Upsala J Med Sci 90: 149-156, 1985 Renal lkansplantation in Uppsala Lars Frodin and Ulla Backman Departments of Urology and Medicine, University Hospital, Uppsala, Sweden ABSTRACT The h i s t o r y and p r o g r e s s o f o r g a n t r a n s p l a n t a t i o n i n Uppsala a r e r e v i e w e d . Renal t r a n s p l a n t a t i o n was begun i n 1969, and t h e programme now c o m p r i s e s 50 t o 60 t r a n s p l a n t s p e r y e a r . S i n c e 1976 t h e o p e r a t i o n i s p e r f o r m e d a t t h e d e p a r t - ment o f u r o l o g y . C l o s e c o l l a b o r a t i o n has been e s t a b l i s h e d w i t h o t h e r d e p a r t - ments i n t h e h o s p i t a l , e s p e c i a l l y w i t h t h e m e d i c a l n e p h r o l o g y u n i t . The i n d i c - a t i o n s f o r a c t i v e management o f u r a e m i c p a t i e n t s have broadened, and m a i n t a i n - i n g r e s o u r c e s on a p a r w i t h t h e demands has c o n s t a n t l y been a problem. T h i s r e - p o r t c o n c e r n s immunosuppressive t h e r a p y , t r a n s p l a n t a t i o n r e s u l t s and r e s e a r c h c o n n e c t e d w i t h t h e t r a n s p l a n t a t i o n programme and d e a l s b r i e f l y w i t h t h e p r o s - p e c t s f o r U p p s a l a a s a t r a n s p l a n t a t i o n c e n t r e i n t h e f u t u r e . INTRODUCTION C l i n i c a l r e n a l t r a n s p l a n t a t i o n was begun i n t h e e a r l y 1960s. I n Uppsala t h e f i r s t r e n a l t r a n s p l a n t was p e r f o r m e d i n June 1969. The f i r s t p a t i e n t was a 30- y e a r - o l d man w i t h p o l y c y s t i c k i d n e y d i s e a s e . A l r e a d y i n t h i s case s p e c i a l Uppsala t r e a t m e n t was used, a s f r o z e n a u t o b l o o d , w h i c h a t t h a t t i m e was t h o u g h t t o s u p p r e s s immunologic r e a c t i o n s between t h e p a t i e n t and t h e donor organ, was i n f u s e d p r e o p e r a t i v e l y and p o s t o p e r a t i v e l y . This p a t i e n t s t i l l has a f u n c t i o n - i n g t r a n s p l a n t and i s i n f u l l - t i m e work. The f i r s t r e n a l t r a n s p l a n t a t i o n was p e r f o r m e d by P r o f e s s o r L a r s Thorkn, head o f t h e s u r g i c a l department who, t o g e t h e r w i t h K a r l - E r i k F j e l l s t r o m , i n c h a r g e o f t h e n e p h r o l o g i c u n i t i n t h e m e d i c a l d e p a r t m e n t and C l a e s Hogman, head o f t h e b l o o d bank, i n t r o d u c e d t h e p r o c e d u r e i n Uppsala. I n i t i a l l y t h e p a t i e n t s remained f o r a few days i n t h e i n t e n s i v e c a r e u n i t and t h e n r e t u r n e d t o t h e n e p h r o l o g y u n i t . D u r i n g t h e f i r s t p o s t o p e r a t i v e weeks j o i n t d a i l y v i s i t s were made. Throughout t h e e v o l u t i o n o f t h i s work, v e r y c l o s e c o l l a b o r a t i o n between t h e i n v o l v e d d e p a r t m e n t s has been t y p i c a l f o r o u r t r a n s p l a n t a t l o n c e n t r e . 149 This collaboration includes surgeons, urologists, nephrologists, clinical im- munologists, radiologists, anaesthesiologists and many scientists involved in basic research within the field. EVOLUTION AND CAPACITY As more and more patients have been accepted f o r dialysis, the numbers of renal transplants have increased over the years. In addition to the centre in Uppsala, dialysis units have been established elsewhere within the health s e r - vice region (Bollnas, Ostersund, Sundsvall, Gavle and Vaster&). The total beds for dialysis were 14 in 1 9 6 9 , and the figure for 1984 is 4 6 . Diabetics have been accepted for active therapy since 1975, and older patients have increas- ingly entered the programme. The need for more transplantations has of course required extension o f re- sources - surgical, medical and in the auxiliary services. Initially the oper- ations were done in the department of surgery as part of the routines there. The first surgical post specifically for transplantation was established in 1 9 7 1 , In 1974 a new department o f urology was opened at the hospital and, as most of the surgeons interested in urology moved to this service, a logical consequence was that the renal transplant programme was taken over by the urology department. In 1 9 7 6 , therefore, this department become wholly respons- ible for transplantations, and one of the associate professors at the depart- ment was delegated to lead the work. As yet, however, no surgeon was working full time with these patients. Not until 1983 was the decision made to permit two surgeons to work f u l l time on the transplantation programme. The waiting list nevertheless has continued to grow, and the number of transplantations has not kept pace. The progress that has been made despite this inadequacy would not have been possible without the extraordinary work done by the nephrologists. Table I surveys the growth of the transplant and dialysis programmes at Uppsala. The number o f transplantations planned for 1985 is 55 - 60, and extension o f the facilities at the departments of uro- logy and nephrology is expected. The numbers of dialyses reflect the growing need f o r active management of renal failure in Uppsala region's total popul- ation of 1.2 rnillion. DONOR ORGANS The Uppsala transplantation centre has used a low percentage (c. 5 % ) of kidneys from living related donors. Initially this was because of the assurned risk of removing an organ from a healthy individual. Although gradually we 150 Table 1. Growth of the renal transplantation and dialysis services in Uppsala" No of No of Approximate no Year transplants dialyses on waiting list 1969 6 - - 1970 11 900 - 1971 20 - - 1972 17 1 900 - 1973 21 - - 1974 30 1 500 - 1975 31 2 400 - 1976 34 2 500 16 1977 26 3 ODD 20 1978 31 4 100 24 1979 30 3 800 15 1980 32 3 100 30 1981 40 3 900 37 1982 42 4 000 37 1983 42 5 500 62 1984 61 6 000 60 Total 474 42 600 301 * - z no figures available are increasing use of such sources, the percentage of living donors still is relatively low at our centre. A contributory factor is that harvesting has al- ways been well organized in the Uppsala region, as a result o f close collabor- ation with the other departments of surgery and anaesthetics within the region. The doctors at the university hospital and elsewhere in the region have shown a highly positive attitude concerning management of uraemic patients. At many regional meetings arranged by different disciplines, harvesting of kidneys has been a topic of discussion. The linking o f the transplantation programme to urology also has had posit- ive effects. Many young urologists thus have worked with problems of uraemic patients during training in Uppsala, and have learned techniques o f harvesting and transplanting kidneys. Vascular access surgery has also been included in their training. Many o f these doctors subsequently work in hospitals within the Uppsala region and contribute considerably to the harvesting prograwme. IS1 Uppsala is one of the centres in "Scandia Transplant", an organization with- in which kidneys are exchanged. Table 2 shows that Uppsala has had the most pos- itive exchange balance of all the Scandinavian centres. This implies possibil- ities for increasing the numbers of cadaver kidney transplantations. Use ofmore living, related donors is another possibility. Table 2. 31/12 1982 Utilization of kidneys in "Scandia Transplant" from 1/6 1969 to -- Donor K i d n e y s Total Exchange centre transferred used locally imported transplanted balance IMMUNOSUPPRESSIVE THERAPY AND RESULTS Immunosuppressive therapy has undergone several modifications since we began to transplant kidneys in 1969. Initially fairly high doses of steroids were given, in accordance with policy in most countries (5). The dosaqe usually was 200-300 mg on the first postoperative day, tapered to a maintenance dose of 5 to 10 mg/day. Azathiaprine was always given together with steroids, beginning with an i n - travenous dose before transplantation. The initial dose usually was 2-3 mg/kg/ day, with tapering thereafter according to evidence of bone-marrow depression or severe infection. Because o f severe side effects, the immunosuppressive therapy was changed in 1980 to the low-dosage schedule introduced by McGeown in Belfast (3). The ster- oid d o s e thus was reduced to 20 mg/day, which was maintained for one month and then very slowly reduced to 5 mg/day. With this therapy there was a high 152 i n c i d e n c e o f a c u t e r e j e c t i o n s . The s u r v i v a l r a t e s o f t r a n s p l a n t s and o f p a t - i e n t s , however, were h i g h e r t h a n i n t h e e a r l i e r p e r i o d ( T a b l e 3 ) . T a b l e 3. p a t i e n t and g r a f t s u r v i v a l ( a p p r o x i m a t e f i g u r e s ) Immunosuppressive t h e r a p y i n d i f f e r e n t p e r i o d s compared w i t h one-year 1969 - 1980 1980 - 1983 1983 - 1984 P r e d n i s o l o n e P r e d n i s o l o n e P r e d n i s o l o n e h i g h dose + l o w dose + l o w dose + a z a t h i o p r i n e a z a t h i o p r i n e c y c l o s p o r i n One-year s u r v i v a l 2-3 mg/kg/day 2-3 mg/kg/day A P a t i e n t s G r a f t s 75 7; 82 % 93 E 37 % 55 z 72 % A f t e r one y e a r with t h i s regimen, we i n t r o d u c e d a m o d i f i e d s t e r o i d sched- u l e , s t a r t i n g with 0.6 mg/day. The a i m was t o d i m i n i s h t h e h i g h i n c i d e n c e o f r e j e c t i o n s w h i l e m a i n t a i n i n g good p a t i e n t s u r v i v a l . I n 1983 we were g i v e n t h e o p p o r t u n i t y t o p a r t i c i p a t e i n a m u l t i c e n t r e s t u d y u s i n g c y c l o s p o r i n A as immunosuppressive a g e n t i n s t e a d o f a z a t h i o p r i n e . With t h i s a g e n t a l o w s t e r o i d r e g i m e n c o u l d be used. D u r i n g t h e f i r s t 10 days t h e p r e d n i s o l o n e dose i s t a p e r e d f r o m 100 mg/day t o 20 mg/day and t h e n s l o w l y re- duced t o 10 mg/day w i t h i n 3 months. The dosage o f c y c l o s p o r i n A s t a r t s with 1 5 mg/kg/day and i s t h e n reduced b y 2 rng e v e r y 1 4 t h day i n accordance w i t h t h e c l i n i c a l p i c t u r e and t h e l e v e l o f c y c l o s p o r i n A i n plasma. With t h i s r e g i m e n t h e g r a f t s u r v i v a l was c o n s i d e r a b l y p r o l o n g e d ( T a b l e 3 ) . There were a l s o l e s s problems w i t h i n f e c t i o n s and t h e i n c i d e n c e o f g r a f t re- j e c t i o n was reduced from about 70 % t o 30 %. The p o s t o p e r a t i v e p e r i o d t h u s b e i n g r e l a t i v e l y u n e v e n t f u l , t h e h o s p i t a l s t a y was s h o r t e n e d t o 3-4 weeks, as compared w i t h 6-8 weeks e a r l i e r . A m a j o r p r o b l e m with c y c l o s p o r i n , however, i s i t s n e p h r o t o x i c e f f e c t , and so f a r t h e l o n g - t e r m r e s u l t s a r e unknown. Hope- f u l l y , some new analogue o f c y c l o s p o r i n w i l l b e f o u n d t o combine t h e same good immunosuppressive a c t i o n w i t h absence o f n e p h r o t o x i c e f f e c t . O t h e r forms o f t h e r a p y have a l s o been t r i e d t o g e t h e r w i t h t h e a b o v e - s t a t e d b a s i c regimens. Thus i n 1975 we s t a r t e d t o g i v e b l o o d t r a n s f u s i o n s t o p r e - v i o u s l y n o n t r a n s f u s e d p a t i e n t s , f o l l o w i n g p o s i t i v e r e s u l t s w i t h t h i s r e g i m e n r e p o r t e d f r o m o t h e r c e n t r e s ( 4 ) . We have a l s o used d o n o r - s p e c i f i c b l o o d t r a n s - f u s i o n s (DST) t o one h a p l o t y p e mismatched l i v i n g r e l a t e d r e c i p i e n t s . Three u n i t s (200 m l ) o f b l o o d f r o m t h e donor were g i v e n t o t h e g r a f t r e c i p i e n t a t 153 intervals of 2 weeks. Up to now 1 2 patients have been treated in this way, and only one has been sensitized. This regimen is still in use in combination with conventional immunosuppressive therapy, with azathiprine and cortisone instead of cyclosporin A, in transplantation from living related donor. Rejection therapy Treatment of acute rejection has been, and still is, increased dose of steroids. The dose usually has been fairly high - about 1 g on 3 successive days. In patients treated with cyclosporin A, rejection therapy consists of a reduced steroid regimen (1.25 g methylprednisolone in 4 divided doses given during 4 days). In the early years we also used local irradiation to treat r e - jection. As the effect was questionable, however, irradiation was abandoned. In 1982 rabbit antithymocyte globulin (RATG) was introduced for treatment o f steroid-resistant allograft rejection (2). The effect was dramatic, and almost all of the patients responded with reduction o f serum creatinine. This effect- ive antirejection treatment, however, increases the incidence of infections and involves risk of malignancy, especially when given in combination with cyclo- sporin A . As techniques of immunosuppression have changed, the overall results as measured by patient and graft survival have improved (Table 3). Many factors other than immunosuppressive therapy have contributed, however. Surgical pro- cedures have been refined, in particular the management of complications. Dia- gnostic techniques have progressed. Gammacamera scintigraphy, ultrasonography and biopsy with advanced histologic methods have become available, and the entire clinical care has become more proficient. A retrospective survey there- fore readily provides an optimistic basis for future prospects. The improve- ments have taken place parallel with acceptance of diabetics and elderly pat- ients for renal transplantation. RESEARCH Since 1968 research on preservation and ischaemia o f kidneys has continu- ously been conducted in Uppsala. Five postgraduates working at the department o f urology have produced doctoral theses in this field. Close and fruitful col- laboration has been established with the renal research group at the Institute of Physiology and at the university's Biomedical Centre in Uppsala. The re- search work begun in 1968 was first conducted at the laboratories o f the Pharmacia company, which has continued to provide sponsorship. Immunologic research at Uppsala University has long traditions. Collaborat- ion with immunologists has intensified in recent years, especially since the appointment o f young surgeons with basic training in immunology to our uro- logic department with its transplantation service. Close contacts have thus been established between basic research and clinical work. Together with the clinicians, the departments of clinical immunology, microbiology and immunology are working on problems relating to the diagnosis, mechanism and therapy of graft rejection. Clinical research has focused on follow-up studies of patients with differ- ent immunosuppressive regimens, and on evaluation of new diagnostic procedures. This research is done together with nephrologists, radiologists and oncolog- ists. Uppsala is one o f the five centres collaborating in a study on cyclo- sporin A. Parallel with this clinical study, Uppsala is conducting a special programme, together with Sandoz Ltd, on the pharmacokinetics of cyclosporin A. Most of the aforementioned departments are also in some way engaged in this project. The field of transplantation brings together workers in basic research and clinical departments in a natural way. We are happy that so many scientists at our university show interest in this work. It is only through such collaborat- ion that clinical progress can be made in organ transplantation. THE FUTURE Conclusions concerning the immediate future are readily deducible from Table 1. The Uppsala region needs expansion of the transplantation service. The current programme envisages 55-60 renal transplants per year, and re- sources for this volume are being provided. The future, however, is largely dependent on political decisions. A question now being discussed is if Uppsala should accept responsibility f o r transplantations within a larger region. This would result in about 85 renal transplants each year. Another question is whether transplantation of pancreas, liver and heart should take place in Uppsala. There is need for 15-20 transplants of liver, 20 of pancreas and at least 20 o f heart in our present region. While awaiting the political decisions, the doctors are preparing the field by extending re- search, acquiring skills in harvesting multiple organs and stimulating inter- est among all categories of hospital workers for organ transplantation. 11 -858572 155 REFERENCES Calne, R.Y., R o l l e s , K., T h i r u , S., McMaster, P., Craddock, G.N., Aziz, S., White, D.J.G., Evans, D.B., Dunn, D.C., Henderson, R.G. & Lewis, P.: C y c l o s p o r i n A i n i t i a l l y as t h e o n l y immunosuppressant i n 34 r e c i p i e n t s o f c a d a v e r l c organs: 3 2 kidneys, 2 pancreases, and 2 l i v e r s . The Lancet 11: Hoitsma, A.J., van L i e r , H.J.J., Reekers, P. & Koene, R.A.P.: Treatment o f a c u t e r e j e c t i o n o f c a d a v e r i c r e n a l a l l o g r a f t s w i t h r a b b i t a n t i t h y m o c y t e g l o b u l i n , Transpl Proc. I n press, 1984. McGeown, M.G., Loughridge, W.G.G., Alexander, J.A., McEvoy, J., Kennedy, J. A., Douglas, J,, Clarke, S.D. & H e w i t t , J . C . : One hundred k i d n e y t r a n s - p l a n t s i n t h e B e l f a s t c i t y h o s p i t a l . The Lancet 1:648-651, 1977. Opelz, G . & T e r a s k i , P . I . : Dominant e f f e c t o f t r a n s f u s i o n s on k i d n e y g r a f t s u r v i v a l . T r a n s p l a n t a t i o n 2 9 2 , 153-158, 1980. Salaman, J.R.: N o n s p e c i f i c Imunosuppression. In: Kidney T r a n s p l a n t a t i o n . P r i n c i p l e s and P r a c t i c e . Ed. M o r r i s , P.J. 2nd E d i t i o n , p . 163, 1984. 1033-1036, 1979. 1 . 2 . 3 . 4. 5. Address f o r r e p r i n t s : L a r s F r o d i n Department o f U r o l o g y U n i v e r s i t y H o s p i t a l 5-751 85 Uppsala Sweden