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1.  Vasopressin and the Regulation of Aquaporin-2 
Clinical and experimental nephrology  2013;17(6):10.1007/s10157-013-0789-5.
Water excretion is regulated in large part through the regulation of the osmotic water permeability of the renal collecting duct epithelium. The water permeability is controlled by vasopressin through regulation of the water channel, aquaporin-2 (AQP2). Two processes contribute: 1) regulation of AQP2 trafficking to the apical plasma membrane; and 2) regulation of the total amount of the AQP2 protein in the cells. Regulation of AQP2 abundance is defective in several water balance disorders including many polyuric disorders and the syndrome of inappropriate antidiuresis (SIADH). Here we review vasopressin signaling in the renal collecting duct that is relevant to the two modes of water permeability regulation.
PMCID: PMC3775849  PMID: 23584881
Vasopressin; trafficking; transcription; polyuria; hyponatremia; SIADH
2.  Overview of the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides 
The nomenclature and classification of vasculitis has been difficult and controversial for many decades. This is problematic for both research on vasculitis as well as clinical care of patients with vasculitis. The first (1994) International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC) proposed names and definitions for the most common forms of vasculitis. Since then, there have been substantial advances in our understanding of vasculitis and changes in medical terminology. In addition, CHCC 1994 did not propose a nomenclature for some relatively common forms of vasculitis, such as vasculitis secondary to other diseases. To address these issues, a second International Chapel Hill Consensus Conference was held in 2012. The goals were to change names and definitions as appropriate, and add important categories of vasculitis not included in CHCC 1994. This overview summarizes the 2012 CHCC and points out the changes compared to the 1994 CHCC. Notable changes include the introduction of new terms such as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and IgA vasculitis, and the inclusion of categories for variable vessel vasculitis and secondary forms of vasculitis.
PMCID: PMC4029362  PMID: 24072416
Vasculitis; classification; Chapel Hill Consensus Conference
3.  A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney 
The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO.
To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks.
CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining.
Furthermore, PCR analysis demonstrated that TGF-β and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis.
We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.
PMCID: PMC4108904  PMID: 22678524
Carbamylated erythropoietin; Remnant kidney; Apoptosis; TGF-β
4.  Mechanisms Stimulating Muscle Wasting in Chronic Kidney Disease: The Roles of the Ubiquitin-Proteasome System and Myostatin 
Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle yielding fragments that are substrates which are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF1 and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting suggesting that therapies which block myostatin could prevent muscle wasting in catabolic conditions.
PMCID: PMC3628947  PMID: 23292175
ubiquitin-proteasome system (UPS); muscle wasting; protein degradation; chronic kidney disease (CKD); caspase-3
5.  Beneficial effect of LDL-apheresis in refractory nephrotic syndrome 
LDL-apheresis is a method to correct dyslipidemia rapidly. It is expected to alleviate the tissue toxicity of persistent dyslipidemia in not only primary, but also in secondary dyslipidemia associated with refractory nephrotic syndrome, and to have a protective effect against glomerular and tubular injury as expected in atherosclerosis. In addition, the effectiveness of LDL-apheresis to promote the remission of nephrotic syndrome has been recognized. In Japan, LDL-A to control hyperlipidemia in patients with refractory nephrotic syndrome associated with focal segmental glomerulosclerosis is covered by national health insurance. Here, the hypothetical mechanism behind its effect and the evidence for its effectiveness over a long period are reviewed.
PMCID: PMC3994285  PMID: 24535024
LDL-apheresis; Nephrotic syndrome; Secondary hyperlipidemia; Lipid nephrotoxicity; Cohort study
6.  The role of a low glomerular density and being overweight in the etiology of proteinuria in CKD patients without known glomerular diseases 
Among the proteinuric patients with chronic kidney disease (CKD) who undergo a renal biopsy, we sometimes encounter those who cannot be classified as having a known primary or secondary glomerular disease. The pathogenesis and pathophysiology of these CKD patients have not been sufficiently elucidated.
We recruited 34 proteinuric patients without known glomerular diseases. The glomerular volumes (GV) of the biopsy specimens from those patients were determined by a morphometric analysis. Glomerular hypertrophy (GH) was defined as having more than 3.6 × 106 μm3. The patients were divided in two groups: those with GH (Group 1) and those without GH (Group 2). We compared the clinical and pathological parameters between Group 1 and Group 2, and among the three groups of patients: non-obese, overweight and obese group.
The patients with Group 1 had significantly higher values for the proportion of males, the body mass index (BMI), uric acid and significantly lower values for the glomerular density (GD). Of note, a multivariate regression analysis revealed that sex, the BMI and GD were significant factors correlated with the mean GV. The values for the mean GV were significantly higher in the overweight and obese groups as compared to the non-obese group, and the values for the GD were significantly lower in the obese group than in the non-obese group.
We identified a subgroup of patients who were characterized as having a high BMI and GV, and a low GD among the proteinuric CKD patients without known glomerular diseases.
PMCID: PMC4271132  PMID: 24509731
Chronic kidney disease; Glomerular hypertrophy; Proteinuria; Overweight; Obesity; Body mass index; Renal biopsy; Glomerular density
7.  Budget impact analysis of chronic kidney disease mass screening test in Japan 
Our recently published cost-effectiveness study on chronic kidney disease mass screening test in Japan evaluated the use of dipstick test, serum creatinine (Cr) assay or both in specific health checkup (SHC). Mandating the use of serum Cr assay additionally, or the continuation of current policy mandating dipstick test only was found cost-effective. This study aims to examine the affordability of previously suggested reforms.
Budget impact analysis was conducted assuming the economic model would be good for 15 years and applying a population projection. Costs expended by social insurers without discounting were counted as budgets.
Annual budget impacts of mass screening compared with do-nothing scenario were calculated as ¥79–¥−1,067 million for dipstick test only, ¥2,505–¥9,235 million for serum Cr assay only and ¥2,517–¥9,251 million for the use of both during a 15-year period. Annual budget impacts associated with the reforms were calculated as ¥975–¥4,129 million for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥963–¥4,113 million for mandating serum Cr assay only and abandoning dipstick test.
Estimated values associated with the reform from ¥963–¥4,129 million per year over 15 years are considerable amounts of money under limited resources. The most impressive finding of this study is the decreasing additional expenditures in dipstick test only scenario. This suggests that current policy which mandates dipstick test only would contain medical care expenditure.
PMCID: PMC4271136  PMID: 24515308
CKD; Budget impact; Dipstick test; Mass screening; Proteinuria; Serum creatinine assay
8.  Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy 
The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity.
We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years.
Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B.
Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.
PMCID: PMC4194014  PMID: 24477513
IgA nephropathy; Disease activity; Underglycosylated IgA; Immune complex; Biomarker
9.  Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout 
Topiroxostat, a selective xanthine oxidase inhibitor, shows effective reduction in the serum urate level in hyperuricemic patients with or without gout. The objective of this study was to evaluate the efficacy and safety of topiroxostat in hyperuricemic stage 3 chronic kidney disease patients with or without gout.
The study design was a 22-week, randomized, multicenter, double-blind study. The enrolled patients were randomly assigned to treatment with topiroxostat 160 mg/day (n = 62) or to the placebo (n = 61). The endpoints were the percent change in the serum urate level, change in the estimated glomerular filtration rate, the urinary albumin-to-creatinine ratio, the proportion of patients with serum urate levels of 356.88 μmol/L or less, blood pressure, and serum adiponectin.
After 22 weeks, although the changes in the estimated glomerular filtration rate and blood pressure were not significant, the percent change in the serum urate level (−45.38 vs. −0.08 %, P < 0.0001) and the percent change in urinary albumin-to-creatinine ratio (−33.0 vs. −6.0 %, P = 0.0092) were found to have decreased in the topiroxostat as compared with the placebo. Although the incidence of ‘alanine aminotransferase increased’ was higher in the topiroxostat, serious adverse event rates were similar in the two groups.
Topiroxostat 160 mg effectively reduced the serum urate level in the hyperuricemic stage 3 chronic kidney disease patients with or without gout.
PMCID: PMC4271138  PMID: 24448692
Hyperuricemia; Gout; CKD; Topiroxostat; FYX-051
10.  Significance of combined cyclosporine−prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial  
Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations.
IMN patients with SRNS (age 16–75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2–3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks.
Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3–1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications.
CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2–3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.
PMCID: PMC4194018  PMID: 24363128
Cyclosporine; Idiopathic membranous nephropathy; Steroid-resistant nephrotic syndrome; Once-a-day administration; Preprandial administration; Therapeutic drug monitoring
11.  Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy  
Dyslipidemia is an independent risk factor for the development and progression of diabetic nephropathy (DN). In this review, we summarize mouse models with both diabetes and dyslipidemia, and their associated complications. We then discuss molecules potentially involved in deterioration of DN by dyslipidemia. We focus especially upon toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), since we have found that their mRNA levels are commonly increased in glomeruli of type 1 (streptozotocin [STZ]-induced) and type 2 (A-ZIP/F-1 lipoatrophic) diabetic mice. Gene expression of MRP8 and Tlr4 is further upregulated during worsening of STZ-induced DN by a high fat diet (HFD). Moreover, these HFD-induced changes are accompanied by enhanced gene expression of CCAAT element binding protein β and phosphorylation of c-Jun N-terminal kinase in the kidney, which have also been reported in pancreatic β cells under diabetic-hyperlipidemic conditions. Effects of a HFD upon DN are cancelled in Tlr4 knockout mice. Macrophages are the predominant source of MRP8 in glomeruli. In cultured macrophages, combinatorial treatment with high glucose and palmitate amplifies MRP8 expression in a Tlr4-dependent manner, and recombinant MRP8 protein markedly increases gene expression of the inflammatory cytokines interleukin-1β and tumor necrosis factor α. Here, we propose ‘macrophage-mediated glucolipotoxicity’ via activation of MRP8/TLR4 signaling as a novel mechanism of pathophysiology for DN.
PMCID: PMC4139582  PMID: 24357461
Diabetic nephropathy; Glucolipotoxicity; Macrophage; Toll-like receptor
12.  Clinical studies of the Research Committee on Intractable Vasculitides, the Ministry of Health, Labour and Welfare of Japan 
In Japan, the Research Committee on Intractable Vasculitides, supported by the Ministry of Health, Labour and Welfare, has been promoting basic and clinical research on vasculitis since 1972. The present Research Committee on Intractable Vasculitides comprises 4 subcommittees under the direction of a Principal Investigator: Basic and Pathological Research Subcommittee, Clinical Research Subcommittee of Small and Medium-sized Vessel Vasculitis, Clinical Research Subcommittee of Large-sized Vessel Vasculitis, and International Cooperation Research Subcommittee. Since 2008, 9 nationwide clinical studies for vasculitis have been conducted and 8 clinical and basic studies are in progress.
PMCID: PMC3824225  PMID: 24091919
Antineutrophil cytoplasmic antibody-associated vasculitis; Eosinophilic granulomatosis with polyangiitis; Granulomatosis with polyangiitis; Microscopic polyangiitis
13.  Estimated glomerular filtration rate and daily amount of urinary protein predict the clinical remission rate of tonsillectomy plus steroid pulse therapy for IgA nephropathy 
This retrospective study was designed to estimate the clinical remission (CR) rate of tonsillectomy plus steroid pulse (TSP) therapy in patients with IgA nephropathy.
Based on 292 of 302 patients with IgA nephropathy treated at 11 Japanese hospitals, we constructed heat maps of the CR rate at 1 year after TSP with the estimated glomerular filtration rate (eGFR), grade of hematuria, pathological grade, number of years from diagnosis until TSP, and age at diagnosis on the vertical axis and the daily amount of urinary protein (urinary protein) on the horizontal axis. We compared subgroups usinge Student’s t test, the chi-square test with Yates correction, or Fisher’s exact probability test.
The first heat map of eGFR and urinary protein showed that the CR rate was 71 % (CR vs. non-CR, 96 vs. 40) in patients with eGFR greater than 30 ml/min/1.73 m2 and 0.3–1.09 g/day of urinary protein. However, the CR rate in patients with more than 1.50 g/day of urinary protein was approximately 30 %. The second heat map of grade of hematuria and urinary protein revealed that the CR rate is 72 % (CR vs. non-CR, 93 vs. 37) in patients with more than 1+ hematuria and 0.3–1.09 g/day of urinary protein; however, it was 28.6 % in patients with no hematuria. The third heat map of pathological grade and urinary protein demonstrated that the highest CR rate was 83 % (CR vs. non-CR, 52 vs. 11) in patients with pathological grade I or II disease and less than 1.09 g/day of urinary protein, as opposed to 22 % (CR vs. non-CR, 9 vs. 32) in patients with pathological grade III or IV disease and more than 2.0 g/day of urinary protein. The fourth heat map of the number of years from diagnosis until TSP and urinary protein revealed that the former did not influence the CR rate in patients with less than 1.09 g/day of urinary protein. However, in patients with more than 1.10 g/day of urinary protein, the CR rate of the subgroup with less than 6 years was 43 % (CR vs. non-CR; 23 vs. 54) compared to 23 % (CR vs. non-CR, 11 vs. 48; P = 0.01) in the subgroup with more than 6 years. The fifth heat map of age at diagnosis and urinary protein showed that the CR rate is approximately 72 % (CR vs. non-CR, 73 vs. 28) in patients older than 19 years at diagnosis with 0.3–1.09 g/day of urinary protein.
The daily amount of urinary protein is an important predictor of the CR rate after TSP in IgA nephropathy patients. Heat maps are useful tools for predicting the CR rate associated with TSP.
PMCID: PMC4139581  PMID: 24052158
Clinical remission; Heat map; IgA nephropathy; Tonsillectomy plus steroid pulse therapy
14.  Safety and efficacy of skin patches containing loxoprofen sodium in diabetic patients with overt nephropathy 
Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy.
Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations.
The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR.
Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.
PMCID: PMC4059959  PMID: 23921417
Skin patches; Loxoprofen; Diabetic nephropathy; Type 2 diabetes; Prostaglandin E2; GFR; NSAIDs
15.  Kidney volume and function in autosomal dominant polycystic kidney disease 
The significance of total kidney volume (TKV) as a biomarker of kidney function in autosomal dominant polycystic kidney disease (ADPKD) is controversial and has been reappraised.
Between 2007 and 2012, 64 patients were followed with a mean 39.7-month observation period. TKV measurements by magnetic resonance imaging and estimation of renal function with estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation and 24-h urine creatinine clearance were repeated annually.
TKV and its adjusted parameters (height-adjusted, body surface area-adjusted and log-converted TKV [log-TKV]) correlated with eGFR significantly. Among them, the correlation coefficient of log-TKV was most significant (r = −0.6688, p < 0.001). The eGFR slope correlated negatively with TKV slope (p < 0.05). TKV increased faster and became larger as chronic kidney disease (CKD) stage advanced. As age advanced, eGFR declined significantly (p < 0.001), but the eGFR slope remained constant. There was no significant correlation between TKV and age, but the log-TKV slope became smaller as age advanced. If baseline TKV was large, the eGFR slope was steeper (p < 0.05), which suggests that eGFR declines faster in patients with larger kidney volume.
TKV is confirmed as a clinically meaningful surrogate marker in ADPKD. Log-TKV correlates with eGFR most significantly. Higher rates of kidney enlargement and larger kidney volume are associated with a more rapid decrease in kidney function. Kidney function decreased faster as CKD stage advanced, but its declining slope did not change significantly by age, at least after ~30 years of age.
PMCID: PMC3923113  PMID: 23864346
Autosomal dominant polycystic kidney disease; Glomerular filtration rate; Kidney volume
16.  Membranoproliferative glomerulonephritis and circulating cryoglobulins 
Previous studies on membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemic glomerulopathy (CG) were based upon case series that were performed before hepatitis C virus (HCV) infection was routinely investigated. Therefore, it remains unknown how far HCV contributes to MPGN or CG, and there have only been a few reports about HCV-negative idiopathic MPGN.
Patients and methods
Thirty-five patients with MPGN diagnosed by renal biopsy who underwent examination for HCV infection at our institute between 1990 and 2008 were recruited for this study. Patients with HCV infection at presentation were included, but patients with complications such as underlying lymphoproliferative disorders, autoimmune diseases like lupus nephritis, infection, and liver disease due to hepatitis B virus or alcohol abuse were excluded. A total of 35 patients were enrolled and they were divided into two groups according to the presence/absence of circulating cryoglobulins (cryo). The 23 patients who had cryo-negative and HCV-negative idiopathic MPGN were divided into subgroups with type 1 and type 3 disease.
In the cryo-positive group (n = 9), 7 patients were positive for HCV infection, while 2 patients were negative. In the cryo-negative group (n = 26), 3 patients were positive for HCV infection, while 23 patients were negative (idiopathic MPGN). Compared with the cryo-negative group, the cryo-positive group had several characteristics such as more severe thrombocytopenia, higher serum immunoglobulin (Ig)G and IgM levels, lower levels of hemolytic complement (CH50) and complement component (C)4, predominant IgM staining, and type 1 histology. Patients with cryo-negative and HCV-negative ‘idiopathic’ MPGN showed predominant staining for IgG in both type 1 and type 3 cases, unlike the predominant staining for IgM in the cryo-positive group. Compared with type 3 cases, type 1 cases had a younger age, lower levels of CH50, C3 and C4, and less proteinuria. In the cryo-positive group, 4 patients (44.4 %) died, with death from B cell lymphoma and liver failure in 2 patients each, while 1 patient (8 %) developed end-stage renal failure requiring dialysis. In contrast, all patients in the cryo-negative group remained alive during follow-up, although 4 patients (2 type 1 cases and 2 type 3 cases) required dialysis.
Cryo-positive MPGN shows a close relationship with HCV infection and IgM, resulting in a poor prognosis. Cryo-negative and HCV-negative idiopathic MPGN has a close relationship with IgG staining, and type 1 cases feature characteristics such as a younger age, more severe hypocomplementemia, and less proteinuria than in type 3 cases.
PMCID: PMC3923107  PMID: 23722669
Membranoproliferative glomerulonephritis; Type 1 and type 3; Type 2;  Cryoglobulin; Cryoglobulinemic glomerulopathy
17.  Epidemiology of vasculitides: differences between Japan, Europe and North America 
The epidemiology of systemic vasculitides differs between Japan, Europe and North America. Takayasu’s arteritis occurs frequently in Japan, unlike giant cell arteritis. A collaborative international study comparing the epidemiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis between Japan and the United Kingdom (UK) demonstrated that microscopic polyangiitis and myeloperoxidase-ANCA were more common in Japan whereas granulomatosis with polyangiitis and pronase 3-ANCA were more common in the UK. These differences may be attributed to differences in latitude and genetic backgounds. These findings provide useful information on the aetiology and pathogenesis of primary systemic vasculitides in various geographical regions.
PMCID: PMC3824199  PMID: 23715862
Microscopic polyangiitis; Granulomatosis with polyangiitis; Takayasu’s arteritis; Giant cell arteritis; Rapidly progressive glomerulonephritis; HLA-DRB1*09:01
18.  Adrenomedullin in peritoneal effluent expressed by peritoneal mesothelial cells 
Adrenomedullin (AM) possesses vasodilative and cell-protective properties. Glycine combines with the C-terminal of AM to form mature, physiologically active AM (mAM). AM is reportedly induced by high glucose condition in vascular endothelial or smooth muscle cells; however, little is known on how AM is activated by amidation. To investigate the behavior of AM in patients undergoing peritoneal dialysis (PD), the concentrations of AM, mAM and CA125 were measured. The mAM to AM ratio (mAM/AM ratio) was also evaluated as a marker of amidation activity.
Twenty patients were recruited for this study. The effluent at the time of the peritoneal equilibration test was collected and AM, mAM and CA125 concentrations were measured. The expression of AM in peritoneal mesothelial cells (PMCs) collected from effluent was also examined with an indirect immunofluorescent method.
Mean values of AM and mAM in effluent were 18.1 ± 1.6 and 4.1 ± 0.3 fmol/mL, respectively. In plasma, they were 42.6 ± 3.3 and 5.6 ± 0.6 fmol/mL, respectively. AM concentrations in effluent did not correlate with plasma AM level but correlated well with the dialysate-to-plasma ratio of creatinine (D/P ratio of creatinine). Moreover, in 7 of 20 cases, concentrations of the mAM and mAM/AM ratio in effluent were higher than in plasma. In effluent, AM concentration but not the mAM/AM ratio correlated with CA125 concentration. Immunocytological study revealed diffuse, cytoplasmic expression of AM in PMCs which were collected from effluent during PD.
AM is expressed by PMCs and actively amidated in the abdominal cavity of patients undergoing PD.
PMCID: PMC3923111  PMID: 23564381
Adrenomedullin; Peritoneal dialysis; Peritoneal mesothelial cells; Amidation
19.  Nationwide survey on current treatments for IgA nephropathy in Japan 
A wide variety of treatments, including tonsillectomy and steroid pulse therapy (TSP), are performed for the various stages of IgA nephropathy (IgAN) in Japan. However, the current status of treatments for IgAN patients in Japan is still unclear. The objective of the present study was to investigate the current status of treatments for IgAN patients.
A nationwide survey was conducted in 2008 by sending questionnaires to the 1,194 teaching hospitals of the Japanese Society of Nephrology (JSN) via Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan.
Among the total 376 hospitals (31.4 %) that responded, 188 hospitals (66.2 % in the internal medicine departments) performed TSP, out of which 137 hospitals (61.4 %) had begun to perform TSP in the period from 2004 to 2008. The following two major steroid pulse protocols in TSP were used: (1) three cycles over 3 consecutive weeks and (2) three cycles every 2 months. Approximately 68 % of pediatric hospitals (68 hospitals) performed combination therapy with prednisolone, azathioprine, heparin-warfarin and dipyridamole. The clinical remission rates for hematuria and proteinuria after TSP tended to be higher than those following other corticosteroid therapies. Almost all hospitals prescribed antiplatelet agents and renin angiotensin system inhibitor (RAS-I).
In addition to popular treatments such as antiplatelet agents and RAS-I, TSP is becoming a standard treatment for adult IgAN patients in Japan.
PMCID: PMC3889220  PMID: 23519367
IgA nephropathy; Nationwide survey; Questionnaire survey; Tonsillectomy and steroid pulse therapy
20.  The role of myeloperoxidase and myeloperoxidase–antineutrophil cytoplasmic antibodies (MPO-ANCAs) in the pathogenesis of human MPO-ANCA-associated glomerulonephritis 
It is well known that antineutrophil cytoplasmic antibodies (ANCAs) are pathogenic and have a diagnostic value for ANCA-associated vasculitis. We demonstrated that a rise in myeloperoxidase (MPO)-ANCA titers during remission is often predictive of a future relapse in MPO-ANCA-associated vasculitis. Pathological examination of renal biopsies indicated that not only MPO-ANCAs, but also extracellular MPO, an in situ immune complex composed of MPO and MPO antibodies, may play important roles in the pathogenesis of glomerular capillary injury in MPO-ANCA-associated vasculitis.
PMCID: PMC3824275  PMID: 23504409
MPO-ANCA-associated glomerulonephritis; Extracellular MPO; MPO-positive cells; In situ immune complex
21.  The effects of tolvaptan on patients with severe chronic kidney disease complicated by congestive heart failure 
Tolvaptan, a diuretic with a new mechanism of action, selectively binds to the vasopressin V2 receptor and inhibits reabsorption of water. Its effect on heart failure is proven, but its benefit for patients with chronic kidney disease (CKD) has not been not confirmed. In this study, we examined the effect of tolvaptan on patients with severe CKD.
We analyzed patients with stage 4 or higher CKD who had congestive heart failure that was resistant to existing diuretics. The patients were administered an initial tolvaptan dose of 7.5 mg/day. We assumed urine volume and urine osmolality to be the main effective endpoint and recorded free water clearance, serum osmolality, serum creatinine (Cr) level, and adverse events.
There was no instance of clinically significant hypernatremia. The urine volume increased significantly (P < 0.0001), as did the urine osmolality (P = 0.0053). Free water clearance showed a tendency to increase, although the difference was not statistically significant. The serum creatinine level did not change significantly, and there was no clear effect on renal function. However, in patients with stage 5 CKD, the serum creatinine level decreased significantly (n = 5, P = 0.0435). There were no adverse events.
We confirmed that tolvaptan has a diuretic effect in patients with both severe CKD and congestive heart failure without causing either clinically significant hypernatremia or an adverse effect on renal function. Tolvaptan is an effective diuretic for patients with CKD.
PMCID: PMC3859890  PMID: 23483323
Tolvaptan; Chronic kidney disease; Diuretic; Congestive heart failure; Renoprotection
22.  Nephrology for the people: Presidential Address at the 42nd Regional Meeting of the Japanese Society of Nephrology in Okinawa 2012 
The social and economic burdens of dialysis are growing worldwide as the number of patients increases. Dialysis is becoming a heavy burden even in developed countries. Thus, preventing end-stage kidney disease is of the utmost importance. Early detection and treatment is recommended because late referral is common, with most chronic kidney disease (CKD) patients remaining asymptomatic until a late stage. Three-quarters of dialysis patients initiated dialysis therapy within 1 year after referral to the facility. Since its introduction in 2002, the definition of CKD has been widely accepted not only by nephrologists but also by other medical specialties, such as cardiologists and general practitioners. Japan has a long history of general screening for school children, university students, and employees of companies and government offices, with everybody asked to participate. The urine test for proteinuria and hematuria is popular among Japanese people; however, the outcomes have not been well studied. We examined the effects of clinical and laboratory data from several sources on survival of dialysis patients and also predictors of developing dialysis from community-based screening (Okinawa Dialysis Study, OKIDS). At an early CKD stage, patients are usually asymptomatic; therefore, regular health checks using a urine dipstick and serum creatinine are recommended. The intervals for follow-up, however, are debatable due to the cost. CKD is a strong risk factor for developing cardiovascular disease and death and also plays an important role in infection and malignancies, particularly in elderly people. People can live longer with healthy kidneys.
PMCID: PMC3751387  PMID: 23392566
Survival; Predictor; Chronic kidney disease (CKD); End-stage kidney disease (ESKD); Proteinuria
23.  Risk factors for increased left ventricular hypertrophy in patients with chronic kidney disease 
Although left ventricular hypertrophy (LVH) has been established as a predictor of cardiovascular events in chronic kidney disease (CKD), the relationship between the prevalence of LVH and CKD stage during the predialysis period has not been fully examined.
We measured left ventricular mass index (LVMI) in a cross-sectional cohort of participants in the Chronic Kidney Disease Japan Cohort (CKD-JAC) study in order to identify factors that are associated with increased LVMI in patients with stage 3–5 CKD. LVH was defined as LVMI > 125 g/m2 in male patients and >110 g/m2 in female patients.
We analyzed baseline characteristics in 1185 participants (male 63.7 %, female 36.3 %). Diabetes mellitus was the underlying disease in 41.3 % of patients, and mean age was 61.8 ± 11.1 years. LVH was detected in 21.7 % of patients at baseline. By multivariate logistic analysis, independent risk factors for LVH were past history of cardiovascular disease (odds ratio [OR] 0.574; 95 % confidence interval [CI] 0.360–0.916; P = 0.020), systolic blood pressure (OR 1.179; 95 % CI 1.021–1.360; P = 0.025), body mass index (OR 1.135; 95 % CI 1.074–1.200; P < 0.001), and serum calcium level (OR 0.589; 95 % CI 0.396–0.876; P = 0.009).
Cross-sectional baseline data from the CKD-JAC study shed light on the association between LVH and risk factors in patients with decreased renal function. Further longitudinal analyses of the CKD-JAC cohort are needed to evaluate the prognostic value of LVH in CKD patients.
PMCID: PMC3824297  PMID: 23318981
Chronic kidney disease; Left ventricular hypertrophy; Hypertension; Body mass index; Albuminuria; Mineral metabolism; Antihypertensive agent
24.  Evaluation of the newly proposed simplified histological classification in Japanese cohorts of myeloperoxidase-anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in comparison with other Asian and European cohorts 
The prognostic value of renal biopsy in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is widely recognized; however, there is no consensus regarding its pathological classification. Berden et al. proposed a new classification of glomerulonephritis in ANCA-associated vasculitis (AAV) categorized into focal, crescentic, mixed, and sclerotic classes and showed its prognostic value in 100 international multicenter cohorts for 1- and 5-year renal outcomes. In order to evaluate whether this new classification has predictive value and reproducibility in Japanese AAV cases, 87 cohorts with only microscopic polyangiitis in 3 limited centers in Japan were analyzed. In addition, those from Japan, Europe (Berden’s cohorts) and China were compared in a recent report.
PMCID: PMC3824231  PMID: 23263238
Anti-neutrophil cytoplasmic antibody; Vasculitis; Renal histology; Glomerulonephritis; Classification; Microscopic polyangiitis; Japan
25.  Profiling of kidney vascular endothelial cell plasma membrane proteins by liquid chromatography–tandem mass spectrometry 
Vascular endothelial cells (VECs) play crucial roles in physiological and pathologic conditions in tissues and organs. Most of these roles are related to VEC plasma membrane proteins. In the kidney, VECs are closely associated with structures and functions; however, plasma membrane proteins in kidney VECs remain to be fully elucidated.
Rat kidneys were perfused with cationic colloidal silica nanoparticles (CCSN) to label the VEC plasma membrane. The CCSN-labeled plasma membrane fraction was collected by gradient ultracentrifugation. The VEC plasma membrane or whole-kidney lysate proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and digested with trypsin in gels for liquid chromatography–tandem mass spectrometry. Enrichment analysis was then performed.
The VEC plasma membrane proteins were purified by the CCSN method with high yield (approximately 20 μg from 1 g of rat kidney). By Mascot search, 582 proteins were identified in the VEC plasma membrane fraction, and 1,205 proteins were identified in the kidney lysate. In addition to 16 VEC marker proteins such as integrin beta-1 and intercellular adhesion molecule-2 (ICAM-2), 8 novel proteins such as Deltex 3-like protein and phosphatidylinositol binding clathrin assembly protein (PICALM) were identified. As expected, many key functions of plasma membranes in general and of endothelial cells in particular (i.e., leukocyte adhesion) were significantly overrepresented in the proteome of CCSN-labeled kidney VEC fraction.
The CCSN method is a reliable technique for isolation of VEC plasma membrane from the kidney, and proteomic analysis followed by bioinformatics revealed the characteristics of in vivo VECs in the kidney.
Electronic supplementary material
The online version of this article (doi:10.1007/s10157-012-0708-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3684716  PMID: 23229650
Vascular endothelial cell plasma membrane; Cationic colloidal silica nanoparticles; Proteomic analysis; Deltex 3-like

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