INTEGRATED PROGRAMME OF DIALYSIS AND RENAL TRANSPLANTATION

Saturday 26 July 1975

INTEGRATED PROGRAMME OF DIALYSIS AND RENAL TRANSPLANTATION Results in 155 Patients

T. H. MATHEW P. VIKRAMAN W. JOHNSON P. J. MORRIS *

V. C. MARSHALL A. V. L. HILL D. MCOMISH PRISCILLA KINCAID-SMITH

Department of Nephrology and University of Melbourne

Departments of Surgery and Medicine at Royal Melbourne Hospital, Melbourne, Australia 155

referred for treatment of irreversible renal failure between Jan. 1, 1970, and Oct. 31, 1974. 8 (5%) patients were not accepted for treatment. An integrated proof and dialysis gramme transplantation (based on a cadaver finding transplant for every patient) has achieved an actuarial survival-rate of 88% at 1 year and 79% at 4 years. Of those surviving at 4 years, 85% are maintained by a functioning transplant. Only 4/122 transplants have been from living related donors. It is suggested that these results demonstrate that cadaveric transplantation, closely integrated with dialysis, offers an acceptable chance of life and full rehabilitation while not demanding from the community an unacceptable percentage of health resources. Sum ary

patients

origin. Patients and Methods

were

Introduction MOST comparisons of dialysis and renal transplantation have shown a better survival for dialysis patients, especially when compared with patients transplanted from cadaver donors.1.2 The difference in survivalrate has influenced patients and physicians to choose dialysis as the definitive treatment and this has happened at a time when the ratio of live/cadaver renal transplants is falling.5 Any advantage transplantation may have in terms of quality of life is unlikely to impress the patient or physician if the mortality risk is significantly different. Hence, for cadaveric renal transplantation to continue to be offered to patients the mortality must approximate that of dialysis alone. The view has developed that an "integrated" approach to dialysis and transplantation allows the best treatment for the individual patient.5 If, in this integrated approach, transplantation is retained as the primary goal for each patient, the fullest use will be • Present address: Nuffield Department of Surgery, Radcliffe Infirmary, Oxford.

7926

made of available resources and the maximum number of patients will be treated.6 We report here our experience with an integrated approach in 155 patients with established renal failure who were referred for treatment between January, 1970, and October, 1974. The programme has achieved an 88% 1-year patient survival and a 79% 4-year patient survival. At 4 years, 85% of surviving patients are maintained by a functioning transplant. All except4 transplants were of cadaveric

Patient Selection Criteria for acceptance on the programme were liberal. Patients with diabetes, previous history of stroke, myocardial infarct, and multisystem disease were among those accepted. Age alone was not a criterion for refusal, although only 5 patients were over 60. Patients were not accepted for treatment if there was severe cardiac dysfunction (usually demonstrated angiographically as severe

narrowing established

uraemia.

in three coronary

vessels), oxalosis, or severe psychosis unresponsive to treatment of the

Integrated Policy The basic premise of the integrated policy was that transplantation should be performed in every patient unless medically contraindicated. Living related donors were encouraged but not aotively sought. Dialysis was begun and performed as though it were to be the long-term definitive treatment; it was not regarded as a temporary treatment during which there could be compromise in the control of hypertension, serum phosphate, or uraemia. Transplantation was done only when the patients were medically fit and as fully rehabilitated as possible. Transplantation was not done as an escape from failed dialysis or because of difficulty in vascular access or because the patient had tired of dialysis. Failing grafts were removed early, especially if the patient showed any sign of toxicity; if the graft were left in, immunosuppression and steroids were given cautiously. If the first transplant failed and there were no medical contraindication to a second, the patient was offered the choice of this or of home dialysis. Hospital Haemodialysis Dialysis was done twice weekly using a 1 sq. m. coil dialyser in a recirculating canister, for 14 hours per week, or a 1 sq. m. flat plate (Kiil) dialyser with single-pass dialysate flow at 500 ml. per minute, for 28 hours a week, or a 1’3 sq. m. hollow-fibre dialyser (C.D.A.K.) using single-pass dialysate flow of 500 ml. per minute, for 20 hours

a

week.

Home Haemodialysis A home hsemodialysis programme began in March, 1972.

138

Dialysis was performed at home three times per week using hollow-fibre (C.D.A.K.) dialysers (1-3 sq. m.) and a single-pass dialysate flow of 300 or 500 ml. per minute, for

a

TABLE I-CAUSES OF RENAL FAILURE FOR 147 PATIENTS ACCEPTED FOR TREATMENT BETWEEN JAN. 1, 1970, AND OCT. 31, 1974

Peritoneal

No.

Cause

total of 27-33 hours per week.

Glomerulonephritis (all types) Pyelonephritis (including reflux) Polycystic kidney disease Analgesic nephropathy ..... Others (diabetes 3, med. cystic disease 2, hypertension 2, gout 2, &c.)

Dialysis

......

......

Dialysis was usually initiated by the repeated puncture technique of peritoneal dialysis so that a patient could phase gradually into the programme and have vascular access established. When vascular access proved difficult or if the hospital haemodialysis programme was temporarily full, a cuffed ’Silastic’ peritoneal catheter was inserted and left in place as long as necessary. PeritQneal dialysis was performed using 2 litre exchanges, hourly cycles (i.e., approximately i-hour dwell-time) for fortyDialysate was eight exchanges (96 litres) per week. available in 1 or 2 litre glass or plastic containers.

......

......

Uncertain

............ —

80 20 15 5

(54-4%) (13-6%) (10-2%) (3’4%)

20 7

(11’2%) (4%)

147

have been stored on a Belzer unit. Comparative results from these two techniques in our hands have previously been reported.9

Selection of Donor-recipient Pairs Results All recipients were tissue typed using a panel of eightySelection ofPatients eight antisera detecting twenty-two HL-A specificities. 155 patients were referred to us for treatment, and All donor-recipient pairs had a direct lymphocytotoxic 147 patients were accepted into the programme cross-match performed by the micromethod of Terasaki. between Jan. 1, 1970, and Oct. 31, 1974. Causes of Priority was given to a recipient sharing three or four renal failure in this group are listed in table I. antigens with the donor, but if this was not achievable 8 (5%) patients were refused treatment-3 because the kidney was allocated to the recipient (with the same of severe cardiac disease, 2 for psychotic depression, red-blood-cell type and with a negative direct lymphocytotoxic cross-match) who had been waiting for the 2 were non-cooperative with medical regimens and longest time. refused further treatment, and 1 patient had oxalosis. -

Transplantation Management This has been described in detail previously.’ In brief, patients were nursed in a low-pathogen single room for the first postoperative week. Discharge to home occurred as soon as feasible and the patient was then reviewed fully each morning for several weeks. Results of pathology and biochemistry tests were available at lunchtime on the day of the visit so that anti-rejection therapy or diagnostic investigations (including renal biopsy) could be instituted without delay. Azathioprine was given in a dose of 1-2 mg. per kg. per day or in a lower dose if there was leukopenia. Until renal function was approaching normal the dose of azathioprine was halved. Prednisolone was given in a dose of 100 mg. per day for the firstweek, then reduced by 10 mg. per day until the level of 60 mg. per day was achieved. Further reduction was begun at 3 weeks after the operation and continued so that the dose was 30 mg. per day at 3 months and 10 mg. per day at 6 months. The prednisolone dose was usually maintained at 10 mg. per day thereafter. In a few patients a higher maintenance dose (e.g., 12-16 mg. per day) seemed necessary to avoid rejection episodes. Acute rejection was treated by increase in steroid dosage (methylprednisolone 1 g. daily intravenously for up to 3 successive days) followed by intravenous heparin for 2-7 days in the steroid nonresponder. Actinomycin C was used as supplemental antirejection therapy in the non-responder. Now that actinomycin C is no longer available, cyclophosphamide (200 mg. i.v. daily for 1-2 days) is being tried. No patient received antilymphocyte globulin.

The

mean

age of those refused treatment

was

48

(range 42-58) years. Of those treated, 98 (66%) were males and 49 (33%) females. The mean age of the treated group was 37-2 (S.D.+13-1, range 7-68) years. Degree of Renal Failure All patients were in irreversible renal failure at the time of entry to the programme. The mean lowest serum-creatinine in the month before starting dialysis was 13-2 (±3-3) mg. per 100 ml. and the mean peak serum-creatinine in the same month was 17-1 (±2-9) mg. per 100 ml.

Donor

Management Management of the cadaver donor always remained the responsibility of the donor’s own attending team until the time of cardiac arrest. Kidneys were not removed until cardiac arrest occurred and death had been certified in the usual manner. Mannitol, diuretics, and generous fluids were usually given, and in most donors a urine volume of greater than 60 ml. per hour was achieved in the hour preceding death. Cause of death was usually head injury, subarachnoid haemorrhage, or stroke. Until January, 1972, simple perfusion of the removed kidney and storage in ice was practised, but subsequently almost all kidneys

Fig. 1-Actuarial survival curve for patients on dialysis, posttransplant patients, grafts, and for the integrated programme. The " integratedand " dialysis" (hxmodialysis and peri’ toneal) curves refer to 147 patients; the "transplant"curves refer to 122 patients and 122 grafts. The numbers of survivors at each time interval are shown.

139

The actuarial survival of

and surviving tion is shown in fig. 2.

plantation,

Iritegrated Patient Survival patients from the time of

starting dialysis, irrespective of whether life was maintransplantation or dialysis (i.e., " inteis shown in fig. 1., The 1-year patient grated "), was survival 88% and the 4-year survival 79%.

tained by

Survival after Cadaveric Transplantation

on

dialysis

A three or four HL-A and recipient was achieved two or more less than two

antigen sharing by donor only 6 times. In 42 pairs were shared and in 76 pairs antigens were common to both donor antigens

and recipient.

Mode of

Survival on Dialysis Because dialysis was used largely

TABLE II-TRANSPLANTATION-RATE

*

Only 4/122 transplants were from a living donor.

period of hospital-based dialysis at therapy. This was peritoneal dialysis in 140/144 patients (97%) and lasted usually initially for 2-4 weeks. The length of time on peritoneal dialysis reflected the pressure on the limited haemodialysis programme. At times up to 8 patients were maintained on peritoneal dialysis. Transplantation had been performed at the time of this analysis (April, 1975) in 122/147 patients. All donors were cadaveric in origin except 4 whose donor was living and related (2 parent-child and 2 identical sibling pairs). The chance of successful transplantation being performed increased with time till, by 4 years, 22/26 (85 %) patients were being maintained by a functioning transplant (table 11). The number of patients having graft nephrectomy, secondary transpatients had

the

start

of

a

transplanta-

Selection of Donor-recipient Pairs

This was taken from the date of first transplantation, and is shown in fig. 1. The 1-year patient survival was 85% and 4-year survival was 76%. Graft survival (primary cadaveric) was 65% at 1 year and 57 % at 4 years.

Therapy Except for 3 patients who were transplanted without being first established on regular dialysis, all

or

The survival of the better matched group at 6 months was not significantly better than those with less than two antigens shared (chi-squared). The direct lymphocytotoxicity cross-match was negative in all instances.

as a

pre-trans-

plantation treatment and the average wait for a transplant was only a few months, the total accumulated experience on dialysis is not large. Survival data, therefore, are drawn from large numbers over short periods of observations. The survival curve for dialysis patients from the time of commencement on the programme to the time of first transplantation is shown in fig. 1 (method of Lewis et al.11). The 1year survival of 92 % is not significantly different from that of post-transplantation. Home Dialysis Of the 147 patients accepted for treatment, 16 (11 %) have been established on home dialysis. 9 of these patients had failed 1 or 2 transplants and due to HL-A antibody formation were unlikely to have another graft without a long wait, 5 elected to have home dialysis in preference to transplantation (2 on medical advice), and 2 patients lived in remote areas and dialysis was used to minimise travel. No patients died on the home dialysis programme, none returned to hospital dialysis, and 4 were successfully transplanted from home.

Waiting-time for Transplant The mean waiting-time for a first cadaveric transplant was 6-5 months and in those receiving a second cadaveric transplant 9-9 months.

Mortality 11 patients died while on dialysis (7 before primary grafting) and 12 patients died with a functioning renal graft. The causes of death are u.:,,1..nt

summarised in table

in.

Discussion This report details the experience in our unit over the past 5 years with an integrated programme of dialysis and transplantation. The results have been achieved despite a low refusal-rate (5%), limited physical facilities, largely cadaveric transplantation in a limited pool of recipients making close tissue matching infrequent, and with a conventional approach to

Fig. 2-Mode of therapy in each of the 147 patients accepted for treatment at the time of analysis (April, 1975).

anti-rejection therapy.

This programme has retained transplantation as its primary goal in all patients without This has been medical contraindications. based on the knowledge that patients prefer successful transplantation to suc-

-

140 TABLE III-CAUSES OF DEATH IN

147 PATIENTS TREATED

cessful dialysis because of the freer and more active life that is possible and because experience has shown that the " load " on health resources (finances, manpower, facilities) of a policy stressing dialysis as the primary goal is so great that constraints appear. These result in an inability to treat all those, presenting with renal failure. These factors would appear to account largely for the striking difference in the number of patients per million of population treated by dialysis and transplantation when a country like Denmark is compared to the United Kingdom or West Germany 1 Patient survival is improving,8,1l-13 and this has happened without jeopardising graft-survival rates. In our experience the same is true and has occurred largely because of the greater willingness not to use high doses of immunosuppression in the face’of graft failure and to return the patient to dialysis before the combination of urxmia, immunosuppression, and infection have wasted both muscles and the will to live. Cadaveric transplantation should in our opinion be performed only on well-dialysed and well-prepared patients and not as an escape from failing dialysis. The concentration of transplantation, hospital dialysis, and home-dialysis training in one geographic area and under the joint control of one team of physicians and surgeons allows, for the patient, the smooth phasing from one stage of treatment to the other and direct continuity of care. This is very important for home-dialysis patients, who might otherwise feel neglected. It is also important for all members of the medical team to share in all forms of therapy so that there is in no sense a competition between one and the other. We have stressed only patient survival. The morbidity of both forms of therapy is considerable, and in making the choice between dialysis and transplantation this must be considered. Careful comparisons are difficult to make, but in the Australian experience 78% of transplanted patients are fully rehabilitated compared to 54% of dialysis patients.14,15 For cadaveric transplantation programmes to succeed an adequate number of donors is essential. In the State of Victoria the donor-procurement rate has varied from 8 to 12 per million per year, and this has been achieved without any concerted effort at donor recruitment. It is our impression that the major determinant of success in donor referral is the attending doctor’s attitude and that this is largely governed by

knowledge of the likely success-rate of the transplantation programme to which he refers his donor patient. Another factor is the quality of the kidney that is transplanted. In this State the viability-rate is almost 100%9 despite all donors having death certified by cardiac arrest before kidneys are procured.

his

BETWEEN

JAN. 1, 1970,

AND APRIL

30, 1975

The success of this programme compares favourwith that achieved by others with home-dialysis alone 11 In 1967 we suggested that cadaveric renal transplantation seemed to offer a more practical solution to the treatment of chronic renal failure than

ably

hxmodialysis. When transplantation is integrated with dialysis, our experience has confirmed that patients are offered an acceptable chance of life

recurrent

and full rehabilitation without

community

an

demanding from the unacceptable percentage of health

resources.

This programme has only been possible because of the continuing cooperation from the honorary medical staff, the medical administration and the various departments, especially biochemistry, microbiology, haematology, and anaesthesia, of the Royal Melbourne Hospital. We thank the director of nursing and the nursing staff, and the dialysis teaching staff, for their dedicated efforts through the years. Requests for reprints should be addressed to T. H. M. REFERENCES

J., Brunner, F. P., Dean, H. V., Haren, H., Parson, F. M., Scharer, K. Proc. Eur. Dialysis Transplant. Ass. 1973, 10,

1.

Gurland,

2.

Lowrie, E. G., Lazarus, M., Mocelin, A. J., Baily, G. L., Hampers, C. L., Wilson, R. E., Merrill, J. P. New Engl. J. Med. 1973, 288,

M.

xvii.

863. 3. De Palma, J. R. Dialysis Transplant. 1975, 4, 15. 4. Salaman, J. R. Br. med. J. 1974, iii, 736. 5. Clunie, G. J., Hartley, L. C. J., Ribush, N. T., Emmerson, B. T., Morgan, T. O. Med. J. Aust. 1971, ii, 403. 6. Mathew, T. H. ibid. 1974, ii, 495. 7. Kincaid-Smith, P., Marshall, V. C., Mathew, T. H., Eremin, J., Brown, R. B., Johnson, W., Lovell, R. R. H., McLeish, D. G., Fairley, K. F., Allcock, E. A., Ewing, M. R. Lancet, 1967, ii, 59. 8. Twelfth Report of the Human Renal Transplant Registry. J. Am. med. Ass. (in the press). 9. Scott, D. F., Whiteside, D., Redhead, J., Atkins, R. C. Br. med. J. 1974, iv, 76. 10. Lewis, E. J., Foster, D. M., De La Pluente, J., Scurlock, G. Ann. intern. Med. 1969, 70, 311. 11. Williams, G. M., Sterioff, S., Rolley, R., Charrche, P., Zachery, J., Cooke, C. R., Walker, W. G. Proc. 5th int. Congr. Transplant. Soc. 1974, abstr. p. 195. 12. Saluatierra, O., Cochrum, K., Belzer, R. O. ibid. p. 192. 13. Tomlinson, S. A., Joslin, M. P., Evans, D. B., Joysey, V. C., Calne, R. Y. Br. med. J. 1974, iv, 533. 14. Disney, A. P. S., Row, G. P. Med. J. Aust. 1974, ii, 651. 15. Third Report by a Sub-Committee: Australian National Renal

Transplant Survey. ibid. 1974, ii, 656.

"

The real question which is hardly ever mentionedlet alone faced-is not just the inadequacy of some immigrant doctors. It is the existence of a system which ensures them the heaviest service responsibilities and the least training opportunities, and which repeatedly refuses to make the slightest change which would help them. Given their man-made predicament, it would be hardly surprising if some immigrant doctors were not inadequate. The ’inescapable conclusion’ is that official committees can sometimes exhibit rather gross complacency."—NICHOLAS BoSANQUET, New Society, July 17, 1975.