TAMIM NABER, MD 9 /15 /2010

Journal Club

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

Initiation of dialysis

Most critical decision to make along the course of chronic renal insufficiency

Negative psychological impact on patients

Important socioeconomic implications

When to start - subject to much controversy

Goals of dialysis

free of uremic symptoms

to control volume overload, acid-base and electrolyte disorders

and to provide a clearance of uremic toxins enough to allow an adequate dietary protein and caloric intake When residual renal function fails to maintain all these

vital functions, we have a solid argument for starting dialysis therapy

Complications That May Prompt Initiation of Kidney Replacement Therapy

Intractable ECV overload Hyperkalemia Metabolic acidosis Hyperphosphatemia Hypercalcemia or hypocalcemia Anemia Neurological dysfunction (eg, neuropathy, encephalopathy) Pleuritis or pericarditis Otherwise unexplained decline in functioning or well-being Gastrointestinal dysfunction (eg, nausea, vomiting, diarrhea,

gastroduodenitis) Weight loss or other evidence of malnutrition Hypertension

When to Initiate??

The key question is whether we have to start dialysis prior to, or after the overt development of these uremic signs and symptoms

The beneficial effects that dialysis can offer to the pre-dialysis renal failure patient

the potential complications of dialysis, and the changes in the way of life that many patients have to endure, are factors which should temper this decision

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

KDOQI.. Timing of Therapy

patients with chronic kidney failure (e.g, GFR < 15 to 20 ml/min) who are not undergoing maintenance dialysis, if protein-energy malnutrition (PEM) develops or persists despite vigorous attempts to optimize protein and energy intake and there is no apparent cause for malnutrition other than low nutrient intake, initiation of maintenance dialysis or a renal transplant is recommended (Opinion)

KDOQI.. Timing of Therapysecond update of the Clinical Practice Guidelines (CPGs) and Clinical Practice Recommendations

(CPRs) 2006

Timing of therapy: When patients reach stage 5 CKD (estimated GFR < 15 mL/min/1.73 m2), nephrologists should evaluate the benefits, risks, and disadvantages of beginning kidney replacement therapy. Particular clinical considerations and certain characteristic complications of kidney failure may prompt initiation of therapy before stage 5 (B)

AJKD VOL 48, NO 1, SUPPL 1, JULY 2006

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)

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

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

Early initiation – Believers..

Bonomini et al, 1985

reported that an early start of dialysis was associated with reduced mortality and morbidity

Among a subset of patients who were subsequently transplanted, there was a survival advantage for those started dialysis early (n=50) vs later (n=96), as well as less vascular calcification, bacterial infection, dyslipidemia and hospitalization!

Early initiation – Believers..

CANUSA Study (McCusker et al 1996)

Significantly poorer survival for patients with lower levels of renal function when starting dialysis

The mean creatinine clearance at the start of dialysis for all patients was 38 L/wk (3.8 ml/min)

12 and 24 month survival for those with creatinine clearance <38 L/wk at start of dialysis was 82.1% and 73.6%, respectively, compared with 94.7% and 90.8%, respectively, for those with creatinine clearance >38 L/wk

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

Early initiation – Believers..

Tattersall et al. ( Am J Nephrol 15: 283 -2 89, 1995)

prospective cohort study of 63 patients in 1991–92

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

Hospitalization length of stay was greater among those with residual Kt/V <1.05 at time of initiation of dialysis

Early initiation – Believers..

Schulman G and Hakim RM Improving outcomes in chronic hemodialysis patients: should

dialysis be initiated earlier? Semin Dial 1996; 9(3):225-9

patients initiated on dialysis with a creatinine clearance > 10 ml/min had an 88% 10- year survival when compared to 55% in those initiated at a creatinine clearance of < 10 ml/min (mean 4 ml/min)

Early initiation

However,

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

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

Lead time bias

Early initiation - skeptics - lead time bias

In the context of initiation of dialysis, lead-time bias refers to the effect whereby measuring survival from the start of dialysis increases apparent survival of those started with more residual renal function i.e., earlier in the course of the disease, than those who start dialysis with less residual renal function

When to initiate dialysis: effect of proposed US guidelines on survival. Korevaar et al. Lancet 2001 Sep 29; 358(9287):1046-1050

In NECOSAD study (Korevaar et al.) estimated the effects of lead-time bias on dialysis survival by using prediction software based on the Finnish Cancer Registry

timely initiation - associated with a small survival benefit of 2.5 months However, the extra time free of dialysis for “late starters ” was only 4.1

months This study suggested that any perceived survival benefit from early

start could be accounted for by lead-time

Early initiation - skeptics – QOL(Korevaar et al 2002)

(Evaluation of DOQI guidelines: Early start of dialysis treatment is not associated with better health-related quality of life. Am J Kidney Dis 2002; 39:108- 1 15)

Prospective cohort study from Holland

38% of 237 incident dialysis patients commenced dialysis late, as defined by the K/DOQI guidelines. Compared with patients who have timely initiation, the HRQOL among late starters was worse during the first 6 months after initiation, but no different at 12 months

Early initiation does not prolong survival?

Impact of timing of initiation of dialysis on mortality. Beddhu et at. JASN 14: 2305-2312, 2003

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)

“ reflect an erroneous GFR estimation by MDRD formula”

Concluded that the data do not support early initiation of dialysis

Early initiation of dialysis increases risk of mortality?

Kazmi et al – Am J Kidney Dis. 2005 Nov;46(5):887-96

undertook an evaluation of the impact of comorbidity on the association between GFR at initiation and death Results: greater GFR at initiation associated with a greater risk for death in all populations

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

Additional research required

(IDEAL) TRIAL THE INITIATING DIALYSIS

EARLY AND LATE

Definite answer?

B R U C E A . C O O P E R , M . B . , B . S . , P H . D . , PA U L I N E B R A N L E Y, B . M E D . , P H . D . , L I L I A N A B U L F O N E , B . P H A R M . , M . B . A . ,

J O H N F . C O L L I N S , M . B . , C H . B . , J O N A T H A N C . C R A I G , M . B . , C H . B . , P H . D . , M A R G A R E T B . F R A E N K E L , B . M . , B . S . , P H . D . ,A N T H O N Y H A R R I S , M . A . , M . S C . , D AV I D W. J O H N S O N , M . B . ,

B . S . , P H . D . , J O A N K E S S E L H U T,J I N G J I N G L I , B . P H A R M . , B . C O M . , G R A N T L U X T O N , M . B . , B . S . ,

A N D R E W P I L M O R E , B . S C . , D AV I D J . T I L L E R , M . B . , B . S . ,D AV I D C . H A R R I S , M . B . , B . S . , M . D . , A N D C A R O L A . P O L L O C K ,

M . B . , B . S . , P H . D . , F O R T H E I D E A L S T U D Y *

A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis

NEJM; vol. 363 no. 7; august 12, 2010

Oversight

RCT

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

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

Approved by the ethic committee at each participating center.

Multi Center/Multinational: Patients recruited at 32 center in Australia and New Zealand “urban and rural locations, general and

university hospitals”/all provided written informed consent

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

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

Safety monitoring committee reviewed blinded data after 50%, and 75% of the predicted 1ry outcome with a stopping rule of a difference between groups at least 3 SD in total number of deaths “P value of 0.003”

Study Design/Outcomes

Study was designed to determine whether initiating dialysis early in people with stage V chronic kidney disease reduces the rate of death from any cause.

1ry outcome: Death from any cause

2ry outcome: included Cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, or new-onset angina), infectious events (death or hospitalization due to any infection-related cause), and complications of dialysis (temporary placement of an access catheter, need for access revision, infection at the access site, or fluid and electrolyte disorders requiring hospitalization, additional dialysis, or both)

Inclusion Criteria Exclusion Criteria

Progressive CKD with estimated GFR 10-15 ml/m/1.73m2 BSA

Failing Kidney Transplant were eligible too..

< 18 year old

GFR <10

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

Recently diagnosed Cancer likely to affect survival

Unable to provide written informed Consent

Methods

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

Early – Start Group Late – Start Group

Commence Dialysis when GFR 10-14

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

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

Dialysis for GFR>7 if the treating physician recommended that they do so**

Study Treatment(Randomly assigned)

Enrollment, Randomization, and Follow up

828 patients from july 2000 – Nov 2008 randomly assigned

244 in New Zealand, 584 in Australia

404 – Early start / 424 – Late start

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.

The two groups did not differ significantly with respect to pharmacologic interventions during the trial period.

Enrollment, Randomization, and Follow up

(Fig. 1)

total of 59 patients who had been randomly assigned to a group had not commenced dialysis by the end of the trial (21 in the early-start group and 38 in the late-start group).

The main reasons were: 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) Death (10 patients in the early-start group and 22 in the late-start

group).

No patient died of uremia.

Patient Characteristics

The Two groups were well matched with respect to all baseline characteristics.

(Table 1)

Initiation of dialysis

The median time for initiation of dialysis was 1.80 months (95% CI, 1.60 to 2.23) in the early-start group, as compared with 7.40 months (95% CI, 6.23 to 8.27) in the late-start group (hazard ratio for commencement of dialysis in the early-start group, 2.09; 95% CI, 1.81 to 2.41; P<0.001) (Fig. 2A)

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

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

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

PD was the initial method of dialysis in the case of 195 patients in the early-start group and 171 patients in the late-start group.

Primary Outcome

total of 307 patients died during the follow-up period — 152 in the early-start group and 155 in the late-start group

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

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)

Early initiation of dialysis did not significantly affect the rate of death from any cause in any of the prespecified subgroups (Fig. 3)

Secondary Outcomes

None of the 2ry outcomes (cardiovascular and infectious events and treatment associated complications, including the use of temporary dialysis catheters) were influenced by the timing of dialysis (Table 2)

No significant difference was observed between the two groups in quality of life, as measured by the Assessment of Quality of Life instrument during the follow-up period of the trial

In Practice

Affected largely by KDOQI guidelines which favors early dialysis-

According to the U.S. Renal Data System, the proportion of patients in whom dialysis was initiated when GFR >10.0 ml/m increased from 19% in 1996 to 45% in 2005!

Conclusions

early initiation of dialysis had no significant effect on the rate of death from any cause or on cardiovascular events, infectious events, or complications of dialysis

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

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

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

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

Initiating dialysis at the right time for a given patient with the most appropriate technique represents a sophisticated exercise of clinical nephrology, which remains, and will remain a balanced mixture of Science and Art

Weakness?

GFR estimate?

Race distribution?

Only small percentage of the screened patients went into Randomization.. Why?

Majority of patients in late group started with GFR>7, and some of the early group started with GFR<10? Overlapping Bias

What’s the physician criteria for starting HD in the late group?

What about those subgroup in the late start that they started HD <7, it would be more informative if we look at them in regard to morbidity and mortality.. They were not mentioned here!!

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)