Serum Sclerostin Levels and Mortality in Hemodialysis Patients: An 8-Year Prospective Study.

INTRODUCTION: Sclerostin is an osteocyte-derived inhibitor of bone formation and is increased in kidney failure. Sclerostin might be involved in the pathogenesis of vascular calcification, but few studies have examined the association between sclerostin and mortality in hemodialysis patients. METHODS: We analyzed a prospective cohort of 654 patients undergoing maintenance hemodialysis. The primary exposure variable was the baseline serum sclerostin level measured at study enrollment. The primary outcome was 8-year all-cause mortality. Mortality risk was assessed using Cox regression models adjusted for potential confounders. RESULTS: During a median follow-up of 7.6 years (interquartile range, 4.1-8.0 years), 229 of the 654 participants died. In a univariate analysis, serum sclerostin levels were not associated with mortality (HR per doubling, 0.94; 95% CI, 0.76-1.17). This result was unchanged after adjustment for age, sex, dialysis vintage, diabetes, prior cardiovascular disease, and body mass index (HR per doubling, 0.92; 95% CI, 0.72-1.17). Similar results were obtained for cardiovascular mortality. CONCLUSION: Serum sclerostin levels were not associated with mortality in maintenance hemodialysis patients. Further research is required to determine the role of sclerostin in vascular calcification and cardiovascular disease in kidney failure.

Continuous intradialytic amino acid infusion from the start of dialysis is better to avoid catabolism under the high-volume pre-dilution on-line HDF.

It was reported that amino acid infusion during hemodialysis is useful for improving nutritional status. The optimal administration method of amino acid infusion under the high-volume pre-dilution on-line HDF (HVPO-HDF) was analyzed in this study. Subjects were 10 patients on maintenance dialysis at our clinic. We performed high-volume pre-dilution on-line HDF. We investigated two methods for administration of Neoamiyu® 200-ml total amino acid (TAA) infusion for patients with renal failure: (1) continuous infusion into the dialysis circuit for 4 h from the start of dialysis to its completion (infusion rate 50 ml/h) and (2) continuous infusion started 1 h before completion of dialysis (infusion rate 200 ml/h), and compared pre- and post-dialysis blood concentrations and leakage of TAA, essential amino acids (EAA), and nonessential amino acids (NEAA) between these methods. Pre-dialysis blood concentrations of amino acids showed no difference between both the groups. Post-dialysis blood concentrations of amino acids were higher in all concentrations were significantly higher with continuous infusion starting 1 h before completion of dialysis. Leakage of amino acids showed no difference between both the groups. The continuous intradialytic amino acid infusion from the start of dialysis is better to avoid catabolism under high-volume pre-dilution on-line HDF.

Metacarpal bone mineral density by radiographic absorptiometry predicts fracture risk in patients undergoing maintenance hemodialysis.

The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guideline update suggests bone mineral density testing to assess fracture risk in patients with chronic kidney disease, but dual-energy X-ray absorptiometry is not available in most dialysis facilities. Radiographic absorptiometry is an inexpensive and quick method for evaluating bone mineral density. Therefore, we analyzed a historical cohort of 456 maintenance hemodialysis patients to determine whether metacarpal bone mineral density measured by digital image processing, a computer-assisted radiographic absorptiometry technique, predicts fracture risk. At baseline, the median metacarpal bone mineral density T-score was -2.05 (interquartile range, -3.35 to -0.99). During a mean follow-up of 5.3 years, there were 16 clinical fractures and 11 asymptomatic vertebral fractures as estimated by height loss. Metacarpal bone mineral density T-score was significantly lower in patients who sustained a clinical fracture than in those remaining event-free. Decreasing metacarpal bone mineral density T-score was significantly associated with increased risk of clinical fracture (hazard ratio, 1.41 per 1 standard deviation decrease in bone mineral density T-score [95% confidence interval, 1.09 to 1.83]; the hazard ratio for lowest versus highest tertile was 4.86 [1.03 to 22.92]. Similar associations were observed between metacarpal bone mineral density T-score and vertebral fracture or any fracture. The results were robust to different analysis strategies and were consistent across different subgroups. Thus, radiographic absorptiometry could be a useful tool for primary screening of hemodialysis patients at high risk for fracture. Additional studies are required to determine the predictive ability of radiographic absorptiometry techniques compared to dual-energy X-ray absorptiometry or other established methods.

Amino acid losses are lower during pre-dilution on-line HDF than HD of the same Kt/V for urea.

In this study, we investigated differences in amino acid losses between HD and pre-dilution on-line HDF with equal Kt/V for urea to determine which modality removes less amino acids from extravascular pools and ensures better nutrition. The subjects were patients receiving pre-dilution on-line HDF (n = 10) or HD (n = 10) at this hospital. Dialysis time was 4 h for all patients. In patients on HD, the blood flow rate was 200 mL/min and the dialysate flow rate was 463 ± 29.3 mL/min. In patients on pre-dilution on-line HDF, the blood flow rate was 240 ± 20 mL/min, the dialysate flow rate was 565.0 ± 42.5 mL/min, and the substitution flow rate (substitution volume) was 252.8 ± 26.4 mL/min (57.0 ± 6.0 L). Kt/V for urea was comparable between patients on HD and patients on pre-dilution on-line HDF (1.46 ± 0.25 vs. 1.46 ± 0.31). Amino acid loss and clear space were evaluated. Patients on pre-dilution on-line HDF lost significantly less glutamine and arginine (p < 0.01 and p = 0.032) and significantly less nonessential amino acids (NEAAs) than patients on HD (p = 0.013). They also had significantly lower clear space of total amino acids (TAAs), NEAAs, essential amino acids (EAAs), and branched-chain amino acids (BCAAs) than patients on HD (Total AA p = 0.019, NEAA p = 0.018, EAA p = 0.024, BCAA p = 0.042). When Kt/V for urea is equal, pre-dilution on-line HDF ensures better nutrition than does HD.

Nutritional status and survival of maintenance hemodialysis patients receiving lanthanum carbonate.

Background: Hyperphosphatemia and poor nutritional status are associated with increased mortality. Lanthanum carbonate is an effective, calcium-free phosphate binder, but little is known about the long-term impact on mineral metabolism, nutritional status and survival. Methods: We extended the follow-up period of a historical cohort of 2292 maintenance hemodialysis patients that was formed in late 2008. We examined 7-year all-cause mortality according to the serum phosphate levels and nutritional indicators in the entire cohort and then compared the mortality rate of the 562 patients who initiated lanthanum with that of the 562 propensity score-matched patients who were not treated with lanthanum. Results: During a mean ± SD follow-up of 4.9 ± 2.3 years, 679 patients died in the entire cohort. Higher serum phosphorus levels and lower nutritional indicators (body mass index, albumin and creatinine) were each independently associated with an increased risk of death. In the propensity score-matched analysis, patients who initiated lanthanum had a 23% lower risk for mortality compared with the matched controls. During the follow-up period, the serum phosphorus levels tended to decrease comparably in both groups, but the lanthanum group maintained a better nutritional status than the control group. The survival benefit associated with lanthanum was unchanged after adjustment for time-varying phosphorus or other mineral metabolism parameters, but was attenuated by adjustments for time-varying indicators of nutritional status. Conclusions: Treatment with lanthanum is associated with improved survival in hemodialysis patients. This effect may be partially mediated by relaxation of dietary phosphate restriction and improved nutritional status.

Restless legs syndrome effectively treated with constant-pressure predilution online hemodiafiltration.

BACKGROUND: We encountered a case of unstable predilution online HDF due to elevated transmembrane pressure (TMP) when performing constant-speed predilution online hemodiafiltration (HDF) as treatment for restless legs syndrome (RLS) in a dialysis patient. We report the effectiveness of incorporating a newly developed constant-pressure predilution online HDF system as a preventive measure against unstable online HDF and frequent adjustment of settings when treating dialysis patients with RLS. CASE PRESENTATION: A 55-year-old man had suffered from RLS and been undergoing constant-speed online HDF with 45 L target predilution and an ABH-21P hemodiafilter. The symptoms of RLS rated 10 on the International Restless Legs Syndrome Rating Scale (IRLS). The α1-microglobulin (α1-MG) removal rate was only 27.8%, so the hemodiafilter was subsequently replaced with a PEPA hemodiafilter. However, episodes of elevated TMP exceeding 250 mmHg occurred frequently after the replacement and were managed by reducing dialysate flow rate. Therefore, we incorporated a constant-pressure predilution online HDF that maintains TMP below 200 mmHg. The amount of replacement was maintained at approximately 43.5 ± 6.98 L and the α1-MG removal rate was 39.5%, with no need to manually reduce the flow rate. The Alb leakage in dialysate waste was 7.9 g. The patient has maintained an IRLS rating of 0 with no RLS symptoms for the past 4 years. CONCLUSIONS: Using the constant-pressure mode enabled achieved the clinical endpoint, namely, resolution of RLS with no need to manually reduce the flow rate.

Protective upregulation of activating transcription factor-3 against glutamate neurotoxicity in neuronal cells under ischemia.

This study evaluates the pathological role of the stress sensor activating transcription factor-3 (ATF3) in ischemic neurotoxicity. Upregulation of the transcript and protein for ATF3 was seen 2-10 hr after reperfusion in the ipsilateral cerebral hemisphere of mice with transient middle cerebral artery occlusion for 2 hr. Immunohistochemical analysis confirmed the expression of ATF3 by cells immunoreactive for a neuronal marker in neocortex, hippocampus, and striatum within 2 hr after reperfusion. In murine neocortical neurons previously cultured under ischemic conditions for 2 hr, transient upregulation of both Atf3 and ATF3 expression was similarly found during subsequent culture for 2-24 hr under normoxia. Lentiviral overexpression of ATF3 ameliorated the neurotoxicity of glutamate (Glu) in cultured murine neurons along with a slight but statistically significant inhibition of both Fluo-3 and rhodamine-2 fluorescence increases by N-methyl-D-aspartate. Similarly, transient upregulation was seen in Atf3 and ATF3 expression during the culture for 48 hr in neuronal Neuro2A cells previously cultured under ischemic conditions for 2 hr. Luciferase reporter analysis with ATF3 promoter together with immunoblotting revealed the possible involvement of several transcription factors responsive to extracellular and intracellular stressors in the transactivation of the Atf3 gene in Neuro2A cells. ATF3 could be upregulated to play a role in mechanisms underlying mitigation of the neurotoxicity mediated by the endogenous neurotoxin Glu at an early stage after ischemic signal inputs.

Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia.

BACKGROUND: Lanthanum carbonate is a non-calcium phosphate binder that is effective for the treatment of hyperphosphatemia. However, it is unknown whether treatment with lanthanum affects survival. METHODS: We retrospectively collected data on maintenance hemodialysis patients at 22 facilities (n = 2292) beginning in December 2008, a time point immediately prior to the commercial availability of lanthanum in Japan. We compared 3-year all-cause mortality among patients who initiated lanthanum (n = 560) and those who were not treated with lanthanum during the study period (n = 560) matched by the propensity score of receiving lanthanum. Several sensitivity analyses were performed to test the robustness of the primary analysis. RESULTS: After the market introduction of lanthanum, the percentage of patients receiving the binder increased gradually to 27%. In the propensity score-matched analysis, the mortality rate for the lanthanum group was not significantly lower than the non-lanthanum group [hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.47-1.09). However, stratification by serum phosphorus disclosed significant survival benefit of lanthanum for patients with serum phosphorus >6.0 mg/dL (HR, 0.52; 95% CI, 0.28-0.95), but not in patients with serum phosphorus ≤6.0 mg/dL (HR, 1.00; 95% CI, 0.55-1.84). The survival benefit of lanthanum in patients with serum phosphorus >6.0 mg/dL was consistent across subgroups and robust in different analytical approaches. CONCLUSIONS: Treatment with lanthanum was independently associated with a significant survival benefit in hemodialysis patients with inadequately controlled hyperphosphatemia. Further studies are required to confirm these findings.

Association of serum sodium levels with fractures and mortality in patients undergoing maintenance hemodialysis.

BACKGROUND: Hyponatremia is implicated in pathological bone resorption and has been identified as a risk factor for bone fracture in the general population. However, there are limited data on the association between serum sodium levels and fracture risk in patients undergoing hemodialysis (HD). METHODS: We analyzed a historical cohort of 2220 maintenance HD patients to examine the association between serum sodium levels and the risk of fracture and mortality. We also examined the association between serum sodium levels and osteoporosis, based on metacarpal bone mineral density, in a subcohort of 455 patients with available data. In addition, we examined the association between serum sodium levels and bone turnover markers in a separate cross-sectional cohort of 654 maintenance HD patients. RESULTS: During a median follow-up of 5.4 years, 712 patients died, 113 experienced clinical fractures, and 64 experienced asymptomatic vertebral fractures. Lower serum sodium levels were associated with an increased risk of mortality (HR 1.06 per 1 mEq/L decrease; 95% CI 1.03-1.09) but not with the risk of clinical fracture (HR 1.04 per 1 mEq/L decrease; 95% CI 0.97-1.11). A similar lack of association was observed for asymptomatic vertebral fracture and any fracture. Serum sodium levels were also not associated with osteoporosis in a subcohort with available data (n = 455) or with bone alkaline phosphatase or tartrate-resistant acid phosphatase-5b in a separate cross-sectional cohort. CONCLUSION: Serum sodium levels were associated with mortality but not with fracture risk, osteoporosis, or bone turnover markers in maintenance HD patients.

Delayed mitochondrial membrane potential disruption by ATP in cultured rat hippocampal neurons exposed to N-methyl-D-aspartate.

Necrotic damage leads to a massive leakage from injured cells of different intracellular constituents such as glutamate (Glu) and ATP, which are believed to play a role in the neuronal survival in the brain. In this study, we evaluated pharmacological properties of ATP, which is shown to be an endogenous inhibitor of N-methyl-D-aspartate (NMDA) receptors, on the neurotoxicity relevant to mitochondrial membrane potential disruption in cultured rat hippocampal neurons. Exposure to Glu or NMDA significantly inhibited cellular viability determined 24 and 48 h later, while simultaneous addition of 1 mM ATP significantly ameliorated the decreased viability in neurons exposed to Glu and NMDA, but not in those exposed to other cytotoxins. Both Glu and NMDA markedly increased intracellular free Ca(2+) levels in a manner sensitive to blockade by the exposure to ATP, but not by that to adenosine. Exposure to ATP significantly delayed the rate of mitochondrial membrane potential disruption induced by Glu and NMDA. These results suggest that extracellular ATP would play a role as an endogenous antagonist endowed to protect rat hippocampal neurons from the excitotoxicity mediated by NMDA receptors in association with the delayed mitochondrial membrane potential disruption after the liberation from adjacent cells under necrotic death.

Interrelationships Between Sclerostin, Secondary Hyperparathyroidism, and Bone Metabolism in Patients on Hemodialysis.

CONTEXT: Sclerostin is an osteocyte-derived inhibitor of bone formation and is increased in kidney failure, but its role in the pathogenesis of renal bone disease remains unknown. OBJECTIVE: We aimed to explore the association of serum sclerostin with bone metabolism in patients undergoing hemodialysis, with a particular focus on parathyroid hormone (PTH)-dependent and PTH-independent pathways. METHODS: This cross-sectional and prospective cohort study included 654 patients undergoing hemodialysis at 10 facilities in Japan. We employed multivariable linear regression to explore whether sclerostin levels were associated with metacarpal bone mineral density (BMD), intact PTH, bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b). We employed mediation analyses to explore whether and to what extent the association of PTH with bone turnover markers is mediated by sclerostin. We also compared sclerostin levels between patients with and without previous or incident fractures. RESULTS: The median sclerostin level in hemodialysis patients was 3- to 4-fold higher than that in healthy individuals. Higher sclerostin levels were associated with higher metacarpal BMD and lower levels of intact PTH, BAP, and TRACP-5b. However, the relationships of sclerostin with bone turnover markers were substantially attenuated after adjustment for PTH. Mediation analysis suggested that the effects of PTH on bone turnover markers were mainly direct rather than mediated by sclerostin. Sclerostin levels were not associated with previous or incident fractures. CONCLUSION: These findings suggest that in patients undergoing dialysis, sclerostin has only a limited role in bone metabolism and may not mediate the effect of PTH on bone turnover.

Assessment of the accuracy of an intermittent-scanning continuous glucose monitoring device in patients with type 2 diabetes mellitus undergoing hemodialysis (AIDT2H) study.

FreeStyle Libre has been approved for use in patients undergoing hemodialysis (HD) in Japan, unlike Europe and the United States; however, evidence regarding its accuracy in such patients is sparse. Forty-one participants with type 2 diabetes undergoing HD were recruited. The overall mean absolute relative difference and mean absolute difference were 23.4% and 33.9 mg/dL, respectively. Sensor glucose levels and capillary glucose levels were significantly correlated (r = 0.858, P < .01), although the sensor glucose levels were significantly lower than the capillary glucose levels. The accuracy of FreeStyle Libre in patients undergoing HD became deteriorated with the days of usage. The percentage of sensor results in Zones A and B in the consensus error grid analysis and in the Clarke error grid analysis were 99.7% and 99.0%, respectively. Its insufficient accuracy necessitates adjunct usage of FreeStyle Libre with self-monitoring of blood glucose in patients undergoing HD.

Carbohydrate Counting: A Simple Method of Dietary Management for Glycemic Control in Japanese Diabetic Hemodialysis Patients.

BACKGROUND: Carbohydrate counting used in dietary therapy for diabetes is based on the concept that the postprandial rise in blood glucose levels is primarily affected by ingested carbohydrates. This method has been widely accepted and used since 1993, when its usefulness was demonstrated in the United States, largely due to the ease with which patients can understand the method. However, in Japan, there is a common misunderstanding that energy intake determines postprandial blood glucose levels. SUMMARY: We examined the effectiveness of using basic carbohydrate counting and advanced carbohydrate counting with Japanese diabetic dialysis patients. With both methods, predialysis blood glucose and HbA1c levels were significantly decreased at the final follow-up compared with preinstruction values. There were no significant changes in other parameters. The carbohydrate counting method was able to be applied independently of, but concurrently with, the control of potassium and phosphorus intake, which is the basis of dietary therapy for dialysis patients. Moreover, those patients who completed the basic carbohydrate counting instruction sessions had a mean relative carbohydrate intake (% of total energy) of 51.0 ± 4.7% per meal, indicating they did not consume a low-carbohydrate diet. Key Messages: At present, there is no literature on carbohydrate counting performed by dialysis patients. Carbohydrate counting is a useful method of dietary management for glycemic control that can be applied independently of, but concurrently with, the control of potassium and phosphorus intake in dietary therapy for dialysis patients.

Increase in the dosage amount of vitamin D3 preparations by switching from calcium carbonate to lanthanum carbonate.

It is widely known that dialysis patients who are administered vitamin D preparations have a better prognosis than patients who are not. In this study, of 22 patients on maintenance dialysis who had been administered calcium (Ca) carbonate in our hospital, we investigated the dosage amount of vitamin D3 preparations after the phosphorus (P) binder was switched from Ca carbonate to the newly developed lanthanum carbonate (LC). After completely switching to LC, the dosage amount of oral vitamin D3 preparation (alfacalcidol equivalent) was significantly increased from 0.094 µg/day to 0.375 µg/day (P = 0.0090). No significant changes were observed in the values of serum corrected Ca, alkaline phosphatase, intact parathyroid hormone and P after switching. The administration of LC enabled complete cessation of the administration of Ca carbonate preparations, and increased the dosage amount of vitamin D3 preparations. Therefore, LC may be a useful P binder to improve patient prognosis.

New method of blood purification (Recycle Filtration System).

OBJECT: We have developed a new blood purification system, the Recycle Filtration System (RFS), because back contamination of endotoxin (ET) from the dialysate in on-line hemodiafiltration (HDF) is a potential problem when a highly permeable membrane is used. METHODS: When the RFS is used for HDF, some of the purified fluid is pumped by a purified fluid pump to the venous side of the blood circuit, and the remainder is returned to the filtrate side of the hemofilter to be used for diffusion. This circuit enables simultaneous diffusion and filtration through the hemofilter. RESULTS: 1. The rate of removal of urea nitrogen (UN) increased with either decreased or increased quantity of recycled filtration flow (QRF). The rate of removal of beta-2-microglobulin (ß2-MG) decreased as QRF increased, but its clearance and removal rate increased as the quantity of drainage flow increased. 2. No significant change in ß2-MG clearance was observed in the filtration unit, even when recycling was continued for 24 h. 3. ET was not detected in the filtration unit, even though its level in the dialysate, which was reconstituted with tap water, was 806.2±105.4 EU/L. CONCLUSION: It is possible to regulate filtration using the RFS by giving importance to the elimination of either small molecules or low-molecular-weight proteins.