e42
Transplantation
& Volume 97, Number 7, April 15, 2014
The efficacy of hyperbaric oxygen therapy has been established for HC because of chemotherapy and/or radiation therapy (10, 11). Hyperbaric oxygen therapy has also been shown effective in the treatment of HC after autologous peripheral blood stem cell transplantation and allogeneic BMT (12Y14). Early hyperbaric oxygen therapy after onset of hematuria was associated with more rapid control of bleeding and decreased transfusion requirements (12). In this report, hyperbaric oxygen therapy was also useful to suppress severe HC and should be considered as one of the treatment options for severe HC, and further clinical trials of HBO therapy in patients with HC after stem cell transplantation are needed. Liren Qian1 Jianliang Shen1 Defeng Zhao1 Shuyi Pan2
unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLAidentical sibling transplantation. Blood 2006; 107: 3065. El-Zimaity M, Saliba R, Chan K, et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. Blood 2004; 103: 4674. Seber A, Shu XO, Defor T, et al. Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant 1999; 23: 35. Childs R, Sanchez C, Engler H, et al. High incidence of adeno- and polyomavirusinduced hemorrhagic cystitis in bone marrow allotransplantation for hematological malignancy following T cell depletion and cyclosporine. Bone Marrow Transplant 1998; 22: 889. Ost L, Lonnqvist B, Eriksson L, et al. Hemorrhagic cystitisYa manifestation of graft versus host disease? Bone Marrow Transplant 1987; 2: 19. Qian L, Shen J. Hydrogen therapy may be an effective and specific novel treatment for acute graft-versus-host disease (GVHD). J Cell Mol Med 2013; 17: 1059. Qian L, Mei K, Shen J, et al. Administration of hydrogen-rich saline protects mice from lethal acute graft-versus-host disease (aGVHD). Transplantation 2013; 95: 658. Qian L, Wu Z, Shen J. Advances in the treatment of acute graft-versus-host disease. J Cell Mol Med 17: 966. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13: 1103. Shameem IA, Shimabukuro T, Shirataki S, et al. Hyperbaric oxygen therapy for control of intractable cyclophosphamideinduced hemorrhagic cystitis. Eur Urol 1992; 22: 263. Stillwell TJ, Benson RC Jr, Burgert EO Jr. Cyclophosphamide-induced hemorrhagic cystitis in Ewing’s sarcoma. J Clin Oncol 1988; 6: 76. Hattori K, Yabe M, Matsumoto M, et al. Successful hyperbaric oxygen treatment of life-threatening hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 27: 1315. Saito S, Kaiho Y, Namina T, et al. A case of severe hemorrhagic cystitis following bone marrow transplantation. Int Urol Nephrol 2004; 36: 349. Hughes AJ, Schwarer AP, Millar IL. Hyperbaric oxygen in the treatment of refractory haemorrhagic cystitis. Bone Marrow Transplant 1998; 22: 585.
www.transplantjournal.com
cycles of consolidation therapy. The transplantation protocol was performed as Daopei Lu et al. described previously (1). The patient did not develop acute graft-versus-host disease (GVHD). On day +40 posttransplantation, he had developed microscopic hematuria and suprapubic pain. Pathogens were negative with the urine culture including virus and bacteria. The specific cause of this patient’s HC remains unknown. He received the therapy of hydratization, alkalization, hemostatic therapy, and blood transfusion. Despite symptomatic treatment, he developed gross hematuria dysuria, hypourocrinia, urinary retention, and continuous bleeding on day +98 posttransplantation. Hyperbaric oxygen therapy at 1.6 atmospheric pressure for 90 min per day was administered to the patient on day +105 posttransplantation. On day +119 post transplantation, microscopic hematuria dysuria disappeared. At follow-up of 5 months posttransplantation, the urine remained clear, and renal and bladder function had completely recovered. The cumulative incidence of HC was 30% among mismatched related donor HSCT (2). Hemorrhagic cystitis is graded as mild (sustained microscopic hematuria), moderate (presence of clots, dysuria, or gross hematuria), and severe (urinary retention, renal failure, and uncontrollable bleeding) (3). Early occurring HC is frequently ascribed to the preparative regimens such as cyclophosphamide, whereas those that occur later after transplantation are more often credited to viral infections such as adenovirus, cytomegalovirus, and BK virus (3, 4). Risk factors for HC were considered as donor types, GVHD (grades II-IV), GVHD prophylaxis, age at HSCT (10Y30 years old), and so on, but the role of GVHD in HC is still controversial (2, 3, 5Y8). Severe HC was once considered as a manifestation of GVHD (5), but Maha ElZimaity et al. and Bedi et al. supposed that the development of grades II to IV acute GVHD was not associated with HC (2, 9).
1
Department of Haematology Navy General Hospital Fucheng Road, Beijing People’s Republic of China 2 Department of Hyperbaric Oxygen Navy General Hospital Fucheng Road, Beijing People’s Republic of China The authors declare no funding or conf licts of interest. Address correspondence to: Liren Qian M.D., Department of Hematology, Navy General Hospital, Fucheng Road, Beijing, 100048, People’s Republic of China. E-mail: [email protected] L.Q. participated in research design, writing of the paper, performance of the research, and data analysis. J.S. participated in research design and performance of the research and contributed new reagents or analytic tools. D.Z. participated in research design and performance of the research and contributed new reagents or analytic tools. S.P. participated in research design and performance of the research. Received 20 December 2013. Accepted 3 January 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9707-e41 DOI: 10.1097/TP.0000000000000049
REFERENCES 1.
Lu DP, Dong L, Wu T, et al. Conditioning including antithymocyte globulin followed by
2.
3. 4.
5.
6.
7.
8. 9.
10.
11.
12.
13.
14.
Kidney Transplantation From a Deceased Donor With Metachromatic Leukodystrophy etachromatic leukodystrophy (MLD) is a lysosomal defect with an incidence of approximately 1:100,000 causing the storage of sulfogalactose-
M
containing lipids, primarily sulfatide (1). The target organ is the brain, and neurodevelopmenta symptoms generally begin before the age of three years. Life
expectancy is abbreviated. Extra-CNS manifestations of MLD are rare. Sulfatide accumulates in other organ systems (2), but only gall bladder disease is consistently
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
* 2014 Lippincott Williams & Wilkins
FIGURE 1. A, Toluidine blue staining of transplanted kidney at the 2-year surveillance biopsy showing intracytoplasmic vacuolated inclusions within renal epithelial cells (arrow). B, Electron micrograph (60,000X) of the 2-year biopsy showing membrane bound laminated inclusions with a targetoid or zebroid morphology. C, Electron micrograph (4000) at the 3-year biopsy showing fragmentation of inclusions within lysosomes. D, Extrusion of inclusions into the urinary space (8000).
associated with MLD (3Y5). We present here our experiences with performing renal transplantation from a patient with MLD. The donor was a male subject diagnosed at age 2 after the development of psychomotor retardation. Metachromatic leukodystrophy was confirmed by identification of arylsulfatase A mutations. At age 10, he experienced an unexplained cardiac arrest and arrived at the hospital in asystole. He was successfully resuscitated, but after neurologic evaluation, brain death was declared. His parents requested that his organs be transplanted. In facing a decision on the suitability of MLD patients as transplant donors, we identified no obvious bar to transplantation of unaffected tissues but found no reports of such transplants as guidance. One kidney was transplanted into a 59-year-old woman with diabetic
nephropathy. The other kidney was dysplastic and was not used. The transplant team considered donor age, size, urine output, and creatinine as criteria for accepting the organ. A pretransplant biopsy was not performed. The recipient’s posttransplant course was uncomplicated, with early graft function. The patient was discharged on standard immunosuppression, which consisted of tacrolimus, mycophenolate mofetil, and low dose prednisone. Allograft function has been excellent, with a baseline serum creatinine of 1.1 mg/dL, which has been stable for 3 years. The patient had one episode of mild cellular rejection, which was treated with pulse steroids. She has had no BK viremia, development of donor-specific antibody, or any other major complications. Kidney allograft biopsies were performed at time zero and at follow-up
e43
after 3, 12, 24, and 36 months. The surveillance biopsy at 2 years showed vacuolated epithelial cells. Vacuoles were irregularly distributed within the tubular cytoplasm and present only in approximately 5% to 10% of tubules (Fig. 1A). Ultrastructural examination revealed concentrically arranged dense laminated inclusions in the areas of vacuolation, with a targetoid or zebroid appearance typical to the storage of sulfatide (Fig. 1B). The size of these inclusions ranged from 1 to 2 KM. These ultrastructural findings were similar in the surveillance biopsies from the first 2 years. At the third year, biopsy inclusions were dispersed within the epithelial cytoplasm and were fragmented and reduced in size (G1 KM) (Fig. 1C). Occasional lamellated particles traversed the cytoplasmic membrane of the proximal tubules akin to exocytosis and were detected in the tubular lumen (Fig. 1D). These findings suggest an improvement of the pathologic features associated with MLD in the transplanted kidney. The heart and liver were also transplanted from the MLD patient. The cardiac graft recipient was a child with a complex congenital heart disease who had been on bilateral ventricular assist devices for 5 months. There were no difficulties with preservation, and cross match was negative. During the initial attempt to separate from bypass, there was immediate biventricular failure. Subsequent attempts to discontinue ECMO over the next 2 weeks were unsuccessful, and support was withdrawn. The parents refused autopsy. The recipient of the liver transplant was an adult with primary biliary cirrhosis. The transplant was uncomplicated, and the patient was discharged on a standard antirejection protocol. The patient was readmitted to hospital 6 days after transplant in shock. She expired 10 days after transplant. Autopsy was declined. Regrettably, the lack of post mortem evaluations in these transplant make it difficult to determine the role of MLD in the outcome; however, the treating teams in both cases determined that recipient-specific factors were the principal drivers of the poor outcome. The decision to include transplant donors with genetic disease presents a significant clinical challenge. The limited organ supply must be
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e44
www.transplantjournal.com
balanced against the risk of organ failure or the inadvertent introduction of genetic or metabolic disease. Families of children with lysosomal storage disorders may have close relationships with medical providers increasing the interest in tissue donation at the time of demise. Disease and organ-specific factors provide guidance for tissues that should be avoided. Renal transplantation from a female donor with unrecognized Fabry disease, a lysosomal disorder of globotriaosylceramide storage, led to premature graft dysfunction in the recipients, an expected complication in this disease (6). Renal transplants from patients with disorders lacking renal pathology, such as ornithine transcarbamylase deficiency, have been performed successfully (7). Other examples of genetic disease risk avoidance are found in ‘‘domino transplants,’’ serial transplants involving a graft to a patient with a metabolic disorder, followed by transplant of the affected organ to a second patient requiring transplantation for an unrelated cause. This is most frequently performed for patients with familial amyloidotic polyneuropathy (8) but has been performed successfully in a case of maple syrup urine disease (9). Complications can arise with this procedure, and a domino transplant of a patient with the peroxisomal defect primary hyperoxaluria led to unacceptable disease-related complications in the recipient of the affected liver (10). Evaluation of the transplanted kidney suggests that a cell extrinsic mitigation of the lysosomal pathology has occurred, with clearance of sulfatide. This improvement likely results from
Transplantation
the uptake of functional lysosomal enzymes from the recipient plasma. This capacity for the import of lysosomal enzymes from blood provides the basis for the use of recombinant enzyme therapies in lysosomal storage defects (11). Future investigations of the surviving renal graft will monitor the sulfatide clearance by the kidney. The excellent clinical result after kidney allograft, and the ability to continue dialysis if acute rejection intervenes, suggests that renal transplantation from MLD patients is safe and effective.
& Volume 97, Number 7, April 15, 2014 ISSN: 0041-1337/14/9707-e42 DOI: 10.1097/TP.0000000000000052
ACKNOWLEDGMENTS The authors thank Daniel Licht and Marta Guttenberg for discussions of the case.
REFERENCES 1. 2.
Neal Sondheimer1 Suganthi Soundararajan2 Sirma H Koutzaki2 Alden M. Doyle3
3.
1 Department of Pediatrics The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine Philadelphia, PA 2 Department of Pathology Drexel University College of Medicine Philadelphia, PA 3 Department of Internal Medicine Drexel University College of Medicine Philadelphia, PA
4.
N.S. was supported by K08HD058022. The authors declare no funding or conflict of interest. Address correspondence to: Neal Sondheimer M.D., Ph.D., ARC1010A, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: [email protected] N.S. participated in research design and in the writing of the paper. S.S. and S.H.K. participated in data analysis. A.M.D. participated in research design and in the writing of the paper. Received 13 November 2013. Accepted 23 December 2013. Copyright * 2014 by Lippincott Williams & Wilkins
5.
6. 7.
8. 9. 10.
11.
Gieselmann V, Kra¨geloh-Mann I. Metachromatic leukodystrophyVan update. Neuropediatrics 2010; 41: 1. Toda K, Kobayashi T, Goto I, et al. Accumulation of lysosulfatide (sulfogalactosylsphingosine) in tissues of a boy with metachromatic leukodystrophy. Biochem Biophys Res Commun 1989; 159: 605. Garavelli L, Rosato S, Mele A, et al. Massive hemobilia and papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics 2009; 40: 284. Siegel EG, Lu¨cke H, Schauer W, et al. Repeated upper gastrointestinal hemorrhage caused by metachromatic leukodystrophy of the gall bladder. Digestion 1992; 51: 121. Oak S, Rao S, Karmarkar S, et al. Papillomatosis of the gallbladder in metachromatic leukodystrophy. Pediatr Surg Int 1997; 12: 424. Basic-Jukic N, Coric M, Kes P, et al. AndersonFabry disease in kidneys from deceased donor. Am J Transplant 2007; 7: 2829. Caballero F, Ris J, Puig M, et al. Successful kidney transplantation from a brain-dead donor with ornithine transcarbamylase deficiency. Transplantation 2013; 96: e63. Wilczek HE, Larsson M, Yamamoto S, et al. Domino liver transplantation. J Hepatobiliary Pancreat Surg 2008; 15: 139. Khanna A, Hart M, Nyhan WL, et al. Domino liver transplantation in maple syrup urine disease. Liver Transpl 2006; 12: 876. Donckier V, Nakadi El I, Closset J, et al. Domino hepatic transplantation using the liver from a patient with primary hyperoxaluria. Transplantation 2001; 71: 1346. Kornfeld S. Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest 1986; 77: 1.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Transplantation
& Volume 97, Number 7, April 15, 2014
The efficacy of hyperbaric oxygen therapy has been established for HC because of chemotherapy and/or radiation therapy (10, 11). Hyperbaric oxygen therapy has also been shown effective in the treatment of HC after autologous peripheral blood stem cell transplantation and allogeneic BMT (12Y14). Early hyperbaric oxygen therapy after onset of hematuria was associated with more rapid control of bleeding and decreased transfusion requirements (12). In this report, hyperbaric oxygen therapy was also useful to suppress severe HC and should be considered as one of the treatment options for severe HC, and further clinical trials of HBO therapy in patients with HC after stem cell transplantation are needed. Liren Qian1 Jianliang Shen1 Defeng Zhao1 Shuyi Pan2
unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLAidentical sibling transplantation. Blood 2006; 107: 3065. El-Zimaity M, Saliba R, Chan K, et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. Blood 2004; 103: 4674. Seber A, Shu XO, Defor T, et al. Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant 1999; 23: 35. Childs R, Sanchez C, Engler H, et al. High incidence of adeno- and polyomavirusinduced hemorrhagic cystitis in bone marrow allotransplantation for hematological malignancy following T cell depletion and cyclosporine. Bone Marrow Transplant 1998; 22: 889. Ost L, Lonnqvist B, Eriksson L, et al. Hemorrhagic cystitisYa manifestation of graft versus host disease? Bone Marrow Transplant 1987; 2: 19. Qian L, Shen J. Hydrogen therapy may be an effective and specific novel treatment for acute graft-versus-host disease (GVHD). J Cell Mol Med 2013; 17: 1059. Qian L, Mei K, Shen J, et al. Administration of hydrogen-rich saline protects mice from lethal acute graft-versus-host disease (aGVHD). Transplantation 2013; 95: 658. Qian L, Wu Z, Shen J. Advances in the treatment of acute graft-versus-host disease. J Cell Mol Med 17: 966. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13: 1103. Shameem IA, Shimabukuro T, Shirataki S, et al. Hyperbaric oxygen therapy for control of intractable cyclophosphamideinduced hemorrhagic cystitis. Eur Urol 1992; 22: 263. Stillwell TJ, Benson RC Jr, Burgert EO Jr. Cyclophosphamide-induced hemorrhagic cystitis in Ewing’s sarcoma. J Clin Oncol 1988; 6: 76. Hattori K, Yabe M, Matsumoto M, et al. Successful hyperbaric oxygen treatment of life-threatening hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 27: 1315. Saito S, Kaiho Y, Namina T, et al. A case of severe hemorrhagic cystitis following bone marrow transplantation. Int Urol Nephrol 2004; 36: 349. Hughes AJ, Schwarer AP, Millar IL. Hyperbaric oxygen in the treatment of refractory haemorrhagic cystitis. Bone Marrow Transplant 1998; 22: 585.
www.transplantjournal.com
cycles of consolidation therapy. The transplantation protocol was performed as Daopei Lu et al. described previously (1). The patient did not develop acute graft-versus-host disease (GVHD). On day +40 posttransplantation, he had developed microscopic hematuria and suprapubic pain. Pathogens were negative with the urine culture including virus and bacteria. The specific cause of this patient’s HC remains unknown. He received the therapy of hydratization, alkalization, hemostatic therapy, and blood transfusion. Despite symptomatic treatment, he developed gross hematuria dysuria, hypourocrinia, urinary retention, and continuous bleeding on day +98 posttransplantation. Hyperbaric oxygen therapy at 1.6 atmospheric pressure for 90 min per day was administered to the patient on day +105 posttransplantation. On day +119 post transplantation, microscopic hematuria dysuria disappeared. At follow-up of 5 months posttransplantation, the urine remained clear, and renal and bladder function had completely recovered. The cumulative incidence of HC was 30% among mismatched related donor HSCT (2). Hemorrhagic cystitis is graded as mild (sustained microscopic hematuria), moderate (presence of clots, dysuria, or gross hematuria), and severe (urinary retention, renal failure, and uncontrollable bleeding) (3). Early occurring HC is frequently ascribed to the preparative regimens such as cyclophosphamide, whereas those that occur later after transplantation are more often credited to viral infections such as adenovirus, cytomegalovirus, and BK virus (3, 4). Risk factors for HC were considered as donor types, GVHD (grades II-IV), GVHD prophylaxis, age at HSCT (10Y30 years old), and so on, but the role of GVHD in HC is still controversial (2, 3, 5Y8). Severe HC was once considered as a manifestation of GVHD (5), but Maha ElZimaity et al. and Bedi et al. supposed that the development of grades II to IV acute GVHD was not associated with HC (2, 9).
1
Department of Haematology Navy General Hospital Fucheng Road, Beijing People’s Republic of China 2 Department of Hyperbaric Oxygen Navy General Hospital Fucheng Road, Beijing People’s Republic of China The authors declare no funding or conf licts of interest. Address correspondence to: Liren Qian M.D., Department of Hematology, Navy General Hospital, Fucheng Road, Beijing, 100048, People’s Republic of China. E-mail: [email protected] L.Q. participated in research design, writing of the paper, performance of the research, and data analysis. J.S. participated in research design and performance of the research and contributed new reagents or analytic tools. D.Z. participated in research design and performance of the research and contributed new reagents or analytic tools. S.P. participated in research design and performance of the research. Received 20 December 2013. Accepted 3 January 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9707-e41 DOI: 10.1097/TP.0000000000000049
REFERENCES 1.
Lu DP, Dong L, Wu T, et al. Conditioning including antithymocyte globulin followed by
2.
3. 4.
5.
6.
7.
8. 9.
10.
11.
12.
13.
14.
Kidney Transplantation From a Deceased Donor With Metachromatic Leukodystrophy etachromatic leukodystrophy (MLD) is a lysosomal defect with an incidence of approximately 1:100,000 causing the storage of sulfogalactose-
M
containing lipids, primarily sulfatide (1). The target organ is the brain, and neurodevelopmenta symptoms generally begin before the age of three years. Life
expectancy is abbreviated. Extra-CNS manifestations of MLD are rare. Sulfatide accumulates in other organ systems (2), but only gall bladder disease is consistently
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
* 2014 Lippincott Williams & Wilkins
FIGURE 1. A, Toluidine blue staining of transplanted kidney at the 2-year surveillance biopsy showing intracytoplasmic vacuolated inclusions within renal epithelial cells (arrow). B, Electron micrograph (60,000X) of the 2-year biopsy showing membrane bound laminated inclusions with a targetoid or zebroid morphology. C, Electron micrograph (4000) at the 3-year biopsy showing fragmentation of inclusions within lysosomes. D, Extrusion of inclusions into the urinary space (8000).
associated with MLD (3Y5). We present here our experiences with performing renal transplantation from a patient with MLD. The donor was a male subject diagnosed at age 2 after the development of psychomotor retardation. Metachromatic leukodystrophy was confirmed by identification of arylsulfatase A mutations. At age 10, he experienced an unexplained cardiac arrest and arrived at the hospital in asystole. He was successfully resuscitated, but after neurologic evaluation, brain death was declared. His parents requested that his organs be transplanted. In facing a decision on the suitability of MLD patients as transplant donors, we identified no obvious bar to transplantation of unaffected tissues but found no reports of such transplants as guidance. One kidney was transplanted into a 59-year-old woman with diabetic
nephropathy. The other kidney was dysplastic and was not used. The transplant team considered donor age, size, urine output, and creatinine as criteria for accepting the organ. A pretransplant biopsy was not performed. The recipient’s posttransplant course was uncomplicated, with early graft function. The patient was discharged on standard immunosuppression, which consisted of tacrolimus, mycophenolate mofetil, and low dose prednisone. Allograft function has been excellent, with a baseline serum creatinine of 1.1 mg/dL, which has been stable for 3 years. The patient had one episode of mild cellular rejection, which was treated with pulse steroids. She has had no BK viremia, development of donor-specific antibody, or any other major complications. Kidney allograft biopsies were performed at time zero and at follow-up
e43
after 3, 12, 24, and 36 months. The surveillance biopsy at 2 years showed vacuolated epithelial cells. Vacuoles were irregularly distributed within the tubular cytoplasm and present only in approximately 5% to 10% of tubules (Fig. 1A). Ultrastructural examination revealed concentrically arranged dense laminated inclusions in the areas of vacuolation, with a targetoid or zebroid appearance typical to the storage of sulfatide (Fig. 1B). The size of these inclusions ranged from 1 to 2 KM. These ultrastructural findings were similar in the surveillance biopsies from the first 2 years. At the third year, biopsy inclusions were dispersed within the epithelial cytoplasm and were fragmented and reduced in size (G1 KM) (Fig. 1C). Occasional lamellated particles traversed the cytoplasmic membrane of the proximal tubules akin to exocytosis and were detected in the tubular lumen (Fig. 1D). These findings suggest an improvement of the pathologic features associated with MLD in the transplanted kidney. The heart and liver were also transplanted from the MLD patient. The cardiac graft recipient was a child with a complex congenital heart disease who had been on bilateral ventricular assist devices for 5 months. There were no difficulties with preservation, and cross match was negative. During the initial attempt to separate from bypass, there was immediate biventricular failure. Subsequent attempts to discontinue ECMO over the next 2 weeks were unsuccessful, and support was withdrawn. The parents refused autopsy. The recipient of the liver transplant was an adult with primary biliary cirrhosis. The transplant was uncomplicated, and the patient was discharged on a standard antirejection protocol. The patient was readmitted to hospital 6 days after transplant in shock. She expired 10 days after transplant. Autopsy was declined. Regrettably, the lack of post mortem evaluations in these transplant make it difficult to determine the role of MLD in the outcome; however, the treating teams in both cases determined that recipient-specific factors were the principal drivers of the poor outcome. The decision to include transplant donors with genetic disease presents a significant clinical challenge. The limited organ supply must be
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e44
www.transplantjournal.com
balanced against the risk of organ failure or the inadvertent introduction of genetic or metabolic disease. Families of children with lysosomal storage disorders may have close relationships with medical providers increasing the interest in tissue donation at the time of demise. Disease and organ-specific factors provide guidance for tissues that should be avoided. Renal transplantation from a female donor with unrecognized Fabry disease, a lysosomal disorder of globotriaosylceramide storage, led to premature graft dysfunction in the recipients, an expected complication in this disease (6). Renal transplants from patients with disorders lacking renal pathology, such as ornithine transcarbamylase deficiency, have been performed successfully (7). Other examples of genetic disease risk avoidance are found in ‘‘domino transplants,’’ serial transplants involving a graft to a patient with a metabolic disorder, followed by transplant of the affected organ to a second patient requiring transplantation for an unrelated cause. This is most frequently performed for patients with familial amyloidotic polyneuropathy (8) but has been performed successfully in a case of maple syrup urine disease (9). Complications can arise with this procedure, and a domino transplant of a patient with the peroxisomal defect primary hyperoxaluria led to unacceptable disease-related complications in the recipient of the affected liver (10). Evaluation of the transplanted kidney suggests that a cell extrinsic mitigation of the lysosomal pathology has occurred, with clearance of sulfatide. This improvement likely results from
Transplantation
the uptake of functional lysosomal enzymes from the recipient plasma. This capacity for the import of lysosomal enzymes from blood provides the basis for the use of recombinant enzyme therapies in lysosomal storage defects (11). Future investigations of the surviving renal graft will monitor the sulfatide clearance by the kidney. The excellent clinical result after kidney allograft, and the ability to continue dialysis if acute rejection intervenes, suggests that renal transplantation from MLD patients is safe and effective.
& Volume 97, Number 7, April 15, 2014 ISSN: 0041-1337/14/9707-e42 DOI: 10.1097/TP.0000000000000052
ACKNOWLEDGMENTS The authors thank Daniel Licht and Marta Guttenberg for discussions of the case.
REFERENCES 1. 2.
Neal Sondheimer1 Suganthi Soundararajan2 Sirma H Koutzaki2 Alden M. Doyle3
3.
1 Department of Pediatrics The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine Philadelphia, PA 2 Department of Pathology Drexel University College of Medicine Philadelphia, PA 3 Department of Internal Medicine Drexel University College of Medicine Philadelphia, PA
4.
N.S. was supported by K08HD058022. The authors declare no funding or conflict of interest. Address correspondence to: Neal Sondheimer M.D., Ph.D., ARC1010A, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: [email protected] N.S. participated in research design and in the writing of the paper. S.S. and S.H.K. participated in data analysis. A.M.D. participated in research design and in the writing of the paper. Received 13 November 2013. Accepted 23 December 2013. Copyright * 2014 by Lippincott Williams & Wilkins
5.
6. 7.
8. 9. 10.
11.
Gieselmann V, Kra¨geloh-Mann I. Metachromatic leukodystrophyVan update. Neuropediatrics 2010; 41: 1. Toda K, Kobayashi T, Goto I, et al. Accumulation of lysosulfatide (sulfogalactosylsphingosine) in tissues of a boy with metachromatic leukodystrophy. Biochem Biophys Res Commun 1989; 159: 605. Garavelli L, Rosato S, Mele A, et al. Massive hemobilia and papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics 2009; 40: 284. Siegel EG, Lu¨cke H, Schauer W, et al. Repeated upper gastrointestinal hemorrhage caused by metachromatic leukodystrophy of the gall bladder. Digestion 1992; 51: 121. Oak S, Rao S, Karmarkar S, et al. Papillomatosis of the gallbladder in metachromatic leukodystrophy. Pediatr Surg Int 1997; 12: 424. Basic-Jukic N, Coric M, Kes P, et al. AndersonFabry disease in kidneys from deceased donor. Am J Transplant 2007; 7: 2829. Caballero F, Ris J, Puig M, et al. Successful kidney transplantation from a brain-dead donor with ornithine transcarbamylase deficiency. Transplantation 2013; 96: e63. Wilczek HE, Larsson M, Yamamoto S, et al. Domino liver transplantation. J Hepatobiliary Pancreat Surg 2008; 15: 139. Khanna A, Hart M, Nyhan WL, et al. Domino liver transplantation in maple syrup urine disease. Liver Transpl 2006; 12: 876. Donckier V, Nakadi El I, Closset J, et al. Domino hepatic transplantation using the liver from a patient with primary hyperoxaluria. Transplantation 2001; 71: 1346. Kornfeld S. Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest 1986; 77: 1.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
