Association between the Cardio-Ankle Vascular Index and Diabetes Mellitus-Related Peripheral Arterial Disease in Chronic Hemodialysis Patients.

BACKGROUND: Peripheral arterial disease (PAD) has increased in association with the increase in the numbers of patients with kidney disease or diabetes. The aim of this study was to assess the prevalence of PAD in hemodialysis patients with diabetes. METHODS: To examine the usefulness of the cardio-ankle vascular index (CAVI) to screen for the presence of PAD, cross-sectional studies of 100 patients undergoing chronic hemodialysis were performed. The CAVI and other inflammatory markers were evaluated. RESULTS: The CAVI was markedly elevated in patients with a history of PAD or cardiovascular disease. When dialysis patients were classified on the basis of CAVI quartiles, increased CAVI was associated with other risk factors for PAD. CONCLUSION: The prevalence of PAD is high in elderly diabetic patients on hemodialysis. The present findings suggest that the CAVI can be a useful index that predicts the occurrence of macrovascular complications in dialysis patients with diabetes.

Neutrophil gelatinase-associated lipocalin levels associated with cardiovascular disease in chronic kidney disease patients.

BACKGROUND: Elevated levels of neutrophil gelatinase-associated lipocalin (NGAL) have been reported in patients with cardiovascular disease (CVD), heart failure, and stroke. We assessed the relationships between serum levels of NGAL and the prevalence of CVD, and clarified the prognostic usefulness of systemic NGAL levels in hemodialysis (HD) patients. METHODS: Eighty-eight HD patients were followed up for 1 year. Logistic regression analyses were used to investigate the relationship between de novo CVD status and NGAL levels as well as other risk factors. RESULTS: During follow-up, CVD events occurred in 20 patients. Initial serum levels of NGAL and brain natriuretic peptide of HD patients with de novo CVD were significantly higher than those of HD patients without de novo CVD. Multivariate logistic regression analyses showed that initial serum levels of NGAL were independent risk factors for de novo CVD in HD patients. When patients were classified on the basis of NGAL quartiles, multiple logistic regression analyses demonstrated that the highest quartile of NGAL level showed an increased odds ratio for the prevalence of CVD. CONCLUSION: These findings suggest that NGAL levels can be used to detect the prevalence of CVD in HD patients with or without diabetes.

Serum level of macrophage colony-stimulating factor and atherosclerosis in hemodialysis patients.

BACKGROUND/AIMS: Atherosclerosis and its related complications are the leading causes of death in the hemodialysis (HD) population. Aortic calcification index (ACI), intima-media thickness (IMT) in common carotid arteries, and electrocardiogram (ECG) are atherosclerotic parameters that are available in usual clinical outpatient settings. Macrophage colony-stimulating factor (MCSF) and monocyte chemoattractant protein-1 (MCP-1) play important roles in atherosclerosis. METHODS: We performed a cross-sectional study of 133 outpatients on maintenance HD in a single HD outpatient center. We measured serum levels of MCSF and MCP-1, determined the ACI using computed tomography scan and the IMT using high-sensitivity ultrasound B-mode imaging, and performed ECGs. RESULTS: Stepwise multivariate regression analysis revealed that the MCSF level correlated with age-adjusted mean and maximum IMT (F = 10.811, p = 0.001, and F = 6.784, p = 0.010, respectively) as well as with the diastolic blood pressure. Age and MCSF level (F = 4.866, p = 0.029) were independently related to an increased ACI. High-sensitivity C-reactive protein (hsCRP) was not related to IMT and ACI. The hsCRP level (chi2 = 5.002, p = 0.025) correlated with ECG changes followed by MCSF (chi2 = 3.940, p = 0.047). MCP-1 was not related to the above atherosclerotic parameters. CONCLUSION: A head-to-head comparison between MCSF and hsCRP revealed that MCSF was more closely associated with IMT and ACI in HD patients.

Distinct diagnostic criteria for ultrasonographic examination of papillary thyroid carcinoma: a multicenter study.

Recent advances permitting high-resolution ultrasonography have made ultrasonographic examination of nodular thyroid diseases an accessible examination for routine practice. However, diagnostic criteria for ultrasonographic examination of thyroid nodules are not surely established. To identify the optimal strategy for well standardized differential diagnosis of papillary thyroid carcinoma and benign nodules, we evaluated the significance of individual ultrasonographic characteristics of thyroid nodules in a multicenter study. Ten characteristics in ultrasonograms from 53 patients scored by 17 investigators from 15 centers were analyzed by t tests and logistic regression analyses. Between benign and papillary thyroid cancer groups, all characteristics but not size or multiplicity of strong echoes, which suggest calcifications, were significant parameters. Logistic regression analyses showed that border character, shape, and internal echo level are highly significant parameters (p < 0.0005). A multiple logistic regression showed to be the most important predictors of pathologic diagnosis. The diagnostic criterion with border character and internal echo level yielded 93% sensitivity and 92% specificity. In conclusion, univariate and multivariate analyses identified border character, shape, internal echo level, but not strong echoes (calcifications), as important characteristics in differentiating papillary thyroid carcinoma from benign nodules. These results will contribute to standardization of accurate ultrasonographic diagnosis of papillary thyroid carcinoma.

Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients.

Accelerated formation and tissue accumulation of advanced glycation end products (AGEs), reflecting cumulative glycemic and oxidative stress, occurs in age-related and chronic diseases like diabetes mellitus (DM) and renal failure, and contributes to vascular damage. Skin autofluorescence (AFR), a noninvasive measurement method, reflects tissue accumulation of AGEs. AFR has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. We assessed the relationship between levels of AFR and the prevalence of cardiovascular disease (CVD), and clarified the prognostic usefulness of skin AFR levels in Asian (non-Caucasian) hemodialysis (HD) patients. AFR was measured with an autofluorescence reader in 64 HD patients. Overall and cardiovascular mortality was monitored prospectively during the 3-year follow-up. During follow-up, CVD events occurred in 21 patients. The deaths of 10 HD patients were associated with CVD. Multivariate logistic regression analyses showed that initial AFR was an independent risk factor for de novo CVD in HD patients with or without diabetes. When patients were classified on the basis of AFR tertiles, Cochran-Armitage analysis demonstrated that the highest tertile of AFR level showed an increased odds ratio for the prevalence of CVD. These findings suggest that AFR levels can be used to detect the prevalence of CVD in HD patients with or without diabetes.

Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin.

Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.

Adenovirus-mediated transfer of thyroid transcription factor-1 induces radioiodide organification and retention in thyroid cancer cells.

Loss of thyroid-specific gene expression and functions accompanied by loss of thyroid transcription factors render them unresponsive to radioiodide therapy in poorly differentiated and anaplastic thyroid cancer. In anticipation of reactivation of thyroid functions, we investigated the effect of thyroid transcription factor-1 (TTF-1) gene transfer on thyroid cancer cells. Reexpression of thyroperoxidase (TPO) and thyroglobulin (Tg) mRNA and protein was detected in poorly differentiated human thyroid cancer cells that were infected with an adenovirus vector containing TTF-1 (AdTTF-1). Although TTF-1 gene transfer faintly induced iodide uptake, the induction of sodium/iodide symporter (NIS) mRNA was not observed in AdTTF-1-infected cells. To analyze the effect of TTF-1 on iodide metabolism, we transfected an NIS expression vector into BHP18-21v cells and cloned a cell line (N-BHP18-21v) that stably expressed NIS. The treatment of N-BHP18-21v cells with AdTTF-1 significantly increased the amount of protein-bound radioiodide and prolonged the iodide efflux. AdTTF-1 injections significantly induced iodide retention and organification in tumors formed from N-BHP18-21v cells in nude mice. These results indicate that AdTTF-1 specifically induces iodide organification and retards iodide efflux in thyroid cancer cells in vitro and in vivo.

Complete remission of diabetic nephropathy in a type 1 diabetic patient with near-nephrotic range proteinuria and reduced renal function.

There is scant knowledge on the changes in renal histological findings in type 1 diabetic patients those initially had nephrotic proteinuria and decreased renal function and later had complete remission of diabetic nephropathy by multifactorial treatment (MFT). A 44-year-old Japanese type 1 diabetic woman (duration of diabetes: 17 years) with massive proteinuria (2.9 g/day) and decreased renal function (creatinine clearance rate (Ccr): 86 mL/min) was admitted. Aggressive MFT was started with intensive insulin treatment, a low protein and low salt diet, angiotensin converting enzyme inhibitor and a diuretic. Her levels of HbA1c decreased to less than 7% within 4 months, and her high blood pressure gradually decreased and remained around mean 116/68 mmHg. Her Ccr level gradually improved and reached 108 mL/min after 78 months. Her first renal biopsy performed before MFT demonstrated diffuse and/or global accumulation of periodic acid-Schiff staining-positive mesangial matrix with increased mesangial matrix/glomerulus ratio and tubulo-interstitial fibrosis. Her second renal biopsy performed 5 years after MFT demonstrated decreased mesangial matrix/glomerulus ratio (42.0+/-4.0% to 29.2+/-1.9% [mean+/-S.D.], p<0.001) and increased her number of glomerular capillaries lumen per glomerulus (47+/-11 to 77+/-12, p<0.006). The number of vascular endothelial growth factor (VEGF)-expressing cells in the glomerular capillary significantly increased. Increased tubulo-interstitial fibrosis and the thickness of glomerular basement membrane (GBM) seen in the first biopsy specimen had decreased in the specimen taken at the second biopsy. Our case provides evidence that glomerular morphological improvements including decreased mesangial deposit and VEGF-related vasculogenesis in response to MFT goes along with functional normalization of diabetic nephropathy, which could not be attained in type 1 diabetic patients that underwent pancreas transplantation.

Focal segmental glomerulosclerosis associated with essential thrombocythemia.

Focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that is characterized by progressive proteinuria and declining renal function. Secondary FSGS is known to be associated with various diseases. However, an association of FSGS with essential thrombocythemia (ET) has been reported in few cases. We report a 76-year-old man who presented with nephrotic syndrome and hepatosplenomegaly. He had thrombocythemia after a splenectomy, which had been carried out at a nearby hospital. A renal biopsy showed that he had focal segmental glomerulosclerosis (FSGS), while assessment of the bone-marrow specimen revealed that he had ET. A possible relationship between FSGS, which occurred in association with a dramatic increase of thrombocytes after a splenectomy in a patient with ET, and increased serum levels of transforming growth factor (TGF)-beta, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF)-BB was suggested.

Extensive pancreatic necrosis in microscopic polyangiitis.

We encountered an 84-year-old woman with microscopic polyangiitis who was found to have pancreatitis on autopsy. The patient was admitted to Yamanashi University Hospital because of fever and progressive renal failure. She was diagnosed with anti-myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-related microscopic polyangiitis (MPA) and was treated successfully with prednisolone pulse therapy. Two months later, she was found unconscious at home and was transferred to hospital, where she died of cardiac arrest after 6 days. Autopsy revealed systemic vasculitis with fibrinoid necrosis (with the most severe form found in the pancreas), interstitial pneumonia, and crescentic glomerulonephritis. A review of the literature revealed that pancreatic involvement in vasculitis, although rare, is one of the complications of MPA; however, the present study is the first report to focus on the pancreatic involvement of MPA. We recommend that nephrologists consider the possibility of pancreatic involvement in this disease.

Activation of peroxisome proliferator-activated receptor-gamma inhibits apoptosis induced by serum deprivation in LLC-PK1 cells.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) belongs to a superfamily of nuclear receptors, which plays important roles in lipid and glucose metabolism. However, expression of PPARgamma in extra-adipose tissues and stimulation of apoptosis by PPARgamma activators has been previously reported. We investigated the functions of PPARgamma using a clonal kidney cell line (LLC-PK1). RT-PCR revealed the expression of PPARgamma in LLC-PK1 cells. The cells accumulated fat droplets and increased beta-oxidation of free fatty acids in response to troglitazone, a ligand for PPARgamma. At physiological concentrations, ligands for PPARgamma including troglitazone, BRL49653, and 15-deoxy-delta-12,14-prostaglandin J(2) inhibited serum-deprivation-induced apoptosis of the cells. On the other hand, PPARalpha activators did not inhibit the apoptosis. Apoptosis of LLC-PK1 cells was determined by a cell viability assay, condensation of the nucleus on fluorescent and electron microscopy, and DNA fragmentation as indicated by the appearance of nucleosomal ladders on an agarose gel. Troglitazone also suppressed serum-deprivation-induced activation of Caspase 3. However, troglitazone did not suppress apoptosis induced by ATP deprivation. Anti-apoptotic effects of troglitazone were partially blocked by a phosphatidylinositol-3-kinase (PI3K) inhibitor, wortmannin, but not by other kinase inhibitors such as PD98059 and AG490. These results suggest that PPARgamma is functionally expressed in LLC-PK1 cells, and its activation inhibits apoptosis induced by serum deprivation, at least in part, through the PI3K pathway.

Suppression of experimental crescentic glomerulonephritis by peroxisome proliferator-activated receptor (PPAR)gamma activators.

BACKGROUND: It has been recently reported that peroxisome proliferator-activated receptors (PPARs)gamma exist in various tissues and that they exibit anti-inflammatory effects. METHODS: We investigated the effects of PPARgamma activators on the development of crescentic glomerulonephritis. Crescentic glomerulonephritis was induced by the injection of rabbit anti-rat glomerular basement membrane antibody in WKY rats. RESULTS: Administration of troglitazone suppressed urinary protein excretion and crescent formation as indicated by crescent scores. Pioglitazone, a PPARgamma activator, mimicked the effect of troglitazone, but bezafibrate, a PPARalpha-activator, did not. Immunohistology revealed that troglitazone and pioglitazone inhibited the infiltration of ED-1-positive monocyte/macrophages and CD8-positive cells into glomeruli. CONCLUSIONS: In the present study, we demonstrated that PPARgamma activators exert antinephritic effects by suppressing the recruitment of inflammatory cells via a PPARgamma-dependent mechanism.