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Revisiting Frontiers of Tolerability and Efficacy in Renal Replacement Therapy
Editorial Revisiting Frontiers of Tolerability and Efficacy in Renal Replacement Therapy Related Article, p. 247
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linical outcomes associated with dialysis therapies depend on the prescribed treatment modality and conditions of treatment delivery. Prescribing dialysis therapy to patients with chronic kidney failure requires considering an impressive array of patient- and technology-related factors, not to mention a variety of care practices.1 The study by Cornelis et al2 in this issue of AJKD examines the combined effects of 2 of the most widely debated and fundamental modifiable factors of the hemodialysis (HD) prescription: treatment modality and treatment duration. Most patients today are treated with high-flux rather than low-flux HD, which reflects the recognition that large, and not just small, uremic toxins must be removed to treat patients with chronic kidney failure. Hemodiafiltration (HDF), an extension of high-flux HD, is an alternative treatment modality that further increases the removal of larger uremic toxins by enhancing convective clearance. The second modifiable factor, treatment duration, has been a subject of debate since the early days of dialysis therapy, with most nephrologists of the opinion that patients derive the greatest benefit from longer and more frequent dialysis sessions.3 Cornelis et al2 explored the interaction of treatment modality and duration with a 232 factorial crossover study design that used each patient as his or her own control. Interventions included duration of the dialysis session (short [4 hours] vs long [8 hours]) and type of solute flux (diffusive flux using high-flux HD vs enhanced convective flux using HDF; in both cases, high-flux membrane dialyzers were used). The primary outcomes were hemodynamic tolerance and solute mass transfer as surrogate markers of the combined effect of time and solute flux prescription. Hemodynamic changes were used as outcome parameters for assessing the tolerability of both treatment time (short vs long) and modality (high-flux HD vs HDF). Hemodynamic assessment was performed using conventional measures such as relative blood volume changes, intermittent blood pressure, ultrafiltration, and weight loss, as well as more sophisticated markers like cardiac output, pulse wave velocity analysis, and microcirculation changes. As expected, ultrafiltration rate (in milliliters per kilogram per hour) was reduced by w50% in both modalities when long treatment times were used. Importantly, thermal balance was matched in the 4 treatment schedules, which suppressed this confounding factor in HDF. Clinical tolerance was not reported. Am J Kidney Dis. 2014;64(2):171-173
Solute mass transfer removal was used to assess the efficacy of treatment time and modality. A valuable feature of the study was analysis of a range of uremic toxins (including both small- and middle-molecularweight substances), which was achieved using direct quantification from spent dialysate samples collected continuously. This direct quantification approach provides a reliable way of estimating direct mass balance and abrogates potential pitfalls that may affect serum solute levels, such as intracorporeal solute sequestration, toxin-binding capacity, blood versus plasma concentration, and hemoconcentration.4 There were 2 major findings in this study. First, longer treatments, regardless of diffusion or convection, provided greater hemodynamic stability. Second, HDF was associated with greater clearance of measured uremic toxins such as phosphate and middle and large molecules, including b2-microglobulin (B2M) and fibroblast growth factor 23 (FGF-23), despite the universal use of high-flux membranes in all study groups. This study provides strong support for 2 fundamental paradigms of dialysis prescription: first, longer sessions (8 hours) are beneficial compared with shorter sessions (4 hours); and second, enhanced convective modalities (HDF) are superior compared with conventional diffusive modalities (high-flux HD) at depleting uremic toxins (inorganic phosphate) and middle molecules (B2M), although both treatment modalities in the study used a polysulfone membrane with the same highsolute permeability. The study demonstrated that, independent of treatment modality (high-flux HD or HDF), extended treatment schedules (ie, 8 hours) virtually abolish hemodynamic consequences induced by shorter dialysis and/or ultrafiltration sessions, thereby facilitating the achievement of dry weight (there was a 10%-15% increase in number of patients who reached the desired dry weight). Impressively, although even in the 4-hour sessions, ultrafiltration rate was low (6-7 mL/kg/h in the 4-hour regimens vs 4-4.5 mL/kg/h in the 8-hour regimens), all hemodynamic parameters evaluated in this study indicated the same patterns, consistent with an apparent benefit of the extended treatment schedule. This improvement in cardiovascular stability cannot be
Address correspondence to Bernard Canaud, MD, PhD, Medical Board, Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.05.006 171
Canaud and Bowry
attributed to thermal balance, which was matched during the 4 treatment schedules of the study; rather, this effect likely results from the preservation of effective blood volume due to adequate matching of the vascular refilling rate (as suggested by the relative stability of residual blood volume changes over various dialysis sessions). Preserving hemodynamic stability is of considerable clinical importance because it reduces the probability of transient ischemic cardiac insult, thus providing a rationale for the cardioprotective effect of extended and convective therapies.5 By combining diffusion and enhanced convection through highly permeable membranes, HDF increased total solute mass transfer removal of phosphate and middle- (B2M) and large-molecule (FGF-23) substances by 30% to 50% depending on operational conditions compared to high-flux HD. It must be noted that the type of dialyzer (FX80; Fresenius Medical Care) used in this study has, by its design and membrane characteristics, enhanced clearance for B2M (ie, middle molecules). This intrinsic property of this advanced dialyzer type tends to minimize differences observed between the performance of high-flux HD and HDF. Furthermore, because long HDF sessions delivering up to 30 L of convective volume are associated with a continuous increase in B2M mass removal (up to 200 mg per session), the data in this study illustrate that long treatment time facilitates solute removal by intracorporeal mass transfer, as well as elimination by dialysis. From a pharmacokinetic perspective, this combined time and convective flux effect also holds true for inorganic phosphate and uremic toxins with low intracorporeal mass transfer. Although recent evidence suggests a possible cardiovascular disease and survival benefit associated with high-volume HDF,6,7 3 recent meta-analyses were unable to support cardiovascular or survival benefit of HDF definitively. Notably, none of these studies considered the role of convective volume as a potential determinant of efficacy and survival benefit.8-10 In the Cornelis et al2 trial, the HDF prescription may have been suboptimal because both the short and long HDF prescriptions were consistent with what is considered low-efficiency HDF. Based on recent clinical studies, the instantaneous ultrafiltration rate and/or total ultrafiltration volume, a surrogate of the convective dose needed to improve patient outcome, may be w100 mL/min (or 6 L/h) in a standard treatment schedule of 4 hours thrice weekly.6,7,11 Accordingly, with more optimal convective dose prescription (ie, increasing convective volume by 30%), one could anticipate an increase of 20%-30% of solute removed by an HDF session on either short or long treatment schedules.12 With this prescription, estimated phosphate mass removal per session would be 1,200 mg in HDF (4 hours) and 2,000 mg in HDF (8 hours),4 and estimated B2M mass removal would be 200 mg in HDF (4 hours) and 260 mg in HDF (8 hours). 172
The findings of this study are crucial for designing both more physiologic and more efficient dialysis treatment modalities. Short HDF (4 hours) is essentially equivalent, solely in terms of performance and solute removal, to long high-flux HD (8 hours). Long HDF (8 hours) with adequate convective volume could provide the optimal platform for developing nocturnal treatment schedules (3 times weekly or alternate-day 4 times weekly) and a more physiologic therapy. Such treatment regimens would be different from those considered in the Frequent Hemodialysis Network Trial, which predominantly focused on the removal of low-molecular-weight solutes by mainly diffusive mechanisms and did not consider the effects of ultrapure dialysate in reducing inflammation and oxidative stress, which might affect long-term clinical outcomes.13,14 The study from Cornelis et al2 suggests that long-term use of HDF could achieve a quasinormalization (or even depletion) of phosphate without using phosphate binders, a decrease in serum B2M levels to 20 mg/L, and a reduction in FGF-23 circulating levels of w30%. The results of Cornelis et al2 warrant further longterm clinical trials using 4- and 8-hour HDF. Such trials will establish the potential clinical benefits of short- and long-duration HDF as the future dialysis treatment modality of choice to reduce the high mortality rate observed among patients with chronic kidney failure. Obviously, the feasibility and costeffectiveness of these schedules, as well as patientreported outcomes, including patient quality of life, need to be examined thoroughly. Bernard Canaud, MD, PhD Sudhir K. Bowry, PhD Fresenius Medical Care Deutschland GmbH Bad Homburg, Germany
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Canaud is Emeritus Professor of Nephrology at Montpellier University I - School of Medicine, Montpellier, France. Drs Canaud and Bowry are employees of Fresenius Medical Care Deutschland GmbH.
REFERENCES 1. Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med. 2010;363:1833-1845. 2. Cornelis T, van der Sande FM, Eloot S, et al. Acute hemodynamic response and uremic toxin removal in conventional and extended hemodialysis and hemodiafiltration: a randomized crossover study. Am J Kidney Dis. 2014;64:247-256. 3. Locatelli F, Canaud B. Dialysis adequacy today: a European perspective. Nephrol Dial Transplant. 2012;27:3043-3048. 4. Lornoy W, De Meester J, Becaus I, Billiouw JM, Van Malderen PA, Van Pottelberge M. Impact of convective flow on phosphorus removal in maintenance hemodialysis patients. J Ren Nutr. 2006;16:47-53. Am J Kidney Dis. 2014;64(2):171-173
Editorial 5. McIntyre CW. Haemodialysis-induced myocardial stunning in chronic kidney disease—a new aspect of cardiovascular disease. Blood Purif. 2010;29:105-110. 6. Maduell F, Moreso F, Pons M, et al. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients. J Am Soc Nephrol. 2013;24:487-497. 7. Tattersall JE, Ward RA; EUDIAL Group. Online haemodiafiltration: definition, dose quantification and safety revisited. Nephrol Dial Transplant. 2013;28:542-550. 8. Nistor I, Palmer SC, Craig JC, et al. Convective versus diffusive dialysis therapies for chronic kidney failure: an updated systematic review of randomized controlled trials. Am J Kidney Dis. 2014;63:954-967. 9. Wang AY, Ninomiya T, Al-Kahwa A, et al. Effect of hemodiafiltration or hemofiltration compared with hemodialysis on mortality and cardiovascular disease in chronic kidney failure: a systematic review and meta-analysis of randomized trials. Am J Kidney Dis. 2014;63:968-978.
Am J Kidney Dis. 2014;64(2):171-173
10. Susantitaphong P, Siribamrungwong M, Jaber BL. Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2013;28:2859-2874. 11. Bowry SK, Canaud B. Achieving high convective volumes in on-line hemodiafiltration. Blood Purif. 2013;35(suppl 1):23-28. 12. Mostovaya IM, Blankestijn PJ, Bots ML, et al; on behalf of The EUDIAL—an official ERA-EDTA Working Group. Clinical evidence on hemodiafiltration: a systematic review and a metaanalysis. Semin Dial. 2014;27:119-127. 13. Rocco MV, Lockridge RS Jr, Beck GJ, et al; Frequent Hemodialysis Network (FHN) Trial Group. The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011;80:1080-1091. 14. Susantitaphong P, Riella C, Jaber JL. Effect of ultrapure dialysate on markers of inflammation, oxidative stress, nutrition and anemia parameters: a meta-analysis. Nephrol Dial Transplant. 2013;28(2):438-446.
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C
linical outcomes associated with dialysis therapies depend on the prescribed treatment modality and conditions of treatment delivery. Prescribing dialysis therapy to patients with chronic kidney failure requires considering an impressive array of patient- and technology-related factors, not to mention a variety of care practices.1 The study by Cornelis et al2 in this issue of AJKD examines the combined effects of 2 of the most widely debated and fundamental modifiable factors of the hemodialysis (HD) prescription: treatment modality and treatment duration. Most patients today are treated with high-flux rather than low-flux HD, which reflects the recognition that large, and not just small, uremic toxins must be removed to treat patients with chronic kidney failure. Hemodiafiltration (HDF), an extension of high-flux HD, is an alternative treatment modality that further increases the removal of larger uremic toxins by enhancing convective clearance. The second modifiable factor, treatment duration, has been a subject of debate since the early days of dialysis therapy, with most nephrologists of the opinion that patients derive the greatest benefit from longer and more frequent dialysis sessions.3 Cornelis et al2 explored the interaction of treatment modality and duration with a 232 factorial crossover study design that used each patient as his or her own control. Interventions included duration of the dialysis session (short [4 hours] vs long [8 hours]) and type of solute flux (diffusive flux using high-flux HD vs enhanced convective flux using HDF; in both cases, high-flux membrane dialyzers were used). The primary outcomes were hemodynamic tolerance and solute mass transfer as surrogate markers of the combined effect of time and solute flux prescription. Hemodynamic changes were used as outcome parameters for assessing the tolerability of both treatment time (short vs long) and modality (high-flux HD vs HDF). Hemodynamic assessment was performed using conventional measures such as relative blood volume changes, intermittent blood pressure, ultrafiltration, and weight loss, as well as more sophisticated markers like cardiac output, pulse wave velocity analysis, and microcirculation changes. As expected, ultrafiltration rate (in milliliters per kilogram per hour) was reduced by w50% in both modalities when long treatment times were used. Importantly, thermal balance was matched in the 4 treatment schedules, which suppressed this confounding factor in HDF. Clinical tolerance was not reported. Am J Kidney Dis. 2014;64(2):171-173
Solute mass transfer removal was used to assess the efficacy of treatment time and modality. A valuable feature of the study was analysis of a range of uremic toxins (including both small- and middle-molecularweight substances), which was achieved using direct quantification from spent dialysate samples collected continuously. This direct quantification approach provides a reliable way of estimating direct mass balance and abrogates potential pitfalls that may affect serum solute levels, such as intracorporeal solute sequestration, toxin-binding capacity, blood versus plasma concentration, and hemoconcentration.4 There were 2 major findings in this study. First, longer treatments, regardless of diffusion or convection, provided greater hemodynamic stability. Second, HDF was associated with greater clearance of measured uremic toxins such as phosphate and middle and large molecules, including b2-microglobulin (B2M) and fibroblast growth factor 23 (FGF-23), despite the universal use of high-flux membranes in all study groups. This study provides strong support for 2 fundamental paradigms of dialysis prescription: first, longer sessions (8 hours) are beneficial compared with shorter sessions (4 hours); and second, enhanced convective modalities (HDF) are superior compared with conventional diffusive modalities (high-flux HD) at depleting uremic toxins (inorganic phosphate) and middle molecules (B2M), although both treatment modalities in the study used a polysulfone membrane with the same highsolute permeability. The study demonstrated that, independent of treatment modality (high-flux HD or HDF), extended treatment schedules (ie, 8 hours) virtually abolish hemodynamic consequences induced by shorter dialysis and/or ultrafiltration sessions, thereby facilitating the achievement of dry weight (there was a 10%-15% increase in number of patients who reached the desired dry weight). Impressively, although even in the 4-hour sessions, ultrafiltration rate was low (6-7 mL/kg/h in the 4-hour regimens vs 4-4.5 mL/kg/h in the 8-hour regimens), all hemodynamic parameters evaluated in this study indicated the same patterns, consistent with an apparent benefit of the extended treatment schedule. This improvement in cardiovascular stability cannot be
Address correspondence to Bernard Canaud, MD, PhD, Medical Board, Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.05.006 171
Canaud and Bowry
attributed to thermal balance, which was matched during the 4 treatment schedules of the study; rather, this effect likely results from the preservation of effective blood volume due to adequate matching of the vascular refilling rate (as suggested by the relative stability of residual blood volume changes over various dialysis sessions). Preserving hemodynamic stability is of considerable clinical importance because it reduces the probability of transient ischemic cardiac insult, thus providing a rationale for the cardioprotective effect of extended and convective therapies.5 By combining diffusion and enhanced convection through highly permeable membranes, HDF increased total solute mass transfer removal of phosphate and middle- (B2M) and large-molecule (FGF-23) substances by 30% to 50% depending on operational conditions compared to high-flux HD. It must be noted that the type of dialyzer (FX80; Fresenius Medical Care) used in this study has, by its design and membrane characteristics, enhanced clearance for B2M (ie, middle molecules). This intrinsic property of this advanced dialyzer type tends to minimize differences observed between the performance of high-flux HD and HDF. Furthermore, because long HDF sessions delivering up to 30 L of convective volume are associated with a continuous increase in B2M mass removal (up to 200 mg per session), the data in this study illustrate that long treatment time facilitates solute removal by intracorporeal mass transfer, as well as elimination by dialysis. From a pharmacokinetic perspective, this combined time and convective flux effect also holds true for inorganic phosphate and uremic toxins with low intracorporeal mass transfer. Although recent evidence suggests a possible cardiovascular disease and survival benefit associated with high-volume HDF,6,7 3 recent meta-analyses were unable to support cardiovascular or survival benefit of HDF definitively. Notably, none of these studies considered the role of convective volume as a potential determinant of efficacy and survival benefit.8-10 In the Cornelis et al2 trial, the HDF prescription may have been suboptimal because both the short and long HDF prescriptions were consistent with what is considered low-efficiency HDF. Based on recent clinical studies, the instantaneous ultrafiltration rate and/or total ultrafiltration volume, a surrogate of the convective dose needed to improve patient outcome, may be w100 mL/min (or 6 L/h) in a standard treatment schedule of 4 hours thrice weekly.6,7,11 Accordingly, with more optimal convective dose prescription (ie, increasing convective volume by 30%), one could anticipate an increase of 20%-30% of solute removed by an HDF session on either short or long treatment schedules.12 With this prescription, estimated phosphate mass removal per session would be 1,200 mg in HDF (4 hours) and 2,000 mg in HDF (8 hours),4 and estimated B2M mass removal would be 200 mg in HDF (4 hours) and 260 mg in HDF (8 hours). 172
The findings of this study are crucial for designing both more physiologic and more efficient dialysis treatment modalities. Short HDF (4 hours) is essentially equivalent, solely in terms of performance and solute removal, to long high-flux HD (8 hours). Long HDF (8 hours) with adequate convective volume could provide the optimal platform for developing nocturnal treatment schedules (3 times weekly or alternate-day 4 times weekly) and a more physiologic therapy. Such treatment regimens would be different from those considered in the Frequent Hemodialysis Network Trial, which predominantly focused on the removal of low-molecular-weight solutes by mainly diffusive mechanisms and did not consider the effects of ultrapure dialysate in reducing inflammation and oxidative stress, which might affect long-term clinical outcomes.13,14 The study from Cornelis et al2 suggests that long-term use of HDF could achieve a quasinormalization (or even depletion) of phosphate without using phosphate binders, a decrease in serum B2M levels to 20 mg/L, and a reduction in FGF-23 circulating levels of w30%. The results of Cornelis et al2 warrant further longterm clinical trials using 4- and 8-hour HDF. Such trials will establish the potential clinical benefits of short- and long-duration HDF as the future dialysis treatment modality of choice to reduce the high mortality rate observed among patients with chronic kidney failure. Obviously, the feasibility and costeffectiveness of these schedules, as well as patientreported outcomes, including patient quality of life, need to be examined thoroughly. Bernard Canaud, MD, PhD Sudhir K. Bowry, PhD Fresenius Medical Care Deutschland GmbH Bad Homburg, Germany
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Canaud is Emeritus Professor of Nephrology at Montpellier University I - School of Medicine, Montpellier, France. Drs Canaud and Bowry are employees of Fresenius Medical Care Deutschland GmbH.
REFERENCES 1. Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med. 2010;363:1833-1845. 2. Cornelis T, van der Sande FM, Eloot S, et al. Acute hemodynamic response and uremic toxin removal in conventional and extended hemodialysis and hemodiafiltration: a randomized crossover study. Am J Kidney Dis. 2014;64:247-256. 3. Locatelli F, Canaud B. Dialysis adequacy today: a European perspective. Nephrol Dial Transplant. 2012;27:3043-3048. 4. Lornoy W, De Meester J, Becaus I, Billiouw JM, Van Malderen PA, Van Pottelberge M. Impact of convective flow on phosphorus removal in maintenance hemodialysis patients. J Ren Nutr. 2006;16:47-53. Am J Kidney Dis. 2014;64(2):171-173
Editorial 5. McIntyre CW. Haemodialysis-induced myocardial stunning in chronic kidney disease—a new aspect of cardiovascular disease. Blood Purif. 2010;29:105-110. 6. Maduell F, Moreso F, Pons M, et al. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients. J Am Soc Nephrol. 2013;24:487-497. 7. Tattersall JE, Ward RA; EUDIAL Group. Online haemodiafiltration: definition, dose quantification and safety revisited. Nephrol Dial Transplant. 2013;28:542-550. 8. Nistor I, Palmer SC, Craig JC, et al. Convective versus diffusive dialysis therapies for chronic kidney failure: an updated systematic review of randomized controlled trials. Am J Kidney Dis. 2014;63:954-967. 9. Wang AY, Ninomiya T, Al-Kahwa A, et al. Effect of hemodiafiltration or hemofiltration compared with hemodialysis on mortality and cardiovascular disease in chronic kidney failure: a systematic review and meta-analysis of randomized trials. Am J Kidney Dis. 2014;63:968-978.
Am J Kidney Dis. 2014;64(2):171-173
10. Susantitaphong P, Siribamrungwong M, Jaber BL. Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2013;28:2859-2874. 11. Bowry SK, Canaud B. Achieving high convective volumes in on-line hemodiafiltration. Blood Purif. 2013;35(suppl 1):23-28. 12. Mostovaya IM, Blankestijn PJ, Bots ML, et al; on behalf of The EUDIAL—an official ERA-EDTA Working Group. Clinical evidence on hemodiafiltration: a systematic review and a metaanalysis. Semin Dial. 2014;27:119-127. 13. Rocco MV, Lockridge RS Jr, Beck GJ, et al; Frequent Hemodialysis Network (FHN) Trial Group. The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011;80:1080-1091. 14. Susantitaphong P, Riella C, Jaber JL. Effect of ultrapure dialysate on markers of inflammation, oxidative stress, nutrition and anemia parameters: a meta-analysis. Nephrol Dial Transplant. 2013;28(2):438-446.
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