Seasonal variation in predialysis systolic blood pressure and cardiovascular events in patients on maintenance hemodialysis.

Predialysis systolic blood pressure (SBP) in patients on hemodialysis (HD) consistently followed a seasonal pattern, reaching a peak in winter and nadir in summer, similar to blood pressure in the general population. However, the relationship between seasonal variations in predialysis SBP and clinical outcomes is still under-investigated in Japanese patients on HD. This retrospective cohort study included 307 Japanese patients undergoing HD for >1 year in three dialysis clinics and evaluated the association between the standard deviation (SD) of predialysis SBP and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) with 2.5 years follow-up. The SD of predialysis SBP was 8.2 (6.4-10.9) mmHg. In the model fully adjusted for the SD of predialysis SBP, predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, C-reactive protein, albumin, hemoglobin, body mass index, normalized protein catabolism rate, and intradialytic SBP decline, Cox regression analyses showed that a higher SD of predialysis SBP (per 10 mmHg) was significantly associated with increased MACE risk (hazard ratio [HR], 1.89; 95% confidence interval [95% CI], 1.07-3.36) and all-cause hospitalization (HR, 1.57; 95% CI, 1.07-2.30). Therefore, greater seasonal variations in predialysis SBP were associated with worse clinical outcomes, including MACEs and all-cause hospitalization. Whether interventions to reduce seasonal variations in predialysis SBP will improve the prognosis of Japanese patients on HD must be investigated further.

Mean annual intradialytic blood pressure decline and cardiovascular events in Japanese patients on maintenance hemodialysis.

An intradialytic systolic blood pressure (SBP) decline, which defines intradialytic hypotension, may be associated with higher all-cause mortality. However, in Japanese patients on hemodialysis (HD), the association between intradialytic SBP decline and patient outcomes is unclear. This retrospective cohort study included 307 Japanese patients undergoing HD over 1 year in three dialysis clinics and evaluated the association between the mean annual intradialytic SBP decline (predialysis SBP-nadir intradialytic SBP) and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) by following up for 2 years. The mean annual intradialytic SBP decline was 24.2 (25-75th percentile, 18.3-35.0) mmHg. In the model fully adjusted for intradialytic SBP decline tertile group (T1, <20.4 mmHg; T2, 20.4 to <29.9 mmHg; T3, ≥29.9 mmHg), predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, use of renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, geriatric nutritional risk index, normalized protein catabolism rate, C-reactive protein, hemoglobin, and use of pressor agents, Cox regression analyses showed that the hazard ratio (HR) was significantly higher for T3 than for T1 for MACEs (HR, 2.38; 95% confidence interval 1.12-5.09) and all-cause hospitalization (HR, 1.68; 95% confidence interval 1.03-2.74). Therefore, in Japanese patients on HD, a greater intradialytic SBP decline was associated with worse clinical outcomes. Further studies are warranted to investigate whether interventions to attenuate the intradialytic SBP decline will improve the prognosis of Japanese patients on HD.

Changes of biomarkers for erythropoiesis, iron metabolism, and FGF23 by supplementation with roxadustat in patients on hemodialysis.

This study aimed to confirm changes in biomarkers of erythropoiesis and iron metabolism and serum fibroblast growth factor 23 (FGF-23) during darbepoetin-α treatment and then switching to the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat. A total of 28 patients on hemodialysis who received weekly doses of darbepoetin-α were switched to roxadustat. Biomarkers for erythropoiesis and iron metabolism and intact and C-terminal FGF-23 were measured in blood samples collected before the HD session on days - 7 (darbepoetin-α injection), - 4, and - 2, and days 0 (switch to roxadustat treatment, three times weekly), 3, 5, 7, 14, 21, and 28. Erythropoietin and erythroferrone levels were elevated on day - 4 by darbepoetin-α injection and decreased to baseline levels at day 0. Levels of erythropoietin were not significantly increased by roxadustat supplementation, but erythroferrone levels were continuously elevated, similar to darbepoetin-α treatment. Hepcidin-25 and total iron binding capacity were significantly decreased or increased in patients treated with roxadustat compared with darbepoetin-α. Changes of intact and C-terminal FGF-23 levels were parallel to changes of phosphate levels during roxadustat treatment. However, the actual and percentage changes of intact FGF-23 and C-terminal FGF-23 in patients with low ferritin levels were greater than those in patients with high ferritin levels. Roxadustat might stimulate erythropoiesis by increasing iron usage through hepcidin-25, which was suppressed by erythroferrone in the physiological erythropoietin condition. Changes of intact FGF-23 and C-terminal FGF-23 levels might be affected by roxadustat in patients on hemodialysis, especially those with a low-iron condition.

Seasonal variation and predictors of intradialytic blood pressure decline: a retrospective cohort study.

The risk factors for intradialytic systolic blood pressure decline remain poorly understood. We aimed to identify clinical and laboratory predictors of the intradialytic systolic blood pressure decline, considering its seasonal variation. In a retrospective cohort of 47,219 hemodialysis sessions of 307 patients undergoing hemodialysis over one year in three dialysis clinics, the seasonal variation and the predictors of intradialytic systolic blood pressure decline (predialysis systolic blood pressure--nadir intradialytic systolic blood pressure) were assessed using cosinor analysis and linear mixed models adjusted for baseline or monthly hemodialysis-related variables, respectively. The intradialytic systolic blood pressure decline was greatest and least in the winter and summer, respectively, showing a clear seasonal pattern. In both models adjusted for baseline and monthly hemodialysis-related parameters, calcium channel blocker use was associated with a smaller decline (-4.58 [95% confidence interval (CI), -5.84 to -3.33], P < 0.001; -3.66 [95% CI, -5.69 to -1.64], P < 0.001) and α blocker use, with a greater decline (3.25 [95% CI, 1.53-4.97], P < 0.001; 3.57 [95% CI, 1.08-6.06], P = 0.005). Baseline and monthly serum phosphorus levels were positively correlated with the decline (1.55 [95% CI, 0.30-2.80], P = 0.02; 0.59 [95% CI, 0.16-1.00], P = 0.007), and baseline and monthly normalized protein catabolic rates were inversely correlated (respectively, -22.41 [95% CI, -33.53 to -11.28], P < 0.001; 9.65 [95% CI, 4.60-14.70], P < 0.001). In conclusion, calcium channel blocker use, α blocker avoidance, and serum phosphorus-lowering therapy may attenuate the intradialytic systolic blood pressure decline and should be investigated in prospective trials.

Erythropoiesis stimulating agents are associated with serum fibroblast growth factor 23 metabolism in patients on hemodialysis.

BACKGROUND: This study aimed to determine associations among short- and long-acting erythropoiesis stimulating agents (ESAs), changes in serum fibroblast growth factor 23 (FGF23) and biomarkers of iron metabolism. METHODS: Among 108 patients on hemodialysis (HD), 44 received every 2 weeks or monthly doses of continuous erythropoiesis receptor activator (CERA), 31 received weekly doses of darbepoetin-α, 24 received three doses per week of epoetin-ß and 9 were not treated with an ESA. Intact and C-terminal FGF23 and transferrin saturation (TSAT), ferritin, erythroferrone and hepcidin 25 were measured in blood samples collected before the HD session at the end of the dialysis week (baseline, Day 0) and on Days 3, 5, 7 and 14 thereafter. RESULTS: Levels of ferritin, hepcidin 25 and erythroferrone as well as TSAT were significantly decreased or elevated in patients treated with CERA compared with other types of ESAs. Levels of C-terminal FGF23 increased in all groups during the observation period. Levels of intact FGF23 and ratios of intact FGF23 to C-terminal FGF23 gradually decreased between Days 3 and 7 in the CERA but not in the other groups. Multivariate models associated changes in hepcidin 25 and phosphate with those of intact FGF23. CONCLUSION: The long-acting ESA CERA might influence levels of intact FGF23 by increasing FGF23 cleavage in patients on HD in association with prolonged hepcidin 25 suppression.

Differential Impacts of Intravenous Iron Administration and Iron-Containing Phosphate Binders on Serum Intact Fibroblast Growth Factor 23 Levels.

AIMS: This study assessed the impact of iron administration on serum fibroblast growth factor 23 (FGF23) levels. METHODS: Of 123 hemodialysis (HD) patients treated with erythropoiesis-stimulating agents, 22 received once-weekly intravenous iron and 17 received daily oral iron with iron-containing phosphate binders. Intact FGF23 and biomarkers of iron metabolism were measured from blood samples drawn before each HD session, at baseline and on days 3, 5, 7, and 14. RESULTS: Phosphate levels did not differ among the 3 groups during the 14-day period. Ferritin levels were significantly increased in both iron treatment groups compared with the non-iron treatment group, but changes in transferrin saturation levels were similar in the intravenous iron and non-iron groups. However, intact FGF23 levels were continuously higher in the intravenous iron group than those in the other groups. CONCLUSION: Intravenous iron administration may influence intact FGF23 levels in HD patients independently of phosphate and iron metabolism.

Clinical Effectiveness of Intermittent Infusion Hemodiafiltration Using Backfiltration of Ultrapure Dialysis Fluid Compared with Predilution On-Line Hemodiafiltration.

BACKGROUND: In conventional hemodialysis (HD) treatment, excessive water removal sometimes induces a rapid drop in blood pressure. Intermittent infusion hemodiafiltration (I-HDF) has been developed to improve patients' peripheral circulation by repeated intermittent infusion during HD treatment. SUMMARY: A prospective, multicenter, parallel group comparative trial examined the clinical effectiveness of I-HDF compared with predilution on-line HDF (pre-HDF), the most popular on-line HDF therapy in Japan. Patients were allocated to 2 groups after matching for age (± 5 years), dry weight (± 5 kg), and presence/absence of diabetes. After informed consent was obtained, 36 patients (18 pairs) participated in the trial. The results showed no difference in clinical condition or quality of life (QOL) scores between the 2 therapy groups. The rate of reduction in systolic blood pressure initially showed no difference between the groups, but decreased slightly as the trial proceeded after changing from HD therapy. There was also no difference in the incidence rate of treatments initially, although this significantly decreased in both groups as the trial proceeded. Rates of ß2-microglobulin removal were significantly higher in the pre-HDF group than in the I-HDF group. At the same time, the amount of albumin leakage during treatment was significantly greater in the pre-HDF group. Key Messages: The clinical condition and QOL of patients receiving I-HDF was not inferior to those receiving pre-HDF. Pre-HDF demonstrated a significantly higher removal rate of middle- and larger-molecular-weight solutes and higher albumin leakage compared with I-HDF.

Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism, and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on Hemodialysis.

BACKGROUND: We aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to determine the effects of erythropoiesis-stimulating agents (ESA), continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) on ERFE production in patients on hemodialysis (HD). METHODS: Blood samples were obtained from 59 patients before HD sessions on day 0 (baseline). Twenty patients who were injected with either CERA (N = 10) or DA (N = 10) at the end of the dialysis week (day 0), who had ferritin ≥ 100 ng/mL and/or transferrin saturation ≥ 20%, and hemoglobin > 9 g/dL were selected from among the 59 patients. Blood was sampled serially before HD sessions on days 3, 5, 7 from patients on DA and on the same days plus day 14 from those on CERA. RESULTS: Levels of ERFE correlated inversely with those of hepcidin 25 and ferritin, and positively with those of soluble transferrin receptor. The hepcidin 25: ERFE ratio and hepcidin 25 levels positively correlated with ferritin levels. Levels of ERFE significantly increased from day 3 of treatment with DA and CERA and decreased by days 7 and 14, respectively. Erythropoiesis-stimulating agents concomitantly decreased levels of hepcidin 25 as those of ERFE increased. CONCLUSION: We identified a novel association between ESA and ERFE in patients on HD. Both DA and CERA increased levels of ERFE that regulated hepcidin 25 and led to iron mobilization from body stores during erythropoiesis.

Effects of Long-Term Erythropoiesis-Stimulating Agents on Iron Metabolism in Patients on Hemodialysis.

Continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) might differently affect iron metabolism and erythropoiesis in patients on hemodialysis (HD). This prospective study examined a cohort of patients on HD who had received either intravenous CERA every 2 or 4 weeks (N = 25) or DA once each week (N = 47). Blood was sampled before HD sessions on days 0, 2, 4, 7 and 14, and on days 0, 3, 5, 7 and 14 from patients who were injected with ESA at the beginning and end of the dialysis week, respectively. Changes in factors indicating erythropoiesis and biomarkers of iron metabolism were examined. Hemoglobin levels were maintained in the target range between 10.0 and 11.0 g/dL and ferritin levels at baseline and during the study period were similar between the DA and CERA groups. Levels of hepcidin 25 decreased from days 2-3 to day 5 and returned to the baseline at day 7 in the DA group, whereas those and transferrin saturation were serially suppressed from days 2-3 to day 14 in the CERA group. Levels of soluble transferrin receptor and reticulocyte counts were significantly elevated from days 4-5 to day 14 by CERA. Both DA and CERA stabilized erythropoiesis, but CERA might mobilize iron from body stores more effectively than DA in patients on HD.

Divergent effects of unilateral and subtotal nephrectomy on insulin sensitivity in rats.

OBJECTIVES: Insulin resistance is associated with chronic renal failure, which may amplify its cardiovascular pathologic manifestations. We previously showed the presence of insulin resistance in mild renal insufficiency due to chronic glomerulonephritis. These observations may be explained by a decrease in insulin sensitivity due to renal dysfunction. The aim of the present study was to evaluate the effects of unilateral and subtotal nephrectomy on insulin sensitivity. METHODS: Unilateral heminephrectomy and five-sixths nephrectomy (5/6Nx) were performed in male Sprague-Dawley rats, measuring steady-state plasma glucose (SSPG) during the insulin suppression test. RESULTS: The glomerular filtration rate (GFR) decreased significantly from sham-operated rats, to unilateral heminephrectomy group, to 5/6Nx rats. SSPG was unexpectedly lower in the unilateral heminephrectomy group than in controls, suggesting that unilateral heminephrectomy increased the sensitivity to insulin despite a mild decrease in renal function. However, when the analysis was limited to the 5/6Nx group, SSPG was inversely correlated with GFR (r = -0.65, p < 0.05). When renal failure caused by 5/6Nx had reached end stage, the rats became insulin resistant, despite a profound reduction in renal mass. CONCLUSION: It is suggested that unilateral heminephrectomy reduced GFR and increased the sensitivity to insulin. When rats became uremic, insulin sensitivity decreased, even, in 5/6Nx.