1 Gambro Research, Lund, Sweden, 2 Centre Hospitalier Universitaire, Hôpitaux de Brabois, Nancy, France, 3 University Hospital, Gent, Belgium, 4 University Hospital, Würzburg, Germany, 5 Silesian University Medical School, Katowice, Poland, 6 McGill University Health Centre, Royal Victoria Hospital, Montreal, Canada, 7 Institut de Génétique Humaine (IGH-CNRS) and University Hospital, Montpellier, France, and 8 University of Heidelberg, Heidelberg, Germany
Keywords: early start; initiation of dialysis; late referral; predialysis management
Introduction
Traditionally, dialysis therapy has been initiated only when considered absolutely necessary; when the remaining renal function is so low that the uraemic syndrome is becoming insupportable or even life-threatening. Such clinical practice can be justified from a medical, a psychological and a socio-economic point of view. It has been believed that the longer the burden of dialysis is postponed, the better for the patient and for society. However, evidence now suggests that malnutrition in renal disease patients develops along with the progression of renal failure, since patients adapt to the lower renal function by reducing their protein intake [1]. Other studies show strong correlation between nutritional status at the start of dialysis and outcome on dialysis [2]. Thus, it has been suggested that starting dialysis at a higher renal clearance than is normally practised, before uraemia and malnutrition have taken their toll, would have a beneficial impact on well being and survival of dialysis patients [3]. An earlier start of dialysis would require significant extension of the resources for dialysis treatment. For additional funds to be allocated to dialysis there is a demand for strong medical evidence of global cost effectiveness in terms of reduced morbidity and mortality. However, no such information is yet available to support the concept of an earlier start of dialysis. On the contrary, the argument of tradition carries considerable weight.
Thus, initiation of dialysis is a hotly debated issue these days and it was the theme of the Dialysis Opinion survey in 1999. Dialysis professionals participating in the ERAEDTA Congress in Madrid and the ASN Meeting in Miami Beach were approached with a questionnaire and a total of 4262 persons responded. Of these 91% were doctors and the geographical mix is shown in Table 1. The results were presented and discussed the following year at the ERAEDTA Congress in Nice by a group of invited experts under the chairmanship of Eberhard Ritz.
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What determines the time for initiation of dialysis?
Question: What do your consider to be the first and most important criterion for judging when to initiate dialysis?
Answer: Uraemic signs and symptoms are considered the first and most important indication for initiating dialysis (38%), but the residual renal clearance is also widely used around the world (32%) (Figure 1a). Nutritional status is regarded to be of considerably less importance, although over 20% of the respondents from North as well as South America placed it first.
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The DOQI guidelines recommend to initiate dialysis when GRF falls below 10.5 ml/min/1.73 m2 [6], while the Canadinan guidelines recommend starting at GFR=12 when there are signs and symptoms and definitely starting at GFR=6 ml/min/1.73m2 [7]. When basing decisions for starting dialysis on measurements of residual renal function it is important to use appropriate techniques. First, GFR should never be estimated from measurements of blood urea or creatinine alone. Secondly, it should be estimated using a method that has been evaluated in patients with the appropriate degree of renal failure. The Cockroft and Gault equation, for example, may only be used when the GRF is greater than 30 ml/min. In advanced renal failure, there are several methods, but the simplest and best seems to be to measure the urea and creatinine clearances using 24-h urine collection, and calculate the GFR as the mean of these values.
Nutritional indices begin to decline when GRF falls below 50 ml/min and a number of studies have documented the increased risk of death of haemodialysis patients suffering from malnutrition. The importance of malnutrition at dialysis initiation has also been underscored. A progressive loss of dry body weight, a spontaneous protein intake<0.8 g/kg/day, and a serum albumin below 40 g/l are important determinants, when deciding to initiate dialysis in chronic renal failure patients, as will be emphasized by the new European guidelines.
There is no single gold standard criterion for deciding when to initiate dialysis. The limited available evidence implemented in the official guidelines suggests that a combination of criteria defining adequate endogenous solute clearance and optimal nutritional status should be used. It should not be acceptable to wait for symptoms, and I am somewhat discouraged that the majority of the respondents in the survey have selected this alternative. We should remember that Dialysis should be initiated to promote wellness and not to rescue from illness.
What is the reason for delayed start of dialysis?
Question: In retrospect, many patients are started on dialysis too late. What is the main reason for delayed start of dialysis?
Answer: The majority of dialysis professionals in all parts of the world feel that late referral of patients to a nephrologist is the main reason for late initiation of dialysis (52%) (Figure 1b). This is more strongly expressed in Europe and America than in Africa and Asia, where patient refusal (23 and 30%) and lack of capacity (20 and 19%) are considered to have more impact than in the rest of the world.
Comments by W. van Biesen
Analysis of a recent European survey shows that only a minority of end-stage renal disease (ESRD) patients are started on renal replacement therapy (RRT) according to the DOQI guidelines [8]. The most obvious reason is the late referral of these patients to the nephrologist. This observation, however, should not distract us from the responsibility of the nephrological community with regard to the problem of starting in time. First, also the patients referred early are often started with residual clearances far below those advised by the DOQI guidelines. This might be due to the insidious evolution of chronic renal failure in some patients, which makes the nephrologist reluctant to alarm the patient by talking about the possibility of RRT. When symptoms appear, the patient is not prepared for RRT and precious time is lost.
Another reason is that the pre-ESRD treatment of patients has only recently received attention [3]. Nephrologists should have strategies for approaching patients with pre-ESRD with clear guidelines on how patients should be prepared and educated for RRT. They should have guidelines and checkpoints, both clinical and biochemical, to fortify their advice to start or postpone the start of RRT. The fact that until now there exists only few, if any, studies that evaluate criteria for starting RRT, is highly symptomatic in this regard.
Besides this direct responsibility there is also an indirect responsibility of the nephrologist, which may be of even greater importance. To understand this, insight in the underlying mechanisms of patient flow is needed. Patients can end up on RRT as a consequence of (i) a slowly progressing chronic renal failure; (ii) an acute deterioration of a pre-existing moderate renal failure; (iii) a non-recovering acute renal failure. In the first case, the nephrologist should educate general physicians on who, when, and how to screen for renal disease, and on how to identify and treat the patients at risk. However, the most important responsibility of the nephrologist is connected with the patient with moderately impaired renal function. Further rapid deterioration of renal function is frequently due to iatrogenic diagnostic or therapeutic procedures. We have observed that the highest percentage of late referral patients comes from general internists and cardiologists, which indicates that screening of renal function in patients at risk before planning certain investigations or starting medications can have a preventive value [9]. In this context, the nephrologist should develop guidelines for prevention of deterioration of renal function in patients at risk.
Adequate and clear guidelines for general practitioners and non-nephrology specialists on when and how to refer patients to a nephrologist should be established and disseminated. Information about the importance of close nephrological follow-up and development of educational programmes for chronic renal failure patients are urgently needed.
Advantage of an early start on dialysis
Question: If the majority of patients were started on dialysis 612 months earlier than what is currently practised, what could be the main advantage?
Answer: The majority of the respondents said that improved quality of life for the patients (39%) and better nutritional status (32%) would be the major advantage, if dialysis were started 612 months earlier than what is practised today (Figure 1c). The quality of life aspect is especially emphasized by the respondents from Central and Eastern Europe, Africa and Asia, while both effects are similarly rated in the rest of Europe and America. It is noteworthy that almost 90% of the respondents find that an earlier start of dialysis would give some major advantage.
Comments by C. Wanner
In the range of GFR 1020 ml/min/1.73 m2 the patient suffers from malnutrition as part of the MIA syndrome (malnutrition/inflammation/atherosclerosis) [10], acidosis leading to muscle wasting and fluid overload causing uncontrolled hypertension. The symptoms are often severe and may be aggravated in the presence of type 2 diabetes mellitus. All-cause mortality shows a sharp increase when GFR drops below 9 ml/ min/1.73 m2. This is based on available observations and uncontrolled studies and shows that a beneficial effect of an early start could be expected, at least as regards the consequences of these three complications.
The best evidence exists with respect to the nutritional status, which has been shown to deteriorate as early as renal function declines [1]. As nutritional status at dialysis start is a prognostic risk factor for mortality, ideally dialysis should be started before such deterioration becomes severe [2].
The leading cause of mortality in dialysis patients is cardiovascular (CV) disease, which is often established long before the start of dialysis. If dialysis or intense, specialized care of CV risk factors could prevent or delay the complications of CV disease, leading to improved quality of life as well as reduced mortality, this would most certainly be seen as an advantage. It should be noted that many of the underlying causes, e.g. anaemia, complex dyslipidaemia, non-traditional risk factors, and the complications from CV diseases in the RRT population may be more intensely treated by nephrologists. However, this does not necessitate being on dialysis.
My conclusion is that the main benefit of an earlier start of dialysis would be for the nutritional status, but important gains would also be made in the other dimensions discussed. I was especially pleased to see that such a large majority of my colleagues seem convinced that there is some advantage to be gained by initiating dialysis earlier than what is commonly practised today; thus supporting the concept of timely initiation.
Disadvantage of an early start on dialysis
Question: If the majority of patients were started on dialysis 612 months earlier than what is currently practised, what could be the main disadvantage?
Answer: Increased cost of dialysis, resulting from an earlier start, is seen as the major disadvantage by 40% of the respondents, while 21% do not see any major disadvantage (Figure 1d). The greatest concern about the cost was expressed by the respondents from Asia (54%) and from the northern and western parts of Europe, including Germany (48%).
Comment by A. Wiecek
When discussing possible disadvantages of an early start, let me emphasize that this does not necessarily mean that the opposite is true, i.e. that there would be advantages of a late start. At the same time as we should avoid starting dialysis too late, we should also avoid starting it too early.
The obvious consequence of an earlier initiation of RRT in a large group of patients is that the cost would increase, since the cost for maintenance dialysis is about five times that of conservative treatment, which is the alternative. However, this would mainly be a socio-economic problem, and as long as it would not lead to rationing of treatment it would have little impact on the patients. It is also a transient problem with the greatest increase of cost occurring when the new protocol for starting patients is initiated.
Of more consequence to the patients is the fact that they would meet the psychological burden of dialysis at an earlier stage. They would also lose the remaining renal function at a faster rate, especially if treated by haemodialysis. The risk for dialysis-related complications, such as CV instabilities especially in the elderly patients, anaphylactic reactions, large blood loss, viral infection, ß2-microglobulin-related amyloidosis and others, increases with the time of exposure, but is on the whole rather limited in a modern dialysis setting [7,11].
In conclusion, I agree with the majority of the respondents that the major disadvantage is clearly of economic nature.
Patient selection for an early start of dialysis
Question: Which patients, among the listed groups, would you mainly select for an earlier start of dialysis?
Answer: When identifying patients who would benefit from an earlier start of dialysis, diabetic patients are selected by an overwhelming majority (90%) (Figure 2a). This is strongly expressed in all areas of the world. The next target group for an early start is malnourished patients (72%), although with a wider geographical distribution of the replies (Figure 2b
). There is also a greater uncertainty, in some cases up to 40%, regarding this patient category. When it comes to the other two potential target groups for an early start, elderly patients and PD candidates, the results are similar. In both cases 38% advocate an earlier start, while the rest of the respondents do not recommend this or have no opinion on the issue (Figure 2c
,d
). The most positive attitude to starting dialysis early in these two patient groups is shown by the German respondents (50%), while the greatest scepticism is seen among the respondents from Italy, Southeast and Eastern Europe, and Africa, where only 30% say yes and over 50% have no opinion.
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The evidence to support these guidelines is not based on firm data. There are studies showing better outcome with earlier starts, worse outcome with later starts, and above all poor outcome with later referrals. But these are all non-controlled studies and the concept of early referral is mixed with early start of dialysis. No trial has compared the outcome of early referral and comprehensive pre-ESRD care with early-start dialysis.
I conclude that there is no firm evidence to support the current, published guidelines for when to initiate dialysis. They are all based on opinion. I will therefore rephrase the question I have been asked to discuss as Do you support the Canadian guidelines for initiating dialysis in each of these patient groups? In each patient group, one can argue both for and against those guidelines.
Diabetics: Current practice is to start diabetics on dialysis earlier than other patients. This has been based on suggestions that it may help avoid the rapid progression of neuropathy. In addition, these patients are often malnourished. Arguing against an earlier start is the difficulty in establishing good vascular access and an overall poorer prognosis, which may not be improved by early dialysis. On balance, I would support earlier starts for the diabetics.
Elderly: Our elderly patients are often malnourished and have heart disease, especially congestive heart failure, which may be improved by dialysis. Furthermore, the intensity of medical attention given by virtue of starting RRT lends support to the patient. Arguing against early dialysis for the elderly is that they are less able to tolerate the complications of dialysis and they are less active and therefore less in need of optimal health status to function with a good quality of life. Finally, the life expectancy of the elderly (>70 years) on RRT is poor and the marginal advantage for survival with earlier start may not be offset by the increased morbidity and costs. Still, I would support the Canadian guidelines for these patients.
Malnourished: These patients do poorly without intervention and nutritional support can be facilitated by the initiation of dialysis. A more liberal dietary prescription and intra-dialytic nutritional supplementation, either IDPN or intra-peritoneal amino acids, are made possible after RRT is started. However, there is no evidence that dialysis actually salvages the malnourished patient. Many patients classified as malnourished may have an inflammatory syndrome, which would not be improved and could even be worsened by dialysis. Nevertheless, on balance I would support the guidelines for these patients.
Peritoneal dialysis candidates: PD is a self-care, home based and generally less expensive form of RRT than haemodialysis. Furthermore, it appears to allow better preservation of residual renal function and incremental dialysis could be easily applied with PD [11]. However, complications such as peritonitis can and do occur on PD [11]. Thus, I believe that dialysis should be started when appropriate for all patients, and not preferentially for PD candidates. This time of initiation is earlier than usual practice for most patients and the modality best suited to that patient should be chosen. Incremental dialysis can be applied to both PD and HD.
Predialysis intervention
Question: Which intervention applied during the predialysis phase do you think would have the greatest impact on the outcome of dialysis?
Answer: Predialysis management is a combination of several interventions and selecting one that may have the greatest impact on outcome is difficult. Still, in most countries a majority identify tight blood pressure control as the key factor (30%) (Figure 3). The exception is Italy, where the other three proposed interventions are selected by 20% each, while blood pressure control is preferred by only 13%. Dietician-supported low-protein diet is favoured by 25% of the respondents in Central, Southeast and Eastern Europe and in Latin America.
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I would like to leave the other alternatives mentioned without discussion, as there is no evidence to support their impact in these patients, and instead mention two other factors that could play a major role on the outcome. The first is to be under the care of a nephrologist [15]. The importance of early referral to a nephrologist has been discussed already and to this I would like to add the observations by a French group who compared the outcome of patients seen by a nephrologist to those not seen by a nephrologist before starting dialysis [16]. The complications during the first 3 months were significantly reduced in the patients who had been cared for by nephrologists. However, there was no difference in the long-term outcome. This underlines the importance of nephrologists in the predialysis care and we must all make an effort to influence our colleagues to change their referral pattern of renal patients. Finally, I would like to include the existence of a functioning vascular access at the start of dialysis among those predialysis procedures that should be given priority. It has been shown that patients without access at the start of dialysis suffer more short-term complications [14].
So in conclusion, there is indirect evidence that tight blood pressure control has a positive impact on cardiovascular mortality. There is also some evidence that early referral to a nephrologist and creation of a dialysis access may improve at least the short-term outcome on dialysis. Still, we should not see these interventions isolated from each other; they are all part of an integrated approach to predialysis care [17].
General discussion
During the general discussion the issue was raised of starting a patient on dialysis in order to be able to include him in the waiting list for transplantation according to the rule of Eurotransplant. There is no similar rule in Canada and pros and cons were discussed.
A question from the audience brought up the difference in mortality rates between predialysis patients and patients on dialysis. Is it ethical to expose somebody to a considerably higher risk of dying by starting him on dialysis? Could an early start of dialysis do more harm than good? During the discussion several speakers from the expert group pointed out that the present mortality among dialysis patients, considering especially the first-year mortality, is a consequence of our current practice of predialysis care, including when to initiate dialysis, and may well reflect that the management is suboptimal [5]. Complications from the predialysis phase, which could have been delayed or even avoided by early referral to a nephrologist and possibly also by an earlier start of dialysis, are carried into the dialysis period, where they take their toll.
The final conclusion from this symposium concerned the importance of educating patients and colleagues about the extension and quality of care that can be offered by nephrologists to renal failure patients long before they need to initiate dialysis treatment.
Notes
Correspondence and offprint requests to: Ingrid Ledebo PhD, Gambro Research, Box 10101, S-220 10 Lund, Sweden.
References