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n e w e ng l a n d j o u r na l

effect should reduce the overall morbidity due to

malaria by reducing the frequency of new infections. Among the four drug combinations studied, dihydroartemisininpiperaquine had the best
efficacy and an acceptable safety profile, with
an additional benefit of a longer post-treatment
prophylactic effect, which supports its suitability
as a chemoprophylaxis or chemoprevention agent.
The trial conducted by Kakuru et al. demonstrates the safety and efficacy of dihydroartemisininpiperaquine as intermittent preventive
treatment for malaria in pregnant women in
Uganda. A total of 300 pregnant women received
either three treatments of sulfadoxinepyrimethamine, three treatments of dihydroartemisinin
piperaquine, or monthly treatment with dihydroartemisininpiperaquine during pregnancy. The
prevalence of histopathologically confirmed placental malaria was significantly higher after
sulfadoxinepyrimethamine treatment (50%) than
it was after three treatments of dihydroartemisininpiperaquine (34%) or after monthly treatment with dihydroartemisininpiperaquine (27%).
The rate of adverse birth outcomes after monthly
dihydroartemisininpiperaquine treatment was
half of that seen in the other treatment groups,
which shows the benefit of effective prevention
of malaria during pregnancy. Similarly, the incidence of symptomatic malaria and the prevalence of parasitemia among pregnant women
were substantially higher in the sulfadoxine
pyrimethamine group than in either dihydroartemisininpiperaquine group; the difference between the sulfadoxinepyrimethamine group and
the monthly dihydroartemisininpiperaquine
group was especially pronounced.
These studies indicate the effectiveness in
pregnancy of artemisinin-based combination
therapy for the treatment of uncomplicated
P.falciparum malaria and the effectiveness of dihydroartemisininpiperaquine for the prevention
of malaria, without evident safety concerns. However, the most effective dosing of artemisininbased combination therapies in pregnant women
is still debated; studies have shown substantially
lower drug concentrations of artemisinin7 and

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partner drugs6 in pregnant women than in nonpregnant women. Prospective pharmacokinetic

studies involving pregnant women and nonpregnant controls are needed to characterize the
pharmacologic properties of these antimalarial
drugs in order to improve treatment. New drugs
in development are still several years away from
clinical use, and evidence-based dosing of currently available antimalarial drugs might increase
their therapeutic lifespan by reducing the risk of
treatment failures and the development of resistance. This might be particularly important in
Southeast Asia, where acquired immunity is lower
and resistance to artemisinin and its partner
drugs is emerging and spreading.8,9
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Centre for Tropical Medicine and Global Health, Nuffield
Department of Clinical Medicine, University of Oxford, Oxford,
United Kingdom, and the MahidolOxford Tropical Medicine
Research Unit, Faculty of Tropical Medicine, Mahidol University,
Bangkok, Thailand.
1. World malaria report 2015. Geneva:World Health Organi-

zation (http://www.who.int/malaria/publications/world-malaria
-report-2015/en/).
2. McGready R, Lee SJ, Wiladphaingern J, et al. Adverse effects
of falciparum and vivax malaria and the safety of antimalarial
treatment in early pregnancy: a population-based study. Lancet
Infect Dis 2012;12:388-96.
3. Guidelines for the treatment of malaria, third edition. Geneva:
World Health Organization, 2015 (http://www.who.int/malaria/
publications/atoz/9789241549127/en/).
4. The PREGACT Study Group. Four artemisinin-based treatments in African pregnant women with malaria. N Engl J Med
2016;374:913-27.
5. Kakuru A, Jagannathan P, Muhindo MK, et al. Dihydroartemisininpiperaquine for the prevention of malaria in pregnancy.
N Engl J Med 2016;374:928-39.
6. Kloprogge F, Piola P, Dhorda M, et al. Population pharmacokinetics of lumefantrine in pregnant and nonpregnant women
with uncomplicated Plasmodium falciparum malaria in Uganda.
CPT Pharmacometrics Syst Pharmacol 2013;2:e83.
7. Tarning J, Rijken MJ, McGready R, et al. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant
and nonpregnant women with uncomplicated malaria. Antimicrob Agents Chemother 2012;56:1997-2007.
8. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med
2014;371:411-23.
9. Amaratunga C, Lim P, Suon S, et al. Dihydroartemisininpiperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis
2016 January 7 (Epub ahead of print).
DOI: 10.1056/NEJMe1601193

Copyright 2016 Massachusetts Medical Society.

HLA-Incompatible Kidney Transplantation Worth the Risk?

LionelP.E. Rostaing, M.D., Ph.D., and Paolo Malvezzi, M.D.
Chronic kidney diseases are a major worldwide prevalence of chronic kidney disease is approxisocietal burden. In the United States, where the mately 14%,1 close to 1 million persons have end982

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Editorials

stage renal disease (ESRD). Of those affected,

700,000 (70.8%) are treated with dialysis, and the
remaining 300,000 (29.2%) with kidney transplantation (i.e., 56 cases per 1 million population).2 Currently, just over 100,000 U.S. patients
with ESRD are on the waiting list for a kidney
transplant, but every year, only 15 to 16% will
receive a kidney transplant, and of those kidneys,
32 to 34% are from live donors.3
Annual U.S. expenditures on the treatment of
chronic kidney disease exceed $48 billion, with
yearly per-patient costs of approximately $89,000
for hemodialysis and $25,000 after the first posttransplantation year. Furthermore, kidney transplantation significantly improves quality of life
and decreases mortality, as shown by Wolfe et al.
in 1999.4
In the early days of kidney transplantation,
patients accepted the risks associated with undergoing delicate surgery and of dying from infection or rejection in the postoperative phase.
Since then, medicine has greatly improved, transplantation procedures have become routine, survival has become prolonged, and complication
rates have decreased, at least for recipients of
ABO- and HLA-compatible transplants. Conversely, for high-risk patients, debate continues as to
whether survival rates after transplantation are
higher than the rates associated with prolonged
dialysis. Today, recipients are often older and
less healthy than in the past, and kidney donors
are scarce. In addition, increasing numbers of
waitlisted patients have HLA sensitization. If such
patients have specific HLA antibodies against the
donor (i.e., donor-specific alloantibodies), then
there is a risk of antibody-mediated rejection,
which inexorably leads to allograft loss, despite
pretransplantation and post-transplantation desensitization therapies and adequate post-transplantation immunosuppression. Thus, it is relevant to question how to select patients who will
benefit the most from kidney transplantation.
And what type of kidney donor should be used
for a given patient?
In the United States and Europe, the donors
of most kidneys are deceased; thus, recipients
often have to wait several years before receiving
a graft. The alternative is live donors, but sometimes the recipient is immunologically incompatible with the potential donor, either because
of blood-group incompatibility or because the
recipient has circulating donor-specific antibodies. Strategies to overcome those obstacles have

been developed over the past 15 years. In pairedexchange programs, an incompatible live-donor
recipient pair can exchange a kidney with another incompatible donorrecipient pair if two
compatible pairs can result.5 However, finding a
donor becomes almost impossible when a patient carries too many anti-HLA antibodies; an
option is pretransplantation desensitization of
the recipient. Various protocols have been developed to attempt to remove all unwanted antibodies; these involve strong immunosuppression
and antibody clearance with the use of apheresis
(e.g., immunoadsorption6 and plasmapheresis)
and B-cell modulating therapies (e.g., administration of high-dose immune globulins or rituximab). Desensitization may also include plasmacell depletion (with bortezomib)7 and complement
inhibition (with eculizumab).8
Until now, it has been unclear whether HLAincompatible kidney transplantation after desensitization would benefit patients with ESRD, even
though a single-center study had encouraging
results.9 This issue of the Journal includes a multicenter study from the United States by Orandi
et al.10 that compares the mortality among patients who received a kidney transplant from an
HLA-incompatible live donor after desensitization with the mortality among patients who
were on the waiting list or received a transplant
from a deceased donor and among those on the
waiting list who did not receive a transplant.
This study clearly showed that HLA-incompatible live-donor kidney transplantation improves
patient survival as compared with waiting for a
compatible transplant, even though the results
are driven mainly by five large centers.
The implications of these results are revolutionary, especially when the numerous contradictory opinions raised by the transplant community
are considered. First, the patients undergoing desensitization are treated with extremely powerful
immunosuppressive regimens, placing them at
higher risk for infection (e.g., with cytomegalovirus
or BK virus) and for new cancer. Although no data
are yet available concerning cancer risk, removing
humoral immunity might enhance this risk. Second, the therapeutics needed to obtain and maintain desensitization increase the financial burden
as compared with the burden associated with
standard kidney transplantation. These expensive
strategies are available only in resource-rich countries with universal health coverage; elsewhere,
they are available only to wealthy patients.

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983

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n e w e ng l a n d j o u r na l

Finally, from an ethical standpoint, it has been

argued that the risk of taking a kidney from an
otherwise healthy person may outweigh the benefit of high-risk transplantation. For example, a
recent study indicated that among live kidney
donors with a median follow-up of 7.6 years, the
risk of ESRD was increased as compared with
healthy persons; however, the magnitude of the
absolute increase in risk was small.11
These differing opinions about who should
undergo transplantation and the risks involved
call for a certain degree of caution. However, the
study by Orandi et al. advocates kidney transplantation from HLA-incompatible live donors
because it may save lives and may be cost-effective over time.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From Clinique de Nphrologie, Unit de Transplantation Rnale, Centre Hospitalier Universitaire (CHU) Grenoble-Alpes,
La Tronche (L.P.E.R., P.M.), and INSERM Unit 563, Federative
Structure of Bio-Medical Research of Toulouse, CHU Purpan,
and Universit Toulouse III Paul Sabatier, Toulouse (L.P.E.R.)
all in France.

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2. United States Renal Data System. 2015 Annual data report

(http://www.usrds.org/adr.aspx).

3. Organ Procurement and Transplantation Network home

page (https://optn.transplant.hrsa.gov/).

4. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mor-

tality in all patients on dialysis, patients on dialysis awaiting

transplantation, and recipients of a first cadaveric transplant.
N Engl J Med 1999;341:1725-30.
5. Fumo DE, Kapoor V, Reece LJ, et al. Historical matching
strategies in kidney paired donation: the 7-year evolution of a
web-based virtual matching system. Am J Transplant 2015;15:
2646-54.
6. Maggioni S, Allal A, Kamar N, Hermelin M, Faubel E, Ros
taing L. Immunoadsorption and hemodialysis as a tandem procedure: a single-center experience of more than 60 procedures.
Int J Artif Organs 2015;38:304-10.
7. Jordan SC, Choi J, Vo A. Kidney transplantation in highly
sensitized patients. Br Med Bull 2015;114:113-25.
8. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 2011;11:240513.
9. Montgomery RA, Lonze BE, King KE, et al. Desensitization
in HLA-incompatible kidney recipients and survival. N Engl J
Med 2011;365:318-26.
10. Orandi BJ, Luo X, Massie AB, et al. Survival benefit with
kidney transplants from HLA-incompatible live donors. N Engl J
Med 2016;374:940-50.
11. Muzaale AD, Massie AB, Wang MC, et al. Risk of end-stage
renal disease following live kidney donation. JAMA 2014;311:
579-86.

1. Chronic kidney disease (CKD) surveillance project. Atlanta: DOI: 10.1056/NEJMe1601379

Centers for Disease Control and Prevention (https:/
/
nccd
.cdc Copyright 2016 Massachusetts Medical Society.
.gov/CKD/SearchResults.aspx?ss=prevalence).

Zika Virus and Microcephaly

EricJ. Rubin, M.D., Ph.D., MichaelF. Greene, M.D., and LindseyR. Baden, M.D.
Zika virus has been sweeping through South and
Central America, with more than a million suspected cases during the past few months, along
with a substantial increase in reporting of infants
born with microcephaly.1,2 Thus far, the two outbreaks have largely been epidemiologically associated in time and geography. However, Mlakar
and colleagues3 now report in the Journal molecular
genetic and electron-microscopic data from a case
that helps to strengthen the biologic association.
This group cared for a pregnant European
woman in whom a syndrome compatible with
Zika virus infection developed at 13 weeks of
gestation while she was working in northeastern
Brazil. She subsequently returned to Europe,
where ultrasonographic examinations performed
late in the pregnancy showed a small fetal head
and brain calcifications as had been seen in
other cases linked to Zika virus.4 After approval
by national and hospital ethics boards, the patient chose a late-pregnancy termination.
At autopsy, the fetal brain was grossly dis984

eased, with findings that included a very small

brain (weight, 84 g), a complete absence of cerebral gyri, severe dilation of both cerebral lateral
ventricles, dystrophic calcifications throughout
the cerebral cortex, and hypoplasia of the brain
stem and spinal cord, including Wallerian degeneration of the long descending spinal tracts.
Particles consistent with Zika virus were visualized on electron microscopy, and a large amount
of viral genomic RNA was present in the brain
but in no other organs. The viral sequence was
similar to that of other recent Zika virus isolates.
No evidence of any fetal genetic abnormalities or
other pathogens was found.
The findings of this case report do not provide absolute proof that Zika virus causes microcephaly. The standard criteria for proving causation (with modifications) are still those that
were formulated by Robert Koch in 1890, which
require the isolation of the causative organism,
reinfection of a susceptible person in whom the
characteristic disease develops, and then repeated

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