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correspondence

n engl j med 363;10 nejm.org september 2, 2010 989

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 domaincontaining 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; theironly feature in common with DENN/MADD is a

DENN domain. They function as guaninenucleo-

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 UniversityMontreal, QC, Canada

No potential conflict of interest relevant to this letter was re-ported.

Sleiman PM, Flory J, Imielinski MN, et al. Variants of1.DENND1B associated with asthma in children. N Engl J Med 2010;

362:36-44.Schievella AR, Chen JH, Graham JR, Lin LL. MADD, a novel2.

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.

Del Villar K, Miller CA. Down-regulation of DENN/MADD,3.

a TNF receptor binding protein, correlates with neuronal cell

death in Alzheimers disease brain and hippocampal neurons.Proc Natl Acad Sci U S A 2004;101:4210-5.

Marat AL, McPherson PS. The connecdenn family, Rab354.

guanine nucleotide exchange factors interfacing with the clath-rin machinery. J Biol Chem 2010;285:10627-37.

Allaire PD, Marat AL, DallArmi C, Di Paolo G, McPherson5.

PS, Ritter B. The Connecdenn DENN domain: a GEF for Rab35mediating cargo-specific exit from early endosomes. Mol Cell2010;37:370-82.

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- 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 guaninenucleotide 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.Childrens Hospital of PhiladelphiaPhiladelphia, PAhakonarson@email.chop.edu

Since publication of their article, the authors report no fur-

ther potential conflict of interest.

Levivier E, Goud B, Souchet M, Calmels TPG, Mornon JP,1.Callebaut I. uDENN, DENN, and dDENN: indissociable domainsin Rab and MAP kinases signaling pathways. Biochem Biophys

Res Commun 2001;287:688-95.

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

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 HospitalEde, the Netherlandsfeithg@zgv.nl

The New England Journal of Medicine

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Th e n e w e n g l a n d j o u r n a l o fmedicine

n engl j med 363;10 nejm.org september 2, 2010990

No potential conflict of interest relevant to this letter was re-ported.

Tonelli M, Pannu N, Manns B. Oral phosphate binders in1.

patients with kidney failure. N Engl J Med 2010;362:1312-24.

Martin KJ, Gonzales EA, Slatopolsky E. Renal osteodystrophy.2.

In: Brenner BM, Levine SA, eds. Brenner & Rectors The kidney.

7th ed. Philadelphia: Saunders, 2004:2255-304.Jaffe JA, Liftman C, Glickman JD. Frequency of elevated se-3.

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 MedicineIndianapolis, INsmoe@iupui.edu

Geoff A. Block, M.D.

Denver NephrologyDenver, CO

Craig B. Langman, M.D.

Northwestern University Feinberg School of MedicineChicago, IL

Drs. Moe, Block, and Langman report receiving consultingfees and grant support from Genzyme; and Drs. Moe and Block,

receiving grant support from Shire. No other potential conflict

of interest relevant to this let ter was reported.

Moe SM, Chen NX. Mechanisms of vascular calcification in1.

chronic kidney disease. J Am Soc Nephrol 2008;19:213-6.

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 therisks 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 informprudent 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 noncalcium-

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 noncalcium-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 AlbertaEdmonton, AB, Canadamtonelli@med.ualberta.ca

Braden Manns, M.D.University of CalgaryCalgary, AB, Canada

Since publication of their article, the authors report no fur-ther potential conflict of interest.

The New England Journal of Medicine

Downloaded from nejm.org by EMI LIA on April 7, 2011. For personal use only. No other uses without permission.

Copyright 2010 Massachusetts Medical Society. All rights reserved.