- Email: [email protected]
Short- and long-term outcomes of combined cardiac and renal transplantation with allografts from a single donor
Short- and Long-Term Outcomes of Combined Cardiac and Renal Transplantation With Allografts From a Single Donor Heyman Luckraz, FRCS,a Jayan Parameshwar, FRCP,a Susan C. Charman, MSc,b John Firth, FRCP,c John Wallwork, FRCS,a and Stephen Large, FRCSa Background: Coexisting end-stage heart and kidney failure can be treated by combined cardiac and renal transplantation. This study reviews the short- and long-term outcomes after such a procedure over a 16-year period at a single institution. Methods: All patients who underwent single-donor simultaneous heart and kidney transplantation during the period of March 1986 to April 2002 (including heart retransplantation) were included (n ⫽ 13). They were listed for combined heart and kidney transplantation as they fulfilled our criteria for irreversible end-stage organ failure. Retrospective review of patient data from the transplant database, patient case notes and post-mortem reports were carried out. Results: The mean (SD) recipient age was 45 (12) years and there were 2 females. The mean pre-operative creatinine level was 724 (415) mol/liter with 9 patients (69.2%) on continuous ambulatory peritoneal dialysis and 2 patients (15.4%) on hemodialysis prior to transplantation. The 30-day mortality rate was 15.4% (2 of 13). For surviving patients the mean creatinine level at hospital discharge was 158 (93) mol/liter. The mean number of acute cardiac rejection episodes per 100 patient-days was significantly lower (p ⫽ 0.01) than that for the heart-only transplant group (n ⫽ 760) during the same period. The median (interquartile range) post-operative survival was 1,969 (620 to 3,468) days. The actuarial survival rates (95% confidence interval) at 1 and 10 years were 77% (54% to 100%) and 67% (40% to 94%), respectively, and were not significantly different from the isolated heart transplant population (p ⫽ 0.68). Only 1 episode of acute renal rejection was diagnosed on clinical grounds, which was treated accordingly. There was no renal allograft loss in the long-term survivors. Conclusions: Combined cardiac and renal transplantation with allografts from the same donor has acceptable short- and long-term outcomes for patients with coexisting endstage cardiac and renal failure. This group of patients may also experience fewer acute rejection episodes post-operatively. J Heart Lung Transplant 2003;22:1318 –1322.
S
ince the first report of combined cardiac and renal transplantation (CCRTx) in 1978,1 the Inter-
national Society for Heart and Lung Transplantation (ISHLT) has recorded over 200 such proce-
From the aTransplant Unit, Papworth Hospital, Cambridge; b MRC Biostatistics Unit, Cambridge; and cRenal Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK. Submitted November 2, 2002; accepted December 22, 2002. Reprint requests: H. Luckraz, FRCS, Transplant Unit, Papworth Hospital, Cambridge CB3 8RE, UK. Telephone: 00-44-1480-830-
541. Fax: 00-44-1480-364-610. E-mail: [email protected] Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter doi:10.1016/S1053-2498(03)00030-5
1318
The Journal of Heart and Lung Transplantation Volume 22, Number 12
Luckraz et al.
1319
TABLE I Pre-operative diagnoses and renal support therapy for each patient Patient
CDx
RDx
RS
POD
Status
1 2 3 4 5 6 7 8 9 10 11 12 13
DCM DCM IHD CAV CAV DCM IHD DCM DCM DCM IHD CAV IHD/BIVAD
Glomerulosclerosis Membranous glomerulonephritis Mesangioproliferative glomerulonephritis Cyclosporine renal toxicity Cyclosporine renal toxicity Failed renal allograft Diabetic end stage kidney damage Polycystic kidneys Focal segmental glomerulonephritis Polycystic kidneys Polycystic kidneys Cyclosporine renal toxicity Renal failure due to heart failure
CAPD CAPD CAPD None CAPD CAPD CAPD CAPD HD CAPD CAPD None HD
5,907 5,010 4,322 3,956 2,886 2,393 1,611 879 473 240 46 13 5
Alive Alive Alive Alive Alive Alive Alive Dead Alive Alive Dead Dead Dead
BIVAD, bi-ventricular assist device; CAPD, continuous ambulatory peritoneal dialysis; CAV, cardiac allograft vasculopathy; CDx, cardiac diagnosis; DCM, dilated cardiomyopathy; HD, hemodialysis; IHD, ischemic heart disease; POD, post-operative survival days; RDX, renal diagnosis; RS, pre-operative renal support.
dures.2 Unfortunately, the first recipient died within 2 weeks of surgery, but interest in this procedure was renewed when we reported our first long-term survivor in 1988.3 The criteria for isolated heart or isolated renal transplantation are well established, but cardiac and renal dysfunction often coexists. The management of such patients is not so clearly established, and many are denied cardiac transplantation on the grounds of impaired renal function, and vice versa. There are occasions when impaired renal function is secondary to cardiac failure and the kidneys can recover after heart transplantation, as described in a single case by Berger-Klein et al.4 However, in patients with established and irreversible renal disease, CCRTx must be considered. In this study we described our experience with CCRTx over a 16-year period in patients who were carefully selected in having irreversible cardiac and renal failure, but no evidence of significant cerebrovascular or peripheral vascular disease.
METHODS Patients who had undergone combined cardiac and renal transplantation with allografts from the same donor (n ⫽ 13) over the period of March 1986 to April 2002 were included. During that same period, 760 isolated heart transplants were carried out at our centre, including those undergoing cardiac retransplantation (n ⫽ 18). The causes of irreversible renal failure for each patient are listed in Table I. Donors were selected on the basis of ABO compatibility and size but not HLA match. All patients
underwent the combined procedure through a standard staged operation with the cardiac allograft being implanted first followed by renal allograft implantation at around 90 minutes after cessation of cardiopulmonary bypass. Induction immunosuppression (for the CCRTx) was done using rabbit anti-thymocyte globulins (RATG) for 3 days, and azathioprine and methylprednisolone. RATG was used as induction immunotherapy for isolated heart transplantation from 1986 until 1994 and in around half of this population thereafter. Azathioprine was administered intravenously (IV) at the time of surgery (2 mg/kg/d) and maintained at the same oral dose thereafter unless significant drug side-effects prevented this. Two of the recipients received mycophenolate mofetil instead of azathioprine. Likewise, 500 mg of methylprednisolone was given at the start of the operation and the same dose administered during allograft reperfusion. A further 3 IV doses (125 mg) were given at 8-hour intervals post-operatively for the first 24 hours. Thereafter, oral prednisolone dose was started at 1 mg/kg/d and tapered to a maintenance dose of 0.2 mg/kg/d. After the first 18 months, many patients were taken off oral steroids. Oral cyclosporine (Neoral) was given from the fourth post-operative day, aiming for trough levels of 300 to 350 ng/ml for the first 3 months, 200 to 250 ng/ml for the next 9 months and 100 to 200 ng/ml after the first year of transplantation. Endomyocardial biopsies were performed according our surveillance protocol or when acute rejection was suspected clinically. Acute cardiac rejection
1320
Luckraz et al.
The Journal of Heart and Lung Transplantation December 2003
was treated with pulsed methylprednisolone (1,000 mg IV for 3 days) if the cardiac biopsy was Grade ⱖ3 (according to the ISHLT grading system) or when clinically indicated. Renal function was monitored by serum creatinine level, with renal biopsy and/or administration of pulsed methylprednisolone if allograft rejection was suspected.
Statistics Data were analyzed retrospectively. Categoric variables are expressed as percentages. Continuous variables are expressed as mean (standard deviation, SD) or median (interquartile range, IQR) and analyzed by Student’s t-test or Mann–Whitney U-test as appropriate. Acute rejection episodes are expressed as the mean number of such episodes per 100 patient-days. Kaplan–Meier methods were used to estimate 1- and 10-year survival rates with 95% confidence intervals (95% CI). p ⬍ 0.05 was used to define statistical significance.
RESULTS There were 13 patients who underwent CCRTx, including 2 females. The causes of end-stage cardiac failure were dilated cardiomyopathy (6 of 13), ischemic heart disease (4 of 13) and cardiac allograft vasculopathy in a previously heart-transplanted recipient (3 of 13). The mean recipient and donor ages were 45 (12) years and 33 (15) years, respectively. Only 2 patients (15.4%) did not require renal support therapy pre-operatively (Table I). The mean pre-operative creatinine was 724 (415) mol/liter, falling to 210 (219) mol/liter within 1 week of CCRTx and being 158 (93) mol/liter at the time of hospital discharge in surviving patients. At the latest follow-up at a median of 2,637 (935 to 4,518) days, the mean creatinine level was 123 (24) mol/liter (Figure 1). The mean ischemic time was 187 (81) minutes. The median intensive-care stay was 4 (2 to 6) days. The mean number of acute cardiac rejection episodes per 100 patient-days was 0.04 as compared with 0.40 in the heart-only transplants (p ⫽ 0.01). Only 1 patient was treated for acute renal rejection with pulsed methylprednisolone on the basis of clinical assessment. There was no renal allograft loss in those patients who survived long term. There were 4 deaths at 5, 13, 46 and 879 days post-operatively. The respective causes of death were donor organ failure, pseudomonas sepsis, multi-organ failure and cardiac failure of unknown origin in the last patient.
FIGURE 1 Creatinine levels at various time intervals (boxplots).
The median post-operative survival was 1,969 (620 to 3,468) days. The actuarial survival rates at 1 and 10 years (Figure 2) were 77% (54% to 100%) and 67% (40% to 94%) for the CCRTx group and 82% (79% to 85%) and 58% (54% to 62%) for the isolated heart transplants, respectively (log rank ⫽ 0.68).
DISCUSSION Combined cardiac and renal transplantation from a single donor is a treatment option for patients with irreversible end-stage heart and kidney failure. It represents ⬍1% of the cardiac transplant workload as reported to the ISHLT.2 However, it is imperative to select the appropriate recipients, otherwise some patients would be “over-treated.”4 Our cardiac re-
FIGURE 2 Cumulative actuarial survival of CCRTx patients (n ⫽ 13) compared with isolated heart transplant recipients (n ⫽ 760).
The Journal of Heart and Lung Transplantation Volume 22, Number 12
cipient selection criteria have been described previously and are rigorously adhered to.5 As for the selection of renal transplantation all the patients described had irreversible organ damage (Table I) with 84.6% (11 of 13) requiring renal support therapy pre-operatively by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The 2 patients who did not require renal support therapy had irreversible renal damage due to cyclosporine toxicity and underwent cardiac retransplantation. Although there was no HLA matching and despite the fact that the kidney has an 18-fold-greater expression for HLA-A,B,C and a 90-fold greater expression for HLA-DR compared with cardiac tissue,6 the renal acute rejection and graft survival rates were better than those described for the isolated cadaveric renal allograft.7 Narula et al,8 reported on the incidence of acute rejection episodes in a CCRTx population (n ⫽ 56) and found that 14% had isolated acute renal rejection; 27% had isolated acute cardiac rejection and 7% had simultaneous acute rejection in both organs. Similar findings have been almost universal among other reports of CCRTx.9 –14 Several mechanisms were postulated for the observed reduction in acute rejection episodes in the transplanted organs in the setting of multiple-organ transplantation, but the reasons for such observations are not entirely clear. An important factor is probably the short cold ischemic time that the kidneys in CCRTx are exposed to (average 6 hours) as opposed the average of nearly 24 hours in isolated kidney transplantation.15 This is associated with a decreased expression of both MHC Class I and II in comparision to kidneys with a longer ischemic time.16 Hence, the reduced levels of MHC expression may be associated with a reduction in immunogeneic activity and thus a reduction in acute rejection episodes. However, the fact that acute rejection rates are not decreased in living donor renal transplantation, wherein ischemic time is very short, means that this cannot be the entire explanation. Another possibility is that there is some degree of graft tolerance when combined organs are transplanted.17,18 This is most commonly seen when the liver is transplanted along with another organ.19 It has been suggested that this tolerance develops due to the presence of leukocytes from the transplanted organ, leading to a tolerant chimeric status.20 Likewise, acute cardiac rejection is not commonly documented in the heart– lung transplant population,21 which is believed to
Luckraz et al.
1321
be due to the presence of bronchus-associated lymphoid tissue (BALT). Donor lymphocytes migrate to the recipient lymphoid organ and bone marrow and interact with recipient hematopoietic cells.22 This may lead to the stimulation of graft reactive or suppressor T cells, which in combination with immunotherapy may induce tolerance.18 There have also been some suggestions that the use of RATG may explain the disparity in acute rejection episodes between the isolated cardiac transplant and the CCRTx groups. RATG was administered to all CCRTx patients as induction immunotherapy as compared with only a few from the isolated heart transplant population in the previously described series. RATG depletes peripheral blood lymphocytes through Fas-mediated apoptosis of the activated lymphocytes.23 Although this reduces the likelihood of acute rejection in the early post-transplantation phase, it fails to account for the long-term protection against newly maturing T cells once RATG therapy has been stopped. Moreover, in our series, ⬎67% of the isolated heart transplant recipients had RATG as induction immunotherapy, although they experienced more acute rejection episodes as when compared with the CCRTx group. It is important to note that acute rejection episodes occurred mostly in isolation in each of the transplanted organs. Therefore, both organs need to be monitored separately either directly as is the case for the heart, with endomyocardial biopsies, or indirectly by serum creatinine levels for renal monitoring. This surveillance protocol may explain the difference in the acute rejection rates reported for the 2 organs in CCRTx (slightly lower for the kidney transplants) as sub-clinical acute renal rejection episodes may be missed. The advantage of using the same donor for multiple allografts is that it avoids the additional antigenic stimulation that would develop in the case of a second unrelated allograft with yet a different set of HLA tissues. The long-term renal allograft survival and patient survival in the CCRTx group compares well with the isolated kidney and heart transplant population. There was no statistical difference in 10-year actuarial survival between the 2 groups. Patient survival was 58% (54% to 62%) and graft survival was 67% (40% to 94%) (p ⫽ 0.68). Last, renal allograft function remained normal despite the use of nephrotoxic immunosuppressive medications such as cyclosporine. At a median
1322
Luckraz et al.
follow-up of 2,637 (935 to 4,518) days the mean serum creatinine level was 123 (23) mol/liter in long-term survivors (9 of 13). In conclusion, in appropriately selected cases, combined cardiac and renal transplantation from a single donor is associated with excellent long-term outcome with regard to patient and renal allograft survival. Most of these patients develop normal cardiac and renal function. REFERENCES 1. Norman JC, Brook MI, Cooley DA, et al. Total support of the circulation of a patient with post-cardiotomy syndrome by a partial artificial heart (Alvad) for 5 days followed by heart and kidney transplantation. Lancet 1978;1:1125–7. 2. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The registry of the International Society for Heart and Lung Transplantation: eighteenth official report–2001. J Heart Lung Transplant 2001;20:805–15. 3. Livesey S, Rolles K, Calne R, Wallwork J, English TAH. Successful simultaneous heart and kidney transplantation using the same donor. Clin Transplant 1988;2:1–4. 4. Bergler-Klein J, Pirich C, Laufer G, Grimm M, Regele H, Mayer G, Oberbauer R. The long-term effects of simultaneous heart and kidney transplantation on native renal function. Transplantation 2001;71:1597–600. 5. Milano CA, Buchan K, Pereras K, Wallwork J. Thoracic organ transplantation at Papworth Hospital. In: Cecka JM, Terasaki P, eds. Clinical transplants. Los Angeles, CA: UCLA Immunogenetics Center, 1999, 273–80. 6. Williams K, Hart D, Fabre J, Morris P. Distribution and quantitation of HLA-ABC and DR (la) antigens on human kidney and other tissues. Transplantation 1980;29:274 –9. 7. Jacobs U, Niese D, Miersch WD, Klehr HU. Acute rejection relapses post-transplant: definition of risk group and evaluation of potent therapeutic regimens. Transplant Int 1996; 9(Suppl):S34 –7. 8. Narula J, Bennett L, Di Salvo T, Hosenpud J, Semigran M, Dec GW. Outcomes in recipient of combined heart– kidney transplantation: multi-organ, same-donor transplant study of ISHLT/UNOS Registry. Transplantation 1997;63:861–7. 9. Vermes E, Kirsch M, Houel R, Legouvelo S, Benvenuti C, Aptecar E, Le Besnerais P, Lang P, Abbou C, Loisance D. Immunologic events and long term survival after combined heart and kidney transplantation: a 12-year single centre experience. J Heart Lung Transplant 2001;20:1084 –91.
The Journal of Heart and Lung Transplantation December 2003 10. Blanche C, Kamlot A, Blanche DA, Kearney B, Wong AV, Czer LSC, Trento A. Combined heart– kidney transplantation with single donor allografts. J Thorac Cardiovasc Surg 2002;122:495–500. 11. Crespo-Leiro MG, Rodriguez JA, Paniagua MJ, Mermida LF, Cuenca JJ, Juffe-Stein A, Gomez-Veiga F, Alonso A, Vilela D, Castro-Beiras A. Combined heart and kidney transplantation. Transplant Proc 1999;31:2513–4. 12. Kocher AA, Khazen C, Ankersmit J, Ofner P, Schlechta B, Ehrlich M, Wolner E, Laufer G. Midterm results after combined heart and kidney transplantation. Transplant Proc 1999;31:3181–3. 13. Colluci V, Quaini E, Magnani P, Colombo T, De Carlis L, Grassi M, Merli M, Pellegrini A. Combined heart and kidney transplantation: an effective therapeutic option—report of six cases. Eur J Cardiothorac Surg 1997;12:654–8. 14. Leeser DB, et al. Simultaneous heart and kidney transplantation in patients with end-stage cardiac and renal failure. Am J Transplant 2001;1:89–92. 15. Castillo-Lugo JA, Brinker KR. An overview of combined heart and kidney transplantation. Curr Opin Cardiol 1999;14:121–5. 16. Shackleton C, Ettinger S, McLoughlin M, Scudamore C, Miller R, Keown P. Effect of recovery from ischaemic injury on Class I and Class II MHC antigen expression. Transplantation 1990; 49:641–4. 17. Bentley FR, Garrison RN. Superior results with kidney–pancreas transplantation. Am Surg 1992;58:136–41. 18. Bahnson HT, Gordon RD. Transplantation of other organs with the heart. Cardiovasc Clin 1990;20:237–48. 19. Lu L, Rudert WA, Qian S, et al. Growth of donor-derived dendritic cells from bone marrow of liver allograft recipients in response to granulocyte/macrophage colony stimulating factor. J Exp Med 1995;182:379. 20. Murase N, Starzl TE, Tanabe M, et al. Variable chimerism, graft versus host disease and tolerance after different kinds of cell and whole organ transplants from Lewis to Brown-Norway rats. Transplantation 1995;60:158. 21. Glanville AR, Imoto E, Baldwin JC, et al. The role of right ventricular endomyocardial biopsy in the long-term management of heart–lung transplant recipients. J Heart Transplant 1987;6:357. 22. Thompson AW, Lu L, Murase N, Demetris AJ, Rao AJ, Stariz TE. Microchimerism, dendritic cell progenitors and transplant tolerance. Stem Cells 1995;13:622. 23. Genestier L, Fournel S, Flacher M, Assossou O, Revillard JP, Bonnefoy-Berard N. Induction of Fas-mediated apoptosis of activated lymphocytes by polyclonal anti-thymocyte globulins. Blood 1998;91;2360– 8.
S
ince the first report of combined cardiac and renal transplantation (CCRTx) in 1978,1 the Inter-
national Society for Heart and Lung Transplantation (ISHLT) has recorded over 200 such proce-
From the aTransplant Unit, Papworth Hospital, Cambridge; b MRC Biostatistics Unit, Cambridge; and cRenal Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK. Submitted November 2, 2002; accepted December 22, 2002. Reprint requests: H. Luckraz, FRCS, Transplant Unit, Papworth Hospital, Cambridge CB3 8RE, UK. Telephone: 00-44-1480-830-
541. Fax: 00-44-1480-364-610. E-mail: [email protected] Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter doi:10.1016/S1053-2498(03)00030-5
1318
The Journal of Heart and Lung Transplantation Volume 22, Number 12
Luckraz et al.
1319
TABLE I Pre-operative diagnoses and renal support therapy for each patient Patient
CDx
RDx
RS
POD
Status
1 2 3 4 5 6 7 8 9 10 11 12 13
DCM DCM IHD CAV CAV DCM IHD DCM DCM DCM IHD CAV IHD/BIVAD
Glomerulosclerosis Membranous glomerulonephritis Mesangioproliferative glomerulonephritis Cyclosporine renal toxicity Cyclosporine renal toxicity Failed renal allograft Diabetic end stage kidney damage Polycystic kidneys Focal segmental glomerulonephritis Polycystic kidneys Polycystic kidneys Cyclosporine renal toxicity Renal failure due to heart failure
CAPD CAPD CAPD None CAPD CAPD CAPD CAPD HD CAPD CAPD None HD
5,907 5,010 4,322 3,956 2,886 2,393 1,611 879 473 240 46 13 5
Alive Alive Alive Alive Alive Alive Alive Dead Alive Alive Dead Dead Dead
BIVAD, bi-ventricular assist device; CAPD, continuous ambulatory peritoneal dialysis; CAV, cardiac allograft vasculopathy; CDx, cardiac diagnosis; DCM, dilated cardiomyopathy; HD, hemodialysis; IHD, ischemic heart disease; POD, post-operative survival days; RDX, renal diagnosis; RS, pre-operative renal support.
dures.2 Unfortunately, the first recipient died within 2 weeks of surgery, but interest in this procedure was renewed when we reported our first long-term survivor in 1988.3 The criteria for isolated heart or isolated renal transplantation are well established, but cardiac and renal dysfunction often coexists. The management of such patients is not so clearly established, and many are denied cardiac transplantation on the grounds of impaired renal function, and vice versa. There are occasions when impaired renal function is secondary to cardiac failure and the kidneys can recover after heart transplantation, as described in a single case by Berger-Klein et al.4 However, in patients with established and irreversible renal disease, CCRTx must be considered. In this study we described our experience with CCRTx over a 16-year period in patients who were carefully selected in having irreversible cardiac and renal failure, but no evidence of significant cerebrovascular or peripheral vascular disease.
METHODS Patients who had undergone combined cardiac and renal transplantation with allografts from the same donor (n ⫽ 13) over the period of March 1986 to April 2002 were included. During that same period, 760 isolated heart transplants were carried out at our centre, including those undergoing cardiac retransplantation (n ⫽ 18). The causes of irreversible renal failure for each patient are listed in Table I. Donors were selected on the basis of ABO compatibility and size but not HLA match. All patients
underwent the combined procedure through a standard staged operation with the cardiac allograft being implanted first followed by renal allograft implantation at around 90 minutes after cessation of cardiopulmonary bypass. Induction immunosuppression (for the CCRTx) was done using rabbit anti-thymocyte globulins (RATG) for 3 days, and azathioprine and methylprednisolone. RATG was used as induction immunotherapy for isolated heart transplantation from 1986 until 1994 and in around half of this population thereafter. Azathioprine was administered intravenously (IV) at the time of surgery (2 mg/kg/d) and maintained at the same oral dose thereafter unless significant drug side-effects prevented this. Two of the recipients received mycophenolate mofetil instead of azathioprine. Likewise, 500 mg of methylprednisolone was given at the start of the operation and the same dose administered during allograft reperfusion. A further 3 IV doses (125 mg) were given at 8-hour intervals post-operatively for the first 24 hours. Thereafter, oral prednisolone dose was started at 1 mg/kg/d and tapered to a maintenance dose of 0.2 mg/kg/d. After the first 18 months, many patients were taken off oral steroids. Oral cyclosporine (Neoral) was given from the fourth post-operative day, aiming for trough levels of 300 to 350 ng/ml for the first 3 months, 200 to 250 ng/ml for the next 9 months and 100 to 200 ng/ml after the first year of transplantation. Endomyocardial biopsies were performed according our surveillance protocol or when acute rejection was suspected clinically. Acute cardiac rejection
1320
Luckraz et al.
The Journal of Heart and Lung Transplantation December 2003
was treated with pulsed methylprednisolone (1,000 mg IV for 3 days) if the cardiac biopsy was Grade ⱖ3 (according to the ISHLT grading system) or when clinically indicated. Renal function was monitored by serum creatinine level, with renal biopsy and/or administration of pulsed methylprednisolone if allograft rejection was suspected.
Statistics Data were analyzed retrospectively. Categoric variables are expressed as percentages. Continuous variables are expressed as mean (standard deviation, SD) or median (interquartile range, IQR) and analyzed by Student’s t-test or Mann–Whitney U-test as appropriate. Acute rejection episodes are expressed as the mean number of such episodes per 100 patient-days. Kaplan–Meier methods were used to estimate 1- and 10-year survival rates with 95% confidence intervals (95% CI). p ⬍ 0.05 was used to define statistical significance.
RESULTS There were 13 patients who underwent CCRTx, including 2 females. The causes of end-stage cardiac failure were dilated cardiomyopathy (6 of 13), ischemic heart disease (4 of 13) and cardiac allograft vasculopathy in a previously heart-transplanted recipient (3 of 13). The mean recipient and donor ages were 45 (12) years and 33 (15) years, respectively. Only 2 patients (15.4%) did not require renal support therapy pre-operatively (Table I). The mean pre-operative creatinine was 724 (415) mol/liter, falling to 210 (219) mol/liter within 1 week of CCRTx and being 158 (93) mol/liter at the time of hospital discharge in surviving patients. At the latest follow-up at a median of 2,637 (935 to 4,518) days, the mean creatinine level was 123 (24) mol/liter (Figure 1). The mean ischemic time was 187 (81) minutes. The median intensive-care stay was 4 (2 to 6) days. The mean number of acute cardiac rejection episodes per 100 patient-days was 0.04 as compared with 0.40 in the heart-only transplants (p ⫽ 0.01). Only 1 patient was treated for acute renal rejection with pulsed methylprednisolone on the basis of clinical assessment. There was no renal allograft loss in those patients who survived long term. There were 4 deaths at 5, 13, 46 and 879 days post-operatively. The respective causes of death were donor organ failure, pseudomonas sepsis, multi-organ failure and cardiac failure of unknown origin in the last patient.
FIGURE 1 Creatinine levels at various time intervals (boxplots).
The median post-operative survival was 1,969 (620 to 3,468) days. The actuarial survival rates at 1 and 10 years (Figure 2) were 77% (54% to 100%) and 67% (40% to 94%) for the CCRTx group and 82% (79% to 85%) and 58% (54% to 62%) for the isolated heart transplants, respectively (log rank ⫽ 0.68).
DISCUSSION Combined cardiac and renal transplantation from a single donor is a treatment option for patients with irreversible end-stage heart and kidney failure. It represents ⬍1% of the cardiac transplant workload as reported to the ISHLT.2 However, it is imperative to select the appropriate recipients, otherwise some patients would be “over-treated.”4 Our cardiac re-
FIGURE 2 Cumulative actuarial survival of CCRTx patients (n ⫽ 13) compared with isolated heart transplant recipients (n ⫽ 760).
The Journal of Heart and Lung Transplantation Volume 22, Number 12
cipient selection criteria have been described previously and are rigorously adhered to.5 As for the selection of renal transplantation all the patients described had irreversible organ damage (Table I) with 84.6% (11 of 13) requiring renal support therapy pre-operatively by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The 2 patients who did not require renal support therapy had irreversible renal damage due to cyclosporine toxicity and underwent cardiac retransplantation. Although there was no HLA matching and despite the fact that the kidney has an 18-fold-greater expression for HLA-A,B,C and a 90-fold greater expression for HLA-DR compared with cardiac tissue,6 the renal acute rejection and graft survival rates were better than those described for the isolated cadaveric renal allograft.7 Narula et al,8 reported on the incidence of acute rejection episodes in a CCRTx population (n ⫽ 56) and found that 14% had isolated acute renal rejection; 27% had isolated acute cardiac rejection and 7% had simultaneous acute rejection in both organs. Similar findings have been almost universal among other reports of CCRTx.9 –14 Several mechanisms were postulated for the observed reduction in acute rejection episodes in the transplanted organs in the setting of multiple-organ transplantation, but the reasons for such observations are not entirely clear. An important factor is probably the short cold ischemic time that the kidneys in CCRTx are exposed to (average 6 hours) as opposed the average of nearly 24 hours in isolated kidney transplantation.15 This is associated with a decreased expression of both MHC Class I and II in comparision to kidneys with a longer ischemic time.16 Hence, the reduced levels of MHC expression may be associated with a reduction in immunogeneic activity and thus a reduction in acute rejection episodes. However, the fact that acute rejection rates are not decreased in living donor renal transplantation, wherein ischemic time is very short, means that this cannot be the entire explanation. Another possibility is that there is some degree of graft tolerance when combined organs are transplanted.17,18 This is most commonly seen when the liver is transplanted along with another organ.19 It has been suggested that this tolerance develops due to the presence of leukocytes from the transplanted organ, leading to a tolerant chimeric status.20 Likewise, acute cardiac rejection is not commonly documented in the heart– lung transplant population,21 which is believed to
Luckraz et al.
1321
be due to the presence of bronchus-associated lymphoid tissue (BALT). Donor lymphocytes migrate to the recipient lymphoid organ and bone marrow and interact with recipient hematopoietic cells.22 This may lead to the stimulation of graft reactive or suppressor T cells, which in combination with immunotherapy may induce tolerance.18 There have also been some suggestions that the use of RATG may explain the disparity in acute rejection episodes between the isolated cardiac transplant and the CCRTx groups. RATG was administered to all CCRTx patients as induction immunotherapy as compared with only a few from the isolated heart transplant population in the previously described series. RATG depletes peripheral blood lymphocytes through Fas-mediated apoptosis of the activated lymphocytes.23 Although this reduces the likelihood of acute rejection in the early post-transplantation phase, it fails to account for the long-term protection against newly maturing T cells once RATG therapy has been stopped. Moreover, in our series, ⬎67% of the isolated heart transplant recipients had RATG as induction immunotherapy, although they experienced more acute rejection episodes as when compared with the CCRTx group. It is important to note that acute rejection episodes occurred mostly in isolation in each of the transplanted organs. Therefore, both organs need to be monitored separately either directly as is the case for the heart, with endomyocardial biopsies, or indirectly by serum creatinine levels for renal monitoring. This surveillance protocol may explain the difference in the acute rejection rates reported for the 2 organs in CCRTx (slightly lower for the kidney transplants) as sub-clinical acute renal rejection episodes may be missed. The advantage of using the same donor for multiple allografts is that it avoids the additional antigenic stimulation that would develop in the case of a second unrelated allograft with yet a different set of HLA tissues. The long-term renal allograft survival and patient survival in the CCRTx group compares well with the isolated kidney and heart transplant population. There was no statistical difference in 10-year actuarial survival between the 2 groups. Patient survival was 58% (54% to 62%) and graft survival was 67% (40% to 94%) (p ⫽ 0.68). Last, renal allograft function remained normal despite the use of nephrotoxic immunosuppressive medications such as cyclosporine. At a median
1322
Luckraz et al.
follow-up of 2,637 (935 to 4,518) days the mean serum creatinine level was 123 (23) mol/liter in long-term survivors (9 of 13). In conclusion, in appropriately selected cases, combined cardiac and renal transplantation from a single donor is associated with excellent long-term outcome with regard to patient and renal allograft survival. Most of these patients develop normal cardiac and renal function. REFERENCES 1. Norman JC, Brook MI, Cooley DA, et al. Total support of the circulation of a patient with post-cardiotomy syndrome by a partial artificial heart (Alvad) for 5 days followed by heart and kidney transplantation. Lancet 1978;1:1125–7. 2. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The registry of the International Society for Heart and Lung Transplantation: eighteenth official report–2001. J Heart Lung Transplant 2001;20:805–15. 3. Livesey S, Rolles K, Calne R, Wallwork J, English TAH. Successful simultaneous heart and kidney transplantation using the same donor. Clin Transplant 1988;2:1–4. 4. Bergler-Klein J, Pirich C, Laufer G, Grimm M, Regele H, Mayer G, Oberbauer R. The long-term effects of simultaneous heart and kidney transplantation on native renal function. Transplantation 2001;71:1597–600. 5. Milano CA, Buchan K, Pereras K, Wallwork J. Thoracic organ transplantation at Papworth Hospital. In: Cecka JM, Terasaki P, eds. Clinical transplants. Los Angeles, CA: UCLA Immunogenetics Center, 1999, 273–80. 6. Williams K, Hart D, Fabre J, Morris P. Distribution and quantitation of HLA-ABC and DR (la) antigens on human kidney and other tissues. Transplantation 1980;29:274 –9. 7. Jacobs U, Niese D, Miersch WD, Klehr HU. Acute rejection relapses post-transplant: definition of risk group and evaluation of potent therapeutic regimens. Transplant Int 1996; 9(Suppl):S34 –7. 8. Narula J, Bennett L, Di Salvo T, Hosenpud J, Semigran M, Dec GW. Outcomes in recipient of combined heart– kidney transplantation: multi-organ, same-donor transplant study of ISHLT/UNOS Registry. Transplantation 1997;63:861–7. 9. Vermes E, Kirsch M, Houel R, Legouvelo S, Benvenuti C, Aptecar E, Le Besnerais P, Lang P, Abbou C, Loisance D. Immunologic events and long term survival after combined heart and kidney transplantation: a 12-year single centre experience. J Heart Lung Transplant 2001;20:1084 –91.
The Journal of Heart and Lung Transplantation December 2003 10. Blanche C, Kamlot A, Blanche DA, Kearney B, Wong AV, Czer LSC, Trento A. Combined heart– kidney transplantation with single donor allografts. J Thorac Cardiovasc Surg 2002;122:495–500. 11. Crespo-Leiro MG, Rodriguez JA, Paniagua MJ, Mermida LF, Cuenca JJ, Juffe-Stein A, Gomez-Veiga F, Alonso A, Vilela D, Castro-Beiras A. Combined heart and kidney transplantation. Transplant Proc 1999;31:2513–4. 12. Kocher AA, Khazen C, Ankersmit J, Ofner P, Schlechta B, Ehrlich M, Wolner E, Laufer G. Midterm results after combined heart and kidney transplantation. Transplant Proc 1999;31:3181–3. 13. Colluci V, Quaini E, Magnani P, Colombo T, De Carlis L, Grassi M, Merli M, Pellegrini A. Combined heart and kidney transplantation: an effective therapeutic option—report of six cases. Eur J Cardiothorac Surg 1997;12:654–8. 14. Leeser DB, et al. Simultaneous heart and kidney transplantation in patients with end-stage cardiac and renal failure. Am J Transplant 2001;1:89–92. 15. Castillo-Lugo JA, Brinker KR. An overview of combined heart and kidney transplantation. Curr Opin Cardiol 1999;14:121–5. 16. Shackleton C, Ettinger S, McLoughlin M, Scudamore C, Miller R, Keown P. Effect of recovery from ischaemic injury on Class I and Class II MHC antigen expression. Transplantation 1990; 49:641–4. 17. Bentley FR, Garrison RN. Superior results with kidney–pancreas transplantation. Am Surg 1992;58:136–41. 18. Bahnson HT, Gordon RD. Transplantation of other organs with the heart. Cardiovasc Clin 1990;20:237–48. 19. Lu L, Rudert WA, Qian S, et al. Growth of donor-derived dendritic cells from bone marrow of liver allograft recipients in response to granulocyte/macrophage colony stimulating factor. J Exp Med 1995;182:379. 20. Murase N, Starzl TE, Tanabe M, et al. Variable chimerism, graft versus host disease and tolerance after different kinds of cell and whole organ transplants from Lewis to Brown-Norway rats. Transplantation 1995;60:158. 21. Glanville AR, Imoto E, Baldwin JC, et al. The role of right ventricular endomyocardial biopsy in the long-term management of heart–lung transplant recipients. J Heart Transplant 1987;6:357. 22. Thompson AW, Lu L, Murase N, Demetris AJ, Rao AJ, Stariz TE. Microchimerism, dendritic cell progenitors and transplant tolerance. Stem Cells 1995;13:622. 23. Genestier L, Fournel S, Flacher M, Assossou O, Revillard JP, Bonnefoy-Berard N. Induction of Fas-mediated apoptosis of activated lymphocytes by polyclonal anti-thymocyte globulins. Blood 1998;91;2360– 8.