Adequacy of Hemodialysis

1. Adequacy of Hemodialysis Dale A. Rowett, M.D. Medical Director, Central CT Dialysis Center Assistant Clinical Professor of Medicine, University of Connecticut School of Medicine Chairman, Fresenius Medical Advisory Board 2007-10

3. What is Adequate Dialysis? In 1981, I opened my first dialysis clinic at Middlesex Hospital; our head nurse was shocked that I was planning 4 hour treatments She had worked at the WHVA Dialysis, doing 6 hour dialysis on all patients

4. Metrics to Measure Adequacy At the opening ceremony for the clinic in 1981, the speaker was the late Peter Lundin, home hemodialysis patient and academic nephrologist He thought that 60% reduction in creatinine was appropriate-no data Formidable goal

5. TAC Urea Lowrie et al, who published the National Cooperative Dialysis study of 151 patients in 1981, thought that following the BUN was not the best way to measure adequacy Developed the time average concentration (TAC) of urea Patients in the high TAC group had higher hospitalization and more withdrawal from the study Lowrie EG et al N Eng J Med 1981; 305 (20) 1176

6. Why was urea chosen? Why not creatinine or beta2 microglobulin? Since the BUN is dependent on both dietary urea production and dialysis removal, it was felt that this would be the best metric It is also easy to measure

7. KT/V In this formula, K is a constant for urea removal, as published in the manufacturer literature of any particular dialyzer T is the time on dialysis V is the volume of total body water Developed in 1985, as TAC urea was not felt to be an adequate marker of adequacy Gotch FA; Sargent JA: A mechanistic analysis of the NCDS. Kidney Int 1985 Sept; 28 (3): 526-534

8. Calculation of KT/V KT/V = -ln (R � 0.03) + [(4 � 3.5R) times (UF divided by W)] where UF is UF volume, W is the post- dialysis weight in kg and R is the ratio of post-dialysis to pre-dialysis BUN

9. Urea Reduction Ratio URR = (1 � [postdialysis BUN divided by predialysis BUN])

10. Equilibrated (Double Pool) KT/V Measurement of post dialysis BUN at the very end of dialysis overestimates the degree of urea removal, as it takes about 30 minutes after dialysis for urea to come out of cells and �equilibrate� with the extra-cellular content eKT/V is about 0.21 lower than sKT/V It is inconvenient to keep the patient an extra 30 minutes

11. Post-dialysis BUN Both access and cardiopulmonary recirculation are prominent at the end of dialysis, so the post dialysis BUN should not be measured immediately during high blood flow Both have pretty much dissipated by two minutes after dialysis

12. Stop dialysate flow technique-for eKT/V In a study of 70 patients in Glasgow, the 30 minute post dialysis BUN was compared with the stop dialysate flow BUN Possible to estimate eKT/V by getting a BUN within 5 minutes of completion A regression equation was generated: 30 min BUN = 1.06 times (5 min BUN) + 0.22 Traylor JP et al. AM J of Kidney Dis 2002 Feb; 39(2): 308-314

13. Methodological limitations of the ESRD Core Indicators Project: an ESRD network's experience with implementing an ESRD quality survey. Medical Review Board of the ESRD Network of New England.33 % of HD units drew post-dialysis blood immediately before the end of the session25 % of HD units drew post-dialysis blood immediately after the end of the session41% of HD units drew post-dialysis blood greater than 5 minutes after reinfusion of bloodOwen WF Jr, Meyer KB, Schmidt G, Alfred HAm J Kidney Dis. 1997;30(3):349.

14. Recommendation Slow the blood flow rate down to 100 ml/min and draw the post-dialysis blood urea 15 seconds later The formula developed in Glasgow can then be used to calculate a true eKT/V

15. What About Residual Function? Several studies indicate improved patient survival if they have RRF of 2 ml/min It is reasonable to measure RRF and add it into the equation for KT/V

16. Adequacy metrics URR-CMS says it should be greater than 65%; 70 % is more reasonable spKT/V-should be greater than 1.4 � 1.6 eKT/V should be greater than 1.2 � 1.4-this is the most accurate metric If a patient is getting metrics equal to or greater than above, is that patient getting adequate dialysis? Maybe not

17. What about KT rather than KT/V? In a study of 40,000 dialysis patients: Black patients have lower KT/V AND lower mortality than white patients Small patients that have similar KT/V to large patients, yet a higher mortality rate KT may be superior to KT/V Owen WF et al. Dose of hemodialysis and survival. JAMA 1988 Nov 25; 280(20): 1764-1768

18. Overview of Dialysis Time The history of dialysis titration Rationale for reconsidering time Associations between time and survival Potential Mechanisms Conclusions

19. Dialysis titration over time

20. National cooperative dialysis study Impetus: Determine best way of addressing ongoing uremia Multi-center randomized trial Time averaged BUN (50 vs 100 mg/dl Session length (2.5-3.5 vs 4.5-5 hours) 151 subjects Mean age 51 years No patients with diabetes, coronary disease, recurrent infections, cancer, anticipated survival less than 3 years Outcomes Primary :modality (medical drop out, hospitalizations) Secondary: mortality

21. National cooperative dialysis study Trial stopped early by data safety monitoring board: Median follow up 48 weeks Primary analysis used week 26 data Results: Urea concentration highly associated with hospitalization Session length not associated with hospitalization No association with mortality-but only 48 weeks Lowrie EG et al: Effect of the hemodialysis prescription of patient morbidity; report from the National Cooperative Dialysis Study. N Eng J Med 1981 Nov 12: 305(20): 1176-1181

22. Dialysis titration over time

23. Mechanistic analysis-1985-Gotch and Sargent Data taken from National Cooperative Dialysis Study Demonstrated increased ability to predict failure when using KT/V as opposed to time averaged BUN Did not consider mortality

24. Dialysis titration over time

25. Owen Study Published 1991 Retrospective analysis of 13,473 patients Looked at the 6 month mortality from October 1990 to March 1991 The odds ratio for death was much higher if the URR was less than 65-69%

26. Identification of a urea removal target with respect to mortality Retrospective analysis: 13,473 patients 6-month mortality Oct 90-Mar 91

27. Dialysis titration over time

28. HEMO study Randomized trial, 2X2: Flux Dose Sp-Kt/V 1.25 Sp-Kt/V 1.65 1,846 subjects

29. Overview The history of dialysis titration Rationale for reconsidering time Associations between time and survival Potential Mechanisms Conclusions

30. Philosophical Considerations There are at least 3 processes happening in parallel during dialysis-removal of small solutes, middle molecules & fluid Under a given paradigm, any of one (or more) of these may be survival limiting If the paradigm changes, reevaluation is necessary

31. Technological developments Widespread introduction of high efficiency dialyzers: enable very rapid removal of small solutes; fundamentally alter the implied relationship between urea kinetics and middle molecule removal and fluid removal If treatments are shortened in response to earlier attainment of Kt/V, may leave insufficient time for these other goals

32. Revisiting HEMO with an eye towards session length HEMO found �no adverse effects of shorter treatment times� However-the study was not optimized to evaluate the effects of treatment time Study was designed to allow time to vary Dialysis was titrated to �the shortest treatment time consistent with the patient�s assigned dose�

33. In essence There has not been a randomized trial of hemodialysis SESSION LENGTH since the National Cooperative Dialysis Study

34. Overview The history of dialysis titration Rationale for reconsidering time Associations between time and survival Potential Mechanisms Conclusions

35. Studies of time Retrospective analysis Japanese cohort 1993-94 (N=53,867) Session length assessed at baseline Outcome: adjusted risk of death at 1-year

36. Studies of time Retrospective analysis Australia/ New Zealand cohort 1997-2004 (N=4,171; incident patients) Session length assessed at 12 months after dialysis initiation Outcome: all cause mortality

37. Studies of time Retrospective analysis Multinational DOPPS cohort 1997-2004 (N=16,333) Session length assessed at study entry Outcome: all cause mortality

38. Studies of time FMC cohort of 8552 incident patients, performed in 2004-5, published 2010 Adjusted for age, sex, access, CHF, Kt/V, hospitalization All had a significantly higher mortality if session length was less than 4 hours Brunelli, Steven, et al

39. Fig. 5A: Case-mix Adjusted Mortality Risk for HD Patients in the US Versus Europe: With and Without Adjustment for Differences in Facility Vascular Access Use

40. Why the dependency on time even when urea kinetics are optimized? Indexing to body size-the V in Kt/V Small people require less KT to achieve the goal KT/V and have higher mortality Kt is associated with survival independent of body size; Kt/V is not Holding Kt/V experimentally, longer treatment results in greater clearance of creatinine, phosphate, beta 2 microglobulin and urea

41. Why the dependency on time when urea kinetics optimized? Change to long treatment time daily dialysis results in improved phosphatemia and decreased necessity for phosphate binders Do we need a new metric? KT?

42. Is ultrafiltration the culprit? CV disease is the leading cause of death in HD patients Intuition suggests that rapid UF causes decreased circulation volume, hypotension Cardiac stunting and ischemic damage Inability to achieve the driest weight can cause cardiac remodeling leading to myopathy and arrhythmia, and arterial stiffness

43. Is ultrafiltration the culprit? Patients changed to long daily dialysis have improvement in LV mass and lower UF rates

44. Is ultrafiltration rate the culprit? Italian study, (published in 2007) of 287 patients found a higher all cause mortality in patients with higher UF rates than others

45. Is ultrafiltration rate the culprit? Multinational DOPPS study (2006) found that all cause mortality in 16,333 patients was significantly greater if more rapid (ml/hour) UF rates were necessary

46. Is ultrafiltration rate the culprit? Post-hoc analysis HEMO Study data (N=1,846) UFR considered at baseline Outcomes: all cause and CV mortality

47. Rapid Fluid Removal During Dialysis is Associated With Cardiovascular Morbidity and Mortality Flythe, JE et al. Kidney Int. 2011, 2011;79(2): 250-257

48. UF rates were divided into 3 categories-less than 10 ml/h/kg, 10-13 ml/h/kg, and more than 13 ml/h/kg The highest UF group was associated with HR (compared to lowest group) of all cause and CV mortality rates of 1.59 and 1.71 respectively The 10-13 group had only a slightly higher mortality than the less than 10 group

49. For a 76 kg person If 4 L of UF were necessary, removing all the fluid in 3 hours would mean a UF rate of 13 ml/h/kg If that same 4 L were removed in 4 hours, the UF rate would be about 10 ml/h/kg The change from 3 to 4 hours of dialysis would decrease mortality rate by 40%

50. Summary Shorter session lengths adversely affect survival even when current metrics of urea kinetics are optimized This would imply a need to extend session length to at least 4 hours and perhaps beyond

51. Summary If this effect is mediated through increased clearance of middle molecules, session length might be safely reduced if metrics of middle molecule adequacy can be established But the rate of fluid removal would still be rapid and necessitate longer dialysis sessions

52. What to do? Hemodialysis treatments of less than 4 hours are associated with higher mortality This association is constant, even in those patients with adequate Kt/V Dialysis patients should have an adequate KT/V AND a minimum of 4 hours thrice weekly

53. Central CT Dialysis Center All incident patients are started on 4 � hours tiw if they have a catheter for access Incident patients are started on 4 hours if they have a fistula or graft

56. Thank you Email: dalerowett@comcast.net Cell: (860) 262-2379