World J. Surg. 16, 118.3-1187, 1992
O
World Journal of Surgery © 1992 by the Soeirt~ lnternationale de Chirurgie
Living Unrelated Donor Kidney Transplantation between Spouses M e h m e t H a b e r a l , M . D . , F . A . C . S . , H u s e y i n Gulay, M . D . , Rifat T o k y a y , M . D . , Z a f e r Oner, M . D . , T a y f u n Enunlu, M . D . , Ph.D., and N e v z a t Bilgin, M.D. Turkish Transplantation and Burn Foundation Hospital, Ankara, Turkey From November 3, 1975 to November 3, 1990, 874 kidney transplants were performed at our centers. Of these, 675 (77.2%) were from living donors and 199 (22.8%) were from cadaver donors. Five hundred eighty (66.4%) of the living donors were first degree related while 99 (11.3%) were unrelated or second degree related donors, 29 of which were spouses. All donor recipient pairs were ABO-compatible, with the exception of one pair. Donor recipient relations were wife to husband in 25 cases and husband to wife in 4 cases. All were first grafts and started functioning during surgery. In this series, the follow-up for the recipients was 4 to 64 months (mean 33.5 ± 4.5 months). One-year patient survival and graft survival rates were 92.4% and 81.9%, respectively. Two-year patient survival and graft survival rates were 92.4% and 78.2%, respectively. The single ABO-incompatible case is also doing well, 21 months postoperatively. This study demonstrates that the interspouse kidney transplantation may be used when cadaver organ shortage is a problem. While providing the couple with a better quality of life, interspouse kidney transplantation also enables the couple to share the joy of giving and receiving the "gift of life" from one another.
The shortage of cadaver kidneys is a reality despite many efforts of ours and others in Turkey and in the world [1-6]. As a result, in developing countries, living related donors have become the main source in obtaining kidneys [7-9]. Even this source remains highly limited for most patients with chronic renal failure. Although not widely accepted due to some ethical issues, the use of unrelated living donors has become another kidney source [7, 10, 11]. However; most transplant centers seek at least an emotional relation for genetically matching unrelated donors as a solution to this ethical issue. As of April 1986, our centers (The Hacettepe University School of Medicine and Turkish Transplantation and Burn Foundation Hospitals) have also adopted this policy. Since that time, 29 interspouse kidney transplantations have been performed. This approach not only provides a solution for restoring a chronic renal failure patient back to normal life, but it also enables the couple to share a better life and the joy of giving and receiving " a gift of life" to and from each other. Materials and M e t h o d s
Of the 874 kidney transplants performed at our centers from November 3, 1975 to November 3, 1991, 675 (77.2%) were from
Reprint requests: Mehmet Haberal, M.D., F.A.C.S., Fevzi Cakmak Cad., 10. Sokak, No: 45, Bahcelievler 06490 Ankara, Turkey.
living donors and 199 (22.8%) were from cadaver donors (Fig. 1). Five hundred eighty (66.4%) of the 874 transplants were from living related donors and 99 (11.3%) were from living unrelated or second degree related (aunts, uncles, nieces, cousins) donors, 29 (3.3%) of which were spouses of the recipients (Fig. 2). All the donor-recipient pairs, except one, were ABO-compatible. In this series, one recipient was of blood group A whose donor was of blood group B. The donor to recipient relationships were wife to husband in 25 cases and husband to wife in 4 cases. Of these 4 wife recipients only 1 woman was found to be sensitized, via pregnancy, to paternal donor antigens. Total lymphocyte crossmatch done using Terasaki trays revealed negative (10% positive) in 2 of the patients. These two crossmatch positive patients subsequently became negative prior to transplantation. Recipient age ranged from 24 to 54 years (mean 36.48 -+ 7.48 years). All were first grafts. HLA-A and B typing showed 4 antigen mismatches in 4 patients, 3 mismatches in 9 patients, 2 mismatches in 11 patients, 1 mismatch in 5 patients, and no mismatch in no patients (Table 1). In this series DR typing could be employed to only 7 of the 29 interspouse transplants. Two of these were 0 DR mismatch, 2 were 1 DR mismatch, 1 was 2 DR mismatch, and 2 were 3 DR mismatch. With the exception of 5 transplants, all the recipients had donor specific blood transfusions (DST) which were administered in 3 sessions, with 150 ml of blood each time and an interval of 10 days. The last transfusion was at least 15 days before the transplantation. Of these 5 patients that did not receive DST, 2 patients were Rh incompatible, 2 were transplanted after our centers quit DST, and 1 was ABO incompatible. Donor specific split-thickness skin grafts were applied t w i c e to the recipient of the ABO incompatible donor with an interval of one month. In our institution, ABO incompatible kidney transplantation is done according to the results of donor specific skin grafting. In two previous studies [3, 12] we found a close correlation with skin graft reaction and kidney graft rejection. Therefore, we are transplanting ABO incompatible kidneys only if donor specific skin graft shows no reaction. In this series, the only ABO incompatible kidney transplantation was done from a B+ wife to an A+ husband. There was a
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Fig. 2. Distribution of kidney donors in 874 transplants done in our
centers from November 3, 1975 to November 3, 1991. mismatch in two of the donor HLA antigens. However, in this particular case, with the use of pre-operative plasmapheresis and the normal immunosuppressive regimen described below, no problem was encountered and the graft is still functioning 14 months postoperatively. With the exception of the first 4 transplants, all recipients underwent two sessions of plasmapheresis (Gambro 2000) within the last two days prior to transplantation. All the patients received triple tow dose immunosuppression with prednisolone, azathioprine, and cyclosporine-A (CsA). Only the first patient did not receive CsA and in 3 patients azathioprine was discontinued several months after the transplantation due to hepatotoxicity. Immunosuppression is started 3 days before the scheduled date of transplantation. Pre-operatively, prednisolone is given 1 mg/kg/day and azathioprine is given 2-2.25 mg/kg/day. CsA is started within 24 hours of the operation with an initial dose of 5-6 mg/kg/day and later adjusted according to the daily measured CsA blood levels to be between 150 ng/ml and 250 ng/ml. Within 12 hours of surgery, 50 mg of prednisolone is administered twice intravenously. On the first postoperative
89
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Fig. 1. Renal transplants done in our centers from November 3, 1975 to November 3, 1991.
day, oral prednisolone dose is increased to 1.5 mg/kg/day and then reduced with 10 mg daily decrements until a dose of 50 mg/day is reached. Thereafter, the daily decrement is reduced to 5 mg until the total daily dose is lowered to 20 mg. This triple low dose immunosuppression is continued for the first 2 months postoperatively after which the prednisolone dose is tapered down to 10 mg/kg/day within 4 to 6 months. The graft and patient survival analysis were done according to the Kaplan-Meier product limit method. Data analysis was done using Mantel-Cox Logrank method [13]. For these analysis BMDP PC90 1L computer was used. Results
Post-transplantation for 4 to 64 months (mean 33.5 +-- 4.5 month), the recipients were held under close observation. With the exception of the last 3 cases, all the other patients were transplanted more than a year ago. After transplantation all the grafts started functioning during the operation without any need for post surgery dialysis. Twelve months after transplantation, 2 recipients became diabetic and 1 of them lost the kidney due to rejection. Three recipients experienced immuran toxicity, but recovered after discontinuation of the drug. Three recipients died, t due to sepsis, 1 due to gastrointestinal hemorrhage, both within the first year of transplantation, and the third due to pancreatitis 3 years post transplant. Eight (27.6%) grafts were lost, 6 due to rejection and 2 due to patient death. In this series, the 1-year patient survival and graft survival rate were 93.1% and 81.9%, respectively. Twenty-one patients were transplanted at least 2 years ago. In this group, the 2-year patient survival and graft survival rate was 90.5% and 76.2%, respectively (Fig. 3). According to the product-limit survival analysis, the mean graft survival time was 48.47 months (limited to 64.33 months and with a standard error of 5.099). The only ABO incompatible
M. Haberal et al.: Interspouse Kidney Transplantation
1185
Table 1. Data from 29 interspouse renal transplants done in our centers. Clinical characteristic Age (yrs) 40 Sex Male Female HLA-A, B mismatch 1
2 3 4 Crossmatch -10% Immunosuppressive therapy CsA + AZA + steroid CsA + steroid Acute rejection episodes (5-90 days) 0 1 2 3 Acute rejection therapy Steroid + OKT3 + plasmapheresis Steroid + plasmapheresis Steroid Chronic rejection episodes (After 90 days) 0 1 4 Chronic rejection therapy Steroid + plasmapheresis Steroid Most recent serum creatinine (mg/dl) ~ 4.50
loo 9o
No. of pts. (%) 6 (20.7) 14 (48.3) 9 (31.0)
8o
•~
N 20
21 (72.4) 6 (20.7) 1 (3.4) 1 (3.4) 6 (75) 1 (12.5) 1 (12.5) 17 (65.4) 7 (26.9) 2 (7.7) 4 (44.4) 5 (55.6) 8 (27.6) 6 (20.7) 2 (6.9) 1 (3.4) 1 (3.4) 3 (10.3)
~Normal serum creatinine is 0.8-1.3 mg/100 ml CsA: Cyclosporine-A; AZA: Azathioprine
interspouse kidney recipient is 21 months post-transplantation with a normally functioning graft. The effects of the age of the recipient, the number of H L A - A and B mismatches, the number of acute or chronic rejection episodes, and postoperative complications on the graft survival were analyzed (Table 2). N o n e o f these factors was statistically significant as far as graft survival is concerned. Discussion
Although the use of unrelated living donors in kidney transplantation remains controversial, many centers have accepted this procedure for certain selective transplant patients [1, 3, 4, 5, 8, 10, 14]. The argument against this procedure is usually ethical but in some o f the literature the success of these transplantations is also questioned [11, 15-18]. The ethical discussions o f the problem conclusively agree on banning the commerce of organs and accepting organs from biologically unrelated donors
I
Graft Survival
50
5 (17.2)
26 (89.7) 3 (10.3)
Patient Survival
60
g~ 4o
27 (93.1) 2 (6.9)
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25 (86.2) 4 (13.8) 11 (37.9) 9 (31) 4 (13.8)
I I-- 7
~ 30
o
6
15
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~4 io
~
iz
2s
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~6
MONTHS Fig. 3. Patient survival and graft survival in 29 interspouse renal transplants done in our centers.
Table 2. Relationship between age, HLA-A, B mismatch, acute and chronic rejection episodes, complications and graft survival. Clinical characteristic Age (yrs) 39 HLA mismatch 1-2 3--4 Acute rejection episodes 0 -t Chronic rejection episodes 0 1 4 Complications None Wound infection Ureter necrosis
Number of grafts functioning (%)
Number of grafts lost (%)
5 (83.3) 8 (57.1) 8 (88.9)
1 (16.7) 6 (42.9) i (ii.1)
12 (75) 9 (69.2)
4 (25) 4 (30,8)
16 (76.2) 5 (62.5)
5 (23.8) 3 (37.5)
16 (94.1) 4 (57.1) 0 (0.0)
1 (5.9) 3 (42.9) 2 (100)
18 (72) 1 (50) I (100)
7 (28) 1 (50) 0 (0)
only if they have an emotional closeness to the recipient [8, 10, 11, 18]. As our centers agree with the ethical requirements regarding the degree of emotional closeness between the donor and the recipient, our first choice, when cadaveric organs cannot be obtained, has become first degree living related donors (parent, sibling, offspring). H o w e v e r , should the transplant patient not have any first degree relatives, then second degree living related donors (uncle, aunt, niece, cousin) are accepted. Very seldom close friends are accepted as donor candidates [2, 8, 10]. Organ donations, according to our regulations, are accepted for altruistic intentions only and any type of organ c o m m e r c e is strictly forbidden. The l - y e a r patient survival rate o f c a d a v e r kidney transplantation is approximately 90% and the graft survival rate ranges from 62% to 86%, depending on the varying results in H L A
1186
typing, immunosuppressive regimens, and ischemia time [7, 11]. Unrelated living donor kidney transplantation results are usually the same as the results of cadaver kidney transplantations as far as the patient survival rate is concerned, which is 90--94%. However, the graft survival rate of 81--89% in living unrelated kidney transplantations is higher than the cadaver kidney graft survival [6, 10, 11, 14, 19, 20]. In our series, most patients received kidneys from donors with 2 or more H L A A and/or B antigen mismatches. Yet, with the immunosuppressive treatment described above, our 1-year and 2-year patient survival rates were 92.4% and 92.4%, and graft survival rates were 81.9% and 78.2%, respectively. These rates are similar to those reported by others [7, 11]. To this, we may add other certain advantages of living donor kidney transplantation over cadaver kidneys such as better physical and immunological preparation of the recipient pre-operatively, the opportunity provided in selecting the best time for operation, minimal ischemia time and therefore immediate graft function during the operation obviating the need for postoperative dialysis. The transplantations performed between spouses carry an emotional aspect to the situation which strengthens the relations between the couple, as one spouse donates the "gift of life" to the other. The motive in medicine is to improve the quality of life and interspouse transplantations are a means of achieving this goal for patients with chronic renal failure. Since organ commerce has only produced ethical controversies along with debasing the human values, it can not be accepted as an alternative to this procedure. In conclusion, our results show that in the case of cadaver organ shortage, unrelated or second degree related organ transplantations (including interspouse transplantations) can be performed successfully and provide a healthier life for both the patient and the family. R~sum~
Nous avons effectu6 874 transplantations r6nales dans nos centres de transplantation entre le 3 Nov, 1975 et le 3 Nov, 1990. Parmi celles-ci, 675 (77.2%) provenaient de donneurs vivants et 199 (22.8%) des reins provenaient de cadavres. Cinq cent quatre vingt des donneurs vivants (66.4%) 6taient parents au premier degr6 alors que 99 (11.3%) 6taient parents au 2~ degr6 ou n'6taient pas parents, parmi lesquels 29 ~Staient des 6poux. Tous les couples donneur/receveur, sauf un, 6taient compatibles dans le syst~me ABO. Le couple donneur/receveur ~Stait femme ~t marl dans 25 cas et mari ii femme dans quatre. I1 s'agissait dans t o u s l e s cas d'une premiX,re greffe et qui a commenc6 ~t bien fonctionner sur la table d'op6ration. Dans cette s6rie, le suivi des receveurs allait de 4 ~ 64 (33.5 --+ 4.5) mois. Les taux de survie des malades et des greffes ~t un an 6taient respectivement de 92.4% et 81.9%. Les taux de survie des malades et des greffes ~ deux ans 6taient respectivement de 92.4% et 78.2%. Le seul cas avec incompatabilit6 ABO va tr~s bien avec un recul de 21 mois. Cette 6tude montre que la transplantation entre 6poux est une solution valable en cas de manque de reins. En plus d'am61iorer la qualit6 de survie du receveur et par lb. m6me du couple, cette vari~t6 de transplantation donne 6galement au couple la possibilit~ d'avoir lajoie de donner et de recevoir un "cadeau de vie" de leur 6poux.
World J. Surg. Vol. 16, No. 6, N o v . ~ e c . 1992
Resumen
En nuestro centro se efectuaron 874 trasplantes renales entre noviembre 3 de 1975 y noviembre 3 de 1990; 675 (77.2%) fueron de donantes vivos y 199 (22.8%) de donantes cadav6ricos; 580 (66.4%) de los donantes vivos fueron familiares de primer grado y 99 (11.3%) fueron donantes no relacionados familiarmente o familiares de segundo grado, de los cuales 29 eran c6nyuges. Todas las parejas donante-recipiente exhibieron compatibilidad ABO, con excepci6n de una. La relaci6n donante-recipiente fue esposa a esposo en 25 casos y esposo a esposa en 4 casos. Todos los injertos eran de primera vez y todos comenzaron a funcionar en la mesa de cirugfa. E1 seguimiento oscil6 entre 4 y 64 meses (33.5 --- 4.5). Las tasas de sobrevida a un afio del paciente y del injerto fueron 92.4% y 81.9% respectivamente; las tasas a dos afios fueron 92.4% y 78.2% respectivamente. El 0nico caso ABO no compatible tambi6n se encuentra bien, a 21 meses en la actualidad. El presente estudio demuestra que el trasplante renal entre esposos puede set utilizado cuando haya escases de 6rganos cadav6ricos. A1 tiempo que permite una mejor calidad de vida, el procedimiento da a la pareja la oportunidad de gozar el hecho de otorgar y de recibir el "regalo de la vida" entre uno y otro. References
1. Bay, W.H., Herbert, L.A.: The living donor in kidney transplantation. Ann. Intern. Med., 106:719, 1987 2. Haberal, M., Gulay, H., Arslan~ G., Bilgin, N.: Cadaver kidney transplantation with prolonged cold ischemia time. Transplant. Proc. 20(Suppl. 1):932, 1988 3. Haberal, M., Gulay, H., Arslan, G., Bilgin, N.: ABO incompatible skin grafting. Transplant. Proc. 21:781, 1989 4. Levey, A.S., Hou, S., Bush, H.L.: Kidney transplantation from unrelated living donors. N. Engl. J. Med. 314:914, 1986 5. McDonald, F.D.: Organ supply: Whither growth? Am. J. Kidney Dis. •2:552, 1988 6. Rapaport, F.T.: Living donor kidney transplantation. Transplant. Proc. 19:169, 1987 7. Abouna, G.M., Kumar, M.S.A., White, A.G., Siva, O.S.G.: Transplantation in Kuwait: A Middle Eastern and North African perspective. Transplant. Proc. 19(Suppi. 2):21, 1987 8. Haberal, M., Sert, S., Aybasti, N., G01ay, H., G6kge, O., Arslan, G., Karamehmeto~]lu, M., Bilgin, N.: Living donor kidney transplantation. Transplant. Proc, 20(Suppl. 1):353, 1988 9. Samhan, M., Abouna, G.M., White, A.G., A1-Abdulla, I.H., Kumur, M.S.A., Panjwani, D., Philips, E.M., Silva, O.S.G.: The use of HLA mismatched living related donor for renal transplantation is justified by the highly successful long-term results. Transplant. Proc. 20:800, 1988 10. Gulay, H., Arslan, G., Sert, S., Haberal, M.: Successful living unrelated donor kidney transplantation. Transplant. Proc. 21:2196, 1989 11. Squitflet, S.P., Pirson, Y., Poncelet, A., Gianello, P., Alexandre, G.P.J.: Unrelated living donor kidney transplantation. Transplant. Int. 3:32, 1990 12. Haberal, M., Gulay, H., Arslan, G., Sert, S., Altunkan, S., Bilgin, N.: ABO incompatible kidney transplantation with donor specific skin graft. Ren. Fail. 13:103, 1991 13. Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., Mcpherson, K., Peto, J., Smith, P.G.: Design and analysis of randomized clinical trials requiring prolonged observation on each patient: II. Analysis and examples. Br. J. Cancer 35:1, 1977 14. Pirsch, J.D., Sollinger, H.W., Kalayo~lu, M., Stratta, R.J., D'AI-
M. Haberal et al.: Interspouse Kidney Transplantation
1187
lessandro, A.M., Armbrust, M.J., and Belzer, F.O.: Living unrelated renal transplantation: Results in 40 patients. Am. J. Kidney Dis. •2:499, 1988 15. Duar, A.S., Satahudeen, A.K., Pingle, A., Woods, H.F.: Ethics and commerce in live donor renal transplantation: Classification of the Issues. Transplant. Proc. 22:922, 1990 16. Reddy, K., Thiagarajan, C.M., Chunmagasundaram, D., Jayachadran, R., Nayar, P., Thomas, S., Ramachadran, V.: Unconventinal renal transplantation in India. Transplant. Proc. 22:910, 1990 17. Salahudeen, A.K., Woods, H.F., Pingle, A., Nur-El Huda Suleyman, M., Shakuntala, K., Nandakumar, M., Yahya, T,M., Daar,
A.S.: High mortality among recipients of bought living unrelated donor kidneys. Lancet 336:725, 1990 18. Sollinger, H.W., Katayoglu, M., Belzer, F.O.: Use of the donor specific transfusion in living unrelated donor-recipient combinations. Ann. Surg. 204:315, t986 19. Bowen, P.A., House, M.A., Baires, D., Kurunsarri, K., Dennis, A.S. Witherington, R., Humphries, A.L.: Successful renal transplantation using distantly related or unrelated living donors with donor specific blood transfusion. Transplantation 39:450, 1985 20. Reding, R., Squifflet, S.P., Pirson, Y., Jamart, J. Alexandre, G.P.J.: Unrelated living donor kidney transplantation, Clinical Transplantation 1:278, 1987
Invited Commentary
Table 1. Patient and graft survival following living-unrelated kidney transplantation. Patient survival
Hans W. Sollingcr, M.D., Ph.D. Departments of Surgery and Pathology, University of Wisconsin School of Medicine, Madison, Wisconsin, U.S.A. This paper by Haberal and coworkers confirms previous reports by our group [1] and others demonstrating the successful use of living unrelated kidney donors. As in other countries, there is an insutficient quantity of cadaveric kidneys in Turkey to transplant all patients opting for a renal transplant. From the large number of live donor transplants performed at the Ankara transplant center, it is obvious that this source of kidneys is being used extensively. Nevertheless, on some occasions, no willing or medically qualified living donor is available, and Haberal and colleagues have shown that living-unrelated transplantation between spouses can be performed with relatively good success rates. In our own center, we have recently reviewed 41 patients who received a living-unrelated kidney transplant in the cyclosporine era [2]. One-year and 4-year patient and graft survival are shown in Table 1. All recipients received 3 donor-specific transfusions prior to transplantation, but as Haberal and associates point out, the use of donor-specific transfusions might not be necessary to accomplish excellent graft survival. When we compared in our own series morbidity and the number of rejection episodes between living-unrelated donors and recipients of cadaver kidneys, no significant differences were seen. These results suggest that living-unrelated donors are a viable alternative when no cadaver kidney is available. Currently at our institution, the average waiting time tbr a cadaveric kidney is 527 days, versus 50 days for an elective living-unrelated transplant. An increasing number of livingunrelated kidneys could ease the growing shortage of cadaveric kidneys. It would shorten the waiting time on dialysis for many end-stage renal disease patients and could significantly reduce the cost of end-stage renal disease health care programs. This fact might be particularly important in countries such as Turkey where the rates of cadaveric organ donation are significantly lower than in the United States or European countries. Haberal and colleagues also point out that living-unrelated donors are only accepted ff a long-term emotional relationship
Type of transplant Living-unrelated Living-related HLA-identical Haplo-identical Mismatched Cadaver
Graft survival~
N 41 58
1 yr (%) 98 100
4 yr (%) 95 100
1 yr (%) 93 100
161 15 706
99 I00 96
93 89 90
95 79 87
4 yr (%) 85 95 86 70 76
"First transplant only
between recipient and donor exists, and this is in concordance with the guidelines put forward by the transplantation societies. Clearly in a situation of husband-wife donation, this emotional relationship is assured. Nevertheless, one could worry to some degree about the uneven ratio of wife-to-husband donations in this series. One might wonder if cultural differences have contributed to this occurrence, or if females were sensitized to their husbands by previous pregnancies. Unfortunately, Haberal and colleagues did not address the issue if, through pre-transplant crossmatching, husbands were excluded from becoming donors. In any event, the authors need to be congratulated for addressing this difficult issue by presenting a relatively large series of live-unrelated donors. Their findings confirming the previously published data from transplant centers in the United States and Europe might contribute to an increased rate of kidney donation in countries where cadaver organ donation is far below the average seen in European countries and North America. References
1. Pirsch, J.D., Sollinger, H.W., Kalayoglu, M., Stratta, R.J., D'Alessandro, A,M,, Ambrust, M.J., Belzer, F.O.: Living-unrelated renal transplantation; Results in 40 patients. Am. J. Kidney Dis. •2:499, 1988 2. Ploeg, R.J., Stegall, M.D., Pirsch, J.D.: Living-unrelated kidney donation: An under-utilized resource? Proceedings of the American Society of Transplant Physicians, llth Annual Meeting, May 26-27, 1992
O
World Journal of Surgery © 1992 by the Soeirt~ lnternationale de Chirurgie
Living Unrelated Donor Kidney Transplantation between Spouses M e h m e t H a b e r a l , M . D . , F . A . C . S . , H u s e y i n Gulay, M . D . , Rifat T o k y a y , M . D . , Z a f e r Oner, M . D . , T a y f u n Enunlu, M . D . , Ph.D., and N e v z a t Bilgin, M.D. Turkish Transplantation and Burn Foundation Hospital, Ankara, Turkey From November 3, 1975 to November 3, 1990, 874 kidney transplants were performed at our centers. Of these, 675 (77.2%) were from living donors and 199 (22.8%) were from cadaver donors. Five hundred eighty (66.4%) of the living donors were first degree related while 99 (11.3%) were unrelated or second degree related donors, 29 of which were spouses. All donor recipient pairs were ABO-compatible, with the exception of one pair. Donor recipient relations were wife to husband in 25 cases and husband to wife in 4 cases. All were first grafts and started functioning during surgery. In this series, the follow-up for the recipients was 4 to 64 months (mean 33.5 ± 4.5 months). One-year patient survival and graft survival rates were 92.4% and 81.9%, respectively. Two-year patient survival and graft survival rates were 92.4% and 78.2%, respectively. The single ABO-incompatible case is also doing well, 21 months postoperatively. This study demonstrates that the interspouse kidney transplantation may be used when cadaver organ shortage is a problem. While providing the couple with a better quality of life, interspouse kidney transplantation also enables the couple to share the joy of giving and receiving the "gift of life" from one another.
The shortage of cadaver kidneys is a reality despite many efforts of ours and others in Turkey and in the world [1-6]. As a result, in developing countries, living related donors have become the main source in obtaining kidneys [7-9]. Even this source remains highly limited for most patients with chronic renal failure. Although not widely accepted due to some ethical issues, the use of unrelated living donors has become another kidney source [7, 10, 11]. However; most transplant centers seek at least an emotional relation for genetically matching unrelated donors as a solution to this ethical issue. As of April 1986, our centers (The Hacettepe University School of Medicine and Turkish Transplantation and Burn Foundation Hospitals) have also adopted this policy. Since that time, 29 interspouse kidney transplantations have been performed. This approach not only provides a solution for restoring a chronic renal failure patient back to normal life, but it also enables the couple to share a better life and the joy of giving and receiving " a gift of life" to and from each other. Materials and M e t h o d s
Of the 874 kidney transplants performed at our centers from November 3, 1975 to November 3, 1991, 675 (77.2%) were from
Reprint requests: Mehmet Haberal, M.D., F.A.C.S., Fevzi Cakmak Cad., 10. Sokak, No: 45, Bahcelievler 06490 Ankara, Turkey.
living donors and 199 (22.8%) were from cadaver donors (Fig. 1). Five hundred eighty (66.4%) of the 874 transplants were from living related donors and 99 (11.3%) were from living unrelated or second degree related (aunts, uncles, nieces, cousins) donors, 29 (3.3%) of which were spouses of the recipients (Fig. 2). All the donor-recipient pairs, except one, were ABO-compatible. In this series, one recipient was of blood group A whose donor was of blood group B. The donor to recipient relationships were wife to husband in 25 cases and husband to wife in 4 cases. Of these 4 wife recipients only 1 woman was found to be sensitized, via pregnancy, to paternal donor antigens. Total lymphocyte crossmatch done using Terasaki trays revealed negative (10% positive) in 2 of the patients. These two crossmatch positive patients subsequently became negative prior to transplantation. Recipient age ranged from 24 to 54 years (mean 36.48 -+ 7.48 years). All were first grafts. HLA-A and B typing showed 4 antigen mismatches in 4 patients, 3 mismatches in 9 patients, 2 mismatches in 11 patients, 1 mismatch in 5 patients, and no mismatch in no patients (Table 1). In this series DR typing could be employed to only 7 of the 29 interspouse transplants. Two of these were 0 DR mismatch, 2 were 1 DR mismatch, 1 was 2 DR mismatch, and 2 were 3 DR mismatch. With the exception of 5 transplants, all the recipients had donor specific blood transfusions (DST) which were administered in 3 sessions, with 150 ml of blood each time and an interval of 10 days. The last transfusion was at least 15 days before the transplantation. Of these 5 patients that did not receive DST, 2 patients were Rh incompatible, 2 were transplanted after our centers quit DST, and 1 was ABO incompatible. Donor specific split-thickness skin grafts were applied t w i c e to the recipient of the ABO incompatible donor with an interval of one month. In our institution, ABO incompatible kidney transplantation is done according to the results of donor specific skin grafting. In two previous studies [3, 12] we found a close correlation with skin graft reaction and kidney graft rejection. Therefore, we are transplanting ABO incompatible kidneys only if donor specific skin graft shows no reaction. In this series, the only ABO incompatible kidney transplantation was done from a B+ wife to an A+ husband. There was a
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Years
BII Cadaver(n=199) l-I Spouses(n=Z9) •
Seconddegreerelated (n-66) Living Re~ated(n-675)
Fig. 2. Distribution of kidney donors in 874 transplants done in our
centers from November 3, 1975 to November 3, 1991. mismatch in two of the donor HLA antigens. However, in this particular case, with the use of pre-operative plasmapheresis and the normal immunosuppressive regimen described below, no problem was encountered and the graft is still functioning 14 months postoperatively. With the exception of the first 4 transplants, all recipients underwent two sessions of plasmapheresis (Gambro 2000) within the last two days prior to transplantation. All the patients received triple tow dose immunosuppression with prednisolone, azathioprine, and cyclosporine-A (CsA). Only the first patient did not receive CsA and in 3 patients azathioprine was discontinued several months after the transplantation due to hepatotoxicity. Immunosuppression is started 3 days before the scheduled date of transplantation. Pre-operatively, prednisolone is given 1 mg/kg/day and azathioprine is given 2-2.25 mg/kg/day. CsA is started within 24 hours of the operation with an initial dose of 5-6 mg/kg/day and later adjusted according to the daily measured CsA blood levels to be between 150 ng/ml and 250 ng/ml. Within 12 hours of surgery, 50 mg of prednisolone is administered twice intravenously. On the first postoperative
89
90
91
Fig. 1. Renal transplants done in our centers from November 3, 1975 to November 3, 1991.
day, oral prednisolone dose is increased to 1.5 mg/kg/day and then reduced with 10 mg daily decrements until a dose of 50 mg/day is reached. Thereafter, the daily decrement is reduced to 5 mg until the total daily dose is lowered to 20 mg. This triple low dose immunosuppression is continued for the first 2 months postoperatively after which the prednisolone dose is tapered down to 10 mg/kg/day within 4 to 6 months. The graft and patient survival analysis were done according to the Kaplan-Meier product limit method. Data analysis was done using Mantel-Cox Logrank method [13]. For these analysis BMDP PC90 1L computer was used. Results
Post-transplantation for 4 to 64 months (mean 33.5 +-- 4.5 month), the recipients were held under close observation. With the exception of the last 3 cases, all the other patients were transplanted more than a year ago. After transplantation all the grafts started functioning during the operation without any need for post surgery dialysis. Twelve months after transplantation, 2 recipients became diabetic and 1 of them lost the kidney due to rejection. Three recipients experienced immuran toxicity, but recovered after discontinuation of the drug. Three recipients died, t due to sepsis, 1 due to gastrointestinal hemorrhage, both within the first year of transplantation, and the third due to pancreatitis 3 years post transplant. Eight (27.6%) grafts were lost, 6 due to rejection and 2 due to patient death. In this series, the 1-year patient survival and graft survival rate were 93.1% and 81.9%, respectively. Twenty-one patients were transplanted at least 2 years ago. In this group, the 2-year patient survival and graft survival rate was 90.5% and 76.2%, respectively (Fig. 3). According to the product-limit survival analysis, the mean graft survival time was 48.47 months (limited to 64.33 months and with a standard error of 5.099). The only ABO incompatible
M. Haberal et al.: Interspouse Kidney Transplantation
1185
Table 1. Data from 29 interspouse renal transplants done in our centers. Clinical characteristic Age (yrs) 40 Sex Male Female HLA-A, B mismatch 1
2 3 4 Crossmatch -10% Immunosuppressive therapy CsA + AZA + steroid CsA + steroid Acute rejection episodes (5-90 days) 0 1 2 3 Acute rejection therapy Steroid + OKT3 + plasmapheresis Steroid + plasmapheresis Steroid Chronic rejection episodes (After 90 days) 0 1 4 Chronic rejection therapy Steroid + plasmapheresis Steroid Most recent serum creatinine (mg/dl) ~ 4.50
loo 9o
No. of pts. (%) 6 (20.7) 14 (48.3) 9 (31.0)
8o
•~
N 20
21 (72.4) 6 (20.7) 1 (3.4) 1 (3.4) 6 (75) 1 (12.5) 1 (12.5) 17 (65.4) 7 (26.9) 2 (7.7) 4 (44.4) 5 (55.6) 8 (27.6) 6 (20.7) 2 (6.9) 1 (3.4) 1 (3.4) 3 (10.3)
~Normal serum creatinine is 0.8-1.3 mg/100 ml CsA: Cyclosporine-A; AZA: Azathioprine
interspouse kidney recipient is 21 months post-transplantation with a normally functioning graft. The effects of the age of the recipient, the number of H L A - A and B mismatches, the number of acute or chronic rejection episodes, and postoperative complications on the graft survival were analyzed (Table 2). N o n e o f these factors was statistically significant as far as graft survival is concerned. Discussion
Although the use of unrelated living donors in kidney transplantation remains controversial, many centers have accepted this procedure for certain selective transplant patients [1, 3, 4, 5, 8, 10, 14]. The argument against this procedure is usually ethical but in some o f the literature the success of these transplantations is also questioned [11, 15-18]. The ethical discussions o f the problem conclusively agree on banning the commerce of organs and accepting organs from biologically unrelated donors
I
Graft Survival
50
5 (17.2)
26 (89.7) 3 (10.3)
Patient Survival
60
g~ 4o
27 (93.1) 2 (6.9)
L___
7o,
25 (86.2) 4 (13.8) 11 (37.9) 9 (31) 4 (13.8)
I I-- 7
~ 30
o
6
15
;s
~4 io
~
iz
2s
i4 do
~6
MONTHS Fig. 3. Patient survival and graft survival in 29 interspouse renal transplants done in our centers.
Table 2. Relationship between age, HLA-A, B mismatch, acute and chronic rejection episodes, complications and graft survival. Clinical characteristic Age (yrs) 39 HLA mismatch 1-2 3--4 Acute rejection episodes 0 -t Chronic rejection episodes 0 1 4 Complications None Wound infection Ureter necrosis
Number of grafts functioning (%)
Number of grafts lost (%)
5 (83.3) 8 (57.1) 8 (88.9)
1 (16.7) 6 (42.9) i (ii.1)
12 (75) 9 (69.2)
4 (25) 4 (30,8)
16 (76.2) 5 (62.5)
5 (23.8) 3 (37.5)
16 (94.1) 4 (57.1) 0 (0.0)
1 (5.9) 3 (42.9) 2 (100)
18 (72) 1 (50) I (100)
7 (28) 1 (50) 0 (0)
only if they have an emotional closeness to the recipient [8, 10, 11, 18]. As our centers agree with the ethical requirements regarding the degree of emotional closeness between the donor and the recipient, our first choice, when cadaveric organs cannot be obtained, has become first degree living related donors (parent, sibling, offspring). H o w e v e r , should the transplant patient not have any first degree relatives, then second degree living related donors (uncle, aunt, niece, cousin) are accepted. Very seldom close friends are accepted as donor candidates [2, 8, 10]. Organ donations, according to our regulations, are accepted for altruistic intentions only and any type of organ c o m m e r c e is strictly forbidden. The l - y e a r patient survival rate o f c a d a v e r kidney transplantation is approximately 90% and the graft survival rate ranges from 62% to 86%, depending on the varying results in H L A
1186
typing, immunosuppressive regimens, and ischemia time [7, 11]. Unrelated living donor kidney transplantation results are usually the same as the results of cadaver kidney transplantations as far as the patient survival rate is concerned, which is 90--94%. However, the graft survival rate of 81--89% in living unrelated kidney transplantations is higher than the cadaver kidney graft survival [6, 10, 11, 14, 19, 20]. In our series, most patients received kidneys from donors with 2 or more H L A A and/or B antigen mismatches. Yet, with the immunosuppressive treatment described above, our 1-year and 2-year patient survival rates were 92.4% and 92.4%, and graft survival rates were 81.9% and 78.2%, respectively. These rates are similar to those reported by others [7, 11]. To this, we may add other certain advantages of living donor kidney transplantation over cadaver kidneys such as better physical and immunological preparation of the recipient pre-operatively, the opportunity provided in selecting the best time for operation, minimal ischemia time and therefore immediate graft function during the operation obviating the need for postoperative dialysis. The transplantations performed between spouses carry an emotional aspect to the situation which strengthens the relations between the couple, as one spouse donates the "gift of life" to the other. The motive in medicine is to improve the quality of life and interspouse transplantations are a means of achieving this goal for patients with chronic renal failure. Since organ commerce has only produced ethical controversies along with debasing the human values, it can not be accepted as an alternative to this procedure. In conclusion, our results show that in the case of cadaver organ shortage, unrelated or second degree related organ transplantations (including interspouse transplantations) can be performed successfully and provide a healthier life for both the patient and the family. R~sum~
Nous avons effectu6 874 transplantations r6nales dans nos centres de transplantation entre le 3 Nov, 1975 et le 3 Nov, 1990. Parmi celles-ci, 675 (77.2%) provenaient de donneurs vivants et 199 (22.8%) des reins provenaient de cadavres. Cinq cent quatre vingt des donneurs vivants (66.4%) 6taient parents au premier degr6 alors que 99 (11.3%) 6taient parents au 2~ degr6 ou n'6taient pas parents, parmi lesquels 29 ~Staient des 6poux. Tous les couples donneur/receveur, sauf un, 6taient compatibles dans le syst~me ABO. Le couple donneur/receveur ~Stait femme ~t marl dans 25 cas et mari ii femme dans quatre. I1 s'agissait dans t o u s l e s cas d'une premiX,re greffe et qui a commenc6 ~t bien fonctionner sur la table d'op6ration. Dans cette s6rie, le suivi des receveurs allait de 4 ~ 64 (33.5 --+ 4.5) mois. Les taux de survie des malades et des greffes ~t un an 6taient respectivement de 92.4% et 81.9%. Les taux de survie des malades et des greffes ~ deux ans 6taient respectivement de 92.4% et 78.2%. Le seul cas avec incompatabilit6 ABO va tr~s bien avec un recul de 21 mois. Cette 6tude montre que la transplantation entre 6poux est une solution valable en cas de manque de reins. En plus d'am61iorer la qualit6 de survie du receveur et par lb. m6me du couple, cette vari~t6 de transplantation donne 6galement au couple la possibilit~ d'avoir lajoie de donner et de recevoir un "cadeau de vie" de leur 6poux.
World J. Surg. Vol. 16, No. 6, N o v . ~ e c . 1992
Resumen
En nuestro centro se efectuaron 874 trasplantes renales entre noviembre 3 de 1975 y noviembre 3 de 1990; 675 (77.2%) fueron de donantes vivos y 199 (22.8%) de donantes cadav6ricos; 580 (66.4%) de los donantes vivos fueron familiares de primer grado y 99 (11.3%) fueron donantes no relacionados familiarmente o familiares de segundo grado, de los cuales 29 eran c6nyuges. Todas las parejas donante-recipiente exhibieron compatibilidad ABO, con excepci6n de una. La relaci6n donante-recipiente fue esposa a esposo en 25 casos y esposo a esposa en 4 casos. Todos los injertos eran de primera vez y todos comenzaron a funcionar en la mesa de cirugfa. E1 seguimiento oscil6 entre 4 y 64 meses (33.5 --- 4.5). Las tasas de sobrevida a un afio del paciente y del injerto fueron 92.4% y 81.9% respectivamente; las tasas a dos afios fueron 92.4% y 78.2% respectivamente. El 0nico caso ABO no compatible tambi6n se encuentra bien, a 21 meses en la actualidad. El presente estudio demuestra que el trasplante renal entre esposos puede set utilizado cuando haya escases de 6rganos cadav6ricos. A1 tiempo que permite una mejor calidad de vida, el procedimiento da a la pareja la oportunidad de gozar el hecho de otorgar y de recibir el "regalo de la vida" entre uno y otro. References
1. Bay, W.H., Herbert, L.A.: The living donor in kidney transplantation. Ann. Intern. Med., 106:719, 1987 2. Haberal, M., Gulay, H., Arslan~ G., Bilgin, N.: Cadaver kidney transplantation with prolonged cold ischemia time. Transplant. Proc. 20(Suppl. 1):932, 1988 3. Haberal, M., Gulay, H., Arslan, G., Bilgin, N.: ABO incompatible skin grafting. Transplant. Proc. 21:781, 1989 4. Levey, A.S., Hou, S., Bush, H.L.: Kidney transplantation from unrelated living donors. N. Engl. J. Med. 314:914, 1986 5. McDonald, F.D.: Organ supply: Whither growth? Am. J. Kidney Dis. •2:552, 1988 6. Rapaport, F.T.: Living donor kidney transplantation. Transplant. Proc. 19:169, 1987 7. Abouna, G.M., Kumar, M.S.A., White, A.G., Siva, O.S.G.: Transplantation in Kuwait: A Middle Eastern and North African perspective. Transplant. Proc. 19(Suppi. 2):21, 1987 8. Haberal, M., Sert, S., Aybasti, N., G01ay, H., G6kge, O., Arslan, G., Karamehmeto~]lu, M., Bilgin, N.: Living donor kidney transplantation. Transplant. Proc, 20(Suppl. 1):353, 1988 9. Samhan, M., Abouna, G.M., White, A.G., A1-Abdulla, I.H., Kumur, M.S.A., Panjwani, D., Philips, E.M., Silva, O.S.G.: The use of HLA mismatched living related donor for renal transplantation is justified by the highly successful long-term results. Transplant. Proc. 20:800, 1988 10. Gulay, H., Arslan, G., Sert, S., Haberal, M.: Successful living unrelated donor kidney transplantation. Transplant. Proc. 21:2196, 1989 11. Squitflet, S.P., Pirson, Y., Poncelet, A., Gianello, P., Alexandre, G.P.J.: Unrelated living donor kidney transplantation. Transplant. Int. 3:32, 1990 12. Haberal, M., Gulay, H., Arslan, G., Sert, S., Altunkan, S., Bilgin, N.: ABO incompatible kidney transplantation with donor specific skin graft. Ren. Fail. 13:103, 1991 13. Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., Mcpherson, K., Peto, J., Smith, P.G.: Design and analysis of randomized clinical trials requiring prolonged observation on each patient: II. Analysis and examples. Br. J. Cancer 35:1, 1977 14. Pirsch, J.D., Sollinger, H.W., Kalayo~lu, M., Stratta, R.J., D'AI-
M. Haberal et al.: Interspouse Kidney Transplantation
1187
lessandro, A.M., Armbrust, M.J., and Belzer, F.O.: Living unrelated renal transplantation: Results in 40 patients. Am. J. Kidney Dis. •2:499, 1988 15. Duar, A.S., Satahudeen, A.K., Pingle, A., Woods, H.F.: Ethics and commerce in live donor renal transplantation: Classification of the Issues. Transplant. Proc. 22:922, 1990 16. Reddy, K., Thiagarajan, C.M., Chunmagasundaram, D., Jayachadran, R., Nayar, P., Thomas, S., Ramachadran, V.: Unconventinal renal transplantation in India. Transplant. Proc. 22:910, 1990 17. Salahudeen, A.K., Woods, H.F., Pingle, A., Nur-El Huda Suleyman, M., Shakuntala, K., Nandakumar, M., Yahya, T,M., Daar,
A.S.: High mortality among recipients of bought living unrelated donor kidneys. Lancet 336:725, 1990 18. Sollinger, H.W., Katayoglu, M., Belzer, F.O.: Use of the donor specific transfusion in living unrelated donor-recipient combinations. Ann. Surg. 204:315, t986 19. Bowen, P.A., House, M.A., Baires, D., Kurunsarri, K., Dennis, A.S. Witherington, R., Humphries, A.L.: Successful renal transplantation using distantly related or unrelated living donors with donor specific blood transfusion. Transplantation 39:450, 1985 20. Reding, R., Squifflet, S.P., Pirson, Y., Jamart, J. Alexandre, G.P.J.: Unrelated living donor kidney transplantation, Clinical Transplantation 1:278, 1987
Invited Commentary
Table 1. Patient and graft survival following living-unrelated kidney transplantation. Patient survival
Hans W. Sollingcr, M.D., Ph.D. Departments of Surgery and Pathology, University of Wisconsin School of Medicine, Madison, Wisconsin, U.S.A. This paper by Haberal and coworkers confirms previous reports by our group [1] and others demonstrating the successful use of living unrelated kidney donors. As in other countries, there is an insutficient quantity of cadaveric kidneys in Turkey to transplant all patients opting for a renal transplant. From the large number of live donor transplants performed at the Ankara transplant center, it is obvious that this source of kidneys is being used extensively. Nevertheless, on some occasions, no willing or medically qualified living donor is available, and Haberal and colleagues have shown that living-unrelated transplantation between spouses can be performed with relatively good success rates. In our own center, we have recently reviewed 41 patients who received a living-unrelated kidney transplant in the cyclosporine era [2]. One-year and 4-year patient and graft survival are shown in Table 1. All recipients received 3 donor-specific transfusions prior to transplantation, but as Haberal and associates point out, the use of donor-specific transfusions might not be necessary to accomplish excellent graft survival. When we compared in our own series morbidity and the number of rejection episodes between living-unrelated donors and recipients of cadaver kidneys, no significant differences were seen. These results suggest that living-unrelated donors are a viable alternative when no cadaver kidney is available. Currently at our institution, the average waiting time tbr a cadaveric kidney is 527 days, versus 50 days for an elective living-unrelated transplant. An increasing number of livingunrelated kidneys could ease the growing shortage of cadaveric kidneys. It would shorten the waiting time on dialysis for many end-stage renal disease patients and could significantly reduce the cost of end-stage renal disease health care programs. This fact might be particularly important in countries such as Turkey where the rates of cadaveric organ donation are significantly lower than in the United States or European countries. Haberal and colleagues also point out that living-unrelated donors are only accepted ff a long-term emotional relationship
Type of transplant Living-unrelated Living-related HLA-identical Haplo-identical Mismatched Cadaver
Graft survival~
N 41 58
1 yr (%) 98 100
4 yr (%) 95 100
1 yr (%) 93 100
161 15 706
99 I00 96
93 89 90
95 79 87
4 yr (%) 85 95 86 70 76
"First transplant only
between recipient and donor exists, and this is in concordance with the guidelines put forward by the transplantation societies. Clearly in a situation of husband-wife donation, this emotional relationship is assured. Nevertheless, one could worry to some degree about the uneven ratio of wife-to-husband donations in this series. One might wonder if cultural differences have contributed to this occurrence, or if females were sensitized to their husbands by previous pregnancies. Unfortunately, Haberal and colleagues did not address the issue if, through pre-transplant crossmatching, husbands were excluded from becoming donors. In any event, the authors need to be congratulated for addressing this difficult issue by presenting a relatively large series of live-unrelated donors. Their findings confirming the previously published data from transplant centers in the United States and Europe might contribute to an increased rate of kidney donation in countries where cadaver organ donation is far below the average seen in European countries and North America. References
1. Pirsch, J.D., Sollinger, H.W., Kalayoglu, M., Stratta, R.J., D'Alessandro, A,M,, Ambrust, M.J., Belzer, F.O.: Living-unrelated renal transplantation; Results in 40 patients. Am. J. Kidney Dis. •2:499, 1988 2. Ploeg, R.J., Stegall, M.D., Pirsch, J.D.: Living-unrelated kidney donation: An under-utilized resource? Proceedings of the American Society of Transplant Physicians, llth Annual Meeting, May 26-27, 1992
