The n e w e ng l a n d j o u r na l of m e dic i n e
c or r e sp ondence
Early versus Late Initiation of Dialysis
To the Editor: In their report on the Initiating
Dialysis Early and Late (IDEAL) study in patients
with stage V chronic kidney disease, Cooper et al.
(Aug. 12 issue)1 state that their results “tip the
balance of evidence toward the view that no bene-
fit of early initiation of dialysis exists.” However,
with respect to the small between-group differ-
ence in the estimated glomerular filtration rate
(GFR) of 2.2 ml per minute per 1.73 m2 of body-
surface area, the individual characteristics of pa-
tients become important. The remarkably high
proportions of male patients (65%) and patients
planning to receive peritoneal dialysis (56%) are
among these factors. In addition, the patients’
mean age of 60 years and their nutritional status
(i.e., a mean albumin level of 38 g per liter and a
mean body-mass index [the weight in kilograms
divided by the square of the height in meters] of
29) favor a positive outcome associated with dialy-
sis, as compared with the majority of patients
starting dialysis in North America and Europe
(i.e., a mean age of 70 years, an albumin level of
30 g per liter, and a body-mass index of 26).2-4
We postulate that the patients in this study were
relatively healthy and thus less susceptible to the
potential complications of a late initiation of di-
alysis. The study shows that in a small group of
this week’s letters
2368 Early versus Late Initiation of Dialysis
2370 Neoadjuvant Chemotherapy or Primary Surgery
in Advanced Ovarian Cancer
2372 Electronic Health Records
2374 Adalimumab Pricing and Market Exclusivity
for Biologics
2368 n engl j med 363;24  nejm.org  december 9, 2010
The New England Journal of Medicine
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selected patients, the initiation of dialysis can be
postponed. However, for the large majority of
patients, late initiation of dialysis remains poten-
tially harmful.
Reinhard Brunkhorst, M.D.
Klinikum Hannover
Hannover, Germany
reinhard.brunkhorst@krh.eu
No potential conflict of interest relevant to this letter was re-
ported.
1. Cooper BA, Branley P, Bulfone L, et al. A randomized, con-
trolled trial of early versus late initiation of dialysis. N Engl J
Med 2010;363:609-19.
2. Beddhu S, Pappas LM, Ramkumar N, Samore M. Effects of
body size and body composition on survival in hemodialysis
patients. J Am Soc Nephrol 2003;14:2366-72.
3. Kaysen GA, Johansen KL, Cheng SC, Jin C, Chertow GM.
Trends and outcomes associated with serum albumin concentra-
tion among incident dialysis patients in the United States. J Ren
Nutr 2008;18:323-31.
4. Bundesverband Niere e.V. (In German.) (http://www
.bundesverband-niere.de/files/QuaSi-Niere-Bericht_2006-2007.pdf.)
To the Editor: Cooper et al. report a similar
outcome in survival in patients with early versus
late initiation of dialysis. The mean estimated
GFR differed only slightly between the two groups
(2.2 ml per minute by the Cockcroft–Gault equa-
tion and 1.8 ml per minute by the Modification
of Diet in Renal Disease [MDRD] equation). How-
ever, there was a great difference in the rate of
uremia, as reported in the Supplementary Appen-
dix (available at NEJM.org) accompanying the
article. Uremia developed in only 5 of 75 patients
(6.7%) in the early-start group, who initiated dialy-
sis with an estimated GFR of less than 10 ml per
minute per 1.73 m2, as compared with 234 of 322
patients (72.7%) in the late-start group, who ini-
tiated dialysis with an estimated GFR of more
than 7.0 ml per minute per 173 m2. Since there is
no specific limit for the estimated GFR that de-
fines the onset of uremia in patients with progres-
 correspondence
sive kidney disease, it is well known that uremic
symptoms may be detectable even in patients with
only moderate kidney insufficiency.1 Thus, it is
surprising that the authors report such different
results. Therefore, it would be helpful not only to
specify the criteria for the diagnosis of uremia
but also to clarify whether these criteria were ap-
plied in a similar way to the two study groups.
Justus Faust, M.D.
Kuratorium für Dialyse und Nierentransplantation
Mainz, Germany
justus.faust@kfh-dialyse.de
Oliver Schreiner, M.D.
Universitätsmedizin der Johannes-Gutenberg-Universität
Mainz, Germany
No potential conflict of interest relevant to this letter was re-
ported.
1. Meyer TW, Hostetter TH. Uremia. N Engl J Med 2007;357:
1316-25.
To the Editor: With respect to the findings of
Cooper et al., more information might reassure
doctors who still believe that late initiation of
dialysis is potentially dangerous for patients with
end-stage renal disease. First of all, such patients
often have malaise, diffuse pruritus, and nausea,
even if their estimated GFR (calculated with the
Cockcroft–Gault equation) is 10 to 15 ml per min-
ute per 1.73 m2. After few hemodialysis sessions,
these patients often say that they feel as if they
have had a rebirth in their quality of life. Second,
the late-start group might have been followed more
closely for clinical evaluation of extracellular-
fluid volume and levels of serum creatinine and
serum potassium, with a potential need for hos-
pitalization. Third, the authors have not provided
data on urinary output for these patients. An in-
creased urinary output in the late-start group
could result in an easier and safer follow-up for
doctors and nurses involved in the trial. More in-
formation on these issues would be much appre-
ciated.
Vincenzo Sepe, M.D.
Fondazione IRCCS Policlinico San Matteo
Pavia, Italy
v.sepe@smatteo.pv.it
Carmelo Libetta, M.D.
Antonio Dal Canton, M.D.
University of Pavia
Pavia, Italy
No potential conflict of interest relevant to this letter was re-
ported.
n engl j med 363;24  nejm.org  december 9, 2010
The New England Journal of Medicine
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To the Editor: The IDEAL study is not represen-
tative of patients with chronic kidney disease in
the United States1 and the United Kingdom2 who
are starting dialysis, so its results must be inter-
preted with caution. Data from the U.S. Renal
Data System (USRDS) suggest that approximate-
ly 50% of incident dialysis patients are more than
65 years old, whereas the mean age in the IDEAL
study was 60 years. Some 40% of IDEAL patients
had cardiovascular disease, whereas USRDS data
suggest that this complication occurs in approxi-
mately 60% of patients with stage 4 or 5 chronic
kidney disease.1 Typically, 14 to 17% of patients
are prescribed an erythropoietin-stimulating
agent in the 3 months preceding the initiation of
dialysis.1 Among patients in the IDEAL study, ap-
proximately 40% were receiving erythropoietin,
which probably explains the increased hemoglo-
bin level among IDEAL patients (about 11 g per
deciliter), as compared with the hemoglobin level
in new dialysis patients in the United States
(about 10 g per deciliter).1 Finally, the use of
renin–angiotensin system blockers and statins
was much higher among patients in the IDEAL
study than in other studies.1
Furthermore, the IDEAL study does not com-
pare outcomes in patients receiving peritoneal
dialysis versus those receiving hemodialysis in
the early- and late-start groups. This may be of
clinical relevance, since residual renal function is
an important determinant of outcome in patients
receiving peritoneal dialysis.3
Neeraj Dhaun, M.B., Ch.B.
David Kluth, M.B., B.S., Ph.D.
Royal Infirmary of Edinburgh
Edinburgh, United Kingdom
ndhaun@staffmail.ed.ac.uk
No potential conflict of interest relevant to this letter was re-
ported.
1. Renal Data System. USRDS 2009 annual data report: atlas of
chronic kidney disease and end-stage renal disease in the United
States. Bethesda, MD: National Institute of Diabetes and Diges-
tive and Kidney Diseases, 2009.
2. The Renal Association UK Renal Registry. The twelfth an-
nual report. December 2009. (http://www.renalreg.com/Reports/
2009.html.)
3. Bargman JM, Thorpe KE, Churchill DN. Relative contribu-
tion of residual renal function and peritoneal clearance to ade-
quacy of dialysis: a reanalysis of the CANUSA study. J Am Soc
Nephrol 2001;12:2158-62.
The authors reply: Brunkhorst and Faust and
Schreiner highlight the differences in estimated
GFR achieved in our trial. According to the pro-
2369
 The n e w e ng l a n d j o u r na l of m e dic i n e

tocol, patients who were assigned to the late-
start group could start dialysis with an estimated
GFR of more than 7.0 ml per minute per 1.73 m2
at the discretion of the treating physician. The
estimated GFR was used as a guide, yet the
more important goal of separation in time to di-
alysis initiation (median, almost 6 months) was
achieved.
Faust et al. question the relative prevalence of
symptoms of uremia before the initiation of di-
alysis in the two groups. The expectation at ran-
domization was that most patients would be
well enough to delay dialysis if they were as-
signed to the late-start group, and uremic symp-
toms were not reported, except when such symp-
toms were an indication to start dialysis. The
diagnosis of uremia and the decision to start
dialysis in the late-start group were left to the
caring physician.
We agree with Sepe et al. that quality of life
is potentially affected by uremia and the initia-
tion of dialysis. As briefly reported in our article,
at regular intervals we performed formal quality-
of-life assessments, which showed no significant
between-group differences in the intention-to-
treat analysis. Full details of these assessments
and a formal economic analysis have been sub-
mitted for publication.
Patients in this study were followed closely
and similarly in each phase of the trial. There
were no differences between the two study groups
in rates of hospital presentation or admission,
length of hospitalization, or the number of out-
patient visits to physicians.
Sepe et al. correctly point out that adequate
residual renal function is required for late-start
patients to remain off dialysis. Nevertheless,
there was no significant difference in rates of
severe fluid and electrolyte disturbance between
the two study groups. As suggested by Dhaun
and Kluth, secondary analyses of residual renal
function and survival rates before and after di-
alysis, according to the method of dialysis used,
are also planned.
Although Brunkhorst and Dhaun and Kluth
correctly observe that mean baseline characteris-
tics of the patients in our trial differ from those
of typical patients initiating dialysis in North
America and Europe, patients in our trial were
similar to incident dialysis patients in Australia
and New Zealand.1 The subgroup analysis shown
in Figure 3 of our article shows that no sub-
group of patients was at risk from late initiation
of dialysis.
Bruce A. Cooper, M.B., B.S., Ph.D.
David C. Harris, M.B., B.S., M.D.
Carol A. Pollock, M.B., B.S., Ph.D.
University of Sydney
Sydney, NSW, Australia
bcooper@med.usyd.edu.au
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Cooper B. Are patients randomized in the IDEAL trial repre-
sentative of the Australian-New Zealand dialysis population?
Nephrology (Carlton) 2008;13:Suppl 3:A107. abstract.

Neoadjuvant Chemotherapy or Primary Surgery in Advanced

Ovarian Cancer
To the Editor: Vergote et al. (Sept. 2 issue)1 re-
port on two treatment strategies, but they also
describe an alarming variability in the rate of op-
timal and complete cytoreduction. The range for
complete cytoreduction at primary debulking var-
ied from 3.9% to 62.9%, with an overall rate of
complete cytoreduction of 19.4%. The data clear-
ly show that there is a widespread lack of surgical
expertise in the management of ovarian cancer.
The rate of complete cytoreduction at primary
laparotomy was less than 12% in six of the seven
participating countries.
It seems clear that the general philosophy in
the surgical community regarding management
of this disease is discordant with the published
data on complete cytoreduction.
The Gynecologic Cancer Intergroup is intend-
ing to redefine “optimal” cytoreduction to mean
no visible residual disease (complete cytoreduc-
tion) rather than 1 cm of residual disease. It is
clear that the time has come to demand high sur-
gical standards in the management of advanced-
stage ovarian cancer to ensure that all women
consistently receive the optimal attempt at cyto-
reductive surgery, whether at primary surgery or
after induction chemotherapy.

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