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Locatelli F, Marcelli D, Conte F, et al. Cardiovascular disease in chronic renal failure: the challenge continues. vol. 15, 2001, pp 35-58.
,8Cozzolino M, Mangano M, Stucchi A, et al. Cardiovascular disease in dialysis patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2018; 33: iii28-iii34.
is responsible for the high risk of CV disease (CVD).2Foley R.N. Parfrey P.S. Sarnak M.J. Epidemiology of cardiovascular disease in chronic renal disease.,5Locatelli F. Pozzoni P. Tentori F. et al.Epidemiology of cardiovascular risk in patients with chronic kidney disease.,9Collins A.J. Foley R.N. Chavers B. et al.US Renal Data System 2013 Annual Data Report., 10Foley R.N. Murray A.M. Li S. et al.Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999., 11Roth G.A. Mensah G.A. Johnson C.O. et al.Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. Furthermore, side-effects of the HD procedure itself, such as the bio-incompatibility of the extra-corporeal circuit,12Impact of the type of dialyser on the clinical outcome in chronic haemodialysis patients: does it really matter?. fluctuations in acid/base equilibrium and intradialytic hypotension (IDH), may contribute to the poor clinical outcome as well.In patients with end-stage kidney disease (ESKD) without residual diuresis, the fluid that accumulates in the interdialytic interval must be removed during the next dialysis. Yet, when the ultrafiltration (UF) rate exceeds the plasma refill rate, blood volume will decline. Combined with insufficient compensatory CV responses to maintain an adequate blood pressure (BP), IDH can occur.13Leypoldt J.K. Cheung A.K. Delmez J.A. et al.Relationship between volume status and blood pressure during chronic hemodialysis., 14van der Sande F.M. Kooman J.P. Leunissen K.M. Intradialytic hypotension--new concepts on an old problem., 15Reeves P.B. Mc Causland F.R. Mechanisms, Clinical Implications, and Treatment of Intradialytic Hypotension. Besides subjective discomfort,16Caplin B, Kumar S, Davenport A. Patients' perspective of haemodialysis-associated symptoms. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2011; 26: 2656-2663.
,17Correa S. Pena-Esparragoza J.K. Scovner K.M. et al.Predictors of Intradialytic Symptoms: An Analysis of Data From the Hemodialysis Study. IDH also induces repetitive ischemia in vital organs, including the heart, brain, kidney and gut.14van der Sande F.M. Kooman J.P. Leunissen K.M. Intradialytic hypotension--new concepts on an old problem.,18Burton J.O. Jefferies H.J. Selby N.M. et al.Hemodialysis-induced repetitive myocardial injury results in global and segmental reduction in systolic cardiac function., 19Eldehni M.T. Odudu A. McIntyre C.W. Randomized clinical trial of dialysate cooling and effects on brain white matter., 20Polinder-Bos H.A. García D.V. Kuipers J. et al.Hemodialysis Induces an Acute Decline in Cerebral Blood Flow in Elderly Patients. Depending on the definition used, IDH occurs in 10-30% of the dialysis sessions.21Kuipers J. Verboom L.M. Ipema K.J.R. et al.The Prevalence of Intradialytic Hypotension in Patients on Conventional Hemodialysis: A Systematic Review with Meta-Analysis. Interestingly, a large retrospective study comparing eight different IDH definitions, revealed that a systolic BP (SBP) 22Flythe J.E. Xue H. Lynch K.E. et al.Association of mortality risk with various definitions of intradialytic hypotension. In addition, it was recently demonstrated that especially early-onset IDH (IDH ≤120 minutes after the start of HD) is associated with a poor prognosis.23Keane D.F. Raimann J.G. Zhang H. et al.The time of onset of intradialytic hypotension during a hemodialysis session associates with clinical parameters and mortality. Notably, both HD with a low dialysate temperature [(Td); cool HD (C-HD)] and online post-dilution hemodiafiltration (shortly HDF), which combines diffusive with convective transport, may lower the frequency of IDH in comparison with ‘standard’ HD (S-HD).24Donauer J, Schweiger C, Rumberger B, et al. Reduction of hypotensive side effects during online-haemodiafiltration and low temperature haemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2003; 18: 1616-1622.
, 25Chesterton L.J. Selby N.M. Burton J.O. et al.Cool dialysate reduces asymptomatic intradialytic hypotension and increases baroreflex variability., 26Mustafa R.A. Bdair F. Akl E.A. et al.Effect of Lowering the Dialysate Temperature in Chronic Hemodialysis: A Systematic Review and Meta-Analysis., 27Maduell F. Moreso F. Pons M. et al.High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients., 28Locatelli F. Altieri P. Andrulli S. et al.Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD. Yet, well executed studies comparing the incidence of IDH in detail between S-HD, C-HD and HDF are lacking.A previous meta-analysis on the individual patient data of four randomized controlled trials 29Peters S.A. Bots M.L. Canaud B. et al.Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials. (RCT) indicated that HDF is associated with a superior overall and CV survival, if compared to S-HD. The largest benefit was observed in patients who achieved the highest convection volume (high-volume [HV]-HDF).29Peters S.A. Bots M.L. Canaud B. et al.Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials. As of yet, however, the mechanism behind this effect is unknown. Since IDH, as above-mentioned, has been associated with a poor clinical outcome and HDF may reduce its incidence, it is conceivable that the superior survival of HDF over HD may be due to more stable intradialytic hemodynamics.Therefore, in the present study, we compared 1) the number of (early) IDH episodes per dialysis session and 2) the intradialytic courses of systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) between S-HD, C-HD, low-volume HDF (LV-HDF) and HV-HDF.
ResultsPatient characteristics As shown in figure 1, 45 fig45 patients were included. Before randomization, 5 patients dropped out due to renal transplantation (n=2), movement to another dialysis facility (n=1), not meeting the required dialysis treatment frequency (n=1) and inability (due to access problems) to achieve a blood flow ≥350 ml/min (n=1). Table 1 summarizes baseline demographical and clinical characteristics, laboratory data, medication and treatment-related parameters. The majority of patients was male (75%) and mean age was 69.7 ± 13.5 years. Median dialysis vintage was 3.0 years (IQR 1.0-5.8).Figure 1Legend to f igure 1. Study flowchart..
Table 1Baseline characteristics of study participants (n=40)
Legend to table 1. Values are number (n) (%) for categorical variables, and mean ± standard deviation or median (interquartile range 25-75%) for continuous variables. Laboratory data are pre-dialytic values. 1Residual diuresis >100 ml/24 hrs.2Foley R.N. Parfrey P.S. Sarnak M.J. Epidemiology of cardiovascular disease in chronic renal disease. In patients with diuresis >100 ml/24 hrs.Abbreviations: BMI= body mass index; HD= hemodialysis; HDF= hemodiafiltration; ESRD= end-stage renal disease; CVD= cardiovascular disease; ACE-I= angiotensin-converting enzyme inhibitor; ARB= angiotensin receptor blocker; ESA= erythropoiesis-stimulating agent; PTH= parathyroid hormone; AVF= arteriovenous fistula; CVC= central venous catheter.
Missing data Of the 40 patients who finished the study, 2 were not exposed to HDF due to technical failure but completed S-HD and C-HD. Two patients withdrew their consent after completing 75% and 50% of the study. The total amount of missing BP values was 126 (6.3%) for S-HD, 81 (4.1%) for C-HD, 91 (4.8%) for LV-HDF and 97 (5.1%) for HV-HDF.
Treatment characteristics Dialysis characteristics are shown in table 2. Mean blood flow was 339 ± 33 ml/min for S-HD, 332 ± 41 for C-HD, 339 ± 36 for LV-HDF and 347 ± 27 for HV-HDF. Mean total UF volume was 2.4 ± 0.7 l/session for C-HD and 2.3 ± 0.7 for the other modalities. Mean total convection volume was 15.1 ± 1.3 l/session for LV-HDF and 22.6 ± 1.1 l/session for HV-HDF. Body temperature appeared to increase similarly during S-HD, LV-HDF and HV-HDF. During C-HD, however, body temperature remained stable (Supplementary table S1).Table 2Dialysis characteristics
Legend to table 2. Mean ± standard deviation for blood flow, dialysate flow, total ultrafiltration (UF) volume; and total convection volume. N/A= not applicable.Hemodynamic stability Intradialytic hypotension Altogether, 6939 BP measurements were performed in 458 dialysis sessions. IDH was observed in 26/117 (22.2%) sessions in S-HD, 16/117 (13.7%) in C-HD, 25/111 (22.5%) in LV-HDF and 17/113 (15.0%) in HV-HDF. As shown in figure 2 and table 3, the average number of IDH episodes per dialysis modality was 0.68/session in S-HD, 0.21/session in C-HD, 0.51/session in LV-HDF and 0.27/session in HV-HDF. While the differences between S-HD, and both C-HD and HV-HDF were highly significant (P-valuesFigure 2Legend to figure 2. Average number of intradialytic hypotensive (IDH, definition see text) episodes per session of each dialysis modality with 95% confidence interval, subdivided into early- and late-onset IDH (resp. ≤120 minutes and >120 minutes after the start of dialysis). S-HD: standard hemodialysis, C-HD: cool hemodialysis, LV- and HV-HDF: low-volume and high-volume hemodiafiltration.
Table 3Average number of IDH episodes (overall and early) per modality
Legend to table 3. Average number of total intradialytic hypotensive (IDH) episodes and early-onset IDH (≤120 minutes after start of dialysis) episodes per session during S-HD, C-HD, LV-HDF and HV-HDF. * P for difference in number of intradialytic hypotensive episodes; # statistically significant after correction for multiple testing by the Holm-Bonferroni method.Early-onset intradialytic hypotension The average numbers of early-onset IDH episodes are shown in figure 2 and table 3. As can be seen from the graph, both early- and late-onset IDH occurred most frequently in S-HD. The number of early-onset IDH episodes differed significantly between S-HD (0.32/session) and both C-HD (0.07/session; PP=0.001). Differences were neither found between C-HD and HV-HDF (P=0.47), nor between HV-HDF and LV-HDF (P=0.09). Sensitivity analysis yielded similar results (Supplementary table S3).Intradialytic courses of blood pressure parameters Although the courses of both SBP, DBP and MAP appeared to decline during all modalities, after correction for multiple testing the intradialytic drops were only significant in the case of S-HD (-6.8, -5.2, -5.2mmHg/session; P for declines: 0.004, P for interaction: 0.006, figure 3 and table 4).Figure 3A. B. C. Legend to figure 3. A. Intradialytic courses of mean systolic blood pressure (SBP); B. mean diastolic BP (DBP); C. mean arterial pressure (MAP) during S-HD, C-HD, LV-HDF and HV-HDF. SBP, DBP and MAP all declined significantly during S-HD (P=0.004, <0.0005, 0.002 resp.).
Table 4Mean intradialytic rate of change of blood pressure
Legend to table 4. Mean intradialytic rate of change per hour for systolic blood pressure (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) in mmHg with 95% confidence interval (CI) and P-values for stratified linear mixed models. *Statistically significant after correction for multiple testing by the Holm-Bonferroni method.Discussion The present analysis clearly shows that S-HD is associated with the highest IDH incidence per session, and both C-HD and HV-HDF with the lowest. To the best of our knowledge, this is the first randomized cross-over study comparing hemodynamic stability during four frequently used intermittent dialysis modalities. We like to recall that, in comparison with S-HD, especially HV-HDF has been associated with a beneficial effect on survival 29Peters S.A. Bots M.L. Canaud B. et al.Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials. and C-HD in particular with a stabilizing effect on intradialytic BP.26Mustafa R.A. Bdair F. Akl E.A. et al.Effect of Lowering the Dialysate Temperature in Chronic Hemodialysis: A Systematic Review and Meta-Analysis.,35Maggiore Q. Pizzarelli F. Zoccali C. et al.Effect of extracorporeal blood cooling on dialytic arterial hypotension.,36Selby NM, McIntyre CW. A systematic review of the clinical effects of reducing dialysate fluid temperature. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2006; 21: 1883-1898.
Therefore, we were especially interested whether the intradialytic hemodynamics differ between S-HD and HV-HDF, and whether C-HD differs from HV-HDF in these respects. Finally, to assess the influence of the convection volume on these parameters, we compared LV-HDF with HV-HDF.An important aspect of our study is the fact that the IDH definition used showed the strongest association with mortality out of eight different IDH definitions.22Flythe J.E. Xue H. Lynch K.E. et al.Association of mortality risk with various definitions of intradialytic hypotension. In addition, the discrimination between IDH with and without symptoms and/or interventions, as used in official guidelines,37Flythe J.E. Chang T.I. Gallagher M.P. et al.Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. was not substantiated by that study.22Flythe J.E. Xue H. Lynch K.E. et al.Association of mortality risk with various definitions of intradialytic hypotension. Therefore, we analyzed all IDH episodes, irrespective of concurrent intradialytic symptomatology and/or subsequent interventions. Since it was recently demonstrated that especially early-onset IDH is associated with an increased mortality risk23Keane D.F. Raimann J.G. Zhang H. et al.The time of onset of intradialytic hypotension during a hemodialysis session associates with clinical parameters and mortality., a post-hoc analysis on this parameter was performed as well. Altogether, our findings largely confirm prior studies, which also reported a lower incidence of IDH during both HV-HDF and C-HD than during S-HD 24Donauer J, Schweiger C, Rumberger B, et al. Reduction of hypotensive side effects during online-haemodiafiltration and low temperature haemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2003; 18: 1616-1622.
,26Mustafa R.A. Bdair F. Akl E.A. et al.Effect of Lowering the Dialysate Temperature in Chronic Hemodialysis: A Systematic Review and Meta-Analysis., 27Maduell F. Moreso F. Pons M. et al.High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients., 28Locatelli F. Altieri P. Andrulli S. et al.Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD.,38Wang A.Y. 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., but a similar incidence during HV-HDF and C-HD.24Donauer J, Schweiger C, Rumberger B, et al. Reduction of hypotensive side effects during online-haemodiafiltration and low temperature haemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2003; 18: 1616-1622.
,39van der Sande F.M. Kooman J.P. Konings C.J. et al.Thermal effects and blood pressure response during postdilution hemodiafiltration and hemodialysis: the effect of amount of replacement fluid and dialysate temperature. Yet, and in contrast to the current analysis, most of these studies were limited by less frequent BP measurements (twice/hour versus four times/hour) and/or the absence of a cross-over design. It should be acknowledged, however, that IDH has not only been associated with mortality, but also with morbidity, most likely due to chronic repetitive perfusion deficits leading to tissue ischemia and organ dysfunction.40Sars B. van der Sande F.M. Kooman J.P. Intradialytic Hypotension: Mechanisms and Outcome.,41Kanbay M. Ertuglu L.A. Afsar B. et al.An update review of intradialytic hypotension: concept, risk factors, clinical implications and management. In fact, several manifestations of organ damage have been described, including myocardial stunning,42Assa S. Hummel Y.M. Voors A.A. et al.Hemodialysis-induced regional left ventricular systolic dysfunction: prevalence, patient and dialysis treatment-related factors, and prognostic significance. brain atrophy and dementia,43Mizumasa T. Hirakata H. Yoshimitsu T. et al.Dialysis-related hypotension as a cause of progressive frontal lobe atrophy in chronic hemodialysis patients: a 3-year prospective study., 44MacEwen C. Sutherland S. Daly J. et al.Relationship between Hypotension and Cerebral Ischemia during Hemodialysis., 45Assimon M.M. Wang L. Flythe J.E. Cumulative Exposure to Frequent Intradialytic Hypotension Associates With New-Onset Dementia Among Elderly Hemodialysis Patients. loss of residual kidney function 46Jansen M.A. Hart A.A. Korevaar J.C. et al.Predictors of the rate of decline of residual renal function in incident dialysis patients. and mesenteric ischemia.47
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