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The new england journal o f medicine

effect should reduce the overall morbidity due to malaria by reducing the frequency of new infec- tions. Among the four drug combinations stud- ied, dihydroartemisinin–piperaquine 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. demon- strates the safety and efficacy of dihydroarte- misinin–piperaquine as intermittent preventive treatment for malaria in pregnant women in Uganda. A total of 300 pregnant women received either three treatments of sulfadoxine–pyrimeth- amine, three treatments of dihydroartemisinin– piperaquine, or monthly treatment with dihydro- artemisinin–piperaquine during pregnancy. The prevalence of histopathologically confirmed pla- cental malaria was significantly higher after sulfadoxine–pyrimethamine treatment (50%) than it was after three treatments of dihydroartemis- inin–piperaquine (34%) or after monthly treat- ment with dihydroartemisinin–piperaquine (27%). The rate of adverse birth outcomes after monthly dihydroartemisinin–piperaquine treatment was half of that seen in the other treatment groups, which shows the benefit of effective prevention of malaria during pregnancy. Similarly, the inci- dence of symptomatic malaria and the preva- lence of parasitemia among pregnant women were substantially higher in the sulfadoxine– pyrimethamine group than in either dihydroar- temisinin–piperaquine group; the difference be- tween the sulfadoxine–pyrimethamine group and the monthly dihydroartemisinin–piperaquine 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 di- hydroartemisinin–piperaquine for the prevention of malaria, without evident safety concerns. How- ever, the most effective dosing of artemisinin- based combination therapies in pregnant women is still debated; studies have shown substantially lower drug concentrations of artemisinin 7 and

partner drugs 6 in pregnant women than in non- pregnant women. Prospective pharmacokinetic studies involving pregnant women and nonpreg- nant 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 cur- rently available antimalarial drugs might increase their therapeutic lifespan by reducing the risk of treatment failures and the development of resis- tance. 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 Mahidol–Oxford 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 treat-

ments in African pregnant women with malaria. N Engl J Med

2016;374:913-27.

5. Kakuru A, Jagannathan P, Muhindo MK, et al. Dihydroarte-

misinin–piperaquine 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 pharmaco-

kinetics 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 pharma-

cokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria. Antimi- crob Agents Chemother 2012;56:1997-2007.

8. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of arte-

misinin resistance in Plasmodium falciparum malaria. N Engl J Med

2014;371:411-23.

9. Amaratunga C, Lim P, Suon S, et al. Dihydroartemisinin-

piperaquine resistance in Plasmodium falciparum malaria in Cam- bodia: 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?

Lionel P.E. Rostaing, M.D., Ph.D., and Paolo Malvezzi, M.D.

982

Chronic kidney diseases are a major worldwide societal burden. In the United States, where the

prevalence of chronic kidney disease is approxi- mately 14%, 1 close to 1 million persons have end-

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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 trans- plantation (i.e., 56 cases per 1 million popula- tion). 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 post- transplantation year. Furthermore, kidney trans- plantation 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 under- going delicate surgery and of dying from infec- tion or rejection in the postoperative phase. Since then, medicine has greatly improved, trans- plantation procedures have become routine, sur- vival has become prolonged, and complication rates have decreased, at least for recipients of ABO- and HLA-compatible transplants. Converse- ly, 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 de- sensitization therapies and adequate post-trans- plantation immunosuppression. Thus, it is rele- vant 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 some- times the recipient is immunologically incom- patible with the potential donor, either because of blood-group incompatibility or because the recipient has circulating donor-specific antibod- ies. Strategies to overcome those obstacles have

been developed over the past 15 years. In paired- exchange programs, an incompatible live-donor– recipient pair can exchange a kidney with an- other incompatible donor–recipient pair if two compatible pairs can result. 5 However, finding a donor becomes almost impossible when a pa- tient carries too many anti-HLA antibodies; an option is pretransplantation desensitization of the recipient. Various protocols have been devel- oped to attempt to remove all unwanted anti- bodies; these involve strong immunosuppression and antibody clearance with the use of apheresis (e.g., immunoadsorption 6 and plasmapheresis) and B-cell modulating therapies (e.g., adminis- tration of high-dose immune globulins or ritux- imab). Desensitization may also include plasma- cell depletion (with bortezomib) 7 and complement inhibition (with eculizumab). 8 Until now, it has been unclear whether HLA- incompatible kidney transplantation after desen- sitization would benefit patients with ESRD, even though a single-center study had encouraging results. 9 This issue of the Journal includes a multi- center study from the United States by Orandi et al. 10 that compares the mortality among pa- tients who received a kidney transplant from an HLA-incompatible live donor after desensitiza- tion 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-incompati- ble 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 revolu- tionary, especially when the numerous contradic- tory opinions raised by the transplant community are considered. First, the patients undergoing de- sensitization 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. Sec- ond, the therapeutics needed to obtain and main- tain desensitization increase the financial burden as compared with the burden associated with standard kidney transplantation. These expensive strategies are available only in resource-rich coun- tries with universal health coverage; elsewhere, they are available only to wealthy patients.

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The new england journal o f medicine

Finally, from an ethical standpoint, it has been argued that the risk of taking a kidney from an otherwise healthy person may outweigh the bene- fit 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 trans- plantation from HLA-incompatible live donors because it may save lives and may be cost-effec- tive over time.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

From Clinique de Néphrologie, Unité de Transplantation Ré- nale, Centre Hospitalier Universitaire (CHU) Grenoble-Alpes, La Tronche (L.P.E.R., P.M.), and INSERM Unité 563, Federative Structure of Bio-Medical Research of Toulouse, CHU Purpan, and Université Toulouse III Paul Sabatier, Toulouse (L.P.E.R.) — all in France.

1. Chronic kidney disease (CKD) surveillance project. Atlanta:

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

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 pro-

cedure: 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 comple-

ment inhibition decreases antibody-mediated rejection in sensi-

tized renal transplant recipients. Am J Transplant 2011;11:2405-

13.

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.

DOI: 10.1056/NEJMe1601379

Copyright © 2016 Massachusetts Medical Society.

Zika Virus and Microcephaly

Eric J. Rubin, M.D., Ph.D., Michael F. Greene, M.D., and Lindsey R. Baden, M.D.

984

Zika virus has been sweeping through South and Central America, with more than a million sus- pected cases during the past few months, along with a substantial increase in reporting of infants born with microcephaly. 1,2 Thus far, the two out- breaks have largely been epidemiologically asso- ciated in time and geography. However, Mlakar and colleagues 3 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 pa- tient chose a late-pregnancy termination. At autopsy, the fetal brain was grossly dis-

eased, with findings that included a very small brain (weight, 84 g), a complete absence of cere- bral 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 de- generation of the long descending spinal tracts. Particles consistent with Zika virus were visual- ized 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 pro- vide absolute proof that Zika virus causes micro- cephaly. The standard criteria for proving causa- tion (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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