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1.
Sci Rep ; 13(1): 93, 2023 01 13.
Article in English | MEDLINE | ID: mdl-36639673

ABSTRACT

Two-thirds of urate is excreted via the renal pathway and the remaining one-third via the extra-renal pathway, the latter mainly via the intestine in healthy individuals. ABCG2, a urate exporter, is expressed in various tissues including the kidney and intestine, and its dysfunction leads to hyperuricemia and gout. ABCG2 is regarded as being responsible for most of the extra-renal urate excretion. However, the extra-renal urate excretion capacity via ABCG2 remains undefined in end-stage kidney diseases. Therefore, we evaluated the capacity of extra-renal ABCG2 using 123 anuric hemodialysis patients whose urate excretion depended on only the extra-renal pathway. ABCG2 function in each participant was estimated based on ABCG2 dysfunctional variants. We computed the uric acid pool (PoolUA) from bodyweight and serum urate level (SUA) using previously reported radio-isotopic data, and we analyzed the association between ABCG2 function and the PoolUA. SUA and PoolUA increased significantly with ABCG2 dysfunction, and extra-renal ABCG2 could excrete up to approximately 60% of the daily uric acid turnover in hemodialysis patients. Our findings indicate that the extra-renal urate excretion capacity can expand with renal function decline and highlight that the extra-renal pathway is particularly important in the uric acid homeostasis for patients with renal dysfunction.


Subject(s)
Gout , Hyperuricemia , Humans , Uric Acid , Kidney/metabolism , Gout/genetics , Gout/metabolism , Renal Dialysis , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism
2.
Kidney Med ; 2(1): 59-67, 2020.
Article in English | MEDLINE | ID: mdl-33015612

ABSTRACT

RATIONALE & OBJECTIVE: Patients with chronic kidney failure have markedly elevated fibroblast growth factor 23 (FGF-23) levels and decreased soluble Klotho levels. However, no studies have examined the effects of hemodialysis initiation on the levels of these hormones and other parameters of mineral metabolism. STUDY DESIGN: Prospective single-arm study. SETTING & PARTICIPANTS: 20 individuals with incident kidney failure initiating hemodialysis. EXPOSURE: Initiation of hemodialysis. Dose adjustments of phosphate binders and vitamin D receptor activators and use of calcimimetics, erythropoiesis-stimulating agents, and intravenous iron were prohibited. OUTCOMES: Changes in serum levels of FGF-23, soluble Klotho, and other biochemical parameters of mineral metabolism, measured before and after each hemodialysis session, for a total of 4 sessions over 5 days. ANALYTICAL APPROACH: Repeated-measures analysis of variance. RESULTS: At baseline, participants had 18-fold higher median FGF-23 levels and 1.6-fold lower mean soluble Klotho levels compared with age- and sex-matched healthy individuals. Initiation of hemodialysis led to progressive reductions in serum phosphorus, intact parathyroid hormone, and FGF-23 levels, with dialysis-related fluctuations. No reductions were observed in levels of α1-microglobulin, which has molecular weight comparable to FGF-23. The magnitude of the FGF-23 level reductions was strongly associated with concomitant changes in serum phosphorus levels but not with the changes in intact parathyroid hormone levels. Soluble Klotho levels did not change after the initiation of hemodialysis. LIMITATIONS: Single-arm design, small sample size, short follow-up period. CONCLUSIONS: Initiation of hemodialysis in patients with chronic kidney failure led to progressive reductions in FGF-23 levels in association with reductions in serum phosphorus levels. These results suggest that phosphorus is a strong inducer of FGF-23 production and that regulation of FGF-23 production is a rapid process.

3.
Sci Rep ; 10(1): 3290, 2020 02 24.
Article in English | MEDLINE | ID: mdl-32094398

ABSTRACT

Possible ectopic parathyroid hormone (PTH) production in adipose tissues surrounding hyperplastic parathyroid glands was examined in patients with secondary hyperparathyroidism (SHPT). In vitro culture of adipose tissues from 31 patients excised during parathyroidectomy showed PTH secretion in 23 (74.2%) patients. In vitro PTH secretion was detected in adipose tissues adhered to the parathyroid glands from 22 (71.0%) patients, in not-adhered adipose from 11 (35.5%) and in the thymus from four (28.6%) patients. Immunohistochemistry revealed colonies of PTH- and GCM2-positive cells intricately intertwined with adipocytes in excised adipose tissues prior to culture. When pieces of parathyroid parenchyma from SHPT patients were transplanted into the thyroid of immunodeficient nude rats with induced SHPT, the transplants secreted human PTH for one to three-and-half months after transplantation and expressed adipocyte markers, PPARγ2 and perilipin A, that the transplants did not express prior to transplantation. These findings indicate the importance of thoroughly removing adipose tissues surrounding the parathyroid glands when performing parathyroidectomy. We speculate that these ectopic PTH-producing cells are parathyroid parenchymal cells pushed out from the glands along with adipocyte progenitors during nodular growth of hyperplastic parenchymal cells and that these cells proliferate in SHPT, forming colonies PTH-producing cells intricately intertwined with adipocytes.


Subject(s)
Adipocytes/metabolism , Adipose Tissue/metabolism , Hyperparathyroidism, Secondary/metabolism , Parathyroid Glands/metabolism , Parathyroid Hormone/metabolism , Animals , Humans , Immunohistochemistry , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/therapy , Male , PPAR gamma/metabolism , Parathyroidectomy , Perilipin-1/metabolism , Rats , Rats, Nude , Renal Dialysis , Thymus Gland/metabolism
4.
J Steroid Biochem Mol Biol ; 167: 48-54, 2017 03.
Article in English | MEDLINE | ID: mdl-27989797

ABSTRACT

Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to treat secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD). Current VDRA therapy often causes hypercalcemia, which is a critical risk for vascular calcification. Previously we have shown that a novel VDRA, VS-105, effectively suppresses serum parathyroid hormone (PTH) without affecting serum calcium levels in 5/6 nephrectomized (NX) uremic rats. However, it is not known whether VS-105 directly regulates PTH gene expression. To study the direct effect of VS-105 on modulating PTH, we tested VS-105 and paricalcitol in the spheroid culture of parathyroid cells from human SHPT patients, and examined the time-dependent effect of the compounds on regulating serum PTH in 5/6 NX uremic rats (i.p. 3x/week for 14days). In human parathyroid cells, VS-105 (100nM) down-regulated PTH mRNA expression (to 3.6% of control) and reduced secreted PTH (to 43.9% of control); paricalcitol was less effective. VS-105 effectively up-regulated the expression of VDR (1.9-fold of control) and CaSR (1.8-fold of control) in spheroids; paricalcitol was also less effective. In 5/6 NX rats, one single dose of 0.05-0.2µg/kg of VS-105 or 0.02-0.04µg/kg of paricalcitol effectively reduced serum PTH by >40% on Day 2. Serum PTH remained suppressed during the dosing period, but tended to rebound in the paricalcitol groups. These data indicate that VS-105 exerts a rapid effect on suppressing serum PTH, directly down-regulates the PTH gene, and modulates PTH, VDR and CaSR gene expression more effectively than paricalcitol.


Subject(s)
Calcitriol/analogs & derivatives , Kidney/metabolism , Parathyroid Glands/metabolism , Parathyroid Hormone/blood , Receptors, Calcitriol/agonists , Receptors, Calcitriol/metabolism , Animals , Calcitriol/chemistry , Down-Regulation , Ergocalciferols/chemistry , Male , Nephrectomy , Parathyroid Glands/cytology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Spheroids, Cellular/metabolism
5.
Clin Exp Nephrol ; 21(4): 563-572, 2017 Aug.
Article in English | MEDLINE | ID: mdl-27757708

ABSTRACT

BACKGROUND: Feasibility of photodynamic therapy (PDT) for secondary hyperparathyroidism (SHPT) was examined in a rat model of SHPT. METHODS: A photosensitizer, 5-aminolevulinic acid (5-ALA), was injected intraperitoneally, and the parathyroid glands were irradiated either after surgical exposure with 385-nm light or transdermally with 630-nm light from a light-emitting diode (LED) lamp. RESULTS: PDT with high 5-ALA and irradiation doses caused severe hypoparathyroidism in SHPT rats within two days. Low-dose invasive PDT reduced intact parathyroid hormone (iPTH) levels in all rats from 748.9 ± 462.6 pg/mL at baseline to 138.7 ± 117.5 pg/mL at week 6, followed by a further decrease to 80.5 ± 54.0 pg/mL at week 9 in 60 % of rats or an increase to 970.0 ± 215.6 pg/mL at week 9 in 40 % of rats. Low-dose noninvasive PDT reduced iPTH levels from 1612.5 ± 607.8 pg/mL at baseline to 591.9 ± 480.1 pg/mL at week 4 in all rats. Thereafter, iPTH levels remained low in 43 % of rats and were 233.7 ± 51.6 pg/mL at week 9, whereas 57 % showed an increase, reaching 3305.9 ± 107.3 pg/mL at week 9. Control SHPT rats had iPTH levels of 2487.8 ± 350.9 and 2974.6 ± 372.1 pg/mL at week 4 and 9, respectively. The parathyroid glands of the rats with low iPTH levels were atrophied and had few parathyroid cells surrounded by fibrotic materials and no recognizable blood vessels. Those of the rats with high iPTH levels showed well-preserved gland structure, clusters of parathyroid cells, and blood vessels. CONCLUSION: These results demonstrate that 5-ALA-mediated PDT for SHPT is feasible.


Subject(s)
Aminolevulinic Acid/administration & dosage , Hyperparathyroidism, Secondary/drug therapy , Kidney Failure, Chronic/complications , Parathyroid Glands/drug effects , Photochemotherapy/methods , Photosensitizing Agents/administration & dosage , Animals , Biomarkers/blood , Disease Models, Animal , Dose-Response Relationship, Drug , Feasibility Studies , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/pathology , Injections, Intraperitoneal , Male , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Hormone/blood , Rats, Sprague-Dawley , Time Factors
6.
Tokai J Exp Clin Med ; 41(3): 135-8, 2016 Sep 20.
Article in English | MEDLINE | ID: mdl-27628605

ABSTRACT

We report a case of peritoneal mesothelioma discovered in a patient during peritoneal dialysis. The patient was a 55-year-old woman who had no history of asbestos exposure. Owing to end-stage kidney failure, she had been undergoing peritoneal dialysis for over 8 years, and she had been diagnosed with encapsulating peritoneal sclerosis. She was admitted to the hospital for intestinal obstruction. Three months later, she noticed an enlarging mass in the epigastric region. Computed tomography showed a 10-cm mass originating in the abdominal wall that had invaded the liver. It was diagnosed as malignant mesothelioma via biopsy. Cases of sarcoma-like mass-forming peritoneal mesothelioma are rare, and there are no prior reports of encapsulating peritoneal sclerosis complicated by malignant peritoneal mesothelioma. Thus, this unique case of peritoneal mesothelioma can provide us with important knowledge about this rare entity.


Subject(s)
Lung Neoplasms/complications , Lung Neoplasms/diagnosis , Mesothelioma/complications , Mesothelioma/diagnosis , Peritoneal Fibrosis/diagnosis , Peritoneal Fibrosis/etiology , Peritoneal Neoplasms/complications , Peritoneal Neoplasms/diagnosis , Biopsy , Female , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Lung Neoplasms/pathology , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Peritoneal Dialysis , Peritoneal Neoplasms/pathology , Tomography, X-Ray Computed
7.
J Clin Endocrinol Metab ; 99(4): E652-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24476081

ABSTRACT

CONTEXT: Klotho is a transmembrane protein that functions as a coreceptor for fibroblast growth factor 23 (FGF23). Klotho is cleaved and released into the circulation; however, the main site of production, physiological role, and regulation of soluble Klotho in humans are largely unknown. OBJECTIVE: The aim of this study was to determine the impact of parathyroidectomy (PTx) on serum FGF23 and soluble Klotho levels in patients with severe secondary hyperparathyroidism. DESIGN AND SETTING: This was a prospective, single-arm trial conducted at Tokai University School of Medicine. PATIENTS: Thirteen hemodialysis patients with severe secondary hyperparathyroidism who were candidates for PTx participated in the study. INTERVENTIONS: All patients underwent total PTx with forearm autotransplantation. MAIN OUTCOME MEASURES: We evaluated changes in serum FGF23 and soluble Klotho levels for 90 days after PTx. Other biochemical parameters related to mineral and bone metabolism were also assessed. RESULTS: At baseline, serum FGF23 levels were markedly elevated, whereas serum soluble Klotho levels were modestly decreased. PTx resulted in a marked, progressive decline in serum FGF23 levels together with significant reductions in serum calcium, phosphorus, and intact PTH levels. The serum soluble Klotho levels were reduced 13% from baseline on the day after PTx; however, these levels then increased progressively, reaching 34% above the postoperative values. CONCLUSIONS: Our results suggest that the parathyroid gland is not the major site of soluble Klotho production in patients with end-stage renal disease, and the production of Klotho by other organ(s) is affected by alterations in mineral metabolism or medications taken after PTx.


Subject(s)
Fibroblast Growth Factors/blood , Glucuronidase/blood , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/surgery , Parathyroidectomy , Renal Dialysis , Aged , Cinacalcet , Female , Fibroblast Growth Factor-23 , Humans , Hyperparathyroidism, Secondary/etiology , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Klotho Proteins , Male , Middle Aged , Naphthalenes/therapeutic use , Postoperative Period , Severity of Illness Index , Solubility
8.
J Artif Organs ; 16(3): 368-75, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23666226

ABSTRACT

Bioartificial renal tubule devices (BTD) use cell therapy to improve conditions commonly observed in recipients of artificial kidneys for treatment of kidney diseases. We previously reported significant improvement of the condition of acute kidney injury (AKI) animals after treatment with BTD prepared with lifespan-extended human renal proximal tubular cells (hRPTEC). However, a major obstacle to use of BTD for patients is their biological safety, because hRPTEC are cultured in medium containing fetal calf serum. To establish the biological safety of BTD, we prepared BTD with lifespan-extended hRPTEC cultured in a newly developed serum-free medium and compared these with BTD prepared with hRPTEC cultured in serum-containing conventional medium. Lifespan-extended hRPTEC cultured in serum-free medium (hRPTEC-SFM) can proliferate similar to hRPTEC cultured in serum-containing conventional medium (hRPTEC-CM). Comparison of leakage and of reabsorption of small molecules for BTD prepared with hRPTEC-SFM (BTD-SFM) with those for our previous BTD prepared with hRPTEC-CM (BTD-CM) showed transportation in these two types of BTD was almost identical. When AKI goats were treated with BTD-SFM for 26 h, increase of survival time and reduction of cytokine expression in blood cells were almost same as for AKI goats treated with BTD-CM. Quantification of the expression of some genes of hRPTEC in BTD revealed significant changes during BTD treatment for AKI goats. In conclusion, lifespan-extended hRPTEC-SFM work as well as hRPTEC-CM, and the biological safety of BTD for patients could be elevated without loss of function by preparation from hRPTEC-SFM.


Subject(s)
Biocompatible Materials , Epithelial Cells/cytology , Kidney Tubules, Proximal/cytology , Materials Testing , Animals , Cells, Cultured , Goats , Humans , Male
9.
Clin Calcium ; 23(2): 165-71, 2013 Feb.
Article in Japanese | MEDLINE | ID: mdl-23354082

ABSTRACT

With progressive loss of kidney function, patients with chronic kidney disease develop multiple mineral metabolism abnormalities. Chronic kidney disease-mineral and bone disorder independently associated with cardiovascular disease and mortality. FGF23 which discovered in late years gave us new knowledge to elucidate these mechanisms. Further elucidation of FGF23-Klotho will help us to improve the understanding of pathogenesis of bone mineral metabolism abnormality.


Subject(s)
Bone and Bones/metabolism , Kidney/metabolism , Animals , Bone Density , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/metabolism , Humans , Kidney Failure, Chronic/metabolism
10.
Nephron Clin Pract ; 124(3-4): 224-31, 2013.
Article in English | MEDLINE | ID: mdl-24503607

ABSTRACT

BACKGROUND/AIMS: Previous studies reported a reduction in parathyroid gland volume during treatment with cinacalcet in patients with secondary hyperparathyroidism (SHPT). However, it remains to be determined whether cinacalcet accelerates apoptosis of hyperplastic parathyroid cells in these patients. METHODS: The study subjects were 16 hemodialysis patients who had undergone parathyroidectomy for severe SHPT. We compared the expression of the apoptotic marker TUNEL and the proliferative marker Ki67 by immunohistochemistry and the expression of CYP27B1 by quantitative real-time PCR in hyperplastic parathyroid glands from patients treated with cinacalcet (cinacalcet group; n = 8) and those not treated with cinacalcet (non-cinacalcet group; n = 8). We also examined the effect of cinacalcet on parathyroid cell death in in vitro cell culture with TUNEL staining, using parathyroid cells from SHPT patients. RESULTS: Compared with the non-cinacalcet group, the expression of TUNEL was significantly increased but was accompanied with significantly increased Ki67 expression in the parathyroid glands from the cinacalcet group. In vitro examination showed dose- and time-dependent increases of apoptotic cells by adding cinacalcet into culture medium. We also found that the expression of CYP27B1 showed a three-fold increase in glands from the cinacalcet group compared to that of the non-cinacalcet group. CONCLUSION: Our data suggest that cinacalcet induces apoptosis of human parathyroid cells, but this effect may be overcome by more aggressive proliferation of parathyroid cells in patients with severe, cinacalcet-resistant SHPT.


Subject(s)
Apoptosis/drug effects , Hyperparathyroidism, Secondary/drug therapy , Naphthalenes/adverse effects , Parathyroid Glands/drug effects , Parathyroid Glands/pathology , Adult , Aged , Apoptosis/physiology , Cells, Cultured , Cinacalcet , Dose-Response Relationship, Drug , Female , Humans , Hyperparathyroidism, Secondary/diagnosis , Male , Middle Aged
11.
Nephrol Dial Transplant ; 27(8): 3091-9, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22467257

ABSTRACT

BACKGROUND: Acute kidney injury (AKI), accompanied by the development of systemic inflammatory response syndrome and multiorgan dysfunction syndrome, is associated with a high risk of death. Bioartificial renal tubule device (BTD) is a cell therapy that improves the conditions common to artificial kidney recipients treated for kidney diseases. In this paper, we describe the establishment of BTD with lifespan-extended human renal proximal tubular epithelial cells. METHODS: AKI goats were established by performing bilateral nephrectomy followed by lipopolysaccharide administration. The AKI goats were treated with BTD or sham-BTD, and the two groups of animals were compared by measuring the respective life spans and the levels of blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and serum electrolytes. The expression levels of inflammatory cytokines were detected by reverse transcription-polymerase chain reaction, and plasma interleukin (IL)-6 levels were measured by enzyme-linked immunosorbent assay. RESULTS: The life span of AKI goats was extended: the lifetime with the BTD treatment compared with sham-BTD. BTD and sham-BTD showed a similar degree of small solute clearance. The expression levels of inflammatory cytokines and plasma IL-6 levels were decreased by the BTD treatment. CONCLUSIONS: BTD treatment results in less damage from endotoxin shock and increased life span in AKI goats. These results suggest that BTD may be a useful component of bioartificial kidneys and should be considered in the next generation of renal replacement therapies.


Subject(s)
Bioartificial Organs , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/physiology , Acute Kidney Injury/genetics , Acute Kidney Injury/physiopathology , Acute Kidney Injury/therapy , Animals , Biomarkers/blood , Cellular Senescence , Cytokines/biosynthesis , Cytokines/genetics , Disease Models, Animal , Epithelial Cells/cytology , Epithelial Cells/physiology , Goats , Humans , Interleukin-6/blood , Kidney Function Tests , Male
12.
Tokai J Exp Clin Med ; 36(4): 128-33, 2011 Dec 20.
Article in English | MEDLINE | ID: mdl-22167496

ABSTRACT

A 55-year-old Japanese man was referred to our hospital because of disturbance of consciousness and hyponatremia. He had been aware of general fatigue, nausea, and headache for two weeks. Tests revealed hyponatremia, plasma hypoosmolarity with urine hyperosmolarity, an elevated level of urine sodium excretion, and normal functions of the kidney, adrenal gland, and thyroid. These findings were compatible with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Head magnetic resonance imaging (MRI) demonstrated a pituitary tumor measuring 20 x 22 x 21 mm that pushed the pituitary stalk upward. Endocrinological evaluations suggested that the pituitary adenoma was non-functional. The pituitary adenoma was surgically removed, and histological examination revealed a biphasic appearance characterized by endocrine cells and a hemangiomatous stroma. After surgery, the patient developed pituitary hypothyroidism, pituitary adrenal insufficiency, and pituitary gonadal failure. Therefore, levothyroxine sodium, 50 µg per day, and hydrocortisone, 10 mg per day, were administered orally. Androgen depot, 250 mg every two months, was also injected intramuscularly. The hyponatremia did not recur, and the patient has done well for the last five years. The pituitary adenoma in this case showed two features: one was the cause of SIADH, and the other was a biphasic histological picture of endocrine cells with a hemangiomatous stroma.


Subject(s)
Adenoma/complications , Hemangioma/complications , Inappropriate ADH Syndrome/etiology , Pituitary Neoplasms/complications , Adenoma/pathology , Adenoma/surgery , Combined Modality Therapy , Hemangioma/pathology , Humans , Hypothyroidism/etiology , Male , Middle Aged , Pituitary Neoplasms/pathology , Pituitary Neoplasms/surgery , Treatment Outcome
13.
Nephrol Dial Transplant ; 26(9): 2761-9, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21421594

ABSTRACT

BACKGROUND: The bioartificial renal tubule device is a cell therapy system for renal failure. The major obstacle in the development of the bioartificial renal tubule device is the obtainment of a large number of viable renal tubule cells to seed on the inner surface of hollow fibers. Although our previous studies had used a transformed cell line, they may be dangerous for clinical uses. Therefore, different approaches to amplify renal proximal tubular epithelial cells (RPTEC) in culture without oncogenes, vectors and carcinogens have been required. METHODS: The limitation of the replicative lifespan of human RPTEC, which is ∼12 population doublings (PDs), was extended by invalidating messenger RNA of cell cycle-related genes with antisense oligonucleotide or small interfering RNA (siRNA). RESULTS: Periodic transfection of siRNA to a tumor suppressor p53 or a cyclin-dependent kinase inhibitor p16(INK4a) extended the lifespan by 33 and 63 PDs, respectively, in 3 months of culture. The siRNA-mediated lifespan extension was controllable because cell division ceased within 2 weeks after the transfection was discontinued. Expressions of γ-glutamyltransferase 1 and glucose transporter 1 were recovered in siRNA-transfected RPTEC cultured on porous membranes. Bioartificial renal tubule devices (0.8 m(2)) constructed with these cells showed reabsorption of water (122.3 ± 4.2 mL/30 min), sodium (18.1 ± 0.7 mEq/30 min) and glucose (121.7 ± 4.4 mg/30 min) after 1 week of circulation. Furthermore, ß2-microglobulin and pentosidine were metabolized by RPTEC in mini-devices (65 cm(2)) within 48 h of circulation. CONCLUSIONS: These approaches enabled us to yield a high enough number of RPTEC for construction of bioartificial renal tubule devices repeatedly. Lifespan-extended RPTEC could recover their specific characteristics by culturing on porous membranes, and bioartificial renal tubule devices constructed with these cells showed good performances of reabsorption and metabolism. SUMMARY: A large number of human renal tubular cells required for construction of the bioartificial renal tubule device were prepared by extending the lifespan of the primary cells by invalidating mRNA of cell cycle-related genes. Constructed bioartificial renal tubule devices with lifespan-extended cells showed good performances of in vitro examination of reabsorption and metabolism. Requiring no oncogenes, vectors or cell cloning, the RNAi-mediated lifespan extension can help advance tissue-replacement therapy as well as basic research.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/metabolism , Epithelial Cells/cytology , Hemofiltration/instrumentation , Kidney Tubules, Proximal/cytology , Kidneys, Artificial , Tumor Suppressor Protein p53/metabolism , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p16/antagonists & inhibitors , Cyclin-Dependent Kinase Inhibitor p16/genetics , Epithelial Cells/metabolism , Glucose Transport Proteins, Facilitative/genetics , Glucose Transport Proteins, Facilitative/metabolism , Humans , Kidney Tubules, Proximal/metabolism , Oligonucleotides, Antisense/pharmacology , Porosity , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , gamma-Glutamyltransferase/genetics , gamma-Glutamyltransferase/metabolism
14.
Am J Kidney Dis ; 57(3): 422-31, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21239096

ABSTRACT

BACKGROUND: Some trials have indicated that coronary artery calcification progresses more slowly in sevelamer-treated dialysis patients than in those using calcium-based binders. Effects of phosphate binders on circulating advanced glycation end products (AGEs) are unknown. STUDY DESIGN: Randomized trial with parallel-group design. SETTING & PARTICIPANTS: 183 adult (aged >20 years) patients on maintenance hemodialysis therapy at 12 dialysis facilities with a mean vintage of 118 ± 89 (median, 108) months. Dialysate calcium concentration was 2.5 mEq/L, and dietary calcium was not controlled. INTERVENTION: Patients were randomly assigned to 12 months of treatment with sevelamer (n = 91) or calcium carbonate (n = 92). OUTCOMES & MEASUREMENTS: Primary outcome measures were change from baseline in coronary artery calcification score (CACS) determined at study entry and completion using multislice computed tomography and the proportion of patients with a ≥ 15% increase in CACS. Blood parameters were determined at study entry and 2-week intervals, and levels of plasma pentosidine, a representative AGE, were determined at study entry, 6 months, and study completion. RESULTS: 79 (86.8%) and 84 (91.3%) patients in the sevelamer and calcium-carbonate arms completed the treatment, respectively. Both binders were associated with an increase in mean CACS: 81.8 (95% CI, 42.9-120.6) and 194.0 (139.7-248.4), respectively (P < 0.001 for both). After adjustment for baseline values, the increase in the sevelamer group was 112.3 (45.8-178) less (P < 0.001). Percentages of patients with a ≥ 15% increase in CACS were 35% of the sevelamer group and 59% of the calcium-carbonate group (P = 0.002). Plasma pentosidine levels increased with calcium carbonate but not [corrected] sevelamer treatment (P < 0.001). Sevelamer use was associated with decreased risk of a ≥ 15% increase in CACS regardless of baseline blood parameters, pentosidine level, and CACS. LIMITATIONS: Treatment duration was relatively short, some sevelamer-treated patients (7 of 79) received calcium carbonate, and washout could not be performed. CONCLUSIONS: The data suggest that sevelamer treatment slowed the increase in CACS and suppressed AGE accumulation.


Subject(s)
Calcinosis/drug therapy , Calcium Carbonate/therapeutic use , Coronary Artery Disease/drug therapy , Glycation End Products, Advanced/blood , Kidney Failure, Chronic/therapy , Polyamines/therapeutic use , Renal Dialysis , Calcinosis/blood , Calcinosis/etiology , Chelating Agents/therapeutic use , Chromatography, High Pressure Liquid , Coronary Artery Disease/blood , Coronary Artery Disease/etiology , Female , Follow-Up Studies , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Male , Middle Aged , Retrospective Studies , Sevelamer , Treatment Outcome
15.
Endocrine ; 38(1): 18-23, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20960097

ABSTRACT

Nuclear genes succinate dehydrogenase B subunit and succinate dehydrogenase D subunit, which encode two mitochondrial complex II subunits, are associated with the development of familial paraganglioma (PGL). Succinate dehydrogenase B subunit gene mutation is highly associated with extraadrenal PGL and subsequent distant metastasis. We describe the case of a 29-year-old Japanese man with a 3-year history of hypertension, headache, and palpitation. Endocrinological examinations showed that the patient had elevated levels of catecholamines, and imaging studies revealed a right paraaortic PGL without distant metastases. The PGL was surgically removed. Genetic analysis of the patient showed a heterozygous thymine deletion at position 470 (c.470delT) in exon 5 of the succinate dehydrogenase B subunit gene complementary DNA. This thymine deletion changed TTG (leucine) to TGA (stop codon) at codon 157 (L157X). It remains unclear whether this mutation was associated with PGL malignancy because the patient has had no metastases for the past 3 years. It has been recently reported that L157X is associated with malignant paraaortic PGL. Thus, strict follow-up is required because this succinate dehydrogenase B subunit gene's nonsense mutation (L157X) may be related to the malignancy.


Subject(s)
Asian People/genetics , Codon, Nonsense , Paraganglioma/genetics , Peripheral Nervous System Neoplasms/genetics , Succinate Dehydrogenase/genetics , Adult , Aorta , Germ-Line Mutation , Humans , Male , Paraganglioma/diagnostic imaging , Paraganglioma/surgery , Peripheral Nervous System Neoplasms/diagnostic imaging , Peripheral Nervous System Neoplasms/surgery , Tomography, Emission-Computed, Single-Photon
16.
Clin Calcium ; 20(7): 1052-9, 2010 Jul.
Article in Japanese | MEDLINE | ID: mdl-20585184

ABSTRACT

Secondary hyperparathyroidism (SHPT) is one of the most important complications of chronic kidney disease. Although 1,25-D pulse therapy is effective for SHPT, hyperplastic parathyroid (PT) cells gradually develop resistance to 1,25-D. Vitamin D(3) receptor (VDR) levels are decreased in the PT glands of dialysis patients and animal models of renal failure. To develop a new approach to such rebellious tissue, recent research has shown that the functionality protein can be adjusted with the gene transfer to the parathyroid. The experiment using adenovirus clarifies that the gene transfer of VDR and calcium sensing receptor is enabled, and such a gene expression is induced. In the recent research, we examined both in vitro and in vivo the potential use of RNAi to suppress PTH production in PT cells of SHPT patients. These results provide the findings to understand the mechanism and new treatment to SHPT.


Subject(s)
Bone Diseases, Metabolic/etiology , Genetic Therapy , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/therapy , Kidney Diseases/complications , Adenoviridae , Chronic Disease , Drug Delivery Systems , Genetic Vectors , Humans , Hyperplasia , Parathyroid Glands/cytology , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Hormone/metabolism , RNA Interference , RNA, Small Interfering/administration & dosage , Receptors, Calcitriol/genetics , Receptors, Calcium-Sensing/genetics
17.
Tokai J Exp Clin Med ; 35(2): 57-61, 2010 Jul 20.
Article in English | MEDLINE | ID: mdl-21319027

ABSTRACT

Functioning black adrenal adenoma (BAA) rarely causes preclinical Cushing's syndrome (CS). In the present case, a 46-year-old Japanese Peruvian woman presented with left flank pain and hypertension. Abdominal computed tomography showed that she had a 15-mm in diameter, round, left adrenal adenoma. She had no physical features of CS, such as moon face, buffalo hump, truncal obesity, or purple striae. Endocrinological examination showed that the plasma adrenocorticotropic hormone (ACTH) level was below the detectable level, despite a serum cortisol level within the normal range. A normal cortisol circadian rhythm was not present. Dexamethasone (1 mg and 8 mg) suppression testing did not decrease serum cortisol levels to the reference levels. These findings were compatible with preclinical CS. The left adrenal adenoma was laparoscopically removed. Examination of the surgical specimen revealed unilateral double adrenal adenomas of the left adrenal gland, one of which was a BAA. The BAA measured 20 × 11 × 10 mm. Microscopically, the BAA showed proliferation of compact cells containing numerous brown-pigmented granules. There were also foci of myelolipomatous degenerative changes in the tumor. The compact cell zones remained in the adrenal cortex adjacent to the BAA showed atrophic change. These findings indicated that BAA appeared to have caused preclinical CS in this patient.


Subject(s)
Adrenal Cortex Neoplasms/complications , Adrenocortical Adenoma/complications , Cushing Syndrome/etiology , Adrenal Cortex Neoplasms/pathology , Adrenocortical Adenoma/pathology , Female , Humans , Middle Aged
18.
Tokai J Exp Clin Med ; 35(2): 78-84, 2010 Jul 20.
Article in English | MEDLINE | ID: mdl-21319031

ABSTRACT

A 56-year-old Japanese woman with adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) was admitted to hospital, where she was diagnosed as having a mediastinal tumor with ectopic ACTH production. The tumor and associated lymph node metastases were resected endoscopically, and the pathological diagnosis was atypical thymic carcinoid. Radiation therapy and administration of metyrapone, an inhibitor of 11b-hydroxylase to decrease the cortisol level, were attempted, but the levels of ACTH and cortisol were unresponsive. Bilateral adrenalectomy and hydrocortisone replacement were performed to ameliorate the patient's hypercortisolism. She subsequently developed multiple vertebral metastases, but was unwilling to undergo chemotherapy. Her condition deteriorated progressively, and she died of heart and respiratory failure 3 years and 6 months after the first admission. Immunostaining for ACTH, chromogranin A, synaptophysin, and neuron-specific enolase was positive in the carcinoid cells. Since somatostatin (SS) and SS analogues inhibit the growth of carcinoid via the SS receptor (SSTR) 2, we evaluated the expression of SSTR2 in the carcinoid cells using reverse transcription-polymerase chain reaction, and this confirmed the expression of SSTR2 in the carcinoid cells. Our experience of this patient with CS due to an ectopic ACTH-producing atypical thymic carcinoid suggests that SS analogues may be useful for treatment of carcinoid showing expression of SSTR2.


Subject(s)
Carcinoid Tumor , Cushing Syndrome/etiology , Mediastinal Neoplasms , Thymus Neoplasms , Adrenocorticotropic Hormone/metabolism , Carcinoid Tumor/complications , Carcinoid Tumor/pathology , Disease Progression , Fatal Outcome , Female , Humans , Mediastinal Neoplasms/complications , Mediastinal Neoplasms/pathology , Middle Aged , Receptors, Somatostatin/genetics , Receptors, Somatostatin/metabolism , Thymus Neoplasms/complications , Thymus Neoplasms/pathology
19.
Endocr J ; 57(1): 31-8, 2010.
Article in English | MEDLINE | ID: mdl-19834252

ABSTRACT

Small-cell carcinoma (SCC) of neuroendocrine type is an uncommon tumor of the endometrium. No previous report has documented Cushing's syndrome due to ectopic ACTH production by SCC of the endometrium. We describe a 56-year-old Japanese woman with SCC of the endometrium and multiple lung metastases presenting as Cushing's syndrome. The patient was referred to our hospital because of general fatigue with facial and leg edema, and multiple nodular lesions in the bilateral lungs on chest X-ray examination. A physical examination revealed that the patient had moon face, buffalo hump, and truncal obesity. Endocrinological examinations confirmed ACTH-dependent Cushing's syndrome. Thoracic computed tomography imaging showed multiple nodular lesions in the bilateral lungs. Abdominal magnetic resonance imaging suggested a malignant tumor of the uterus. The patient received a lung tumor biopsy and surgical hysterectomy. The endometrial carcinoma was histologically a SCC admixed with endometrioid adenocarcinoma. The SCC of the endometrium showed immunoreactivity for pro-opiomelanocortin, ACTH, and vimentin, but not for thyroid transcription factor-1. The lung biopsy specimen had the same features. These findings indicated that the SCC originated from the endometrium, and the ectopic ACTH-producing tumor caused Cushing's syndrome. This study provides the evidence that SCC of endometrial origin was an ectopic ACTH-producing tumor causing Cushing's syndrome.


Subject(s)
Carcinoma, Small Cell/complications , Cushing Syndrome/etiology , Endometrial Neoplasms/complications , Carcinoma, Small Cell/diagnosis , Carcinoma, Small Cell/surgery , Cushing Syndrome/diagnosis , Diagnosis, Differential , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/surgery , Fatal Outcome , Female , Humans , Hysterectomy , Immunohistochemistry , Magnetic Resonance Imaging , Middle Aged , Tomography, X-Ray Computed
20.
Ther Apher Dial ; 13 Suppl 1: S20-7, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19765255

ABSTRACT

A 6-month observational study was conducted in 61 patients (33 men and 28 women, mean age 54.8 +/- 12.4 years) treated with cinacalcet in whom parathyroid intervention was indicated. Thirty-seven patients had baseline intact parathyroid hormone (iPTH) levels of >500 pg/mL, but only five still had levels this high after 6-month cinacalcet therapy. No patients had phosphorus (P), calcium (Ca), or iPTH levels within the target range at baseline, but six patients (9.8%) reached all three target ranges after treatment. The stratum with many patients who had 2-4 enlarged parathyroid glands shifted toward the low PTH groups (iPTH < 300 pg/mL) with treatment. There was less of a tendency for patients with more enlarged glands, that is, 10 mm or larger at baseline, to have a higher PTH level after cinacalcet treatment. There was no significant difference in the total volume of parathyroid glands after treatment, since some glands enlarged while others shrank. These findings indicate cinacalcet to be a potentially useful treatment. Our results suggest that 80% of cases indicated for parathyroid intervention could avoid such interventional therapies with cinacalcet administration. However, the variability in the gland-shrinking effect of cinacalcet on parathyroid glands merits further study.


Subject(s)
Hyperparathyroidism, Secondary/drug therapy , Naphthalenes/therapeutic use , Parathyroid Glands/drug effects , Parathyroid Hormone/blood , Adult , Aged , Calcium/blood , Cinacalcet , Female , Humans , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/physiopathology , Kidney Failure, Chronic/complications , Male , Middle Aged , Naphthalenes/pharmacology , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Phosphorus/blood , Renal Dialysis , Severity of Illness Index , Treatment Outcome
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