Dr Naber takes us to a historical review of when to start dialysis to the first randomized trial!

1. TamimNaber, MD 9/15/2010 Journal Club

2. Bruce A. Cooper, M.B., B.S., Ph.D. et al, NEJM; vol. 363 no. 7; august 12, 2010 A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis

4. Negative psychological impact on patients

5. Important socioeconomic implications

7. to control volume overload, acid-base and electrolyte disorders

8. and to provide a clearance of uremic toxins enough to allow an adequate dietary protein and caloric intake

10. Hyperkalemia

11. Metabolic acidosis

12. Hyperphosphatemia

13. Hypercalcemia or hypocalcemia

14. Anemia

15. Neurological dysfunction (eg, neuropathy, encephalopathy)

16. Pleuritis or pericarditis

17. Otherwise unexplained decline in functioning or well-being

18. Gastrointestinal dysfunction (eg, nausea, vomiting, diarrhea, gastroduodenitis)

19. Weight loss or other evidence of malnutrition

21. KDOQI.. Timing of Therapy When to Initiate Dialysis : K t/V urea Criterion (Opinion) patients should be advised to initiate some form of dialysis when the weekly renal Kt/V urea < 2.0. Unless: 1. Stable or increased edema-free body weight. 2. No Nutritional indications 3. Complete absence of clinical signs or symptoms attributable to uremia. A weekly Kt/V urea of 2.0 approximates a kidney urea clearance of 7 mL/min and a kidney creatinine clearance that varies between 9 to 14 mL/min/1.73 m 2

23. Nephrol Dial Transplant (2005) Dialysis should be instituted whenever evidence of uremia is present, or blood pressure and hydration status cannot be controlled, or when a deterioration of the nutritional status is noticed. In any case, dialysis should be started before the GFR is <6 ml/min/1.73 m2 (creatinine clearance 8 ml/min/1.73 m2). (Evidence level C) To ensure that dialysis is not started at a GFR of <6 ml/min/1.73 m2, initiation at the level between 8 and 10 ml/min should be considered. Diabetic patients may require an earlier start. (Evidence level C)

24. The CARI Guidelines – Caring for Australians with Renal Impairment, February 2005 No recommendations possible based on Level I or II evidence Commence dialysis at first indication of malnutrition suspected to be due to uremia and unresponsive to dietary intervention or correction of other reversible causes. (Level III evidence) Look for evidence of malnutrition once a GFR of 15–20 mL/min/1.73 m2 is found, and monthly from GFR < 10 mL/min/1.73 m2. Use of absolute indications for dialysis initiation is a historical concept which is no longer valid, and their presence suggests delayed initiation. However, in some patients with co-morbid conditions, dialysis may be indicated for these reasons even when GFR is greater than 10 mL/min/1.73m2

25. Postulate and practice Several series of patients taken onto RRT - (weekly Kt/V) at the start of dialysis - markedly lower than that of DOQI guidelines Ranging between 0.68, 0.72 and 1.05 in patients reviewed in USA, Canada and UK If DOQI guidelines are to be followed - dialysis needs to be started between 20 and 11 months earlier Heavy additional burden Must be justified by more convincing evidence to demonstrate unequivocal benefit from early initiation of dialysis Prospective, controlled, randomized trials

28. Cont’d CANUSA study.. In the CANUSA study, there was a survival advantage for higher total (residual plus dialysis) Kt/V up to 2.0, and possibly up to 2.3 This study was not designed to examine time of initiation of dialysis

30. demonstrated reduced survival in patients with less residual renal function at start of dialysis, although these patients were also significantly older and had significantly more co-morbidity

33. early initiation of dialysis expose patients : complications of dialysis, unnecessary lifestyle restriction, potential increased cost, patient fatigue

34. No RCTs - Confounding influences in other studies include referral time bias, age, co-morbidity, patient compliance and starting time bias

36. timely initiation - associated with a small survival benefit of 2.5 months

37. However, the extra time free of dialysis for “late starters ” was only 4.1 months

40. Post-hoc analysis of the MDRD study, comparing early (predicted MDRD GFR>7.5 ml/min; N = 1,444) with late (predicted GFR <7.5 ml/min); N = 1,476), higher MDRD GFR at initiation was associated with an increased risk of death in multivariate Cox model (hazard ratio 1.27 for each 5 ml/min increase)

41. “ reflect an erroneous GFR estimation by MDRD formula”

43. Patients in the general dialysis population who initiated dialysis therapy at a GFR >10 mL/min/1.73 m2 had a 42% increased risk for death compared with patients with a GFR < 5 mL/min/1.73 m2 at initiation of dialysis therapy after adjusting for all covariates

45. A Randomized, Controlled Trial of Early versus Late Initiation of DialysisNEJM; vol. 363 no. 7; august 12, 2010 Bruce A. Cooper, M.B., B.S., Ph.D., Pauline Branley, B.Med., Ph.D., LilianaBulfone, B.Pharm., M.B.A., John F. Collins, M.B., Ch.B., Jonathan C. Craig, M.B., Ch.B., Ph.D., Margaret B. Fraenkel, B.M., B.S., Ph.D., Anthony Harris, M.A., M.Sc., David W. Johnson, M.B., B.S., Ph.D., Joan Kesselhut, Jing Jing Li, B.Pharm., B.Com., Grant Luxton, M.B., B.S., Andrew Pilmore, B.Sc., David J. Tiller, M.B., B.S., David C. Harris, M.B., B.S., M.D., and Carol A. Pollock, M.B., B.S., Ph.D., for the IDEAL Study*

47. Funded by the National Health and Medical Research Council of Australia and others

48. Conducted in accordance of Helsinski, the Good Clinical Practice guidelines of the International Conference on Harmonization, and local regulatory requirements.

49. Approved by the ethic committee at each participating center.

50. Multi Center/Multinational:

51. Patients recruited at 32 center in Australia and New Zealand “urban and rural locations, general and university hospitals”/all provided written informed consent

52. Blinded statistical personnel, and an independent end-point committee unaware of the treatment assignments.

53. Owing to the nature of the intervention, it wasn’t possible to conceal the treatment assignments from the patients, nurses, or investigators

55. 1ry outcome: Death from any cause

57. GFR <10

58. Plan to receive live donor kidney transplant within the next 12 months

59. Recently diagnosed Cancer likely to affect survival

60. Unable to provide written informed ConsentMethods

61. GFR Estimate? Cockroft-Gault equation For comparison, they also calculated the estimated GFR at baseline and at the start of dialysis with the use of the Modification of Diet in Renal Disease (MDRD) equation

63. Planned method of dialysis “PD vs HD” specified before randomization by the choice of the patient and treating physician

64. Continue to receive Medical care and commence dialysis when GFR 5-7

66. 244 in New Zealand, 584 in Australia

67. 404 – Early start / 424 – Late start

68. Median duration of follow up was 3.64 years, (range, 0.03 to 9.15) in the early-start group and 3.57 years (range, 0.02 to 8.78) in the late-start group.

70. The main reasons were:

71. GFR that had not fallen to the assigned range for initiation of dialysis (6 patients in the early-start group and 8 in the late-start group)

72. Death (10 patients in the early-start group and 22 in the late-start group).

75. GFR was 12.0 ml per minute in the early-start group, as compared with 9.8 ml per minute in the late-start group

76. In the early-start group, 75 (18.6%) started dialysis with an estimated GFR of less than 10.0 ml per minute

77. In the late-start group, 322 (75.9%) started dialysis with an estimated GFR of more than 7.0 ml per minute.

79. The causes of the deaths are summarized in (Table 2)

80. There was no significant difference in survival between patients in the late-start group and patients in the early-start group (hazard ratio for death in the early-start group, 1.04; 95% CI, 0.83 to 1.30; P = 0.75) (Fig. 2B)

83. with careful clinical management of CKD, dialysis can be delayed for some patients until the GFR drops below 7.0 ml/m, or until more traditional clinical indicators for the initiation of dialysis are present

84. all the previous studies were nonrandomized and were subject to potential confounding factors that do not apply to the IDEAL trial!

85. Dialysis should not be started on the basis of an estimate of GFR alone

86. the most important parameters to be considered being; uremic, adequate control of blood pressure, and quality of nutritional status

88. What about us?When would you initiate dialysis on ESRD patient? N = 19 Favors early start RRT= 5 (26%) Attendings N= 12 (17% favors early start) Fellows N= 7 (43% favors early start)