Kanji Shishido

Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients

BACKGROUND AND OBJECTIVES Here, we assessed the impact of oxidized high-density lipoprotein (oxHDL), dysfunctional HDL, on mortality and cardiovascular disease (CVD) events in prevalent HD patients and compared oxHDL to interleukin-6 (IL-6), a strong predictor of CVD events in HD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS This prospective study examined a cohort of prevalent HD patients (n=412). Blood samples were obtained at baseline to measure lipids, high-sensitive C-reactive protein (hsCRP), IL-6, oxidized low-density lipoprotein, N-terminal pro B-type natriuretic peptide, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase, adiponectin, and oxHDL. Carotid intima-media thickness (CIMT) was assessed at baseline and 3-year follow-up. Nutritional status was assessed by subjective global assessment (SGA), body mass index, and geriatric nutritional risk index (GNRI). After the baseline assessment, study patients were prospectively followed up (mean observational period, 40 months). RESULTS At baseline, patients with high oxHDL had a worse nutritional state and higher HDL-cholesterol (HDL-chol), ICAM-1, and adiponectin levels and a higher oxHDL/HDL-chol ratio than low oxHDL patients. A combination of high oxHDL and high IL-6 was significantly associated with increased CIMT at baseline and a larger increase in CIMT at 3-year follow-up. High oxHDL did not predict all-cause mortality; however, it was significantly associated with CVD-related mortality and composite CVD events, particularly with concomitant high IL-6. These associations were confirmed in multivariate Cox hazard models adjusted with confounding variables. CONCLUSIONS High oxHDL, particularly with concomitant high IL-6, may be associated with an increased risk of CVD events and CVD-related mortality in prevalent HD patients.

Assessment of Myeloperoxidase and Oxidative α1-Antitrypsin in Patients on Hemodialysis

BACKGROUND AND OBJECTIVES The present study assesses the effects of the oxidative stress marker, myeloperoxidase (MPO), and the possible MPO-related oxidative stress marker, oxidative alpha(1)-antitrypsin (oxAT), on carotid intima-media thickness (CIMT) and protein-energy wasting (PEW) in patients on hemodialysis (HD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Blood samples were obtained from 383 patients before HD to measure WBC count, serum albumin, lipids, high-sensitivity C-reactive protein (CRP), alpha(1)-antitrypsin (AT), interleukin-6, oxidative LDL-C, MPO, and oxAT. We assessed both CIMT and the geriatric nutritional risk index (GNRI) in this cross-sectional competitive study. RESULTS Levels of MPO and oxAT correlated. Myeloperoxidase was associated with max-CIMT, and oxAT correlated with max-CIMT and GNRI. Multivariate linear regression models showed that MPO and oxAT were independent predictors of increasing max-CIMT, whereas oxAT, but not MPO, independently correlated with GNRI. In four combined MPO and oxAT groups classified according to median values, a multinomial logistic regression model showed that high MPO together with high oxAT was independently associated with increased max-CIMT. Moreover, the OR for max-CIMT with positive PEW and high MPO was significantly increased in the four groups with combined MPO and PEW. CONCLUSIONS High MPO with high oxAT and high MPO with PEW seem to contribute to plaque formation in patients on HD, whereas elevated MPO or oxAT alone might not predict increasing CIMT. In contrast, a high oxAT value seems to be an independent predictor of PEW in patients on HD.

Oxidized High-Density Lipoprotein Is Associated with Protein-Energy Wasting in Maintenance Hemodialysis Patients

BACKGROUND AND OBJECTIVES Oxidized HDL (oxHDL) may behave as proinflammatory HDL because of reduced anti-inflammatory capacity and is considered a risk factor for mortality in patients on maintenance hemodialysis (MHD). The study presented here assessed the effect of oxHDL on protein-energy wasting (PEW) in MHD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective study examined a cohort of MHD patients (n = 176) who were not taking lipid-lowering drugs. Blood samples were obtained to measure albumin, lipids, high-sensitivity C-reactive protein (hsCRP), oxidized LDL (oxLDL), and oxHDL. PEW was assessed by subjective global assessment (SGA) and geriatric nutritional risk index (GNRI). Measurements and assessment of nutritional status were followed up 1 year later. RESULTS OxHDL was significantly increased in patients with PEW at baseline. High oxHDL and high hsCRP were significantly associated with PEW, and receiver operating characteristic curves for oxHDL and hsCRP showed statistically similar accuracy for predicting SGA-positive status. According to multivariate regression models, high oxHDL had a significant influence on PEW in patients, particularly those with high hsCRP. Decreased changes in GNRI and high prevalence of SGA-positive status at 1 year were more common in patients with high oxHDL at baseline and 1 year later than in patients with low oxHDL at both time points. CONCLUSIONS A high oxHDL state may be associated with PEW estimated by GNRI and SGA, particularly concomitant with inflammation in MHD patients.

Detection of Peripheral Artery Disease by Duplex Ultrasonography among Hemodialysis Patients

BACKGROUND AND OBJECTIVES Peripheral arterial disease (PAD) is a known predictor of cardiovascular morbidity and mortality among hemodialysis patients. Although ankle-brachial BP index (ABI) is a simple and reliable test for PAD screening, its sensitivity has been suggested to decrease among dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a cross-sectional outpatient cohort study to examine prevalence of PAD among hemodialysis patients using duplex ultrasonography of the lower extremity artery. We also evaluate the influence of increased arterial stiffness on impaired accuracy of ABI for PAD screening. RESULTS Of 315 total patients, 23.8% had PAD. PAD was associated with younger age, diabetes, current smoking, atherosclerotic comorbidities, increased total cholesterol levels, increased triglyceride levels, and lower Kt/V. The receiver operating characteristic analysis (area under the receiver operating characteristic curve = 0.846) showed that sensitivity and specificity of ABI values for PAD were 49.0 and 94.8%, respectively. An ABI cut-off value of 1.05 resulted in the best sensitivity (74.5%) and specificity (84.4%). There was a significant difference in sensitivity of ABI levels <0.9 for detecting PAD among patients in different brachial-ankle pulse wave velocity quartiles. In patients with the highest brachial-ankle pulse wave velocity quartile, PAD was most prevalent (46.5%), and ABI had the highest accuracy in detecting PAD (area under the curve, 0.933). CONCLUSIONS These results suggest that duplex ultrasonography was a useful tool for screening asymptomatic PAD among hemodialysis patients and that the diagnostic value of ABI for PAD was affected by various factors.

Combination therapy with sevelamer hydrochloride and calcium carbonate in Japanese patients with long-term hemodialysis: alternative approach for optimal mineral management.

Abstract:  Calcium (Ca) overload by Ca‐containing phosphorus (P) binder has been suggested to be implicated in the pathogenesis of soft tissue and vascular calcification, which contribute to increased morbidity and mortality of cardiovascular disease in patients undergoing dialysis. Recently, a noncalcium P binder, sevelamer hydrochloride (sevelamer), has become available in Japan. However, Japanese patients undergoing dialysis might be less tolerant of sevelamer treatment, and it is likely to cause hypocalcemia because their dietary Ca intake is less than that in European and American patients. We evaluated the effects of combination therapy with sevelamer and calcium carbonate (CC) on mineral metabolism in Japanese hemodialysis patients, as an alternative form of P management. A total of 210 hemodialysis patients were enrolled, and were given a small dose of sevelamer (0.75–1.5 g/day) on CC treatment. Sevelamer dose was gradually increased, while CC decreased during 24 weeks. Five patients discontinued sevelamer treatment because of severe constipation, anorexia, and parathyroidectomy for severe secondary hyperparathyroidism. After 24 weeks, the dose of sevelamer was significantly increased to 3.29 g/day (initial dose: 1.47 g/day), while CC was decreased by 54%. Adjusted serum Ca significantly decreased (9.63 ± 0.57–9.45 ± 0.67 mg/dL; P = 0.0012), although serum P increased (5.89 ± 1.32–6.25 ± 1.32 mg/dL; P = 0.017). Serum intact PTH (iPTH) significantly increased in patients with a low or normal iPTH level (≤300 pg/mL), while it did not change in patients with secondary hyperparathyroidism (>300 pg/mL). The results suggest that the therapeutic regimen is more tolerant and reduces Ca load in Japanese hemodialysis patients while avoiding hypocalcemia. In addition, the mitigated Ca overload could improve PTH hyposecretion in patients with adynamic bone disease, which is associated with soft tissue calcification and higher mortality in uremia

Treatment of Hyperphosphatemia With Bixalomer in Japanese Patients on Long-Term Hemodialysis With Gastrointestinal Symptoms

Bixalomer (Bix) is an amine‐functional polymer, non‐calcium‐containing phosphate (P) binder, and has been clinically available in Japan recently. Bix is expected to cause fewer gastrointestinal (GI) side‐effects as compared with sevelamer hydrochloride (SH), because of less expansion of Bix in the GI tract. In this prospective observational study, we evaluated changes in GI symptoms by the Gastrointestinal Symptom Rating Scale (GSRS) score in long‐term hemodialysis (HD) outpatients with SH‐associated GI symptoms who switched to Bix from SH. A total of 114 patients (age 63.7 ± 10.8 year (mean ± SD), female 65.5%, HD vintage 11.2 ± 8.6 years, diabetes mellitus 27.4%) were enrolled. The GSRS score was checked at 0 and 12 weeks after the start of Bix. Bix was started at the initial dose of 750 mg/day, and then was titrated. Serum albumin, P and corrected calcium levels did not significantly change during Bix treatment. However, serum low‐density lipoprotein‐cholesterol and bicarbonate levels significantly increased during Bix treatment (P < 0.001). In GSRS scores, total and domain‐specific scores, including constipation, diarrhea, reflux and abdominal pain were significantly reduced at 0, 4, 12 and 24 weeks as compared with those at 0 weeks (P < 0.05). This study shows that Bix was well tolerated and managed hyperphosphatemia effectively after switching from SH in Japanese patients on long‐term HD. In addition, Bix might be less often associated with GI symptoms as compared with SH.

N-Terminal Pro-B-Type Natriuretic Peptide as a Biomarker for Loss of Muscle Mass in Prevalent Hemodialysis Patients.

Protein-energy wasting (PEW) is common in hemodialysis (HD) patients. A recent study demonstrated that a high level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be associated with PEW in those patients. This prospective study aimed to assess the association of NT-proBNP with body composition and muscle loss. A cohort of prevalent HD patients (n = 238) was examined. Blood samples were obtained at baseline to measure high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), adiponectin and NT-proBNP. Nutritional status and changes in muscle mass were assessed by subjective global assessment, percentage creatinine generation rate (%CGR), creatinine index (CI) and lean body mass (LBM) estimated by dual-energy X-ray absorptiometry (DXA). The %CGR and CI were calculated five times for one year, and DXA was performed at baseline and one year later. Cardiac function was estimated by ultrasonography at baseline. NT-proBNP was significantly higher in HD patients with PEW. High NT-proBNP was associated with cardiac dysfunction, increased levels of hsCRP and IL-6, and serially decreased levels of the indexes for muscle mass. Multiple regression analysis adjusted with confounders showed that NT-proBNP was an independent predictor for decrease in LBM and serial lower levels of %CGR and CI. In conclusion, the present study demonstrated a novel association between NT-proBNP and muscle loss. NT-proBNP may be an independent biomarker for malnutrition in HD patients, especially in patients with muscles loss, regardless of chronic inflammation, cardiac dysfunction, or overhydration.

Assessment of Inflow of Endotoxin and Its Fragments in Patients on Maintenance Hemodialysis

Background: We estimated the flow of endotoxins (ET) from dialysates into the blood of patients on hemodialysis (HD) using limulus amebocyte lysate (LAL) assays and endotoxin activity (EA) determined by neutrophil respiratory burst activity. Methods: A cross-sectional study compared groups given ultrapure bicarbonate (n = 15; group A), acetate-free bicarbonate dialysates (n = 20; group B) and conventional bicarbonate dialysate (n = 23; group C). A prospective study of group C examined the effect of changing the purity of the dialysate. Biomarkers of inflammation and oxidative stress were measured and ET in blood was assessed by LAL assays and EA. Results: Serum ET levels did not differ among the groups, whereas EA and the biomarkers were significantly increased in group C compared with those in groups A and B. HD using conventional dialysate was independently associated with an increase in EA. Purifying the dialysate significantly decreased EA in group C. Conclusion: Measuring EA is useful to assess the influence of dialysate contamination in HD patients.

Comparison of oral falecalcitriol and intravenous calcitriol in hemodialysis patients with secondary hyperparathyroidism: a randomized, crossover trial.

BACKGROUND Falecalcitriol is a novel vitamin D analog, which has a greater potential to suppress parathyroid hormone (PTH) and a longer half-life. There are few studies to compare clinical effects of oral falecalcitriol treatment with those of intravenous calcitriol treatment. METHODS Twenty-one patients with moderate to severe SHPT were included in a random 2 x 2 crossover trial with the two vitamin D analogs (12 weeks for each treatment). The primary endpoint measure was a decrease in serum intact PTH (iPTH) level, and the secondary outcome measures included changes in serum calcium (Ca), phosphate (P), and metabolic bone marker levels. RESULTS Both treatments decreased iPTH and whole PTH (wPTH) levels by similar degrees (iPTH, -200.1 +/- 107.0 with falecalcitriol vs. -200.8 +/- 114.9 pg/ml with calcitriol, p = 0.9895; wPTH, -137.1 +/- 73.1 with falecalcitriol vs. -120.4 +/- 81.1 pg/ml with calcitriol, p = 0.5603). Serum Ca, P, and Ca x P product levels at the end of each treatment were comparable and the frequencies of hypercalcemia and hyperphosphatemia were also similar during each treatment period. Although intravenous calcitriol treatment significantly changed intact osteocalcin and cross-linked N-telopeptide of type I collagen after 12 weeks, oral falecalcitriol treatment did not change any bone metabolic marker level. CONCLUSION The present study showed that oral falecalcitriol treatment is effective for PTH suppression, and Ca and P metabolism in hemodialysis patients with moderate to severe SHPT, as well as intravenous calcitriol administration.

Effects of 22-Oxacalcitriol and Calcitriol on PTH Secretion and Bone Mineral Metabolism in a Crossover Trial in Hemodialysis Patients With Secondary Hyperparathyroidism

Abstract:  The purpose of this crossover comparison study is to elucidate the differences between the effects of a novel calcitriol analog, 22‐oxacalcitriol, and calcitriol on parathyroid hormone (PTH) and bone mineral metabolism in hemodialysis patients with secondary hyperparathyroidism (SHPT). Twenty‐three patients with moderate to severe SHPT were included in a random 2 × 2 crossover trial with two vitamin D analogs (12 weeks for each treatment). Two patients withdrew during the run‐in period for personal reasons. Serum electrolyte, bone metabolic marker, intact PTH (iPTH) and whole PTH (wPTH) levels were measured periodically. The primary endpoint measure was a decrease in serum iPTH level, and the secondary outcome measures included changes in serum calcium (Ca), phosphate (P), and metabolic bone marker levels. Both treatments decreased iPTH and wPTH levels by similar degrees. Serum Ca, P, and Ca × P product levels at the end of each treatment were comparable and the frequencies of hypercalcemia and hyperphosphatemia were also similar during each treatment period. 22‐Oxacalcitriol significantly decreased the levels of bone metabolic markers, namely, bone‐specific alkaline phosphate, intact osteocalcin, pyridinoline, and cross‐linked N‐telopeptide of type I collagen, after a 12‐week treatment. In contrast, calcitriol did not change any of the levels of bone metabolic markers. The present study showed that 22‐oxacalcitriol is equally effective for PTH suppression, and Ca and P metabolism. In addition, 22‐oxacalcitriol might have putative actions on bone remodeling independent of its PTH suppression. Further study is necessary to confirm the effects of 22‐oxacalcitriol on bone metabolism in SHPT.