Search

The National Health Insurance (NHI) special health checkup system in Japan targets the NHI population aged 40–74 years. Since 2015, the Kagawa NHI special health checkup was initiated in a prefecture-wide chronic kidney disease (CKD) initiative, including renal examination as an essential item in NHI health checkups. Here, we aimed to investigate the effects of the prefecture-wide CKD initiative. We conducted a retrospective cohort survey using the Kagawa National Health Insurance database created by the Kagawa National Health Insurance Organization. Results of the NHI health checkup (2015–2019) and prefecture-wide outcomes (2013–2019) were analyzed. The prevalence of CKD among examinees who underwent the NHI health checkup increased from 17.7% in 2015 to 23.2% in 2019. The percentage of examinees who completed a medical visit was 29.4% in 2015. After initiation of the initiative, the NHI health checkup coverage rate increased significantly, from a mean (standard deviation) of 40.8% (0.4%) to 43.2% (1.1%) (p = 0.04). After the start of the CKD initiative, we found an increase in the prevalence of CKD and the NHI health checkup coverage rate.

Spin wave propagation in a magnonic crystal excited at a specific wavenumber was investigated by micromagnetic simulation modelling with meander-shaped antennae. The dispersion relation when excited at wave number k which corresponds to the boundary of the Brillouin zone, shows a pair of strong spots that originate from the magnonic upper and lower bands. When excited at wavenumber slightly offset from k above, additional strong spots appear and it shows intensity nonreciprocity reversal. It can be interpreted in terms of the repeated or reduced zone scheme of the Brillouin zone. These characteristics have the potential for novel control of nonreciprocity.

Background Post-transplantation de novo and recurrent immunoglobulin A (IgA) deposition (IgAD) in the allograft is commonly observed. However, the association between post-transplantation IgAD and reduced allograft function has not been determined. We therefore investigated the association between reduced allograft function and post-transplantation IgAD using serial allograft biopsies. Methods IgAD was retrospectively analyzed in 45 adults who underwent kidney transplantation for chronic glomerulonephritis, including IgA nephropathy, at Kagawa University Hospital. Allograft biopsy samples were obtained from per protocol biopsies obtained 1 and 3 years after transplantation, as well as from episode biopsies. Factors contributing to post-transplantation IgAD were assessed by calculating adjusted odds ratios (AORs) using logistic regression analysis. Results Of the 45 recipients, 18 had post-transplantation allograft IgAD. The estimated glomerular filtration rates (eGFR) 1, 2, and 3 years after transplantation were lower in the recipients with than without IgAD. Urinalysis was normal in 61% of recipients with IgAD. Reduced allograft function (eGFR 2 ) 1 year after transplantation was significantly associated with post-transplantation IgAD (AOR = 34.4 [95% CI = 2.35–502], P = .01). Conversely, blood concentrations of mycophenolic acid and latent IgAD from donor kidneys were not significantly associated with post-transplantation IgAD. Conclusion Reduced allograft function may be associated with post-transplantation IgAD in the allograft.

Objectives Damage and detachment of podocytes and loss into the urine have been implicated in the progression of kidney diseases. The purpose of this study was to investigate the potential role of urine cytology based on SurePath™ combined with immunoenzyme staining using Wilms’ tumour 1 (WT1) antibody as a podocyte marker in the discrimination of normality and non-renal urinary tract disease from kidney disease. Methods Sixty-six patients with kidney disease, 45 patients with lower urinary tract disease and 30 healthy volunteers were examined. Urine cytology slides were prepared using the SurePath method and immunoenzyme stained with WT1 antibody, and the number of WT1-positive cells was counted. Results In kidney disease, WT1-positive cells were found in 33 (50%) of 66 samples. No WT1-positive cells were found in 45 patients with lower urinary tract disease or in 30 healthy volunteers. The positive rates for WT1 varied with disease type, but not significantly: immunoglobulin A (IgA) nephropathy, (14/23); membranous glomerulonephritis, (4/10); Henoch–Schonlein purpura nephritis, (3/5); diabetic glomerulopathy, (5/5); minor glomerular abnormality/minimal change nephrotic syndrome (0/4). Conclusions The results suggest that WT1 immunoenzyme staining of urine cytology can be used to detect some types of kidney disease.

The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the intrarenal activity of the renin-angiotensin system. Little is known about the circadian rhythm of AGT levels in plasma or urine. In this short article, making use of data in plasma and urine of healthy volunteers and patients with chronic kidney diseases, we first report that we were unable to find evidence for a circadian rhythm of AGT under any condition. Next we critically discuss to what degree elevated urinary AGT levels might be considered an independent biomarker that is not simply the non-specific consequence of proteinuria.

In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time-dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations.

The cyclin-dependent kinase inhibitor p21 plays important roles in chronic renal disorders; however, its roles in response to acute renal stress are unclear. Here we evaluated p21 in acute kidney injury and ischemic preconditioning using wild-type and p21 knockout mice that underwent renal ischemia followed by reperfusion. The decline in renal function and histological changes were worse in the knockout than in wild-type mice. Ischemia/reperfusion increased p21 expression in the kidney of wild-type mice compared with sham surgery, suggesting p21 may confer tolerance to ischemia/reperfusion injury. We next tested whether p21 is associated with the protective effect of ischemic preconditioning, an established method to reduce ischemia/reperfusion injury. Ischemic preconditioning attenuated ischemia/reperfusion injury in wild-type but not p21-knockout mice. This preconditioning decreased the number of proliferating tubular cells before but increased them at 24 h after ischemia/reperfusion in the kidneys of wild-type mice. In p21-knockout mice, ischemic preconditioning did not change the number of proliferating cells before but decreased them after ischemia/reperfusion. Ischemic preconditioning increased renal p21 expression and the number of cells in the G1 phase of the cell cycle before ischemia/reperfusion compared with sham surgery. Thus, renal p21 is essential for the beneficial effects of renal ischemic preconditioning. Transient cell cycle arrest induced by ischemic preconditioning by a p21-dependent pathway seems to be important for subsequent tubular cell proliferation after ischemia/reperfusion.

Background. High-normal albuminuria (HNA) is an independent predictor of cardiovascular risk in the generalpopulation. Although hypertensive donor (HTD) candidates with HNA were considered acceptable donors by theAmsterdam Forum 2004, the transplant prognosis of HTDs with HNA has not been determined. Therefore, weinvestigated the transplant prognosis of HTDs with HNA.Methods. We retrospectively analyzed 52 adult living-donor kidney transplants performed at Kagawa UniversityHospital. HNA was defined as albuminuria of 15 to 30 mg/g Cr. Changes in kidney function of donors and recipientswere assessed up to 2 years after transplantation.Results. Overall, 38 donors were normotensive and 14 were hypertensive. Nine of 14 HTDs exhibited HNA beforedonation. More HTDs with HNA had arteriosclerotic vasculopathy or glomerulosclerosis than did normotensivedonors (NTDs). Hypertension and the degree of albuminuria did not affect the donors’ posttransplantation kidneyfunction. The risk of discompensatory changes in kidney function after donation was significantly higher in HTDswith HNA than in NTDs (odds ratio, 10.5; 95% confidence interval, 1.51Y72.9; P=0.02). In multivariate analysis, thecoexistence of hypertension and HNA was not significantly associated with discompensatory changes after donation(adjusted odds ratio, 6.04; 95% confidence interval, 0.19Y192; P=0.31). Recipients of HTDs with HNA had similarallograft survival rates but lower allograft function compared with recipients of NTDs.Conclusions. Although further studies are needed to confirm our results, the short-term prognosis of living-donorkidney transplantation was similar between HTDs with HNA and NTDs.Keywords: High-normal albuminuria, Hypertension, Living-donor kidney transplantation, Marginal donor,Preimplantation kidney biopsy.(Transplantation 2013;00: 00Y00)

Objective It has been reported that hyporesponsiveness to erythropoiesis-stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA. Design and Method We measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI). Results A significant correlation (p280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (≥280) and a high ferritin level (≥100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (

Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality.We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography.The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself.Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.

Background: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient’s kidney function (allograft function) later in life. Methods: We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. Results: Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. Conclusions: The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.

Background Peripheral arterial disease (PAD) is a major complication of haemodialysis (HD), especially in patients with diabetes mellitus. Although previous reports have indicated that low-density lipoprotein apheresis (LDL-A) improves arteriosclerosis in PAD patients, the mechanism by which LDL-A affects PAD is still unclear. In this study, we tested the hypothesis that LDL-A attenuates reactive oxygen species (ROS) production in HD patients with PAD. Methods Twenty HD patients with PAD were investigated in this study. Clinical effects were evaluated by thermography and angiography. Oxidative stress in serum was evaluated by thiobarbituric acid reactive substances (TBARS) and expression of p22phox mRNA. Results Ischaemic symptoms due to PAD were gradually improved in 13 patients (65%) after LDL-A. One session of LDL-A removed approximately 75% of LDL from serum. Some patients exhibited dramatic improvement of severe symptoms of PAD such as skin ulcers after serial performance of LDL-A. The levels of LDL cholesterol, malondialdehyde-modified LDL, high-sensitivity C-reactive protein, vascular endothelial growth factor, international normalized ratio of pro-thrombin time and bradykinin were decreased after a single session of LDL-A, although there were no additional changes after 10 sessions of LDL-A. The levels of fibrinogen and p22phox mRNA were decreased by a single session of LDL-A, and these decreases continued over the entire period of treatment. TBARS was decreased after a course of LDL-A. Conclusions LDL-A improved ischaemic symptoms in HD patients with PAD by reducing ROS production in leucocytes. We conclude that LDL-A is an effective therapy for patients with HD complicated by PAD.

Background Peritoneal mesothelial cells play an important role in peritoneal dialysis and are often exposed to dialysis fluid containing high glucose levels. Loss of peritoneal function is a major complication associated with long-term peritoneal dialysis. In this study, we hypothesized that high glucose levels induce apoptosis, and that insulin attenuates this apoptosis in peritoneal mesothelial cells. To clarify this hypothesis, we examined the effects of insulin on the phosphatidylinositol 3-kinase/Akt signaling pathway and apoptosis in rat peritoneal mesothelial cells. Methods Phosphorylated insulin receptor and Akt were detected by western blot analysis. Apoptosis was evaluated by measuring caspase 3 activity and by TUNNEL staining. Results Insulin (100 nmol/L) increased tyrosine phosphorylation of insulin receptor in peritoneal mesothelial cells. Furthermore, insulin (1-100 nmol/L) dose-dependently stimulated Akt phosphorylation. Treatment with the phosphatidylinositol 3-kinase inhibitors wortmannin (100 nmol/L) and LY294002 (10 micromol/L) attenuated insulin-induced Akt phosphorylation, indicating that insulin phosphorylates Akt via a phosphatidylinositol 3-kinase-dependent pathway. Insulin attenuated caspase 3 activity and decreased the number of TUNNEL-positive cells. The phosphatidylinositol 3-kinase inhibitors and overexpression of a dominant-negative mutant of Akt inhibited the effect of insulin on apoptosis. Conclusions The present data indicate that insulin attenuates high glucose-induced apoptosis via the phosphatidylinositol 3-kinase/Akt signaling pathway in peritoneal mesothelial cells. Therefore, the insulin signaling pathway may play a protective role in peritoneal function.

Immune reactive cytokines, such as interferon (IFN)-gamma, have multiple effects in glomerulonephritis. Superoxide anions (O(2)(-)), which are associated with the progression of glomerulonephritis, are mainly generated by nicotinamide adenine dinucleotide phosphate (reduced form) NAD(P)H oxidases. We determined the effects of IFN-gamma on O(2)(-) production, phosphorylation of signal transducer and activator of transcription (STAT)-1alpha, and the mRNA and protein expressions of p22phox and Nox1, components of NAD(P)H oxidases, in human mesangial cells (HMCs). Significant increases in O(2)(-) production with IFN-gamma were completely abolished by the flavin-containing enzyme inhibitor, diphenyleneiodonium (10 micromol/l), and the Janus-activated kinase (JAK)2 inhibitor, AG490 (100 micromol/l). Phosphorylated STAT-1alpha was detected after 5 min of IFN-gamma stimulation using Western blot analysis, and binding to the gamma-activating site was observed from 30 min to 4 h, thereafter by electrophoretic mobility shift assay (EMSA). Super-shift analysis in EMSA revealed that the main transcription factor was STAT-1alpha. IFN-gamma significantly increased the expression of p22phox mRNA and protein, although expression was inhibited by AG490. These data suggest that IFN-gamma stimulates O(2)(-) production in HMCs via the JAK-STAT pathway and NAD(P)H oxidase.

Recent studies have indicated that derangement of peritubular capillary (PTC) circulation with consequent tubulointerstitial hypoxia plays a pivotal role in the pathogenesis of renal injury. The present study was performed to determine whether azelnidipine, a new dihydropyridine calcium channel blocker, attenuates angiotensin II (AngII)-induced peritubular ischemia in anesthetized rats. The superficial PTCs were visualized directly using an intravital fluorescence videomicroscope system, and the PTC blood flow was evaluated by analyzing the velocity of fluorescein isothiocyanate-labeled erythrocytes. Intravenous infusion of AngII (50 ng/kg/min, 10 min) significantly increased mean arterial pressure (MAP) and renal vascular resistance (RVR) (by 35 +/- 3% and 110 +/- 32%, respectively), and decreased total renal blood flow (RBF) and PTC erythrocyte velocity (by -34 +/- 4 and -37 +/- 1%, respectively). Treatment with azelnidipine (5 microg/kg/min i.v., 10 min) had no effect on basal MAP, RBF, RVR, or PTC erythrocyte velocity. However, azelnidipine markedly attenuated the AngII-induced increases in MAP (7 +/- 3%) and RVR (40 +/- 4%) and decreases in RBF (-24 +/- 1%) and PTC erythrocyte velocity (-22 +/- 1%). Similar attenuation in the AngII-induced responses of MAP, RBF, RVR, and PTC erythrocyte velocity were observed in rats treated with a higher dose of azelnidipine (20 microg/kg/min i.v., 10 min), which significantly decreased basal MAP and RVR and increased RBF and PTC erythrocyte velocity. These data suggest that calcium channel blockade attenuates AngII-induced peritubular ischemia, which may be involved in its beneficial effects on renal injury.

SUMMARY: Background: Leptin has been shown to function as an inhibitor of appetite and energy expenditure accelerator. However, it was recently reported that leptin has other important functions as a fibrogenetic factor and a novel, independent risk factor for coronary heart disease. The present study aimed to assess the blood concentration of leptin in acute uraemic rats by using various peritoneal dialysis (PD) solutions. Methods: To induce acute renal failure, the bilateral renal arteries were ligated via a mid-abdominal incision 1 h before starting PD. Rats were divided into four groups: 13.6 g/L glucose-containing dialysate (group L); 38.6 g/L glucose-containing dialysate (group H); 13.6 g/L glucose- and 25 g/L mannitol-containing dialysate with equal osmotic pressure to the dialysate of group H (group M); and renal failure without PD (group F). The concentrations of glucose, urea nitrogen (UN), leptin and insulin were measured at 0, 2 and 4 h after starting PD. Results: We observed significant blood UN suppression in all dialysed groups. Blood glucose was significantly higher in rats treated with the high glucose solution than in those treated with the low glucose solution. Insulin and leptin significantly increased in the high glucose solution group. There was a strong correlation between the blood glucose and insulin levels. We also found a strong correlation between the percentage changes in blood glucose and leptin. The relationship between the percentage changes in insulin and leptin were weak but significant. Conclusion: The high glucose PD solution resulted in increased circulating levels of leptin, glucose, and insulin, suggesting that these changes are linked with PD performed with glucose-based dialysis fluid.

Tadashi Sofue,1 Masashi Inui,2 Taiga Hara,1 Yoko Nishijima,1 Kumiko Moriwaki,1 Yushi Hayashida,3 Nobufumi Ueda,3 Akira Nishiyama,4 Yoshiyuki Kakehi,3 Masakazu Kohno1 1Division of Nephrology and Dialysis, Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Kagawa, 2Department of Urology, Tokyo Women's Medical University, Tokyo, 3Department of Urology, 4Department of Pharmacology, Kagawa University, Kagawa, Japan Background: Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU. Methods: Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (

In the intrarenal renin-angiotensin system, angiotensinogen levels are well known to be increased in diabetes, and these enhanced intrarenal angiotensinogen levels may initiate the development and accelerate the progression of diabetic nephropathy. However, the specific localization of the augmented angiotensinogen in proximal tubule segments in diabetes is still unknown. We investigated the detailed localization of angiotensinogen in 3 proximal tubule segments in the diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. We also prepared OLETF rats treated with angiotensin II type 1 receptor blocker, olmesartan or with a combination of vasodilator agents. Moreover, biopsied samples of human kidney cortex were used to confirm the results of animal studies. We examined the co-localization of angiotensinogen with segment-specific markers by double staining using fluorescence in situ hybridization and/or immunofluorescence. Angiotensinogen mRNA expression was barely detectable in segment 1. In segment 3, the area of angiotensinogen mRNA expression was augmented in the OLETF rats compared with the LETO rats. Angiotensinogen protein expression areas in segments 1 and 3 were also increased in the OLETF rats compared with the LETO rats. Chronic treatment with olmesartan ameliorated these areas of augmented angiotensinogen expression. Biopsied human kidney samples showed similar results. These data suggest that the augmented angiotensinogen mRNA levels in segment 3 and angiotensinogen protein levels in segments 1 and 3 may contribute to the progression of diabetic nephropathy.

Recent basic and clinical data demonstrated that the intrarenal renin-angiotensin system (RAS) plays an important role in the progression of chronic kidney disease (CKD). The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the activity of the RAS in the kidney. We previously reported that the healthy volunteers do not have a circadian rhythm of AGT level in urine (Hypertension. 2011;57:e78) or in plasma (Hypertension. 2012;60:A399). However, the circadian rhythm of AGT level in urine and in plasma in patients with CKD has not been reported yet. Therefore, this study was performed to investigate the circadian rhythm of AGT level in urine and in plasma in patients with CKD. We recruited 6 CKD patients with continuous proteinuria admitted to the Kagawa University Hospital from 06/2011 to 10/2011 for the purpose of diagnostic renal biopsy. Plasma samples were collected at 06:00, 12:00, and 18:00. Urine samples were collected at 06:00, 09:00, 12:00, and 18:00. Plasma renin activities (PRAs), plasma and urinary AGT concentrations, and urinary albumin (Alb) concentration were measured using commercially available kits. The urinary concentrations of AGT and Alb were normalized by the urinary concentration of creatinine (Cr) (UAGT/Cr and UAlb/Cr, respectively). PRA (2.07 +/- 0.77 ng of angiotensin I/mL/hr at 06:00, 2.45 +/- 0.77 at 12:00, and 2.58 +/- 0.76 at 18:00, P = 0.8853) or plasma AGT (19.9 +/- 2.4 μg/mL at 06:00, 24.1 +/- 3.1 at 12:00, and 23.0 +/- 3.9 at 18:00, P = 0.6300) did not show a circadian rhythm. Moreover, UAlb/Cr (511 +/- 319 mg/g Cr at 06:00, 827 +/- 459 at 09:00, 1479 +/- 862 at 12:00, and 1370 +/- 818 at 18:00, P = 0.6964) or UAGT/Cr (54 +/- 22 μg/g Cr at 06:00, 119 +/- 41 at 09:00, 350 +/- 194 at 12:00, and 198 +/- 104 at 18:00, P = 0.3035) did not show a circadian rhythm. In conclusion, in addition to healthy volunteers, patients with CKD do not have a circadian rhythm of AGT level in urine or in plasma.

Background Mineral and bone disorder (MBD) is a major complication of chronic kidney disease and remains a major problem even after kidney transplantation. Although early steroid withdrawal protocols have beneficial effects on mineral and bone metabolism, they are also associated with significantly increased rates of acute allograft rejection (AR). Recently, patients have been treated with early rapid corticosteroid reduction protocols, but it is still unclear whether these protocols reduce the rate of MBD. The aim of this study was to evaluate the effects of early rapid corticosteroid reduction on MBD after kidney transplantation. Methods We retrospectively evaluated 34 adult kidney transplant recipients who were treated with an early rapid corticosteroid reduction protocol. Glucocorticoid treatment was reduced to methylprednisolone 4 mg/d at 1 month after transplantation. Results The AR rate at 3 years after transplantation was 15%. Bone mineral density was slightly decreased in the femur at 4 months after transplantation but returned to the preoperative level by 24 months after transplantation. There was no significant decrease in the bone mineral density of the lumbar spine during the first year after transplantation. Urinary deoxypyridinoline levels and plasma osteocalcin levels returned to the normal range during the follow-up period. Bone mineral density tended to be lower in female patients than male patients and in patients who underwent long-term pretransplant dialysis than those who did not undergo long-term pretransplant dialysis. Conclusion The present study found that MBD was temporary in kidney transplant recipients who were treated with an early rapid corticosteroid reduction protocol and that these patients did not have an increased AR rate.

Others and we showed the increased levels of intrarenal angiotensinogen (AGT) in diabetic humans, mice, and rats. However, the precise localization of the augmented AGT mRNA and protein in proximal tubule segments of kidneys in diabetes remains to be established. To investigate the detailed localization of AGT in 3 proximal tubule segments of the kidneys in diabetes, the Otsuka Long-Evans Tokushima fatty (OLETF) rat (15 weeks) and the age-matched genetic control, the Long-Evans Tokushima Otsuka (LETO) rat were used. Kidney tissues were also prepared from OLETF rats that were administered with angiotensin II type 1 receptor blocker, olmesartan (0.02% in chow) or a combination of vasodilator agents (0.03% hydralazine, 0.006% reserpine, and 0.012% hydrochlorothiazide in chow; HRH). Moreover, biopsied samples of human kidney cortex were obtained by fine-needle aspiration to confirm the below-mentioned results of the rat localization study. Using 3-μm sections of zinc-saturated formalin-fixed paraffin-embedded slides, we examined the co-localization of AGT mRNA or protein with segment-specific protein markers (Segment (S)1-specific anti-sodium glucose cotransporter 2 antibody, S2-specific anti-carbonic anhydrase IV antibody, and S3-specific anti-ecto-adenosine triphosphatase antibody) by double staining using fluorescence in situ hybridization and/or immunofluorescence. AGT mRNA expression was not recognized much in S1 segments of either OLETF or LETO rat kidneys. In S3 segments, the AGT mRNA expression area was augmented in the OLETF rats than in the LETO rats (2.31 ± 0.02-fold; P = 0.0029). AGT protein expression areas in S1 and S3 segments were also increased (8.50 ± 2.78-fold; P = 0.0476, and 3.71 ± 0.83-fold; P = 0.0317, respectively). Chronic treatment with olmesartan, but not with HRH, ameliorated the augmented AGT mRNA and protein expression areas. AGT mRNA and protein expression areas in S2 segments were unchanged in OLETF rats compared with LETO rats. Biopsied samples of human kidney cortex showed the same results as for rat AGT mRNA and protein expression in the S1 and S2 segments. These data suggest that the augmented AGT mRNA in S3 and AGT protein in S1 and S3 play an important role in the development and the progression of diabetic nephropathy.

Diabetic nephropathy is a major complication in type 2 diabetes mellitus and a leading cause of end-stage renal failure.1 The first sign of diabetic nephropathy is the appearance of albumin in the urine (microalbuminuria).2 Although the mechanisms underlying the occurrence of microalbuminuria in type 2 diabetes are extremely complex, the potential role of the renin-angiotensin system has been suggested.3,4,5,6,7,8,9,10,11 Large-scale clinical trials have shown that in hypertensive type 2 diabetic patients with microalbuminuria, lowering blood pressure by blockade of the renin-angiotensin system with angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors is more effective in reducing microalbuminuria than any other conventional antihypertensive therapies.3,4,5,6,7 These findings suggest that the antialbuminuric effects of renin-angiotensin system inhibition are independent of their blood pressure-lowering effects.12 Recently, the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study was conducted to examine if an ARB can prevent the onset of microalbuminuria.13 It has been demonstrated that early treatment with the ARB, olmesartan, significantly reduced the occurrence rate of microalbuminuria in type 2 diabetes patients.14 However, the precise mechanisms by which intensive Ang II blockade during a prediabetic state prevents the occurrence of microalbuminuria are not completely understood. A growing body of evidence has indicated that one of the most important mechanisms in the development of albuminuria is injury to glomerular epithelial cells (podocytes).15,16,17 Therefore, we hypothesized that the beneficial effect of an ARB on the onset of microalbuminuria is associated with its protective effect on podocyte injury. In particular, we aimed to characterize the mechanisms by which microalbuminuria develops in early type 2 diabetic nephropathy by focusing on the heterogeneity of glomerular podocyte abnormalities in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit pathological features of renal injury similar to those found in human type 2 diabetic patients with hypertension, obesity, and hyperinsulinemia.10,11,18,19,20

Intrarenal renin-angiotensin system (RAS) plays an important role for the pathogenesis of renal injuries. Experimental studies have demonstrated that angiotensinogen levels in renal tissues reflect the activity of intrarenal RAS. However, dynamics of urinary angiotensinogen have not been investigated in detail. Therefore, we examined the preservation conditions of the measured values of urinary angiotensinogen concentrations and an ultradian rhythm of urinary angiotensinogen excretion in humans. Urine samples were collected from 24 healthy volunteers. The urinary concentrations of angiotensinogen were measured by using ELISA. Two different urine preservation conditions were examined. One cycle of freeze-and-thaw did not change the measured values of urinary angiotensinogen concentrations. Moreover, to keep urine samples at room temperature for 12 hours did not change the measured values of urinary angiotensinogen concentrations. Thus, preservation conditions do not change the measured values of urinary angiotensinogen concentrations. Regarding an ultradian rhythm, blood pressure and the urinary concentrations of angiotensinogen were measured at 09:00, 13:00, and 16:00. The averaged levels of blood pressure were similar over the time. The average of urinary angiotensinogen/creatinine (Cr) ratios was 8.73 ± 1.15 ng/mg Cr at 09:00, 9.53 ± 1.58 ng/mg Cr at 13:00, and 8.58 ± 1.26 ng/mg Cr at 16:00. The urinary angiotensinogen excretion in healthy volunteers does not have an ultradian change during the daytime (P = 0.482). This may be another indication that the intrarenal RAS is independent of the systemic RAS. We have to pay attention to these findings in handling urine samples for measurements of angiotensinogen.

Objective— We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor. Methods and Results— Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by 3 H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and α-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 μg/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes. Conclusion— Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor–dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia.

Objective Clinical studies indicate that the remission, regression or both of nephrotic-range albuminuria are exerted by angiotensin II receptor blockers (ARBs) in diabetes. The current study was performed to test the hypothesis that these effects of ARBs are associated with regression of glomerular podocyte injury. Methods We examined the effects of an ARB, olmesartan, on glomerular podocyte injury in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty rats with overt albuminuria. Results At baseline (55-week-old), diabetic Otsuka-Long-Evans-Tokushima-Fatty rats showed severe albuminuria with desmin-positive areas (an index of podocyte injury) in both superficial and juxtamedullary glomeruli, and podocyte injury was much greater in juxtamedullary than in superficial glomeruli. At 75-week-old, Otsuka-Long-Evans-Tokushima-Fatty rats had developed more severe albuminuria and superficial glomerular podocyte injury, whereas juxtamedullary glomerular podocyte injury did not advance further. Olmesartan (10 mg/kg per day) decreased albuminuria and superficial glomerular desmin staining to levels that were lower than those at baseline, whereas advanced juxtamedullary glomerular podocyte injury was not changed. Conclusion The current study demonstrates for the first time that juxtamedullary glomerular podocyte injury reaches a severe condition at an earlier time than superficial glomerular podocyte injury during the progression of overt albuminuria in type 2 diabetic rats. Our data also support the hypothesis that the antialbuminuric effects of ARBs are associated with regression of superficial glomerular podocyte injury in type 2 diabetes with nephrotic-range albuminuria.

Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using 3 H-labeled 2-deoxy- d -glucose uptake. Aldosterone (1–100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 μmol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 μmol/L; n=4). Treatment with antioxidants, N -acetylcysteine (10 mmol/L), or ebselen (40 μmol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 μmol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 μmol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.

56歳,女性.遺伝子診断にて淡蒼球ルイ体歯状核赤核変性症(dentaterubral-pallidoluysian atrophy, DRPLA)と診断されていた.ネフローゼ症候群を呈したため,腎生検を施行し巣状糸球体硬化症(focal segmental glomerulosclerosis, FSGS)と診断し,ステロイドパルス療法にて不完全寛解に導入できた. DRPLAは稀な症例であり,過去メサンジウム増殖性糸球体腎炎の合併例が報告されているが, FSGSの合併例は初めてであるので報告した.

Background Early graft thrombosis and bleeding complications remain important causes of early graft loss following kidney transplantation in patients with antiphospholipid syndrome. Anti-β2-glycoprotein I IgG is a disease-specific antibody in patients with antiphospholipid syndrome. Although plasmapheresis is partially effective for antibody removal, the optimal treatment allowing successful transplantation in patients with antiphospholipid syndrome has not been established. This is the first report of a patient with antiphospholipid syndrome who successfully underwent living-donor kidney transplantation following prophylactic plasmapheresis for removal of anti-β2-glycoprotein I IgG. Case presentation A 37-year-old Japanese female was scheduled to undergo a living-donor kidney transplant from her mother. At age 25 years, she experienced renal vein thrombosis, was diagnosed with antiphospholipid syndrome secondary to systemic lupus erythematosus, and was subsequently treated with prednisolone and warfarin. At age 37 years, she was diagnosed with end stage kidney disease, requiring maintenance hemodialysis because of recurrent renal vein thrombosis despite taking anticoagulation therapy. The pretreatment protocol consisted of prophylactic plasmapheresis plus full anticoagulation therapy to counteract the risks of early graft thrombosis. Anticardiolipin and anti-β2-glycoprotein I IgGs were successfully removed by both double filtration plasmapheresis and plasma exchange. The allograft kidney began to function soon after transplantation. No obvious thrombotic complications were observed after transplantation, although anti-β2-glycoprotein I IgG increased to the level observed before plasmapheresis. One year after transplantation, the patient’s kidney function remains stable while receiving anticoagulation therapy as well as a maintenance immunosuppressive regimen. Conclusion Prophylactic plasmapheresis plus full anticoagulation therapy may be an effective strategy in patients with antiphospholipid syndrome undergoing living-donor kidney transplantation.