Chiharu Ito

Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease.

BackgroundKlotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD).MethodsThe levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system.ResultsThe amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r = 0.407, p < 0.01) and the serum Klotho levels (r = 0.232, p < 0.01). However, a stepwise multiple regression analysis identified eGFR to be a variable independently associated only with the log-transformed value of the amount of 24-hr urinary excreted Klotho but not with the log-transformed serum Klotho concentration. Despite the strong correlation between random urine protein-to-creatinine ratio and the 24 hr urinary protein excretion (r = 0.834, p < 0.01), a moderate linear association was observed between the log-transformed value of the amount of 24 hr urinary excreted Klotho and that of the urinary Klotho-to-creatinine ratio (Klotho/Cr) in random urine specimens (r = 0.726, p < 0.01).ConclusionsThe amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully.

Successful gene transfer using adeno-associated virus vectors into the kidney: comparison among adeno-associated virus serotype 1-5 vectors in vitro and in vivo.

Background/Aim: Gene transfer into the kidney has great potential as a novel therapeutic approach. However, an efficient method of gene transfer into the kidney has not been established. We explored the transduction efficiency of renal cells in vitro and in vivo using adeno-associated virus (AAV) serotype 1–5 vectors encoding the β-galactosidase gene. Methods: In the in vitro study, rat kidney epithelial cell line NRK52E cells were transfected with AAV serotype derived vectors. In the in vivo study, AAV serotype derived vectors were selectively injected into the kidney using a catheter-based gene delivery system in rats and mice mimicking the clinical procedure. The efficiency of gene expression was histologically evaluated on the basis of the β-galactosidase expression. Results: AAV serotype 1, 2, and 5 vectors transduced in rat kidney epithelial cell line NRK52E cells in vitro, whereas AAV serotype 3 or 4 vectors showed no transduction. In addition, the kidney-specific injection of AAV serotype 2 vectors successfully transduced in tubular epithelial cells, but not in glomerular, blood vessel, or interstitial cells in vivo, whereas the rest of the serotypes showed no transduction. Conclusion: Since kidney-specific gene delivery via the renal artery by catheterization is highly feasible in humans, these findings provide useful information for promising strategies in renal gene therapy.

Clinical Features of Malignant Hypertension with Thrombotic Microangiopathy

Thrombocytopenia, microangiopathic hemolytic anemia, and elevated serum lactate dehydrogenase (LDH) clinically characterize thrombotic microangiopathy (TMA), which is frequently recognized among patients with malignant hypertension (MH). Sixteen consecutive patients with MH were retrospectively investigated over a 7-year period and clinical features of the subjects with TMA were evaluated. We confirmed TMA relevant to MH by the normalization of the platelet count and LDH after adequate blood pressure (BP) control was achieved. Thrombotic microangiopathy was found in 7 (44%) of 16 patients. All 7 patients had an elevated plasma renin activity (PRA). Although no significant differences were observed in PRA, the patients with TMA had a significantly higher plasma aldosterone (ALDO) (median: 403 pg/ml; IR: 305 to 568) in comparison to those without TMA (median: 220 pg/ml; IR: 147 to 287; p = 0.013). Overall, ALDO correlated with LDH (r = 0.634, p = 0.0095). However, no significant association was observed between PRA and LDH (r = 0.336, p = 0.2263). The median platelet count nadir of the patients with TMA was 8.4 × 104 per μl (IR: 7.15 to 9.95). Thrombocytopenia and elevated LDH were normalized, along with a gradual improvement of BP within an average of 5 days and 21.7 days, respectively. These results suggest that ALDO, but not PRA, may act as a potent indicator of the magnitude of vascular and organ damage related to TMA among patients with malignant hypertension (MH).

Microscopic Hematuria and Diabetic Glomerulosclerosis – Clinicopathological Analysis of Type 2 Diabetic Patients Associated with Overt Proteinuria

Background/Aims: The information available concerning the qualitative and quantitative clinical variables in cases with pathologically defined diabetic glomerulosclerosis (DGs) has been insufficient so far. In addition, the prevalence and composition of nondiabetic renal disease (NDRD) among proteinuric diabetics still remain to be delineated. Methods: The glomerular pathology, clinical correlates, and the prevalence of NDRD were retrospectively analyzed in 50 type 2 proteinuric diabetics who underwent a renal biopsy between 1990 and 2006. The patients were divided into two groups according to clinical and pathological features. Thereafter, the diagnostic contribution of the laboratory and clinical variables that were significant between the two groups were determined by logistic regression analysis. Results: There were 34 cases with pure DGs and 15 cases (30%) had NDRD with or without DGs. Although the difference in the prevalence of microscopic hematuria between these two groups was significant, it was no longer statistically significant when the patients were limited to nephrotic cases. We identified 14 hematuric cases with pathologically defined DGs, and they all had a significantly lower renal function than nonhematuric patients with DGs. The prevalence of nephrotic syndrome and retinopathy were significantly higher in the cases with hematuric DGs than in the cases with nonhematuric DGs. Based on a logistic regression analysis, the presence of nephrotic syndrome and known duration of diabetes were identified to be significant predictors for hematuria with DGs. Conclusions: Our observations suggest that the presence of hematuria may be a common feature for DGs with nephrotic syndrome.

Comparison of phenotype and outcome in microscopic polyangiitis between europe and Japan.

Objective. There are differences between Europe and Japan in the incidence and antineutrophil cytoplasmic antibody (ANCA) serotype of patients with microscopic polyangiitis (MPA). However, differences in phenotype or outcome have not been explored. We aimed to identify differences in phenotype and outcome of MPA between Europe and Japan. Methods. Sequential cohorts of patients with MPA and renal limited vasculitis were collected from European and Japanese centers (n = 147 and n = 312, respectively). Trial databases from the European Vasculitis Society and the Japanese patients with Myeloperoxidase (MPO)-ANCA-Associated Vasculitis (JMAAV) trial were studied (n = 254 and n = 48, respectively). We evaluated baseline characteristics including ANCA status and organ involvement, treatment, survival, and renal survival. Differences in survival and renal survival were studied using multivariate analysis. Results. The non-trial cohorts showed patients with MPA in Japan had a higher age at onset, more frequent MPO-ANCA positivity, lower serum creatinine, and more frequent interstitial pneumonitis than those in Europe (all p < 0.01). Comparisons between the trial databases demonstrated similar results. Cumulative patient survival and renal survival rates were not different between Europe and Japan (p = 0.71 and p = 0.38, respectively). Multivariate analysis identified age at onset, serum creatinine, gastrointestinal, and respiratory involvement as factors with higher risk of death. For endstage renal failure, serum creatinine and use of plasma exchange were identified as factors with higher risk, and immunosuppressant use as lower risk factors. Conclusion. Phenotypes in patients with MPA were different between Europe and Japan. However, the outcomes of patient survival and renal survival were similar.

Febuxostat for Hyperuricemia in Patients with Advanced Chronic Kidney Disease

Febuxostat is a nonpurine xanthine oxidase (XO) inhibitor, which recently received marketing approval. However, information regarding the experience with this agent among advanced chronic kidney disease (CKD) patients is limited. In the current study, we investigated the effects of oral febuxostat in patients with advanced CKD with asymptomatic hyperuricemia. We demonstrated, for the first time, that not only the serum levels of uric acid (UA) but also those of 8-hydroxydeoxyguanosine, an oxidative stress marker, were significantly reduced after six months of febuxostat treatment, with no adverse events. These results encouraged us to pursue further investigations regarding the clinical impact of lowering the serum UA levels with febuxostat in advanced CKD patients in terms of concomitantly reducing oxidative stress via the blockade of XO. More detailed studies with a larger number of subjects and assessments of the effects of multiple factors affecting hyperuricemia, such as age, sex, and dietary habits, would shed light on the therapeutic challenges of treating asymptomatic hyperuricemia in patients with various stages of CKD.

Central venous stenosis among hemodialysis patients is often not associated with previous central venous catheters.

It is widely assumed that central venous stenosis (CVS) is most commonly associated with previous central venous catheterization among the chronic hemodialysis (HD) patients. We evaluated the validity of this assumption in this retrospective study. The clinical records from 2,856 consecutive HD patients with vascular access failure during a 5-year period were reviewed, and a total of 26 patients with symptomatic CVS were identified. Combined with radiological findings, their clinical characteristics were examined. Only seven patients had a history of internal jugular dialysis catheterization. Diagnostic multidetector row computed tomography angiography showed that 7 of the 19 patients with no history of catheterization had left innominate vein stenosis due to extrinsic compression between the sternum and arch vessels. These patients had a shorter period from the time of creation of the vascular access to the initial referral (9.2 ± 7.6 months) than the rest of the patients (35.5 ± 18.6 months, p = 0.0017). Our findings suggest that cases without a history of central venous catheterization may not be rare among the HD patients with symptomatic CVS. However, those still need to be confirm by larger prospective studies of overall chronic HD patients with symptomatic CVS.

Cilostazol enhances IL-1β-induced NO production and apoptosis in rat vascular smooth muscle via PKA-dependent pathway

Interleukin-1beta (IL-1beta) stimulates nitric oxide (NO) production and induces apoptosis in several tissues. Cilostazol is a Type 3 phosphodiesterase inhibitor. We investigated whether cilostazol affects IL-1beta-induced NO production and apoptosis in rat vascular smooth muscle cells. Cilostazol (100 nM-10 microM) potentiated NO production triggered by IL-1beta. The mRNA and protein expression of inducible NO synthase was also upregulated by cilostazol. KT5720, an inhibitor of protein kinase A, and N(G)-monomethyl-L-arginine, an inhibitor of NO synthase, abrogated cilostazol-enhanced IL-1beta-stimulated NO production and apoptosis. These results shows that cilostazol potentiates IL-1beta-induced NO production via PKA-pathway and thereafter augments apoptosis via NO-dependent pathway.

Reduced hydration status characterized by disproportionate elevation of blood urea nitrogen to serum creatinine among the patients with cerebral infarction

The significance of fluid metabolism among the patients with cerebral infarction has barely mentioned in the literature despite the several reports suggesting the potential risk of reduced hydration status for the development of cerebral infarction. The aim of the this study is to explore the validity of the presumable relationship between hydration status and cerebral infarction. Ninety-seven patients with cerebral infarction from April 1, 2008 to March 31, 2009 were retrospectively investigated, and their hydration status were evaluated by using several clinical parameters such as a blood urea nitrogen to serum creatinine (BUN/Cr) ratio of >25 and plasma osmolality. Subjects with active infection, congestive heart failure, hepatic failure, gastrointestinal bleeding, or a malignancy were excluded since these conditions should modulate the absolute value of BUN/Cr ratio without a change in hydration status. Twenty-eight patients (29%) were considered as having reduced hydration status. The BUN/Cr ratio decreased significantly after the initiation of medical support (median 21.3; IR: 18.1-24.6), including oral or parenteral fluid supplementation, in comparison to the values at the time of patient admission (median 30.0; IR: 26.8-40.7; p<0.0001). Similar decreases were also observed in the hematocrit, hemoglobin, and plasma osmolality. The group considered to have reduced hydration status had a significantly higher prevalence of cardioembolic stroke than the other subjects. The hydration status may be a contributing factor to subtypes of cerebral infarction. Whether our findings are also the case with overall patients with cerebral infarction should be evaluated in greater detail.

Metabolic and hemodynamic advantages of an acetate-free citrate dialysate in a uremic case of congenital methylmalonic acidemia.

ethylmalonic acidemia (MMA) is an or-ganic acidemia in the class of diseasescaused by enzymatic defects in the catabolism ofbranched-chain amino acids (valine, isoleucine,methionine, and threonine), odd-chain fatty ac-ids,andcholesterol.MMAisanautosomalreces-sive disorder caused by a deficiency in methyl-malonyl–coenzyme A (CoA) mutase (encoded bythe