1. Hemodialysis adequacy & Outcome: from NCDS to HEMO & MPO
Saeed M.G Al-GHAMDI, FRCPC, FACP
King Faisal Specialist Hospital & Research Center-Jeddah

2. Beginning of Hemodialysis

3. National Cooperative Dialysis Study
NCDS
Lowrie eg; Laird NM, PARKER TF; SARGENT JA New England journal of medicine November 12;305(20):

4. Lowerie EG, et al, N Engl J Med 1981, Nov, 12; 305(20): 1176-81
Effect of hemodialysis prescription of patients morbidity: Report of NCDS
151 patients
4 treatment groups
Long dialysis
Short dialysis
High time-average urea concentration
Low time-average urea concentration
Protein intake was not restricted
Lowerie EG, et al, N Engl J Med 1981, Nov, 12; 305(20):

5. Lowerie EG, et al, N Engl J Med 1981, Nov, 12; 305(20): 1176-81
NCDS: Results
No difference in mortality between groups
Withdrawal was higher in the high urea group
Hospitalization was higher in higher urea group
Morbidity was higher in the high ATC-urea
Morbidity may be decreased by prescription associated with more efficient removal of urea if adequate protein intake
Lowerie EG, et al, N Engl J Med 1981, Nov, 12; 305(20):

6. Mechanistic analysis of NCDS
Gotch used NCDS data and introduced kt/v of urea
Efficiency of urea removal (small toxins)
Dietary protein intake
Kt/v is an important measure of clinical outcome
Gotch, FA, Sargent,JA KI 1985; 28:

7. Kt/v: Single pool Vs double pool
Urea is equilibrated between muscles and plasma water
Single pool kt/v (non- equilibrated): blood urea is measured at end of dialysis from circuit
Double pool kt/v (equilibrated): venous sample post dialysis (30 minutes)
Single pool kt/v is 0.20 higher than double pool

8. Kt/v: Practice & Recommendations
Slow the pump to 100 ml/minute
Obtain urea sample 15 seconds later
Target kt/v of 1.2 (URR of 65%)
The mean delivered sp-kt/v in USA: 1.5, more than 90% above 1.2
The mean kt/v in Europe:
KDOQI , AJKD 2006, EBPG, NDT 2002
USRDS 2007, EBPG, DOPPS 2004

9. Optimal Dialysis dose
Is the summation of clinical and biochemical parameters which refer to the adequately delivered dose of dialysis , in which patient has no symptoms which could be attributed to under-dialysis and more importantly, to a measurable value at which the dialysis patient has the lowest morbidly and mortality

10. High kt/v: Positive observational studies
Survival in long-term hemodialysis patients: results from the annual survey of the Japanese society of dialysis therapy. Shinazato et al, NDT 1997; 12:884-8
Body size, dose of hemodialysis and mortality. Wolfe RA et al, AJKD 2000; 35: 80-88
Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients. Port FK, et al, JASN 2002; 13:

11. High kt/v: negative observational study
The dose of hemodialysis and patient mortality. Held PJ et al, KI 1996; 50:550-6

12. Eknoyan G et al New Engl J Medicine 2002; 347: 2010
Effect of Dialysis Dose and Membrane Flux in Maintenance Hemodialysis HEMO study
Eknoyan G et al New Engl J Medicine 2002; 347: 2010

13. HEMO study: Design 1846 prevalent patients in 72 dialysis units in USA
RCT: mean follow up of 2.8 year
Two-by-two factorial design
Standard dose: sp- kt/v 1.25 or URR 65%
High dose: sp-kt/v 1.65 or URR of 75%
Low-flux
High-flux

14. HEMO study: Outcomes Primary outcome: Secondary outcome:
Death from any cause
Secondary outcome:
Rate of hospitalizations (excluding access)
Composite outcome
First hospitalization from cardiac cause or death from any cause (ACM)
First hospitalization from infectious cause or death
First decline of 15% in serum albumin from baseline value or death

15. HEMO Study Eknoyan G et al New Engl J Medicine 2002; 347: 2010

16. HEMO Study Eknoyan G et al New Engl J Medicine 2002; 347: 2010

17. HEMO Study : Primary outcome Eknoyan G et al New Engl J Medicine 2002; 347: 2010

18. HEMO Study Eknoyan G et al New Engl J Medicine 2002; 347: 2010

19. HEMO Study : Primary outcome Eknoyan G et al New Engl J Medicine 2002; 347: 2010

20. HEMO Study : Secondary outcome Eknoyan G et al New Engl J Medicine 2002; 347: 2010

21. HEMO conclusion: Primary outcome
Neither the difference between the two dose groups nor the difference between flux groups were significant
After adjustment of base-line factors
High dose group: risk of death 4% lower P= 0.53
High-flux group: risk of death 8% lower P= 0.23

22. HEMO conclusion: Secondary outcomes
The risk of main secondary outcome was the same for both dialysis dose groups and for both flux groups.

23. HEMO study: Conclusion
Among patients undergoing maintenance hemodialysis who were receiving thrice-weekly treatment lasting hours each, neither a higher dose nor the use of high-flux membranes significantly improved survival or reduced morbidity
This support the current guidelines of single-pool kt/v of , and make no recommendation for or against routine use of high-flux membranes

24. HEMO study: Subgroup analysis
In high-flux there is significant reduction in RR of death (20%) from cardiac causes and combined outcome of first hospitalization or death from cardiac cause
Longer dialysis duration
High-flux dialysis for > 3.7 year has 32% lower risk of death when compared with low-flux
Cheung A, et al , JASN 2003; 14:

25. HEMO Study: Subgroup analysis
Sex and dialysis dose
Women with high dose has 19% lower risk of death
Men with high dose has 16% higher risk of death
Beta-2-microglobulin: serum level correlated with mortality particularly from infectious causes

26. Effect of Membrane Permeability on Survival of Hemodialysis Patients (MPO Study)
Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, Jacobson SH, Czekalski S, Ronco C, Vanholder R,
JASN 2009; 20:

27. MPO: Hypothesis
Mortality in dialysis patients 24% in USA and 14-26% in Europe
Retention of high MW molecules may be implicated in the high mortality
High-flux membranes can remove those molecules
Epidemiologic data suggested benefits
Only one underpowered RCT which did not show benefit

28. MPO Study: Design RCT: 59 European study centers
738 incident hemodialysis patients
Follow up from years (mean 3 year)
Patients were randomized to receive high or low-flux membrane according to
Low albumin <4 g/dl (567 patients)
Normal albumin > 4 g/dl (171 patients)
Minimal single-pool kt/v of 1.2

29. MPO study; Methodology Locatelli, F. et al
MPO study; Methodology Locatelli, F. et al. J Am Soc Nephrol 2009;20:

30. MPO study: Results: Kaplan-Meier survival curves for the complete intention-to-treat population (Log-rank test P = 0.214) Locatelli, F. et al. J Am Soc Nephrol 2009;20: Locatelli, F. et al. J Am Soc Nephrol 2009;20:

31. MPO study : Results Kaplan-Meier survival curves for the population of patients with serum albumin <=4 g/dl (Log-rank test P = 0.032

32. MPO study : Results Kaplan-Meier survival curves for the subpopulation of patients with diabetes (Log-rank test P = 0.039) Locatelli, F. et al. J Am Soc Nephrol 2009;20:

33. MPO study: Results Locatelli, F. et al
MPO study: Results Locatelli, F. et al. J Am Soc Nephrol 2009;20:

34. MPO: Conclusions
No significant effect of permeability on survival was found in the population as a whole
High-flux showed significant survival benefit in high risk population (RR reduction of 37%)
High-flux showed significant survival benefit in diabetics (adjusted risk reduction of 38%)

35. HEMO & MPO: Differences
Europe
Membrane flux in high risk groups
USA
Dialysis dose
Membrane flux
RCT
Incident patients
Mostly Prevalent patients
Enrollment
yes no
Risk stratification
3-7 year (3 y)
2.8 years
Duration

37. How can we decrease morbidity and mortality in HD patients?

38. How can we reduce morbidity and mortality in HD patients?
Attention to traditional and non-traditional risk factors
Anemia
Hypertension
CKD-MBD
Individualization of dialysis therapy
High flux for high risk group or non-transplant patients
High dose kt/v for women

39. Future attempt to lower M&M
More refinement of our dialysis prescription
Treatment Time
Daily dialysis or Quotidian

40. Survival on dialysis according to country and DM
Hull, AR, Parker, TF III, Am J Kidney Dis 1990; 15:375, and Charra, B, Calemard, E, Ruffet, M, et al, Kidney Int 1992; 41:1286.

48. Conclusions
Targeting high kt/v has no significant impact on mortality, and the current kt/v >1.2 is still holding
High-flux membrane might be of benefit in high risk group and in chronic HD patients
Longer treatment time of dialysis probably is more important than kt/v
CKD-MBD has major impact on morbidity and mortality

49. Conclusion
The focus to reduce morbidity and mortality may be directed to lowering traditional and non-traditional risk factors in dialysis population

50. Thank You