The Impact of 1,000 Renal Transplants at One Center OSCAR SALVATIERRA, JR., M.D., NICHOLAS J. FEDUSKA, M.D., KENT C. COCHRUM, D.V.M., JOHN S. NAJARIAN, M.D.,* SAMUEL L. KOUNTZ, M.D.,t FOLKERT 0. BELZER, M.D.t

A large, comprehensive renal transplant program has a major impact not only on patient care, but also on the medical center itself and the larger community. The program at this center has advanced from 15 transplants in 1964 to 141 transplants in 1976. Fifty-nine per cent of patients transplanted have functioning kidneys at this time, including 76 children. Rehabilitation was equal to prerenal disease level in 91% of 169 recipients who lived five years with a functioning graft. Basic research in such diverse areas as renal preservation and immunology, as well as clinical research in optimum immunosuppressive therapy, resulted in significant contributions. Refinement of the mixed lymphocyte culture improved livingrelated graft survival at two years: 100%0/ for HLA-identical and 91% for non-HLA-identical grafts, compared to 66%o reported by the Transplant Registry for the combined group. Modification of immunosuppression improved patient survival at two years: 100o and 86% for recipients of living-related and cadaver grafts, respectively, compared to 83%o and 65% reported by the Transplant Registry. The complexity of care of the patient with end-stage renal failure has required active interaction between transplant surgeons and almost every major specialty. The vast clinical material has been a great asset for training transplant surgeons, nephrologists, fellows and residents of multiple specialties, and medical students. The medical center's relationship with communities within a 250 mile radius has been strengthened, as reflected in patient referrals and the development of a multi-community-supported organ procurement system, which has allowed us to perform over 100 cadaver transplants per year for the past three years. Thus the performance of 1,000 renal transplants at this center has resulted not only in rehabilitation of many renal failure patients, but also in expanded and improved research and teaching capabilities, bringing support from multiple

medical disciplines and the general community.

FIRST RENAL TRANSPLANT at the University of California, San Francisco, was performed in January, 1964 by Dr. John Najarian. Thirteen years later in mid-January 1977, the one thousandth renal transplant was performed at this center. This large comprehensive renal transplant program has had a major impact not only on patient care, but also on the T HE

Presented at the Annual Meeting of the American Surgical Association. Boca Raton, Florida, March 23-25, 1977. * University of Minnesota Hospital, Minneapolis, Minnesota. t Downstate New York Medical Center, Brooklyn, New York. t University of Wisconsin Hospitals, Madison, Wisconsin. Supported in part by U. S. Public Health Service Grant # USPHS AM- 1 1290.

424

Transplant Service, Department of Surgery, University of California, San Francisco, California medical center itself and the larger community. Fiftynine per cent of patients transplanted have functioning kidneys at this time, including 76 children. The performance of 1000 renal transplants at this center has not only resulted in rehabilitation of many renal failure patients, but also in expanded and improved research and teaching cababilities, bringing support from multiple medical disciplines and the general com-

munity. Materials and Methods The results of 1000 consecutive renal allografts performed at the University of California, San Francisco since January, 1964 have been tabulated and analyzed. The clinical experience in transplantation was divided into two time periods based on the temporal relationship to uniform preservation of all cadaver kidneys by hypothermic pulsatile perfusion. Thus transplants performed from 1964 to 1967 are considered as a separate group from transplants performed since 1968, when all cadaver kidneys were uniformly stored by perfusion preservation. Graft and patient survival curves for transplants performed since 1968 were calculated by actuarial methods.10 Graft loss is calculated on the basis of the date of transplant nephrectomy or, in cases of retained failed grafts, the date that the patient was returned to maintenance dialysis. Graft loss also includes death of a patient from any cause. The data on patient survival includes all deaths occurring within three months after transplant nephrectomy and reinstitution of maintenance dialysis, and in addition, any subsequent deaths which may have had any relationship to the transplant. In computing patient survival, individuals who receive retransplants of a different donor source were withdrawn alive from the analysis of the previous donor source at the time of retransplantation, and

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RENAL TRANSPLANTS

150 r-

140I z

120 1-

-I

100 F_ CADAVER

z FIG. 1. Renal Transplants by Year and Donor Source. LL

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401 z

201 0 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976

YEAR then subsequently included as of the date of retransplantation in analysis with the new donor source. The rehabilitation status of all patients who survived five years or longer with functioning grafts was systematically reviewed and assessed. Pertinent data of patient status at five years post-transplantation was derived from patient, family, medical records, and staff caring for the patient at that time. Patients were considered to have been rehabilitated if they were able to both physically and psychologically lead active lives that included tasks identical or perceived as equivalent to those in which they had engaged prior to the onset of renal failure. In evaluating the results of basic and clinical research such as the mixed lymphocyte culture, optimum immunosuppressive therapy, influence of presensitization on graft survival, effect of HLA match grade on primary cadaver graft survival, graft and patient survival results pertinent to these studies are separately analyzed and reported. The impact of the transplant program on the medical center itself and training, as well as the medical center's relationship with communities in northern California are evaluated and discussed separately. Results The 1000 renal transplants were performed in 862 patients (485 male and 377 female). Figure outlines the number of transplants performed by year and donor source. Fifteen transplants were performed in 1964 while 141 transplants were carried out in 1976. Of the

1000 transplants, 279 were from living related donor sources, 17 from living unrelated donors, and 704 from cadaver donors. The ages of the 862 recipients at the time of their initial transplant ranged from 18 months to 60 years (Table 1). Fifty-nine per cent of patients transplanted (506/862) presently have functioning grafts. Seventy-six of these recipients were children at the time of transplantation.

Graft and Patient Survival From 1964 through 1967, 83 transplants were performed in 72 patients. The results without exclusion and 100%1o followup during this early pioneering phase of the program are summarized in Table 2. A total of 17 unrelated donors were utilized through 1971, with three of these recipients presently alive with normal renal function. These were primarily performed at a time when availability of donor kidneys was low compared to patient need. TABLE 1. Age of Recipients at First Transplant Donor Source

Age

Cadaver

Living

Total

1-10 11-20 21-30 31-40 41-50 51-60 Total

22 73 133 147 154 57 586

23 48 104 58 35 8 276

45 121 237 205 189 65 862

SALVATIERRA AND OTHERS

426

TABLE 2. 1964-1967 Transplant Experience

Kidney Donor Source Living related Living unrelated Cadaver

83

Patient Status

Alive With living related graft With living unrelated graft Without graft With new graft after 1967 Expired

27 1 5 3 36

Total

72

100%

100%

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- HLA IDEMNTICAL, N:a3 . .PRIMARY NON HLA IDNTICAL. N:159 - - SECOND TRANSPLANT NON HLA IDENTICAL, N: 12

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FIG. 2. Graft Survival Living Related, 1968-1976.

' 57% 57% 57% .-- 0- -O- -- -.- -0- -*

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Rehabilitation Assessment of the degree of rehabilitation in patients with long-term functioning grafts was evaluated in 169 recipients who lived five years with a functioning graft. Functioning transplants in these patients represented 106 living-related grafts, 60 cadaver grafts, and three living-unrelated grafts. Eighteen of these five-year surviving kidneys represented re-transplants. The serum creatinine at five years was 2 mg% or less in all but 16 of the 169 recipients (eight living-related and eight cadaver). Figure 5 illustrates that satisfactory rehabilitation of patients with long-term functioning transplants is generally achieved. The two longest survivors with functioning livingrelated grafts (almost 13 years) were 15 years and 48 years at the time of transplantation. Both of these recipients have normal renal function and have been

Graft and patient survival was separately evaluated on all living-related and cadaver transplants carried out since January, 1968, without exclusions, and with a minimum of three months followup on the last patient entered into the survival determinations. Figure 2 demonstrates graft survival from living related donor sources. The only HLA identical graft loss resulted from recipient death in an auto accident almost three years after transplantation (creatinine 1.1 mg%). Graft survival of 677 first, second and third cadaver transplants performed since 1968 is shown in Figure 3. Forty per cent five-year graft survival was achieved in primary cadaver transplantation. There were four

90

o

fourth cadaver transplants that are not separately shown in Figure 3 and that did not achieve one year graft survival. There was one single fifth transplant with normal function at time of the recipient's death two years after transplantation. Overall patient survival among recipients of livingrelated and cadaver grafts since 1968 is illustrated in Figure 4. Improved patient survival attained since 1972 is later discussed.

Number 66 7 10

Total

Ann. Surg.

1

2 YEARS

3

1

J

3

4

5

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RENAL TRANSPLANTS

427 - IMARY TRANSPLANTS. N:z57 .- .2ND TRANSPLANTS N:94 - - 3RD TRANSPLANTS, N: 16

o-

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5 FIG. 3. Graft Survival, ne Cadaver Transplants, 19681976

% 42# *2

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A.

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YEARS fully rehabilitated without medical problems. The two longest survivors of cadaveric transplantation (nine years) were four years and 16 years of age at the time of transplantation. The first recipient underwent transplantation after bilateral nephrectomy and pulmonary resection for extensive Wilms tumor with pulmonary

metastasis, unresponsive to irradiation and chemotherapy. This patient is doing well with normal renal function and without tumor recurrence. The second recipient also has normal renal function and is employed full-time after completing college. Another example of rehabilitation potential is the birth of eight

100%

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D TRANSPANTS, NON HLA IDENTICALo N: 170 4

1

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SALVATIERRA AND OTHERS

428

100

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z LU

creatinine of 0.8 mgo whose renal biopsy at 26 months shows diffuse intercapillary glomerulosclerosis with occasional nodular formation, and with afferent and efferent glomerular arteriolar subintimal hyaline ACTIVITY EQUIVALENT depositions, suggesting recurrent Kimmelstiel-Wilson TO PRE-RENAL FAILURE disease. ACTIVITY IMPROVED,

BUT NOT EQUIVALENT TO PRE-RENAL FAILURE

60

cL

z LU

40

LJ cL

20

0

91%

Ann. Surg. * October 1977

9%

FIG. 5. Rehabilitation Status, Patients with five Years Graft Function.

normal children by female transplant recipients, including a set of twins. In addition, many male recipients have now fathered children.

Transplantation in Systemic Diseases The etiology of renal failure in our series is similar to that reported by the Transplant Registry.1 During recent years, however, there has been an increased incidence of transplantation in patients with systemic diseases. For example, 10 patients with systemic lupus erythematosus have received kidneys and are alive at least one year after transplantation, eight with excellent renal function (three living-related and five cadaver grafts). The overall results with insulindependent juvenile diabetics, however, have not been as encouraging. Of 43 patients, nine are recipients of living-related grafts and are alive, with excellent rehabilitation and normal functioning grafts. Of 34 recipients of cadaveric grafts, one year patient survival is 75% while one year graft survival is only 32%. The diabetic recipients of cadaver grafts have generally reflected the highest risk transplant patients and the mortality in part reflects progression of advanced vascular disease present at the time of transplantation. In patients with systemic lupus erythematosus and diabetes mellitus, recurrent disease in the allograft has not been evident, except in one patient. This is a 40year-old diabetic recipient of a cadaver graft, with a

Basic and Clinical Research In addition to the survival and rehabilitation achieved with clinical transplantation, concurrent basic and clinical research has been an important and integral facet of the transplant program. Research at this and other institutions has resulted in better understanding of the pathophysiology of transplantation. A brief description of some basic and clinical research carried out at this institution is presented, demonstrating its influence on improving patient and graft survival and the ability of our center to accommodate to increased regional demand for transplantation. Morphologic Investigation of Pathologic Changes in Renal Homotransplantation Two of the earliest studies investigating the morphologic changes occurring in renal homotransplantation were performed at this institution12'13 and involved light, fluorescent, and electron-microscopic studies of functioning renal homotransplants. Difficulty was demonstrated even then in distinguishing histologic changes of rejection from a stable clinical course. For this reason renal biopsies have not been used to diagnose rejection, except in unusual circumstances. In addition to the clinical manifestations of rejection, hippurate renal scintiphotography with its simplicity and safety has instead proved to be the principal method of graft evaluation.21 Development and Successful Use of Perfusion Preservation The development of successful pulsatile perfusion preservation of canine kidneys was initially reported from this institution.2 Subsequently, the first clinical application of perfusion preservation in the storage of a transplanted cadaver kidney was carried out in August, 1967.3 Since 1968, all cadaver kidneys procured by our transplant team have been uniformly preserved by continuous preservation with cryoprecipitated plasma, initiated immediately after cadaver donor nephrectomy. With this method of preservation, we have successfully used even suboptimal donors (donors with serum creatinines as high as twice normal), and thereby greatly increased our pool of available kidneys. No nonviable kidneys have been transplanted in a consecutive series of more than 700 cadaver kidneys

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RENAL TRANSPLANTS

harvested by this institution.'7 The incidence of posttransplant dialysis for acute tubular necrosis has been 24% (mean: three dialyses per patient dialysed). No contaminated kidneys have been transplanted and wound infections have been infrequent. Other technical complications relating to procurement and preservation methods have been minimal; e.g. primary ureteral leaks are less than one per cent.'6 The paucity of these problems has allowed us to perform more than 100 cadaver transplants per year for the past three years. In addition, the absence of strict time constraints between procurement and transplantation has permitted semi-elective surgery, a major factor in the growth of our program and present transplant capability. Even a sudden influx of a large number of cadaver organs has been effectively managed. Pharmacological Management of Donors In 1966 mannitol diuresis was shown to be extremely important in protecting the living-related donor kidney from acute tubular necrosis." Tubular necrosis has since been effectively eliminated in the living-related postoperative course, and for the past six years not a single living-related recipient has required dialysis for this condition. Our initial results with hyporthermic pulsatile perfusion preservation in non-heart-beating cadavers were disappointing as far as immediate renal function post-transplantation was concerned. Subsequent studies in the laboratory revealed the influence and detrimental effects of agonal renal vasospasm and it was demonstrated that renal vasospasm could be completely prevented by alpha adrenergic blockade prior to cardiac arrest.5 Since 1968, all cadaver donors have been pretreated with either phenoxybenzamine or phentolamine, which has contributed to a marked improvement in immediate function rate of cadaver grafts.

Hemodynamic Evaluation of Human Renal Allografts The first study evaluating renal hemodynamics following human transplantation was carried out at this institution by means of catheters placed in the transplanted renal artery and vein and exteriorized into the anterior abdominal wall.9 Initial measurement of renal hemodynamics was begun within three hours after transplantation and followed through up to two weeks following transplantation. This pioneering study showed that marked vasodilatation and a low filtration fraction were frequently characteristic of uncomplicated renal transplantation and that early rejection was expressed by measurable decreases in the clearance of PAH and Inulin despite maintenance of renal blood flow.

429

Correlation Between Mixed Lymphocyte Culture Stimulation and Graft Survival

Refinement of the two-way mixed lymphocyte culture (MLC) and its prospective application has improved living-related graft survival at two years7 to 100% for HLA-identical pairs (n = 35) and 91% for non-HLAidentical grafts (n = 82), compared to a combined 66% two-year survival reported by the Transplant Registry for both HLA-identical and non-identical living-related grafts.' The 91% graft survival for non-HLA-identical grafts, prospectively selected by MLC, compares to a previous two-year graft survival of 63% (n = 89) in nonHLA-identical grafts transplanted at this center (p < 0.001). With living-related recipients currently doing so well, management of these patients has been greatly simplified. Since MLC testing in its present form requires five days incubation for quantitation of DNA synthesis, its prospective use in selection of cadaveric donorrecipient pairs is precluded. However, its retrospective use did demonstrate a positive correlation between the degree of MLC stimulation and graft survival in unrelated donor-recipient pairs. Two-year cadaveric graft survival with low MLC stimulation was 70%o (n = 115), while graft survival was only 24% (n = 105) with high MLC stimulation (p < 0.001). Prospective application of the MLC to cadaver renal transplantation will have to await development of longer consistent methods of renal preservation, a shorter reliable MLC test, or further elaboration in matching at the D locus, which is presently being carried out at this and other centers.

Development of a 39-Hour Lymphokine Indicator Test as Another Means of Histocompatibility Testing We have recently reported our preliminary results utilizing a lymphokine indicator test measuring leukocyte inhibitory factors (LIF) as a means of histocompatibility matching.8 Twelve one haplotype-matched LIF-negative living-related grafts have been transplanted and all grafts are functioning normally 6-15 months after transplantation. In cadaveric recipients at risk 6-15 months, graft survival in the LIF-negative group has been 75% (n = 16), while the LIF-positive pairs had an overall graft survival of 45% (n = 22). Of particular interest has been an 87% graft survival in LIF-negative and low MLC donor-recipient pairs, and a 20Wo graft survival in pairs with positive LIF and high MLCs. We are continuing our evaluation of the LIF test as a histocompatibility marker and are currently transplanting living-related pairs with high MLC reactions and negative LIF results. We anticipate that we

430

SALVATIERRA AND OTHERS

may be able to additionally select out living-related pairs with predictably good results, although not in the category achieved by low MLC stimulation. By providing the most optimally matched donor possible for each recipient, whether the donor is livingrelated or cadaver, further improvement of overall patient and graft survival should be obtained.

Improved Patient Survival by Modification ofImmunosuppressive Therapy

Since September, 1972 additional emphasis has been placed upon improving patient survival, principally accomplished by abolishing prolonged high-dose immunosuppressive therapy after transplantation.20 The results show that with low immunosuppression, patient survival has markedly improved without impairing graft survival. Since September, 1972, two-year patient survival of recipients of living-related grafts has been 100%, and, subsequently, only two recipients of livingrelated grafts have died: one recipient of an HLAidentical graft died at 34 months with normal renal function in an auto accident, while one recipient of a

Ann. Surg. X October 1977

non-HLA identical graft died at 30 months with normal renal function from chronic active hepatitis. Patient survival for recipients of cadaver grafts (includes recipients of multiple cadaver grafts) was determined for three time periods (Fig. 6). Patient survival in the group transplanted since September 1972 shows marked improvement over those recipients of cadaver grafts before then (p < 0.005). Primary cadaver recipient patient survival at two and four years as reported by the latest Transplant Registry is 65% and 55%, respectively.1 The foremost reason for improved patient survival in patients transplanted since 1972 is a marked decrease in death from infection. However, because of increased transplantation in higher risk patients, such as insulin-dependent juvenile diabetics and older patients, there has been some increase in mortality from cardiovascular causes. Nevertheless, the quality of life of the cadaver graft recipient has been enhanced and management of these patients has been greatly facilitated. Because of decreased mortality and side effects from steroids, an increasing number of patients are being referred for cadaveric transplantation.

100 1/" - 12176, N:601

1/62/" sn2, N-185 _91 % -

90

n9/72- 12176.

_

N 46

C-

0 .,

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64%

.

\ ***.1 _2

n w

z UJ

80H

-

@0% FIG.

.

% -w

74% *-F.0 0*

069...0

73%

7 .6.0

70%

70h-

L 0

I 1

2

YEARS

3

i

3

4

6.

Patient

Survival,

Cadaver Recipients.

431

RENAL TRANSPLANTS

Vol. 186.9 No. 4

-

3 MATCH, N-41 -- 2 MATCH, N:146 --1 MATCH, N:258 .... 0 MATCH. N120 (4 MATcH, N:2 1 LOST lIt MONTH and 1 FUNCTiONING AT 36 MONTHS)

90

80 I-

70 -L

FIG. 7. Primary Cadaver Transplants, 1968-1976, 567 Total.

nx

.09053%

__47%

__ _.

49%

.... 41%

45% - 42%

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401

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I

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3

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-q_. J 5

YEARS Influence of HLA Match Grade Allograft Survival

on

Cadaver Renal

An updated analysis of 567 consecutive primary cadaver renal transplants performed since 1968 in our heterogeneous northern California population has continued to show no influence of HLA match grade on renal allograft survival (Fig. 7).19 Mismatches and matches of specific antigens, cross reacting groups of antigens and effect of match at both locus A and B have been evaluated. There has been no significant effect on graft survival except when mismatches against donor A2 occured, with 26% two-year graft survival in the mismatched group compared to a 51% two-year graft survival in the no mismatch group (p < 0.005). These results have allowed us to use almost all organs procured by our own transplant team to meet the increasing needs for cadaveric transplantation in our geographic region. Organs have been shared when no cross-match and ABO-compatible recipients are available locally. The Influence of Hyperimmunization

on

Graft Survival

Graft survival rate has been evaluated in hyperimmunized recipients with greater than 50% frequency of preformed antibodies to selected panel cells.6'18 This includes recipients of primary cadaver grafts, sec-

ondary cadaver grafts, and living-related grafts. Our results indicate that good graft survival can be obtained in hyperimmunized recipients of primary cadaver renal allografts (p < 0.05 when compared to non-hyperimmunized cadaver graft recipients) (Fig. 8). However, sensitization following rejection of an allograft appears to confer a less favorable prognosis. In 18 hyperimmunized recipients of secondary cadaver grafts, only six grafts are surviving after six months and only four have survived one year (two with normal renal function). Since the number of sensitized patients who await renal transplantation is increasing, there should be no hesitation in proceeding with transplantation with primary grafts, but a guarded prognosis must be maintained for hyperimmunized recipients of secondary cadaver grafts. Evaluation of Immunosuppressive Potency of AntiHuman Thymocyte Globulin Immunosuppressive potency of rabbit anti-human thymocyte globulin (RAHTG) was evaluated as an adjunctive immunosuppressive agent in 100 recipients of primary cadaver renal allografts.14 This study was performed in a prospective, double blind, controlled fashion. In the low dose utilized, RAHTG was demonstrated to have an immunosuppressive potency that decreased the number of rejection episodes (p < 0.05)

Ann. Surg. * October 1977

SALVATIERRA AND OTHERS

432

-

6%

*f

LL

-~S9% A&

59% ,0-O-a

59%

FIG. 8. Primary Cadaver Transplants, 57 Hyperim59a% munized Recipients.

0

40' L 0

1

±

3

2

3

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5

YEARS and prolonged the interval between transplantation and the first rejection episode (p < 0.005). However at one year, no difference in graft survival between the ATG treated and control groups was found. Data describing the donor and recipient clinical course were reported at our institution and sent to the National Naval Medical Research Institute for independent processing and evaluation. The early immunosuppressive effect shown by the relative low dosage of RAHTG indicates the need for additional trials with dose regimens based on immunologic monitoring. Renal Transplantation without Diversion in Patients with Abnormal Lower Urinary Tracts

Controversy exists as to whether or not native urinary bladders are adequate receptacles for the transplanted ureter in renal failure patients with abnormal lower urinary tracts. Published reports appear to favor renal transplantation with external urinary diversion. Twelve consecutive patients with abnormal lower urinary tracts (spinal cord injuries and meningomyelocoeles not transplanted) have undergone renal transplantation with successful rehabilitation of the urinary bladder.15 This group includes long term defunctionalized and small-capacity bladders, i.e. 10 cc's. The results have indicated that optimum rehabilitation without urinary diversion of the transplanted ureter can be obtained if certain principles of evaluation and management are carried out.

Impact on Medical Center and Training The complexity of care of the end-stage renal failure patient has required active interaction between transplant surgeons and almost every major medical specialty. On our Transplant Service, there is full time participation and commitment by general surgery, urology, nephrology, and clinical pharmacology, representing total integration of surgical and medical disciplines on one team in the management of renal failure patients. This includes full-time specialty participation and interaction at both the attending and house staff level. Thus optimum patient management has been achieved by this cooperative and multidisciplinary approach. In addition, the transplant surgeon has actively interacted with other major subspecialty areas such as orthopedics, neurology and neurosurgery, infectious disease, hematology, cardiology, psychiatry, radiology, pathology, pediatrics. For example, 53 hip arthroplasties for aseptic necrosis have been performed by the orthopedic service on transplant recipients. Medical Education

Eight transplant surgery fellowships have been completed at this institution, with five transplant surgeons now heading transplantation programs. In addition, three former attending transplant surgeons at this institution are presently chairmen of surgical departments with active transplantation programs.

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Nineteen nephrology fellows have had extensive rotations on the Transplant Service fulfilling transplant training requirements for their fellowships. The vast clinical material available on the Transplant Service has been a great asset not only for training of transplant surgeons and nephrologists, but also for residents of multiple specialties and medical students. The subspecialties enumerated above have by their interaction with the Transplant Service also exposed their own house staff and medical students to the varied diseases and pathological processes in the patient material. For example, transplantation has made it possible to treat and further assess the natural course of the insulindependent juvenile diabetic who previously succumbed to his illness when end-stage renal failure occurred. Optimum therapy of the diabetic with renal failure has involved not only the transplant surgeon and nephrologist, but the endocrinologist, ophthalmologist, neurologist, and vascular surgeon. Enhancement of the Medical Center's Relationships with Surrounding Communities

The Medical Center's relationship with communities within a 250 mile radius has been strengthened, as reflected in increased patient referral and the development of a multi-community-supported organ procurement system which has allowed us to perform more than 100 cadaver transplants per year for the past three years. In order to treat as many patients with end-stage renal disease in our geographic area as possible, we have attempted to insure an adequate supply of cadaver organs by developing our own donor sources. The response from community hospitals, and also community-supported organizations such as the Kidney Foundation and local procurement agencies, has been an important stimulus to active participation by the various hospitals. Our transplant team has now traveled to 82 different community hospitals in northern California and Nevada to procure kidneys, and in most instances these hospitals have provided us with multiple kidney donors. Thirty-two private dialysis facilities use our center as an outlet for transplantations, and an average of 250 patients are maintained on our cadaver waiting list. There has also been extensive inter-institutional cooperation, as exemplified by the relationship with the Stanford University Cardiac Transplant Service. Members of the UCSF Renal Transplant Service have participated in joint procurement operations in almost all instances of cardiectomy for cardiac transplantation at Stanford University. These combined procurements have consistently yielded kidneys of excellent physio-

logical potential, demonstrating the feasability of this practice, in spite of the fact that cardiectomy for transplantation precedes retrieval of the kidneys, and special requirements of the donor heart necessitate some modifications in the pharmacologic management of the donor. Active lobbying efforts by transplant surgeons, nephrologists and neurosurgeons from this and other institutions in California have eventually resulted in the enactment of two important laws in this state. Legislation was enacted in late 1974 stating that a patient can be declared dead if by usual and customary standards of medical practice, irreversible cessation of brain function has occurred. The important aspect of this legislation was that it was the first of its kind recognizing the concept of "brain death" without attempting to define it. The legal recognition that a person can be dead, although his circulatory and respiratory systems are temporarily maintained by artificial means, was of great importance to organ transplantation in California. The California statute of 1974 is the first brief, simple statement acknowledging "brain death", similar to the one that was subsequently adopted by the House of Delegates of the American Bar Association in 1975.22 The second law, as in other states, was driver's license legislation enacted in 1976. Thus with application for a new or renewed driver's license, the applicant will be given the opportunity to indicate preferences for use of his organs for transplantation at the time of death. Although this legislation actually links donor identification to the driver's license, this law probably has its greatest potential in increasing public awareness to the need for organ donation. In order to enhance public awareness of the new law allowing Californians to place on the back of their driver's license consent of an anatomic gift, the transplant staff at this institution has also been active with other state transplant surgeons and interested laymen in providing informational brochures in field offices of the State Department of Motor Vehicles, stimulation of media coverage of the new law and of the need for donors in general, and the development of billboard and poster materials to inform Californians of the new law. Another important consideration in enhancing the medical center's interaction with northern California communities has been the willing and active participation of the transplant staff in community hospital and lay public education programs. Acknowledgments The authors wish to especially recognize with gratitude the encouragement and gracious assistance of Doctors J. Englebert

434 SALVATIERRA Dunphy and Paul Ebert in their initial and continued support of the program. The authors also acknowledge the participation of Doctors Donald Potter, William Amend, Flavio Vincenti, Floyd Rector, Henry Grausz, Deanne Hanes, in many phases of this program. In addition, the authors gratefully express their appreciation to the following technicians for their continuous and unselfish support: Rob Duca, Ken Stieper, Robert Hoffman and Joe Mitchell. There are also many nursing personnel and staff without whose participation in the program, the achievements accomplished would not have been possible.

AND OTHERS

10. 1 1. 12. 13.

References 1. Advisory Committee to the Renal Transplant Registry: The Thirteenth Report of Human Renal Transplant Registry. Transplant. Proc., 9:9, 1977. 2. Belzer, F. O., Ashby, B. S. and Dunphy, J. E.: 24-hour and 72-hour Preservation of Canine Kidneys. Lancet, 2:536, 1967. 3. Belzer, F. O., Ashby, B. S., Gulyassy, P. F. and Powell, M.: Successful Seventeen-hour Preservation and Transplantation of Human Cadaver Kidney. N. Engl. J. Med., 278:608, 1968. 4. Belzer, F. O., Perkins, H. A., Fortmann, J. L., et al.: Is HLA Typing of Clinical Significance in Cadaver Renal Transplantation. Lancet, 1:774, 1974. 5. Belzer, F. O., Reed, T. W., Pryor, J. P., et al.: Cause of Renal Injury in Kidneys Obtained from Cadaver Donors. Surg. Gynecol. Obstet., 130:467, 1970. 6. Belzer, F. O., Salvatierra, O., Cochrum, K. C. and Perkins, H. A.: Good Kidney Graft Survival in Hyperimmunized Patients. Transplant. Proc., 7 (Suppl. 1): 71, 1975. 7. Cochrum, K. C., Salvatierra, 0. and Belzer, F. O.: Correlation Between MLC Stimulation and Graft Survival in Living Related and Cadaver Transplants. Ann. Surg., 180:617, 1974. 8. Cochrum, K. C., Salvatierra, O., Cullen, B. L., et al.: Leukocyte Migration Inhibitory Factor (LIF) as an Indicator of Mixed Lymphocyte Culture (MLC) Reactivity. Transplant. Proc., 9:97, 1977. 9. Kountz, S. L., Truex, G., Earley, L. E. and Belzer, F. O.: Serial DISCUSSION

PROFESSOR LARS-ERIK GELIN (Sweden): The pioneering efforts of the transplant team in San Francisco have deeply influenced our program during the years, and we indeed have appreciated the knowledge presented from them. The advancement of transplantation gave, no doubt, a new dimension to surgical science and raised many new ethical, biological, and practical questions. The impact of these problems, in terms of advancement of science, including the clarification of the concept of death, a broadened international cooperation, awareness of human integrity and dignity, cannot yet be fully appreciated. With the possibility of survival that transplantation gave the patient in terminal renal failure, the demands on the transplant surgeon rapidly grew, and long before they had become organized and were ready to meet the demands from the patients, different transplant programs were developed. Our initial situation in 1965 was that there were almost no dialysis facilities available. So our program was designed to use transplantation as the treatment of choice, with a goal to master the quantitative problem in the care of all uremic patients in our region, using early retransplantation as treatment for graft failure. Economic calculations based on an incidence of 50 new patients per million per year suggested that renal transplantation as the treatment of choice should result in a stabilization in the demands on resources within a ten-year period, while with chronic dialysis as the treatment of choice this would not occur until after 25 years, and at a cost ten times higher.

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Ann. Surg. * October 1977

Hemodynamics After Renal Allotransplantation in Man. Circulation, 41:217, 1970. Merrel, M. and Shulman, L. E.: Determinations of Prognosis in Chronic Disease, Illustrated by Systemic Lupus Erythematosus. J. Chronic Dis., 1:12, 1955. Najarian, J. S., Gulyassy, P. P., Stoney, R. J., et al.: Protection of the Donor Kidney During Homotransplantation. Ann. Surg., 164:398, 1966. Rock, R., Rosenau, W. and Najarian, J. S.: A Clinicopathological Study of Human Renal Homotransplantation. Surg. Gynecol. Obstet., 125:289, 1967. Rosenau, W., Lee, J. C. and Najarian, J. S.: A Light, Fluorescence and Electron Microscopic Study of Functioning Human Renal Transplants. Surg. Gynecol. Obstet., 128:62, 1969. Salvatierra, O., Belzer, F. O., Cochrum, K. C. and Sells, K.: Evaluation of Immunosuppressive Potency of Rabbit Antihuman Thymocyte Globulin. (In preparation). Salvatierra, O., Emmott, C., Cochrum, K. C., et al.: Renal Transplantation without Diversion in Patients with Abnormal Lower Urinary Tracts. (In preparation). Salvatierra, O., Kountz, S. L. and Belzer, F. O.: Prevention of Ureteral Fistula after Renal Transplantation. J. Urol., 112: 445, 1974. Salvatierra, O., Olcott, C., Cochrum, K. C., et al.: Procurement of Cadaver Kidneys. Urol. Clin. North Am., 3:457, 1976. Salvatierra, O., Perkins, H. A., Amend , W. J., et al.: The Influence of Presensitization on Graft Survival Rate. Surgery, 81:146, 1977. Salvatierra, O., Perkins, H. A., Cochrum, K. C., et al.: HLA Typing and Cadaver Graft Survival. Transplant. Proc. 9: 495, 1977. Salvatierra, O., Potter, D., Cochrum, K. C., et al.: Improved Patient Survival in Renal Transplantation. Surgery, 79:166, 1976. Salvatierra, O., Powell, M. R., Price, D. C., et al.: The Advantages of 131 1-Orthoiodohippurate Scintiphotography in the Management of Patients after Renal Transplantation. Ann. Surg., 180:336, 1974. Stuart, F. P.: Progress in Legal Definition of Brain Death and Consent to Remove Cadaver Organs. Surgery, 81:68, 1977.

The gradual development of dialysis capacity and increasing competence in transplantation led to a rapid increase in the number of patients demanding kindey transplantation with us. (Slide) But from 1972, as seen from the slide, there seemed to be a balance in number of patients awaiting transplantation, as defined by the end of each year. We have recently reviewed our ten-year series (1%5-1975) of 705 transplants given to 514 patients, of which 85% were donated cadaveric grafts. In order to evaluate the risks involved when either chronic dialysis or renal transplantation is used as the treatment of choice for chronic renal failure, we took the survival figures of chronic dialysis from the EDTA report for the same ten-year period. (Slide) And in Europe chronic dialysis has been used in such an overwhelmingly dominating way that it is to be considered as the treatment of choice. The survival figures from the two groups are given as actuarial curves in this slide. As seen, transplantation during the first ten-year period was followed by a 15% higher first year mortality. However, after three years of treatment approximately an equal percentage of patients remained alive on the two programs. After the third year there was a better survival of patients who received transplantations than those treated by chronic dialysis. This is probably a consequence of a superior metabolic rehabilitation achieved with a well-functioning graft resulting in a retardation of an otherwise progressive vascular disease which follows uremia, and which is so poorly controlled with dialysis. When comparing the risks involved with the two methods of treatment, it is important, then, to bear in mind that an initial higher risk