Long-term effect of cinacalcet hydrochloride on abdominal aortic calcification in patients on hemodialysis with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is one of the common complications in dialysis patients, and is associated with increased risk of vascular calcification. The effects of cinacalcet hydrochloride treatment on bone and mineral metabolism have been previously reported, but the benefit of cinacalcet on vascular calcification remains uncertain. The aim of this study was to evaluate the impact of cinacalcet on abdominal aortic calcification in dialysis patients. SUBJECTS AND METHODS: Patients were on maintenance hemodialysis with insufficiently controlled SHPT (intact parathyroid hormone [PTH] >180 pg/mL) by conventional therapies. All subjects were initially administered 25 mg cinacalcet daily, with concomitant use of calcitriol analogs. Abdominal aortic calcification was annually evaluated by calculating aortic calcification area index (ACAI) using multidetector computed tomography (MDCT), from 12 months before to 36 months after the initiation of cinacalcet therapy. RESULTS: Twenty-three patients were analyzed in this study. The mean age was 59.0±8.7 years, 34.8% were women, and the mean dialysis duration was 163.0±76.0 months. After administration of cinacalcet, serum levels of intact PTH, phosphorus, and calcium significantly decreased, and mean Ca × P values significantly decreased from 67.4±7.9 mg(2)/dL(2) to 52±7.7 mg(2)/dL(2). Although the ACAI value did not decrease during the observation period, the increase in ACAI between 24 months and 36 months after cinacalcet administration was significantly suppressed. CONCLUSION: Long-term administration of cinacalcet was associated with reduced progression of abdominal aortic calcification, and achieving appropriate calcium and phosphorus levels may reduce the rates of cardiovascular events and mortality in patients on hemodialysis.

The serum vaspin levels are reduced in Japanese chronic hemodialysis patients.

BACKGROUND: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients. METHODS: Healthy Japanese control volunteers (control; n = 95, 49.9 ± 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 ± 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system. RESULTS: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; Vaspin High group), while the rest of the population exhibited lower levels (< 3 ng/ml; Vaspin Low group). By comparing the patients in the Vaspin Low group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 ± 0.24 ng/ml) than in the HD patients (0.32 ± 0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects. CONCLUSIONS: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin Low group.

Peritoneovenous shunting for refractory ascites results in worsening of nephrotic syndrome.

Peritoneovenous shunt (PVS) is accepted as a treatment for refractory ascites due to liver cirrhosis. Infection is a well-known complication of shunting. However, the effects of PVS in terms of complications for renal disease are unclear. We encountered a case involving a 52-year-old man with alcoholic liver cirrhosis and complications of nephrotic syndrome that were worsened by PVS. He received PVS for refractory ascites due to alcoholic liver cirrhosis before coming to our hospital for evaluation for liver transplantation. Nephrotic syndrome was then identified due to cirrhosis-related membranoproliferative glomerulonephritis (MPGN). Prednisolone was administrated at 60 mg/day for MPGN. On day 5, he showed grade IV hepatic encephalopathy (West Haven criteria). Tapering prednisolone and intestinal cleansing with lactulose treatment improved hepatic encephalopathy, but hyperammonemia persisted and the PVS was removed. After shunt removal, urinary protein levels decreased from 4-6 g/day to 0.3-0.5 g/day and ammonia levels decreased. PVS may increase the excretion of urinary protein and increase ammonia levels in patients with complications of glomerulonephritis.

The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome: a randomized controlled trial.

BACKGROUND: In nephrotic syndrome, the combination of furosemide and albumin infusion is a standard regimen to treat systemic edema. The efficacy of synthetic human atrial natriuretic peptide (hANP) for nephrotic syndrome to ameliorate the systemic edema and retain renal functions has not been fully demonstrated. TRIAL DESIGN: We conducted a prospective, randomized, controlled, open-label clinical trial. Patients were randomly assigned by a stratified biased coin design. METHODS: A total of 12 patients with nephrotic syndrome between the ages of 20 to 79 years were enrolled and randomly assigned to either the conventional (CON) group treated with furosemide and albumin, and hANP group, in which carperitide was administered in addition to the conventional therapies. The primary end points were: (1) the differences in serum creatinine levels, and (2) the reduction of total dosage of furosemide and albumin by the treatments of hANP. Secondary end points were body weight, systolic blood pressure, heart rate, serum protein, albumin, and urinary protein excretion. RESULTS: A total of 13 patients were enrolled, and one patient was excluded due to severe pneumonia. In both hANP (n = 7) and CON (n = 5) groups, body weight was reduced after 2-week treatments. Serum creatinine levels at follow-up significantly increased compared with baseline. The increase in serum creatinine levels (Δ serum creatinine) was smaller in the hANP group compared with the CON group (P = 0.31). The serum uric acid, serum urea nitrogen, and urinary protein excretion were reduced in the hANP group, and increased in the CON group, though these differences were not statistically significant. The usage of hANP significantly reduced the total dosage of furosemide (P < 0.05) during the treatment periods. No adverse effects were observed. CONCLUSIONS: The concomitant use of synthetic hANP with conventional therapies is beneficial for reducing the dosage of loop diuretics, and the elevation of serum creatinine and uric acid may be avoided.

Effluent free radicals are associated with residual renal function and predict technique failure in peritoneal dialysis patients.

OBJECTIVE: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD. METHODS: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months. RESULTS: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma ß(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005). CONCLUSIONS: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients.

Icodextrin increases technique survival rate in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: There are still controversies whether peritoneal dialysis (PD) with icodextrin preserves residual renal and peritoneal membrane functions in patients with diabetes. However, there are no randomized controlled and long-term clinical trials in newly started PD patients with diabetic nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Forty-one patients with diabetic nephropathy with ESRD were enrolled and randomly assigned to the glucose group (GLU) treated with 8 L of 1.5% or 2.5% glucose or an icodextrin group (ICO) treated with 1.5 or 2.0 L of 7.5% icodextrin-containing solutions. Technique failure, body fluid management, glucose and lipid metabolism, and residual renal and peritoneal functions and were evaluated over 2 years. RESULTS: The technique survival rate was 71.4% in ICO and 45.0% in GLU, with most of the technique failure due to volume overload. ICO showed significantly better cumulative technique survival. Net ultrafiltration volume was significantly higher in ICO throughout the study period. There were no beneficial effects of icodextrin on hemoglobin A1c, glycoalbumin, and lipid profile at 24 months. Urine volume and residual renal function declined faster in ICO, but there were no significant differences between the two groups. For peritoneal function, no differences were observed in dialysis-to-plasma creatinine ratios during the observation. CONCLUSIONS: In PD therapy for diabetic nephropathy, the use of icodextrin-containing solutions has a beneficial effect on technique survival, but there are no apparent benefits or disadvantages in residual renal and peritoneal functions compared with conventional PD with glucose solution.

Effects of icodextrin peritoneal dialysis solution on the peritoneal membrane in the STZ-induced diabetic rat model with partial nephrectomy.

BACKGROUND: Application of icodextrin-based peritoneal dialysis fluid (PDF) provides a potential benefit in patients with diabetes and end-stage renal failure treated with continuous ambulatory peritoneal dialysis (CAPD) because of better ultrafiltration capacity and avoidance of direct glucose exposure. We examined the effect of glucose and icodextrin-based PDF on histological alterations of peritoneal membranes. METHODS: Thirty-two male Wistar rats were divided into four groups: control Wistar rats with non-treated (n = 8), streptozotocin (STZ)-induced diabetic rats with 5/6 kidney ablation (n = 8), STZ-induced diabetic rats with 5/6 kidney ablation injected with a standard lactate-buffered 4.25% glucose-based PDF (Dianeal; n = 8) and STZ-induced diabetic rats with 5/6 kidney ablation injected with 7.5% icodextrin-based PDF (Extraneal; n = 8). Intraperitoneal injection was performed once daily with an instillation volume of 20 ml per injection during 8 weeks. RESULTS: Chronic high-glucose-based PDF exposure resulted in increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expression, accumulation of advanced glycation end-products (AGEs), and up-regulation of the receptor for AGE (RAGE), which were ameliorated in the icodextrin-based PDF group. The peritoneal damages, such as neoangiogenesis and submesothelial fibrosis, were significantly reduced in icodextrin-based PDF compared to high-glucose-based PDF. CONCLUSIONS: Long-term in vivo exposure to high glucose-based PDF promotes the fibrosing process of peritoneal membranes. Icodextrin-based PDF may be helpful in slowing the PDF-induced deterioration of peritoneal function and prolonging the use of peritoneal dialysis in patients with diabetes.

Unique microstructures and podocytic infolding in glomerular basement membrane associated with collagen diseases: a report of three cases.

Unique renal histopathological appearances, consisting of podocytic infolding and microstructures in the glomerular basement membrane (GBM) were identified in the renal biopsies from three patients with collagen diseases such as systemic lupus erythematosus (lupus nephritis, class II) and Sjögren's syndrome. In each case, the GBM contained microstructures, including microspheres and microtubular structures, accompanied by podocytic infolding into the GBM when examined by electron microscope. The size of the microstructures in the GBM ranged from 40 to 160 nm. Glomerular endothelial cells also seemed to be infolded in the GBM in a case with lupus nephritis. The response to glucocorticoid therapy was favorable in two cases. The cause of these morphological changes in the GBM might be associated with autoimmune disorders.

[Infection and chronic kidney disease].

Many pathogens are thought to be involved in the development and progression of chronic kidney disease (CKD). The mechanism of kidney damage due to infection includes direct invasion of pathogens and deposition of antigen-antibody complex by immunological reaction. As to renal dysfunction induced by bacterial infection, some cases of poststreptococcal glomerulonephritis present progressive decline of glomerular filtration rate (GFR). Methicillin resistant Staphylococcus aureus (MRSA)-related glomerulonephritis and infectious endocarditis are known to cause acute renal failure, which clinicians often find difficulty in the treatment. Chronic pyelonephritis by repetitive vesicoureteral reflux or nephrolithiasis also cannot be disregarded. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the most recognized etiology of virus associated nephropathy, and the representative histological changes are membranous nephropathy and membranoproliferative glomerulonephritis, respectively. Furthermore, morbidity of human immunodeficiency virus (HIV) associated nephropathy is increasing, reflecting the prolonged survival of HIV-infected patients. Thorough preventive/therapeutic strategies should be taken against these infections for improving clinical outcome.

Procollagen C-proteinase enhancer-1 (PCPE-1) interacts with beta2-microglobulin (beta2-m) and may help initiate beta2-m amyloid fibril formation in connective tissues.

Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although beta(2)-microglobulin (beta2-m) is the major structural component of beta2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhancer-1 (PCPE-1) as a new interacting protein with beta2-m by screening a human synovium cDNA library. The interaction of beta2-m with full-length PCPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, beta2-m appeared to interact with PCPE-1 via the NTR (netrin-like) domain and not via the CUB (C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, beta2-m co-localized and formed a complex with PCPE-1. beta2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate beta2-m amyloid fibril formation from monomeric beta2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of beta2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of beta2-m may be linked to subsequent beta2-m amyloid fibril formation, the disruption of the interaction between beta2-m and PCPE-1 may prevent beta2-m amyloid fibril formation and therefore PCPE-1 could be a new target for the treatment of DRA.

The role for HNF-1beta-targeted collectrin in maintenance of primary cilia and cell polarity in collecting duct cells.

Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1alpha, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1beta and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to gamma-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1beta and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1beta regulated genes.

Elevated serum interleukin-18 levels might reflect the high risk of hospitalization in patients on peritoneal dialysis.

BACKGROUND: Interleukin (IL)-18 is a potent pro-inflammatory cytokine and plays a central role in atherosclerotic plaque rupture and accelerates atherosclerosis. AIM: The aim of this study was to determine serum IL-18 levels in patients on peritoneal dialysis (PD) and to assess their relationship with hospitalization. METHODS: Forty-three PD patients and 20 healthy individuals were enrolled in this study. We investigated the relationship of the serum concentrations of IL-18 and other well-established atherosclerotic markers, such as asymmetric dimethylarginine (ADMA). Hospitalization data from over a 18-month period were prospectively obtained on all 43 PD patients. Classic factors were entered into a Cox regression model to predict first hospitalization. RESULTS: The serum levels of IL-18 in patients on PD were significantly higher than those of healthy individuals (228.5 +/- 140.3 pg/mL vs 154.8 +/- 44.7 pg/mL, P < 0.05, respectively). Furthermore, serum IL-18 levels showed a positive correlation with duration of PD, serum beta2 microglobulin and serum ADMA levels. Mean serum levels of IL-18 were significantly higher among patients who had experienced at least one hospitalization than those who had not (279.9 +/- 164.3 vs 158.5 +/- 43.9 pg/mL, P = 0.0426). Furthermore, the relative risk for first hospitalization for each increase in IL-18 (pg/mL) levels was associated with a 1.182 (95% confidence interval, 1.012-1.364; P = 0.0071) increase in the risk for future hospitalization events. CONCLUSION: The present study suggests the elevated serum IL-18 levels might increase the risk for future hospitalization in patients on PD.

Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience.

Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to d-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl-choline and H(2)O(2). Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.

Renal-specific oxidoreductase biphasic expression under high glucose ambience during fetal versus neonatal development.

BACKGROUND: Renal-specific oxidoreductase (RSOR) has been recently identified in mice kidneys of diabetic animals, and it is developmentally regulated. Its expression during fetal, neonatal, and postnatal periods was assessed under high glucose ambience. METHODS: Whole-mount immunofluorescence and confocal microscopy were performed to assess the effect of high glucose on the morphogenesis of mice fetal kidneys. RSOR mRNA and protein expression was assessed by competitive polymerase chain reaction (PCR) and immunoprecipitation methods in embryonic kidneys (day E13 to E17) subjected to high glucose ambience and by Northern and Western blot analyses of kidneys of newborn and 1-week-old mice with hyperglycemia. The spatiotemporal changes in the RSOR expression were assessed by in situ hybridization analyses and immunofluorescence microscopy. In addition, the extent of apoptosis in the kidneys was determined by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay. RESULTS: Whole-mount microscopy of the embryonic metanephroi revealed a dose-dependent disruption in the ureteric bud iterations with reduced population of the nascent nephrons. Both gene and protein expressions were reduced in day E13 to E17 metanephroi, while increased in kidneys of newborn and 1-week-old mice. In day E13 and day E15 kidneys, the RSOR was expressed in the ureteric bud branches and some of the immature tubules, and its expression was reduced with high glucose treatment. In day E17 kidneys the RSOR was expressed in the tubules of the deeper cortex, and its expression was marginally decreased. In newborn kidneys, this enzyme was expressed in the subcortical tubules and it spread to the entire width of the renal cortex in hyperglycemic state. In 1-week-old mice kidneys, the RSOR was localized to the entire cortex, and in animals with blood glucose above 300 mg/dL, its intensity increased with extension of expression into the outer medullary tubules. A dose-dependent fulminant apoptosis was observed in day E13 to E17 kidneys subjected to high glucose ambience. In newborn and 1-week-old mice control kidneys, the apoptosis was minimal although slightly increased during hyperglycemia. CONCLUSION: High glucose has a differential effect on the RSOR expression in kidneys during the embryonic versus neonatal/postnatal period. This may partly be related to the differential degree of apoptosis, a process reflective of oxidant stress that is seen in diabetic milieu, which as previously has been shown to adversely effect the modulators of fetal development and thereby the morphogenesis of the kidney and RSOR expression.

Cell biology of diabetic kidney disease.

In large part cellular dysfunctions induced by chronic hyperglycemia are similar in type-1 and -2 diabetes. In both instances chronic hyperglycemia induces injury to a multitude of organs by affecting various target cells. The cells affected may include those derived from of epithelial or mesenchymal progenitors; and at times hyperglycemia may induce phenotypic changes with epithelial-mesenchymal transformation. In the majority of target cells the high-glucose ambience activates various intracellular pathways that are similar except for minor exceptions that are related to the selective expression of various molecules in a given cell type. Keeping in perspective a common paradigm applicable to most of the cells, a brief discussion of different hyperglycemia-induced cellular events pertaining to various pathways is described in this review. They include fluxes of glucose intermediaries in various cellular metabolic pathways, generation of advanced glycation end products (AGEs) and their extra- and intracellular effects, the role of protein kinase C, transforming growth factor-beta, guanosine triphosphate-binding proteins and reactive oxygen species (ROS) in various cellular signaling events. The latter, i.e., ROS, may be central to several intracellular pathways and modulate various events in a reciprocal manner. The information compiled under various subtitles of this synopsis is derived from an enormous amount of literature data summarized in several recent excellent reviews, and thus further reading of them is suggested to gather detailed comprehensive information on each of the subjects.

Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity.

There is a rapid global rise in obesity, and the link between obesity and diabetes remains somewhat obscure. We identified an adipocytokine, designated as visceral adipose tissue-derived serpin (vaspin), which is a member of serine protease inhibitor family. Vaspin cDNA was isolated by from visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of abdominal obesity with type 2 diabetes. Rat, mouse, and human vaspins are made up of 392, 394, and 395 amino acids, respectively; exhibit approximately 40% homology with alpha1-antitrypsin; and are related to serine protease inhibitor family. Vaspin was barely detectable in rats at 6 wk and was highly expressed in adipocytes of visceral WATs at 30 wk, the age when obesity, body weight, and insulin levels peak in OLETF rats. The tissue expression of vaspin and its serum levels decrease with worsening of diabetes and body weight loss at 50 wk. The expression and serum levels were normalized with the treatment of insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats. Administration of vaspin to obese CRL:CD-1 (ICR) (ICR) mice fed with high-fat high-sucrose chow improved glucose tolerance and insulin sensitivity reflected by normalized serum glucose levels. It also led to the reversal of altered expression of genes relevant to insulin resistance, e.g., leptin, resistin, TNFalpha, glucose transporter-4, and adiponectin. In DNA chip analyses, vaspin treatment resulted in the reversal of expression in approximately 50% of the high-fat high-sucrose-induced genes in WATs. These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity.

Hyperglycemia: its imminent effects on mammalian nephrogenesis.

A sustained exposure of the mammalian embryo to very high glucose ambience is associated with a multitude of congenital birth defects, including those of the cardiovascular, CNS, skeletal and urogenital systems during the first 6-8 weeks of gestation in humans. These urogenital abnormalities may be associated with "caudal regression syndrome" or may occur alone in the form of partial or total renal agenesis. Similarly, an increase in the incidence of morphogenetic defects is observed in the offspring of streptozotocin-induced diabetic rats and mice, and also in non-obese diabetic mice. In certain cases, failure during the growth of the lower parts of embryos or newborn mice involving the genitourinary system has been observed in animals with severe diabetes. Investigators have utilized whole organ culture systems to delineate the mechanisms relevant to dysmorphogenesis of the embryonic metanephros. A marked dysmorphogenesis of the metanephros is observed upon treatment with a high concentration of D: -glucose. Associated with it are changes that include branching dysmorphogenesis of the ureteric bud iterations, reduced population of nascent nephrons, decreased expression of basement membrane proteoglycans, depletion of ATP stores, and fulminant apoptosis of the cells at the interface of mesenchyme and ureteric bud epithelium. The latter findings suggest that disruption of epithelial:mesenchymal interactions may be the major event responsible for the metanephric dysmorphogenesis induced by high glucose ambience.

The critical role of SRC homology domain 2-containing tyrosine phosphatase-1 in recombinant human erythropoietin hyporesponsive anemia in chronic hemodialysis patients.

The molecular mechanism of anemia that is hyporesponsive to recombinant human erythropoietin (rHuEPO) in hemodialysis patients without underlying causative factors has not been investigated fully in hematopoietic stem cell system. Circulating CD34+ cells (1 x 10(4)) were isolated from rHuEPO hyporesponsive hemodialysis patients (EPO-H; n = 9), patients who were responsive to rHuEPO (EPO-R; n = 9), and healthy control subjects (n = 9). The patients with known causes of EPO hyporesponsiveness were eliminated from the current study. The cells were cultured in STEM PRO 34 liquid medium, supplemented with rHuEPO, IL-3, stem cell factor, and granulocyte-macrophage colony stimulating factor for 7 d and then transferred to a semisolid methylcellulose culture medium for performing burst forming unit-erythroid (BFU-E) colony assay. Expression of src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) was assessed with Western blot analysis. In EPO-H patients, SHP-1 antisense or scrambled S-oligos were included in the culture medium, and its effects were evaluated. The number of circulating CD34+ cells was not statistically different among the three groups, and their proliferation rates were similar for 7 d in culture. However, BFU-E colonies were significantly decreased in EPO-H patients compared with EPO-R and control groups. The mRNA and protein expression of SHP-1 and p-SHP-1 was significantly increased, whereas that of p-STAT5 was reduced in EPO-H patients. The inclusion of SHP-1 antisense S-oligo in culture suppressed SHP-1 protein expression associated with p-STAT5 upregulation, increase in p-STAT5-regulated genes, and partial recovery of BFU-E colonies. In EPO-H hemodialysis patients, the EPO signaling pathway is attenuated as a result of dephosphorylation of STAT5 via upregulation of SHP-1 phosphatase activity, and SHP-1 may be a novel target molecule to sensitize EPO action in these patients.

Intravenous vitamin D therapy reduces PTH-(1-84)/large C fragments ratio in chronic hemodialysis patients.

BACKGROUND: Renal osteodystrophy is one of the major complications in patients with chronic renal failure. Large C-PTH fragments are secreted from the parathyroid glands and exert antagonistic actions against PTH-(1-84). The PTH-(1-84)/large C-PTH fragments ratio reflects both biosynthesis and processing of PTH; however the alteration of the ratio under vitamin D therapy has not been investigated. METHODS: Seventeen hemodialysis patients with intact PTH levels of >300 pg/ml were enrolled. Calcitriol or maxacalcitol were administered intravenously for 78 weeks. Intact PTH, PTH-(1-84), and the PTH-(1-84)/large C-PTH fragments ratio were measured at 0, 13, 26, 52 and 78 weeks. RESULTS: Intact PTH and PTH-(1-84) levels, which were 492.0 +/- 115.7 and 303.4 +/- 105.4 pg/ml, respectively, at baseline, significantly decreased at the end of the study to 268.9 +/- 121.9 (p < 0.0001) and 190.7 +/- 106.9 pg/ml (p = 0.0008), respectively. In contrast, large C-PTH fragments, which were 152.7 +/- 53.5 pg/ml at baseline, did not significantly change at 78 weeks (144.5 +/- 72.2 pg/ml, p = 0.7612). Consequently, the PTH-(1-84)/large C-PTH fragments ratio was significantly reduced from 2.25 +/- 1.31 to 1.47 +/- 0.89 (p = 0.0004). CONCLUSION: The PTH-(1-84)/large C-PTH fragments ratio reflects the change of PTH biosynthesis, processing and secretion from the parathyroid glands, and it may be a beneficial marker to evaluate the overall biological PTH action and predict bone turnover status in hemodialysis patients under intravenous vitamin D therapy.