser treatment (p = 0.0027)., Conclusions: Ser interfered with albumin internalization through the caveolae into GEnCs and podocytes and reduced albuminuria. Dynamin inhibitors may serve as a novel therapeutic option for reducing albuminuria in glomerulonephritis., (© 2019 S. Karger AG, Basel.)

Previously, we reported the short-term effects of tacrolimus in treating lupus nephritis (LN); however, long-term data are lacking. We conducted a retrospective study of 26 adult patients with LN. Tacrolimus was initiated at a dose of 3 mg/day after induction therapy. We retrospectively collected data on renal response; modified lupus nephritis disease activity index (m-LNDAI), including hematuria, proteinuria, complement 3, anti-double-stranded DNA antibody, and estimated glomerular filtration rate (eGFR); and prednisolone (PSL) dose. Three patients discontinued tacrolimus treatment because of related complications, including acute myeloblastic leukemia, tremor, or a general personal choice or a desire to become pregnant. We analyzed data from 23 patients who were treated with tacrolimus over a 5-year period. The mean urinary protein/creatinine ratio decreased from a baseline of 0.24 (min 0.00-max 4.20) to 0.00 (0.00-7.05) at 5 years (p = 0.0134), while eGFR levels remained unchanged throughout the 5 years. The mean m-LNDAI decreased from a baseline of 3.00 (0.00-12.0) to 2.00 (0.00-4.00) at 5 years (p = 0.0074). The mean PSL dose decreased from a baseline of 0.33 (0.00-0.75) mg/kg/day to 0.15 (0.15-0.33) at 5 years (p = 0.001). Our results suggest that tacrolimus is potentially effective for treating LN and that the current dosage was generally well tolerated for long-term maintenance treatment in our patients with LN.

As immunotactoid glomerulopathy (ITG) is a very rare primary glomerular disease, no standard treatment has been established. It has been reported that ITG progresses to end-stage renal disease at a high rate. Here, we report a case of ITG exhibiting nephrotic syndrome treated by administration of a single dose of rituximab every 6 months for 4 years. In this case, complete remission (CR) was not achieved with steroids alone, but was achieved through long-term depletion of B cells by administration of rituximab. This is the first report that single-dose rituximab every 6 months for 4 years not only achieved CR of ITG, but also allowed steroid tapering.
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Many countries including Japan have adapted acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP). DTaP vaccine coverage is approximately >90%, but pertussis re-emergence has been observed since 2000 in Japan. In the present study, anti-pertussis antibodies were investigated among school-age children and adolescents from 2013 to 2015. The positive rate of anti-pertussis toxin (PT) antibodies was higher among children aged 12-13 years (60.0%. 95%CI; 56.0-63.9%) in 2014 and 18-19 years (73.0%. 95%CI; 61.4-82.6%) in 2013, compared with 6-7 years (47.1%. 95%CI; 40.7-53.6%). The mean PT antibody titer was higher among children aged 12-13 years (23.8 EU/ml. 95%CI; 21.9-25.8) in 2014 and 18-19 years (29.3 EU/ml. 95%CI; 23.0-35.6) in 2013, compared with 6-7 years (18.3 EU/ml. 95%CI; 15.5-21.2). Distributions of pertussis antibodies and mean titers at their same grade of school-age were similar from 2013 to 2015. Although school-age children were immunized with 4 doses of DTaP, the data suggested the decay of vaccine-acquired immunity and possibility of asymptomatic infection in school age, indicating the additional DTaP vaccination before the entry of elementary school, preventing household contact., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been reported to have beneficial effects in patients with IgA nephropathy (IgAN). Although DHA and EPA have different mechanisms of action, no study to date has assessed their individual actions in patients with IgAN. This study therefore analyzed the effects administering DHA in addition to EPA for the treatment of IgAN. Methods Twenty-one IgAN patients who were being treated with EPA (1,800 mg/day) were switched to EPA (1,860 mg/day) and DHA (1,500 mg/day). The changes in their clinical parameters from 6 months before to 6 months after switching treatment were analyzed. Results The triglyceride levels did not change during treatment with EPA alone, but tended to decrease-although not to a statistically significant extent-after the switch. The patients' low-density-lipoprotein cholesterol, blood pressure, proteinuria, and hematuria levels were similar before and after switching. The estimated glomerular filtration rate (eGFR) tended to decrease during EPA therapy, but became stable after switching and the median %⊿eGFR changed from -7.354% during EPA therapy to +1.26% during the 6 months after switching to EPA and DHA therapy (p=0.00132), and renal the function remained stable for another 6 months. Moreover, the median %⊿eGFR during the 6 months after switching was significantly higher in comparison to IgAN patients who were treated with EPA alone as a control (-3.26%, p=0.0361). No clinical parameters were independently associated with a stable renal function without switching to DHA/EPA. Conclusion The addition of DHA to EPA stabilized the renal function of IgAN patients, and it seemed that there were pleiotropic effects beyond the improvement of the clinical parameters.

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that affects multiple organs and tissues. Lupus nephritis (LN) is a serious complication of SLE, which occurs at a high rate. Conventional treatment strategies of LN have been widely accepted by two concepts such as induction therapy and maintenance therapy. In LN induction therapy until recently, cyclophosphamide in combination with prednisone (PSL) has been the standard method of treatment for proliferative forms of LN. In the latest review, the combination of mycophenolate mofetil (MMF) is also considered a standard treatment option. Furthermore, a multi-target therapy with tacrolimus (Tac) added to PSL and MMF, with reference to a regimen after organ transplantation has also been reported. In LN maintenance therapy, although recent reports have demonstrated that MMF, azathioprine, and Tac in combination with PSL may prevent renal flares, there is no definite opinion in the period of use or the method of tapering. On the contrary, there are also concepts of two mechanisms of therapy for LN, such as a treatment based on the immunological mechanism as an autoimmune disease and a treatment based on the non-immunological mechanism as a chronic kidney disease. Nephrologists need to continue searching for the best-mix treatment regimen according to various clinical findings. We review the options available for the treatment of LN, and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE., (© 2018 S. Karger AG, Basel.)

We previously described albumin endocytosis through caveolae in human renal glomerular endothelial cells (HRGECs). This suggested a new albumin transcytosis pathway, in addition to the fenestral pathway. As a next step, we investigated albumin transcytosis in HRGECs after caveolar endocytosis. HRGECs were incubated with Alexa Fluor 488-labeled bovine serum albumin from 0 to 360 min. Next, markers for endosomes, endoplasmic reticulum (ER), golgi apparatus (GA), lysosomes, and proteasomes and Fc receptors, microtubules, and actin were monitored by immunofluorescence. Labeled albumin co-localization with endosomes was gradually and significantly increased and it was significantly higher than with the other markers at any timepoint. Albumin, placed on inside of the Transwell membrane, diffused through HRGEC monolayers during a 360 min incubation period. This transportation of albumin through HRGECs was inhibited by methyl beta cyclodextrin (MBCD), a caveolae disrupting agent. MBCD also decreased albuminuria, causing decreased caveolin-1 (Cav-1) expression on glomerular capillaries, in puromycin aminonucleoside induced nephrotic mice. Albumin transcytosis depends on early endosomes, but not on other organelles, Fc receptors, or cytoskeletal components. Caveolae disruption prevented albumin transportation through HRGECs and decreased albuminuria in nephrotic mice. This newly described caveolae-dependent albumin pathway through glomerular endothelial cells is a potential pathogenetic mechanism for albuminuria, independent of the fenestrae., (© 2017 Wiley Periodicals, Inc.)

Background: Treatment of IgA nephropathy (IgAN) in Japan has recently changed, from oral prednisolone (oPSL) to tonsillectomy plus steroid pulse (TSP) therapy. However, a few studies have compared their efficacy and safety., Methods: IgAN patients diagnosed in our institution between 1991 and 2013, treated with TSP or oPSL, aged ≥16 years, with ≥1 g/day proteinuria, and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m 2 , and no other renal disease were selected. Baseline clinical and histological findings, clinical outcomes, and adverse events were compared. Clinical remission (CR) was defined as <0.3 g/day proteinuria and <5 urinary red blood cells per high-powered field., Results: Sixty-six patients were identified; after propensity score adjustment, 26 patients were selected in each group. CR rates were significantly higher at 12 (30.8 % vs. 3.9 %), 36 (47.3 % vs. 7.9 %), and 72 (57.8 % vs. 20.1 %) months (p < 0.01), and the renal survival rate, defined as the development of a 25 % reduction from baseline eGFR, was significantly higher at 12 (96.2 % vs. 69.2 %), 36 (96.2 % vs. 61.5 %), and 72 (96.2 % vs. 41.0 %) months in the TSP than the oPSL group (p < 0.001). Multivariate analysis showed that TSP was the only independent factor associated with CR (hazard ratio, 3.58; 95 % confidence interval, 1.32-10.91, p = 0.01). The number of patients with adverse events was significant lower in TSP group than in oPSL group (11.5 % vs. 34.6 %, p = 0.04)., Conclusions: CR rates are higher; protection of renal function and prevention from adverse events were superior with TSP than with oPSL in patients with IgAN and moderate-to-severe proteinuria.

The embryonic-maternal interface of the placental labyrinth, allantois, and yolk sac are vital during embryogenesis; however, the precise mechanism underlying the vascularization of these structures remains unknown. Herein we focus on the role of inositol 1,4,5-trisphosphate (IP3) receptors (IP3R), which are intracellular Ca(2+) release channels, in placentation. Double knockout (DKO) of type 1 and 3 IP3Rs (IP3R1 and IP3R3, respectively) in mice resulted in embryonic lethality around embryonic day (E) 11.5. Because IP3R1 and IP3R3 were co-expressed in endothelial cells in the labyrinth, allantois, and yolk sac, we investigated extra-embryonic vascular development in IP3R1- and IP3R3-DKO mice. The formation of chorionic plates and yolk sac vessels seemed dysregulated around the timing of the chorio-allantoic attachment, immediately followed by the disorganization of allantoic vessels, the decreased expression of the spongiotrophoblast cell marker Tpbpa and the growth retardation of the embryos in DKO mice. Fluorescent immunohistochemistry demonstrated downregulation of a vascular endothelial marker, CD31, in labyrinth embryonic vessels and poor elongation of extra-embryonic mesoderm into the labyrinth layer in DKO placenta, whereas the branching of the DKO chorionic trophoblast was initiated. In addition, allantoic and yolk sac vessels in extra-embryonic tissues were less remodeled in DKO mice. In vitro endothelial cord formation and migration activities of cultured vascular endothelial cells derived from human umbilical vein were downregulated under the inhibition of IP3R. Our results suggest that IP3R1 and IP3R3 are required for extra-embryonic vascularization in the placenta, allantois, and yolk sac. This is the first demonstration of the essential role of IP3/IP3Rs signaling in the development of the vasculature at the embryonic-maternal interface., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study is designed to evaluate which factors would relate to deterioration of renal function (DRF) after delivery in pregnant women with chronic kidney disease (CKD)., Materials and Methods: This study included 156 singleton pregnancies of 139 women with CKD at our institution from 2001 to 2010. DRF was defined as the shift of CKD stage into another more severe stage. The relevant variables were compared between women who had DRF (n = 39) and the controls (n = 117)., Results: The number of transplantation or dialysis cases after delivery was 5.8%. DRF occurred in 25% of the study patients. From a logistic regression model, the factors that influence DRF were the presence of glomerulonephritis [odds ratio (OR) 3.56, 95% confidence interval (CI) 1.18-10.81], significant proteinuria prior to pregnancy (≥3 g/d or 3+ more dipstick; OR 3.43, 95% CI 1.14-10.33), and treatment with antiplatelet agents (OR 0.30, 95% CI 0.09-0.94). Receiver-operating characteristic curve analysis confirmed that the estimated glomerular filtration rate (eGFR) of 75 mL/min/1.73 m(2) or more before conception is not a risk factor for DRF after delivery (negative predictive value 0.788)., Conclusion: This was the first report to reveal a clear cutoff value regarding DRF in pregnant woman with CKD. There is an almost 78% risk of developing DRF after delivery in patients showing eGFR of 75 mL/min/1.73 m(2) or more before conception., (Copyright © 2016. Published by Elsevier B.V.)

Background: Dental plaque formed on tooth surfaces is a complex ecosystem composed of diverse oral bacteria and salivary components. Accumulation of dental plaque is a risk factor for dental caries and periodontal diseases. L-arginine has been reported to decrease the risk for dental caries by elevating plaque pH through the activity of arginine deiminase in oral bacteria. Here we evaluated the potential of L-arginine to remove established oral biofilms., Methods: Biofilms were formed using human saliva mixed with Brain Heart Infusion broth supplemented with 1 % sucrose in multi-well plates or on plastic discs. After washing the biofilms with saline, citrate (10 mM, pH3.5), or L-arginine (0.5 M, pH3.5), the retained biofilms were analyzed by crystal violet staining, scanning electron microscopy, and Illumina-based 16S rDNA sequencing., Results: Washing with acidic L-arginine detached oral biofilms more efficiently than saline and significantly reduced biofilm mass retained in multi-well plates or on plastic discs. Illumina-based microbiota analysis showed that citrate (pH3.5) preferentially washed out Streptococcus from mature oral biofilm, whereas acidic L-arginine prepared with 10 mM citrate buffer (pH3.5) non-specifically removed microbial components of the oral biofilm., Conclusions: Acidic L-arginine prepared with citrate buffer (pH3.5) effectively destabilized and removed mature oral biofilms. The acidic L-arginine solution described here could be used as an additive that enhances the efficacy of mouth rinses used in oral hygiene.

Endothelial dysfunction is often found in both hyperuricemia and hemodialysis patients. Recent studies have shown that treating hyperuricemia with allopurinol improves endothelial dysfunction. This study is performed to assess the effect of febuxostat on endothelial dysfunction in hemodialysis patients with hyperuricemia. We randomly assigned 53 hemodialysis patients with hyperuricemia to a febuxostat (10 mg daily) group and a control group and measured flow-mediated dilation, serum uric acid (UA) levels, systolic and diastolic blood pressure, malondialdehyde-modified low-density lipoprotein (MDA-LDL), and highly sensitive C-reactive protein (hsCRP) at baseline and at the end of a 4-week study period. Flow-mediated dilation increased from 5.3% ± 2.4% to 8.9% ± 3.6% in the febuxostat group but did not change significantly in the control group. Treatment with febuxostat resulted in a significant decrease in serum UA level and a significant decrease in MDA-LDL compared with baseline, but no significant difference was observed in hsCRP level or blood pressure. No significant differences were observed in the control group. Febuxostat improved endothelial dysfunction and reduced serum UA levels and oxidative stress in hemodialysis patients with hyperuricemia., (© 2015 International Society for Hemodialysis.)

Podocyte injury contributes to the development of focal segmental glomerulosclerosis (FSGS). Endocapillary hypercellularity, which is one of the pathological characteristics of FSGS, suggests that glomerular endothelial injury may also be involved in the pathogenesis of FSGS. In electron micrographs of patients with FSGS (n = 43), we conducted morphometric measurements of foot process width (FPW) and podocyte detachment (PD) as markers of podocyte injury and subendothelial widening (SW) of the glomerular basement membrane as a marker of endothelial injury and compared them to those in patients with minimal change nephrotic syndrome (MCNS; n = 11) and control kidney donors (n = 5). Associations between ultrastructural and clinical parameters were analyzed according to the FSGS variants defined by the Columbia classification. FPW was significantly higher in the FSGS group than that in the MCNS and control groups, particularly in the collapsing, tip, and cellular variants of FSGS. Percentage of glomerular basement membrane (GBM) length showing PD and SW was significantly increased in the FSGS group, especially in the collapsing, cellular, and not otherwise specified variants. In FSGS, FPW was inversely correlated with disease duration, but not with proteinuria. Finally, the percentage of GBM length with SW significantly correlated with clinical parameters indicative of poor prognosis, such as lower remission rate and lower estimated glomerular filtration rate at the final observation. Quantitative measurement of podocyte and endothelial injury by electron microscopy might be useful for evaluating histological activity and predicting prognosis in FSGS.

Background: High uric acid level is a known risk factor for deterioration of renal function in chronic kidney disease (CKD), but its influence on the progression of IgA nephropathy (IgAN) remains unclear., Methods: Adult IgAN patients (n = 611) were classified according to CKD stage. Renal survival rates and clinical and histological findings were compared between patients with high (H-UA) and normal (N-UA) uric acid levels in different CKD stages., Results: The proportion of patients with H-UA increased significantly with increasing CKD stage (stage G1, 12.3%; stage G2, 19.0%; stage G3a, 43.7%; stage G3b-4, 69.0%; P < 0.001). The 30-year renal survival rate was similar in patients with H-UA and N-UA in CKD stages G1, G2, and G3b-4, but was significantly lower in patients with H-UA than with N-UA in CKD stage G3a (24.7 vs. 51.9%; P = 0.0205). The clinical findings were similar in patients with H-UA and N-UA, but the interval from onset to biopsy differed between groups. The proportion of patients with global sclerosis was significantly higher in patients with H-UA than with N-UA in CKD stage G3a (33.3 vs. 11.4%; P = 0.0005), but the Oxford classifications were similar between groups. Multivariate Cox regression analysis identified H-UA (HR 1.36, 95% CI 1.07-1.72, P = 0.011) and a large amount of proteinuria (HR 1.38, 95% CI 1.09-1.74, P = 0.0084) as independent predictors of end-stage renal disease., Conclusions: H-UA induced global glomerular sclerosis and accelerated the progression of IgAN in CKD stage G3a.

Caveolae on human renal glomerular endothelial cells (HRGECs) are increased in glomerular disease and correlate with the degree of albuminuria. To assess the mechanism by which caveolae contribute to albuminuria, we investigated whether albumin enters into HRGECs through caveolae. HRGECs were incubated with Alexa Fluor 488 labeled BSA or transferrin, followed by immunofluorescence localization with antibody to caveolin-1 (Cav-1), the main structural protein of caveolae, or clathrin, the major structural protein of clathrin coated pits, to assess whether BSA colocalized with Cav-1. HRGECs were also incubated with albumin and caveolae disrupting agents, including methyl beta cyclodextrin (MBCD) and nystatin, to determine whether disrupting caveolae interfered with albumin endocytosis into HRGECs. HRGECs were also incubated with albumin after transfection with Cav-1 small interfering RNAs (siRNAs). Labeled BSA colocalized with Cav-1, but not with clathrin. In contrast, labeled transferrin colocalized with clathrin, but not with Cav-1. Incubation of HRGECs with MBCD or nystatin, or transfection with Cav-1 siRNA, significantly reduced the intracellular amounts of albumin and Cav-1, relative to normal HRGECs, as shown by western blotting and immunofluorescence. These findings indicate that albumin enters HRGECs through the caveolae, suggesting that caveolae play an important role in the pathogenesis of albuminuria by providing a pathway through which albumin can enter glomerular endothelial cells., (© 2015 Wiley Periodicals, Inc.)

Background: Neoadjuvant chemotherapy has been increasingly utilized in the treatment of breast cancer patients. However, there are no established surrogate markers predicting the response to subsequent adjuvant therapy and clinical outcome of patients. In particular, whether primary or lymph nodes metastasis should be evaluated for these analyses has remained unknown. Therefore, in this study, we first evaluated the differences in biomarkers between primary and metastatic cancer tissues in the patients undergoing neoadjuvant chemotherapy. We then correlated the findings with the clinical outcomes of these patients., Methods: We examined 49 patients receiving neoadjuvant chemotherapy and subsequent surgery with lymph node metastasis. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 were all immunohistochemically evaluated in core needle biopsy samples from primary and metastatic tumors following chemotherapy., Results: No statistically significant differences in these markers were detected between the primary tumor and metastatic lymph nodes following therapy, but the Ki-67 labeling index was significantly higher in metastatic lymph nodes than in primary tumor (p = 0.017). The patients associated with luminal A type carcinoma in their lymph nodes following chemotherapy demonstrated significantly better clinical outcomes (disease-free survival: p = 0.0045, overall survival: p = 0.0006) than those who were not., Conclusion: These data indicate that subtype classification following chemotherapy, in the metastatic lymph nodes rather than primary tumor could predict long-term outcomes of patients undergoing neoadjuvant chemotherapy.

Monocytes and kidney-resident macrophages are considered to be involved in the pathogenesis of renal ischemia-reperfusion injury (IRI). Several subsets of monocytes and macrophages are localized in the injured tissue, but the pathologic roles of these cells are not fully understood. Here, we show that CD169(+) monocytes and macrophages have a critical role in preventing excessive inflammation in IRI by downregulating intercellular adhesion molecule-1 (ICAM-1) expression on vascular endothelial cells. Mice depleted of CD169(+) cells showed enhanced endothelial ICAM-1 expression and developed irreversible renal damage associated with infiltration of a large number of neutrophils. The perivascular localization of CD169(+) monocytes and macrophages indicated direct interaction with blood vessels, and coculture experiments showed that the direct interaction of CD169(+) cell-depleted peripheral blood leukocytes augments the expression levels of ICAM-1 on endothelial cells. Notably, the transfer of Ly6C(lo) monocytes into CD169(+) cell-depleted mice rescued the mice from lethal renal injury and normalized renal ICAM-1 expression levels, indicating that the Ly6C(lo) subset of CD169(+) monocytes has a major role in the regulation of inflammation. Our findings highlight the previously unknown role of CD169(+) monocytes and macrophages in the maintenance of vascular homeostasis and provide new approaches to the treatment of renal IRI., (Copyright © 2015 by the American Society of Nephrology.)

Purpose: A number of studies have reported on decline in glomerular filtration rate (GFR) after donation in Japanese living kidney donors. The purpose of the present study was to examine the clinicopathological factors associated with changes in GFR after donation in living kidney donors., Methods: We reviewed the charts of living kidney donors (n = 294) and monitored estimated GFR (eGFR) values from the time of 0-h kidney biopsy until 3 years after donation. We assessed donor age, gender, body mass index, blood pressure, urinalysis, and several other clinical parameters including the severity of glomerulosclerosis and arteriosclerosis., Results: The grade of arteriosclerosis in 0-h biopsy specimens was higher in the older donor group (57-76 years) than in the younger donor group (30-56 years). Mean donor eGFR at the time of the donation was 80.1 ± 13.6 ml/min/1.73 m(2). Most of the living kidney donors in this study developed stage 3 chronic kidney disease (CKD). The mean changes in eGFR at 1-3 years after donation showed a steady state that was distinct from the generally accepted notion that GFR declines with age. Multivariate regression analyses showed that the changes in eGFR were negatively associated with age (r = -0.21, P < 0.001) and preoperative eGFR (r = -0.18, P < 0.001), but not associated with the grade of glomerulosclerosis and arteriosclerosis., Conclusion: Donor age and pre-GFR at the time of nephrectomy were associated with decline in kidney function in living kidney donors after donation. Most of the donors developed stage 3 CKD within 3 years after donation but without subsequent progression, at least for several years.

Objective: Immunoglobulin A nephropathy (IgAN) exhibits a peak onset that coincides with the reproductive age. Therefore, many young women with IgAN may become pregnant. However, the outcome of pregnancy in women with renal diseases remains controversial, and the characteristics and outcome of pregnancy in IgAN patients must be further evaluated., Methods: A prospective follow-up study of 64 pregnant women with IgAN was performed by analyzing the laboratory data and prognosis. To clarify the influence of renal insufficiency, we compared these patients according to the chronic kidney disease (CKD) stage with special attention to CKD stage 3 [N=16 in total, N=9 for estimated glomerular filtration rate (eGFR) ≥45 mL/min, N=7 for <45 mL/min]., Results: We found that pregnancy and delivery did not produce any significant changes in the renal function for patients with CKD stage 3 (≥45 mL/min) at five years after delivery, although proteinuria was elevated at 30 weeks of pregnancy and at three months after delivery. However, only for patients with CKD stage 3 (<45 mL/min) was there a significant deterioration in the eGFR at five years after delivery. Additionally, the data of pregnant women with CKD stage 3 were compared with those of 22 nonpregnant women with similar clinical and demographic characteristics., Conclusion: Pregnant patients with IgAN (CKD stage 3, eGFR ≥45 mL/min) did not exhibit any significant reduction in the renal function at five years after delivery as compared with the baseline, which was similar to the findings in nonpregnant patients. Thus, while pregnancy with CKD stage 3 (eGFR ≥45 mL/min) was not a risk factor, patients with CKD stage 3 (eGFR <45 mL/min) showed a worsened renal function five years after delivery.

Bacteroides is one of the most predominant groups of human gut microbiota. Recent metagenomic analyses and studies on gnotobiotic mice demonstrated the tight association of Bacteroides with epithelial function, the gut immune system and systemic metabolism in the host. The mariner family transposon shows relatively low target site specificity and has hosts ranging from prokaryotes to eukaryotes. Thereby, random mutagenesis using the mariner family transposon is expected to identify key molecules for human-Bacteroides symbiosis. In this study, we constructed the plasmid pMI07 to deliver the gene cassette (ermF/ITR), which harbors the erythromycin resistant marker (ermF) and the inverted repeat sequences (ITRs) recognized by Himar1 transposase, to Bacteroides via electrotransformation. pMI07 successfully delivered ermF/ITR to the Bacteroides genomes and generated thousands of insertion mutants/μg of pMI07 in B. thetaiotaomicron, B. fragilis, B. ovatus, and also, although to a lesser extent, B. vulgatus. Analyses of the ermF/ITR insertion sites in B. thetaiotaomicron and B. vulgatus revealed that the cassette targeted the dinucleotide TA and integrated into the genomes in an unbiased manner. The data reported here will provide useful information for transposon mutagenesis in Bacteroides species, which will enable identification of the genes responsible for their unique phenotypes., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A follow-up questionnaire survey was conducted with 29 cat owners who adopted cats from an animal hospital in Japan. Physical characteristics were found to be important factors for the owners when choosing a cat. There were significant differences between impression of the cat for the owners at present and images of their ideal cats, and the levels of aggression and activeness of the cats at present were rated higher than their ideal cats. A significant negative correlation was found between the degree of satisfaction with the cat and occurrence of house soiling; thus, some behavioral problems may deteriorate the relationship between the owner and the cat.

Background: The renoprotective pleiotropic effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has recently been reported by several investigators. However, the effect of statins on IgA nephropathy (IgAN) is still unknown., Methods: We selected 24 IgAN patients who had newly started statin therapy and were not treated with steroids and immunosuppressive agents during the observation period. We analyzed and compared clinical findings 1 year before and after treatment., Results: Mean age was 50.5 ± 9.91 years and mean blood pressure was 90.9 ± 10.8 mmHg. Renal function was slightly deteriorated, serum creatinine was 1.03 (0.71-1.24) mg/dL and estimated glomerular filtration rate (eGFR) was 55.8 ± 22.8 mL/min. Lipid metabolism was poorly controlled [total cholesterol 247.7 ± 35.7 mg/dL, low-density lipoprotein cholesterol 151.5 (140.8-172.8) mg/dL, and triglyceride 163.0 (126.3-243.8) mg/dL]. Mild urinary abnormality was observed [proteinuria: 0.50 (0.22-1.29) g/g creatinine, urinary red blood cells 1.0 (0.2-5.0) per high power field]. After 1 year of statin treatment, lipid control was significantly better than at baseline. Proteinuria was not significantly decreased but renal function was improved. eGFR changed from a -5.9% decrease to a 2.4% increase (p = 0.0098)., Conclusion: Our results indicated that statins stabilized the renal function of IgAN patients independent of their reduction of proteinuria.

Background: Little is known about the long-term prognosis of patients with IgA nephropathy (IgAN)., Methods: This retrospective cohort analysis evaluated clinical and histological findings at the time of renal biopsy, initial treatment, patient outcomes over 30 years, and risk factors associated with progression in 1,012 patients diagnosed with IgAN at our center since 1974., Results: Of the 1,012 patients, 40.5% were male. Mean patient age was 33±12 years and mean blood pressure was 122±17/75±13 mmHg. Mean serum creatinine concentration was 0.89±0.42 mg/dL, and mean estimated glomerular filtration rate (eGFR) was 78.5±26.2 ml/min/1.73 m2. Mean proteinuria was 1.19±1.61 g/day, and mean urinary red blood cells were 36.6±35.3/high-powered field. Histologically, mesangial hypercellularity was present in 47.6% of patients, endothelial hypercellularity in 44.3%, segmental sclerosis in 74.6%, and tubular atrophy/interstitial fibrosis in 28.8% by Oxford classification. Initial treatment consisted of corticosteroids in 26.9% of patients, renin-angiotensin-aldosterone system inhibitor in 28.9%, and tonsillectomy plus steroids in 11.7%. The 10-, 20-, and 30-year renal survival rates were 84.3, 66.6, and 50.3%, respectively. Tonsillectomy plus steroids dramatically improved renal outcome. Cox multivariate regression analysis showed that higher proteinuria, lower eGFR, and higher uric acid at the time of renal biopsy were independent risk factors for the development of end stage renal disease (ESRD)., Conclusions: IgAN is not a benign disease, with about 50% of patients progressing to ESRD within 30 years despite treatment.

Objectives: The Vasculitis Damage Index (VDI) is used to define the degree of damage occurring in patients with systemic vasculitis. We conducted a retrospective study of 30 patients with microscopic polyangiitis (MPA) and renal-limited vasculitis (RLV)., Methods: The clinical data and VDI of the 30 patients enrolled in the study were collected and assessed for a period of 5 years., Result: The VDI score, which was 2.5 at 1 year after the initial diagnosis, increased gradually to 4.3 at 5 years post-diagnosis. The degrees of musculoskeletal and ocular damage significantly increased during the 5-year period (p = 0.001 and p = 0.002, respectively). The most frequent damage items in the VDI were cataract (13 %), hypertension (12 %), diabetes mellitus (9 %), and osteoporosis (6 %). The VDI score was significantly higher in the groups of patients who showed relapse or MPA than in the groups of patients who did not show relapse or RLV at 5 years (p = 0.02 and p = 0.03, respectively). In addition, a significant correlation was found between the VDI score at 5 years and the Birmingham Vasculitis Activity Score at diagnosis (p = 0.04, r = 0.4)., Conclusion: The VDI was found to be a useful tool for determining the severity of damage caused by disease and the effects of treatment. The individual contributions of the VDI items may also be applied to treatment decisions.

Objectives: To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN., Methods: Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of κ-LCs, λ-LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled., Results: Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary λ-FLC levels were significantly correlated with the urinary protein-creatinine ratio in the class III/IV LN subset (rs = 0.67, P < 0.01). Moreover, the LC-secreting CD19(-)/CD138(+) cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138(+) cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary λ-FLCs could not be detected in any of the patients., Conclusion: The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN.

Androgen receptor and androgen metabolizing enzymes, 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase1 (5α1), are frequently detected in primary tumor of breast cancer, but their status in metastatic lymph nodes has not been examined. The biological role of androgen in breast cancer and its metastatic process also remain unknown. In this study, we used immunohistochemistry to localize the expression of androgen receptor, 17βHSD5, and 5α1 in primary tumors and paired metastatic lymph nodes and correlated the findings with clinicopathologic factors of individual patients. Approximately 70% of primary tumors and paired metastatic lymph nodes expressed androgen receptor, with significant correlation between both lesions. However, 17βHSD5 and 5α1 immunoreactivity was decreased in metastatic lymph nodes. Alone or in tandem with androgen receptor, 5α1 was associated with significantly lower Ki-67 index, lower pathologic grade, and higher estrogen receptor positivity, but androgen receptor/5α1 double positivity in lymph nodes was associated with larger lymph node metastasis and higher TNM stage. In conclusion, androgen receptor immunoreactivity remained stable during the process of metastasis, whereas androgen-metabolizing enzymes decreased. Although results of our study and previous reports imply additional roles of androgen metabolism in the metastasis process, especially conversion by 5α1, there may be divergence between its effects on primary tumor and those in metastatic lymph nodes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Steroid-dependent minimal-change nephrotic syndrome (MCNS) requires administration of prolonged courses of prednisolone (PSL); therefore, a paradigm shift from such toxic 'non-specific' therapies to selective immunomodulating regimens is necessary for these cases., Methods: To assess the therapeutic effects of rituximab (an anti-CD20 antibody) in adult patients with steroid-dependent MCNS, we performed a prospective trial of the effects of a single dose of rituximab administered twice at an interval of 6 months in 25 MCNS patients. We evaluated the biochemical parameters and compared the clinical findings between the 12-month period before and 12-month period after the first rituximab infusion., Results: A significant reduction in the number of relapses and the total dose and the maintenance dose of PSL administered was observed during the 12-month period after the first rituximab infusion when compared with the findings during the 12-month period before the first rituximab infusion [25 (100%) versus 4 (16%), P < 0.001; 8.2 versus 3.3 g, P < 0.001; 26.4 mg/day at baseline versus 1.1 mg/day at 12-month, P < 0.0001]. Complete remission was achieved/maintained in all patients undergoing B-cell depletion. Four of 17 patients with B-cell repletion developed relapse., Conclusions: Our results revealed that rituximab therapy was associated with a reduction in the number of relapses and in the total dose of PSL needed. Therefore, rituximab appears to be a useful therapeutic agent for adult patients with steroid-dependent MCNS. These results suggest that this treatment is rational and should be considered as an important option in the management of adult patients with steroid-dependent MCNS.

Metabolic syndrome (MetS) is a risk factor for the development of diabetes and cardiovascular disease, and recently was linked to incident chronic kidney disease (CKD). The purpose of this study is to examine whether MetS is associated with CKD progression in Japanese at a single center. Outcome variables were a decrease in estimated glomerular filtration rate (eGFR) of 50 % or 25 ml/min/1.73 m(2), end-stage renal disease (ESRD), death, or a composite outcome of all three. There were 213 subjects in the analysis, 40.4 % of whom met the criteria for MetS. The group of subjects with MetS had higher urinary albumin-to-creatinine (UACR) levels. Survival curves stratified by MetS status showed early separation of the curves and a significantly higher survival rate in the group without MetS (P = 0.0086). Comparisons with normoalbuminuria and microalbuminuria showed that macroalbuminuria was equally associated with predicted composite outcome (GFR, ESRD, or death) both in the presence and absence of MetS. Multivariate analyses for all covariates showed that eGFR (hazard ratio (HR) 8.286, 95 % confidence interval (CI) 2.360-28.044, P = 0.0012) and the UACR (HR 2.338, 95 % CI 1.442-3.861, P = 0.0005) at baseline were independently associated with the composite outcomes. The results show that MetS was associated with albuminuria in a cohort of Japanese CKD patients, and both MetS and albuminuria were independently associated with CKD progression.

Purpose: To the best of our knowledge, no study has compared intermittent steroid pulse therapy, according to Pozzi's regimen, with versus without tonsillectomy., Methods: In this retrospective cohort analysis, we compared clinical findings, histological findings according to the Oxford classification, and complete remission rates (RR), defined in terms of urinary protein excretion (U-Prot <0.3 g/g creatinine) and urinary red blood cell count (U-RBC <5/high-power field), after 1 year of treatment in patients with IgA nephropathy (IgAN), who received tonsillectomy with steroid pulse therapy (TSP group, n = 26) or steroid pulse therapy alone (SP group, n = 15)., Results: The baseline clinical and histological characteristics did not differ between the two groups. The RR for U-Prot analyzed by the Kaplan-Meier method did not differ between the groups (76.9 vs. 53.3 %). However, the RR for U-RBC was significantly higher in the TSP than in the SP group (88.4 vs. 33.3 %, log-rank test; P = 0.0008). The RRs for U-Prot and U-RBC were significantly higher in the TSP group than in the SP group (69.2 vs. 13.3 %, log-rank test; P = 0.0019). Cox's regression analysis showed that combination therapy was associated with higher RR (odds ratio, 12.5; 95 % confidence interval, 2.91-86.7; P = 0.0002)., Conclusions: Tonsillectomy combined with steroid pulse therapy achieved higher RR after 1 year of treatment, compared with steroid pulse monotherapy in patients with IgAN. The long-term effects on renal survival should be analyzed in further studies.

We investigated the risk factors for recurrence of IgA nephropathy after kidney transplantation. Of the 184 recipients of allografts for end-stage renal disease caused by primary IgA nephropathy at our institution and affiliated hospitals between 1990 and 2005, 70 developed recurrent IgA nephropathy (group 1), while the remaining 114 did not develop recurrent IgA nephropathy (group 2). The diagnosis of recurrent IgA nephropathy was based on case and/or protocol renal biopsies. We examined the risk factors for recurrence of IgA nephropathy by comparing the two groups. In addition, we also investigated the risk factors for graft loss in the patients with recurrent IgA nephropathy. The recipient's age at transplantation was significantly younger in group 1 than in group 2 (33.4 ± 10.4 vs. 36.7 ± 10.7, P = 0.037). No significant influence of the immunosuppressive regimens used was observed on the likelihood of recurrence of IgA nephropathy. In the analysis of the risk factors for graft loss, the mean age of the donor was significantly higher in the patient group with graft loss (59.1 ± 9.5 vs. 53.9 ± 9.0, P = 0.033), and the serum creatinine level at one year after surgery was also significantly higher in the patient group with graft loss (1.62 ± 0.52 vs. 1.34 ± 0.34, P = 0.022). Recipients with recurrent IgA nephropathy after transplantation, especially younger patients, need to be followed up carefully., (© 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.)

Background: Pathogenesis and clinical prognosis of membranoproliferative glomerulonephritis (MPGN) has not yet been established., Methods: We conducted a retrospective study of 41 patients with MPGN (type I and III) and examined the renal survival. In addition, factors contributing to survival time were analyzed., Results: Fourteen patients (34 %) were classified into the renal death group. Patients with nephrotic syndrome and positive C1q staining of glomerular deposits showed a particularly poor prognosis. Significantly higher frequency of nephrotic syndrome and higher urinary protein excretion were observed in the renal death group (p = 0.0002, p = 0.0002) than in the renal survival group. The intensity of C1q staining was positively correlated with the severity of the proteinuria (p = 0.004). Factors that influenced the survival time were positive C1q staining of glomerular deposits (p = 0.003), presence of nephrotic syndrome (p = 0.004), serum albumin (p = 0.02), and proteinuria (p = 0.04)., Conclusions: C1q staining in glomerular deposits and nephrotic syndrome were important factors influencing the prognosis and outcome in MPGN patients. C1q deposition may play a key role in the pathogenesis of MPGN, as evidenced by numerous observations, such as induction of proteinuria.

Objective: The beneficial effects of renin-angiotensin-aldosterone system inhibitors (RASI) and the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on IgA nephropathy (IgAN) have been reported. However, it is unknown whether these agents have any synergistic interactions., Methods: We divided 38 IgAN patients into two groups: an EPA group (n=18) treated with RASI plus EPA and a DILAZEP group (n=20) treated with RASI plus dilazep dihydrochloride. We analyzed the clinical and histological background of each patient, any relevant clinical findings obtained one year after treatment and any factors significantly related to decreases in proteinuria., Results: The clinical findings were largely similar between the groups, except for body mass index (24.9±4.5 in the EPA group vs. 21.4±2.1 in the DILAZEP group, p=0.0041) and total cholesterol (median: 206.0 vs. 177.5 mg/dL, p=0.0493). The histological findings, evaluated according to the Oxford classification, were also similar between the groups. At one year after treatment, the EPA group demonstrated a significantly decreased mean blood pressure (from 94.7±9.0 to 86.4±7.2 mmHg, p=0.0007) and a significantly decreased median level of proteinuria (from 0.80 to 0.41 g/g creatinine, p<0.001). In the DILAZEP group, the mean blood pressure significantly decreased (from 95.2±13.2 to 88.1±7.7 mmHg, p<0.001) without any significant decrease in the median level of proteinuria (from 0.88 to 0.60 g/g creatinine). According to a multivariate logistic analysis, EPA was found to be the only independent factor related to decreases in proteinuria (odds ratio = 5.073, 95% CI: 1.18-26.7, p=0.0285)., Conclusion: We conclude that EPA accelerates the effects of RASI and thus decreases the proteinuria observed in patients with IgAN.

Objective: IgA nephropathy (IgAN) is widely regarded as a slowly progressive disease. However, a minor population of patients present with a rapidly progressive form of glomerulonephritis (RPGN)., Methods: We studied 25 cases of IgAN who presented with RPGN. The laboratory data, histology, and five-year prognosis after diagnostic renal biopsy were evaluated. We compared the data of these patients with those of 495 patients with the non-RPGN type. In addition, we divided the patients with the RPGN type of IgAN into a group with reduced renal function and a group with maintained renal function, and compared the data between the two groups., Results: In the 'RPGN type', the serum creatinine levels and a 24-hour urinary protein excretion were significantly higher than in the non-RPGN type. Histological examinations showed that the rates of endocapillary hypercellularity and tubular atrophy/interstitial fibrosis were significantly higher in the patients with the RPGN type. In the comparison between the groups with reduced and maintained renal functions, the former group exhibited higher levels of proteinuria, serum creatinine and crescent formation than the latter group., Conclusion: The RPGN type of IgAN was significantly worse in terms of the renal survival rate at five years than the non-RPGN type. Intensive and active treatments are necessary for this minor population, according to the guideline for the management of RPGN.

Kabuki syndrome has long been clinically defined based mainly on its characteristic eye features. The recent discovery of MLL2 as a causative gene of Kabuki syndrome has enabled the extreme end of the phenotype to be explored. We herein report on two patients with striking visible congenital staphyloma at birth. A diagnosis of Kabuki syndrome was subsequently made in both patients based on a constellation of characteristic eye features, cardiac abnormalities and severe developmental delay, and finally by the confirmation of MLL2 mutations. In conclusion, congenital corneal staphyloma is a complication of Kabuki syndrome with MLL2 mutations., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: IgA nephropathy with nephrotic syndrome (nephrotic IgAN) is a rare form of IgAN. Its prognosis and response to steroid therapy are still controversial because the differential diagnosis between nephrotic IgAN and minimal change nephrotic syndrome with IgA depositions is sometimes confused., Methods: In this retrospective cohort analysis, we accurately diagnosed 42 cases of nephrotic IgAN (4.4%) from 954 IgAN patients, according to the Oxford classification. We analyzed the clinical and histological data, prognosis, and response to steroid therapy., Results: In nephrotic IgAN, mean estimated glomerular filtration rate (eGFR) was 51.1 ± 24.6 ml/min, proteinuria was 5.71 ± 2.56 g/day, and urinary red blood cells were 51.0 ± 37.8 high power field. Both active and chronic histological lesions were observed. Cumulative renal survival rate was significantly lower in nephrotic IgAN than in non-nephrotic IgAN (the control group consisted of 47 non-nephrotic IgAN patients diagnosed between 1995 and 1996) (log-rank test: P < 0.0001). The cases with steroid therapy significantly improved their prognosis, though their male-to-female ratio and blood pressure level measured at renal biopsy were significantly lower than in the cases without steroid therapy. Steroid therapy was particularly effective in cases with low-grade tubular atrophy and interstitial fibrosis (T-grade in Oxford classification). Without steroid therapy, lower eGFR and higher T-grade were independent risk factors for severe outcome by multivariate Cox regression., Conclusion: Nephrotic IgAN is a very severe form of IgAN, with renal dysfunction, massive hematuria, and active and chronic histopathological lesions. Renal outcome is severe; however, steroid therapy can improve prognosis in cases with higher eGFR and lower T-grade, according to the Oxford classification.

Background: Blockade of the renin-angiotensin-aldosterone system is a therapeutic mainstay in patients with chronic kidney disease (CKD). However, the renoprotective effect of the novel direct renin inhibitor aliskiren is unknown., Materials and Methods: We performed a prospective study in 10 CKD patients. All 10 patients with persistent proteinuria (urinary protein-to-creatinin ratio 0.3-3.5 g/g), despite good blood pressure control (<130/80 mmHg) with olmesartan, were started on 150 mg/day aliskiren. Clinical parameters were examined before and after 4, 8, 12, and 16 weeks of treatment., Results: Urinary protein-to-creatinine ratio significantly decreased by about 40% at 16 weeks from baseline (P = 0.0002), although estimated glomerular filtration rate and blood pressure did not change throughout the study period. Plasma renin activity also decreased significantly from baseline (P = 0.019), although plasma aldosterone concentration did not change., Conclusions: Aliskiren combined with olmesartan reduces proteinuria in CKD patients.

Lupus nephritis is a common complication of systemic lupus erythematosus (SLE) which is associated with significant morbidity and mortality. The concept of two phases of therapy for lupus nephritis, such as an induction phase and a maintenance phase, is widely accepted. Since the renal involvement in SLE is heterogeneous, the treatment of lupus nephritis is governed by its pathological type and ranges from nonspecific measures, such as maintenance of adequate blood pressure control and blockade of the renin-angiotensin-aldosterone system, to the use of immunosuppressive agents. Cyclophosphamide (CYC) in combination with prednisone has been the standard method of treatment of the proliferative forms of lupus nephritis. However, the high rates of progression to end-stage renal disease coupled with the adverse effects of CYC and prednisone have led to an intensive search for more effective and less toxic therapies for lupus nephritis. We review the options available for the treatment of proliferative and membranous lupus nephritis and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE.

Background: The adaptation of steroid therapy and the effect of renin-angiotensin-aldosterone system inhibitors (RASIs) for advanced immunoglobulin A nephropathy (IgAN) patients with impaired renal function are still controversial., Methods: We divided 63 IgAN patients with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m(2) and proteinuria ≥ 0.5 g/day into two groups: the RASI group (RASI, n = 33), treated with RASIs alone; and the combination group (COMBI, n = 30), treated with corticosteroids and RASIs. We analyzed the clinical and histological background, renal survival rate, and the risk factors for progression., Results: Renal function (mean eGFR: COMBI 46.4 vs. RASI 47.0 ml/min/1.73 m(2)), the amount of proteinuria (median: COMBI 1.39 vs. RASI 1.17 g/g creatinine) and histological backgrounds were not significantly different between the groups, but urinary red blood cells (U-RBCs) were significantly higher in the COMBI group than in the RASI group (median: COMBI 30.0 vs. RASI 10.0 counts/high-power field, P = 0.0171). The serial change in proteinuria did not differ until 5 years after treatment, but U-RBCs were significantly decreased in both groups (P < 0.0001), and eGFR was significantly decreased in the RASI group (P < 0.001) but not in the COMBI group. The results for each year after treatment did not differ significantly between both groups. The renal survival rate was not significantly different between the groups. There was no independent risk factor for progression by Cox regression analysis., Conclusion: Combination therapy with steroids and RASIs was not superior to monotherapy with RASIs for advanced IgAN with impaired renal function.

Focal segmental glomerulosclerosis (FSGS) involves considerable histological heterogeneity in terms of location and quality of the glomerular segmental lesions. The present study investigated the heterogeneity of segmental lesions in each variant of FSGS, determined by the Columbia classification, and its clinical relevance. All glomerular segmental lesions of 80 cases of primary FSGS were evaluated histologically based on location [tip (TIP), perihilar (PH), or not otherwise specified (NOS)], and quality (cellular or fibrous). Among the 1,299 glomeruli of the 80 biopsy specimens, 210 glomeruli (16.2%) had segmental lesions, comprising 57 (27%) cellular TIP, 4 (2%) fibrous TIP, 42 (20%) cellular NOS, 86 (41%) fibrous NOS, and 21 (10%) fibrous PH lesions. Each case was also classified into one of the five histological variants of the Columbia classification: collapsing (COL), TIP, cellular (CEL), PH, or NOS. Overlap of segmental lesions in different location categories was seen in the COL, TIP, and PH variants, and heterogeneity of quality was apparent in the COL and CEL variants. Histological findings of the CEL variant (endocapillary hypercellularity) were observed in nine of the 13 COL variants. Both location and quality correlated with disease duration, degree of proteinuria, and histological severity of global glomerular sclerosis and tubulo-interstitial lesions. These results demonstrated the histological heterogeneity of glomerular segmental lesions in all variants of the Columbia classification, except NOS. However, the fidelity of location and dominance of histological features were generally conserved in the TIP and PH variants. The COL and CEL variants warrant further investigation because of their overlapping histological findings and apparent histological heterogeneity in the glomerular segmental lesions.

We present two cases with steroid-resistant nephrotic syndrome (SRNS) and two cases with steroid-dependent nephrotic syndrome (SDNS) due to focal segmental glomerulonephritis (FSGS) who were treated with a single dose of rituximab (375 mg/m(2)). Although the two cases with SRNS showed no response, the two cases with SDNS achieved complete remission. The patients in whom the peripheral B-cell counts subsequently increased after the administration of rituximab demonstrated a relapse. Rituximab may be an effective treatment agent for SDNS with FSGS and the peripheral B-cell count may be a useful marker in such patients for preventing disease relapse.

Objective: We conducted a cohort study to identify the risk factors for vitamin D deficiency in predialyzed patients with chronic kidney disease (CKD)., Methods: An observational study of 135 outpatients with stage 3-5 CKD was undertaken. Clinical and biochemical parameters were analyzed in terms of nutritional status, inflammation, and mineral metabolism in relation to serum levels of 25-hydroxyvitamin D [25(OH)D]. Levels of 25(OH)D lower than 15 ng/mL were considered to be deficient., Results: The 25(OH)D-deficient group had a higher body mass index (24.1±4.2 kg/m(2) vs. 22.5±4.0 kg/m(2), p=0.0322), and had more diabetic patients (27.9% vs. 3.6%, p=0.0003). The multivariate analysis revealed that body mass index (odds ratio=2.758; 95% CI, 1.048-7.721; p=0.0398), the presence of diabetes (odds ratio=7.792; 95% CI, 1.808-55.439; p=0.0043), lower hemoglobin concentration (odds ratio=0.297; 95% CI, 0.099-8.732; p=0.821), higher serum levels of non-HDL cholesterol (odds ratio=3.570; 95% CI, 1.449-9.442; p=0.0053) and triglyceride (odds ratio=2.447; 95% CI, 0.779-1.776; p=0.0258) were the factors associated with low 25(OH)D levels., Conclusion: Vitamin D deficiency was common among the predialysis CKD patients, and the factors identified as being associated with vitamin D deficiency were diabetes and obesity.

Background: There are few reports analyzing the effects of angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) on the long-term renal survival of advanced immunoglobulin A nephropathy (IgAN) patients., Patients and Methods: In this retrospective cohort analysis, we divided 66 IgAN patients with an estimated glomerular filtration rate (eGFR) <60 ml/min into three groups: ACEI group (n = 20, treated with ACEIs), ARB group (n = 23, treated with ARBs), and control group (n = 23, treated with antiplatelet agents), and analyzed the clinical and histological background, renal survival rate until the primary endpoint of 50% decrease of eGFR from baseline, and the secondary endpoint of progression to end-stage renal disease, and the risk factors for progression., Results: The clinical and histological background without serum IgA and C3 were not significantly different among the three groups. The renal survival rate until the primary and secondary endpoints was significantly higher in the ACEI and ARB groups than in the control group. The independent risk factors for progression were higher mean blood pressure (hazard ratio [HR] 1.76, P = 0.04), higher histological grade (HR 2.54, P = 0.0184) at baseline, and without ACEIs or ARBs (HR 7.09, P = 0.001), but decreased proteinuria and blood pressure. The risk factors with resistance to ACEIs or ARBs were higher blood pressure and lower eGFR at baseline. There was no difference regarding the survival rate and the risk for progression between ACEI s and ARBs., Conclusion: ACEIs or ARBs were effective for long-term renal survival of advanced IgAN, although proteinuria and blood pressure did not decrease.

Background: We reported that nephrin is phosphorylated at Y1204 and Y1228 under normal conditions and that the phosphorylation is decreased in puromycin nephrosis and in human minimal change nephrosis. These results indicate that the phosphorylation of nephrin is important for maintaining normal podocyte function. However, little is known about the regulation of nephrin phosphorylation. Here, we investigated whether glucocorticoid, a drug used to treat glomerular diseases with proteinuria, might affect the phosphorylation of nephrin., Methods: Human cultured podocytes transiently expressing human nephrin were treated with dexamethasone (Dex), and the phosphorylation of nephrin was determined by immunoblot with the anti-pY1228 antibody., Results: Dex treatment for 24 h increased the phosphorylation of nephrin; this increased phosphorylation was inhibited by the glucocorticoid receptor antagonist but not by the mineral corticoid receptor antagonist. A shorter incubation time (30 min) did not increase the phosphorylation, and actinomycin D and cycloheximide treatments abolished the increased phosphorylation. The activation of Src-family kinases was correlated with nephrin phosphorylation, both of which were abolished by small interfering RNA (siRNA) treatment for serum/glucocorticoid-induced kinase 1 (SGK1)., Conclusions: These results clarify a novel action of glucocorticoid on nephrin phosphorylation through SGK1. Glucocorticoid treatment for human glomerulonephritis may exert its function by regulating the phosphorylation of nephrin.

Barttin, a gene product of BSND, is one of four genes responsible for Bartter syndrome. Coexpression of barttin with ClC-K chloride channels dramatically induces the expression of ClC-K current via insertion of ClC-K-barttin complexes into plasma membranes. We previously showed that stably expressed R8L barttin, a disease-causing missense mutant, is retained in the endoplasmic reticulum (ER) of Madin-Darby canine kidney (MDCK) cells, with the barttin β-subunit remaining bound to ClC-K α-subunits (Hayama A, Rai T, Sasaki S, Uchida S. Histochem Cell Biol 119: 485-493, 2003). However, transient expression of R8L barttin in MDCK cells was reported to impair ClC-K channel function without affecting its subcellular localization. To investigate the pathogenesis in vivo, we generated a knockin mouse model of Bartter syndrome that carries the R8L mutation. These mice display disease-like phenotypes (hypokalemia, metabolic alkalosis, and decreased NaCl reabsorption in distal tubules) under a low-salt diet. Immunofluorescence and immunoelectron microscopy revealed that the plasma membrane localization of both R8L barttin and the ClC-K channel was impaired in these mice, and transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) as well as thiazide-sensitive chloride clearance were significantly reduced. This reduction in transepithelial chloride transport in tAL, which is totally dependent on ClC-K1/barttin, correlated well with the reduction in the amount of R8L barttin localized to plasma membranes. These results suggest that the major cause of Bartter syndrome type IV caused by R8L barttin mutation is its aberrant intracellular localization.

Congenital heart defects (CHDs) occur in 0.5-1% of live births, yet the underlying genetic etiology remains mostly unknown. Recently, a new source of myocardial cells, namely the second heart field (SHF), was discovered in the splanchnic mesoderm. Abnormal development of the SHF leads to a spectrum of outflow tract defects, such as persistent truncus arteriosus and tetralogy of Fallot. Intracellular Ca(2+) signaling is known to be essential for many aspects of heart biology including heart development, but its role in the SHF is uncertain. Here, we analyzed mice deficient for genes encoding inositol 1,4,5-trisphosphate receptors (IP(3)Rs), which are intracellular Ca(2+) release channels on the endo/sarcoplasmic reticulum that mediate Ca(2+) mobilization. Mouse embryos that are double mutant for IP(3)R type 1 and type 3 (IP(3)R1(-/-)IP(3)R3(-/-)) show hypoplasia of the outflow tract and the right ventricle, reduced expression of specific molecular markers and enhanced apoptosis of mesodermal cells in the SHF. Gene expression analyses suggest that IP(3)R-mediated Ca(2+) signaling may involve, at least in part, the Mef2C-Smyd1 pathway, a transcriptional cascade essential for the SHF. These data reveal that IP(3)R type 1 and type 3 may play a redundant role in the development of the SHF., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Initial reports claim that WNK4 localization is mainly at intercellular junctions of distal convoluted tubules (DCT) and cortical collecting ducts (CCD) in the kidney. However, we recently clarified the major targets of WNK4 kinase to be the OSR1/SPAK kinases and the Na-Cl co-transporter (NCC), an apical membrane protein in the DCT, thus raising the question of whether the cellular localization of WNK4 is at intercellular junctions. In this study, we re-evaluate the intrarenal and intracellular immunolocalization of WNK4 in the mouse kidney using a newly generated anti-WNK4 antibody. By performing double immunofluorescence of WNK4 with several nephron-segment-specific markers, we have found that WNK4 is present in podocytes in glomeruli, the cortical thick ascending limb of Henle's loop including macula densa, and the medullary collecting ducts (MCD), in addition to the previously identified nephron segments, i.e., DCT and CCD. These results are consistent with the finding that WNK4 constitutes a kinase cascade with OSR1/SPAK and NCC in the DCT, and highlights a novel role for WNK4 in nephron segments newly identified as being WNK4-positive in this study.

Aims: The aim of this study was to demonstrate expression of cell membrane invagination 'caveolae' in glomeruli and to correlate this with functional and structural characteristics of the human glomerular diseases., Methods: The expression of caveolin-1 (Cav-1), which is the main component of caveolae, was examined in the glomeruli, and the relationship between Cav-1 expression and pathological and clinical findings was determined in 99 patients with glomerular disease and in 50 renal transplantation donors as controls., Results: Cav-1 was expressed very weakly in the controls, and the area of Cav-1 expression relative to the total glomerular area was 0.57±0.65%. However, the area of Cav-1 expression was significantly larger in each glomerular disease (IgA nephropathy, 1.05±1.36%, p<0.05; crescent glomerulonephritis, 1.86±1.19%, p<0.001; minimal change disease, 2.38±1.24%, p<0.001; focal segmental glomerulosclerosis, 2.88±2.05%, p<0.01; membranous nephritis, 4.27±2.95%, p<0.001; membranoproliferative glomerulonephritis, 4.49±3.15%, p<0.001; and diabetic nephropathy, 2.45±1.52%, p<0.001; compared with the controls. Cav-1 expression was significantly decreased in glomerular disease treated with steroids. Co-localisation of Cav-1 and the endothelial marker 'pathologische anatomie leiden-endothelium' was prominent in an immunofluorescence study, and caveolae on the glomerular endothelial cells were observed in electron microscopy., Conclusions: The expression of Cav-1 was significantly increased in the glomeruli of patients with glomerular disease, and it was related to urinary albumin excretion. Cav-1 expression and caveolae were observed in glomerular endothelial cells. It is hypothesised that they play a role in the recovery phase of capillary injury or endocytosis of albumin into endothelial cells. Basic research should be performed to elucidate the role played by Cav-1 and caveolae.