Gotch, Gentile D, Keen M
The incident patient cohort study design with uncontrolled dose may
result in substantial overestimation of mortality as a function
of peritoneal dialysis dose
42nd Annual Conference of the ASAIO
ASAIO J
(May) 42:(2):102 1996
In this important abstract Gotch and colleagues point out a problem
that occurs when attempts are made to examine correlations between
small solute clearance and mortality in a cohort of dialysis patients
in whom the dialytic dose is not controlled. CANUSA was a non-
interventional study of an incident cohort of PD patients. Total
solute clearance fell during the course of this study because of
decline in residual function. In most cases, no intervention was made
to compensate for this decrease by raising dialytic clearance. The
analysis was done by correlating clearance levels at the beginning of
each six month period with deaths that occurred during that six month
period.
Gotch argues that the flaw here is that by the time that a
death occurs the clearance may be significantly less than it was at
the beginning of the relevant six month period. For example, a
patient who has a KT/V of 2.0 per week at the beginning of a six month
period, but who dies in the fifth month of that period, may have a
much lower KT/V at the time the death occurs. From his own data,
Gotch suggests that the average decrease in residual renal clearance
in CAPD patients is 0.2 units of KT/V per week every six months, and
11 liters creatinine clearance every week every six months. He points
out, however, that there is a very large range of changes in residual
function over six months, varying, in his study, from +0.48 units of
KT/V per week to -0.88. He, thus, concludes that mean KT/V and
creatinine clearance levels at the beginning of each six month
interval overestimate the mean doses being delivered during those six
month periods by a substantial amount, and that this, therefore,
results in an overestimation of the clearance level associated with a
given mortality rate.
His practical conclusion from this is that
mortality in CANUSA may not continue to fall linearly as clearance
rises up to a KT/V of 2.3. Rather, the rise may only continue up to a
dose of 2.1 or 2.2 a week.
Comment:
This is an important point. There are no obvious flaws in the
argument, and it does emphasize the difficulty of examining small
solute clearance in PD patients in non-interventional cohort studies
because of the inexorable fall in clearance that occurs due to
declining residual renal function. It is much more difficult to
analyze relationships between clearances and outcomes when clearances
are not fixed, but rather are changing all the time. This is a valid
point and is, to some extent, a `plug' for the authors' own study in
PD adequacy which is presently underway and which attempts to maintain
a small solute clearance of a constant level in two randomized groups.
One objection worth making is, that the relationship between
small solute clearance and outcome in dialysis patients may not be an
immediate one. Hemodialysis studies, such as the NCDS, suggest that
the effects of low dialytic dose may not manifest as changes in
mortality for many months, or even years. Thus, the clearance at the
beginning of a six month period in which a patient dies may be just as
relevant as that on the day the patient actually dies. Clearly,
randomized studies where small solute clearance is made constant have
the greatest potential to answer our questions in this important area.
A second point that is not mentioned is that CANUSA is, in any case,
somewhat confounded by residual renal function. The relationship
being examined between risk of mortality and small solute clearance is
in fact a relationship between risk or mortality and residual renal
function, as distinct from dialytic clearance. This further
emphasizes the need to do randomized studies where the effects of
residual renal and peritoneal clearance can be examined
separately.
ERRORS IN DIALYSIS DOSE INTERPRETATION: THE FALLACY OF THE MEAN.
Gotch [presentation at NIH Workshop on Peritoneal Dialysis,
Bethesda, May 6-7, 1996]
Following on from the above ASAIO abstract, Gotch presented a further
critique of the CANUSA study and of a number of other hemodialysis
adequacy studies when he presented at the NIH PD Workshop in Bethesda
in early May. His argument here is very important for evaluation of
both hemodialysis and PD adequacy studies. In essence, he is saying
that studies which attempt to correlate the mean value of clearances
in a given population, with the relative risk of mortality in that
population, have an inherent flaw. This is because variance of
clearance values around the mean tends to be quite large in these
studies. For example, a population with a mean KT/V of 1.33 per
treatment in hemodialysis will typically include a substantial number
of patients with a KT/V <1.1, as well as a substantial number with a
KT/V >1.5.
To make this point, Gotch examines two recent important
retrospective hemodialysis studies by Hakim [AJKD 23: 661, 1994] and
Parker [AJKD 23: 670, 1994]. Both dealt with changes in mortality
after a whole population had their dialytic dose increased. Combining
data from both studies, Gotch found that the minimum risk of mortality
occurred when the mean population equilibrated KT/V was 1.33, but that
this in fact corresponded to a situation where each individual in the
population achieved an equilibrated KT/V >1.03 per treatment. He
therefore concludes that there are no outcome data showing a decline
in the risk of mortality with equilibrated KT/Vs above 1.03 per
treatment in hemodialysis.
The recent Hakim and Parker studies, he
argues, should not be misinterpreted to suggest otherwise. Because of
this, there is a spurious overestimation of mortality risk relative to
KT/V when correlation is done to mean KT/Vs and there are substantial
variances on that mean. He contrasts this with studies such as that
by Owen et al [NEJM 329:1001, 1993] where populations were classified
on the basis of relatively small differences in clearance [e.g.,
60-65% reduction in blood urea] so that there was no great variance in
clearance within a given group, resulting in more valid conclusions.
Gotch goes on to apply these same principles to the CANUSA study. He
again makes the point that the KT/V in CANUSA was measured every six
months and that mortality over the next six months was correlated to
mean population values. He also shows, using data from his own PD
adequacy study, that the fall in residual function that occurs in PD
patients varies greatly from patient to patient. Thus, we are again
looking at a study where a population mean KT/V is being used and
where there is a wide variance. Gotch thus goes on to calculate that
a population with a mean KT/V of 2.3 would have the same relative risk
of mortality as a population in which everybody received a weekly KT/V
>2.03. He thus concludes that in PD there is no outcome data
suggesting that risk of mortality declines once weekly KT/V exceeds
2.03. Again, he uses this as justification to call for randomized
clinical trials in this area and, of course, the point here is that he
himself is running a controlled trial comparing KT/Vs of 1.7 versus
2.1 a week in PD.
In general, Gotch's points are well taken. There are strong
arguments in favour of randomized trials to resolve these important
issues in both types of dialysis. One criticism, with regard to
Gotch's analysis of CANUSA, is that he presumes a non-linear
relationship between small solute clearance and risk of mortality.
This presumption is based on the experience in hemodialysis studies.
The CANUSA authors, however, claim to show an approximately linear
relationship between small solute clearance and predicted two year
survival and so do not share this presumption. However, it should be
pointed out again that CANUSA itself is confounded by the fact that
all the variation in dialytic dose with time was due to a decrease in
residual function rather than to alterations in peritoneal
clearances.
A second assumption that Gotch makes is that there is kinetic dose
equivalency between the mid-week pre-dialysis urea in hemodialysis and
the ongoing constant blood urea in CAPD. He uses this to derive one
of the functions on which he bases his analysis. This assumption is
implicitly based on the Peak Concentration Hypothesis of Keshaviah.
This of course has not been validated and has recently been questioned
in studies by Depner.
Nevertheless, these two presentations confirm that Dr. Gotch
continues to have the ability to offer challenging and iconoclastic
insights on the topic of adequacy of dialysis!
(Peter G. Blake, M.D., Victoria Hospital, London, Ontario)
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42nd Annual Conference of the ASAIO
Basic peritoneal dialysis :
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CRF: Problem Areas :
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