transplante renal hla

8/18/2019 Transplante Renal Hla

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n engl j med 374;10 nejm.org March 10, 2016982

effect should reduce the overall morbidity due tomalaria by reducing the frequency of new infec-tions. Among the four drug combinations stud-ied, dihydroartemisinin–piperaquine had the bestefficacy and an acceptable safety profile, withan additional benefit of a longer post-treatmentprophylactic 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 preventivetreatment for malaria in pregnant women inUganda. A total of 300 pregnant women receivedeither three treatments of sulfadoxine–pyrimeth-amine, three treatments of dihydroartemisinin–piperaquine, or monthly treatment with dihydro-artemisinin–piperaquine during pregnancy. Theprevalence of histopathologically confirmed pla-cental malaria was significantly higher aftersulfadoxine–pyrimethamine treatment (50%) thanit 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 monthlydihydroartemisinin–piperaquine treatment washalf of that seen in the other treatment groups, which shows the benefit of effective preventionof 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 andthe monthly dihydroartemisinin–piperaquinegroup was especially pronounced.

These studies indicate the effectiveness inpregnancy of artemisinin-based combinationtherapy for the treatment of uncomplicatedP. falciparum malaria and the effectiveness of di-hydroartemisinin–piperaquine for the preventionof malaria, without evident safety concerns. How-

ever, the most effective dosing of artemisinin-based combination therapies in pregnant womenis still debated; studies have shown substantiallylower drug concentrations of artemisinin7 and

partner drugs6 in pregnant women than in non-pregnant women. Prospective pharmacokineticstudies involving pregnant women and nonpreg-nant controls are needed to characterize thepharmacologic properties of these antimalarialdrugs in order to improve treatment. New drugsin development are still several years away from

clinical use, and evidence-based dosing of cur-rently available antimalarial drugs might increasetheir therapeutic lifespan by reducing the risk oftreatment failures and the development of resis-tance. This might be particularly important inSoutheast Asia, where acquired immunity is lowerand resistance to artemisinin and its partnerdrugs is emerging and spreading.8,9

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

From the Centre for Tropical Medicine and Global Health, NuffieldDepartment of Clinical Medicine, University of Oxford, Oxford,

United Kingdom, and the Mahidol–Oxford Tropical MedicineResearch 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 effectsof falciparum and vivax malaria and the safety of antimalarialtreatment in early pregnancy: a population-based study. LancetInfect Dis 2012;12:388-96.3. Guidelines for the treatment of malaria, third edition. Geneva:World Health Organizat ion, 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 pregnantand 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 Med2014;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 Dis2016 January 7 (Epub ahead of print).DOI: 10.1056/NEJMe1601193Copyright © 2016 Massachusetts Medical Society.

HLA-Incompatible Kidney Transplantation — Worth the Risk?Lionel P.E. Rostaing, M.D., Ph.D., and Paolo Malvezzi, M.D.

Chronic kidney diseases are a major worldwidesocietal 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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stage renal disease (ESRD). Of those affected,700,000 (70.8%) are treated with dialysis, and theremaining 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 kidneytransplant, 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 ofchronic kidney disease exceed $48 billion, with yearly per-patient costs of approximately $89,000for hemodialysis and $25,000 after the f irst post-transplantation year. Furthermore, kidney trans-plantation significantly improves quality of lifeand 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, survival has become prolonged, and complicationrates have decreased, at least for recipients ofABO- and HLA-compatible transplants. Converse-ly, for high-risk patients, debate continues as to whether survival rates after transplantation arehigher than the rates associated with prolongeddialysis. Today, recipients are often older and

less healthy than in the past, and kidney donorsare scarce. In addition, increasing numbers of waitlisted patients have HLA sensitization. If suchpatients have specific HLA antibodies against thedonor (i.e., donor-specific alloantibodies), thenthere is a risk of antibody-mediated rejection, which inexorably leads to allograft loss, despitepretransplantation and post-transplantation de-sensitization therapies and adequate post-trans-plantation immunosuppression. Thus, it is rele- vant to question how to select patients who willbenefit the most from kidney transplantation.

And what type of kidney donor should be usedfor a given patient?

In the United States and Europe, the donorsof most kidneys are deceased; thus, recipientsoften have to wait several years before receivinga graft. The alternative is live donors, but some-times the recipient is immunologically incom-patible with the potential donor, either becauseof blood-group incompatibility or because therecipient 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 twocompatible pairs can result.5 However, finding adonor becomes almost impossible when a pa-tient carries too many anti-HLA antibodies; an

option is pretransplantation desensitization ofthe recipient. Various protocols have been devel-oped to attempt to remove all unwanted anti-bodies; these involve strong immunosuppressionand antibody clearance with the use of apheresis(e.g., immunoadsorption6 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 complementinhibition (with eculizumab).8

Until now, it has been unclear whether HLA-incompatible kidney transplantation after desen-sitization would benefit patients with ESRD, eventhough a single-center study had encouragingresults.9 This issue of the Journal includes a multi-center study from the United States by Orandiet al.10 that compares the mortality among pa-tients who received a kidney transplant from anHLA-incompatible live donor after desensitiza-tion with the mortality among patients who were on the waiting list or received a transplantfrom 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 improvespatient survival as compared with waiting for acompatible transplant, even though the resultsare 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 communityare considered. First, the patients undergoing de-sensitization are treated with extremely powerfulimmunosuppressive regimens, placing them at

higher risk for infection (e.g., with cytomegalovirusor BK virus) and for new cancer. Although no dataare yet available concerning cancer risk, removinghumoral immunity might enhance this risk. Sec-ond, the therapeutics needed to obtain and main-tain desensitization increase the financial burdenas compared with the burden associated withstandard kidney transplantation. These expensivestrategies are available only in resource-rich coun-tries with universal health coverage; elsewhere,they are available only to wealthy patients.





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Finally, from an ethical standpoint, it has beenargued that the risk of taking a kidney from anotherwise healthy person may outweigh the bene-fit of high-risk transplantation. For example, arecent study indicated that among live kidneydonors with a median follow-up of 7.6 years, therisk of ESRD was increased as compared with

healthy persons; however, the magnitude of theabsolute increase in risk was small.11

These differing opinions about who shouldundergo transplantation and the risks involvedcall for a certain degree of caution. However, thestudy by Orandi et al. advocates kidney trans-plantation from HLA-incompatible live donorsbecause it may save lives and may be cost-effec-tive over time.

Disclosure forms provided by the authors are available withthe 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, FederativeStructure 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 homepage (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 awaitingtransplantation, 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 transplantat ion in highlysensitized pat ients. 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. Desensitizationin HLA-incompatible kidney recipients and survival. N Engl JMed 2011;365:318-26.

10. Orandi BJ, Luo X, Massie AB, et al. Survival benefit withkidney transplants from HLA-incompatible live donors. N Engl JMed 2016;374:940-50.11. Muzaale AD, Massie AB, Wang MC, et al. Risk of end-stagerenal disease following live kidney donation. JAMA 2014;311:579-86.

DOI: 10.1056/NEJMe1601379Copyright © 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.

Zika virus has been sweeping through South andCentral America, with more than a million sus-pected cases during the past few months, along with a substantial increase in reporting of infantsborn with microcephaly.1,2 Thus far, the two out-breaks have largely been epidemiologically asso-ciated in time and geography. However, Mlakarand colleagues3 now report in the Journal moleculargenetic and electron-microscopic data from a casethat helps to strengthen the biologic association.

This group cared for a pregnant European

woman in whom a syndrome compatible withZika virus infection developed at 13 weeks ofgestation while she was working in northeasternBrazil. She subsequently returned to Europe, where ultrasonographic examinations performedlate in the pregnancy showed a small fetal headand brain calcifications as had been seen inother cases linked to Zika virus.4 After approvalby 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 smallbrain (weight, 84 g), a complete absence of cere-bral gyri, severe dilation of both cerebral lateral ventricles, dystrophic calcifications throughoutthe cerebral cortex, and hypoplasia of the brainstem 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 amountof viral genomic RNA was present in the brainbut in no other organs. The viral sequence was

similar to that of other recent Zika virus isolates.No evidence of any fetal genetic abnormalities orother 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, whichrequire the isolation of the causative organism,reinfection of a susceptible person in whom thecharacteristic disease develops, and then repeated




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