The prognosis of subjects showing a reduced estimated glomerular filtration rate without albuminuria in Japanese patients with type 2 diabetes: a cohort study for diabetic kidney disease.

BACKGROUND: To determine the renal and cardiovascular prognosis and all-cause mortality of Japanese patients with type 2 diabetes showing a reduced estimated glomerular filtration rate (eGFR) without albuminuria. METHODS: A population of 675 patients with type 2 diabetes was prospectively observed for 4 years to determine the renal and cardiovascular outcomes and mortality. The subjects were divided into the four groups: those with a preserved eGFR and no albuminuria (n = 306), a preserved eGFR and albuminuria (n = 151), a reduced eGFR and no albuminuria (n = 96), and a reduced eGFR and albuminuria (n = 122). The Cox proportional hazard model and Fine and Gray method were used to assess between-group differences in the risk of mortality and cardiovascular events. RESULTS: In the group with a reduced eGFR, the eGFR value did not significantly change in the subjects without albuminuria (0 ± 8 mL/min/1.73 m2), whereas it decreased continuously in those with albuminuria (-6 ± 12 mL/min/1.73 m2). The incidence of cardiovascular events was significantly (P = 0.03) higher in the subjects with albuminuria (17%) than those without albuminuria (7%) in the group with a reduced eGFR. Cardiovascular events were significantly (P < 0.01) more frequent in the group with a reduced eGFR than in those with a preserved eGFR in both subjects with and without albuminuria. CONCLUSIONS: The risk of end-stage kidney disease in non-albuminuric subjects with a reduced eGFR is considered to be low. We should focus on cardiovascular prognosis, because these patients are still at high risk of cardiovascular events, even though the prognosis is better in comparison to albuminuric patients.

Prevalence of Fabry disease in dialysis patients: Japan Fabry disease screening study (J-FAST).

BACKGROUND: In Fabry disease, progressive glycolipid accumulation leads to damage in kidney and other organs. This study was designed to determine the prevalence rate of Fabry disease in Japanese dialysis patients. METHODS: All dialysis patients agreeing to Japan Fabry disease screening study (J-FAST) with informed consent were selected except for Fabry disease. The screening was performed by a method of measuring plasma and/or leukocytes lysosomal α-galactosidase A protein level and α-galactosidase A activity. If positive, genetic analysis was carried out upon patient's agreement. RESULTS: J-FAST dealt with 8547 patients (male 5408, female 3139). At the tertiary examination, 26 out of 8547 patients were found to be positive. Six out of 26 patients could not accept genetic analysis because of death. Remaining 20 patients agreed with genetic analysis; then 2 patients (male 2, female 0) had a variation of the α-Gal gene and 11 patients showed E66Q variations. Therefore, the frequency of Fabry disease in J-FAST was 0.04 % (2/5408) in males and 0 % (0/3139) in females, and then 0.02 % (2/8547) in all patients. The presumptive clinical diagnoses of end-stage kidney disease (ESKD) were 10 chronic glomerulonephritis, 7 diabetic nephropathy, 3 unknown etiology, 3 nephrosclerosis, 1 gouty nephropathy, 1 autosomal dominant polycystic kidney disease and 1 renal tuberculosis among 26 tertiary positive patients. Two male Fabry patients were initially diagnosed as nephrosclerosis and chronic glomerulonephritis. CONCLUSIONS: The prevalence rate of Fabry disease in J-FAST was 0.02 %. Moreover, Fabry disease could not be ruled out as the clinical diagnosis of ESKD.

Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10.

Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1ß, IL-6, transforming growth factor-ß1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.

ASC in renal collecting duct epithelial cells contributes to inflammation and injury after unilateral ureteral obstruction.

Inflammation plays a crucial role in the pathophysiological characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a multiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X7-potassium efflux and reactive oxygen species-dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.

Validation of the Japanese histologic classification 2013 of immunoglobulin A nephropathy for prediction of long-term prognosis in a Japanese single-center cohort.

BACKGROUND: A new Japanese histologic classification (JHC) of immunoglobulin A nephropathy (IgAN) for prediction of long-term prognosis was proposed in 2013. The goal of this study was to validate the JHC system in a Japanese single-center cohort. METHODS: A retrospective study was conducted in 198 Japanese adult patients with IgAN. Clinical findings including blood pressure, urinary protein, estimated glomerular filtration rate (eGFR), and outcomes were evaluated in these patients. The glomerular lesion percentage score (GLPS) [number of glomeruli with cellular crescents, fibrocellular crescents, global sclerosis, segmental sclerosis, or fibrous crescents/number of total obtained glomeruli × 100 (%)] was assessed in each patient and categorized into histologic grades (HGs) of HG1 (<25 %), HG2 (25-49 %), and HG3/4 (≥50 %). Associations of GLPS (HG) with disease progression (50 % eGFR decline or end-stage renal disease requiring dialysis) within 10 years after biopsy and the rate of annual eGFR decline were examined. RESULTS: During a median follow-up period of 12.0 years after biopsy, disease progression occurred in 12.8 % (12/94) of HG1 patients, 32.3 % (21/65) of HG2 patients, and 46.2 % (18/39) of HG3/4 patients. The risk of disease progression was significantly higher in the HG2 and HG3/4 groups than in the HG1 group (odds ratios: 3.3 and 5.9 vs. 1). A higher GLPS was significantly associated with a higher risk of disease progression and a greater annual eGFR decline. CONCLUSION: The newly proposed JHC system 2013 based on GLPS (HG) was well correlated with long-term prognosis in our cohort of Japanese adult patients with IgAN.

[Comparison of benefits to non-dialysis CKD patients between darbepoetin alpha and epoetin beta pegol].

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients. METHODS: This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated. RESULTS: No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA. CONCLUSIONS: It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Peritoneal fibrosis induced by intraperitoneal methylglyoxal injection: the role of concurrent renal dysfunction.

BACKGROUND: Peritoneal fibrosis (PF) is a serious pathophysiology of peritoneal dialysis (PD). An ongoing focus of research is the potential fibrogenic nature of methylglyoxal (MGO) in conventional PD fluid (PDF). The aim of the current study was to explore the effects of the uremic milieu on the promotion of PF by MGO using rats with adenine-induced renal failure (RF). METHODS: Adenine-treated Sprague-Dawley rats were randomly assigned to receive continuous peritoneal injections of PDF with or without MGO for three weeks or were left untreated for the same duration. Rats without RF were also assigned to three groups. The peritoneal histology and expression levels of type I collagen, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (αSMA), Snail, matrix metalloproteinase-2 (MMP-2), advanced glycation end-products (AGEs) and the receptor for AGE (RAGE) were then analyzed. RESULTS: Peritoneal treatment with 5 mM MGO accelerated the fibrous peritoneal thickening progression promoted by exposure to standard PDF in the rats with RF, but not in the rats with a normal renal function. Treatment with MGO significantly augmented the proliferation of mesenchymal-like mesothelial cells, accumulation of AGE, de novo expression of αSMA and RAGE and gene expression of type I collagen, TGF-ß1, Snail and MMP-2, whereas both MGO and RF alone had, at most, marginal effects on the changes in these biological parameters. CONCLUSIONS: In the present study, the adverse effects of MGO on the peritoneum became more prominent under conditions of a uremic milieu. These findings imply that MGO and uremia act cooperatively to induce PF.

Fabry disease: experience of screening dialysis patients for Fabry disease.

The prevalence rate for Fabry disease is conventionally considered to be 1 case in 40,000; however, due to increased screening accuracy, reports now suggest that prevalence is 1 case in 1,500 among male children, and it is likely that the clinical importance of the condition will increase in the future. In dialysis patients to date, prevalence rates are between 0.16 and 1.2 %. Globotriaosylsphingosine (Lyso-GL-3), which is a substrate of α-galactosidase A (α-Gal A), has surfaced as a new biomarker, and is also effective in the determination and monitoring of the effects of enzyme replacement therapy. In terms of genetic abnormalities, the E66Q mutation has recently become a topic of discussion, and although doubts have been expressed over whether or not it is the gene responsible for Fabry disease, there is still a strong possibility that it is a functional genetic polymorphism. At present, the standard treatment for Fabry disease is enzyme replacement therapy, and in order to overcome the problems involved with this, a method of producing recombinant human α-Gal A using methanol-assimilating yeast, and chemical or medicinal chaperone treatment are of current interest. Migalastat hydrochloride is known as a pharmacological chaperone, but is currently in Phase III global clinical trials. Adding saposin B to modified α-N-acetyl galactosaminidase is also under consideration as a treatment method.

Medication-prescribing patterns of primary care physicians in chronic kidney disease.

BACKGROUND: We investigated the medication-prescribing patterns of primary care physicians in chronic kidney disease (CKD). SUBJECTS AND METHODS: This cross-sectional study included 3,310 medical doctors who graduated from Jichi Medical University. The study instrument was a self-administered questionnaire to investigate their age group, specialty, workplace, existence of a dialysis center at workplace, and their prescription frequencies (high, moderate, low, very low) of the following agents--calcium (Ca) inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonist (ARBs), statins, anti-platelet agents, erythropoietin (Epo), AST-120, vitamin D, and sodium hydrogen carbonate (NaHCO(3)). RESULTS: From a total of 933 responses, 547 (61.0 %) medical doctors prescribed medication for CKD. The prescription frequencies of Ca inhibitors, ACEIs, and ARBs were high (>90 %, high + moderate), those of statins, anti-platelet agents, Epo, and AST-120 were moderate (90-50 %, high + moderate), and those of vitamin D and NaHCO(3) were low (<50 %, high + moderate). The primary care physician's specialty was significantly associated with their prescription frequency of Ca inhibitors (p < 0.01). Their workplace was significantly associated with their prescription frequency of ACEIs (p < 0.01), ARBs (p < 0.01), Epo (p < 0.01) and vitamin D (p < 0.01). The existence of a dialysis center at their workplace was significantly associated with their prescription frequency of Epo (p < 0.01), vitamin D (p < 0.01) and NaHCO(3) (p < 0.01). Their age was not associated with their prescription frequency of any agents. CONCLUSION: Antihypertensives were highly prescribed, and vitamin D and NaHCO(3) were less prescribed by primary care physicians for CKD. There were certain associations between the prescribing patterns of primary care physicians for CKD and their specialty, workplace and the existence of a dialysis center at their workplace.

Clinical impact of albuminuria and glomerular filtration rate on renal and cardiovascular events, and all-cause mortality in Japanese patients with type 2 diabetes.

BACKGROUND: The number of patients suffering from diabetic nephropathy resulting in end-stage kidney disease is increasing worldwide. In clinical settings, there are limited data regarding the impact of the urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR) on renal and cardiovascular outcomes and all-cause mortality. METHODS: We performed a historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers. Risks for renal events (requirement for dialysis or transplantation, or half reduction in eGFR), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), and all-cause mortality were assessed according to UACR and eGFR levels. RESULTS: During follow-up (median 7.0 years, interquartile range 3.0-8.0 years), 419 renal events, 605 cardiovascular events and 236 deaths occurred. The UACR levels increased the risk and the adjusted hazard ratios for these three events. In addition to the effects of UACR levels, eGFR stages significantly increased the adjusted hazard ratios for renal events and all-cause mortality, especially in patients with macroalbuminuria. Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for each event. CONCLUSIONS: Increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality in Japanese patients with type 2 diabetes, whereas the association between high levels of UACR and reduced eGFR was a strong predictor for renal events.

Primary care physicians' own exercise habits influence exercise counseling for patients with chronic kidney disease: a cross-sectional study.

BACKGROUND: The appropriate exercise counseling for chronic kidney disease (CKD) patients is crucial to improve their prognosis. There have been few studies about exercise counseling by primary care physicians for CKD patients. We investigated primary care physicians' exercise counseling practices for CKD patients, and the association of these physicians' own exercise habits with exercise counseling. METHODS: The population of this cross-sectional study was 3310 medical doctors who graduated from Jichi Medical University from 1978 to 2012. The study instrument was a self-administered questionnaire that was mailed in August 2012 to investigate their age class, specialty, workplace, exercise habits, and practices of exercise counseling for CKD. RESULTS: 581 (64.8%) medical doctors practiced the management of CKD among a total of 933 responses. These 581 medical doctors were defined as CKD primary care physicians and their answers were analyzed. CKD primary care physicians' own exercise habits (frequencies and intensities) were as follows: frequencies: daily, 71 (12.1%); ≥ 2-3 times/week, 154 (26.5%); ≥ 1 time/week, 146 (25.1%); and ≤ 1 time/month, 176 (30.2%); intensities: high (≥ 6 Mets), 175 (30.1%); moderate (4-6 Mets), 132 (22.7%); mild (3-4 Mets), 188 (32.3%); very mild (<3 Mets), 47 (8.1%); and none, 37 (6.4%). The CKD primary care physicians' exercise recommendation levels for CKD patients were as follows: high, 31 (5.3%); moderate, 176 (29.7%); low, 256 (44.0%); and none, 92 (15.8%). The CKD primary care physicians' exercise recommendations for CKD patients were significantly related to their own exercise frequency (p < 0.001), but they were not related to their age, specialty, workplace, or exercise intensity. CONCLUSIONS: CKD primary care physicians' exercise recommendation level for CKD patients was limited. In addition, CKD primary care physicians' own exercise habits influenced the exercise counseling for CKD patients. The establishment of guidelines for exercise by CKD patients and their dissemination among primary care physicians are needed.(University Hospital Medical Information Network Clinical Trial Registry. number, UMIN000011803. Registration date, Sep/19/2013).

Association between abnormal myocardial fatty acid metabolism and cardiac-derived death among patients undergoing hemodialysis: results from a cohort study in Japan.

BACKGROUND: Detecting myocardial ischemia in hemodialysis patients is crucial given the high incidence of silent ischemia and the high cardiovascular mortality rates. Abnormal myocardial fatty acid metabolism as determined by imaging with (123)I-labeled BMIPP (ß-methyl iodophenyl-pentadecanoic acid) might be associated with cardiac-derived death in hemodialysis patients. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Asymptomatic hemodialysis patients with one or more cardiovascular risk factors, but without known coronary artery disease, were followed up for 3 years at 48 Japanese hospitals (406 men, 271 women; mean age, 64 years). PREDICTOR: Baseline BMIPP summed scores semiquantified using a 17-segment 5-point system (normal, 0; absent, 4). OUTCOMES: Cardiac-derived death, including cardiac and sudden death. MEASUREMENTS: HRs were estimated using a Cox model for associations between BMIPP summed scores and cardiac-derived death, adjusting for potential confounders of age, sex, body mass index, dialysis duration, and cardiovascular risk factors. RESULTS: Rates of all-cause mortality and cardiac-derived death were 18.5% and 6.8%, respectively. Cardiac-derived death (acute myocardial infarction [n = 10], congestive heart failure [n = 13], arrhythmia [n = 2], valvular heart disease [n = 1], and sudden death [n = 20]) accounted for 36.8% of all-cause deaths. Cardiac-derived death (n = 46) was associated with age, history of heart failure, and BMIPP summed scores of 4 or higher (HR, 2.9; P < 0.001). Three-year cardiac-derived death-free survival rates were 95.7%, 90.6%, and 78.8% when BMIPP summed scores were 3 or lower, 4-8, and 9 or higher, respectively. BMIPP summed score also was a predictor of all-cause death (HR, 1.6; P = 0.009). LIMITATIONS: Sudden death of unknown cause was considered to have been cardiac derived, although a coronary origin was not confirmed. CONCLUSIONS: Abnormal myocardial fatty acid metabolism is associated with cardiac-derived death in hemodialysis patients. BMIPP single-proton emission computed tomography appears clinically useful for predicting cardiac-derived death in this population.

Promoter methylation confers kidney-specific expression of the Klotho gene.

The aging suppressor geneKlotho is predominantly expressed in the kidney irrespective of species. Because Klotho protein is an essential component of an endocrine axis that regulates renal phosphate handling, the kidney-specific expression is biologically relevant; however, little is known about its underlying mechanisms. Here we provide in vitro and in vivo evidence indicating that promoter methylation restricts the expression of the Klotho gene in the kidney. Based on evolutionary conservation and histone methylation patterns, the region up to -1200 bp was defined as a major promoter element of the human Klotho gene. This region displayed promoter activity equally in Klotho-expressing and -nonexpressing cells in transient reporter assays, but the activity was reduced to ∼20% when the constructs were integrated into the chromatin in the latter. Both endogenous and transfected Klotho promoters were 30-40% methylated in Klotho-nonexpressing cells, but unmethylated in Klotho-expressing renal tubular cells. DNA demethylating agents increased Klotho expression 1.5- to 3.0-fold in nonexpressing cells and restored the activity of silenced reporter constructs. Finally, we demonstrated that a severe hypomorphic allele of Klotho had aberrant CpG methylation in kl/kl mice. These findings might be useful in therapeutic intervention for accelerated aging and several complications caused by Klotho down-regulation.

Patients with adult minimal change nephrotic syndrome treated with long-term cyclosporine did not experience a reduction in their eGFR.

BACKGROUND: The long-term efficacy and safety of cyclosporine (CyA) in the treatment of adult minimal change nephrotic syndrome (MCNS) was examined. METHODS: The medical record of 15 patients diagnosed with MCNS by renal biopsy and treated with CyA for at least 2 years were reviewed. RESULTS: The mean administration period of CyA was 78.3 months. The mean CyA dose for the induction period was 2.1 ± 0.9 mg/kg and 1.7 ± 1.0 mg/kg for the maintenance period. The mean dose of prednisolone used during the induction period was 20.3 mg and 2.7 mg during the maintenance. The frequency of MCNS relapse was decreased to 0.5 times/year in patients treated with CyA, compared to treatment without CyA (2.4 times/y). Two cases of mild liver damage and 3 cases of elevated blood pressure were observed during the administration of CyA. These adverse effects improved after reducing the CyA dose or treatment with an antihypertensive agent. A decrease in the estimated glomerular filtraion rate (eGFR) was not associated with long-term CyA use. CONCLUSION: At our institution, patients who were treated for MCNS with CyA for at least 2 years experienced no deterioration in renal function.

The origin of idiopathic renal arteriovenous malformation with giant twin aneurysms.

A 50-year-old female patient who presented with intermittent gross hematuria was referred to our hospital. Three-dimensional computed tomography (3D-CT) revealed a left renal arteriovenous malformation (AVM). Because she declined to undergo additional therapy including surgical treatment, we observed the clinical course of renal AVM for 7 years using 3DCT. When the 3D-CT showed gradual enlargement of the aneurysms concurrent with the onset of clinical symptoms (cardiomegaly and hypertension), we performed simple left nephrectomy. After the operation, the cardiomegaly and hypertension returned to normal, and gross hematuria did not recur. Based on the macro-anatomical findings of the resected kidney and the observation of the natural course, this case strongly supported the hypothesis that the renal AVM had existed from birth and enlarged gradually to eventually produce the typical signs and symptoms.

Japan Diabetic Nephropathy Cohort Study: study design, methods, and implementation.

BACKGROUND: Diabetic nephropathy, leading to end-stage renal disease, has a considerable impact on public health and the social economy. However, there are few national registries of diabetic nephropathy in Japan. The aims of this prospective cohort study are to obtain clinical data and urine samples for revising the clinical staging of diabetic nephropathy, and developing new diagnostic markers for early diabetic nephropathy. METHODS: The Japanese Society of Nephrology established a nationwide, web-based, and prospective registry system. On the system, there are two basic registries; the Japan Renal Biopsy Registry (JRBR), and the Japan Kidney Disease Registry (JKDR). In addition to the two basic registries, we established a new prospective registry to the system; the Japan Diabetic Nephropathy Cohort Study (JDNCS), which collected physical and laboratory data. RESULTS: We analyzed the data of 321 participants (106 female, 215 male; average age 65 years) in the JDNCS. Systolic and diastolic blood pressure was 130.1 and 72.3 mmHg, respectively. Median estimated glomerular filtration rate (eGFR) was 33.3 ml/min/1.73 m(2). Proteinuria was 1.8 g/gCr, and serum levels of albumin were 3.6 g/dl. The majority of the JDNCS patients presented with preserved eGFR and low albuminuria or low eGFR and advanced proteinuria. In the JRBR and JKDR registries, 484 and 125 participants, respectively, were enrolled as having diabetes mellitus. In comparison with the JRBR and JKDR registries, the JDNCS was characterized by diabetic patients presenting with low proteinuria with moderately preserved eGFR. CONCLUSIONS: There are few national registries of diabetic nephropathy to evaluate prognosis in Japan. Future analysis of the JDNCS will provide clinical insights into the epidemiology and renal and cardiovascular outcomes of type 2 diabetic patients in Japan.

A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis.

IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63-year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease.

Cetuximab-induced nephrotic syndrome in a case of metastatic rectal cancer.

Proteinuria is common adverse effect that occurs after the use of bevacizumab, but it occurs rarely during administration of cetuximab. We report the first case of nephrotic syndrome induced by cetuximab after completing mFOLFOX6 with bevacizumab followed by sLV5FU2 with bevacizumab for metastatic rectal cancer. Prior to the administration of cetuximab, the patient had never presented proteinuria. After the completion of the loading (400 mg/m(2)) and two subsequent maintenance (250 mg/m(2)) infusions of cetuximab, edema of the lower extremities occurred concomitantly with facial acneiform rash. Based on the laboratory data, diagnosis of nephrotic syndrome was made and secondary diseases of nephrotic syndrome were excluded. Oral administration of prednisolone (0.6 mg/kg/day) was initiated, resulting in no response. The trigger of nephrotic syndrome other than cetuximab was not suggested and attention on occurrence of proteinuria must be devoted to this medicine.

Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules.

Claudin-2 is highly expressed in tight junctions of mouse renal proximal tubules, which possess a leaky epithelium whose unique permeability properties underlie their high rate of NaCl reabsorption. To investigate the role of claudin-2 in paracellular NaCl transport in this nephron segment, we generated knockout mice lacking claudin-2 (Cldn2(-/-)). The Cldn2(-/-) mice displayed normal appearance, activity, growth, and behavior. Light microscopy revealed no gross histological abnormalities in the Cldn2(-/-) kidney. Ultrathin section and freeze-fracture replica electron microscopy revealed that, similar to those of wild types, the proximal tubules of Cldn2(-/-) mice were characterized by poorly developed tight junctions with one or two continuous tight junction strands. In contrast, studies in isolated, perfused S2 segments of proximal tubules showed that net transepithelial reabsorption of Na(+), Cl(-), and water was significantly decreased in Cldn2(-/-) mice and that there was an increase in paracellular shunt resistance without affecting the apical or basolateral membrane resistances. Moreover, deletion of claudin-2 caused a loss of cation (Na(+)) selectivity and therefore relative anion (Cl(-)) selectivity in the proximal tubule paracellular pathway. With free access to water and food, fractional Na(+) and Cl(-) excretions in Cldn2(-/-) mice were similar to those in wild types, but both were greater in Cldn2(-/-) mice after i.v. administration of 2% NaCl. We conclude that claudin-2 constitutes leaky and cation (Na(+))-selective paracellular channels within tight junctions of mouse proximal tubules.

A Case of Diabetic Chorea Secondary to Appetite Loss Due to COVID-19 Vaccination.

A 76-year-old woman with type 2 diabetes mellitus was admitted to our hospital with a complaint of involuntary movements of the limbs and face. Brain MRI demonstrated a bilateral high signal of putamen on the T1 weighted image, and she was diagnosed with diabetic chorea. She took a second dose of the COVID-19 vaccine 28 days before admission and lost her appetite. Consequently, her HbA1c level on admission decreased from 13.5% to 10.0% in 28 days. This case suggests that diabetic chorea could be induced by the rapid amelioration of a hyperglycemic state due to appetite loss after COVID-19 mRNA vaccination.