Department of Nephrology, University Hospital of North Staffordshire, Stoke-on-Trent, UK
Correspondence and offprint requests to: Professor Simon J. Davies, Department of Nephrology, University Hospital of North Staffordshire, Princes Road, Hartshill, Stoke-on-Trent ST4 7LN, UK. Email: SimonDavies1{at}compuserve.com
Keywords: anuria; inflammation; LV hypertrophy; survival analysis
The value of residual renal function to patients treated with peritoneal dialysis (PD) is beyond dispute. CANUSA was the first study to demonstrate this, initially expressing the benefit in terms of small solute clearance in combination with peritoneal clearances, although on re-analysis this benefit could be reduced to the simplest of all measuresresidual urine volume [1,2]. Nevertheless, CANUSA is often misrepresented. It is the preservation of renal function, not its initial value, that confers benefit, and CANUSA is often taken as evidence that PD as a modality is intrinsically dependent on residual function to deliver adequate patient outcomes. We now know from the NECOSAD database that residual function is equally beneficial to haemodialysis patientsagain a benefit that can be reduced to a measure of urine volume [3]. ADEMEX has confirmed that residual renal and peritoneal clearances are not equivalent in survival terms [4], and EAPOS shows that good results can be achieved in anuric patients using ambulatory peritoneal dialysis (APD) [5]. Clearly residual renal function gives patients something that neither dialysis modality cansomething that we need to understand better.
Taken in this context, the article by Wang and colleagues in this edition of NDT examining the differing factors that predict survival in PD patients according to whether they have residual renal function or not is certainly of interest [6]. In a prospective study of prevalent patients they related 30 month mortality to a number of potentially predictive covariates, including those that are well known such as diabetic status and those that are perhaps less conventional, although of increasing interest, e.g. inflammation and measures using C-reactive protein (CRP) [7]. Their analytical approach was to divide their PD population into two groups, those with residual function (glomerular filtration rate
1 ml/min per 1.73 m2) and those who are completely anuric, and then determine if the relative importance of these predictors differs. As would be anticipated, these two groups are very different, most notably in the length of time they have already been on dialysis, which is typically more than twice as long in the anuric patients (median 48 vs 18 months). They found, using Cox regression, that whereas age, cardiovascular co-morbidity and raised CRP were associated with increased mortality in the anuric subjects, serum albumin concentration, reduced left ventricular mass and amount of residual renal function were protective in the group with preserved urine output.
How can we interpret these observations? Before drawing conclusions, it is necessary to consider how the study design and in particular the approach to data analysis contribute to their findings. Apart from the important differences in mean baseline characteristics between the groups, we need to pay attention to three other factors: the comparative spread of data at baseline, the number of end-points and the proportionality of risk. Taken in reverse order, it is apparent from the KaplanMeier survival curves that the risk of death in these two groups is not proportional, with a higher early death risk in the anuric patient group. In fact, the 4-year actuarial survival does not look so very different, whereas the maximal difference between the two groups is apparent at between 2 and 3 years follow-up. Correctly, therefore, the authors have not combined these two groups in the same Cox model (which assumes proportional death risk) but rather constructed separate models, feeding in the same covariates and drawing attention to differences in their prediction. Nevertheless, it needs to be remembered that risk of death in these two groups appears to be fundamentally different. This is likely to be a function of selection bias, for example differences in primary diagnosis, prevalence of cardiovascular disease and the differential transplant rates resulting in informative censoring, i.e. preferential removal of patients with low mortality risk from the group with residual renal function.
The number of end-points, with almost twice as many deaths in the anuric group will also mean that the potential predictive power of the Cox regression models will be different. Roughly speaking, one independent covariate might be expected for every 10 end-points. On univariate analysis, four covariates were close to predicting survival in the patients with residual function (P<0.1) whereas eight were identified in the anuric group. In other words, the group with residual function was relatively underpowered compared with the anuric group in statistical terms, which might explain why a covariate expected to predict death, such as age, is a significant predictor in the latter but not the former. This does not, of course, mean that the presence of residual function abolishes age as an important predictor of survival!
Finally, the range of baseline values must be considered. This is most obvious when considering the predictive power of residual renal function, which, as this was a prevalent patient cohort, reflects to some extent the relative preservation of this valuable commodity. A better way to analyse this would have been to treat residual function as a time-related covariate, which would probably have increased further its importance in the model. Clearly this cannot, by definition, be a predictor in the anuric patients. This issue, however, is perhaps less obvious for other covariates such as CRP. The CRP concentrations at baseline were different not only in their median value but also in their spread, with more variability in the anuric group. This in itself will make CRP more likely to be a predictor, and care should be taken in assuming that it is qualitatively as opposed to quantitatively more important in these patients compared with those with residual renal function; there simply may not be enough patients with sufficiently variable CRP levels in this group to detect an effect.
With these considerations in mind, what can we conclude from the study of Wang et al. [6]? Certainly residual renal function seems to be as important in Chinese PD patients as it is in Europeans, North Americans and Mexicans. The authors are also to be congratulated on giving us further insight as to the potential role of several predictors of outcome, in particular CRP, left ventricular mass and their relationship to conventional predictors such as age and co-morbidity. Are patients with or without residual function truly qualitatively different as suggested by the authors? The many baseline and statistical differences between the comparator groups in this study are too diverse to conclude this. Perhaps the best way of interpreting their results is to consider the two groups of patients as snapshots taken at two different stages in the overall trajectory that is progressive renal failure. As patients proceed along this pathway, different aspects assume varying importance, but the underlying processprogressive uraemiais the same. Important aspects of evolving renal failure might become more apparent late in the course of disease, but might still exert influence before this and as such should still be tackled as early as possible.
Conflict of interest statement. None declared.
[See related article by Wang et al. (this issue, pp. 396403)].
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