Early dialysis initiation and renal function trajectory

In the USA between 1996 and 2008, early dialysis initiation (at an estimated glomerular filtration rate (eGFR) of >10 mL min−1 per 1.73 m2) increased from 20 to 52%, and patients starting dialysis at an eGFR >15 mL min−1 per 1.73 m2 increased by 1% per year from 4 to 18% (Fig. 1) [1]. The 2006 US National Kidney Foundation and the 2002 European guidelines for dialysis initiation both support dialysis at an eGFR of 15 mL min−1 per 1.73 m2 in the presence of symptoms associated with renal failure or patients’ comorbidities [2, 3]. The per cent of the new dialysis starts in the USA with four-variable Modification of Diet in Renal Disease calculated estimated glomerular filtration rate ≥15 mL min−1 per 1.73 m2 at the time of dialysis initiation. The randomized controlled trial of early versus late dialysis initiation, the IDEAL study, used the Cockcroft–Gault GFR equation, which is approximately 3 mL min−1 higher than the Modification of Diet in Renal Disease (MDRD) equation used for chronic kidney disease classification, and used in the study by Evans [4]. The results from IDEAL demonstrated that waiting until eGFR reached 7.2 mL min−1 per 1.73 m2 (mean starting eGFR in the late-start group) did not negatively affect survival [5]. To date, observational studies including over 1.2 million patients have failed to find a benefit of early versus late dialysis initiation [5–13]. In the two most recently published studies, one from Taiwan with 23 351 patients and one from the USA with 896 546 patients, late initiation was defined as eGFR <3.27 and 5 mL min−1 per 1.73 m2, respectively [12, 13]. The study by Evans adds another report that makes it clear of the need to end the trend in the USA and the rest of the economically advantaged world towards early dialysis initiation. The Swedish population-based cohort study published in the present issue of Journal of Internal Medicine provided the opportunity to examine the relationship between level of residual renal function and death with or without dialysis treatment. The results of the Swedish study showed that for nondialysed patients, an eGFR of <7.5 mL min−1 per 1.73 m2 provides a significantly higher mortality risk than an eGFR of 7.5–10 mL min−1 per 1.73 m2 (hazard ratio 4.65). An advantage of the study was the complete follow-up of the population within the Swedish medical system with presumably accurate information concerning deaths. It is interesting that of the 901 patients who qualified for inclusion, approximately 10% died before any renal replacement therapy (RRT) was initiated and 5% did not start dialysis. Cardiovascular disease was the most common cause of death in those who died before or after dialysis initiation. Renal disease was listed as the cause of death in only 8% of the patients who died before RRT and in 10% of those receiving dialysis. Thus, the higher risk of death in patients who did not start dialysis at eGFR <7.5 mL min−1 per 1.73 m2, compared with patients who did not start dialysis but had an eGFR of 7.5–10 mL min−1 per 1.73 m2, is probably not because of uraemia if the listed causes of death are accurate. European guidelines recommend the preparation of a patient for dialysis at a GFR of 8 mL min−1 per 1.73 m2 (average of urea and creatinine clearance) to be sure they start dialysis at a GFR of 6 mL min−1 per 1.73 m2. The poorer survival in the Swedish study of the dialysed versus the nondialysed subjects who reached an eGFR of <7.5 mL min−1 per 1.73 m2 can be used as an argument against this recommendation. Further research is required to address this important issue of whether there is a level of eGFR at which dialysis initiation is mandatory for patient survival. The large observational studies that examined the relationship between initial level of renal function and survival did not exclude patients with acute renal failure, or acute chronic renal failure. In these populations, if the acute renal failure does not improve, the patient may become dialysis dependent [6–13]. These patients have an acute event that rapidly eliminates their residual kidney function. If these patients are excluded, the rate of decline in eGFR per year using the four-variable MDRD equation (mL per minute (1.73 m2 year)−1, defined as the ‘renal function trajectory’ (in mL min−1 per 1.73 m2), becomes a critical factor in the determination of when to initiate preparations for dialysis. The Swedish cohort, with a mean initial eGFR of 16 mL min−1 per 1.73 m2, had a renal function trajectory of 5.5 in the late-start group and 4.2 in the early-start group over a period of approximately 1.5 years of follow-up. In a primarily male US veteran cohort with a mean initial eGFR of 17.7 mL min−1 per year, O’Hare et al. found that older age was associated with a lower renal function trajectory: approximately 3.4 at 65–74 years, 1.9 at 75–84 years and 1.3 above 85 years [14]. In the USA, patients over 75 years old are the fastest growing segment of the incident dialysis population [1]. The Swedish study excludes patients aged 75 and older, which partly explains the higher trajectory than reported by O’Hare ands colleagues. Levin et al. reported the renal function trajectory in a Canadian population of patients with eGFR <30 mL min−1 per 1.73 m2 referred for nephrology consultation. The cohort with a renal function trajectory of more than five were termed ‘rapid progressors’. A total of 76% of these rapid progressors went on to dialysis, versus only 27% of those patients with a trajectory below five [15]. The mean rate of change of eGFR was 2.65 mL per minute (1.73 m2 year)−1 [15], which again is lower than that reported in the Swedish cohort [4]. Several factors may explain the faster renal function trajectory in the Swedish study compared with the US and Canadian studies. One is the fact that the mean age in the Swedish study was about 57 years compared to 70 in the US study and 67 in the Canadian study. In addition, the Swedish population had a high incidence of heavy proteinuria with 72% of the patients having >1 g protein in a 24-h urine, compared with approximately 30% in the Canadian study. Proteinuria is the most powerful predictor of renal function trajectory [16]. Evans used a linear trend model of creatinine trajectory. This may not be applicable to some patients with stage 4 or 5 chronic kidney disease, whose pattern may be one of periods of decline and periods of stable renal function. Some patients may have an increase in their eGFR. The Swedish study excluded patients whose eGFR improved from <20 to more than 20 mL min−1 per 1.73 m2. The results from the late-start population in the Swedish study mirror those from other observational studies [6–10]. Compared with early starters, these late starters were younger and had fewer comorbidities including a lower percentage of diabetes (43.3 vs. 23.6%). The faster renal function trajectory in the late-start group accounted for the fact that the time to dialysis initiation was the same in the two groups. With regard to the decision to initiate dialysis, it seems reasonable to suggest earlier dialysis preparation and initiation in patients with a more rapid rate of renal function decline (See Renal function trajectory). Evans considered loss of residual renal function as a possible explanation for the increase in mortality before dialysis initiation in the 7.5 mL min−1 per 1.73 m2 vs. the 7.5–15 mL min−1 per 1.73 m2 group as well as in the early-start group, after dialysis initiation. Loss of residual eGFR, once dialysis is started, needs to be a key consideration in the decision to initiate dialysis. In a prospective Dutch study on haemodialysis and peritoneal dialysis patients, it was found that over 50% of a patient’s residual renal function may be lost after 6 months of dialysis [17]. Randomized controlled trials in haemodialysis and peritoneal dialysis patients failed to show a survival benefit of either peritoneal or haemodialysis clearance [2]. In contrast to this, even low levels of endogenous renal function are associated with improved survival, nutrition and quality of life [18]. None of these benefits has been shown to relate to dialytic clearance. In conclusion, early dialysis initiation at eGFR above 10 mL min−1 per 1.73 m2 may not be justified and may be harmful. The level of renal function at which dialysis initiation provides a survival benefit is not known. The decision to prepare a patient for dialysis needs to be made in the light of their renal function trajectory which may be temporarily influenced by reversible episodes of acute renal failure. More research is needed to explore the factors that affect renal function trajectory and to determine at what level of renal function the benefit of dialysis outweighs the risk and the adverse quality of life and cost issues relating to lifelong dialytic therapy. No conflict of interest was declared.

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