Kidney Podocyte Zebra Bodies after Lung Transplantation for Lymphangioleiomyomatosis.

A 55-year-old woman showed progressive renal dysfunction after unilateral deceased-donor lung transplantation for lymphangioleiomyomatosis. A kidney biopsy showed a striped pattern of interstitial fibrosis, suggesting calcineurin inhibitor toxicity, and zebra body accumulation predominantly in the podocytes, characteristics of Fabry disease. Nevertheless, she had no extra-renal symptoms of the disease, and gene testing identified no known pathogenic variant or exon deletion. Our case report and literature review suggest that this atypical lysosomal inclusion may be phospholipidosis induced by sertraline. Potential underlying etiologies linking zebra body deposits may be not only hereditary but also drug-induced phospholipidosis.

Renal-limited ANCA-associated vasculitis during erlotinib treatment for lung carcinoma.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had clinical success in the treatment of non-small cell lung carcinoma (NSCLC). An effect of this drug on kidney has not been clarified and the occurrence of glomerulonephritis related to EGFR-TKI has rarely been reported. We present the case of a 71-year-old man with NSCLC who developed proteinuria and microscopic hematuria with the rise in a titer of MPO-ANCA, when 2 years and 3 months passed since the initiation of erlotinib, one of oral EGFR-TKI. Two serial biopsies support that ANCA-associated vasculitis may have been modified by the persistent use of erlotinib. We initiated intravenous pulse therapy with methylprednisolone followed by oral prednisone. The proteinuria has decreased and serum CRP was normalized. However, the serum creatinine level and hematuria did not change during the treatment period. While EGFR inhibition is implicated in protective control for glomerulonephritis, it may exacerbate vasculitis. Close monitoring of the kidney function and urinary findings is required during the use of EGFR inhibitors, such as erlotinib, because it may cause renal adverse events.

Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance.

AIMS: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants. METHODS: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data. RESULTS: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance. CONCLUSIONS: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.

Regional Variance of the Early Use of Tolvaptan for Autosomal Dominant Polycystic Kidney Disease.

Background: The development and prompt dissemination of the first drug against a particular disease can contribute to improvements in national health status and medical economy end points and are assumedly affected by socioeconomic factors that have yet to be analyzed. Tolvaptan, a vasopressin receptor 2 antagonist, was developed to treat hyponatremia, congestive heart failure, and cirrhosis ascites, although the approved indications may differ among countries. In Japan, high-dose tolvaptan tablets were approved as the first drug for autosomal dominant polycystic kidney disease (ADPKD) in 2014. This study aimed to better understand the factors that influence the total number of regional prescriptions of tolvaptan for ADPKD since its launch. Methods: The National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data was used as a national claim-based database. In each of the 47 prefectures in Japan, the total prescribed number of 30 mg tolvaptan tablets between 2015 and 2017 was examined. The parameters explaining the prescription variation among regions were then examined by correlation analysis. Results: Prescriptions for high-dose tolvaptan increased substantially 2 years after the drug's approval; however, the increase differed by approximately 21-fold between regions. Population density was positively associated with prescribed 30 mg tolvaptan tablets per 1000 population in 2015 (r=0.47, P<0.001). In addition, the increase in prescribed number of tablets per 1000 population was correlated with population density in 2016-2017 (r=0.30, P=0.04). Conclusions: This macro perspective analysis revealed an urban-rural inequity in prescriptions for the newly approved drug for ADPKD. Further studies are needed to elucidate the factors affecting the geographic variation.

Renal Effects after Pembrolizumab Treatment for Non-small Cell Lung Carcinoma.

Immune checkpoint inhibitors (CPIs), including pembrolizumab, are becoming common oncological treatments. CPIs have been associated with a significant risk of developing immune-related adverse events (irAEs), such as nephritis and interstitial nephritis. However, the occurrence of glomerulonephritis has only rarely been reported. We herein present the case of a 75-year-old woman with non-small cell lung carcinoma (NSCLC) who developed proteinuria and microscopic hematuria during treatment with pembrolizumab. Renal biopsy revealed tubulointerstitial nephritis and IgA nephropathy. Considering that a urinalysis showed no abnormality before treatment, the condition might have been induced by pembrolizumab. In this report, we focus on the correct diagnosis and management of renal irAEs, which remain controversial.

Renal thrombotic microangiopathy during nintedanib treatment for idiopathic pulmonary fibrosis
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Agents that block vascular endothelial growth factor (VEGF) and its downstream pathway have been reported to be associated with nephrotoxicity including hypertension, proteinuria, and renal dysfunction. Bevacizumab, a monoclonal antibody against VEGF, is known to cause thrombotic microangiopathy (TMA), while tyrosine kinase inhibitors (TKIs) that block VEGF downstream are mainly associated with minimal change disease or focal segmental glomerulosclerosis. The question regarding the source of the diverse phenotypes of nephrotoxicity associated with these agents remains enigmatic. Nintedanib, a multitargeted TKI, blocks fibroblast growth factor and platelet-derived growth factor receptor as well as VEGF receptor, and is indicated for the treatment of idiopathic pulmonary fibrosis. We describe a case of a 45-year-old male who presented with isolated proteinuria of 1.3 g/g Cr 3 years after beginning nintedanib treatment. The kidney biopsy revealed histological features consistent with renal TMA. He underwent single lung transplantation 6 months later, which enabled cessation of nintedanib, and, 1 month later, his proteinuria results were negative. Unlike other types of TKIs, the pathological findings of nintedanib-induced nephrotoxicities have been limitedly reported. This is the first case of isolated proteinuria likely caused by nintedanib-induced TMA.

Prognostic factors of Erdheim-Chester disease: a nationwide survey in Japan.

Erdheim-Chester disease is a rare histiocytosis with insufficient clinical data. To clarify the clinical features and prognostic factors of Erdheim-Chester disease, we conducted a nationwide survey to collect the detailed data of 44 patients with Erdheim-Chester disease in Japan. The median age of onset of the participants was 51 (range: 23-76) years, and the median number of involved organs per patient was 4 (range: 1-11). The existence of central nervous system disease was correlated with older age (P=0.033), the presence of cardiovascular lesions (P=0.015), and an increased number of involved organs (P=0.0042). The median survival from the onset was 10.4 years, and >3.0 mg/dL C-reactive protein level at onset was associated with worse outcome (median survival, 14.6 vs. 7.4 years; P=0.0016). In a multivariate analysis, age >60 years (hazard ratio, 25.9; 95% confidence interval, 2.82-237; P=0.0040) and the presence of digestive organ involvement (hazard ratio, 4.74; 95% confidence interval, 1.05-21.4; P=0.043) were correlated with worse survival. Fourteen patients had available histological samples of Erdheim- Chester disease lesions. BRAFV600E mutation was detected in 11 patients (78%) by Sanger sequencing. A correlation between BRAF mutation status and clinical factors was not observed. Our study revealed that age and digestive organ involvement influence the outcome of Erdheim-Chester disease patients, and an inflammatory marker, such as C-reactive protein, might reflect the activity of this inflammatory myeloid neoplasm.

The Longitudinal Study of Liver Cysts in Patients With Autosomal Dominant Polycystic Kidney Disease and Polycystic Liver Disease.

INTRODUCTION: Although polycystic liver disease (PCLD) is one of the extrarenal complications in patients with autosomal dominant polycystic kidney disease (ADPKD), longitudinal changes and the association with total liver volume (TLV) have not been clearly elucidated yet. METHODS: Patients with ADPKD were chosen who underwent computed tomography or magnetic resonance imaging twice or more during August 2003 through December 2015. TLV, each cyst volume, and the proportion of parenchyma were measured. The natural history of liver cysts and the association between TLV and liver cysts were evaluated. To compare with liver cysts in ADPKD patients with PCLD, simple liver cysts in patients without ADPKD were also evaluated. RESULTS: TLV at baseline and its growth rate in all the patients with ADPKD, whose serum creatinine, estimated glomerular filtration rate, and total kidney volume were 1.45 mg/dl (0.76-2.32 mg/dl), 38.5 ml/min per 1.73 m2 (18.7-57.9 ml/min per 1.73 m2), and 1394 ml (773-2861 ml), were 1431 ml (1062-1749 ml) and -0.95%/yr (-3.16 to 4.94%/yr), respectively, in the observation period (median, 1063 days). Neither TLV nor its growth rate was significantly different between ADPKD patients with PCLD and those without PCLD. The growth rate of 79 liver cysts was 39.5%/yr (17.5-80.8%/yr) in PCLD patients with ADPKD. It was significantly larger than that of 60 simple liver cysts in the non-ADPKD group, 11.0%/yr (-2.2 to 33.1%/yr). Moreover, the proportion of parenchyma reduced, whereas that of total cyst volume increased significantly (P = 0.001). DISCUSSION: The reduction of parenchyma was accompanied by the growth of liver cysts during time course in PCLD patients with ADPKD.

Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1α expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.

Umbilical Cord Blood Transplantation-associated Nephrotic Syndrome Successfully Treated by Low-density Lipoprotein Apheresis.

The development of nephrotic syndrome (NS) after umbilical cord transplantation (UBT) has been reported in only four cases to date. We herein report the case of a 50-year-old woman who developed NS 94 days after UBT. She fell into oliguria and required dialysis. A kidney biopsy revealed focal and segmental glomerulosclerosis. Although glucocorticoid monotherapy did not improve her condition, the addition of low-density lipoprotein (LDL) apheresis resulted in remission of NS, a drastic improvement in her renal function, and withdrawal from dialysis. To the best of our knowledge, this is the first report of UBT-associated NS treated with LDL apheresis.

The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3. METHODS: We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP. RESULTS: The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002). CONCLUSIONS: PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.

High-throughput screening identified disease-causing mutants and functional variants of α-galactosidase A gene in Japanese male hemodialysis patients.

Fabry disease is a genetic disorder caused by deficient activity of lysosomal enzyme α-galactosidase A (GLA) and end-stage renal disease (ESRD) will be present after accumulation of glycosphingolipids within the kidney. Undiagnosed atypical variants of Fabry disease, which are limited to renal involvement, were found in several ESRD patient populations. On the other hand, unexpectedly high frequencies of male subjects having the c.196G>C nucleotide change (p.E66Q) showing low α-GLA activity have been reported on Japanese and Korean screening for Fabry disease. However, several evidences indicate the c.196G>C is not a pathogenic mutation but is a functional polymorphism. In the present study, high-throughput screening of serum GLA could successfully indentify two Fabry disease patients in a cohort consisted of 1080 male hemodialysis patients. Moreover, our serum assay was able to distinguish two patients with disease-causing genetic mutations (p.G195V and p.M296I) from eight functional variants that showed relatively decreased enzyme activity (p.E66Q). In conclusion, high-throughput serum enzyme assay distinctly identified disease-causing mutants and functional variants of GLA gene in Japanese male hemodialysis patients. In addition, our results underscore the high prevalence of not only undiagnosed Fabry patients but functional variants of p.E66Q among the ESRD population.

Combination of two urinary biomarkers predicts acute kidney injury after adult cardiac surgery.

BACKGROUND: Urinary L-type fatty acid-binding protein (L-FABP) has not been evaluated for adult post-cardiac surgery acute kidney injury (AKI) to date. This study was undertaken to evaluate a biomarker panel consisting of urinary L-FABP and N-acetyl-ß-D-glucosaminidase (NAG), a more established urinary marker of kidney injury, for AKI diagnosis in adult post-cardiac surgery patients. METHODS: This study prospectively evaluated 77 adult patients who underwent cardiac surgery at 2 general hospitals. Urinary L-FABP and NAG were measured before surgery, at intensive care unit arrival after surgery (0 hours), 4, and 12 hours after arrival. The AKI was diagnosed by the Acute Kidney Injury Network criteria. RESULTS: Of 77 patients, 28 patients (36.4%) developed AKI after surgery. Urinary L-FABP and NAG were significantly increased. However, receiver operating characteristic (ROC) analysis revealed that the biomarkers' performance was statistically significant but limited for clinical translation (area under the curve of ROC [AUC-ROC] for L-FABP at 4 hours 0.72 and NAG 0.75). Urinary L-FABP showed high sensitivity and NAG detected AKI with high specificity. Therefore, we combined these 2 biomarkers, which revealed that this combination panel can detect AKI with higher accuracy than either biomarker measurement alone (AUC-ROC 0.81). Moreover, this biomarker panel improved AKI risk prediction significantly compared with predictions made using the clinical model alone. CONCLUSIONS: When urinary L-FABP and NAG are combined, they can detect AKI adequately, even in a heterogeneous population of adult post-cardiac surgery AKI. Combining 2 markers with different sensitivity and specificity presents a reasonable strategy to improve the diagnostic performance of biomarkers.

A novel mechanism in maggot debridement therapy: protease in excretion/secretion promotes hepatocyte growth factor production.

Maggot debridement therapy (MDT) is effective for treating intractable wounds, but its precise molecular mechanism, including the association between MDT and growth factors, remains unknown. We administered MDT to nine patients (66.3 ± 11.8 yr, 5 male and 4 female) with intractable wounds of lower extremities because they did not respond to conventional therapies. Significant increases of hepatocyte growth factor (HGF) levels were observed in femoral vein blood during 48 h of MDT (P < 0.05), but no significant change was found for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-ß1 (TGF-ß1), or tumor necrosis factor-α (TNF-α). We conducted NIH-3T3 cell stimulation assay to evaluate the relation between HGF and protease activity in excretion/secretion (ES) derived from maggots. Compared with the control group, HGF was significantly higher in the 0.05 µg/ml ES group (P < 0.01). Furthermore, protease inhibitors suppressed the increase of HGF (P < 0.05). The HGF expression was increased in proportion to the ES protein concentration of 0.025 to 0.5 µg/ml. In fact, ES showed stronger capability of promoting HGF production and less cytotoxicity than chymotrypsin or bromelain. HGF is an important factor involved in cutaneous wound healing. Therefore, these results suggest that formation of healthy granulation tissue observed during MDT results from the increased HGF. Further investigation to identify molecules enhancing HGF expression by MDT will contribute greatly to drug target discovery for intractable wound healing therapy.

Differences in associated factors between aortic and mitral valve calcification in hemodialysis.

Increased prevalence of aortic and mitral valve calcification has been reported in patients on hemodialysis, but it remains unknown whether aortic and mitral valve calcification arise from similar pathogenesis. We detected heart valve calcification using two-dimensional echocardiography, and we related valve calcification to various clinical parameters in patients treated with hemodialysis three times a week for more than 1 year. In 112 patients (77 men and 35 women, age 67+/-10 years, duration on hemodialysis 95+/-67 months), aortic and mitral valve calcification were observed in 84 (75.0%) and 58 (51.7%) patients, respectively. Aortic valve calcification was associated with increased age, higher serum calcium, lower serum albumin, lower total cholesterol and higher high-sensitivity C-reactive protein. Multivariate analysis showed that increased age and higher serum calcium were independently associated with aortic valve calcification. Conversely, mitral valve calcification was associated with increased age, higher high-sensitivity C-reactive protein and higher serum beta(2)-microglobulin, but not with higher serum calcium. In multivariate analysis, increased age and higher serum beta(2)-microglobulin were independently associated with mitral valve calcification. Serum beta(2)-microglobulin was associated with longer duration on hemodialysis, malnutrition inflammation (lower serum albumin and higher high-sensitivity C-reactive protein) and dyslipidemia. Considering the results in previous studies showing that the distribution of beta(2)-microglobulin amyloid deposition was consistent with that of tissue calcification in patients on hemodialysis, beta(2)-microglobulin may have pathogenic roles in valve calcification.

Impact of coronary artery calcification in hemodialysis patients: Risk factors and associations with prognosis.

The risk factors of coronary artery calcification (CAC) and the impact of CAC on cardiovascular events, cardiovascular deaths, and all-cause deaths in hemodialysis (HD) patients have not been fully elucidated. We examined the CAC score (CACS) in 74 HD patients using electron-beam computed tomography. Fifty-six patients underwent a second electron-beam computed tomography after a 15-month interval to evaluate CAC progression. We evaluated (1) the risk factors for CAC and its progression and (2) the impact of CAC on the prognosis. In the cross-sectional study, HD vintage and high-sensitive C-reactive protein (hsCRP) were the independent risk factors for CAC. In the prospective cohort study, delta CACS (progression of CAC) was significantly correlated with hsCRP, fibrinogen, and serum calcium level in the univariate analysis. Stepwise multiple regression analysis revealed that only hsCRP was the independent risk factor for CAC progression in HD patients. Kaplan-Meier survival analysis revealed that cardiovascular events (P<0.0001), cardiovascular deaths (P=0.039), and all-cause deaths (P=0.026) were significantly associated with CACS. In conclusion, CAC had significantly progressed in HD patients during the 15-month observation period. Microinflammation was the only independent risk factor for CAC progression in HD patients. The advanced CAC was a significant prognostic factor in HD patients, i.e., which was strongly associated with future cardiovascular events, cardiovascular deaths, and all-cause deaths.

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease.

Hypertension has an important function in the formation of renal arterio-arteriolosclerosis. However, renal arterio-arteriolosclerosis is sometimes found in biopsy specimens of normotensive patients, which indicates unknown factors may contribute to renal arterio-arteriolosclerosis. In this study, we aimed to evaluate the effects of glucose metabolism/insulin resistance on renal arterio-arteriolosclerosis. Forty-eight patients with biopsy-proven non-diabetic chronic glomerular disease were included. Renal arterio-arteriolosclerosis was evaluated as the percentage of vessels showing hyaline changes or wall thickening. We correlated renal arterio-arteriolosclerosis with clinical parameters including indices obtained by 75 g oral glucose tolerance test. Of the 48 patients, 30 had hypertension. The results of univariate analysis showed significant association of renal arterio-arteriolosclerosis with hypertension, increased serum creatinine (S-Cr), hypertriglyceridemia, increased 2-h plasma glucose (PG) and increased 2-h plasma insulin (PI). In stepwise multiple regression analysis, hypertension (beta=0.344, P=0.009), S-Cr (beta=0.287, P=0.03) and 2-h PG (beta=0.274, P=0.03) were independently associated with renal arterio-arteriolosclerosis. Eleven of the 30 hypertensive patients did not have renal arterio-arteriolosclerosis. The hypertensive patients with renal arterio-arteriolosclerosis showed significantly higher 2-h PG (134+/-25 vs. 106+/-26 mg per 100 ml, P=0.008) and higher 2-h PI (67.7+/-34.9 vs. 48.3+/-30.0 microU ml(-1), P=0.04) compared with those without renal arterio-arteriolosclerosis, but the difference in S-Cr was not significant. Postprandial hyperglycemia and hyperinsulinemia may contribute to the formation of renal arterio-arteriolosclerosis independently of hypertension.

Association of heart valve calcification with malnutrition-inflammation complex syndrome, beta-microglobulin, and carotid intima media thickness in patients on hemodialysis.

Heart valve calcification is an important predictor for all-cause and cardiovascular mortality in hemodialysis patients. Recently, serum beta(2)-microglobulin has been associated with cardiovascular disease in the non-hemodialysis population, but the relationship between serum beta(2)-microglobulin and valve calcification remains unknown. In this cross-sectional study, we recorded the patients' clinical parameters, including serum beta(2)-microglobulin, and related these parameters to the number of calcified valves detected by echocardiography. The patients included 80 males and 35 females (age 67 +/- 10 years; duration on hemodialysis 96 +/- 67 months). Calcification of the aortic and mitral valves was observed in 89 (77.4%) and 59 patients (51.3%), respectively. Fifty-one patients (44.3%) showed calcification of both valves. In univariate analysis, age (r = 0.301, P = 0.001), serum albumin (r = -0.219, P = 0.01), calcium (r = 0.205, P = 0.02), high sensitivity C-reactive protein (r = 0.209, P = 0.02), and beta(2)-microglobulin (r = 0.206, P = 0.02) significantly correlated with the number of calcified valves. Stepwise multiple regression analysis showed that age (beta = 0.389, P < 0.001) and calcium (beta = 0.223, P = 0.01) were independent determinants for valve calcification (r(2) = 0.195). In addition, carotid intima media thickness was significantly higher in patients with valve calcification compared with those without valve calcification. Our results suggested the impacts of calcium metabolism and malnutrition-inflammation complex syndrome on valve calcification. In addition, serum beta(2)-microglobulin may be another potential marker of cardiovascular complications in patients on hemodialysis.