Dialysis Unplugged: Dialytic Treatment Time - Is More Better?

Dr. Steven Brunelli

Editor - What about the effect of dialysis treatment time? Is more better? To review this topic I invited Steve Brunelli and Jay-R Lacson who have recently written on this topic to provide us with their thoughts.
Dr. Brunelli is a renal epidemiologist at Brigham and Women's Hospital and Harvard Medical School. His research focuses on identification of potentially modifiable risk factors for cardiovascular morbidity and mortality among hemodialysis patients. He also serves as the Director of Dialysis Services at Brigham and Women's Hospital. Dr. Eduardo Lacson is a nephrologist and epidemiologist at Fresenius Medical Care North America (FMCNA) and Vice President, Clinical Science Epidemiology & Research (FMCNA).
 
Commentary - Steven M. Brunelli, Eduardo Lacson Jr

Recently, we published a commentary piece describing the evolution of dialysis treatment time and its potential effects on patient morbidity and mortality. Herein we capitulate the salient details of our analysis, and refer the reader to our recent article for fuller detail.(1)

Hemodialysis has been widely available in the US for nearly 40 years. Over that time, the delivery of dialysis has evolved markedly, particular with respect to treatment time. In the early-to-mid 1970’s treatment times tended to be long (on the order of 6+ hours), as was necessitated by available technologies. Thereafter, there was a trend to shorter treatment times, which was motivated by patient and physician preference, increasing demand for services and economic considerations and made possible through technical improvements in dialyzers, delivery equipment and dialysate preparation and composition. However, shorter treatment times may not be a panacea and may engender implicit trade offs in terms of patient outcomes.

Treatment time was largely lost in the shuffle in the early 1980s in favor of urea kinetics. In 1981, results of the National Cooperative Dialysis Study were reported. The study was designed to identify appropriate benchmarks for dialysis adequacy so as to minimize morbidity. Patients were randomized (separately) to high vs. low time average blood urean nitrogen (BUN) levels and long vs. short treatment time. The study found that high time average BUN was potently associated with the composite endpoint of hospitalization or treatment withdrawal, whereas treatment time was not (though narrowly missed significance; p=0.056).(2) Of note, the study was not powered to detect differences in mortality, both through design and due to early termination. Nonetheless, urea kinetics became the benchmark though which dialysis adequacy was measured, and were later formalized into the Kt/V metric. Observational studies done throughout the late 1980s and 1990’s demonstrated that urea clearance to a Kt/V of ~1.2 (or equivalent) and beyond was associated with improved survival. In the early 2000s, results from the HEMODIALYSIS Study were published and demonstrated no benefit of urea clearances beyond an equilibrated Kt/V of 1.05 (roughly equivalent to a single pool Kt/V of 1.2) versus 1.45.(3) Over this same period, little attention was paid to treatment time as in independent factor. A few studies did attempt to address the issue, but did not adequately distinguish the effects of treatment time from urea clearance and/or underlying health status.

It is important to note that urea clearance targets remain important and necessary; the question is whether they are sufficient. Since the time of the National Cooperative Dialysis Study, further improvements in dialyzer efficiency and use of greater blood and dialysate flow rates have made it possible to achieve urea clearance targets more rapidly. As a result, there is less available time over which to middle molecules (removal of which is more time-dependent for urea regardless of dialyzer efficiency) and particularly fluid. Such considerations have motivated a number of observational studies demonstrating that longer treatment times (particularly those of 4+ hours)—within the context of thrice weekly in-center hemodialysis—are associated with improved patient survival, independent of (and among patients with adequate) urea clearance.(4-7) Concordantly, studies have found that more gradual fluid removal is also associated with improved survival.(4, 8, 9) Furthermore, longer treatment time provides the opportunity for greater fluid removal, increasing the probability of achieving euvolemia, which may be contributory to the observed favorable cardiovascular outcomes.

Recently, there has been heightened interest in quotidian dialysis, in which total dialysis time is increased either by virtue of longer or more frequent treatments. The Frequent Hemodialysis Trial Network study demonstrated that daily dialysis is associated with improvement in left ventricular geometry, but was underpowered to detect differences in clinical outcomes.(10) Observational studies suggest that quotidian dialysis is associated with benefits vis-à-vis blood pressure, phosphatemia, sleep quality and possibly survival (though the latter may be inherently confounded). Frequent and extended dialysis remain promising, potentially paradigm changing therapeutic alternatives to conventional thrice weekly hemodialysis.

Further research is needed to better delineate potential benefits of extended/frequent dialysis and to determine how best to integrate them into widespread clinical practice. In the meantime, the best available evidence suggests that for patients who remain on traditional hemodialysis, it is best to target both adequate urea clearance and treatment time of 4+ hours (in the majority of patients) to maximize health benefits.

References:
1. Lacson E Jr, Brunelli SM. Hemodialysis treatment time: a fresh perspective. Clin J Am Soc Nephrol. 2011 Oct;6(10):2522-30. Epub 2011 Sep 1. PubMed PMID:21885788.
2. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription of patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med. 1981 Nov 12;305(20):1176-81. PubMed PMID: 7027040.
3. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, Allon M, Bailey J, Delmez JA, Depner TA, Dwyer JT, Levey AS, Levin NW, Milford E, Ornt DB, Rocco MV, Schulman G, Schwab SJ, Teehan BP, Toto R; Hemodialysis (HEMO) Study Group. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med. 2002 Dec 19;347(25):2010-9. PubMed PMID: 12490682.
4. Saran R, Bragg-Gresham JL, Levin NW, Twardowski ZJ, Wizemann V, Saito A, Kimata N, Gillespie BW, Combe C, Bommer J, Akiba T, Mapes DL, Young EW, Port FK. Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS. Kidney Int. 2006 Apr;69(7):1222-8. PubMedPMID: 16609686.
5. Marshall MR, Byrne BG, Kerr PG, McDonald SP. Associations of hemodialysis dose and session length with mortality risk in Australian and New Zealand patients. Kidney Int. 2006 Apr;69(7):1229-36. PubMed PMID: 16609687.
6. Brunelli SM, Chertow GM, Ankers ED, Lowrie EG, Thadhani R. Shorter dialysis times are associated with higher mortality among incident hemodialysis patients. Kidney Int. 2010 Apr;77(7):630-6. Epub 2010 Jan 20. PubMed PMID: 20090666; PubMedCentral PMCID: PMC2864594.
7. Miller JE, Kovesdy CP, Nissenson AR, Mehrotra R, Streja E, Van Wyck D, Greenland S, Kalantar-Zadeh K. Association of hemodialysis treatment time and dose with mortality and the role of race and sex. Am J Kidney Dis. 2010 Jan;55(1):100-12. Epub 2009 Oct 22. PubMed PMID: 19853336; PubMed Central PMCID: PMC2803335.
8. Flythe JE, Kimmel SE, Brunelli SM. Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality. Kidney Int. 2011 Jan;79(2):250-7. Epub 2010 Oct 6. PubMed PMID: 20927040; PubMed Central PMCID:PMC3091945.
9. Movilli E, Gaggia P, Zubani R, Camerini C, Vizzardi V, Parrinello G, Savoldi S, Fischer MS, Londrino F, Cancarini G. Association between high ultrafiltration rates and mortality in uraemic patients on regular haemodialysis. A 5-year prospective observational multicentre study. Nephrol Dial Transplant. 2007 Dec;22(12):3547-52. Epub 2007 Sep 21. PubMed PMID: 17890254.
10. FHN Trial Group, Chertow GM, Levin NW, Beck GJ, Depner TA, Eggers PW, Gassman JJ, Gorodetskaya I, Greene T, James S, Larive B, Lindsay RM, Mehta RL, Miller B, Ornt DB, Rajagopalan S, Rastogi A, Rocco MV, Schiller B, Sergeyeva O, Schulman G, Ting GO, Unruh ML, Star RA, Kliger AS. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010 Dec 9;363(24):2287-300. Epub 2010 Nov 20. Erratum in: N Engl J Med. 2011 Jan 6;364(1):93. PubMed PMID: 21091062; PubMed Central PMCID: PMC3042140.