Comparison between liquid chromatography/tandem mass spectroscopy and a novel latex agglutination method for measurement of hepcidin-25 concentrations in dialysis patients with renal anemia: A multicenter study.

Background and aims: Hepcidin-25 is an iron regulatory factor that plays an important role in anemia in patients with chronic kidney disease. Although liquid chromatography/tandem mass spectroscopy (LC-MS/MS) is the gold standard for measuring hepcidin-25 concentrations, results cannot be obtained immediately at clinical sites. In contrast, the latex immunoassay (LIA) can be performed using general clinical laboratory equipment, and the results can be obtained quickly. The aim of this study was to evaluate hepcidin-25 concentrations obtained by LC-MS/MS and a novel LIA method and compare the two methods. Materials and methods: Hepcidin-25 was measured by LIA and LC-MS/MS in 182 hemodialysis patients. A hepcidin-25-specific reagent and an automatic analyzer were used for LIA, and a commercially available system was used for LC-MS/MS. The Passing-Bablok regression analysis method was used. Results: On Passing-Bablok regression analysis, the slope was 1.000, with an intercept of 0.359. Very strong associations were obtained, and the measured values were almost identical. Conclusion: The hepcidin-25 concentrations measured using LIA and those measured by LC-MS/MS were significantly correlated. LIA can be performed using general clinical examination equipment and has a higher throughput than LC-MS/MS. Therefore, measurement of hepcidin-25 concentrations by LIA can be useful for routine laboratory testing.

Validation of the patient State Index for monitoring sedation state in critically ill patients: a prospective observational study.

PURPOSE: The Patient State Index (PSI) is a newly introduced electroencephalogram-based tool for objective and continuous monitoring of sedation levels of patients under general anesthesia. This study investigated the potential correlation between the PSI and the Richmond Agitation‒Sedation Scale (RASS) score in intensive care unit (ICU) patients and established the utility of the PSI in assessing sedation levels. METHODS: In this prospective observational study, PSI values were continuously monitored via SedLine® (Masimo, Irvine, CA, USA); the RASS score was recorded every 2 h for patients on mechanical ventilation. Physicians and nurses were blinded to the PSI values. Overall, 382 PSI and RASS score sets were recorded for 50 patients. RESULTS: The PSI score correlated positively with RASS scores, and Spearman's rank correlation coefficient between the PSI and RASS was 0.79 (95% confidence interval [CI]: 0.75‒0.83). The PSI showed statistically significant difference among the RASS scores (Kruskal‒Wallis chi-square test: 242, df = 6, P < 2.2-e16). The PSI threshold for distinguishing light (RASS score ≥ - 2) sedation from deep sedation (RASS score ≤ - 3) was 54 (95% CI: 50-65; area under the curve, 0.92 [95% CI: 0.89‒0.95]; sensitivity, 0.91 [95% CI: 0.86‒0.95]; specificity, 0.81 [95% CI: 0.77-0.86]). CONCLUSIONS: The PSI correlated positively with RASS scores, which represented a widely used tool for assessing sedation levels, and the values were significantly different among RASS scores. Additionally, the PSI had a high sensitivity and specificity for distinguishing light from deep sedation. The PSI could be useful for assessing sedation levels in ICU patients. University Hospital Medical Information Network (UMIN000035199, December 10, 2018).

Catheter-related thrombosis after cardiac surgery in patients with both central venous and pulmonary artery catheters inserted into the right internal jugular vein: a single-center, prospective, observational study.

Central venous catheters (CVCs) and pulmonary artery catheters (PACs) are widely used in intensive care and perioperative management. The detection and prevention of catheter-related thrombosis (CRT) are important because CRT is a complication of catheter use and can cause pulmonary embolism and bloodstream infection. Currently, there is no evidence for CRT in patients using both CVC and PAC. We conducted a single-center, prospective, observational study to identify the incidence, timing, and risk factors for CRT in patients undergoing cardiovascular surgery and using a combination of CVC and PAC through the right internal jugular vein (RIJV). Out of 50 patients, CRT was observed using ultrasonography in 39 patients (78%), and the median time of CRT formation was 1 day (interquartile range: 1-1.5) after catheter insertion. The mean duration of PAC placement was 3 days (interquartile range: 2-5), and the maximum diameter of CRT was 12 mm (interquartile range: 10-15). In short-axis images, CRT occupied more than half of the cross-sectional area of the RIJV in five patients (10%), and CRT completely occluded the RIJV in one patient (2%). Platelet count, duration of PAC placement, and intraoperative bleeding amount were found to be high-risk indicators of CRT. In conclusion, patients who underwent cardiovascular surgery and using both CVC and PAC had a high incidence of CRT. Avoiding unnecessary PAC placement and early removal of catheters in patients at high risk of developing CRT may prevent the development of CRT.

Elobixibat alleviates chronic constipation in hemodialysis patients: a questionnaire-based study.

BACKGROUND: Hemodialysis patients are prone to constipation, which can adversely affect their quality of life (QOL). Elobixibat, a highly selective inhibitor of the ileal bile acid transporter, can increase the bile acid level in the colon and, subsequently, enhance colonic motility and secretion. In hemodialysis patients with chronic constipation, it may have a novel action mechanism. However, the effect of elobixibat on such patients' QOL had not been reported. This study aimed to evaluate the effect of elobixibat on the QOL of hemodialysis patients with chronic constipation. METHODS: This was a multicenter, observational study that used the Japanese version of the Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire on 27 patients (18 men and nine women, age range 47-90 years), who satisfied the Rome 3 diagnostic criteria for functional constipation and were already taking other drugs for constipation. These patients were administered elobixibat 10 mg/day and were asked to respond to the PAC-QOL questionnaire at baseline and after 4 weeks. Bayesian statistics were used to confirm our results. RESULTS: The number of spontaneous bowel movements per week increased significantly from 2.6 ± 1.2 to 4.1 ± 2.1 (p < 0.001), and the Bristol Stool Form Scale score significantly improved from 1.9 ± 0.8 to 3.6 ± 0.7 (p < 0.001). The Cronbach's alpha was 0.95, and the Guttman split-half reliability coefficient was 0.90. There were significant decreases in the physical discomfort scores from 1.94 ± 0.79 to 0.97 ± 0.72 (p < 0.001); psychosocial discomfort from 1.16 ± 0.93 to 0.63 ± 0.58 (p < 0.001); worries/ concerns from 1.84 ± 0.73 to 1.27 ± 0.59 (p < 0.001), and satisfaction from 2.79 ± 0.61 to 1.98 ± 0.77 (p < 0.001). The total PAC-QOL score significantly decreased from 1.83 ± 0.79 to 1.17 ± 0.56 (p < 0.001). Bayesian statistics confirmed the results' significance. CONCLUSIONS: Elobixibat reduced the PAC-QOL scores for hemodialysis patients with chronic constipation and improved the patients' QOL. It may serve as a new option for treating constipation in hemodialysis patients.

Carnitine Profile by Tandem Mass Spectrometry and Dialysis Patients.

BACKGROUND: Carnitine deficiency is a common condition in hemodialysis patients. Therefore, abnormalities in fatty acid metabolism and organic acid metabolism are also common in dialysis patients. Tandem mass spectrometry is a standard technique in pediatric and neonatal medicine. However, it could be a new powerful tool in other fields for estimating the state of intracellular fatty acid metabolism. SUMMARY: Tandem mass spectrometry has recently revealed the relationships between carnitine profile and dialysis patients' anemia, reduced physical function, and survival rate. Fatty acid and organic acid metabolism, which could previously only be evaluated qualitatively, can now be quantitatively assessed. Key Message: The applications of tandem mass spectrometry are expected to expand not only in the field of dialysis but also in clinical medicine in general.

Association between 4-year all-cause mortality and carnitine profile in maintenance hemodialysis patients.

BACKGROUND: Patients on dialysis are in a chronic carnitine-deficient state. This condition may be associated with abnormalities of the fatty acid and organic acid metabolisms. Carnitine is required for ß-oxidation of the long-chain fatty acids; therefore, carnitine deficiency decreases the efficiency of ATP synthesis and may incur death. However, the details of this association remain unknown. We examined the relationship between ß-oxidation efficiency represented by the carnitine profile and 4-year all-cause mortality in hemodialysis patients. METHODS: The carnitine profiles of 122 hemodialysis patients were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The associations between the 4-year all-cause mortality and carnitine profile as well as the clinical backgrounds of the patients were investigated. A survival analysis was conducted by the Kaplan-Meier survival method and multivariable Cox proportional hazard analysis. The bootstrap method was performed to confirm the stability and robustness of our model. RESULTS: Of the 122 subjects analyzed, 111 were selected and 24 died during the observation period. Stepwise multivariable Cox regression demonstrated that diabetes state [Hazard ratio (95% confidence interval), 4.981 (2.107-11.77)], age [HR (95% CI), 1.052 (1.014-1.091)], and the acetylcarnitine/(palmitoylcarnitine+octadecenoylcarnitine) [C2/(C16+C18:1)] ratio [HR (95% CI), 0.937 (0.904-0.971)] were independent significant factors of 4-year all-cause mortality. The bootstrap method confirmed the significance of these three factors. CONCLUSION: The 4-year all-cause mortality negatively correlated with the C2/(C16+C18:1) ratio. Improvement of the impaired ß-oxidation state after L-carnitine administration may ameliorate prognosis.

Ferritin: Diversity and Management of Ferritin Measurement Methods.

BACKGROUND: Serum ferritin is one of the most important and widely used markers of iron metabolism, and is a recommended standard index of iron dynamics in guidelines for renal anemia in many countries. However, serum ferritin measurement has several disadvantages. For example, it is prone to being influenced by underlying disease, and there is considerable systematic bias among different methods of measurement. SUMMARY: Systematic bias affects not only the measurement results, but also the therapeutic strategy to be used in accordance with the relevant guidelines, and consequently the cost of medical treatment. Key Messages: Manufacturers should reduce variability in their serum ferritin assay kits. Researchers should take into account propagation of error in the analysis of measurement values, and clinicians should evaluate laboratory data with care.

Intermittent Infusion Hemodiafiltration: The Principle and Its Clinical Application.

The present study aimed to propose a new hemodiafiltration (HDF) method (intermittent infusion HDF) that repeats intermittent infusion during hemodialysis to temporarily enhance peripheral circulation and improves solute removal efficiency through (a) correcting blood distribution (increase in effective vascular surface area), (b) stirring body fluids, and (c) promoting solute removal and examining its clinical effects.

Association between Increases in Normalized Protein Catabolic Rate and Increases in Creatinine Generation Rate in Dialysis Patients.

The older dialysis population is growing, and malnutrition and wasting syndrome are great concerns in this population. The management of these syndromes includes appropriate nutritional intake and physical activity. However, whether management in the form of an increase in protein intake has a beneficial effect on muscle mass has not been demonstrated. In this study, we investigated an association between changes of normalized protein catabolic rate (nPCR), as a proxy for protein intake and percent creatinine generation rate (%CGR), as a proxy for muscle mass in patients receiving hemodialysis. Multiple linear regression models were employed, and we included several sensitivity analyses. The results showed that increases in nPCR were associated with increases in %CGR. The association was stronger in patients with baseline %CGR levels below 100%. This was the first study to demonstrate that an increase in dietary protein intake might increase the muscle mass, but this study had certain limitations. Future interventional studies will be needed to investigate whether increases in protein intake have a beneficial effect on sarcopenia, protein-energy wasting, and frailty.

Association between resistance to erythropoiesis-stimulating agents and carnitine profile in patients on maintenance haemodialysis.

OBJECTIVE: Patients on dialysis are in a chronic carnitine-deficient state. This condition may be associated with abnormalities in fatty acid and organic acid metabolism; however, the details are unknown. We investigated the association between carnitine profiles before and after dialysis and the erythropoiesis-stimulating agent (ESA) resistance index (ERI), which is a significant prognostic factor in patients on maintenance haemodialysis. METHODS: This was a cross-sectional study. We measured the carnitine profile of 79 patients on maintenance haemodialysis before and after dialysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The associations between the ERI and pre-dialysis carnitine profile, removal rate of various carnitines, and previously-reported ERI-related factors were investigated. Significant factors were determined with stepwise multiple regression analysis and validated with the bootstrap method. SPSS version 22.0 was used for analysis, and P < 0.05 was considered statistically significant. RESULTS: The removal rate of long-chain acylcarnitine with dialysis was lower than that of short-chain or medium-chain acylcarnitines. Stepwise multiple regression analysis (n = 79) demonstrated that 3-hydroxy isovalerylcarnitine (C5-OH, P < 0.001, ß = -0.469) and stearoylcarnitine (C18, P < 0.001, ß = 0.390) were independent significant factors (R2 = 0.239) of ERI. The bootstrap method similarly indicated these two to be significant factors. CONCLUSION: ERI positively correlated with long-chain C18 acylcarnitine and negatively correlated with short-chain C5-OH acylcarnitine. C5-OH and C18 acylcarnitines at baseline might be contributing factors in distinguishing responders from nonresponders after L-carnitine administration.

Inter-Method Variability of Ferritin and Transferrin Saturation Measurement Methods in Patients on Hemodialysis.

Serum ferritin level and transferrin saturation (TSAT) are widely used to evaluate iron status in patients with chronic kidney disease, and are also important variables for performing statistical analyses. Many guidelines have set control targets or upper limits for these markers. Inter-method variability is an important consideration in iron control and statistical analysis. We used 10 ferritin assay kits and five iron/unsaturated iron-binding capacity/total iron-binding capacity assay kits to determine ferritin levels and TSAT in 114 patients on maintenance dialysis, and evaluated measurement bias using Passing-Bablok regression analyses. The variance of distributions categorized by differences in assay kits was examined using Fisher's exact test. Slopes ranged from 1.00 to 1.63 (1.00 to 0.61) for ferritin and 1.00 to 1.10 (1.00 to 0.91) for TSAT. The distribution according to the 2015 JSDT Guideline for Renal Anemia in Chronic Kidney Disease significantly changed (P = 0.01). TSAT thus provides more precise control than ferritin in multi-center comparisons where no particular assay is specified. Developers must reduce variability in serum ferritin assay kits. Researchers must analyze measured values by taking into account the propagation of errors, and clinicians must evaluate laboratory data carefully.

Alport syndrome and pregnancy: Good obstetric and nephrological outcomes in a pregnant woman with homozygous autosomal recessive Alport syndrome.

We describe the course of pregnancy in a 27-year-old woman with homozygous autosomal recessive Alport syndrome. Genetic analysis revealed a homozygous COL4A4 mutation in exon 36 (c.3307G > A) with p.G1102R inherited from her parents (who were parallel cousins) 1 year before conception. Before pregnancy, the patient's renal function and blood pressure were normal, and her urinary protein excretion was below 2 g/day. The pregnancy course was uneventful in the first and second trimesters. She was detected to have nephrotic-range proteinuria during the third trimester, but was observed closely on an outpatient basis without any medications, as her general condition was good, her renal function and blood pressure remained stable, and the fetal well-being was maintained. At 39(+0) weeks of pregnancy, she vaginally gave birth to an appropriate-birthweight infant and her urinary protein excretion returned to pre-pregnancy level. This is the first report of pregnancy in a patient with autosomal recessive Alport syndrome with good obstetric and nephrological outcomes in the absence of any treatment or hospitalization.

Comparison between consecutive and intermittent steroid pulse therapy combined with tonsillectomy for clinical remission of IgA nephropathy.

BACKGROUND: In recent years, tonsillectomy and steroid pulse (TSP) therapy have been widely performed in Japan. However, there is no consensus about the treatment protocol and indication. METHODS: In this retrospective analysis, we compared patients who received tonsillectomy plus intermittent steroid pulse (SP) therapy three times in 6 months (ISP group, n = 44) with patients who received tonsillectomy plus 3 weeks of consecutive SP therapy (CSP group, n = 46) within 1 year after renal biopsy. These two different protocols were performed at two different institutions. We analyzed the clinical and histological background and clinical remission (CR), defined as disappearance of urine abnormalities at 18 months after starting treatment. RESULTS: Before treatment, there was no significant difference in the clinical findings except for sex between the two groups. In ISP group and CSP group, mean estimated glomerular filtration rate was 82.1 ± 20.9 and 85.9 ± 19.1 ml/min/1.73 m(2), median proteinuria was 0.55 and 0.56 g/day, and median urinary red blood cells were 20 (10-20) and 20 (6-30)/high power filed. The histological (H) grade was lower in the CSP than the ISP group (p = 0.022). The remission rate of proteinuria, hematuria, and rate of CR by the Kaplan-Meier method and logrank test were significantly higher in the CSP group than in the ISP group (CSP vs. ISP group; proteinuria: 97.8 vs. 77.3 %, p < 0.001, hematuria: 97.8 vs. 75.0 %, p = 0.005, CR: 95.6 vs. 63.6 %, p < 0.001). In the Cox proportional hazard model (forced entry), SP protocol and proteinuria before treatment were significantly associated with CR [SP protocol: hazard ratio (HR) 2.50, 95 % confidence interval (CI) 1.46-4.30, p = 0.001, proteinuria: HR 0.81, 95 % CI 0.68-0.96, p = 0.013)]. However H-grade was associated with remission of proteinuria (H-grade: hazard ratio (HR) 0.56, 95 % confidence interval (CI) 0.37-0.85, p = 0.006), and this result meant histological bias affected the remission of proteinuria. CONCLUSIONS: The difference of the protocol of TSP therapy may have some effect on the CR of IgAN, though the histological bias was observed in this study. The appropriate protocol and indication of TSP therapy must be analyzed and determined in the randomized controlled trial.

Rituximab treatment for adult patients with focal segmental glomerulosclerosis.

We present two cases with steroid-resistant nephrotic syndrome (SRNS) and two cases with steroid-dependent nephrotic syndrome (SDNS) due to focal segmental glomerulonephritis (FSGS) who were treated with a single dose of rituximab (375 mg/m(2)). Although the two cases with SRNS showed no response, the two cases with SDNS achieved complete remission. The patients in whom the peripheral B-cell counts subsequently increased after the administration of rituximab demonstrated a relapse. Rituximab may be an effective treatment agent for SDNS with FSGS and the peripheral B-cell count may be a useful marker in such patients for preventing disease relapse.

Impact of the Fukushima Daiichi Nuclear Power Plant accident on hemodialysis facilities: an evaluation of radioactive contaminants in water used for hemodialysis.

Following the crisis at the Fukushima Daiichi Nuclear Power Plant caused by the 2011 Tohoku earthquake and tsunami, radioactive substances ((131) I, (134) Cs, (137) Cs) were detected in tap water throughout eastern Japan. There is now concern that internal exposure to radioactive substances in the dialysate could pose a danger to hemodialysis patients. Radioactive substances were measured in three hemodialysis facilities before and after purification of tap water for use in hemodialysis. Radioactive iodine was detected at levels between 13 and 15 Bq/kg in tap water from the three facilities, but was not detected by reverse osmosis membrane at any of the facilities. We confirmed that the amount of radioactive substances in dialysate fell below the limit of detection (7-8 Bq/kg) by reverse osmosis membrane. It is now necessary to clarify the maximum safe level of radiation in dialysate for chronic hemodialysis patients.