Renal Division, Department of Medicine, University Hospital, 185, De Pintelaan, 9000 Ghent, Belgium
Keywords: initiation of RRT; Kt/Vurea; NECOSAD
Although more than four decades have passed since the introduction of maintenance haemodialysis in 1960 [1], there are no uniform objective criteria regarding the level of renal function at which renal replacement therapy (RRT) should be initiated. Nephrologists initiate RRT in most cases on the basis of the observation of uraemic symptoms and changes of laboratory parameters, such as plasma creatinine concentration and/or creatinine clearance [2]. However, the occurrence of uraemic symptoms varies from patient to patient [3], so there is substantial variation in the timing of initiation of RRT [46]. For example, the study by Obrador et al. [6] revealed that a substantial fraction of patients (23%) in the USA started dialysis at levels of predicted glomerular filtration rate (GFR) below 5 ml/min.
At what level of GFR is RRT to be started? Recent recommendations
In an attempt to improve the quality and outcome of dialysis care, the US National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) was established. The primary objective of DOQI was to improve patient outcomes and survival by providing recommendations for optimal clinical practices. In 1997, this resulted in the publication of a number of clinical practice guidelines [7]. According to these guidelines, RRT should be started when renal Kt/Vurea falls below 2.0/week. This value equals a creatinine clearance of about 14 ml/min. A lower Kt/Vurea would be acceptable only if the protein equivalent of total nitrogen appearance, normalized to body weight (nPNA), remains above 0.8 g/kg/day, and if uraemic symptoms are absent.
In 1999, the Canadian guidelines were published [8]. According to these recommendations, RRT should be initiated when the GFR is less than 12 ml/min, if there are clinical signs and symptoms of uraemia, if there is clinical evidence of malnutrition based on the subjective global assessment (SGA), or if the nPNA is greater than 0.8 g/kg/day. If there are no uraemic symptoms or evidence of malnutrition, the patient should be followed monthly. When the GFR is less than 6 ml/min, initiation of RRT is recommended in all patients. It should be emphasized that both the DOQI and the Canadian guidelines are opinion and not evidence-based.
Several studies from the USA [6] and Europe [5,9] reported lower renal Kt/Vurea or creatinine clearance values at the start of RRT in many patients. In the European survey of Van Biesen et al. [9], only 13% of the patients started at values of residual renal function as recommended by DOQI.
The recent DOPPS registry compared renal function at the time of initiation of haemodialysis in Europe and the USA between 1998 and 1999. It shows that the mean estimated GFR among incident patients in 1998 were 8.4 ml/min in Europe and 11.1 ml/min in the USA; in 1999 the values were 8.6 and 10.8 ml/min, respectively [10]. It seems thus, that compared with the past both in Europe and the USA, there is a tendency to start dialysis at higher GFR.
The results of the NECOSAD Registry
Two recently published prospective cohort studies, based on the NECOSAD registry in The Netherlands have addressed these issues again [11,12]. In the first study [11], the relationship of different levels of residual renal function with parameters of nutritional status and of renal Kt/Vurea and nPNA was investigated in 114 incident Dutch patients with chronic renal failure who all had received pre-end-stage renal disease care. Only 10% of the patients fulfilled the DOQI criterion of Kt/Vurea greater than 2.0/week, but 69% of the patients met the nPNA norm of 0.8 g/kg/day. Seventy-one per cent of these patients had a normal nutritional status as scored by SGA and also other parameters of nutritional status, such as body mass index, and serum albumin fell within the normal range in the majority of the patients. In the second study [12], 94 (37%) of 253 patients started dialysis treatment later than recommended by the USA guideline. There was an increased mortality risk for these patients compared with those who started dialysis on time, although the difference was not significant [adjusted hazard ratio 1.66 (95% CI 0.952.89)]. The adjusted difference in estimated survival time after 3 years on dialysis treatment was only 2.5 months (1.14.0) in favour of the timely starters. Conversely, the average delay in dialysis initiation in the late starters was 4.1 months. Seemingly, this effect by and large compensated for the gain in survival due to a timely start, resulting in a similar time free of dialysis. Although it was found that a higher residual renal function at the start of dialysis was associated with better survival, the authors concluded that an earlier start of chronic dialysis than currently applied in The Netherlands, and probably in other developed countries, is not warranted.
The problem of the optimal moment to start RRT is an important one and has many medical, ethical and socio-financial implications.
What are the caveats?
To obtain strictly scientific, evidence-based information regarding the impact of optimal time of initiation of RRT on the outcome of dialysis patients would require a prospective, long-term and perfectly randomized study of a large cohort of patients. It is doubtful that such a trial will ever be done. Patients would be eligible for entry only when their level of renal function was within a certain range, assuming the level of renal function could be estimated accurately and conveniently. At that time, the patients would have to be randomized into the study, and early intervention would have to begin before renal function fell below the threshold level for intervention in the control group. A large number of drop-outs from the early intervention group to the control group could be expected, which would minimize the difference in outcomes between the randomized groups.
The problem of lead-time bias
Accordingly, we will have to continue with analysing retrospective data. One of the main drawbacks in such an analysis is the lead-time bias. Lead-time is defined by Webster's dictionary as the amount of time required to produce a project. Lead-time is thus the interval between the start of a study and a defined event. In the context of initiation of dialysis, lead-time bias refers to the effect whereby measuring survival from the start of dialysis increases the apparent survival of those started with higher residual renal function; those patients who started earlier in the course of their disease than those who start later are automatically at an advantage.
It is not easy to correct for lead-time bias in a retrospective study. For example, in the study by Korevaar et al. [12] the authors claim that they have corrected for lead-time. However, in order to calculate the progression of the residual renal function in the NECOSAD patients the authors do not use the data of renal function of the actual patients in their study, but use literature data on the progression rate of a historical control group from other countries and populations. It has to be admitted that this is a rather weak standard to support the vision of the authors regarding the correction for lead-time bias. It would have been more accurate to include clearance data or evolution of the reciprocal of creatinine of the study group rather than using data from the literature.
Another important bias is that the NECOSAD Registry includes only patients who had actually started dialysis. It is obvious that patients who had already died before they were able to start (late) dialysis were not included: this is a substantial bias in favour of late start, as only the patients fit enough to survive the late start of dialysis were included.
In this context, it is remarkable to note, based on the latest figures of the USRDS 2001 database, that The Netherlands with a take-on rate on dialysis of approximately 9095 incident patients per million population score much lower than their neighbouring countries Belgium and Germany which both show an incidence of dialysis patients above 150 per million population [13]. It can thus not be excluded that some selection bias is present in the NECOSAD Registry. The possibility should be considered that this rather low take-on rate results in another selection bias, i.e. the exclusion of patients with the worst clinical condition. This has two practical consequences: (i) the possibility of finding a difference might have been reduced, if mostly patients in relatively good clinical condition were submitted for analysis; (ii) the conlusions might not be representative of experience in other countries with different, more liberal take-on rates.
In addition, the authors also correct survival for comorbidity. For the late starters, the comorbidity is registered at the moment of start of dialysis. To further minimize the effect of lead-time bias one should have registered the comorbidity at the moment that late starters were eligible for the DOQI criteria, i.e. at the same residual renal function as the timely starters. Now, the late starters who survive their dialysis-free period, end up with more comorbidity, which is then corrected for. Thus, cause and consequence are mixed up by this approach, once again diluting the potential positive effects of timely start.
Statistical problems with the NECOSAD study
Also, the interpretation of the results is subject to criticism. Despite the fact that there was no statistically significant difference in survival between the timely starters and the late starters, a survival benefit in favour of timely starters was calculated: a 2 year survival of 75% (CI 6485) in late and 84% (CI 7790) in timely starters, and a hazard ratio for late starters of 1.66 (CI 0.952.89). An alternative and, in our opinion, more accurate interpretation of these results is simply that there is insufficient data (probably due to the small patient number) to prove that there is a difference. It is probable that with a greater patient sample there would have been a statistically significant difference in survival. The authors also claim that the survival advantage is only 2.5 months over a 3 year period. We wonder how the 3 year period was calculated as inclusion of the patients started in January 1997 and the study ended in August 2000: the maximum follow-up period was thus 32 months. For most patients, it will have been far lower than this period however, as (cited from the methods) the number of centers increased steadily during this period, meaning that most centres (and thus patients) were only included when the study was already ongoing. The survival advantage of 2.5 months has thus not to be valued against 3 years, but probably only to a far shorter period of follow-up.
We point to minor flaws, such that even in the late starters, the mean nPNA at start was 0.7 g/kg/day, which is only slightly below the value of 0.8 recommended by DOQI, so that the separation of the timely vs late starters might be suboptimal. In the same context, it is not clear on which criteria the patients were actually started: it seems to us that all patients were started when they had symptoms, and only retrospectively was there a small difference in Kt/V. If this is true, then none of the patient's starts was timely as all of them were started when they had symptoms.
Furthermore, the quality of the delivered dialysis (in terms of adequacy etc.) was unclear in the dialysed patients.
The topic of costs of timely start has not been addressed in the NECOSAD papers. It might well turn out that global cost, including hospitalisation and medication was lower in the timely starters than in the late starters. There is also no analysis of patient satisfaction, or quality of life. It is thus not correct in our opinion to conclude that timely start would have negative effects on patients and dialysis resources, as this aspect was not addressed in this study. Even if it were true that timely start increases cost of treatment (which remains unproven), we strongly advocate that a difference should be made between a medical and a political approach in cost estimation. If studies show a survival benefit of timely start, the price the community accepts to pay for such an improvement is to be judged by the politicians, and to a lesser extent by the medical community.
Are the results definitive?
In conclusion, despite our great admiration for the energy and discipline our Dutch colleagues show in realizing the interesting NECOSAD Registry, we believe that it is too early to make an in-depth conclusion, based on the present data. Although we agree that initiation of dialysis should not only be based on numbers derived from laboratory reports, the conclusion that the guidelines as formulated by DOQI are not useful in The Netherlands (and possibly other countries) is too premature. A much larger study, where at least the evolution of the renal function of patients long before start of dialysis is taken into account, is needed to clarify this important issue.
Notes
Correspondence and offprint requests to: Norbert Lameire, MD, Renal Division, University Hospital, 185, De Pintelaan, B-9000 Ghent, Belgium. Email: norbert.lameire{at}rug.ac.be
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