Background: Online haemodiaﬁltration (OL-HDF) has been shown to reduce all-cause mortality versus conventional haemodialysis (HD); however, it is not always available. In these situations, a novel class of membranes with a higher pore size, medium cut-off (MCO) dialysers, could be promising. The aim of this study is to evaluate the efﬁcacy of an MCO dialyser in the removal of small and medium-size molecules and compare it with standard high-ﬂux (HF) dialysers in HD and OL-HDF. Methods: In this crossover study, 18 prevalent HD patients were studied in three single mid-week dialysis treatments during three consecutive weeks as follows: ﬁrst week with OL-HDF with a standard HF dialyser, second week with conventional HD with a standard HF dialyser and third week with conventional HD with an MCO dialyser. Reduction ratios (RRs) of different-sized molecules and albumin losses were collected for the different dialysers. Results: MCO HD provided a greater reduction of middle and larger middle molecules compared with standard HF HD [rate reduction (RR) b2-microglobulin 74.7% versus 69.7%, P¼0.01; RR myoglobin 62.5% versus 34.3%, P¼0.001; RR prolactin 60% versus 32.8%, P¼0.001; RR a1-glycoprotein 2.8% versus 0.1%, P¼0.01]. We found no difference in the clearance of small and larger middle molecules comparing MCO HD with OL-HDF. Albumin losses were 0.03 g/session with MCO HD and 3.1 g/session with OL-HDF (P¼0.001). Conclusion: MCO HD is superior to standard HF HD in the removal of middle and larger middle molecules and it is not inferior to OL-HDF in the clearance of small and larger middle molecules. Thus it could be an alternative in patients in which it is not possible to perform OL-HDF. Key words: chronic haemodialysis, dialysis, dialysis adequacy, haemodialysis, uraemic toxins Received: 3.10.2017. Editorial decision: 19.12.2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy004/4909823 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| A. Garcia Prieto et al. Patients. Patients included were >18 years old, had no renal Introduction residual function and were on OL-HDF treatment for a period of Patients with end-stage renal disease (ESRD) undergoing >3 months before enrolment. They had to be clinically stable, chronic intermittent haemodialysis (HD) have a higher risk of defined as no hospitalization during the 3 months prior to inclu- cardiovascular (CV) morbidity and mortality. This could be sion. Exclusion criteria were patients who were not receiving explained by an ageing population with an increased prevalence OL-HDF, showed residual renal function, were not clinically sta- of comorbid factors such as diabetes and hypertension  and ble or patients who declined to participate in the study. also by risk factors due to uraemia itself, leading to chronic inflammation and mineral disorders. Uraemic toxins are classi- Dialysis sessions. Treatments and dialysers were compared in a fied into small (<500 Da), middle molecular (>500 Da) water- single mid-week treatment during three consecutive weeks: soluble solutes and protein-bound substances . Retention of first week with OL-HDF with a standard HF dialyser, second uraemic toxins in the middle molecular range, which are poorly week with conventional HD with a standard HF dialyser and removed by conventional HD modalities , has been associated third week with conventional HD with an MCO dialyser. In the with pathological features of uraemia and might play an impor- rest of the sessions of the week, they received OL-HDF with tant role in the adverse outcomes in dialysis patients due to CV their current prescription and dialysers. disease . Therefore, in recent decades, efforts have focused The sessions were 4 h long and the dialysis treatments were on improving the clearance of larger middle molecules in dialy- based on their current prescription, with no restriction on blood sis. High-flux (HF) membranes, which allow the clearance of flow. The OL-HDF sessions were performed in post-dilution middle molecules such as b2-microglobulin by convective trans- mode with no restriction on the total convective ultrafiltration port, were introduced years ago. However, no clinical benefit of volume. In every session the ultrafiltration flow rate was HF versus low-flux membranes was shown in two randomized adjusted to reach dry weight. Any individual anticoagulant clinical trials (the MPO and HEMO studies), except in subgroup treatment was continued as previously prescribed. analyses [5, 6]. The development of online haemodiafiltration (OL-HDF) techniques that combine diffusive and convective Dialysers and techniques transport has resulted in markedly enhanced clearance of mid- OL-HDF was performed using FX CorDiax 1000 dialyser dle to large molecules. Its benefits to patient survival were first (Fresenius Medical Care, Bad Homburg, Germany), HF HD was pointed out by retrospective studies [7–10] and afterwards con- performed using FX CorDiax 80 dialyser (Fresenius Medical Care firmed by large randomized clinical trials like the Convective and MCO dialysis was performed using Theranova 500 dialyser Transport Study CONTRAST study , the Turkish study  (MCO, Gambro Dialysatoren, Hechingen, Germany, a subsidiary and the Estudio de Supervivencia de Hemodiafiltraciu ˆ ˚ n On-Line of Baxter International). Dialyser membrane characteristics are (ESHOL)  study, whose main conclusion was that high- described in Table 1. Monitors used were models 5008 efficiency post-dilution OL-HDF reduces all-cause mortality (Fresenius Medical Care), AK 200 Ultra (Gambro Baxter) and compared with conventional HD, especially when higher con- ARTIS (Gambro Baxter). vective volumes are achieved. Unfortunately, OL-HDF techni- ques are not available for every patient for different reasons, Samples. The efficacy of each treatment was analysed by meas- including vascular access dysfunction, water treatment systems uring the reduction rates of substances with different molecular unable to provide ultrapure water or economic problems, even weights, which are shown in Table 2. though OL-HDF can be considered cost effective compared with We obtained in each mid-week dialysis samples before and HF HD . In these situations, a novel class of membranes with after the dialysis sessions. We estimated the rate reduction (RR) a higher pore size designed to increase the removal of larger of small and medium-size molecules. The RR was calculated: middle molecules in conventional HD, called medium cut-off (MCO) dialysers, could be promising . However, since they RR ð%Þ¼½1 ðC =C Þ 100; post pre have been recently introduced, there is a lack of evidence on their use. There is only one study so far that compares the effi- where C and C are measured plasma concentrations of the pre post cacy of MCO dialysers with HD and OL-HDF using contemporary solute before and at the end of study treatments, respectively. HF dialysers, concluding that MCO HD removes a wide range of Albumin losses were determined with MCO dialyser and in middle molecules more effectively than HF HD and even OL-HDF by measuring albumin levels in the dialysis fluid at 0, 5, exceeds the performance of OL-HDF for large solutes . 15, 30, 60, 120 and 240 min of the dialysis session with an The main objective of the present study was to evaluate the inverse pump and measured albumin concentration using an efficacy of an MCO dialyser in the removal of small and autoanalyser (Dimension RXL, DADE, Siemens, Erlangen, medium-size molecules, as well as albumin losses. The second Germany). The dialysate flux values were recorded at these objective was to compare the efficacy of the MCO dialyser with time points. Thus, assuming that albumin losses decrease over HF HD and OL-HDF using contemporary HF dialysers. time during the session, we estimated the minimum amounts of total leakage in each period: Materials and methods Rate of leakage ¼ dialysate flux ðmL=minÞ 0 Concentration ðmg=mLÞ: Design of the study This transversal study was performed in patients with ESRD We did not collect albumin losses from HF HD because of from the Dialysis Unit of Gregorio Maranon ~ Hospital in Madrid, their small quantity. Serum, plasma and spent dialysate sam- Spain. Informed consent was obtained. The study was con- ples were collected and sent to our laboratory under standar- ducted according to the Declaration of Helsinki. dized conditions. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy004/4909823 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Efficacy and comparison of medium cut-off dialyser | 3 Table 1. Characteristics of dialysis membranes in study dialysers Inner Wall Effective diameter thickness surface UF coefficient a a 2 (lm) (mm) Membrane polymer area (m ) (mL/h/mmHg) KoA urea Theranova 180 35 Polyarylethersulphone–PVP blend 2 59 FX CorDiax 80 185 38 Polysulphone–PVP blend 1.8 64 1429 FX CorDiax 1000 210 35 Polysulphone–PVP blend 2.3 68 1421 According to manufacturer’s instructions for use. KoA, urea mass transfer coefﬁcient; PVP, polyvinylpyrrolidone; UF, ultraﬁltration. Table 2. Molecular weights of the different analysed substances Safety No adverse events were recorded among our population during Molecular the duration of the study or a 7-day period after each treatment. Substance weight (Da) Urea 60 Discussion Creatinine 113 Phosphate 30 To our knowledge, this is one of the first studies that provides b2-microglobulin 11 000 clinical experience with this novel class of dialysis membranes. Cystatin C 13 000 The objective was to evaluate the efficacy of MCO dialyser in Myoglobin 17 800 the removal of small and middle molecules and compare it with Prolactin 23 000 HD and OL-HDF using contemporary HF dialysers. The choice to a1-glycoprotein 41 000 compare with FX CorDiax dialysers was based on their wide use in Europe and reports indicating they achieve significantly greater middle molecule removal than other HF dialysers. Our Statistical analysis results are strong, conclusive and similar in terms of efficacy to Analyses were performed using SPSS analysis software version those obtained with OL-HDF. 20.00 (SPSS, Chicago, IL, USA). Treatment effects were evaluated Even though convective volumes reached during our OL- using a two-sided significance level of 0.05. The distribution of HDF sessions were 28 L on average, which has been shown to variables was analysed using the Kolmogorov–Smirnov test. reduce all-cause mortality in the ESHOL study , probably Values are given as mean (SD) or median (interquartile range). because of an enhanced clearance of middle-size molecules, the Continuous variables were compared using statistics for results obtained with the MCO dialyser in conventional HD are repeated measurements (analysis of variance). comparable with those in OL-HDF. When we analysed the RRs of small-size molecules, such as urea, creatinine and phos- Results phate, we found no significant differences between the MCO dialyser and OL-HDF. Regarding middle-size molecules, Baseline characteristics although the RRs of most of the molecules analysed were A total of 18 patients were included in the study. Patient and slightly but significantly higher with OL-HDF, there were no sig- treatment characteristics are shown in Table 3. nificant differences in the RRs of b2-microglobulin between the MCO dialyser and OL-HDF, which is the principal middle-size Removal of small and middle molecules during HD and molecule whose levels predict mortality in dialysis patients, as shown in a post hoc analysis of the HEMO study . OL-HDF Our RR of middle molecules obtained with MCO dialyser is RRs of medium- and small-size molecules in each treatment are comparable with those obtained by Kirsch et al.  in study 1 of shown in Table 4. their trial, in which mean dialysis time was 4 h (RR b2-microglo- In our study, the MCO dialyser achieved a significantly bulin 71.5–72% in Kirsch et al.’s study versus 74.7% in our study; higher mean RR of middle-size molecules, such as b2-microglo- myoglobin 63.1–67% in Kirsch et al.’s study versus 62.5% in our bulin, cystatin C, myoglobin, prolactin and a1-glycoprotein study). The RRs obtained in study 2 of Kirsch et al.’s trial were (P < 0.01), compared with HF HD (Table 2). The RRs of small mol- higher because mean dialysis time was longer (4–5 h) and thus ecules such as urea, creatinine and phosphate were also higher they cannot be directly compared with our results. Moreover, with the MCO dialyser, yet the differences were not statistically our patients reached higher convective volumes in OL-HDF significant. compared with Kirsch et al.’s study (28 versus 21 L/session), Compared with HDF, removal of larger-size solutes such as which enhances the clearance of middle molecules. This a1-glycoprotein was greater with MCO HD (2.46 0.08% versus explains that our RR of middle molecules with MCO dialyser, 2.86 0.18%), yet not significant (P ¼ 0.9), whereas there was no though comparable with those obtained by Kirsch et al., are difference in RRs of small molecules. lower than those obtained with our OL-HDF. That could also explain the lower albumin losses with MCO HD compared with Albumin removal during MCO HD and OL-HDF OL-HDF we found in our study. Nevertheless, we estimated the Albumin removal with MCO dialyser (0.036 0.01 g/session) was minimum amounts of total albumin leakage with each dialyser significantly lower (P < 0.001) compared with OL-HDF based on the albumin concentration in the dialysate fluid at (3.16 0.6 g/session). different points and dialysate flow, but we did not correct by Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy004/4909823 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| A. Garcia Prieto et al. Table 3. Baseline characteristics of the study population (N ¼ 18) Age (years), mean6 SD 656 13 Sex (M/F), n/n 9/9 CKD aetiology (%) Glomerular 44.4 Diabetes mellitus 33.3 Policystic disease 16.7 Tumoural 5.6 Vascular access (AVF) (%) 88.9 Dialysis vintage (months), median (IQR) 75 (35–108) Predialysis haematocrit (%), mean6 SD 32.26 6.4 Effective dialysis time (h), mean6 SD 46 0.05 Blood ﬂow at 30 min (mL/min), mean6 SD 4506 80 Kt/V per session, mean6 SD FX1000 FX80 Theranova 1.96 0.6 1.86 0.4 1.96 0.4 Ionic dialisance per session (mL/min), mean6 SD 2846 40 266.16 23 277.86 33 Convective volume during OL-HDF sessions (L/session), mean6 SD 286 8 Interdialytic weight gain (kg), mean6 SD 1.86 0.7 Ultraﬁltration volume (L/session), mean6 SD 2.16 1.2 CKD, chronic kidney disease; AV, arteriovenous ﬁstulae; IQR, interquartile range. Table 4. Comparison of RR with each molecule using HF HD with enhanced pressures required for reaching these volumes may FX80 dialyser, HD with MCO Theranova dialyser and OL-HDF using cause the leakage of certain substances such as albumin [18, FX1000 dialyser 19]. Nevertheless, there is yet no evidence on the clinical impact of these losses . We analysed albumin losses with MCO dial- FX80 Theranova FX1000 yser, as the higher pore size could lead to increased leakage, but Substance HD HD OL-HDF P-value instead we found significantly lower albumin losses compared Urea 82.3 (4.39) 83.5 (7.15) 85.4 (3.91) ns with OL-HDF. Thus this potential but questionable limitation of Creatinine 74.8 (4.92) 75.7 (7.47) 77.4 (5.90) ns OL-HDF concerning albumin losses should not represent a prob- Phosphate 58.8 (10.63) 60.5 (11.62) 61.4 (11.62) ns lem when using MCO dialysers. b2-microglobulin 69.7 (6.57) 74.7 (8.09)* 81.2 (4.29)* <0.001 A limitation of this study was the small sample size, which Cystatin C 63.8 (4.79) 71.6 (7.45)** 78.9 (4.87)* <0.001 could explain why some of our results, although clinically rele- Myoglobin 34.3 (7.88) 62.5 (8.66)* 72.4 (7.31)* <0.001 vant, did not reach significant differences. Moreover, we per- Prolactin 32.8 (9.79) 60 (8.20)* 69.2 (9.13)* <0.001 formed just one session with each dialyser, as it was designed a1-glycoprotein 0.1 (6.85) 2.8 (18.79)** 2.4 (7.98)* 0.02 as a transversal study, although follow-up could have added All values presented as mean (SD). more information in terms of CV events and survival. This could *P < 0.001 versus HD. also explain the fact that we found no adverse events in our **P < 0.05 versus HD. population, differing from the results provided in Kirsch et al. ns, non-signiﬁcant. , where adverse events were recorded in >50% of patients. However, our results are positive, strong and promising, espe- cially for patients who are not candidates for OL-HDF. ultrafiltration volume, which could explain the difference To conclude, in light of the results of this study we can say between our results and those obtained by Kirsch et al. that MCO dialyser is superior to conventional HD with standard The RR of larger middle molecules such as a1-glycoprotein HF dialysers in the removal of middle and larger middle mole- was higher with the MCO dialyser than with OL-HDF, although cules and it is not inferior to OL-HDF in the clearance of small the differences did not reach statistical significance, probably and larger middle molecules. Thus it could be an alternative in due to the reduced population included in our study. On the patients in which it is not possible to perform OL-HDF. other hand, when we compared the RR between MCO dialyser with a standard dialyser in conventional HD, we found greater clearance of small, middle and larger middle molecules with Conflict of interest statement MCO dialyser, which was statistically significant for middle and larger middle molecules, including b2-microglobulin, cystatin C, None declared. prolactin, myoglobin and a1-glycoprotein. Our findings agree with those obtained by Kirsch et al. in References a randomized clinical trial and show that this novel class of membranes offers an opportunity to improve the removal of 1. Registro Espanol ~ de Enfermos Renales. Informe 2013 y evolu- uraemic toxins in every HD patient, not only in candidates for cio ´ n 2007–2013. Nefrologı´a 2016; 36: 97–120 OL-HDF. 2. Lisowska-Myjak B. Uremic toxins and their effects on multi- In recent years there has been controversy concerning the ple organ systems. Nephron Clin Pract 2014; 128: 303–311 3. Vanholder RC, Eloot S, Glorieux GL. Future avenues to decrease benefits and risks of increasing convective volumes in OL-HDF because, due to their inner diameter and pore size, the uremic toxin concentration. Am J Kidney Dis 2016; 67: 664–676 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy004/4909823 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Efficacy and comparison of medium cut-off dialyser | 5 with high-ﬂux dialysis: results from the Turkish OL-HDF 4. Glorieux G, Vanholder R. New uraemic toxins—which sol- utes should be removed? Contrib Nephrol 2011; 168: 117–128 Study. Nephrol Dial Transplant 2013; 28: 192–202 5. Eknoyan G, Beck GJ, Cheung AK et al.Effect of dialysis dose 13. Maduell F, Moreso F, Pons M et al. High-efﬁciency postdilu- and membrane ﬂux in maintenance hemodialysis. NEngl J tion online hemodiaﬁltration reduces all-cause mortality in Med 2002;347:2010–2019 hemodialysis patients. J Am Soc Nephrol 2013; 24: 487–497 6. Locatelli F, Martin-Malo A, Hannedouche T et al. Effect 14. Ramponi F, Ronco C, Mason G et al. Cost-effectiveness analy- of membrane permeability on survival of hemodialysis sis of online hemodiaﬁltration versus high-ﬂux hemodialy- patients. J Am Soc Nephrol 2009; 20: 645–654 sis. Clinicoecon Outcomes Res 2016; 8: 531–540 7. Canaud B, Bragg-Gresham JL, Marshall MR et al.Mortality risk 15. Boschetti-de-Fierro A, Voigt M, Storr M et al. MCO mem- for patients receiving hemodiaﬁltration versus hemodialysis: branes: enhanced selectivity in high-ﬂux class. Sci Rep 2015; European results from the DOPPS. Kidney Int 2006; 69: 2087–2093 5: 18448 8. Jirka T, Cesare S, Di Benedetto A et al. Mortality risk for 16. Kirsch AH, Lyko R, Nilsson LG et al. Performance of hemo- patients receiving hemodiaﬁltration versus hemodialysis. dialysis with novel medium cut-off dialyzers. Nephrol Dial Kidney Int 2006; 70: 1524, author reply 1524–1525 Transplant 2017; 32: 165–172 17. Cheung AK, Rocco MV, Yan G et al. Serum beta-2 microglobu- 9. Panichi V, Rizza GM, Paoletti S et al. Chronic inﬂammation and mortality in haemodialysis: effect of different renal lin levels predict mortality in dialysis patients: results of the replacement therapies. Results from the RISCAVID study. HEMO study. J Am Soc Nephrol 2006; 17: 546–555 Nephrol Dial Transplant 2008; 23: 2337–2343 18. Tsuchida K, Minakuchi J. Albumin loss under the use of the 10. Vilar E, Fry AC, Wellsted D et al. Long-term outcomes in high-performance membrane. Contrib Nephrol 2011; 173: online hemodiaﬁltration and high-ﬂux hemodialysis: acom- 76–83 parative analysis. Clin J Am Soc Nephrol 2009; 4: 1944–1953 19. Vega A, Quiroga B, Abad S et al. Albumin leakage in online 11. Grooteman MPC, van den Dorpel MA, Bots ML et al. Effect of hemodiaﬁltration, more convective transport, more losses? online hemodiaﬁltration on all-cause mortality and cardio- Ther Apher Dial 2015; 19: 267–271 vascular outcomes. J Am Soc Nephrol 2012; 23: 1087–1096 20. Macı ´as N, Vega A, Abad S et al. Is high volume online hemo- 12. Ok E, Asci G, Toz H et al. Mortality and cardiovascular diaﬁltration associated with malnutrition? Ther Apher Dial events in online haemodiaﬁltration (OL-HDF) compared 2017; 21: 361–369 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy004/4909823 by Ed 'DeepDyve' Gillespie user on 12 July 2018
Clinical Kidney Journal – Oxford University Press
Published: Feb 26, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera