ULTRAFILTRATION RATE AND OUTCOME EVIDENCE
Three observational studies have demonstrated associations between greater ultrafiltration rates and mortality. Using the Dialysis Outcomes and Practice Patterns Study cohort, Saran et al. found an association between ultrafiltration rates above 10 ml/h/kg and higher all-cause mortality (adjusted hazard ratio 1.09, P = 0.02). Surprisingly, the authors found no association between higher ultrafiltration rates and cardiovascular mortality. This analysis was followed by an Italian study in which Movilli et al. demonstrated that for every 1 ml/h/kg increase in ultrafiltration rate, there was a 22% increase in mortality risk (P < 0.01). In secondary analyses, authors identified an ultrafiltration rate of 12.4 ml/h/kg as the most discriminatory cut-point for predicting 2-year mortality . In a post-hoc analysis of the Hemodialysis (HEMO) study, Flythe et al. employed a ultrafiltration rate threshold of 13 ml/h/kg, finding that patients with ultrafiltration rates above 13 ml/h/kg had a 59% increased risk of all-cause mortality and 71% increased risk of cardiovascular mortality (P < 0.001 for both). Ultrafiltration rates of 10–13 ml/h/kg were not associated with outcomes in the full cohort, but were among patients with heart failure. When ultrafiltration rate was considered as a spline, ultrafiltration-associated risks were shown to rise markedly between 10 and 13 ml/h/kg .
To date, there have been no clinical trials evaluating the effect of ultrafiltration rates on outcomes. We are left to interpret and apply observational data, but in doing so, we must be mindful of their limitations. Residual confounding is an inherent limitation of observational studies. Even the most optimally composed models cannot fully account for all confounding. Confounders are factors associated with both the exposure of interest and the outcome, and are ‘not’ factors recognized as intermediaries along the causal pathway between exposure and outcome . All three ultrafiltration rate studies included numerous potential confounders as covariates in multivariable analyses, but consideration of residual confounding from unmeasured patient health status, selective hemodialysis treatment prescription practices, and residual kidney function is warranted. All ultrafiltration rate studies included markers of health such as albumin, blood pressure, and comorbidities, but these variables fall short in fully capturing patient resiliency, leaving open the possibility of residual confounding from health status. Second, frailer patients may receive shorter treatments due to prior hemodialysis intolerance or a lower body weight-conferred ability to achieve clearance benchmarks in shorter time. Additionally, shorter sessions may be selectively prescribed to nonadherent patients with histories of early hemodialysis termination. Thus, patients with longer treatment times and associated lower ultrafiltration rates may be healthier. Flythe et al. accounted for confounding from hemodialysis intolerance by employing prescribed rather than delivered treatment time, but this approach does not address confounding from selective hemodialysis prescriptions. In a separate analysis, Flythe et al. examined treatment time and outcomes among patients with adequate urea clearance matched on body weight; a finding that patients with longer treatment times had better survival than patients of the same weights with shorter treatment times. While this study did not directly address ultrafiltration rates, it suggests that slower fluid removal facilitated by longer treatment times may be advantageous independent of body weight.
Third, confounding from residual kidney function must be considered. Greater residual kidney function is associated with better clinical outcomes . Patients requiring greater ultrafiltration rates often have less native kidney function, rendering statistical control for urine output critical. Saran et al. did not consider residual kidney function in their analyses. Flythe et al. included a binary variable (urine output ≤ versus >200 ml/day). This is a coarse dichotomy. Patients with 2000 ml urine per day may have better outcomes than patients with 250 ml urine per day – a difference not accounted for by Flythe et al. In contrast, Movilli et al. restricted their study to patients with a urine output of 150 ml/day or less. This study provides the most compelling support for the ultrafiltration rate–outcome association absent confounding from residual kidney function .
Analytical decisions should also be considered when weighing observational data. All three studies considered ultrafiltration rates as baseline mean values. Movilli et al. employed a mean ultrafiltration rate over 30 days (approximately 13 treatments) and Flythe et al. used the mean ultrafiltration rate in the HEMO study prerandomization period (1–4 treatments). Saran et al. also used a mean, but did not report the number of treatments considered. Arithmetic means are sensitive to extreme values. Outlier values for ultrafiltration rate will have a greater influence on means derived from relatively few treatments, and thus may alter outcome associations. Additionally, when using a single, time-fixed mean ultrafiltration rate as the exposure, the corresponding implicit assumption is that each individual's ultrafiltration rate during follow-up is equivalent to the mean ultrafiltration rate captured at baseline. In reality, ultrafiltration rates are dynamic and fluctuate with treatment time and interdialytic weight gain (IDWG) changes, both factors altered by ambient health status. None of the existing studies considered time-varying confounders. Studies employing ultrafiltration rate as a time-varying exposure and considering time-varying confounders would enhance the evidence base.
Finally, Flythe et al. have been criticized for including IDWG in their multivariable models, as IDWG is highly correlated with ultrafiltration rate [2,3,6]. Similar choices were made in the two other ultrafiltration rate studies, with Movilli et al. including IDWG and Saran et al. including intradialytic weight loss in models. Collinearity between ultrafiltration rate and IDWG could lead to unreliable effect estimates from model imprecision. In repeat analyses of the HEMO study without multivariable model inclusion of IDWG, Flythe et al. report similar magnitudes of association between ultrafiltration rates and outcomes, providing reassurance that estimates were minimally affected by IDWG inclusion (unpublished data).
POTENTIAL MECHANISTIC PATHWAYS
Although existing observational data have potential shortcomings, the demonstrated ultrafiltration rate–outcome association is supported by evidence from mechanistic studies. Such studies point to ultrafiltration-induced hypoperfusion of vital vascular beds as outcome mediators (Fig. 2). Ultrafiltration-induced intravascular volume depletion diminishes coronary blood flow, leading to cardiac ischemia, as evidenced by myocardial wall stunning on echocardiography and troponin elevation [10–12]. Repetitive cardiac ischemia leads to ventricular remodeling and downstream effects of heart failure and arrhythmia [13,14]. Recurrent hemodialysis-induced myocardial stunning has been linked to greater ejection fraction declines . Dialysis patients are especially vulnerable to reduced myocardial oxygen supply due to a high burden of small-vessel disease and high oxygen-requiring, hypertrophied ventricles. Notably, more frequent hemodialysis – a schedule characterized by lower IDWG and ultrafiltration rates – is associated with reduced myocardial stunning . Collectively, these data support greater ultrafiltration rates as a contributor to adverse cardiovascular outcomes.
Ultrafiltration-induced ischemia is not limited to the heart and likely impacts both the brain and gut. Chronic cerebral hypoperfusion among hemodialysis patients has been linked to white matter changes, dementia, and depression . Cooled dialysate may improve white matter changes via vasoconstriction [17▪]. Additionally, ultrafiltration-induced gut ischemia may lead to bacterial translocation from the gut to the bloodstream. Increased blood endotoxin has been associated with cardiac stunning, and more frequent hemodialysis regimens are associated with lower endotoxin levels [18,19]. Hemodialysis-induced endotoxemia represents a plausible link between intradialytic hemodynamics and chronic inflammation [18,20].
Beyond its direct end-organ effects, ultrafiltration-induced hypotension and cramping (ultrafiltration-related or not) may result in interventions with unintended, deleterious consequences. Such events often lead to early ultrafiltration termination, halting fluid removal before the target weight can be achieved, thereby introducing harm from volume overload. Over time, target weights may be adjusted upward to match postdialysis weights, leaving patients chronically volume-expanded. Chronic volume expansion has been linked to adverse cardiovascular outcomes through ventricular hypertrophy and fibrosis, and eventual heart failure and arrhythmias [13,21–23]. Not surprisingly, recent data link more frequent missed target weights to adverse cardiovascular outcomes [24,25▪]. In addition to hemodialysis truncation, hypotension or patient cramping may lead to normal or hypertonic saline administration. These interventions put patients at risk for failed target weight achievement, greater IDWG from positive sodium balance, and exacerbated hypervolemia [26,27].
ULTRAFILTRATION RATE: RISK MARKER OR INDEPENDENT RISK FACTOR?
Whereas the proposed physiologic links between rapid ultrafiltration rates and outcomes are compelling, ultrafiltration rate is a composite metric, dependent on two factors: IDWG and treatment time. Both factors have been independently associated with greater mortality, and both are plausible drivers of the ultrafiltration rate–outcome association. Prior studies have shown that greater amounts of IDWG associate with adverse outcomes in a dose–response pattern [28–30]. Volume overload from frequent high IDWG can lead to maladaptive cardiac structural changes. Additionally, intradialytic hypotension is more prevalent among patients with greater IDWG [31▪]. More frequent intradialytic hypotension is associated with all-cause and cardiovascular mortality [31▪,32▪]. Thus, it is plausible that either volume overload or end-organ damage from intradialytic ischemia drive the observed ultrafiltration rate–outcome association. Similarly, shorter treatment time has been linked to greater mortality in observational studies across various cohorts using a variety of methodologies [4,8,33,34]. Shorter treatment time may impact mortality through both clearance and volume pathways, making treatment time a plausible mediator of the ultrafiltration rate–outcome association.
Flythe et al. explored the roles of treatment time and IDWG in the ultrafiltration rate–outcome association by matching patients with identical IDWGs and examining the treatment time and mortality association, and then, separately, matching patients with identical treatment times and examining the IDWG and mortality association. The authors excluded patients not meeting estimated Kt/V standards to limit confounding from clearance. Findings demonstrated that both treatment time and IDWG play significant roles in the ultrafiltration rate–mortality association, independent of one another . Finally, the role of chronic volume expansion in ultrafiltration-related outcomes must be considered. Rapid ultrafiltration rates indirectly contribute to chronic volume expansion when hemodialysis is terminated early, ultrafiltration rates are decreased, or target weights are adjusted upward due to cramping or hypotension.
It is certainly physiologically plausible that greater ultrafiltration rates are independent risk factors for morbidity and mortality, but, it is also conceivable that their harm stems from hypervolemia, rendering them surrogate risk markers. Existing data do not allow us to fully distinguish the individual influences of ultrafiltration rate, IDWG, treatment time, and chronic hypervolemia on outcomes. Evidence supporting these fluid-related factors as critical contributors to adverse outcomes is strong, but the optimal approach to reducing their risks is less obvious due to measure inter-relationships.
INTERVENTIONS TO REDUCE ULTRAFILTRATION RISK
Ultrafiltration rate reduction is achieved by IDWG decrease or treatment time extension. Dietary restrictions, with salt restriction of greater import than fluid restriction, are physiologically sound approaches to IDWG reduction; however, patients are poorly adherent. In a survey of over 400 patients prescribed fluid restrictions, more than 40% reported nonadherence on a near-daily basis [36▪]. Psychological and behavioral interventions may improve adherence, but sustainability of these efforts has not been studied [37–39]. Use of lower dialysate sodium is an additional method for curbing IDWG. However, this intervention remains controversial as observational studies of the dialysate sodium–mortality association have yielded mixed results [40–42]. Diuretics may lessen IDWG among patients with residual kidney function, but this approach has not been fully evaluated. Dialysis prescription changes such as increased hemodialysis frequency to reduce IDWG and treatment time extension to allow more gradual fluid removal are other options, but patients are generally averse to more frequent and longer hemodialysis. Flythe et al.[36▪] surveyed 600 hemodialysis patients and found that only 12% were willing to add a fourth-weekly treatment and 21% were willing to increase treatment time by 30 min in exchange for liberalized fluid intake.
Some experts have suggested imposing ultrafiltration rate thresholds (such as 13 ml/h/kg) to reduce ultrafiltration-related risk [2,3]. Patients presenting with fluid gains requiring ultrafiltration rates above the threshold would require treatment time extension or additional treatments. Patients declining treatment time extension would have ultrafiltration rates capped, leaving them above their prescribed target weights at hemodialysis conclusion. Whereas it is plausible that the mere mention of treatment time extension would motivate patients to limit IDWG, it is equally plausible that ultrafiltration needs would remain unchanged and patients declining treatment time extension would become volume-expanded. Rigorous investigation of the effect of ultrafiltration rate thresholds on volume status, fluid-related hospitalizations, and other adverse outcomes including patient-centered outcomes are needed prior to threshold adoption. Other potential treatment changes to reduce rapid ultrafiltration rate harm include chilled dialysate, ultrafiltration profiling (decelerating ultrafiltration rate to match declining plasma refill rate), and sequential dialysis (isolated ultrafiltration followed by combined hemodialysis and ultrafiltration). These methods have been incompletely studied and their effects on cardiac stunning, target weight achievement, and cardiovascular outcomes are unknown.
The relative importance of ultrafiltration rate, IDWG, treatment time, and chronic volume expansion to clinical outcomes is unknown. In cases of high weight gain or chronic volume expansion, clinicians face the conundrum of choosing between rapid fluid removal and a ‘dry’ patient, and slower fluid removal and a ‘wet’ patient. It is plausible, and in the authors’ opinions, likely, that exposure to high ultrafiltration rates for isolated time periods in the name of target weight achievement or challenge is preferable to low ultrafiltration rates and unchallenged, hypervolemic states. Existing data do not allow us to make these distinctions. Imposing ultrafiltration rate thresholds without understanding their effect on other fluid measures is premature. Prospective study of these issues is needed before optimal fluid standards can be incorporated into quality programs.
Additionally, we lack prospective trial data confirming the effects of fluid-related factors on morbidity and mortality. Such studies should evaluate not only cardiovascular endpoints but also patient-reported outcomes, including intradialytic symptoms, recovery time, and quality of life. We must place greater emphasis on identifying ultrafiltration rate-mitigation strategies that are acceptable to patients. Patient-dependent strategies, such as dietary restrictions and willingness to extend treatment time have proven unsuccessful. An increased focus on hemodialysis procedural alterations such as cooled dialysate and different fluid removal patterns may be prudent, but remain understudied. Finally, objective measures of volume status are needed. Improved accuracy in determining total body euvolemia would obviate the need for target weight probing (with or without high ultrafiltration rates) and would limit subclinical hypervolemia.
Observational data suggest an association between greater ultrafiltration rates and mortality among hemodialysis patients. Recurrent end-organ hypoperfusion and its downstream consequences of cardiac remodeling, brain white matter damage, and gut-related systemic endotoxemia, are possible mechanisms underlying these associations. Despite the plausible and observational data-supported association between rapid ultrafiltration rates and outcomes, we lack randomized trials confirming these findings. In conducting such trials, patient strategy acceptance must be given high priority as clinical trials will be for naught if patients are unwilling to adopt the identified, evidence-based intervention.
Financial support and sponsorship
M.M.A is supported by NIH grant T32 DK007750.
Conflicts of interest
J.E.F. has received speaking honoraria from Dialysis Clinic Incorporated.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1▪. Weiner DE, Brunelli SM, Hunt A, et al. Improving clinical outcomes among hemodialysis
patients: a proposal for a ‘volume first’ approach from the chief medical officers of US dialysis providers. Am J Kidney Dis 2014; 64:685–695.
This study reports the consensus opinions on volume control of 14 of the largest dialysis providers in the United States.
2. Agar JW. Personal viewpoint: limiting maximum ultrafiltration rate
as a potential new measure of dialysis adequacy. Hemodial Int 2015; doi: 10.1111/hdi.12288. [Epub ahead of print].
4. Saran R, Bragg-Gresham JL, Levin NW, et al. Longer treatment time
and slower ultrafiltration in hemodialysis
: associations with reduced mortality in the DOPPS. Kidney Int 2006; 69:1222–1228.
5. Movilli E, Gaggia P, Zubani R, et al. Association between high ultrafiltration rates and mortality in uraemic patients on regular haemodialysis. A 5-year prospective observational multicentre study. Nephrol Dial Transplant 2007; 22:3547–3552.
6. Flythe JE, Kimmel SE, Brunelli SM. Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality. Kidney Int 2011; 79:250–257.
7. Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed.2008; Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 101–105.
8. Flythe JE, Curhan GC, Brunelli SM. Shorter length dialysis sessions are associated with increased mortality, independent of body weight. Kidney Int 2013; 83:104–113.
9. Vilar E, Farrington K. Emerging importance of residual renal function in end-stage renal failure. Semin Dial 2011; 24:487–494.
10. Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis
-induced cardiac injury: determinants and associated outcomes. Clin J Am Soc Nephrol 2009; 4:914–920.
11. Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis
-induced repetitive myocardial injury results in global and segmental reduction in systolic cardiac function. Clin J Am Soc Nephrol 2009; 4:1925–1931.
12. Selby NM, Fluck RJ, Taal MW, McIntyre CW. Effects of acetate-free double-chamber hemodiafiltration and standard dialysis on systemic hemodynamics and troponin T levels. ASAIO J 2006; 52:62–69.
13. McMullen JR, Sherwood MC, Tarnavski O, et al. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 2004; 109:3050–3055.
14. Gao XM, Wong G, Wang B, et al. Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens 2006; 24:1663–1670.
15. Jefferies HJ, Virk B, Schiller B, et al. Frequent hemodialysis
schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning). Clin J Am Soc Nephrol 2011; 6:1326–1332.
16. Eldehni MT, McIntyre CW. Are there neurological consequences of recurrent intradialytic hypotension? Semin Dial 2012; 25:253–256.
17▪. Eldehni MT, Odudu A, McIntyre CW. Randomized clinical trial of dialysate cooling and effects on brain white matter. J Am Soc Nephrol 2015; 26:957–965.
This study reports randomized controlled trial data suggesting that dialysis hemodynamic-related brain injury may be reduced by cooling the dialysate.
18. McIntyre CW, Harrison LE, Eldehni MT, et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:133–141.
19. Jefferies HJ, Crowley LE, Harrison LE, et al. Circulating endotoxaemia and frequent haemodialysis schedules. Nephron Clin Pract 2014; 128 (1–2):141–146.
20. McIntyre CW, Odudu A. Hemodialysis
-associated cardiomyopathy: a newly defined disease entity. Semin Dial 2014; 27:87–97.
21. Sharpe N. Left ventricular remodeling: pathophysiology and treatment. Heart Fail Monit 2003; 4:55–61.
22. Shivalkar B, Flameng W, Szilard M, et al. Repeated stunning precedes myocardial hibernation in progressive multiple coronary artery obstruction. J Am Coll Cardiol 1999; 34:2126–2136.
23. Ritz E, Wanner C. The challenge of sudden death in dialysis patients. Clin J Am Soc Nephrol 2008; 3:920–929.
24. Movilli E, Camerini C, Gaggia P, et al. Magnitude of end-dialysis overweight is associated with all-cause and cardiovascular mortality: a 3-year prospective study. Am J Nephrol 2013; 37:370–377.
25▪. Flythe JE, Kshirsagar AV, Falk RJ, Brunelli SM. Associations of posthemodialysis weights above and below target weight with all-cause and cardiovascular mortality. Clin J Am Soc Nephrol 2015; 10:808–816.
This study reports an association between frequent missed target weight (both above and below target weight) and increased all-cause and cardiovascular mortality.
26. Kooman JP, van der Sande F, Leunissen K, Locatelli F. Sodium balance in hemodialysis
therapy. Semin Dial 2003; 16:351–355.
27. Song JH, Park GH, Lee SY, et al. Effect of sodium balance and the combination of ultrafiltration profile during sodium profiling hemodialysis
on the maintenance of the quality of dialysis and sodium and fluid balances. J Am Soc Nephrol 2005; 16:237–246.
28. Kimmel PL, Varela MP, Peterson RA, et al. Interdialytic weight gain
and survival in hemodialysis
patients: effects of duration of ESRD and diabetes mellitus. Kidney Int 2000; 57:1141–1151.
29. Kalantar-Zadeh K, Regidor DL, Kovesdy CP, et al. Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis
. Circulation 2009; 119:671–679.
30. Holmberg B, Stegmayr BG. Cardiovascular conditions in hemodialysis
patients may be worsened by extensive interdialytic weight gain
. Hemodial Int 2009; 13:27–31.
31▪. Stefánsson BV, Brunelli SM, Cabrera C, et al. Intradialytic hypotension and risk of cardiovascular disease. Clin J Am Soc Nephrol 2014; 9:2124–2132.
This study reports an association between intradialytic hypotension and cardiovascular morbidity and mortality, as well as an association between greater interdialytic weight gain and more prevalent intradialytic hypotension.
32▪. Flythe J, Xue H, Lynch K, et al. Association of mortality risk with various definitions of intradialytic hypotension. J Am Soc Nephrol 2015; 26:724–734.
This study reports an association between intradialytic hypotension, defined as nadir intradialytic SBP below 90 mmHg, and greater mortality. Other hypotension definitions based on nadir thresholds, varying blood pressure falls, and inclusion of symptoms and interventions did not associate with mortality.
33. Brunelli SM, Chertow GM, Ankers ED, et al. Shorter dialysis times are associated with higher mortality among incident hemodialysis
patients. Kidney Int 2010; 77:630–636.
34. Tentori F, Zhang J, Li Y, et al. Longer dialysis session length is associated with better intermediate outcomes and survival among patients on in-center three times per week hemodialysis
: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2012; 27:4180–4188.
35. Flythe JE, Curhan GC, Brunelli SM. Disentangling the ultrafiltration rate
-mortality association: the respective roles of session length and weight gain. Clin J Am Soc Nephrol 2013; 8:1151–1161.
36▪. Flythe JE, Mangione TW, Brunelli SM, Curhan GC. Patient-stated preferences regarding volume-related risk mitigation strategies for hemodialysis
. Clin J Am Soc Nephrol 2014; 9:1418–1425.
This study reports the results of a patient preferences in fluid management survey showing that patients are generally averse to treatment time extension and extra dialysis treatments even in the setting of liberalized fluid intake.
37. Sharp J, Wild MR, Gumley AI. A systematic review of psychological interventions for the treatment of nonadherence to fluid-intake restrictions in people receiving hemodialysis
. Am J Kidney Dis 2005; 45:15–27.
38. Sharp J, Wild MR, Gumley AI, Deighan CJ. A cognitive behavioral group approach to enhance adherence to hemodialysis
fluid restrictions: a randomized controlled trial. Am J Kidney Dis 2005; 45:1046–1057.
39. Bellomo G, Coccetta P, Pasticci F, et al. The effect of psychological intervention on thirst and interdialytic weight gain
in patients on chronic hemodialysis
: a randomized controlled trial. J Ren Nutr 2015; 25:426–432.doi: 10.1053/j.jrn.2015.04.005. [Epub ahead of print].
40. Mc Causland FR, Brunelli SM, Waikar SS. Dialysate sodium, serum sodium and mortality in maintenance hemodialysis
. Nephrol Dial Transplant 2012; 27:1613–1618.
41. Hecking M, Karaboyas A, Saran R, et al. Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis
patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2012; 59:238–248.
42. Hecking M, Karaboyas A, Saran R, et al. Dialysate sodium concentration and the association with interdialytic weight gain
, hospitalization, and mortality. Clin J Am Soc Nephrol 2012; 7:92–100.
Keywords:Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
hemodialysis; interdialytic weight gain; treatment time; ultrafiltration rate