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adult donors. Nephrol Dial Transplant 2006; 21: 2596. Varela-Fascinetto G, Bracho E, Da´vila R, et al. En bloc and single kidney transplantation from donors weighing less than 15 kg into pediatric recipients. Transplant Proc 2001; 33: 2034. Laube GF, Kellenberger CJ, Kemper MJ, et al. Transplantation of infant en bloc

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kidneys into paediatric recipients. Pediatr Nephrol 2006; 21: 408. Lau KK, Berg GM, Schjoneman YG, et al. Pediatric en bloc kidney transplantation into pediatric recipients. Pediatr Transplant 2010; 14: 100. Afanetti M, Niaudet P, Niel O, et al. Pediatric en bloc kidney transplantation into pediatric recipients: the French

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experience. Pediatr Transplant 2012; 16: 183. Laurence JM, Sandroussi C, Lam VW, et al. Utilization of small pediatric donor kidneys: a decision analysis. Transplantation 2011; 91: 1110. Kayler LK, Magliocca J, Kim RD, et al. Single kidney transplantation from young pediatric donors in the United States. Am J Transplant 2009; 9: 2745.

Combined Heart and Liver Transplantation Against Positive Cross-Match for Patient With Hypoplastic Left Heart Syndrome n 18-year-old woman with history of three-stage palliation for hypoplastic left heart syndrome culminating in Fontan, presented with heart failure and cardiac cirrhosis. She was EpsteinBarr virus (EBV) negative. Her cytotoxic panel-reactive antibody (LabScreen PRA; One Lambda Inc., Canoga Park, CA) was 20% class I and 51% class II positive with calculated PRA of 92%. The patient was listed as status 1A for combined heart and liver transplantation (CHLTx). A 22-year-old white man, inhouse donor with a gunshot wound to the head, EBV-positive, became available 1 month after listing. Despite positive pretransplant T and B complement-dependent lymphocytotoxic cross-matches we proceeded with CHLTx. Cardiac transplantation was performed first. Cold ischemic time was 100 min. Plasmapheresis was performed before cardiac reperfusion, and the patient was weaned from cardiopulmonary bypass with satisfactory cardiac graft function. The liver transplantation was performed as a second step. In this case of the EBV-negative recipient and therefore anticipated increased risk for developing posttransplant lymphoprolipherative disorder (PTLD), T cellYdepleting antibodies induction therapy was avoided (1), and immunosuppressive induction therapy with intravenous bisiliximab was given on postoperative days 1 and 4. Tacrolimus was initiated on postoperative day 4 when serum creatinine fell less than 2 mg/dL and gradually increased to obtain blood levels of 10 to 12 ng/mL. Twelve weeks after transplantation, the level was reduced to 8 to 10 ng/mL. Mycophenolate mofetil was initiated 2 g per day on postoperative day 1. Administration of steroids was started intraoperatively with 1 g methylprednisolone sodium succinate

A

followed by prednisone 2 mg/kg per day tapered to 0.2 mg/kg per day within 14 days after transplantation and then slowly weaned during the subsequent 6 months. Postoperatively, cardiac and liver function normalized, and patient was discharged to home 15 days after CHLTx. Donor-specific antibodies (DSA) were assessed by solid-phase assay at 1 week, 1, 2, 4, 5, 6, 7 months, and 1 and 2 years. Mean fluorescence intensity of DSA significantly decreased during the first posttransplant week, rebounded slightly at 1 month and then gradually disappeared over 4 months (Fig. 1). Weakly positive C4d staining was shown on cardiac biopsies up to 6 weeks after transplantation and then resolved. Unfortunately, in the setting of EBV mismatch, 9 months after transplantation, the patient developed PTLD: monoclonal large B-cell lymphoma involving small bowel and brain. Tacrolimus and mycophenolate mofetil were discontinued, and she was maintained

on low immunosuppression with Sirolimus 0.5 mg per day. She was treated with rituximab, cyclophosphamide, highdose methotrexate, however, the magnetic resonance imaging showed increasing brain lesions, and she proceeded with brain radiation and three courses of T-cell EBV immune infusions, which resulted in a dramatic response. At 2 years after CHLTx, the patient has done well clinically, regained normal functional status and has been rejection free with no evidence of coronary vasculopathy on maintenance immunosuppression with sirolimus 0.5 mg per day and prednisone 2.5 mg per day. Cardiac allograft function and liver function tests remain normal. Positron emission tomography showed no evidence of residual malignant disease, her cerebrospinal fluid analysis showed no evidence of lymphoma, and EBV DNA remained undetectable. Advances in pediatric cardiology and surgery have led to a significant increase in the number of adults with

FIGURE 1. MFIs of anti-HLA antibodies since the day of surgery up to 2 years. MFI, mean fluorescence intensity; HLA, human leukocyte antigen.

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Letters to the Editor

* 2014 Lippincott Williams & Wilkins

palliated complex congenital heart disease (2Y4). Liver cirrhosis develops frequently in adults with Fontan circulation and may preclude isolated heart transplantation. Simultaneous CHLTx can be a life-saving procedure (5); however, experience remains small. The UNOS (United Network for Organ Sharing) registry from October 1987 to March 2014 includes 163 cases of CHLTx; 31 (19%) of them were performed in surgically corrected congenital heart disease. These historic data analysis showed discouraging outcomes with 5year survival of 27% in congenital heart disease recipients compared to 48% in CHLTx recipients due to other causes (the majority of them had familial amyloidosis). This reflects the fact that compared to other transplant recipients, the adults with failing Fontan circulation introduce a particular set of challenges because of associated multiorgan failure, protein-losing enteropathy, and malnutrition. Recent improvements in surgical technique, anesthesiology, and critical care medicine have extended surgical feasibility and have made simultaneous CHLTx an acceptable therapy for endstage heart failure with cardiac cirrhosis in selected adolescents and young adults with congenital heart disease and complex thoracic and abdominal anatomy (6, 7). Moreover, CHLTx remains the only option for long-term survival among these young patients population and indications for CHLTx will likely increase (6). High sensitization because of previous blood transfusions and homograft implantation represents an additional significant problem in patients with failed Fontan circulation. Preformed anti-HLA antibodies increase the incidence of rejection, accelerate vasculopathy, and decrease long-term survival (8). It is difficult to find a suitable donor for highly sensitized patients and waiting list time may be prohibitive. Several desensitization approaches have been described; however, the efficacy of these treatments is variable (8, 9). In our case, we thought that desensitization treatment would be insufficient in the context of high PRA. Numerous reports of combined kidney and liver transplantation against a positive cross-match suggest that the liver graft may protect the kidney graft from the damage (10Y13). Moreover, even the transplantation of an auxiliary segmental liver graft neutralized preformed anti-HLA antibodies (14).

Limited data in CHLTx suggest that the liver might protect the heart from rejection and attenuate progression of vasculopathy (5, 15). A successful ‘‘reversed order’’ CHLTx in a highly sensitized recipient with positive crossmatch has been reported: the liver graft was implanted first and protected the subsequently transplanted cardiac allograft from hyperacute rejection (16). A profound and sustained decrease in DSA was reported immediately after liver transplantation. Our case illustrates successful CHLTx with heart transplantation performed as a first step and the liver transplantation as a second step. An advantage of this technique was a reduction in cardiac ischemic time and minimal surgical deviation from the standard procedures of isolated heart transplantation and isolated heart and isolated liver transplantation (5, 17). Plasmapheresis and induction immunosuppression protected the heart from hyperacute rejection until the liver had time to reduce the DSA levels. In this patient’s case, asymptomatic antibody-mediated rejection gradually resolved with routine immunosuppression only. During 2 years of follow-up, there has been no clinical rejection, no vasculopathy, and anti-HLA antibodies remained low even in the presence of a low maintenance immunosuppression with sirolimus and prednisone due to an episode of PTLD. There is a paucity of experience with CHLTx in recipients with positive cross-match, and the role of liver graft in preventing of cardiac antibody-mediated rejection is still unclear. This case shows a successful simultaneous CHLTx against a positive cross-match in a patient with hypoplastic left heart syndrome and suggests that the liver graft may protect he cardiac graft from damage due to circulating preformed antibodies. The liver graft may have a protective role of the heart graft function not only in the initial phase but also in the midterm follow-up. Combined heart and liver transplantation may benefit the growing population of sensitized Fontan patients with advanced liver disease. Eugenia Raichlin1,5 John Y. Um2 Kim F. Duncan2 Ioana Dumitru1 Brian D. Lowes1 Michael Moulton2 Catherine L. Gebhart3

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Wendy J. Grant4 James M. Hammel2 1

Division of Cardiology University of Nebraska Medical Center Omaha, NE 2 Division of Cardiovascular and Thoracic Surgery University of Nebraska Medical Center Omaha, NE 3 Division of Pathology and Microbiology University of Nebraska Medical Center Omaha, NE 4 Division of Surgery University of Nebraska Medical Center Omaha, NE The authors declare no funding and conflicts of interest. 5 Address correspondence to: Eugenia Raichlin, M.D., University of Nebraska Medical Center, Omaha, NE 68198-2265. E-mail: [email protected] Received 21 April 2014. Accepted 9 October 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9812-e99 DOI: 10.1097/TP.0000000000000542

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Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of posttransplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004; 4: 87. Stamm C, Friehs I, Mayer JE Jr, et al. Longterm results of the lateral tunnel Fontan operation. J Thorac Cardiovasc Surg 2001; 121: 28. Ono M, Boethig D, Goerler H, et al. Clinical outcome of patients 20 years after Fontan operationVeffect of fenestration on late morbidity. Eur J Cardiothorac Surg 2006; 30: 923. Mitchell ME, Ittenbach RF, Gaynor JW, et al. Intermediate outcomes after the Fontan procedure in the current era. J Thorac Cardiovasc Surg 2006; 131: 172. Raichlin E, Daly RC, Rosen CB, et al. Combined heart and liver transplantation: a singlecenter experience. Transplantation 2009; 88: 219. Hollander SA, Reinhartz O, Maeda K, et al. Intermediate-term outcomes after combined heart-liver transplantation in children with a univentricular heart. J Heart Lung Transplant 2013; 32: 368. Hill AL, Maeda K, Bonham CA, Concepcion W. Pediatric combined heart-liver transplantation performed en bloc: a singlecenter experience. Pediatr Transplant 2012; 16: 392. Tambur AR, Bray RA, Takemoto SK, et al. Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection. Transplantation 2000; 70: 1055. Patel J, Everly M, Chang D, et al. Reduction of alloantibodies via proteasome inhibition

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in cardiac transplantation. J Heart Lung Transplant 2011; 30: 1320. Manez R, Kelly RH, Kobayashi M, et al. Immunoglobulin G lymphocytotoxic antibodies in clinical liver transplantation: studies toward further defining their significance. Hepatology 1995; 21: 1345. Leca N, Warner P, Bakthavatsalam R, et al. Outcomes of simultaneous liver and kidney transplantation in relation to a high level of preformed donor-specific antibodies. Transplantation 2013; 96: 914. Fung J, Griffin M, Duquesnoy R, et al. Successful sequential liver-kidney transplantation

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in a patient with performed lymphocytotoxic antibodies. Transplant Proc 1987; 19(1 Pt 1): 767. lye MW, Duffy BF, Phelan DL, et al. Protective effects of liver transplantation on a simultaneously transplanted kidney in a highly sensitized patient. Transplantation 1990; 50: 1051. Olausson M, Mjornstedt L, Norden G, et al. Successful combined partial auxiliary liver and kidney transplantation in highly sensitized cross-match positive recipients. Am J Transplant 2007; 7: 130.

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Everolimus-Induced Posterior Reversible Encephalopathy Syndrome and Bilateral Optic Neuropathy After Kidney Transplantation verolimus is a mammalian target of rapamycin inhibitor mainly used to prevent organ transplant rejection. In comparison to cyclosporine, everolimus safety profile was shown to be good without neurotoxicity (1, 2). To our knowledge, there is no report of any everolimusinduced posterior reversible encephalopathy syndrome (PRES) or optic neuropathy (ON). Cases of cyclosporine, tacrolimus, and more recently sirolimus-induced PRES (3Y5) and ON have been described (3, 6, 7). We report the first case of a severe neurotoxic side effect of everolimusPRES associated with bilateral ON.

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CASE REPORT A 54-year-old woman was referred for acute, severe bilateral vision loss, and headaches. She received a first livingrelated renal transplant in 1976 for an immunoglobulin A nephropathy. She eventually lost her first transplant in 2012 due to chronic dysfunction. She received a second brain-death-donor transplant 10 months before presentation. She was given our usual immunosuppressive protocol for high-risk patients (high PRA and retransplant), including thymoglobulin induction and maintenance with steroids, MMF, and Tacrolimus. Renal function remained stable with a serum creatinine level around 90 to 110 Kmol/L and an estimated glomerular filtration rate between 47 and 60 mL per min. Immunosuppression had to be adjusted 5 months later because renal function deteriorated due to tacrolimus nephrotoxicity and BK virus replication. Tacrolimus was withdrawn, and

everolimus was introduced. An unusually high dose of the latter had to be given to reach a through level between 4 and 8 ng/mL. Subsequently, renal function returned to previous level, and BK virus replication was no longer detectable. Visual acuity was limited to hand motions in both eyes. On fundus examination, both optic discs were swollen with no retinal abnormalities (Fig. 1A). Fluorescein angiography (Fig. 1B) and optic coherence tomography confirmed the optic disc edema. Goldman visual field demonstrated bilateral central scotoma. Clinical examination was otherwise unremarkable, and blood pressure was normal. There was no history of malnutrition or restricted diet. Human immunodeficiency virus, syphilis, herpes family viruses, Borrelia burgdorferi, JC virus, and adenovirus serologies were negative. Tuberculosis testing (Tuberculosis skin test or PPD and Quantiferon Gold) was negative. Leber ON and Devic syndrome were ruled out. Lumbar puncture, abdominal and thoracic computed tomography scan, and cardiovascular workup were normal. Initial magnetic resonance imaging of the brain was normal. Several days after presentation, the patient presented generalized seizures. A second brain magnetic resonance imaging showed multiple bilateral T2-weighted hypersignals in the white matter of the occipital regions consistent with a PRES (Fig. 1C). Everolimus that had been recently started was incriminated because none of the other medications taken by the patient was known to be associated

with PRES. Given the severity of the neurologic and ophthalmologic symptoms, no dose reduction was attempted. Immediate and complete withdrawal was decided to maximize the patient’s chances of recovery. Everolimus was replaced by belatacept. Clinical stabilization was obtained after everolimus withdrawal. Visual acuity after 6 months of follow-up remained at counting fingers in the right eye and improved to 20/63 in the left eye. Renal function remained stable throughout follow-up until today.

DISCUSSION Posterior reversible encephalopathy syndrome is an association of acute or subacute clinical and neuroimaging features first described in 1996 by Hinchey (8). The most common symptoms are headaches, altered mental status, seizures, and visual abnormalities ranging from blurred vision to hemianopia, visual neglect, and cortical blindness. Neuroimaging abnormalities are consistent with bilateral white matter edema in the posterior, especially the parieto-occipital portions of the cerebral hemispheres (8). Etiologies of PRES are multiple but the most common are acute hypertension, fluid retention, use of immunosuppressive agents, immune conditions, sepsis, and shock (9, 10). Posterior reversible encephalopathy syndrome has been associated with other immunosuppressants, such as cyclosporine and tacrolimus (calcineurin inhibitors) and more recently mammalian target of rapamycin inhibitor sirolimus (5). To date, no everolimus-induced PRES with ON has

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Combined heart and liver transplantation against positive cross-match for patient with hypoplastic left heart syndrome.

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