State of the art

The first clinical lung transplantation (LTx) was performed by Dr. James Hardy at the University of Mississippi in June 1963 (1). In Germany, the first isolated LTx was performed by Prof. Hans G. Borst at the Hannover Medical School (MHH) in 1988. One year later the first bilateral-sequential LTx was performed, again at the MHH. At present, allogeneic LTx is considered to be the only approach to treat patients with terminal pulmonary failure from parenchymal, bronchial, or pulmonary-vascular pathologies. LTx can be performed as single lung (SLTx), bilateral lung (DLTx) or heart-LTxs (HLTx) (2). Indications include chronic obstructive lung diseases (COPD) and other kinds of lung emphysema (e.g. a-1-antitrypsin deficiency), parenchymal disease (e.g. idiopathic pulmonary fibrosis), genetic disorders such as cystic fibrosis, vascular diseases (e.g. primary pulmonary hypertension), chronic infections (such as bronchiectasis), and less frequent indications including lymphangioleiomyomatosis or sarcoidosis.



Figure. 1: Number of interventions and long-term survival after LTx worldwide (source: ISHLT)

Compared to other Western European or North American countries, the number of LTx per million residents in Germany is low. In 2001, 1.7 LTx/million residents have been performed in Germany (3). Access to treatment, therefore, is very limited. A very high mortality rate can be observed prior to LTx, compared to other types of solid organ transplantations. During the last years, the waiting-list mortality was about 30% at the MHH with a differential death rate for various underlying diseases (4, 5). In Germany, about 600 to 800 patients are waiting for a LTx, with only around 200 LTx being performed per year (3). The age limits of LTx candidates have been extended in recent years, now including pediatric patients, as well as recipients of more than 60 years of age. As a consequence, more donor organs have to be provided, in order to permit transplantation of all patients with terminal lung failure, according to the guidelines of the "Bundesärztekammer" (6).

Besides widening of the criteria for organ donation, xenotransplantation and procurement of lungs from "non heart beating donors" may have an impact. At present, the transfer of porcine lungs is performed in large animal models using non-human primates (7). However, due to very short survival times, regulatory problems to be expected, as well as potential infections risks, pulmonary xenografts cannot be expected to become a realistic clinical alternative to allografts within the next years. In contrast, lungs harvested from "non heart beating donors" would immediately increase postmortem organ donation rates significantly (8-10).

Many academic centers have not included LTx into their clinical programs, not only due to an extremely high pre-operative mortality, but also because of the high post-operative attrition rate. Worldwide, mortality after LTx presently amounts to approximately 25% in the first year and about 50% after 5 years (Fig. 1).

In spite of considerable progress in LTx, survival rates are significantly lower than for heart-, kidney- or liver transplantation. Successful induction of donor-specific tolerance could represent a breakthrough in LTx. Induction of peripheral or central tolerance has been achieved in small animal models, however, many protocols are not applicable under clinical conditions. One major problem is that, hitherto, donor-specific tolerance could not be induced after transplantation of the donor organ. Protocols, suitable for postoperative tolerance induction would be indispensable for allogeneic LTx with very limited ischemic periods between organ harvest and transplantation.



Figure. 2: Causes of death after lung and heart/lung Tx (MHH)

During the first year after transplantation, acute pulmonary dysfunction (mainly caused by ischemia reperfusion damage), infections and acute rejection represent the main causes of death (Fig. 2). After the first year, many patients develop a chronic dysfunction of the graft due to fibrotic obliteration of the bronchioles (bronchiolitis obliterans syndrome, BOS), which is regarded as an alloreactive response, resulting in chronic rejection (11). A number of arguments have been used to explain this complication by pathophysiologic effects of chronic rejection. For instance, there is an increasing incidence of BOS (ISHLT, fig. 2) over time, which also appears after other types of organ transplantation (e.g. kidney, heart). Second, BOS does not occur after pulmonary autotransplantation (12).

As in cardiac transplantation, the impact of infectious complications on the BOS pathology has been discussed, also. In addition, abnormal healing processes following the generalized insult during the complex process of transplantation has been implicated. We could show that approximately 30% of parenchymal cells will undergo programmed cell death and apoptosis within the first 2 hours after experimental LTx (13). Pathomechanistically, this could indeed result in abnormal reparation processes, potentially triggering the onset of BOS. Concurrent with our results, recent data of the ISHLT indicate that prolonged ischemic times may have a significant influence on the incidence of BOS (14).

A most critical factor in LTx remains organ preservation. Initially, preservation strategies, successfully applied in kidney and liver transplantation, were based on solutions providing intracellular potassium concentrations (15). Such strategies, however, could ultimately not be applied successfully in LTx, as severe ischemia reperfusion injuries were seen even in light of short ischemic times of up to 6 hours. More recently, preservation solutions providing low potassium concentrations were developed (16) providing significantly improved pulmonary function after experimental LTx (17, 18). Since then, these preservation solutions have been introduced into clinical practice with great success (19), and ischemic times of up to 12 hours can now be tolerated (20). However, further optimiziation of lung preservation is necessary, especially in view of the potential use of non heart beating donors.

Against the background of an extreme pre- and postoperative risk of clinical LTx, compared to other types of solid organ transplantation, exploration of promising alternatives for current therapies in terminal lung failure have to be investigated. As such, concepts of regenerative therapy, currently under experimental investigation should be tested for their potential application in lung disease. Approaches using cell therapy, similar to those being explored for myocardial failure (21), or the use of in vitro generated tissue for implantation, however, have not been investigated for pulmonary structures.

In summary notwithstanding the successful development of clinical lung transplantation towards a standardized and in many instances, successful therapy, a number of important problems remain unsolved:

The alloreactive immune response against the graft currently is suppressed pharmocologically in a non-specific manner. Induction of donor specific tolerance could not be translated into clinical practice, yet.
Despite a continuous progress in development of improved immunosuppressive protocols, many pulmonary grafts are lost due to BOS. Understanding of underlying mechanisms as well as methods for early diagnosis, prevention and improved treatment would allow for better survival rates and improvement in quality of life.
As indicated by increasingly growing waiting lists, donor shortage represents the single most important limiting factor for a broad application of LTx. Long-term xenotransplantation may play a role, however, in view of currently unsolved problems (e.g. rejection and incompatible physiology), clinical application does not seem to be readily available.
Concepts of regenerative medicine, including stem cell technologies and tissue engineering to repair damaged segments or compartments of the lung are promising, which in turn could reduce the number of necessary LTx, but have not been explored so far.
The high mortality on the waiting list and after transplantation results in considerable psychological problems in affected patients, which may have a significant additional impact on pre- and post-operative complications. Today, no standardized preventive or therapeutic psychological modalities have been developed.

1. Hardy, J.D., W.R. Webb, M.L. Dalton, and e. al. 1963. Lung homotransplantation in man. JAMA 186:1065.
2. Patterson, G.A. 1997. Indications. Unilateral, bilateral, heart-lung, and lobar transplant procedures. Clin Chest Med 18, no. 2:225.
3. Bruckenberger, E. 2001. Herzbericht 2001, 14. Bericht der Arbeitsgruppe Krankenhauswesen der AOLG.
4. De Meester, J., J.M. Smits, G.G. Persijn, and A. Haverich. 1999. Lung transplant waiting list: differential outcome of type of end-stage lung disease, one year after registration. J Heart Lung Transplant 18, no. 6:563.
5. De Meester, J., J.M. Smits, G.G. Persijn, and A. Haverich. 2001. Listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the Eurotransplant experience. J Heart Lung Transplant 20, no. 5:518.
6. Schreiber, H.-L., and A. Haverich. 2000. Richtlinien für die Warteliste und für die Organvermittlung. Dt Ärztebl 97:385.
7. Platt, J., V. DiSesa, D. Gail, and J. Massicot-Fisher. 2002. Recommendations of the National Heart, Lung, and Blood Institute Heart and Lung Xenotransplantation Working Group. Circulation 106, no. 9:1043.
8. Steen, S., T. Sjoberg, L. Pierre, Q. Liao, L. Eriksson, and L. Algotsson. 2001. Transplantation of lungs from a non heart beating donor. Lancet 357, no. 9259:825.
9. Kootstra, G., J. Kievit, and A. Nederstigt. 2002. Organ donors: heartbeating and non-heartbeating. World J Surg 26, no. 2:181.
10. Rega, F.R., E.J. Vandezande, N.C. Jannis, G.M. Verleden, T.E. Lerut, and D.E. Van Raemdonck. 2003. The role of leukocyte depletion in ex vivo evaluation of pulmonary grafts from (non-)heart-beating donors. Perfusion 18 Suppl 1:13.
11. Wahlers, T., A. Haverich, H.J. Schafers, S.W. Hirt, H.G. Fieguth, M. Jurmann, C. Zink, and H.G. Borst. 1993. Chronic rejection following lung transplantation. Incidence, time pattern and consequences. Eur J Cardiothorac Surg 7, no. 6:319.
12. Haverich, A., K.D. Dawkins, J.C. Baldwin, B.A. Reitz, M.E. Billingham, and S.W. Jamieson. 1985. Long-term cardiac and pulmonary histology in primates following combined heart and lung transplantation. Transplantation 39, no. 4:356.
13. Fischer, S., S.D. Cassivi, A.M. Xavier, J.A. Cardella, E. Cutz, V. Edwards, M. Liu, and S. Keshavjee. 2000. Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation. Ann Surg 231, no. 3:424.
14. Hosenpud, J.D., L.E. Bennett, B.M. Keck, M.M. Boucek, and R.J. Novick. 2001. The Registry of the International Society for Heart and Lung Transplantation: eighteenth Official Report-2001. J Heart Lung Transplant 20, no. 8:805.
15. Haverich, A., W.C. Scott, and S.W. Jamieson. 1985. Twenty years of lung preservation--a review. J Heart Transplant 4, no. 2:234.
16. Keshavjee, S.H., F. Yamazaki, P.F. Cardoso, D.I. McRitchie, G.A. Patterson, and J.D. Cooper. 1989. A method for safe twelve-hour pulmonary preservation. J Thorac Cardiovasc Surg 98, no. 4:529.
17. Keshavjee, S.H., F. Yamazaki, H. Yokomise, P.F. Cardoso, J.B. Mullen, A.S. Slutsky, and G.A. Patterson. 1992. The role of dextran 40 and potassium in extended hypothermic lung preservation for transplantation. J Thorac Cardiovasc Surg 103, no. 2:314.
18. Struber, M., J.M. Hohlfeld, S. Fraund, P. Kim, G. Warnecke, and A. Haverich. 2000. Low-potassium dextran solution ameliorates reperfusion injury of the lung and protects surfactant function. J Thorac Cardiovasc Surg 120, no. 3:566.
19. Warnecke, G., M. Struber, J.M. Hohlfeld, J. Niedermeyer, S.P. Sommer, and A. Haverich. 2002. Pulmonary preservation with Bretscheider's HTK and Celsior solution in minipigs. Eur J Cardiothorac Surg 21, no. 6:1073.
20. Fischer, S., A. Matte-Martyn, M. De Perrot, T.K. Waddell, Y. Sekine, M. Hutcheon, and S. Keshavjee. 2001. Low-potassium dextran preservation solution improves lung function after human lung transplantation. J Thorac Cardiovasc Surg 121, no. 3:594.
21. Stamm, C., B. Westphal, H.D. Kleine, M. Petzsch, C. Kittner, H. Klinge, C. Schumichen, C.A. Nienaber, M. Freund, and G. Steinhoff. 2003. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361, no. 9351:45