Is it really better to start dialysis as late as possible?

DT Advance Access published online on August 14, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp410

Is it really better to start dialysis as late as possible?
James Tattersall

Department of Renal Medicine, Leeds Teaching Hospitals, Leeds, West Yorkshire, UK

Correspondence and offprint requests to: James Tattersall; E-mail: Jamestattersall@nhs.net

Keywords: comorbidity; creatinine; eGFR; mortality; start dialysis

In the publication by Stel et al. in this journal, data from European registries are presented which show that the lower the eGFR at the start of dialysis, the better the outcome (in terms of longer survival) [1]. This could be taken as evidence that it may be better to delay the start of dialysis as long as possible, rather than starting at a specific level of eGFR. In recent years, there has been a tendency to start dialysis at higher eGFR [2], could this tendency be counter-productive?

Stel's paper describes a significant correlation between eGFR at the start of dialysis and subsequent mortality rate. Patients starting dialysis with eGFR <8 ml/min/1.73 m2 had a yearly mortality rate of 17.9% compared to 25.9% when starting with eGFR >10.5 ml/min/1.73 m2. These results were obtained from a registry observational study on over 11 000 European dialysis patients. There is no doubt that this correlation is genuine. It has also been described in registries in the United States [3–5] Canada and Scotland [6]. Furthermore, the data fail to suggest any lower limit for eGFR, below which mortality starts to rise. In Stel's paper, the patients with the lowest category of eGFR, <6 ml/min/1.73 m2, also had the lowest annual mortality rate of 16%.

These observational findings are potentially subject to confounding effects. In Stel's study, patients starting dialysis at higher eGFR tended to be older and have higher comorbidity. Current clinical practice, as recommended by guidelines, is to start dialysis in patients with higher comorbidity at an earlier stage in their CKD progression. Furthermore, patients who are symptomatic are likely to be started on dialysis immediately rather than waiting for the eGFR level to fall to a specific level. It may be the higher comorbidity that accounts for the mortality, not the higher eGFR. In Stel's study, adjustment of mortality rates for documented comorbidity reduced the relationship between eGFR and mortality but did not eliminate it.

It is already accepted that dialysis patients with low serum creatinine have a significantly increased mortality rate [7]. Serum creatinine is generated from muscle and dietary protein intake. Low serum creatinine implies low muscle mass, inactivity and malnutrition. The serum creatinine level is dependent on the generation rate just as much as the clearance rate. For this reason, serum creatinine alone is not used to estimate adequacy of dialysis. On the other hand, we accept the use of eGFR, which is calculated directly from serum creatinine, as a marker of the adequacy of renal function in the period before dialysis starts. It may be that high eGFR is a marker for a low creatinine generation rate rather than adequate renal function. Only relatively fit patients who can maintain muscle mass may be capable of generating enough creatinine to cause a high serum creatinine and low eGFR. One study, in which creatinine clearance was measured (using urine collections) as well as predicted from serum creatinine, found that only the predicted clearance was associated with mortality [5].

So, at what level of eGFR should we be starting dialysis? Clearly, there has to be a lower limit of GFR, below which survival is not possible. In haemodialysis, this lower limit of clearance has been established as a URR of ~33% thrice weekly [8], this is roughly equivalent [9] to a renal urea clearance of 4–6 ml/min or GFR around ~6 ml/min. ‘Adequate’ levels of haemodialysis have been established at around twice this level. Since urea is more easily cleared by dialysis compared to higher molecular weight toxins and the kidney is better at clearing these higher molecular weight toxins than dialysis, urea or creatinine-based clearance measures relatively underestimate the effect of kidney function compared to dialysis. A GFR of 12 ml/min delivered by the kidney certainly delivers more benefit to the patient and with fewer adverse effects compared to an adequate dialysis with equivalent renal urea clearance of 12 ml/min. There is some evidence that selected patients with low comorbidity can be maintained safely with ‘conservative’ care at GFR down to 6 ml/min [10,11]. Such ‘conservative’ care requires strict attention to the complications of uraemia (e.g. abnormalities of nutrition, acid–base, fluid, bone and mineral metabolism).

Previous study has shown that late referral with urgent unprepared dialysis start is a predictor of high mortality rate [12–14]. Much of the comorbidity of dialysis patients is acquired before dialysis starts and is potentially preventable through medical care delivered in a pre-dialysis clinic. Patients starting dialysis with a central venous catheter as access are at risk of infection and have higher mortality rate compared to those who start dialysis with a fistula [15].

Earlier studies investigating the ideal time to start dialysis [16,17] tended to include a disproportionately high number of patients referred late and started urgently in the ‘late’ start groups. Patients with ‘early’ start were more likely to have benefited from pre-dialysis care and to have a fistula. These studies may also have been affected by the ‘lead-time bias’ where the increased period of life before dialysis starts in the patients started ‘late’ is not taken into account [18]. These confounding effects may account for the apparent benefit of starting dialysis early.

At present, we can be certain that adequate preparation and preventative medical care in the period before dialysis starts reduce mortality of dialysis. This means that patients should be referred early enough. Once the patient is receiving adequate nephrology care and is prepared for dialysis, the criteria for deciding when to start dialysis is not so certain. It is possible that eGFR, while an excellent tool to identify and stage CKD, may not be of much help in deciding when to start dialysis. Future RCTs may help us to determine the optimal time to start dialysis, particularly if clearance is measured, rather than predicted from serum creatinine.

Conflict of interest statement. None declared.

References
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Received for publication: 15. 7.09
Accepted in revised form: 17. 7.09

http://ndt.oxfordjournals.org/cgi/content/full/gfp410