COMMENTARY

Initiating Dialysis: When is the right time?

One of the central functions for a nephrologist is managing the patient’s transition from native kidney function to renal replacement therapy. This is a tumultuous time for patients, families and caregivers. There are both human and financial consequences. Using an evidence-based approach to determining the right time to initiate dialysis is important.

In a commentary titled “When to Start Dialysis: Updated Guidance Following Updated Guidance Following Publication of the Initiating Dialysis Early and Late (IDEAL) Study, posted on Medscape 8/15/11, but published in NDT in July 2011 (1) Tattersall and co-workers have updated the original 2002 European Guideline (Table 1) on initiation of dialysis (2). The new updated guideline is shown in Table 2.

Table 1: 2002 Guideline I.3

1. Dialysis should be instituted whenever the glomerular filtration rate (GFR) is <15 mL/min and there is one or more of the following: symptoms or signs of uraemia, inability to control hydration status or blood pressure or a progressive deterioration in nutritional status. In any case, dialysis should be started before the GFR has fallen to 6 mL/min/1.73m², even if optimal pre-dialysis care has been provided and there are no symptoms.
2. High-risk patients e.g. diabetics may benefit from an earlier start. (Evidence level: C)
3. To ensure that dialysis is started before the GFR is 6 mL/min, clinics should aim to start at 8–10 mL/min. (Evidence level: C)

Table 2: 2012 Guideline I.3

1. Patients with advanced CKD should be prepared for dialysis, kidney transplant or conservative care before their CKD becomes symptomatic. For patients who are expected to require dialysis, this includes advance preparation of appropriate access. This process also includes careful observation for signs and symptoms of uraemia and should, ideally, be started while GFR is >15 mL/min/1.73m². Supervision in a dedicated clinic for patients with advanced CKD is recommended (1C, Strong recommendation based on low-quality evidence).
2. In patients with a GFR <15 mL/min/1.73m², dialysis should be considered when there is one or more of the following: symptoms or signs of uraemia, inability to control hydration status or blood pressure or a progressive deterioration in nutritional status. It should be taken into account that the majority of patients will be symptomatic and need to start dialysis with GFR in the range 9–6 mL/min/1.73m² (1A Strong recommendation based on high-quality evidence).
3. High-risk patients e.g. diabetics and those whose renal function is deteriorating more rapidly than eGFR 4 mL/min/year require particularly close supervision. Where close supervision is not feasible and in patients whose uraemic symptoms may be difficult to detect, a planned start to dialysis while still asymptomatic may be preferred (1C Strong recommendation based on low-quality evidence).
4. Asymptomatic patients presenting with advanced CKD may benefit from a delay in starting dialysis in order to allow preparation, planning and permanent access creation rather than using temporary access (2C Weak recommendation based on low-quality evidence).

Interestingly, a Perspective article in the June 9 issue of the New England Journal of Medicine (3), a sentence also caught my attention that neither the reviewers nor the editors at the Journal modified before publication: "Nephrology guidelines recommend initiating dialysis when the estimated glomerular filtration rate (GFR) falls below 15 ml per minute in patients with diabetes or 10 ml per minute in patients without diabetes." I am confident that most nephrologists will agree that the practice of Healthy Start needs to be updated in the face of new evidence. 

The healthy start concept led to the start of dialysis at a higher eGFR levels. In the United States, the percentage of patients starting dialysis with eGFR greater than 10 ml/min per 1.73 more than doubled between 1996 and 2005, from 25 to 54%, whereas in France it has been stable at 30% since the beginning of the Renal Epidemiology and Information Network (REIN) Registry in 2002.

The reasons invoked for “Healthy Start” were: 1.) Better survival, 2.)  Liberalization of protein intake in the diet, which would reduce the risk of malnutrition; and, 3.) The general sense that dialysis should be started in hemodialysis patients to at least at a level of renal function equivalent to that used as “optimal” clearance in patients undergoing PD.

However, the “The Initiating Dialysis Early and Late” (IDEAL) study, a randomized trial conducted between July 2000 and November 2008 in 32 Australian-New Zealand centers should change minds. In IDEAL, published in the New England Journal of Medicine (4), 828 adults with a mean age of 60.4 years were recruited. There were 542 men and 286 women. 355 subjects had diabetes. Patients were randomized to one of two arms: an early-start group (CG-GFR 10-15 ml/min) and a late-start group (CG-GFR 5.0-7.0 ml/min). With the early start group the median time to the initiation of dialysis was1.80 months (95% CI, 1.60 to 2.23), whereas for the late start group the median time to initiation was 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. The primary outcome in the study was death from any cause. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died with early initiation, (hazard ratio 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis). The main advantage of the IDEAL study was its design – by randomizing subjects the survivor bias or 'healthy cohort effect' that was regarded as a powerful confounder in co morbidity-adjusted observational studies was eliminated.

The IDEAL study demonstrated that that is no survival disadvantage in starting dialysis when patients become symptomatic rather than simply on the basis of a number -- an estimation of GFR by the Cockcroft-Gault equation. Waiting gained patient’s time without any apparent risk.

Rosansky recently published an observational analysis in 81,176 nondiabetic, 20- to 64-year-old, in-center incident hemodialysis patients that supports the observations from IDEAL (5). In this regard, I would recommend readers to an excellent review by Steve Rosansky and colleagues (6) in CJASN that critically evaluates the evidence supporting healthy start, but which basically comes down in favor of the updated European Guideline by Tattersal and colleagues.

References

1. Tattersall JE, Pedrini L, Martin-Malo AM. When to start dialysis. Nephrol Dial Transplant 2002; 17 (Suppl 10): 10.

2. Tattersall J, Dekker F, Heimbürger O, Jager KJ, Lameire N, Lindley E, Van Biesen W, Vanholder R, Zoccali C; ERBP Advisory Board. When to start dialysis: updated guidance following publication of the Initiating Dialysis Early and Late (IDEAL) study. Nephrol Dial Transplant. 2011 Jul;26(7):2082-6. Epub 2011 May 5.

3. Raghavan R, Nuila R. Survivors--dialysis, immigration, and U.S. law. N Engl J Med. 2011 Jun 9;364(23):2183-5.

4. Cooper BA, Branley P, Bulfone L, Collins JF, Craig JC, Dempster J, Fraenkel MB, Harris A, Harris DC, Johnson DW, Kesselhut J, Luxton G, Pilmore A, Pollock CA, Tiller DJ; IDEAL Study Steering Committee. The Initiating Dialysis Early and  Late (IDEAL) study: study rationale and design. Perit Dial Int. 2004 Mar-Apr;24(2):176-81. PubMed PMID: 15119639.

5. Rosansky SJ, Eggers P, Jackson K, Glassock R, Clark WF. Early start ofhemodialysis may be harmful. Arch Intern Med. 2011 Mar 14;171(5):396-403. Epub 2010 Nov 8.

6. Rosansky S, Glassock RJ, Clark WF. Early start of dialysis: a critical review. Clin J Am Soc Nephrol. 2011 May;6(5):1222-8.