Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Calcitriol therapy is a central strategy for the treatment of uremic secondary hyperparathyroidism. Although indiscriminate use of calcitriol may lead to worse outcomes, it is difficult to make a decision to discontinue calcitriol therapy when its parathyroid suppression effect remains unsatisfactory. In this study, intravenous calcitriol was administered to 120 chronic hemodialysis patients. Therapy continued for 48 weeks or until plasma intact parathyroid hormone (iPTH) levels decreased to below 300 pg/ml or until the development of any significant adverse effect. Of the 120 patients, the treatment goal was achieved in 47 patients during the first 4 weeks, in 10 during the next 4 weeks, and in 22 patients thereafter. Logistic regression analysis and stepwise regression analysis revealed that iPTH levels were the only significant predictor of the response to calcitriol therapy at weeks 0 and 4. Besides iPTH, the inorganic phosphate (P) levels were another significant predictor of the ultimate response to calcitriol therapy at week 8. The point of best discrimination for successful treatment was P = 6.0 mg/dl at week 8, or P level at week 8/pretreatment P level = 1.0. In conclusion, the P level at week 8 is a predictor of the response to calcitriol therapy for uremic secondary hyperparathyroidism. Changes in treatment are recommended if patients show unsatisfactory parathyroid suppression with a hyperphosphatemic tendency.

DOI： 10.1007/s00774-007-0809-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background Impaired renal function is associated with poor outcomes among patients with chronic heart failure (CHF). However, the long-term changes in renal function in CHF patients without renal insufficiency at initial diagnosis remain unclear.
Methods and Results Retrospective analysis of patients presenting with idiopathic dilated cardiomyopathy (IDCM) from 1984 to 2003 and who had normal renal function defined as estimated creatinine clearance (eCcr) >= 60ml/min at the first diagnosis. Cumulative event proportions and renal insufficiency defined as eCcr < 60ml/min were calculated by the Kaplan-Meier method. The predictors of renal insufficiency were evaluated by logistic regression analysis. Impaired renal function developed in 20% during an 8-year follow-up and in 50% during a 20-year follow-up. Advanced age at the first diagnosis, high frequency of admissions, and hypotension during the clinical course were associated with the occurrence of impaired renal function. Beta-blocker therapy was a negative predictor of renal insufficiency.
Conclusions In patients with IDCM without renal insufficiency at initial diagnosis, worsening renal function occurred during the follow-up period. Frequent admissions, hypotension, and lacking ss-blocker therapy were associated with a poor prognosis in renal function.

DOI： 10.1253/circj.71.1927

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Megalin is expressed at the apical membranes of proximal tubule cells, acting as an endocytic receptor for a variety of ligands filtered by glomeruli. Megalin, also known as a Ca(2+)-binding receptor, is thought to be involved in systemic and intrarenal calcium and phosphate homeostasis. The complex of 25( OH) D(3) and vitamin D-binding protein is endocytosed via megalin into proximal tubule cells, leading to the activation of 25( OH) D3 to 1, 25( OH) D3 in the cells. Megalin knockout mice revealed impaired osteogenesis due to vitamin D deficiency. Megalin is also involved in the metabolism of parathyroid hormone and the regulation of the sodium phosphate cotransporter NaPi-IIa. Decreased expression of megalin may be associated with the pathogenesis of hyperphosphaturia observed in patients with Dent's disease. Further studies will elucidate more detailed roles of megalin in pathological states and the mechanisms for interacting with other molecules for the endocytic functions.

DOI： 10.1111/j.1744-9987.2007.00514.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Serum levels of cystatin C, an endogenous cysteine protemase inhibitor, are often used as an indicator of glomerular filtration rate. Although it is known that cystatin C is filtered by glomeruli and metabolized in proximal tubule cells (PTC), the precise molecular mechanism underlying this process is undetermined. Using quartz-crystal microbalance analyses, we demonstrate that cystatin C binds directly to megalin, an endocytic receptor in PTC, in a Ca(+)-dependent manner. We also find that cystatin C is endocytosed specifically via megalin in rat yolk sac epithelium-derived L2 cells which share a variety of characteristics with PTC. Finally, it? vivo studies using kidney-specific megalin knockout mice provide evidence that megalin mediates proximal tubular uptake of cystatin C. We conclude that megalin is an endocytic receptor of cystatin C in PTC. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.04.072

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: Mutations of the endosomal chloride/ proton exchanger gene, CLCN5, cause Dent's disease, an X-linked recessive proximal tubular disorder. The renal endocytic system was found to be affected in clcn5 knockout mice. However, the impaired endocytic machinery of Dent's disease patients has not been thoroughly investigated. Methods: The CLCN5 gene was sequenced in a Japanese patient with Dent's disease and his family. The loss-of-function phenotype of the missense CLCN5 mutation was investigated by gene expression in Xenopus oocytes and CHO cells. Immunohistochemical analysis was performed on kidney biopsy specimens for endocytic machinery proteins, megalin, cubilin, and disabled-2 (Dab2) in proximal tubules. Results: Genomic analysis revealed a novel G-to-A transition at the first nucleotide of the 333rd codon of CLCN5, causing a substitution of glycine with arginine. Inefficient expression of the mutant gene in Xenopus oocytes resulted in abolished chloride currents. Impaired N-glycosylation of the mutant protein was evident in the DNA-transfected CHO cells. Proximal tubular expression of megalin, cubilin, and Dab2 was markedly reduced and irregular staining in some portions was observed in the patient compared with controls. Conclusions: A novel G333R CLCN5 mutation caused defective expression of megalin, cubilin, and Dab2 in a patient with Dent's disease. Copyright (c) 2007 S. Karger AG, Basel.

DOI： 10.1159/000111253

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Patients who have renal failure and are on dialysis therapy experience serious complications caused by low-molecular-weight uremic toxin proteins normally filtered by glomeruli and metabolized by proximal tubule cells (PTC). Dialysis-related amyloidosis is one such complication induced by systemic deposition of amyloid proteins derived from 12-kD beta(2)-microglobulin (beta(2)-M). Despite the use of high-flux membrane hemodialysis devices and direct absorbent columns, the removal of beta(2)-M is suboptimal, because the effects are transient and insufficient. Megalin is expressed in the apical membranes of PTC and recognized as a multiligand endocytic receptor that binds numerous low-molecular-weight proteins, including, beta(2)-M. This study tested the feasibility of an intra corporeal therapeutic model of continuous beta(2)-m removal using megalin-expressing cell implantation. By cell association and degradation assays, rat yolk sac-derived L2 cells were identified to internalize and degrade beta(2)-M via megalin. The cells were effectively implanted within the subcutaneous tissues of nude mice using a type I collagen scaffold and a method inducing local angiogenesis. After nephrectomy and intraperitoneal injection with I-125-beta(2)-m, it was found that the implanted cells took up the labeled ligand, efficiently removing it from the blood. Bioengineered implantation of megalin-expressing cells may represent a new supportive therapy for dialysis patients to compensate for the loss of renal protein metabolism and remove uremic toxin proteins.

DOI： 10.1097/01.ASN.0000078804.98322.4A

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DOI： 10.2169/internalmedicine.42.436

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.91.3494

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Other Link： https://jlc.jst.go.jp/DN/JALC/00162769883?from=CiNii

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

Kidney-targeted gene transfer is expected to revolutionize the treatment of renal diseases. Previous gene transfer methods using nonviral vectors administered via renal arterial, pelvic, or ureteric routes into the glomerulus, tubules, or interstitial fibroblasts have resulted in low-level expression for <1 month. The peritubular capillaries (PTC) network is one of the main targets of kidney transplant rejection and of progressive tubulointerstitial fibrosis, which typifies all progressive renal diseases. To access the PTC, we retrogradely injected a lacZ expression plasmid in Ringer's solution into the renal vein of rats. We detected lacZ expression exclusively in the interstitial fibroblasts near the PTC of the injected kidney by immunoelectron microscopic analysis. Nephrotoxicity attributable to gene transfer was not apparent. We then used a rat erythropoietin (Epo) expression plasmid vector, pCAGGS-Epo, in a reporter assay. We obtained maximal Epo expression when the DNA solution was injected within 5 sec, and with a volume of 1.0 ml. We observed a dose-response relationship between serum Epo levels and the amount of injected DNA up to 100 μg. We detected the transgene-derived Epo mRNA by reverse transcription polymerase chain reaction only in the kidneys injected with pCAGGS-Epo. After an injection of 100 mg of pCAGGS-Epo, the serum Epo levels peaked at 208.3 +/- 71.8 mU/ml at week 5, and gradually decreased to 116.2 +/- 38.7 mU/ml at week 24. A similar pattern was obtained using smaller doses of plasmid, 2 μg or 30 μg of pCAGGS-Epo. Transgene-derived Epo secretion resulted in significant erythropoiesis. This novel technique is simple and safe, allowing high-level and long-term stable gene expression specific to the fibroblasts near the PTC, and should have therapeutic value for future applications in humans.

DOI： 10.1089/10430340252792585

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01159&link_issn=&doc_id=20180220110017&doc_link_id=10.2169%2Fnaika.107.315&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.107.315&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：Japan Heart Foundation  

われわれは,先天性aneurysmal typeの右腎動静脈瘻のため,高拍出性心不全を発症した1例を経験したので報告する.症例は70歳の女性で,息切れと全身性浮腫のため当院に入院した.精査の結果,先天性と考えられたaneurysmal typeの巨大右腎動静脈瘻が認められた.心臓カテーテル検査では,肺動脈楔入圧28/7(14)mmHg,肺動脈圧43/17(26)mmHg,右心房圧19/7(11)mmHg,心係数8.5L/min/m2,左右シャント率73.7%と高拍出性心不全状態であった.右腎摘出術を施行し,治癒した.高拍出性心不全を伴った腎動静脈瘻はまれである.

DOI： 10.11281/shinzo1969.37.8_672

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Language：Japanese   Publisher：新潟医学会  

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