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The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial.
Lorentz, CU, Tucker, EI, Verbout, NG, Shatzel, JJ, Olson, SR, Markway, BD, Wallisch, M, Ralle, M, Hinds, MT, McCarty, OJT, et al
Blood. 2021;(22):2173-2184
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Abstract
End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor XI (FXI) and blocks its activation by activated FXII, but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis. Patients were randomized to receive a single predialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio, and safety and preliminary efficacy were compared with placebo and observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer. This trial was registered at www.clinicaltrials.gov as #NCT03612856.
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Impact of twice- or three-times-weekly maintenance hemodialysis on patient outcomes: A multicenter randomized trial.
Dai, L, Lu, C, Liu, J, Li, S, Jin, H, Chen, F, Xue, Z, Miao, C
Medicine. 2020;(20):e20202
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AIM: Maintenance hemodialysis (MHD) frequency is associated with survival and complication rates. Achieving the optimal balance between healthcare, quality of life (QOL), and medical costs is challenging. We compared complications, inflammatory status, nutritional status, and QOL between patients with different MHD frequencies. MATERIAL AND METHODS This was a multicenter randomized trial of patients treated between May 2011 and August 2017 at 3 tertiary hospitals in Wenzhou. Patients were grouped according to their treatment schedule over 1 year: twice-weekly or 3-times-weekly. Complications, biochemistry parameters, and QOL (KDQOL-SFTM 1.3 scale) were assessed. RESULTS One hundred forty patients were included aged 29 to 68 years (mean age, 50.9 ± 4.3 years). There were no significant differences in infection, heart failure, or cerebral hemorrhage complications between the 2 groups (P = .664). Pre-dialysis hemoglobin, high-sensitivity C-reactive protein, serum albumin, total cholesterol, triglyceride, calcium, phosphate, parathyroid hormone, and ejection fraction were similar in both groups (P > .05). After 1 year of MHD, both groups exhibited significant improvements in these parameters (all P < .05) with no significant differences between groups. Serum creatinine, blood urea nitrogen (BUN), and weekly standard hemodialysis treatment adequacy did not improve after treatment (all P > .05), although a difference in BUN was observed between the 2 groups (P < .001). QOL was superior in the twice-weekly group than in the 3-times-weekly group (all P < .05), except for social support, which was slightly better in the 3-times-weekly group than in the twice-weekly group. CONCLUSIONS Twice- and 3-times-weekly MHD resulted in comparable inflammatory and nutritional clinical outcomes and adverse events. QOL was better for the twice-weekly schedule. Even for patients with economic constraints, twice- or 3-times-weekly MHD should be selected with caution after consideration of BUN levels at baseline.
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Efficacy and safety of trelagliptin in Japanese patients with type 2 diabetes with severe renal impairment or end-stage renal disease: Results from a randomized, phase 3 study.
Kaku, K, Ishida, K, Shimizu, K, Achira, M, Umeda, Y
Journal of diabetes investigation. 2020;(2):373-381
Abstract
INTRODUCTION To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease. MATERIALS AND METHODS This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug. RESULTS Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively. CONCLUSIONS Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population.
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Comparison of the effect of linear and step-wise sodium and ultrafiltration profiling on dialysis adequacy in patients undergoing hemodialysis.
Hamidi, M, Roshangar, F, Khosroshahi, HT, Hadi, H, Ghafourifard, M, Sarbakhsh, P
Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2020;(1):44-52
Abstract
Patients with chronic renal failure undergoing hemodialysis (HD) need to receive adequate dialysis. Dialysis inadequacy leads to an increase in the side effects and even frequent hospitalizations as well as increased therapeutic costs. Considering the fact that improving the adequacy of dialysis is one of the goals of nursing care in these patients, this study aimed to compare the effect of linear and step-wise sodium-ultrafiltration (UF) profiling on HD adequacy. This study is a clinical trial; a total of 32 patients from two dialysis centers in East Azerbaijan province were selected and randomly divided into two groups. Each patient underwent HD for three sessions by routine method, three sessions by linear sodium profile and UF, and three sessions by the step-wise sodium profile and UF. At the end of each HD method, Kt/V was calculated to determine the adequacy of dialysis. Data analysis was performed using Statistical Package for the Social Sciences software version 13 with generalized estimating equation statistical test. According to the results of this study, there was a statistically significant difference between the mean of adequacy of dialysis (Kt/V) in the three treatment methods (P <0.05), in which the mean score of dialysis adequacy in step-wise method was 0.14 more than the routine method, and in the linear method, it was 0.21 more than the routine method. The mean Kt/V scores were 1.24, 1.31, and 1.10 in the step-wise method, linear method, and routine method, respectively(P <0.05). The results of this study indicate that simultaneous application of sodium and UF profiles is effective in the hemodynamic stability of patients, which reduces uncomfortable complications during dialysis. Therefore, in order to improve dialysis adequacy and prevent the complications, usage of sodium and UF profiles is recommended.
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Hemodynamic and perceptual responses to blood flow-restricted exercise among patients undergoing dialysis.
Clarkson, MJ, Brumby, C, Fraser, SF, McMahon, LP, Bennett, PN, Warmington, SA
American journal of physiology. Renal physiology. 2020;(3):F843-F850
Abstract
End-stage kidney disease is associated with reduced exercise capacity, muscle atrophy, and impaired muscle function. While these may be improved with exercise, single modalities of exercise do not traditionally elicit improvements across all required physiological domains. Blood flow-restricted exercise may improve all of these physiological domains with low intensities traditionally considered insufficient for these adaptions. Investigation of this technique appeals, but is yet to be evaluated, in patients undergoing dialysis. With the use of a progressive crossover design, 10 satellite patients undergoing hemodialysis underwent three exercise conditions over 2 wk: two bouts (10 min) of unrestricted cycling during two consecutive hemodialysis sessions (condition 1), two bouts of cycling with blood flow restriction while off hemodialysis on 2 separate days (condition 2), and two bouts of cycling with blood flow restriction during two hemodialysis sessions (condition 3). Outcomes included hemodynamic responses (heart rate and blood pressure) throughout all sessions, participant-perceived exertion and discomfort on a Borg scale, and evaluation of ultrafiltration rates and dialysis adequacy (Kt/V) obtained post hoc. Hemodynamic responses were consistent regardless of condition. Significant increases in heart rate, systolic blood pressure, and mean arterial blood pressure (P < 0.05) were observed postexercise followed by a reduction in blood pressures during the 60-min recovery (12, 5, and 11 mmHg for systolic, diastolic, and mean arterial pressures, respectively). Blood pressures returned to predialysis ranges following the recovery period. Blood flow restriction did not affect ultrafiltration achieved or Kt/V. Hemodynamic safety and tolerability of blood flow restriction during aerobic exercise on hemodialysis is comparable to standard aerobic exercise.
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Consequences of Supraphysiological Dialysate Magnesium on Arterial Stiffness, Hemodynamic Profile, and Endothelial Function in Hemodialysis: A Randomized Crossover Study Followed by a Non-Controlled Follow-Up Phase.
Del Giorno, R, Lavorato Hadjeres, S, Stefanelli, K, Allegra, G, Zapparoli, C, Predrag, L, Berwert, L, Gabutti, L
Advances in therapy. 2020;(12):4848-4865
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INTRODUCTION Increasing dialysate magnesium (D-Mg2+) appears to be an intriguing strategy to obtain cardiovascular benefits in subjects with end-stage kidney disease (ESKD) on hemodialysis. To date, however, hemodialysis guidelines do not suggest to increase D-Mg2+ routinely set at 0.50 mmol/L. METHODS A randomized 4-week crossover study aimed at investigating the consequences of increasing D-Mg2+ from 0.50 to 0.75 mmol/L on arterial stiffness, hemodynamic profile, and endothelial function in subjects undergoing hemodialysis. The long-term effect of higher D-Mg2+ on mineral metabolism markers was investigated in a 6-month follow-up. Data were analyzed by linear mixed models for repeated measures. RESULTS Data of 39 patients were analyzed. Pulse wave velocity and pulse pressure significantly decreased on the higher D-Mg2+ compared with the standard one by - 0.91 m/s (95% confidence interval - 1.52 to - 0.29; p = 0.01) and - 9.61 mmHg (- 18.89 to - 0.33, p = 0.04), respectively. A significant reduction in systolic blood pressure of - 12.96 mmHg (- 24.71 to - 1.22, p = 0.03) was also observed. No period or carryover effects were observed. During the long-term follow-up phase the higher D-Mg2+ significantly increased ionized and total serum Mg (respectively from 0.54 to 0.64 and from 0.84 to 1.07 mmol/L; mean percentage change from baseline to follow-up + 21% and + 27%; p ≤ 0.001), while parathormone (PTH) decreased significantly (from 36.6 to 34.4 pmol/L; % change - 11%, p = 0.03). CONCLUSIONS Increasing dialysate magnesium improves vascular stiffness in subjects undergoing maintenance hemodialysis. The present findings merit a larger trial to evaluate the effects of 0.75 mmol/L D-Mg2+ on major clinical outcomes. TRIAL REGISTRATION The study was retrospectively registered on the ISRCTN registry (ISRCTN 74139255) on 18 June 2020.
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Automated individualization of dialysate sodium concentration reduces intradialytic plasma sodium changes in hemodialysis.
Ságová, M, Wojke, R, Maierhofer, A, Gross, M, Canaud, B, Gauly, A
Artificial organs. 2019;(10):1002-1013
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In standard care, hemodialysis patients are often treated with a center-specific fixed dialysate sodium concentration, potentially resulting in diffusive sodium changes for patients with plasma sodium concentrations below or above this level. While diffusive sodium load may be associated with thirst and higher interdialytic weight gain, excessive diffusive sodium removal may cause intradialytic symptoms. In contrast, the new hemodialysis machine option "Na control" provides automated individualization of dialysate sodium during treatment with the aim to reduce such intradialytic sodium changes without the need to determine the plasma sodium concentration. This proof-of-principle study on sodium control was designed as a monocentric randomized controlled crossover trial: 32 patients with residual diuresis of ≤1000 mL/day were enrolled to be treated by high-volume post-dilution hemodiafiltration (HDF) for 2 weeks each with "Na control" (individually and automatically adjusted dialysate sodium concentration) versus "standard fixed Na" (fixed dialysate sodium 138 mmol/L), in randomized order. Pre- and post-dialytic plasma sodium concentrations were determined at bedside by direct potentiometry. The study hypothesis consisted of 2 components: the mean plasma sodium change between the start and end of the treatment being within ±1.0 mmol/L for sodium-controlled treatments, and a lower variability of the plasma sodium changes for "Na control" than for "standard fixed Na" treatments. Three hundred seventy-two treatments of 31 adult chronic hemodialysis patients (intention-to-treat population) were analyzed. The estimate for the mean plasma sodium change was -0.53 mmol/L (95% confidence interval: [-1.04; -0.02] mmol/L) for "Na control" treatments and -0.95 mmol/L (95% CI: [-1.76; -0.15] mmol/L) for "standard fixed Na" treatments. The standard deviation of the plasma sodium changes was 1.39 mmol/L for "Na control" versus 2.19 mmol/L for "standard fixed Na" treatments (P = 0.0004). Whereas the 95% CI for the estimate for the mean plasma sodium change during "Na control" treatments marginally overlapped the lower border of the predefined margin ±1.0 mmol/L, the variability of intradialytic plasma sodium changes was lower during "Na control" versus "standard fixed Na" treatments. Thus, automated dialysate sodium individualization by "Na control" approaches isonatremic dialysis in the clinical setting.
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Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study.
Rostoker, G, Loridon, C, Griuncelli, M, Rabaté, C, Lepeytre, F, Ureña-Torres, P, Issad, B, Ghali, N, Cohen, Y
EBioMedicine. 2019;:461-471
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis. METHODS Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy. FINDINGS PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5-14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27-11%)) or mild iron overload (PDFF: 5% (0.30-11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 μmol/g, final 160 μmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 μmol/g, final: 45 μmol/g; P = 0.002). INTERPRETATION Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients. TRIAL REGISTRATION NUMBER (ISRCTN): 80100088.
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Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial.
Block, GA, Rosenbaum, DP, Yan, A, Chertow, GM
Journal of the American Society of Nephrology : JASN. 2019;(4):641-652
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BACKGROUND Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. METHODS In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. RESULTS Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. CONCLUSIONS Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.
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Single-center, real-world experience with granulocyte colony-stimulating factor for management of leukopenia following kidney transplantation.
Hamel, S, Kuo, V, Sawinski, D, Johnson, D, Bloom, RD, Bleicher, M, Goral, S, Lim, MA, Trofe-Clark, J
Clinical transplantation. 2019;(6):e13541
Abstract
BACKGROUND Leukopenia is a frequent complication following kidney transplantation. Granulocyte colony-stimulating factor (G-CSF) has been used to accelerate white blood cell (WBC) count recovery; however, published experience in kidney transplantation is limited. METHODS We retrospectively reviewed our kidney transplant recipients from January 2012 to September 2016 with a G-CSF order to evaluate leukopenia management (defined as WBC <3000 cells/μL). RESULTS Thirty-six recipients were included. On average, G-CSF treatment began at 98 ± 38 days. At G-CSF initiation, mean WBC count was 1240 ± 420 cells/μL and absolute neutrophil count (ANC) was 653 ± 368 cells/μL. Mean G-CSF dose was 4.6 ± 1.2 mcg/kg/dose (total 11.8 ± 9.0 mcg/kg), 77.8% of recipients were prescribed G-CSF as outpatients, and overall, median time to WBC count recovery was 9 (IQR 4-14) days. Changes in immunosuppression and prophylaxis regimens for leukopenia were also common. Within 1 month following leukopenia onset, no patients experienced acute rejection and 5 (14%) developed infection requiring hospitalization or opportunistic infection. CONCLUSION In kidney recipients with leukopenia, G-CSF may be helpful to achieve WBC count recovery in addition to changes in immunosuppression and prophylaxis medications. Prospective, randomized data are still needed to determine optimal G-CSF dosing in this population.