Cyclosporin A in Cardiac Transplantation: Medium-term Results in 62 Patients

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1 Cyclosporin A in Cardiac Transplantation: Medium-term Results in 62 Patients Mohsin Hakim, F.R.C.S., M.R.C.P., John Wallwork, B.Sc., F.R.C.S., and Terence English, B.Sc., F.R.C.S. ABSTRACT Between March, 1982, and October, 1984, 62 patients underwent orthotopic cardiac transplantation in our institution. Immunosuppression was based on cyclosporin A (Cy A) and low-dose steroids with an initial 10- day course of antithymocyte globulin. Follow-up ranged between 39 and 71 months (mean, 51.7 months). Actuarial survival at 1 year through 5 years was 80.6%, 77.4%, 74.2%, 7l.4%, and 63.5%, respectively. Graft atheroma led to graft failure in 6 patients, 4 of whom died between 23 and 55 months after transplantation and 2 of whom had a repeat transplantation at 32 and 53 months. Diastolic hypertension (90 mm Hg or higher) developed in 88% of patients at 1 year. Chronic renal impairment was evident in all patients who survived for 2 years. Mean serum creatinine preoperatively and at 1 year through 4 years was 1.49? 0.08 mgh00 ml (? the standard error), 2.01 f 0.09 mg/100 ml, 2.07? 0.09 mg/100 ml, mg/l00 ml, and mg/loo ml, respectively. End-stage renal failure requiring regular hemodialysis developed in 3 patients, 2 of whom died. We conclude that in addition to graft atheroma, Cy A-related nephrotoxicity is emerging as a major cause of medium-term and long-term morbidity and mortality. The use of lower doses of Cy A in a tripletherapy protocol, that is, Cy A, azathioprine, and low-dose steroids, could help reduce the extent of renal impairment. With the introduction of cyclosporin A (Cy A) as the main immunosuppression agent, cardiac transplantation entered an accelerated phase with considerable increase in both the number of transplantations and the number of institutions involved. Clinical experience in various centers has demonstrated distinct advantages of Cy A over conventional immunosuppression with azathioprine and steroids [I, 21. Between March, 1982, and October, 1984, Cy A was used in combination with lowdose steroids in our institution. Later, this regimen was changed through the use of clinical trials of various immunosuppressive regimens, and since April, 1986, we have been using triple therapy comprising Cy A, azathioprine, and low-dose steroids. Here we report our early experiences with the use of Cy A in combination with low-dose steroids with a follow-up ranging between 39 and 71 months. From the Department of Cardiothoraac Surgery, Papworth Hospital, Cambridge, England. Accepted for publication June 8, Address reprint requests to Dr. Hakim, Division of Thoracic and Cardiovascular Surgery, Mayo Clinic, Rochester, MN Material and Methods Between March, 1982, and October, 1984, 62 patients received orthotopic cardiac transplants. These patients all met the selection criteria described by Baumgartner and associates [3]. Age ranged from 16 to 52 years (mean, 39.9 years). There were 57 male and 5 female patients. Twenty-nine patients had ischemic heart disease, 27 had idiopathic cardiomyopathy, and 4 had severely impaired ventricular function secondary to valvular disease. Two patients had previously undergone heart transplantation, and cardiac failure secondary to graft atherosclerosis had developed. Both patients had been treated with conventional immunosuppression for control of rejection of the first graft. The immunosuppressive regimen, however, was changed to Cy A and low-dose steroids for the second transplant. Four of the 62 patients subsequently received another transplant. Recipients for a given donor heart were selected on the basis of ABO blood group compatibility, height, weight, and level of pulmonary vascular resistance. All recipients had had full tissue typing for Classes I and I1 of major histocompatibility antigens and had been tested against a random panel of lymphocyte donors for specific antibodies. Only those recipients showing the presence of preformed antibodies underwent crossmatching between recipient serum and donor lymphocytes before Donors The criteria used for selecting cardiac donors have been outlined by our group [4]. Geographically, only4 (6.1%) of 66 donors were local. One donor heart came from continental Europe, and the rest came from various tenters within the United Kingdom. The cause of death was cerebral trauma in 48 donors (72.7%) and nontraumatic intracerebral hemorrhage in 12 donors (18.2%). Other causes accounted for the death of 6 donors (9.1%). There were 57 male and 9 female donors. Age ranged between 16 and 45 years (mean, 24 years). All donor hearts were removed at other hospitals, and myocardial protection was achieved by cold cardioplegic arrest with St. Thomas s solution (10 ml per kilogram of body weight) followed by simple cold preservation at 4 C. Total graft ischemia time ranged from 96 to 260 minutes (mean, 163 minutes). Immunosuppression Initially we avoided the use of antithymocyte globulin (ATG) as a prophylactic agent against rejection. We based this policy on the results of the early experience at Stanford with Cy A, low-dose steroids, and ATG [5]. 495 Ann Thorac Surg 46: , Nov Copyright by The Society of Thoracic Surgeons

2 496 The Annals of Thoracic Surgery Vol 46 No 5 November 1988 Table 1. Immunosuppressive Regimen (Protocol 11) Intravenous Antithymocyte Time Cyclosporin A Oral Prednisolone Methylprednisolone Globulin Preoperatively Perioperatively 9 mgikg orally Postoperatively 18 mg/kg/day in two divided doses commencing when the patient is extubated and taking oral fluids Maintenance Reduce weekly by 2 mgikg/day to 10 mg/ kg/daf mg 5 mgikg (slow intravenous infusion) mg on discontinua mg/kg/day comrnencing 24 hr postop and reducing to 0.3 mg/ kglday at 2 wk tion of bypass 125 mg every 8 hours (3 Single daily dose for doses) 10 d as a slow intravenous infusion 0.2 mg/kg/day..... See text for details. Table 2. Reduction of Cyclosporin A Dose with Time following Cardiac Transplantation No. of Mean Dose Time Patients (mgkg/day) 1 Month f Months f Year f Years f Years f Years f 0.72 Data are shown f the standard error. However, the incidence of early rejection in our first 6 patients was considered too high, and consequently we modified our protocol to include an initial 10-day course of intravenously administered equine ATG (Table 1). ATG was given in a daily dose with the object of reducing the T-cell fraction of the total lymphocyte count to 10% or to an absolute T-cell count of approximately 100 cells per cubic milliliter. The preoperative dose of Cy A was either reduced or totally omitted in patients with impaired renal function. The maintenance dose of Cy A was adjusted according to the patient s renal function, or if the plasma Cy A levels fell outside the range of 200 to 500 ng per milliliter using radioimmunoassay. Generally, the dose of Cy A has been gradually reduced with time (Table 2). Evidence of rejection was obtained from clinical and electrocardiographic changes. Suspicion of rejection on these grounds was always confirmed by endomyocardial biopsy before appropriate therapy was instituted. Early rejection was treated with pulse therapy of 1 gm of methylprednisolone intravenously daily for 3 days. Severe rejection episodes were treated with a 3- to 5-day course of equine ATG as well. Late rejection (more than six weeks postoperatively) was treated by increasing the oral steroid dose to 1 mg/kg/day and then reducing it to 0.3 mg/kg/day over two weeks. Follow-up All living patients were followed up until the end of January, Follow-up ranged between 39 and 71 months (mean, 51.7 months). Results Survival or Quality of Life Nineteen patients died during follow-up. Eleven died early (within 3 months after transplantation), and 8 died late (more than 3 months after operation). The causes of early death were as follows: acute rejection, 6 patients; infection, 3; donor heart failure, 1 patient; and multifactorial, 1. The causes of late death were as follows: graft atherosclerosis, 4 patients; renal failure, 2; malignancy, 1 patient; and acute rejection, 1. The 1-year survival (percent of patients surviving 1 year after transplantation) was as follows: 71.4% for 1982, 78.9% for 1983, and 86.2% for The actuarial survival curve shows the cumulative proportion surviving to be 80.6% at 1 year, 77.4% at 2 years, 74.2% at 3 years, 71.4% at 4 years, and 63.5% at 5 years (Fig 1). The Nottingham Health Profile was used to provide a quantitative measurement of the patient s health before and at intervals after transplantation [6]. The profile measures the patient s own perception of his or her health state through responses to a series of statements relating to distress in six dimensions: physical mobility, pain, sleep, energy, social isolation, and emotional reactions. A score of 0 to 100 is calculated for each dimension, and the higher the score, the greater the level of limitation and distress. Table 3 shows the mean scores from Nottingham Health Profiles completed preoperatively and at various times postoperatively. Paired comparison tests on data from the profiles showed a significant improvement (p < 0.01) in all six dimensions at 3 months following Questionnaires con-

3 497 Hakim et al: Cyclosporin A in Cardiac Transplantation PROPORTION SURVIVING PROPORTION FREE OF REJECTION I YEARS POST-TRANSPLANTATION Fig 1. Actuarial survival following cardiac transplantation with the use of cyclosporin A and low-dose steroids MONTHS POST-TRANSPLANTATION Fig 2. Actuarial curve showing the proportion of recipients free from rejection following cardiac Table 3. Mean Nottingham Health Profile Scores before and after Cardiac Transplantation Dimension After Transplantation Before Transplantation 3 Months 1 Year 2 Years (N = 54) (N = 29) (N = 29) (N = 30) ~ Physical mobility Pain Sleep Energy Social isolation Emotional reactions Table 4. Chronological Pattern of Acute Cardiac Rejection Months since Transplantation Variable Fatal rejections Nonfatal rejections Total rejections No. of patients at risk Rejection per patient ceming working status showed that 70% of those who survived for 2 years or more were employed, were at university, or had returned to being a housewife. Rejection The chronological pattern of acute rejection is shown in Table 4. To date, 53.8% of the total number of rejection episodes and 85.7% of the fatal rejection episodes occurred during the first 3 months. The incidence during the first 3 months was 0.8 rejection episode per patient. The actuarial curves for freedom from rejection are shown in Figure 2. Of the patients who received prophylactic ATG, 44.6% remained free from rejection at 3 months compared with 33.3% of those having operation before the introduction of ATG. Infection BACTERIAL INFECTION. The majority (62.9%) of bacterial infections occurred during the first 3 months. The most common site of infection was the lung. The incidence of

4 498 The Annals of Thoracic Surgery Vol 46 No 5 November 1988 Table 5. Bacterial Infections No. of Early No. of Late Episodes Episodes No. of Site of Infection (< 3 mo) Causative Organism (> 3 mo) Causative Organism Deaths Respiratory tract 11 Pneumococci, enterococci, 6 Pneumococci, enterococci, 1 (early) Citrobacter, Staph. aureus, Strep. viridans, Pneumocystis Klebsiella, E. coli, Pseudornonas Urinary tract 4 Klebsiella 2 Coliforms 0 Sternal wound 2 Staph. albus, Pseudomonas Septicemia 5 Staph. albus, enterococci, Cit- 3 Staph. albus, enterococci, Kleb- 0 robacter, E. coli, Strep. viri- siella, Strep. viridans duns Miscellaneous Endocarditis Staph. albus 1 (late). Cholecystitis Klebsiella 0 "The primary cause of death in this patient was Cy A-related renal failure. Staph. = Staphylococcus; E. = Escherichia; Strep. = Streptococcus. bacterial infection was 0.35 episode per patient during the first 3 months. There was one fatal episode of Escherichia coli infection, which caused extensive bilateral pneumonia and death 7 days after Table 5 shows the sites and causative organisms of both early and late bacterial infections. VIRAL INFECTION. Primary cytomegalovirus (CMV) occurred in 13 patients who had previously been seronegative for CMV antibodies. One of them died. Reactivation of CMV occurred in 17 patients who had been seropositive prior to The symptoms were generally less severe than with primary infections. The role of the transplanted heart in the transmission of CMV has been previously reported [7]. The time at which CMV infections became evident ranged from 28 to 83 days (mean, 45 days). Infection with herpes simplex virus occurred in 7 patients. Oral ulcers developed in 6 of them and keratoconjunctivitis, in 1 patient. Nine patients had a serological rise of antibody titers against Epstein-Barr virus between 2 and 33 months (mean, 16.9 months) postoperatively. Eight of the patients were asymptomatic; in the other, Epstein-Barr virus-related lymphoproliferative disorder developed. The case of this patient will be discussed later. PROTOZOAL AND FUNGOUS INFECTION. Primary toxoplasmosis developed in 3 patients between 20 and 35 days postoperatively. One of them died of disseminated toxoplasmosis. Reactivation of previously acquired Toxoplasma gondii occurred in 2 patients in this group at 60 and 75 days postoperatively. Transmission of T. gondii with the transplanted heart, diagnosis, treatment, and prophylaxis have been reported previously by our group [81. Pneumocystis carinii pneumonia developed in 4 patients between 110 and 193 days (mean, 138 days) after One patient who had a primary CMV infection also sustained severe Candida esophagitis requiring treatment with intravenous administration of amphotericin B. Malignancy Malignant disease developed in 2 patients during follow-up. The first patient was diagnosed to have small cell carcinoma of the lung 1 year after The tumor did not respond to a course of chemotherapy, and the patient died of disseminated disease 15 months following This patient had been a heavy smoker until the An Epstein-Barr virus-related lymphoproliferative disorder developed in the other patient 5 months after Initially this was a polyclonal disease confined to the lymphoreticular system; it regressed in response to a reduction in the intensity of immunosuppression and the use of acyclovir as an antiviral agent [9, 101. Subsequently, however, the lymphoproliferative process changed to monoclonal, and tumor deposits developed in several extranodal sites. A combination of radiotherapy and chemotherapy produced remission of the tumor. The patient is alive 46 months following Hypertension Four patients (6.5%) had been on antihypertensive treatment prior to Postoperatively, however, 37 (72.5%) of the 51 patients who survived for 3 months had diastolic hypertension (90 mm Hg or higher), and by the end of the first year, 44 (88%) of the 50 survivors had diastolic hypertension. No new cases of hypertension occurred after the first year following The development of hypertension appeared to be independent of patient age, sex, or reason for Nifedipine, a calcium antagonist, has been used as the main antihypertensive agent in the majority of the

5 499 Hakim et al: Cyclosporin A in Cardiac Transplantation Table 6. Angiographic Diagnosis of Coronary Artery Disease in Cardiac Transplant Recipients" Variable 2 Years 3 Years 4 Years (N = 48) (N = 28) (N = 19) Time Total no. of abnormal 11 (22.9) 13 (46.4) 9 (47.4) angiograms Grade I disease Grade II disease Grade 111 disease "Numbers in parentheses are percentages. Grade I = irregularity or minimal narrowing; Grade I1 = major stenosis (> 50%); Grade Ill = occlusive disease. Table 7. Changes in Serum Creatinine h els after Cardiac Transplantation Using Cyclosporin A" No. of Patients Serum Creatinine (mg/loo ml) Preoperative f Months postoperative f Year f Years f Years f Years f 0.33.Serum creatinine levels are shown as the mean 5 the standard error. patients. In 5 patients, however, hypertension has become increasingly difficult to control, and the nifedipine dose has had to be increased. Two of these 5 patients also required an additional antihypertensive agent. The increased resistance of hypertension to treatment could have been caused by the major deterioration in renal function that occurred in these 5 patients between 1 year and 3 years after Graft Atheroma Coronary angiography was carried out for 48 patients at 2 years, 28 patients at 3 years, and 19 patients at 4 years. Angiographic evidence of coronary artery disease was found in 22.9%, 46.4%, and 47.4% of patients at 2,3, and 4 years, respectively (Table 6). Coronary artery disease led to graft failure in 6 patients. Four of these patients died 23, 33, 48, and 55 months following Two patients had a repeat transplantation at 32 and 53 months. The extent of coronary artery disease had been underestimated angiographically in 2 of the 4 patients who died because it involved mainly the small intramyocardial vessels. Nephrotoxicity Sixty patients (96.8%) had a degree of nephrotoxiuty in the early postoperative period. It was exhibited by a rise in serum urea and creatinine levels and the absence of the usual diuretic response following cardiac This early acute renal impairment resolved spontaneously within 2 to 3 days in response to appropriate adjustment of Cy A dose. Chronic renal impairment was common. All of the 48 patients who have survived for 2 years have abnormal renal function. The mean values for serum creatinine preoperatively and at various times postoperatively are shown in Table 7. IMMUNOCONVBRSION FOR NEPHROTOXICITY. The progressive deterioration of renal function has compelled us to review the immunosuppressive protocol in a total of 11 patients between 2 and 4 years after The serum creatinine in these patients had increased to levels consistently higher than 2.8 mgi100 ml. In 4 of these patients (Group l), Cy A had to be discontinued at 3 years (3 patients) and 4 years (1 patient). Their serum creatinine level had ranged between 5.3 and 6.1 mg/100 ml (mean, 5.7 mg/loo ml). In this group, a baseline right ventricular biopsy was carried out, and when no acute rejection changes were evident, Cy A was rapidly withdrawn over a period of a few days. Concomitantly, azathioprine was introduced at a dose of 2 mg/kglday and the dose was subsequently titrated against the white cell count. At the same time, oral administration of prednisolone was increased to 1 mg/kg/day and then gradually reduced by 5 mglday to a maintenance dose of 0.3 mglkglday. The other 7 patients whose immunosuppressive therapy was reviewed (Group 2) required a marked reduction in the Cy A dose to 2 to 3 mg/kg/day. Their serum creatinine level ranged between 2.8 and 5.2 mg/100 ml (mean, 3.5 mg/loo ml). Concomitantly with the reduction of Cy A dose, azathioprine was added at a dose of 2 mg/kg/day, which was subsequently titrated against the white cell count. These 7 patients have been maintained on triple therapy-azathioprine, low-dose prednisolone, and low-dose Cy A. RESULTS OF IMMUNOCONVERSION. In the two conversion groups, 1 patient died of renal failure 3 years after He had received hemodialysis for a few days before he died of uremic respiratory failure. Another patient sustained progressive renal impairment, which required frequent hemodialysis. Subsequently he received a renal transplant 4 years following cardiac The renal transplant functioned well, but a severe wound infection developed and the patient died of septicemia four weeks later. A third patient is currently receiving hemodialysis for end-stage renal failure and is waiting for a renal transplant to become available. Five other patients showed only slight improvement in renal function after 6 months with the mean serum creatinine level decreasing from 3.7 to 2.7 mg/100 ml. In the remaining 3 patients, renal function improved substantially with the mean serum creatinine level decreasing from 3.2 to 1.8 mg/l00 ml after 6 months. Acute rejection occurred in 4 patients (36.4%) in the conversion groups within 3 months of the changeover. Rejection was treated initially with a transient increase

6 500 The Annals of Thoracic Surgery Vol 46 No 5 November 1988 in oral steroids, but subsequently required more intensive therapy with intravenously administered methylprednisolone to improve the histological changes. Comment Over the past decade, immunosuppression for cardiac transplantation has undergone a series of modifications, the most remarkable of which was the introduction of cyclosporine by the Stanford group in Our experience at Papworth Hospital with the use of Cy A and low-dose steroids has confirmed the superiority of this regimen over conventional immunosuppression. The steroid-sparing effect of Cy A has been a major advantage with a reduction in the incidence of fatal infections. Cy A has also reduced the incidence and severity of rejection episodes, has substantially improved survival during the first 3 months, and has had a major impact on actuarial survival at all late follow-up intervals. It is also clear from analysis of the Nottingham Health Profile scores that a large number of patients attain an essentially normal state of health soon after operation. Prolonged surivival has, however, increased the importance of the long-term complications of cardiac transplantation and of immunosuppressive therapy. The initial fears of a carcinogenic effect of Cy A and the possibility of increased risk of lymphoma have not materialized. The incidence of lymphoma among cardiac transplant recipients treated with conventional immunosuppression has been reported to be 4.8% after the first transplantation, but increasing to 40% after a repeat transplantation [ll]. Our experience confirms the low incidence of lymphoma among Cy A-treated cardiac transplant recipients even with concomitant use of prophylactic ATG. The incidence of angiographically visible coronary artery disease in this series is 47.4% at 4 years after This suggests that the incidence of graft atheroma has remained unchanged since the introduction of Cy A [ll, 121. The follow-up, however, is shorter than that with the conventionally treated group, and it is possible that hypertension, which is seen almost uniformly among Cy A recipients, might increase the incidence of graft atheroma in the long term. Uniquely associated with the use of Cy A has been the development of hypertension and nephrotoxicity. Diastolic hypertension occurred in 88% of patients at l year in this series. This is in contrast to the incidence of less than 20% in patients receiving azathioprine and steroids [21. The mechanism responsible for the development of hypertension remains unclear. There is evidence to suggest an aberration in the central nervous system control of blood pressure [13]. A possible renal etiology of hypertension has also been investigated. Plasma renin activity, however, was found to be reduced in the Cy A- treated patients [14]. Salt and water retention secondary to abnormal renal tubular function has been postulated as a cause of hypertension. In our experience, Cy A- related hypertension has responded in the majority of patients to a combination of diuretics and calcium antagonists. In 5 patients, however, hypertension proved resistant to treatment and necessitated increased doses of the calcium antagonist and the addition of a beta blocker in 2 patients. The increased resistance of hypertension to treatment could have been caused by the major deterioration in renal function of these 5 patients, which occurred between 1 year and 3 years after The potential adverse effects of hypertension and antihypertensive medication on cardiac transplant recipients are not yet known and would require longer periods of follow-up to be fully evaluated. The possibility of an increased incidence of graft atheroma has been mentioned. The most important complication associated with long-term use of Cy A is chronic nephrotoxicity. In our experience, this occurred in all recipients who have survived for more than 2 years. The mean serum creatinine level increased by almost 40% at the end of the second year and almost 60% at 4 years. Initially this renal damage was thought to be reversible on withdrawal of Cy A or a reduction of the dose. However, when nephrotoxicity was proven to be irreversible, it became clear that a large number of surviving patients were at risk for a similar fate [14]. This compelled us to review the immunosuppressive protocol in 11 patients between 2 and 4 years after The serum creatinine in these patients had increased to levels consistently higher than 2.8 mg/100 ml. This cutoff point is higher than that used for immunoconversion in other centers and in retrospect, interventions should have been undertaken earlier at higher levels of renal function [15, 161. The incidence and severity of acute rejection precipitated by immunoconversion in our series are similar to those reported by other groups. However, we have been less successful in reversing the deterioration of renal function, and 3 patients progressed to end-stage renal failure. Only 3 of the 11 patients in the conversion groups have shown a clear improvement in renal function. We conclude that with better control of acute rejection and infection, the use of Cy A and low-dose steroids has greatly improved survival following cardiac Cy A, however, seems to have had no impact on the incidence of graft atheroma. It is even conceivable that Cy A-related hypertension might ultimately increase the incidence of graft atheroma. Cy A-related nephrotoxicity has also emerged as an important determinant of morbidity and mortality among the medium-term and long-term survivors. The incidence and severity of acute nephrotoxicity during the early postoperative period have been reduced with the use of a short course of ATG, which allows a gradual introduction of Cy A until therapeutic levels are reached. The severity of chronic renal impairment, on the other hand, could be reduced with the use of multiple immunosuppression agents in the maintenance protocols. This would allow the use of Cy A in lower doses without running the risk of underimmunosuppression.

7 501 Hakim et al: Cyclosporin A in Cardiac Transplantation Our preliminary experience with the use of triple therapy (Cy A, azathioprine, and low-dose steroids) since April, 1986, has shown real advantages for this regimen in regard to the extent and rate of progression of renal impairment. However, a longer follow-up is necessary to reach a more definite conclusion. We are greatly indebted to Noreen Caine and David Spiegelhalter for their contribution to this work and statistical analysis of the data. We are also very grateful to Jane Irvine for her excellent secretarial assistance. References 1. Oyer PE, Stinson EB, Jamieson SW, et al: Cyclosporin A in cardiac allografting: a preliminary experience. Transplant Proc 15:1247, Barnhart GR, Goldman MH, Hastillo A, et a1 Comparison of immunosuppression therapy following heart transplantation: pre-transfusion/azathioprine/atg/prednisolone versus cyclosporidprednisolone. J Heart Transplant 4381, Baumgartner WA, Reitz BA, Oyer PE, et al: Cardiac homotransplantation (monograph). Curr Prob Surg 161, English TAH, Spratt P, Wallwork J, et al: Selection and procurement of hearts for Br Med J 288:1889, Oyer PE, Stinson EB, Reitz BA, et al: Preliminary results with Cydosporin A in clinical cardiac In White DJG (ed): Cyclosporin A. New York, Elsevier, 1982, pp McEwen J: The Nottingham health profile: a measure of perceived health. In Teeling-Smith G (ed): Measuring the Social Benefits of Medicine. London, Office of Health Economics, 1983, pp Hakim M, Wreghitt TG, English TAH, et al: Significance of donor-transmitted disease in cardiac J Heart Transplant 4302, Hakim M, Esmore D, Wreghitt T, et al: Toxoplasmosis in cardiac Br Med J , Hanto D, Frizzera G, Gajl-Peczalska KJ, et al: Epstein-Barr virus-induced B-cell lymphoma after renal transplantation: acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med , Starzl TE, Porter KA, Iwatsuki S, et al: Reversibility of lymphoma and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1:583, Bieber CP, Hunt SA, Schwinn DA, et al: Complications in long-term survivors of cardiac Transplant Proc 13207, Zusman DR, Stinson EB, Oyer PE, et al: Determinants of accelerated graft atherosclerosis (AGAS) in conventional and cyclosporin-treated heart transplant recipients (abstract). J Heart Transplant 4:587, Thompson ME, Shapiro AP, Johnson AM, et al: New onset of hypertension following cardiac transplantation: a preliminary report and analysis. Transplant Proc , Myers BD, Ross J, Newton L, et al: Cyclosporin-associated chronic nephrotoxicity. N Engl J Med 311:699, Griffith BP, Hardesty RL, Trento A, Bahnson HT Five years of heart transplantation in Pittsburgh. J Heart Transplant 449, Hunt SA, Stinson EB, Oyer PE, et a1 Results of "immunoconversion" from cyclosporin to azathioprine in heart transplant recipients with progressive nephrotoxicity. Transplant Proc 19:2522, 1987