correspondence
is mediated by a “death domain” in DENN/MADD,
represses TNF-receptor signaling.2,3 In fact, the
DENND1B protein is a member of a three-gene
DENN domain–containing family, comprising
DENND1A, DENND1B, and DENND1C (also known
as connecdenn 1, 2, and 3, respectively).4 These
proteins do not contain a death domain and have
not been linked to TNF-receptor signaling; their
only feature in common with DENN/MADD is a
DENN domain. They function as guanine–nucleo­
tide exchange factors for the guanosine triphos-
phatase (GTPase) Rab35 and mediate endosomal-
membrane trafficking.4,5
Andrea L. Marat, B.Sc.
Peter S. McPherson, Ph.D.
McGill University
Montreal, QC, Canada
No potential conflict of interest relevant to this letter was re-
ported.
1. Sleiman PM, Flory J, Imielinski MN, et al. Variants of
DENND1B associated with asthma in children. N Engl J Med 2010;
362:36-44.
2. Schievella AR, Chen JH, Graham JR, Lin LL. MADD, a novel
death domain protein that interacts with the type 1 tumor ne-
crosis factor receptor and activates mitogen-activated protein
kinase. J Biol Chem 1997;272:12069-75.
3. Del Villar K, Miller CA. Down-regulation of DENN/MADD,
a TNF receptor binding protein, correlates with neuronal cell
death in Alzheimer’s disease brain and hippocampal neurons.
Proc Natl Acad Sci U S A 2004;101:4210-5.
4. Marat AL, McPherson PS. The connecdenn family, Rab35
guanine nucleotide exchange factors interfacing with the clath-
rin machinery. J Biol Chem 2010;285:10627-37.
5. Allaire PD, Marat AL, Dall’Armi C, Di Paolo G, McPherson
PS, Ritter B. The Connecdenn DENN domain: a GEF for Rab35
mediating cargo-specific exit from early endosomes. Mol Cell
2010;37:370-82.
Oral Phosphate Binders in Patients with Kidney Failure
To the Editor: In their review article on phos-
phate binders, Tonelli et al. (April 8 issue)1 dis-
miss aluminum-containing binders because of
their well-known toxicity. Yet such drugs remain
a cornerstone in the treatment of hyperphos-
phatemia in most underdeveloped countries.
This, of course, is the consequence of the pro-
hibitively expensive alternatives. Furthermore,
aluminum toxicity is a problem that becomes
manifest after the long-term ingestion of a large
amount of aluminum-containing phosphate
binders.2 The continuous monitoring of alumi-
num levels has shown that it is not a great prob-
lem today in the Western world.3 Since low-dose
aluminum (i.e., 2 g daily) is probably not toxic for
n engl j med 363;10  nejm.org  september 2, 2010
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
The Authors Reply: The 1q31 locus contains
DENND1B, a gene expressed by natural killer cells
and dendritic cells. DENN-containing proteins
have been shown to interact with GTPases of the
Rab family and other proteins, such as MADD,
suppression of tumorigenicity 5 (ST5), and SET
binding factor 1 (SBF1), in the regulation of MAP
kinase signaling pathways.1 In view of the signifi-
cant sequence homology between DENND1B and
MADD as well as the other DENN-containing genes
involved in MAP kinase signaling, including ST5
and SBF1,1 we predicted an interaction between
DENND1B and the gene encoding TNF-α receptor
type 1 (TNFR1) (see Correction in this issue).
Since the publication of our manuscript,
McPherson and colleagues published two articles
in which the authors demonstrate that the DENN
domain can act as a guanine–nucleotide ex-
change factor. Although their studies shed light
on the function of the DENN domain, they do
not ascribe a function to the DENND1B protein,
nor do they elucidate its binding partners. Fur-
ther characterization of the protein to determine
its function is therefore required.
Patrick M.A. Sleiman, Ph.D.
Hakon Hakonarson, M.D., Ph.D.
Children’s Hospital of Philadelphia
Philadelphia, PA
hakonarson@email.chop.edu
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Levivier E, Goud B, Souchet M, Calmels TPG, Mornon JP,
Callebaut I. uDENN, DENN, and dDENN: indissociable domains
in Rab and MAP kinases signaling pathways. Biochem Biophys
Res Commun 2001;287:688-95.
patients with a reduced life expectancy (e.g., pa-
tients older than 75 years of age receiving dialy-
sis), it would be foolish not to try to cut expenses
by administering phosphate binders that contain
aluminum. Furthermore, in the Netherlands, alu-
minum levels are monitored frequently, which
would probably detect problems with high levels.
I believe it would be wise and cost-effective to
determine which dose of aluminum-containing
phosphate binders is safe, as determined by alu-
minum levels.
Geert W. Feith, M.D., Ph.D.
Gelderse Vallei Hospital
Ede, the Netherlands
feithg@zgv.nl
989
 The n e w e ng l a n d j o u r na l
No potential conflict of interest relevant to this letter was re-
ported.
1. Tonelli M, Pannu N, Manns B. Oral phosphate binders in
patients with kidney failure. N Engl J Med 2010;362:1312-24.
2. Martin KJ, Gonzales EA, Slatopolsky E. Renal osteodystrophy.
In: Brenner BM, Levine SA, eds. Brenner & Rector’s The kidney.
7th ed. Philadelphia: Saunders, 2004:2255-304.
3. Jaffe JA, Liftman C, Glickman JD. Frequency of elevated se-
rum aluminum levels in adult dialysis patients. Am J Kidney Dis
2005;46:316-9.
To the Editor: We agree with the main conclu-
sion reached by Tonelli et al. that hard clinical
data are lacking to show the superiority of one
phosphate binder over another. However, we dis-
agree that in the absence of such data, the least
expensive drug should be first in line. Given the
paucity of hard-end-point trials for any drug cur-
rently given to patients receiving dialysis, we would
argue that the physician should evaluate all avail-
able evidence. Multiple studies have described
the role of calcium in vascular calcification in
vitro, and studies involving multiple models of
chronic kidney disease in animals have shown
that calcium-based phosphate binders are associ-
ated with increased arterial calcification and pro-
gression of renal disease, as compared with
phosphate binders that do not contain calcium.1
None of these studies were included in the review
by Tonelli et al. Therefore, the conclusion that
the cheapest drug, calcium carbonate, should be
used despite the absence of long-term safety
studies would mean that cost trumps science. The
pendulum has swung too far in the wrong direc-
tion, moving us from making decisions on the ba-
sis of basic science without clinical proof to the
other extreme in which patient managers choose
a therapy on the basis of accounting principles
alone.
Sharon M. Moe, M.D.
Indiana University School of Medicine
Indianapolis, IN
smoe@iupui.edu
Geoff A. Block, M.D.
Denver Nephrology
Denver, CO
Craig B. Langman, M.D.
Northwestern University Feinberg School of Medicine
Chicago, IL
Drs. Moe, Block, and Langman report receiving consulting
fees and grant support from Genzyme; and Drs. Moe and Block,
receiving grant support from Shire. No other potential conflict
of interest relevant to this letter was reported.
1. Moe SM, Chen NX. Mechanisms of vascular calcification in
chronic kidney disease. J Am Soc Nephrol 2008;19:213-6.
990 n engl j med 363;10  nejm.org  september 2, 2010
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
The authors reply: Feith suggests that our re-
view unduly dismisses aluminum-based agents.
We agree that these drugs can lower phosphate
levels, but the goal of treatment is to improve
clinical outcomes. As stated in our article, the
potential for toxicity with aluminum is irrefut-
able; monitoring aluminum levels is possible
but is resource-intensive. We believe that the
risks of long-term aluminum use outweigh its
potential benefits but recognize that others may
disagree.
Moe et al. should acknowledge that the care
of dialysis patients in the United States and most
other countries is funded by public health care
systems within a finite budget. Paying for the
speculative benefit of phosphate binders that do
not contain calcium means that less money re-
mains to fund therapies known to benefit pa-
tients with kidney disease or other conditions.
Physicians have the necessary expertise to inform
prudent choices about how best to use scarce
health care funds. Voluntarily absenting our-
selves from such discussions by pretending that
economic considerations should be left to “pa-
tient managers” means that funding decisions
will be made by others whose understanding may
be more superficial.
To date, the wide uptake of non–calcium-
based phosphate binders has been driven more
by marketing than by science. Models in animals
and in vitro studies are essential to generate new
hypotheses but should not be used to make
treatment decisions in humans. Uncritical adop-
tion of unproven therapies removes the incentive
for manufacturers to fund properly conducted
studies that can determine whether such drugs
truly improve outcomes — and does a disservice
to our current and future patients. As stated in
our article, the theoretical and experimental ra-
tionale for non–calcium-based phosphate binders
is strong. It is now time to do adequately pow-
ered, randomized trials that can inform clinical
practice.
Marcello Tonelli, M.D.
Neesh Pannu, M.D.
University of Alberta
Edmonton, AB, Canada
mtonelli@med.ualberta.ca
Braden Manns, M.D.
University of Calgary
Calgary, AB, Canada
Since publication of their article, the authors report no fur-
ther potential conflict of interest.