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Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5-20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS-331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on- and off-dialysis studies. On the contrary, GS-331007 exhibited a 30% reduction in the area under the plasma concentration-time curve from time 0 to 24 h (AUC 0-24h ) on dialysis days compared with non-dialysis days (AUC 0-24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS-331007 was 9.35 (8.72-15.11) and 8.89 (8.52-14.07) mL/min, respectively. Subsequently, an alternate-day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The worldwide burden of HCV infection among hemodialysis patients has not been systematically examined., Methods: A systematic literature search was conducted in MEDLINE and Scopus to determine the worldwide prevalence of HCV infection, risk factors, and clinical outcomes among hemodialysis patients. Random-effect models and meta-regressions were used to generate pooled estimates and assess heterogeneity., Results: Four hundred and seven studies with 1,302,167 participants were analyzed. The pooled prevalence of HCV infection was 21%. The highest prevalence was observed in Africa (28%) and low-income countries (48.5%). A significant prevalence decline was observed following the publication year and was also inversely related to GDP and total population of each country. Factors associated with HCV positivity included younger age, longer dialysis duration, more blood transfusions, and dialyzer reuse. The pooled unadjusted hazard ratio for all-cause mortality was 1.12 (95% CI 1.03-1.22), and the adjusted hazard ratio was 1.21 (95% CI 1.12-1.30) in HCV-infected compared to non-HCV infected patients., Conclusions: HCV infection among hemodialysis patients is a worldwide shared burden and is associated with a higher risk of death. Avoiding unnecessary blood transfusion and dialyzer reuse should be encouraged to prevent HCV transmission in hemodialysis units., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Although high-volume postdilution online hemodiafiltration (ol-HDF) is superior to high-flux HD in removing all kinds of uremic toxins and improving survival, this treatment is not available in most HD centers. The present study was conducted to compare the effectiveness in removals of protein-bound (indoxyl sulfate [IS]), middle-molecule [beta-2 microglobulin (B2M) and alpha-1 microglobulin (A1MG)], and small-molecule uremic toxins between super high-flux HD (SHF-HD), HD with a novel SHF dialyzer and high-volume postdilution ol-HDF in a noninferiority fashion. Fifteen prevalent HD patients were randomly allocated into two sequences of 12-week treatment periods of SHF-HD treatment and later high-volume postdilution ol-HDF period or vice versa. Each treatment period was divided by a wash-out phase of 4-week high-flux HD. Twelve of 15 patients could complete the study. When compared with high-volume postdilution ol-HDF (convective volume of 24.4 ± 3.52 L), SHF-HD provided comparable reduction ratio values of IS, B2M, and A1MG with mean difference of 5.87 (95% confidence interval [CI] -1.63, 13.37), 1.98 (95% CI,-0.21, 4.18), and 22.96 (95% CI, -1.91, 47.83), respectively. The spKt/Vurea was not different. The predialysis levels of all uremic toxins at baseline and after 12-week treatment did not differ between both groups. Although albumin loss in dialysate in SHF-HD was greater than high-volume postdilution ol-HDF, the serum albumin levels after 12-week SHF-HD treatment were significantly higher than baseline. In conclusion, SHF-HD provides noninferior effectiveness to high-volume postdilution ol-HDF in removing various uremic toxins with significantly increased serum albumin levels despite higher albumin loss. SHF-HD might be an effectively alternative treatment when high-volume postdilution ol-HDF is not available., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background: We performed a systematic review and meta-analysis to examine factors associated with HBV immune response in dialysis patients, and the association between the immune response to the HBV vaccine and mortality., Methods: Electronic databases were searched for studies of dialysis patients that compared the characteristics of HBV vaccine responders and non-responders. Mortality was also analyzed according to the vaccine immune response (defined by hepatitis B surface antibody titer > 10 mIU/mL). Random-effects model meta-analyses were performed to compute a weighted mean difference (WMD), a pooled odds ratio (OR), and a pooled risk ratio (RR) between groups., Results: We identified 61 studies with a total of 6628 dialysis patients who completed the course of HBV vaccination, 4582 responders (69%) and 2046 non-responders (31%). By meta-analysis, relative to non-responders, HBV vaccine responders had a higher dialysis adequacy as measured by Kt/V (WMD 0.08, P < 0.001), a higher serum albumin (WMD 0.12 gm/dL, P < 0.001), a higher normalized protein catabolic rate (WMD 0.12 gm/kg/day, P = 0.001), a higher hemoglobin (WMD 0.15 gm/L, P = 0.03), and a higher parathyroid hormone level (WMD 44 pg/mL, P = 0.004). HBV vaccine responders were younger (WMD - 4.68 years, P < 0.001), had been on dialysis for longer (WMD 2.60 months, P < 0.001), were less likely to have diabetes mellitus (pooled OR 0.65, P < 0.001), and were less likely to carry the human leukocyte antigen (HLA) DR3 (pooled OR 0.38, P = 0.01). Compared to non-responders, HBV vaccine responders had lower risk for all-cause mortality (pooled RR 0.64, P < 0.001), and lower risk for cardiovascular-related mortality (pooled RR 0.74, P = 0.02)., Conclusion: In dialysis patients, the lack of immune response to the HBV vaccine is associated with older age, diabetes mellitus, HLA-DR3 status, shorter time on dialysis, lower nutritional status, lower hemoglobin, lower PTH level, and lower dialysis adequacy. Tackling some of these modifiable factors might improve the HBV vaccine immune response.

Background: Although the levels of intact parathyroid hormone (iPTH) are well-controlled following the Kidney Disease Outcomes Quality Initiative guideline, the incidence of osteoporosis and fracture are still high in haemodialysis (HD) patients. This study was conducted to investigate the correlation between bone turnover markers, bone mineral density (BMD), and bone histomorphometry in HD patients., Methods: Twenty-two chronic HD patients were enrolled. Serum levels of bone turnover markers were measured. Double tetracycline-labelled iliac crest bone specimens were evaluated using specialized a computer program (Osteomeasure). The types of bone histomorphometry were classified based on turnover, mineralization and volume. BMD and coronary artery calcification were also determined., Results: Bone histomorphometry revealed osteitis fibrosa (50%), adynamic bone disease (45%) and mixed uremic osteodystrophy (5%). Serum iPTH level predicted high bone turnover with area under the receiver operating characteristic (ROC) of 0.833 (95% CI = 0.665-1.000, P = 0.008). Serum TRAP-5b also had ROC of 0.733 (95% CI = 0.517-0.950, P = 0.065). In addition, when using serum iPTH (cut-off 484.50 ng/mL) or serum TRAP-5b (cut-off 1.91 pg./mL) to predict high turnover, the sensitivity was 0.917. On the other hand, when both iPTH and TRAP-5B were above these cut-off, the specificity was 1.000. Low BMD and severe vascular calcification were commonly identified. However, there were no significant correlations between bone biomarkers and BMD or severe vascular calcification., Conclusion: Although iPTH levels were close to the target of Kidney Disease Outcomes Quality Initiative guideline, abnormal bone histomorphometry, BMD, and severe vascular calcification are still common. Bone biopsy is still crucially required as an accurate diagnostic tool in providing optimal guide for the treatment. © 2019 Asian Pacific Society of Nephrology., (© 2019 Asian Pacific Society of Nephrology.)

Background: Secondary hyperparathyroidism (SHPT) is associated with high incidences of cardiovascular disease, bone fracture, and mortality. This study was conducted to demonstrate the effectiveness of cinacalcet treatment on chronic kidney disease-mineral bone disorder (CKD-MBD) markers in chronic hemodialysis patients with severe SHPT., Methods: In phase 1, 30 adult HD patients were randomized to cinacalcet or control groups for 12 weeks to explore the achievement of >30% reduction of iPTH. In phase 2, 45 patients were participated to further explore the effect of cinacalcet on CKD-MBD parameters for 24-week follow up and 12 additional weeks after cinacalcet discontinuation., Results: In phase 1, the baseline serum iPTH levels were not different [1374 (955, 1639) pg/mL in the control group vs. 1191 (1005, 1884) pg/mL in the cinacalcet group], the percentage of patients achieving iPTH target were significantly higher in the treatment group [80% vs. 13%, p = .001]. In phase 2, the significant reductions of iPTH, FGF-23, tartrate-resistant acid phosphatase 5b, and slightly decreased size of parathyroid gland and stabilized vascular calcification were observed at 24-week follow up and markedly rebounded after discontinuation of cinacalcet., Conclusions: The effectiveness of cinacalcet were still obviously demonstrated even in chronic HD patients with severe SHPT. In addition, the improvements of bone markers and FGF-23, and stabilization of vascular calcification were observed. Therefore, cinacalcet can provide salutary effects on CKD-MBD in severe SHPT and might be an initially effective PTH-lowering therapy prior to surgical parathyroidectomy as well as an alternative treatment in the patients unsuitable for surgery., Clinical Trial Registration: ClinicalTrials.gov: NCT02056730. Date of registration: February 4, 2014.

Background: Arterial stiffness (AS) and vascular calcification are significantly related to a high cardiovascular mortality risk in hemodialysis (HD) patients. Intravenous sodium thiosulfate (IV STS) can prevent and delay the vascular calcification progression in uremic states; however, the STS effect on AS has not been assessed. This study aimed to evaluate the STS efficacy on vascular calcification and AS in HD patients., Methods: Fifty HD patients with abnormal AS, as measured via the cardio-ankle vascular index (CAVI ≥8), were prospectively randomized to open-label 12.5 g IV STS during the last HD hour twice weekly for 6 months (n = 24) or the usual care (control group; n = 26). Patients and treating physicians were not blinded. The CAVI, coronary artery calcification (CAC) score, hemodynamics, and biochemical parameters were measured at the baseline and at 3 and 6 months., Results: All the baseline parameters were comparable. The IV STS significantly reduced the CAVI when compared to the control group (mean CAVI difference = -0.53; 95% CI -1.00 to -0.06; p = 0.03). A significant CAVI improvement was seen in those patients without diabetes mellitus. The natural logarithm of the CAC volume score was significantly increased in the control group. The high sensitivity C-reactive protein level was slightly lowered in the IV STS group (not significant)., Conclusion: The intradialytic STS treatment significantly reduced the AS, as measured by the CAVI, and stabilized the vascular calcification in the HD patients. STS may be a novel therapeutic strategy for delaying and treating the structural and functional vascular wall abnormalities in HD patients., (© 2018 S. Karger AG, Basel.)

Hypercytokinemia plays a central role in pathogenesis and is related to the high mortality in sepsis-related acute kidney injury (AKI). Besides the established cytokines, vascular endothelial growth factor (VEGF) is demonstrated as an important factor in enhancing vascular leakage in sepsis. This prospective randomized trial was conducted to compare the efficacy of cytokine removal between online hemodiafiltration (HDF), which combines convective and diffusive solute removal, and high-flux hemodialysis (HD). Twenty-eight sepsis-related AKI patients were included and randomized into online HDF and high-flux HD. The percentages of the reduction ratio in plasma cytokines were measured as primary outcomes. Other clinical parameters were determined as secondary outcomes. When compared with high-flux HD, online HDF provided significantly greater percentages of the reduction ratio in plasma cytokine levels, including VEGF (P < 0.001), IL-6 (P = 0.001), IL-8 (P = 0.021), IL-10 (P = 0.011), and tumor necrosis factor-α (P = 0.029). There were no significant differences in intradialytic blood pressures. Online HDF revealed better renal recovery and shorter length of hospitalization than high-flux HD. In conclusion, online HDF in sepsis-related AKI could provide significantly better removal of VEGF and other cytokines and these were associated with better renal outcome than high-flux HD. Thus, online HDF would offer a potential role in hypercytokinemic state in sepsis-related AKI., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

Chronic volume overload resulting from interdialytic weight gain and inadequate fluid removal plays a significant role in poorly controlled high blood pressure. Although bioimpedance has been introduced as an accurate method for assessing hydration status, the instrument is not available in general hemodialysis (HEMO) centers. This study was conducted to explore the correlation between hydration status measured by bioimpedance and blood pressure parameters in chronic HEMO patients. Multifrequency bioimpedance analysis was used to determine pre- and post-dialysis hydration status in 32 stable HEMO patients. Extracellular water/total body water (ECW/TBW) determined by sum of segments from bioimpedance analysis was used as an index of hydration status. The mean age was 57.9 ± 16.4 years. The mean dry weight and body mass index were 57.7 ± 14.5 kg and 22.3 ± 4.7 kg/m(2), respectively. Pre-dialysis ECW/TBW was significantly correlated with only pulse pressure (r = 0.5, P = 0.003) whereas post-dialysis ECW/TBW had significant correlations with pulse pressure, systolic blood pressure, and diastolic blood pressure (r = 0.6, P = 0.001, r = 0.4, P = 0.04, r = -0.4, and P = 0.02, respectively). After dialysis, the mean values of ECW/TBW, systolic blood pressure, mean arterial pressure, and pulse pressure were significantly decreased. ECW/TBW was used to classify the patients into normohydration (≤ 0.4) and overhydration (>0.4) groups. Systolic blood pressure, mean arterial pressure, and pulse pressure significantly reduced after dialysis in the normohydration group but did not significantly change in the overhydration group. Pre-dialysis pulse pressure, post-dialysis pulse pressure, and post-dialysis systolic blood pressure in the overhydration group were significantly higher than normohydration group. Due to the simplicity and cost, blood pressure parameters, especially pulse pressure, might be a simple reference for clinicians to determine hydration status in HEMO patients., (© 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.)

Background: In Thailand, dialysate endotoxin contamination levels vary from less than 0.001 to 2.0 EU/ml. This difference has prompted an investigation on the production of proinflammatory cytokines and counter-inflammatory mediators of peripheral blood mononuclear cells (PBMCs) after high-flux dialysis., Methods: Patients from four hemodialysis (HD) centers who met the inclusion/exclusion criteria were enrolled into the study. PBMCs were isolated by Ficoll density gradient centrifugation and cultured. Supernatants were tested for interleukin 6 (IL-6), IL-1β and IL-1 receptor antagonist (IL-1Ra) concentration by ELISA., Results: HD centers 1, 2, 3 and 4 had mean dialysate endotoxin contamination levels of 0.001, 0.026, 0.558 and 1.960 EU/ml, respectively. HD center 4 had the highest levels of IL-6 (1,052.3 ± 240.7 pg/10(6) PBMCs), IL-1β (1,297.1 ± 334.6 pg/10(6) PBMCs) and IL-1Ra (2,713.4 ± 1,255.3 pg/10(6) PBMCs). There were no significant differences in cytokine production between HD centers 1 and 2., Conclusion: Our study showed that ultrapure dialysate can minimize the risk of stimulating inflammatory cells. Ultrapure dialysate may prevent or delay endotoxin exposure-related complications., (Copyright © 2011 S. Karger AG, Basel.)

Objective: To evaluate 25 hydroxyvitamin D (25-OH-D) deficiency in a cohort ofpredialysis CKD patients and the treatment effect and safety of high dose ergocalciferol supplement in predialysis CKD., Material and Method: Fifty-six predialysis CKD patients who came for a regular visit at a single hospital with calculated glomerular filtration rate < or =60 mL/min/1.73 m2 were screened for 25-OH-D levels. Forty-four patients with 25-OH-D deficiency were recruited into this prospective observational study that examined the effect of high dose oral ergocalciferol supplementation. After eight weeks, 37 patients completed the follow-up and biochemical parameters were reevaluated and analyzed., Results: The mean 25-OH-D level of 56 patients was 25.6 +/- 8 ng/mL. Forty-four (78.5%) patients had 25-OH-D levels less than 30 ng/mL and four (7.1%) had severe deficiency with the level less than 15 ng/mL. High dose ergocalciferol supplement successively increased 25-OH-D levels in 35 (95%) patients. 25-OH-D levels increased significantly from 22 +/- 4.8 to 34.5 +/- 10.8 ng/mL after eight weeks (p < 0.001). During the study period, there were no changes in serum calcium, phosphate, and PTH. There was no other side effect associated with the treatment., Conclusion: 25-OH-D deficiency were found in this cohort of predialysis CKD patients. Ergocalciferol was a safe and effective supplement for the 25-OH-D in predialysis CKD.

Abnormal immune function in chronic hemodialysis (HD) patients could impair immunologic responsiveness to various vaccinations. Such inadequate response makes the HD patients to be at risk of certain fatal but preventable diseases including rabies. Although the effectiveness of rabies vaccination has been established in healthy subjects, the responsiveness of the current rabies vaccination has never been examined in HD patients. The effectiveness of post-exposure rabies vaccine was assessed in 20 stable thrice-a-week chronic HD patients who received adequate dialysis and did not have history of rabies vaccination during the last 20 years. All participants received the standard intradermal Thai Red Cross post-exposure rabies vaccination. Blood samples were obtained for determination of rabies neutralizing antibody (Nab) before the first dose (day 0) and on days 14 and 90 after vaccination. Prior to simulated vaccination, six of twenty patients already had Nab titers above the protective levels of 0.5IU/mL while the remaining fourteen patients showed undetectable Nab. All subjects reached Nab titers above 0.5IU/mL(acceptable level for rabies protection) by days 14 after vaccination. The geometric mean titers (GMTs) on days 14 after vaccination were 3.2+3.1IU/mL (range 0.81-9.17IU/mL). At day 90 after vaccination, 13 of 14 patients had Nab titers above the protective levels, resulting in the response rate of 92.8%. The GMTs of Nab on day 90 after vaccination were 5.09+1.79IU/mL (0.42-25.0IU/mL). There were no correlations between Nab titers and patient characteristics. No serious adverse reactions were detected. In conclusion, chronic HD patients receiving adequate dialysis have excellent protective immunological response after intradermal post-exposure rabies vaccination as WHO recommendation.

Background: The new dry weight (DW) assessment technique by intradialytic sequential bioimpedance analysis (BIA) was evaluated in this study., Methods: Intradialytic changes in the ratio of resistance at baseline per each time point (R(0)/R(t)) determined by a total body single-frequency BIA were recorded in 19 hemodialysis patients. The bioimpedance DW (BIADW) could be drawn from a time point at which R(0)/R(t) was constant., Results: After the first session where the previous DW was prescribed, the participants could be divided into 2 groups: the under BIADW and over BIADW groups. In the under BIADW group, the BIADW was achieved earlier than the previous DW. The intradialytic symptoms disappeared without changes in the home-monitored mean blood pressure and antihypertensive agents at 1-month follow-up. In the over BIADW group, the BIADW could be obtained in the following sessions and the prescribed DW could be gradually reduced. The home-monitored mean blood pressure was decreased and the numbers of antihypertensive drugs were reduced., Conclusion: Intradialytic single-frequency BIA assessment can be used as a tool to accurately determine the DW., (Copyright 2009 S. Karger AG, Basel.)

Measurement of the vascular access flow rate (Q(a)) is a widely accepted method for surveillance and predicting access failure. Among current practical methods, the ultrasound dilution technique is standard, but this requires a costly device available in few hemodialysis (HD) centers. Here, we devised a simple hemoglobin dilution technique to accurately measure Q(a) without the need for any special machines. Before HD, values of Q(a) were determined in each of 30 patients by hemoglobin dilution and then, in the same session, by ultrasound dilution. There was a significant correlation between the two techniques using automated hemoglobin and hematocrit or centrifuge-measured hematocrit levels to calculate HD fluid-derived Q(a) values. Our study shows that the HD dilution technique, using no special device, is economical, highly accurate, and easy to perform, and can be used as an alternative to standard ultrasound dilution for vascular access surveillance.

Objective: The targets of dialysis per session, in terms of Kt/V and URR are well established for thrice-a-week hemodialysis (HD). The target values of these parameters could not be applied for the patients undergoing twice-a-week HD, which is performed in several developing countries. The equivalent renal urea clearance EKR (EKR [mL/min) = G (mg/min)/TAC (mg/mL)], which measures urea clearance in a continuous fashion, has been used in comparing amount of dialysis among the different modalities. For any chronic dialysis regimens the target EKRc, which was normalized to urea volume of distribution of 40 L, would be above 13 mL/min. Therefore, there is no data available regarding Kt/V, URR, and EKRc for twice-a-week HD., Material and Method: The EKRc of 26 Thai patients treated with twice-a-week high flux HD were measured monthly for 12 months. The Kt/V, URR, and serum albumin were also measured monthly., Results: Overall, the mean EKRc of 294 patient-month analysis was 11.68 +/- 0.16 mL/min. Monthly EKRc had a high correlation to Kt/V (r = 0.80) and URR (r = 0.82). When serum albumin was employed as a surrogate marker for treatment failure, ROC analysis revealed that EKRc above 13 mL/min had 90% and 100% probabilities to maintain monthly and 12-month serum albumin levels above 4 gm/dL, respectively. To obtain the target EKRc above 13 mL/min at 90 and 95% confidence, the values of Kt/V per session were 2.11 and 2.25, respectively while those of URR were 82.89 and 84.52%, respectively., Conclusion: For twice-a-week HD, to have the EKRc level above 13 mL/min, at 95% confidence, the Kt/V should exceed 2.2 and the URR should exceed 85% per session.

Methods and Results: Oxidative stress was examined in 19 erythropoietin-treated haemodialysis patients who were receiving 100 mg of iron sucrose every 2 weeks by two intravenous methods, rapid injection and slow infusion. There were no significant differences in incidence of iron oversaturation state between the two methods. Regarding oxidative stress markers, the values of plasma and red blood cell thiobarbituric acid reactive substances (TBARS) expressed in terms of malonyldialdehyde (MDA) equivalents following the two methods did not increase, and the values of area under the curve (AUC) of both markers were not different between both regimens. Also, there were no significant differences in the values of plasma and AUC of anti-oxidant markers including total anti-oxidant status, reduced thiols, and vitamin E among both periods treated with two intravenous iron methods., Conclusion: As such, both intravenous iron methods could be safely used without enhancing oxidative stress in haemodialysis patients. The rapid injection method would be the preferred method of intravenous iron administration because it is more convenient while still retaining the safety profile.

Convective-controlled double high flux hemodiafiltration (CC-DHF) was set-up using two high flux dialyzers. The convection occurred in the first while the fluid replacement took place in the second dialyzer. The system of CC-DHF basically resembled that of hemodiafiltration. CC-DHF was performed in 9 chronic hemodialysis Thai patients who had been treated with high flux hemodialysis for at least 6 months. When compared with high flux hemodialysis, CC-DHF could provide higher Kt/Vurea (2.4+/-0.4 vs. 2.0+/-0.4, p<0.05) and beta2-microglobulin clearance (106.2+/-15.4 vs. 48.9+/-6.1 ml/min, p<0.01). Following 6-month therapy of CC-HDF, the predialysis beta2-microglobulin levels were reduced by 12.7% while the values of Kt/Vurea were consistently higher than 2.7. The quality of life consistently improved during the 6 months of CC-DHF treatment. There were no differences in clinical and technical complications between CC-DHF and high flux hemodialysis. In conclusion, CC-DHF could provide performance comparable to hemodiafiltration without the need for expensive hemodiafiltration machines.