Waitlist Mortality in Lung Transplant Candidates in Japan.

Abstract

LUNG TRANSPLANTATION IN JAPAN Lung transplantation has dramatically evolved in recent decades and has become the preferred treatment procedure for end-stage pulmonary disease. Despite the worldwide transplant success, Japan is lagging behind in achieving a social consensus on brain death. The Japanese Organ Transplantation Act has been issued in October 1997, legalizing the transplantation of organs from brain-dead donors.1 Yet, the number of organ donations has remained very small as the Act requires written documentation of consent before brain death while not supporting donation of brain-dead donors under the age of 15. Thus, the annual number of deceased-donor lung transplants has remained in the single digits for the first 10 years during which living-donor lung transplants dominated the field (Figure 1A). However, the number of brain-dead donors substantially increased after implementation of the revised Act in July 2010, leading to a switch in the ratio of living- and deceased-donor transplants. After 2010, the annual number of deceased-donor lung transplants rose from 50 to 70 cases and remained steady until today. By the end of 2020, 835 lung transplants, including 584 deceased-donor and 251 living-donor cases, have been performed in Japan.2 Nevertheless, the number of lung transplant candidates has been rising and steadily outnumbered that of transplant recipients.2FIGURE 1.: Current circumstances of lung transplant in Japan. A, Lung transplant candidates listed with the Japan Organ Transplant Network (solid line) and lung transplant recipients (bar charts) with breakdown of procedure type. B, Lung transplant programs and volumes in Japan. Fujita-Health is a newly certified center. C, Waitlist characteristics and mortalities at Tohoku University Hospital (1998–2020).LUNG TRANSPLANT PROGRAMS AND THE ASSESSMENT OF TRANSPLANT CANDIDACY IN JAPAN There are 10 lung transplant centers in Japan, which are affiliated with hospitals of Universities in Tohoku, Dokkyo-Medical, Tokyo, Chiba, Fujita-Health, Kyoto, Osaka, Okayama, Fukuoka, and Nagasaki (Figure 1B). As of the end of 2020, Kyoto University has been the leading lung transplant center performing most of the deceased-donor procedures in Japan (n = 159), followed by Tohoku (n = 122) and Okayama (n = 110), with living-donor lungs mostly performed in Kyoto (n = 104), followed by Okayama (n = 94) and Tokyo (n = 15).2 Although the revised lung allocation in the United States has reduced mortality rates for waitlisted patients and improved outcomes for recipients,3–5 the allocation policy in Japan has remained unchanged over the last decade. Briefly, patients with advanced pulmonary disease are referred to a lung transplant center for an extensive evaluation through a 2-step assessment by regional and central committees. Members of regional committees consist of pulmonologists and thoracic surgeons in the regional hospitals, whereas the central committee represents a subsidiary organization of the Japanese Respiratory Society.6 As specific guidelines for the selection of lung transplant candidates are currently lacking in Japan, the assessment by regional and central committees aims to provide an impartial evaluation. LUNG ALLOCATION AND WAITING TIME IN JAPAN After approval for transplant candidacy, patients are registered with the Japan Organ Transplant Network (JOTN) and listed at the respective transplant center.7 The current system of the JOTN allocates deceased-donor lungs to candidates on the waitlist based on (1) donor age (<18-y-old preferentially to <18-y-old candidates), (2) lung volume match (within ±30% of the predicted vital capacity), (3) compatible ABO blood type (preferentially identical), and (4) waiting time (priority for patients longer on the waitlist). Additionally, a negative complement-dependent cytotoxicity T-cell cross-match using current or historic sera is needed.8 Given that urgency is not considered, expected waiting time is a critical component of the recipient selection. Most relevantly, the mean waiting time is over 900 days, resulting into an approximately 50% mortality rate.1,7 To mitigate the scarcity of donated lungs, Japanese transplant centers adopted several policies, including strict age limits for listing (<60 and <55 y for a single and bilateral lung transplant, respectively), preference of single over bilateral lungs to maximize access, and performing living-donor transplants for patients too ill to wait for deceased-donor lungs when 2 immediate family members are available as donors. Approximately one-third (251/835) of all lung transplants in Japan are currently from living donors. Notably, living-donor transplants do not require registration with JOTN. WAITLIST MORTALITY BASED ON THE DISEASE CATEGORY IN JAPAN The high waitlist mortality prompted a detailed analysis. Between 1998 and 2020, 1787 patients were registered for lung transplants with JOTN; 368 (20.6%) were listed at Tohoku University Hospital, and outcomes (for transplants, waitlist morbidity and mortality) have been reviewed (Figure 1C). As of the end of 2020, 35.6% (131/368) patients have been transplanted with either living or deceased donor, while 20.1% (74/368) and 44.3% (163/368), respectively, continued to wait or have died while waiting. Five patients underwent living-donor transplant without having been registered with JOTN. Underlying diseases included obstructive lung disease, pulmonary vascular disease, suppurative lung disease, interstitial lung disease, and chronic allograft dysfunction/status postbone marrow transplantation (summarized as allogeneic disease) (Table 1). Patients with interstitial lung disease showed the highest mortality with 57.7% (79/137), followed by those with suppurative disease with 54.3% (19/35), allogeneic disease with 43.5% (10/23), vascular disease with 43.4% (36/83), and obstructive lung disease with 21.1% (19/90). TABLE 1. - Patients listed for lung transplants at Tohoku University Hospital between 1998 and 2020 Obstructive lung disease (n = 90) Lymphangioleiomyomatosis 59 Chronic obstructive pulmonary disease 19 Bronchiolitis obliterans 9 Others 3 Pulmonary vascular disease (n = 83) Primary pulmonary hypertension/pulmonary arterial hypertension 63 Secondary pulmonary hypertension/Eisenmenger syndrome 15 Connective tissue disease–associated pulmonary hypertension 2 Others 3 Suppurative lung disease (n = 35) Bronchiectasis 34 Cystic fibrosis 1 Interstitial lung disease (n = 137) Idiopathic pulmonary fibrosis 70 Connective tissue disease–associated interstitial lung disease 30 Drug-induced interstitial lung disease 6 Pleuroparenchymal fibroelastosis 6 Nonspecific interstitial pneumonia 6 Others 19 Allogeneic disease (n = 23) Graft-vs-host disease posthematopoietic stem cell transplant 13 Chronic lung allograft dysfunction 10 CONCLUSION This report shows waiting times for lung transplants in Japan are extremely long with a high mortality on the waitlist. Clearly, increasing the number of deceased-donor organs could address the long waiting time and waitlist mortality; accordingly, all transplant centers should closely collaborate with the Japanese government to advance deceased-donor organ donation.