The British Journal of Surgery Vol. 68: No.1: January 1981

Br. J. Surg. Vol. 68 (1981) 1-6 Printed in Great Britain

Renal transplantation-I 5 years' experience* V E R N O N M A R S H A L L ?

SUMMARY In Australia, it has been logistically possible, with integratedprogrammes of dialysis and transplantation, to usefinite resources optimally for the treatment ofpatients presenting with terminal renal failure (30 per million population per year), Transplantation is offered as dejni- tive treatment in most instances. Transplantation rates (20 per million per year) will need to increase to meet the continuing demand, if the results of transplantation remain unchanged.

Patient survival after transplantation is approximately doper cent at I year, 5Oper cent at 5 years and20per cent at 15 years. Most grafts are from cadavers. Graft survival of 60per cent at I year thereafter declines steadily with a 3 per cent graft loss per year. Patient andgrafi survival are adversely affected by increasing age, and the use of cadaver rather than living donors. Graft survival is superior with a 4 antigen match on H L A A and B matching, and is significantly lower in patients receiving no blood transfusions prior to transplantation.

Long term morbidity is significant in two-thirds of patients receiving grafts. Problems include chronic rejec- tion and toxic effects of immunosuppression. The in- creased tumour risk after transplantation (which in Australia has been mostly skin tumours) is of major concern; 30 per cent of patients by I0 years have developed cancer.

RENAL transplantation surgery has made rapid ad- vances since its tentative beginnings more than 20 years ago. In the early 1950s in Boston, Hume and his colleagues performed a series of kidney grafts from cadavers to unmodified recipients with chronic renal failure. The first renal transplant in Australia was performed in 1956 by Professor Maurice Ewing, but it was not until the early 1960s that the establishment of a standard immunosuppressive regimen using azathio- prim and steroids enabled clinical renal transplantation to establish itself as a definitive method of treatment of terminal renal failure. This paper will consider the present prospects of treatment of terminal renal failure by transplantation. Advances in basic and clinical immunology, genetics and preservation are pre- requisites for accurate evaluation of the future prospects from renal transplantation.

It should no longer be necessary to stress that the best possible treatment for terminal renal failure is by an integrated programme of dialysis and transplantation. The aims of this programme should be to offer the majority of patients a renal transplant as a definitive

treatment. The integrated dialysis programme will in- corporate haemodialysis and peritoneal dialysis, and should aim to have as many patients as possible dialysing in the home. Home haemodialysis and chronic ambulatory peritoneal dialysis use finite resources most effectively. Prospects of rehabilitation by the various methods of treatment emphasize these points (1) (Table r). Quantitatively and qualitatively, rehabilitation is best with a well-functioning renal allograft. The table is drawn from European experience but is mirrored by Australian findings. Using such an integrated approach in Australia and New Zealand it has been possible to provide treatment for the majority of those presenting with terminal renal failure (2). Of surviving patients in Australia (170 per million or approximately 2500 patients) half are supported by dialysis and half (85 per million or 1200 patients) have a functioning transplant. About half the patients on dialysis are in the home. The transplantation rate of 20 er million (approximately

tries. The vast majority of grafts (95 per cent) are still from cadaver donors. Such a transplantation rate currently allows coping with an influx of 30 new patients per million per year. If the success rate remains cons- tant, the rate of transplantation needs to increase further to avoid a progressive increase in the backlog of patients on dialysis awaiting transplantation. Over the past 15 years, more than 3000 transplants have been performed in Australia and New Zealand. Sixty per cent of the patients survive, and 80 per cent of the survivors have a functioning graft. The mean time on dialysis awaiting transplantation is currently 9 months. When consider- ing progress in transplantation surgery, an appropriate ledger would show certain credits and debits.

An asset of transplantation is that effective treatment of an otherwise fatal disease is now possible, based on integrated programmes of transplantation and dialysis. Results of patient treatment have shown steady im- provement, even with a relatively unselected policy of admission to the programme; and it is logistically possible to treat most patients with irreversible disease who require treatment (2&30 patients per million yearly).

Also, and of considerable importance, arising out of such progress there has been a massive stimulus of

300 grafts yearly) is excee (P ed by few European coun-

* Based on a paper delivered at a symposium on advances in vascular surgery, Meeting of the Association of Surgeons of Great Britain and Ireland, Norwich, 1979.

Monash University Department of Surgery, Prince Henry's Hospital, Melbourne, Australia.

2 V. Marshall

40.

39’

20 .

10 .

1 5 10 15 YEARS Fig. 1. Patient survival curves comparing 15 years’ experience of Australian renal transplantation (n = 2314) and rectal carcinoma (n = 1206). Patient mortality is 3-5 per cent yearlj. after firstyear. .

Table I: REHABILITATION TO POTENTIAL OCCUPATION (EUROPEAN EXPERIENCE)

Transplantation Livlng donor 15 Cadaver 65

Home dialysis 65 Hospital dialysis 35

interest and knowledge in a variety of interrelated basic and clinical fields such as nephrology, immunology, genetios and cancer.

The s igdcant debits of the ledger must not be overlooked, and the remainder of this presentation will concentrate predominantly on these.

The cost equivalent of this mode of treatment is high, but it is a cost which the Public appears willing to give. It is certainly a field in whch cost consciousness has been high From the onset, and capital and maintenance costs of transplantation and dialysis in our community are under continuing review. They compare, for example, in capital costs with the acquisition of a motor car. Maintenance and total expenditure still read reasonably when compared with the overall yearly expenditure on agents such as antispasmodics or analgesics.

Estimates of costs of home dialysis per patient are about $15 OOO (c. €7500) in the first year, with mainten- ance costs of about S10 000 (c. €5000) yearly thereafter. Costs of renal transplantation are less: about $10 000 (c. E50oO) in the first year with maintenance costs of $1000-4OOO (c. €500-2000) in subsequent years.

The ledger, however, would not merely be concerned with monetary costs. Other queries would highlight the problem of immunologically mediated rejection (which often remains resistant to treatment). The continuing mortality and morbidity of transplantation remain high. Long term problems will be seen to emphasize the cumulative risks of non-specific immunosuppression.

Patient survival after transplantation Analysis of total Australian or individual large centre results can now provide actuarial survival curves up to 15 years, although it will be appreciated that the numbers at the end of the curve are low even in the

combined experience. In recent years the survival of patients has steadily im roved. In Oxford, a recent series showed an actuariafpatient survival of 94 per cent at 1 and 2 years (3). In all centres the major mortality is in the first year, but with cadaver transplantation a death rate of between 3 and 5 per cent continues after the first year, as does a continuing graft loss of similar degree. These results of patient mortality still compare favourably with the treatment of many carcinomas; comparison with mortality from carcinoma -of the rectum is shown in Fig. 1. This shows actuarial patient survival from all Australian transplants (23 14 patients) and a similarly uncorrected actuarial survival curve in a group of patients with carcinoma of the rectum (1206 patients) treated by an individual surgeon (E. S. R. Hughes). The curves are strikingly similar, with patient survival at 1 year, 5 years and 15 years in each case of approximately 80 per cent, 50 per cent and 20 per cent. In both instances survival figures would be improved by corrections for population age.

Graft survival after transplantation In contrast to the steady improvement in results of patient survival in recent years, graft survival after renal transplantation from an unrelated cadaver donor has remained unchanged over the past decade (Fig. 2). These results emphasize the imperfections of current immunosuppressive regimens, in regard to early and delayed graft failure.

In the Melbourne series depicted, early graft failures following renal transplantation from the cadaver result in a 60 per cent graft survival at 1 year. Thereafter the yearly graft loss continues at a steady linear rate of 3 per cent per year with graft survival of 50 per cent and 30 per cent at 5 and 10 years respectively.

Factors determining survival Age and associated disease As expected, patient survival after transplantation decreases with age (Fig. 3, Table ZI). At 12 months after transplantation, the difference is 6 per cent per decade, and this spread increases to 10 per cent er decade by 5 years after transplantation. Patients un&r the age of 30 years have a survival at 1 year of 85 per cent and at 5 years of 70 per cent; while patients over 55 years have

Rend transplantation 3

-ACTUARIAL 1' GRAFT WRVlva

YEARLY GRAFT LOSS i 3 % A m FIRST

4 0 -

3 0 -

20 -

10 - L . . . . l . . . . l

1 5 10 15 YEARS

Fig. 2. Graft survival after first cadaver renal graft from a consecutive series of 200 grafts (Royal Melbourne Hospital).

I 2 3 4 5 YEARS AFTER TRANSPLANT

Fig. 3. Effect of patient a e on survival in Australian experience of cadaver renal trampfantation. Age groups illustrated are patients less than 30 years and over 55 years at time of transplantation and patients in the decade 36-45 years.

Table Ik EFFECT OF AGE ON PATIENT SURVIVAL AFII%R TRANSPLANTATION

Survival (%) 1 yr 5 yr

< 30 40 > 55

85 70 75 55 60 38

survival at 1 year of 60 per cent and at 5 years of 38 per cent. Average recipient age at the time of transplan- tation has steadily increased in Australia. In the past 12 months the average age has been 40 years, for which the survival expectancy at 1 year is 75 per cent and at 5 years approximately 55 per cent.

Presence of associated disease is also a determinant of survival, and is influenced by increasing age. Generalized vascular disease associated with renal failure accounts for an increased incidence of cardiac and cerebral complications in patients treated by dia- lysis or transplantation.

Type of treatment Patients treated by dialysis alone will tend to be a selected group. Most patients in Australia will be eligible for transplantation, with lone term dialysis reserved for patients with specific medical contraindi- cations to transplantation. However, the addition of dialysis survival data from patients prior to transplan- tation gives a reasonably accurate dialysis mortality risk. This discloses that patient survival at 1 year will be about 10 per cent better than in transplant patients, but by 5 years the survival is similar to that after transplan- tation. The continuing mortality of 3-5 per cent yearly is mainly due to deaths from vascular disease and from metabolic and other problems of dialysis.

Living donors Graft survival is convincingly superior when renal grafts are performed from living related donors. The Melbourne experience indicates that both early and late graft failures are significantly less in recipients of grafts from live donors. As anticipated, mortality and mor- bidity from the toxic effects of immunosuppressive control of rejection are also less with grafts from living donors. Patient and graft survival after 5 years are approximately 80 per cent and 75 per cent respectively. Only a small fraction of total grafts can, however, be provided by live donors (about 5 per cent in total Australian experience). At Prince Henry's Hospital in Melbourne the proportion has been higher, and 22 of 139 grafts (16 per cent) in the past 7 years have been from living donors, with a marked improvement in patient and graft survival from that obtained with cadaver grafts (4).

HLA typing and tramfusion Analysis of HLA A and B locus matching, considering donor antigen com atibility with recipient antigens, has given various res& in different countries. Most ana- lyses have demonstrated notably superior graft survival with a 4 antigen match, and the Australian ex rience is similar. The improved survival at 5 years is oEhe order of 10-20 per cent. However, in the Australian series, no significant differences in graft survival at any time u to

Presence of a positive T cell cross-match due to 5 years occurred between 0, 1,2 and 3 antigen matc R es.

4 V. Marshall

allo-antibodies is a clear contraindication to transplantation.

Matching for HLA-DR appears to exert a greater influence on graft survival than HLA A and B series antigens in some series. In an Australian multi-centre prospective trial, preliminary results have not shown significant differences between early graft survival in two groups of patients, with grafts allotted on the basis of matching for the A and B series in one group, and for DR in the other.

Patients receiving blood transfusions prior to grafting have a better 1-year survival than those patients receiv- ing no transfusions (3). Although this observation has yet to be unequivocally demonstrated in a prospective trial, the evidence from sequential series has become so persuasive that many units now pursue a policy of active transfusion of dialysed patients, and the potential hazards of sensitization to a subsequent graft have not proved in practice to be of major concern. Early results of a prospective clinical trial in Australia have shown significantly lower graft survival in the patient group receiving no transfusions (2).

Continuing mortality and morbidity after transplantation Continuing problems after transplantation will next be reviewed by analysis of a series of patients operated on in Melbourne between 1965 and 1969; so that there is a minimum patient follow-up of 10 years (Table IIr) . A total of 68 patients received 78 grafts (68 first grafts, 9 second grafts and 1 third graft). Of these 68 patients, 24 survive-a patient survival of from 10 to 15 years of 35 per cent. Primary graft survival over the same period was 25 per cent (17 out of 68). Of the 24 surviving patients, 3 are surviving with a second graft and 4 are on dialysis.

Rehabilitation has been excellent in 80 per cent of the patients and 2 women have had successful pregnancies. Most of the deaths occurred in the first year after transplantation, but chronic persisting attrition of grafts, and patients, with late deaths has continued over succeeding years out to 1 death 14 years after transplantation.

Only 1 in 3 of the survivors had a totally benign course throughout. Two out of 3 survivors had multiple problems which have required additional procedures, These continuing problems after the first year are listed below. Chronic rejection: Chronic rejection is the most impor- tant factor in determining prognosis. Chronic persisting rejection causes a yearly graft loss of 3-5 per cent which appears to be steady and progressive (Fig. 2). Improvement in patient survival in recent years has been as a result of a deliberate policy tq accept this attrition rate as inevitable, to predict early the need for re- transplantation in individual patients and to accept chronic graft failure while continuing minimal im- munosuppression. The original graft needs to be re- moved only if infected or infarcted, and patients should be retransplanted before azotaemia causes deterioration of health; thus retransplantation is indicated before serum creatinine rises to greater than 0.6 mmol/l. The patient's condition is thus kept optimum for each procedure, and surgical aspects of importance 'include the avoidance of transplanting non-viable kidneys, the use of effective preservation which gives a low frequency of early non-function, thus enabling early diagnosis of rejection to be made, and the optimal treatment of early and late surgical complications.

Infective complications: As a corollary of non-specific immune depression, infective complications remain a continuing problem after transplantation. Infective complications seen in a consecutive series of 200 first cadaver transplants include the following: the oro- pharynx, urinary tract, chest, skin and superficial tissues, septicaemia, oesophagus, pancreas, brain and meninges, liver, wounds and tendon sheaths. The frequency of infections is arranged in descending order, and it can be seen that local wound complications are rare. On the other hand, viral and fungal infections of the mouth and pharynx, particularly herpes simplex and moniliasis, are common, as are urinary and pulmonary infections. Opportunistic infections in the immuno- depressed individual have included a variety of local or systemic infections. Monilia, listeria, nocardia, crypto- coccus, pneumocystis and mycobacterial infections have all been seen.

Even with stable immunosuppression, of particular concern is the incidence of sudden and unheralded septicaemia, which has been a cause of tragic late deaths after a short and fulminating illness. Vascular complications-renal artery stenosis: General vascular complications have been considered pre- viously. Associated disease and increased age are the major risk factors. Late renal artery stenosis is seen as a complication in a number of patients. Estimates of frequency are difficult without arteriography in all patients, but it may be seen as a problem at some stage in about 10 per cent of patients. It occurs in two main forms.

First, there may be a localized narrowing of the main renal vessel. This is most usually post-anastomotic, and it may follow end-to-end or end-to-side anastomoses, and may occur whether or not a cuff of donor aorta is included in the anastomosis. Its causes are probably multiple, but intimal damage from perfusion cannulas, or from excessive traction during removal, or the haemodynamic effects of redundancy and kinking of the renal vessel probably all play a part. In many such instances rejection is absent or minimal, and the con- dition will respond very well to restorative surgery. The options available include refashioning of the anasto- mosis by transforming it from end-to-side to end-to-end or vice versa.

The second type of renal artery stenosis is a diffuse pruning of the vessels including the small arteries. Multiple and diffuse strictures and narrowing are common and may affect several segmental vessels. Rejection is severe and causal and there is no indication for surgery.

The indications for surgery in the first group are similar to those for renal artery stenosis in the non- transplanted kidney-that is to say, an association of resistant hypertension with deterioration of renal func- tion aided by estimation of renin levels in the venous effluent from the kidney. Lute ureteric obstruction: Another mechanical problem seen may be a later ureteric obstruction. This does not usually occur at the site of uretero-neocystostomy, but at the pelvi-ureteric junction of the transplanted kidney, and it appears similar to primary pelvi-ureteric hydro- nephrosis in non-transplanted kidneys. It is not usually related to rejection and may have an excellent response to corrective pyeloplasty. Lymph collection-lymphocele: Collections of clear lymph developing in the vicinity of the transplanted kidney have been diagnosed with increasing frequency

Renal transplantation 5

Table 111: RENAL TRANSPLANTATION FROM CADAVERS ROYAL MELBOURNE HOSPITAL

Survivors 1%5-69

No. No. ' % ~~

Patients Grafts

1st 2nd 3rd

68 24 35 78 68 17 25

3 33 9 1 -

following the advent of ultrasonography. It is probable that small asymptomatic ones are relatively frequent and may resolve spontaneously. Lymphoceles can occur despite meticulous attention to tying off host lymphatics at the time of clearing the iliac vessels for transplan- tation. There seems, however, little doubt that the main contribution is from host lymphatics, and lymphograms may show the cut ends of lymphatics spilling contrast material into the cystic cavity. Large, persisting and recurrent lymphoceles, although unusual, can be a taxing problem and may be seen in up to 5 per cent of renal transplants. They usually cause obstructive symp- toms within the first few months after transplantation. They form bi-lobed swellings extending from deep in the pelvic cavity upwards to lie between the transplanted kidney and the bladder. They may then displace the bladder to the opposite side and the ureter is commonly bowed over the central isthmus of the swelling. A swollen leg on the same side as the transplant may be a symptom and bi-manual examination will reveal a mass arising from the pelvis, which may extend above and around the transplanted kidney. Up to 2 1 of fluid may be contained in such lymphoceles. The internal lining has a smooth and glistening serosal surface and the cyst fluid is clear, with few lymphocytes on microscopy apd with the composition of interstitial fluid. Symptomatic lymphoceles are best treated by radiological and ,dltra- sonic localization and by an initial percutaneous need- ling if they are accessible suprapubically. Recurrence after needling on one or two occasions, with continuing evidence of functional deterioration due to obstruction, should be treated by internal fenestration of the cyst into the peritoneal cavity. An intraperitoneal approach is the preferred one and the operation is usually simple and effective under such circumstances. Bone and joint disease: This is a common cause of disability in late survivors and occurs in approximately 10 per cent of patients. It affects particularly the proximal weight bearing joints such as the hips. Symptoms of limp, pain and deformity may require joint replacement, and the results in our experience have been excellent and encouragingly (and rather surpris- ingly) free of infective and other operative complications. Increased turnour risk: This has emerged as one of the most significant and worrying late complications, par- ticulary as the risk appears to be cumulative and progressive. A specific risk has been recognized for many years of lymphoid tumours developing after transplantation. Reticulum cell sarcoma has an inci- dence 80 times that in non-transplanted patients. Kaposi's haemangiosarcoma and other lymphoid tumours may also be seen. These lymphoid tumours have a particular predilection for the central nervous system and carry a very poor prognosis. A wide range of visceral carcinomas have also been reported. These also carry a poor prognosis (5; 6).

In the Australian experience by far the commonest tumours have been those of the skin. These follow a pattern of progressive development and recurrence, resulting in a steadily increasing cumulative risk as time progresses after transplantation (2). A common pattern is the sequential development of crops of solar keratoses on ex osed hands and face within 12 months of transprant at ion. In subsequent years keratoacanthomas develop; these are atypical, do not regress spon- taneously and may recur after an initial and incomplete regression (7). They are far more aggressive than those seen in the normal population and may metastasize to lymph nodes. Their prevalence blends into the develop- ment of squamous cell carcinomas in situ, ultimately invasive squamous cell carcinomas (commonly of ana- plastic type) occur. An increased incidence of basal cell carcinomas and of melanomas also occurs, but squam- ous cell carcinomas are far more common. Thus the normal Australian ratio of squamous to basal tumours (1 : 4 or 1 : 5) is reversed. Of all skin cancers reported in the Australian transplant experience, 75 per cent were squamous cell tumours and only 25 per cent were basal cell tumours.

The types of cancers seen in the present series are as outlined (Table ZV). Cancer occurred in 13 patients, several having multiple tumours. Of the 10 patients who developed skin cancer, several developed literally scores of tumours in an unstable field of origin affecting the face or hands or both. The risk was progressive (Table V). An incidence of 20 per cent (1 3 out of 68 patients) of cancer occurred overall. However, of those survivors who lived for 10 years or more after transplantation, 30 per cent have developed cancer (6 out of 17) and there has been one late death from metastatic cancer of the skin at 5 years after transplantation.

Fortunately, in most instances the development of skin cancer can be treated satisfactorily, and preventive measures are also taken. All patients are given advice regarding the risks of excessive solar exposure, and are supplied with para-amino benzoic acid solar protective creams. Synergism between the oncogenic effects of immunosuppressive agents and of solar exposure are highlighted by the Australian experience, with an increasing frequency of skin carcinomas progressively as latitude approaches the equator. Thus a cumulative risk of 30 per cent in patients surviving 10 years in Melbourne compares with a risk of 40 per cent after 8 years in Sydney (2) (16 out of 41 patients) and of 45 per cent after 9 years in Brisbane (8).

The continuing morbidity and mortality of transplan- tation after the first year can be expressed by summariz- ing the major problems (Table Vf) . These summate to a considerable morbidity, so that of 17 atients who survived for more than 10 years, 12 gad multiple problems requiring additional procedures.

Causes of late deaths Initial good progress is no guarantee of freedom from unheralded late complications; 13 deaths have occurred more than 5 years after transplantation. Generalized vascular problems with cardiac and cerebral vascular occlusions have accounted for almost half the deaths (Table VZZ). Deaths have also been caused by sudden overwhelming infection, by rejection and by cancer.

The progressive cancer risk has emerged as a severe problem. In the ostensibly sun-blessed country of Australia cancer has become a very significant cause of

6 V.Marshall

Tabk IV: CANCER AFIXR TRANSPWATION

Total patients 68 Patients developing cancer 13

Skin cancer 10 Cervical cancer 3 Visccral cancer 1

Table V CADAVERIC RENAL TRANSPLANTATION: CANCER RISK

% No.

All patients 20 (13 : 68) Patients surviving 30 (6 : 17)

Death from cancer 1

Table VI: CAUSES OF LATE MORBIDITY AND MORTALITY AFIXR TRANSPLANTATION Chronic rejection: 3-5 per cent graft loss yearly Infective complications: risk of late septicaemia Vascular and metabolic

Cardiac and cerebral complications Bone and joint disease causing late complications

Mechanical complications: 5-10 per cent Renal artery stenosk Ureteric obstruction Lymphocele

Increased tumour risk Lymphomas and wsceral tumours Skin tumours: progressive and cumulative risk

10 years after transplantation

30 per cent at 10 years

Table VII: CADAVERIC RENAL TRANSPLANTATION CAUSES OF 13 DEATHS AFIXR 5 YEARS

6

3 3

Vascular Myocardial

Septicaemia Rejection Cancer 1

Cerebral Other

morbidity and death by 10 years after transplantation, and the risk is cumulative and progressive.

The debit part of the transplantation ledger has been deliberately stressed in this presentation. It should be pointed out that although two of three late survivors develop complications, in most instances these can be dealt with very successfully. It should also be noted that

one in three of the long term survivors will be expected to have a trouble-free course.

Conclusim Despite its long term hazards and complications, renal transplantation remains the best treatment for the majority of patients with terminal renal failure. Used as the preferred major form of treatment it allows optimal use of finite resources to give the best treatment for most patients with terminal renal failure. Reverting finally to our ledger, I therefore believe transplantation has more than paid its way since starting 15 years ago; and I h d it difficult to imagine that it will not advance further over the next 15 years.

Acknowledgements I am grateful to Drs A. Disney, T. Matthew, D. Pugsley and Professor A. G. R. Sheil and to the Dialysis and Transplantation Sub-Committee of the Australasian Societ of Nephrology and the Australian Kidney Foundation for lata from the Combined Dialysis and Transplantation Registry; and to my colleagues at Prince Henrys Hospital (Drs R. Atkins, D. Scott and N. Thomson) and at the Royal Melbourne Hospital (Dr A. D'Apice, Professors G. Clunie and P. Kincaid-Smith) for data regarding the Melbourne series.

References 1. ROBINSON B.H.B., VEREBRSTRAETEN P. and HAWKINS J. B.

(4.): Dialysis. Transplantation. Nephrology. London: Pitman Medical, 1976 13,49.

2. Australian and New Zealand Combined Dialysis and Transplant Registry: Reports. May 1979 and March 1980.

3. MORRISP. J . , B ~ S H O P D . . P E L ~ W S G . ~ ~ ~ ~ . : Resultsfromanew renal transplantation unit. h c e t 1978; 2 1353-6.

4. THOMSON N. M., SCOTT D. F., MARSHALL v. c. et al.: Living related renal transplantation: Experience in 22 cases. Aust. NZ. J . Surg. 1979; 4 9 608-12.

5. PENN 1.: Development of cancer asacomplication ofclinical transplantation. Transplant Proc. 1977; 9 1121.

6. SHEIL A. 0. R.: Cancer in rend allografts in recipients in Australia and New aaland. Transplant Proc. 1977; 9: 1133.

7. MARSHALL v.: Premalignant and malignant skin tumoursin immunosuppressed patients. Transphtation 1974; 17 272.

cancer in Caucasian renal allograft recipients living in a subtropical climate. Surgery 1980. (In the press.)

8. HARDIE 1. R., STRONG R. W., HARTL@Y L. C. 1. et d.: Skin

Paper accepted 22 July 1980.