Long-Term

Complications Leslie

of Cardiac Transplantation W. Miller

ARDIAC TRANSPLANTATION has evolved greatly over the past two decades, C from a desperate, experimental procedure with an expected l-year survival rate of only 20% in 1968’,* to a recognized treatment for end-stage heart failure that has a current success rate of nearly 90% at 1 year and 70% at 5 years.3 Although over 105 heart transplantations were performed in 52 centers in 17 countries around the world within the first year following the initial clinical experience in Cape Town, South Africa,4 it quickly became apparent that transplantation physicians and surgeons were unprepared to successfully manage the delicate balance between rejection and infection. As a result cardiac transplantation was largely abandoned (with the exception of the pioneering work performed at Stanford University) until the early 1980s when the more powerful and selective immunosuppressant cyclosporine became available. The significant improvements in survival rate associated with its use resulted in a dramatic increase in the number of transplantations performed each year, reaching a current average of 1,600 transplants performed per year in the United States and 2,500 worldwide.3 To date, there have been over 12,000 heart transplant procedures peformed with nearly 7,500 living recipients. Ninety percent of these procedures have been performed in the past 7 years. Despite the improved survival rate, it is interesting to note that the major complications reported today are virtually unchanged from reviews on this topic nearly a decade ago5-” in both the pre-cyclosporine and early cyclosporine eras. However, our understanding of the mechanisms involved in each of these complications and our approach to their management has been markedly enhanced. The field of organ transplantation and immunology is evolving rapidly and no one article can do complete justice to all the advances or cite all of the excellent work performed in this field. This review will focus on the current understanding of the diagnosis, pathogenesis, and treatment of the major long-term complications observed in cardiac transplantation today. Progress

in Cardiovascular

Diseases,

Vol XXXIII,

No 4 (January/February),

REJECTION

Allograft rejection has been one of the leading causes of morbidity and mortality in cardiac transplant recipients despite every immunosuppressive regimen tried since the inception of this procedure over 20 years ago.5B11-20 Although patient selection and improved immunosuppressive therapy have played important roles in the increased survival rate associated with heart transplantation today, the accurate diagnosis and effective treatment of allograft rejection remains one of the most critical determinants of both short- and long-term survival. There have been a number of advances in our understanding of the immunology involved in the rejection process as was recently reviewed by Marboe21 and Krensky et alZ2; however, this review will focus primarily on the classification, diagnosis, treatment, and prevention of cardiac allograft rejection. The detection of cardiac allograft rejection is based largely on the pioneering investigations by Lower and Shumway at Stanford University.23.24They observed that the rejection process was associated with, and often preceded by, a decrease in the summated voltage of the R wave amplitude on surface electrocardiogram (EKG), which was presumably due to myocardial edema.” Using this modality alone to judge the presence or absence of rejection and adjust immunosuppression, Lower and Shumway were able to successfully maintain laboratory animals in excess of 230 days.23.24This technique was then adopted clinically as one of the primary criteria used to diagnose allograft rejection.“-13 Unfortunately, it is not well correlated with rejection using cyclosporine-based therapy.25 In addition to EKG criteria, ultrasonic echocardiography often demonstrated increased thickness of the left ventricular wall and increased diameter of the right ventricular chamber,Ih but From the Department of Internal Medicine, Division of Cardiology, St Louis University Medical Center, St Louis. MO. Address reprints requests to Leslie W. Miller, MD, FACC, Division of Cardiology, St Louis University Medical Center, 3635 Viita at Grand, St Louis, MO 63110. Copyright 0 1991 by U! B. Saunders Company 0033-062Ol91l3304-0004$5.00/O 1991:

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was not as sensitive or specific as the electrocardiographic findings.” Rejection could not be detected clinically until it evolved to a severe grade. Often manifest by signs of congestive heart failure or decrease in exercise tolerance,12-14the initial treatment for allograft rejection consisted of an increase in maintenance immunosuppression,s~13 primarily corticosteroids and/or lymphocyte antibody agents, such as antilymphocyte sera or equine and rabbit antithymocyte globulin.27-29 In the early 197Os, Phillip Caves3”.“’ at Stanford first reported the enhanced ability to diagnose rejection using bioptome forceps that were inserted through the internal jugular vein, allowing sampling and histological evaluation of endomyocardial tissue for the presence of rejection. This procedure was associated with limited morbidity and could be performed on an as-needed basis to confirm the clinical suspicion of allograft rejection. After several years of experience, Billingham developed the first grading scale for classifying the histological severity of rejection on endomyocardial biopsy.32 A number of modifications of Billingham’s original grading scale have been reported by McAllister33*34 and others,35-37 somewhat in response to the unique histological findings that are associated with cyclosporine and lymphocyteantibody therapy. The problems created by a variety of grading systems have been recently reviewed by Billingham. These grading systems all basically represent additional subcategories of the original Billingham classification in which a grade 0 indicated no evidence of rejection, grade 1 indicated mild rejection, and grades 2 and 3 indicated moderate and severe rejection, respectively. Although grade 1 biopsies showed some evidence of rejection, only grades 2 and 3 were treated with “pulsed” high-dose rejection therapy. The histological criteria used to grade biopsies include an analysis of the number of foci of lymphocytic infiltration, their location-whether endocardial, perivascular, or interstitial-and most importantly, the presence or absence of myonecrosis.39-46This latter finding has been one of the primary criteria used to signal the need for bolus antirejection therapy. Although endocardial biopsy remains the current “gold standard” for the diagnosis of cellular rejection, there are several possible errors in interpreting the pres-

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ence or severity of rejection38-41 including the “quilty effect” (an accumulation of B cells on the surface of the endocardium with no or minimal infiltration deeper into the myocardium), lymphocytic infiltration confined to the endocardium or perivascular spaces, old biopsy sites, and areas of subendocardial injury caused by preservation or high catecholamine use in the donor prior to procurement. At least 4 to 5 adequate pieces of tissue must be obtained at each biopsy to allow adequate sensitivity to establish the diagnosis of rejection, and although autopsy studies have shown the rejection process to be multifocal and nonuniform, biopsy of the right ventricle is as reliable and safer than biopsy of the left ventricle.47-49 Rejection has been classified by a number of terms, including mild, moderate, and severe to describe the severity of a rejection episode; hyperacute, acute, and chronic to describe the time of occurrence; and cell mediated or antibody mediated (humoral) to describe the basic effector mechanisms. The term “chronic” rejection has been used to infer an ongoing process and a causal role of the frequency or severity of rejection in the development of the accelerated coronary vasculopathy seen in cardiac transplant patients. To date, this association is not well supported and the term “chronic rejection” should not be regarded as a separate form of rejection. It will be discussed later in the section on coronary artery disease. Acute cellular rejection is the mechanism and type for the vast majority of all rejection episodes and may occur from 5 days to several years posttransplant. Data show that 90% of all rejections occur within the first 6 months and is quite rare after 1 year without significant alteration in immunosuppression.50’s’ The percentage of patients free of acute allograft rejection varies considerably, largely due to the lack of a uniform grading system. Data from the Working Group of Transplant Cardiologists (WGTC):l including over 700 patients who received transplants in 1989, has shown the rejection-free incidence varies from a high of 90% to a low of 10% of patients, but in 1989 an average of 46% of patients had no rejections, 30% had a single rejection, and 24% had more than one rejection. There was an average of 1.0 rejection per patient in the first year posttransplant. Only 15% of all rejection episodes required more

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than a single “course” of therapy, and only 8% to 9% presented with hemodynamic compromise.5’ Initially, endocardial biopsy was used only to confirm clinical evidence of rejection, but now it is used on a predetermined “surveillance” basis. Although the incidence of rejection is decreasing, our current biopsy frequency and subsequent histological analysis does not seem adequate to identify which biopsies will progress to rejection. Hershkowitz5’ evaluated a number of histological findings on biopsies and found that only interstitial edema and perivascular infiltrate with intermyocyte extension correlated with subsequent development of rejection. Billingham53 has observed that over 40% of biopsies classified as mild rejection will regress and not require bolus therapy without any significant alteration in immunosuppression. Duquesnog and other investigators55,56 have observed that cell cultures from endocardial biopsy specimens showing no histological evidence of rejection when given interleukin (IL) 2 supplementation often grew cytotoxic lymphocytes. This technique may help identify patients at risk of subsequent rejection. Anderson55 has done doseresponse curves on these cells cultured from endocardial biopsies using a variety of antirejection agents, including ATG, methylprednisolone, and cyclosporine, and has found variable median lethal dose (LD5,,) values, often severalfold above therapeutic concentrations. Further investigation is needed in this important area to assess the sensitivity and specificity of this technique, especially after 6 to 12 months when biopsy frequency would be limited and the time delay for cell growth would not be a significant limitation. Although acute cellular rejection accounts for the vast majority of all cardiac allograft rejection, another type of rejection has been reported that is due to the humoral immune system (or antibody mediated) and is referred to as “vascular” rejection. This type of rejection is responsible for the “hyperacute” rejection that occurs in the operating room at the time of transplantation57 and is due to circulating preformed HLA class I antibodies in the recipient that react aggressively with an antigen(s) on the surface of endothelial cells of the allograft for which they have a directed specificity. Clinically, the allograft functions poorly from the time of

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exposure to the recipient’s circulation, often never demonstrating spontaneous electrical activity, difficulty in capture with direct pacemaker wires, and marked inotropic requirements to maintain blood pressure and cardiac output. Eventually the graft becomes cyanotic and tetanic (stone heart). Plasmapheresis5* in this setting may not be very effective and mechanical support (ideally a total artificial heart to remove the source of antigen) or emergent retransplant may be the only means to save the patient. The prognosis with this entity is extremely poor.59 To avoid these severe complications, a preoperative lymphocytotoxic antibody screen is performed (reported as percent reactive antibody [PRA]) for all patients placed on a cardiac transplant waiting list. This test detects the presence of circulating HLA class I antibodies. If preformed antibodies are detected, additional tests, such as the use of dithiothreiotol,60S61 can identify the immunoglobulin class of the antibody. Those patients who have circulating IgG type class I antibodies are at high risk of hyperacute rejection and require either direct crossmatch with the prospective donor or knowledge of donor HLA profile. In contrast, IgM antibodies frequently represent autoantibodies, and patients can be safely transplanted “across” these specificities as they do not effect the outcome.62 The role of the preoperative lymphocytotoxic antibody screens in predicting subsequent rejection and outcome is controversial,b3~h5 largely due to the variable techniques used to perform the screens.M.65 Although “vascular” rejection was previously described in the renal transplant literature:’ little attention was paid to this entity in cardiac transplantation away from the hyperacute intraoperative setting until Hershkowitz67 described the adverse prognosis of patients in whom endocardial biopsy showed lymphocytic arteritis (a form of humoral-mediated rejection). Recently, however, a number of report?‘* have focused on the significance and varied presentation of a delayed form of antibody-mediated rejection that occurs within the first 4 to 17 days posttransplant. Histologically, this type of rejection is characterized by endothelial cell proliferation, immunoglobulin and complement deposition on the vascular endothelium, with hemorrhage, polymorphonuclear lymphocytes, and occasionally eosinophils in the interstitium.7’ Hammond

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and coinvestigators from the Utah transplantation program7’ observed a significant incidence of this type of rejection soon after completion of a prophylactic 2 week perioperative course of monoclonal antilymphocyte antibody therapy (OKT3). High-dose steroid therapy, with or without vincristine,73 at or near completion of this therapy blunted the proliferation of committed cytotoxic T cells and abrogated the incidence significantly. The incidence of vascular rejection as defined by the presence of immunoglobulin on the vascular endothelium has recently been reported to occur in as high as 25% of all biopsies from the Utah group,74 although only a fraction of those had hemodynamic compromise or required altered immunosuppression. The demonstration of immunoglobulin on the vascular endothelium following use of antilymphocyte sera may not only represent antibody directed against class I or II molecules on the surface of endothelial cells, but may also be secondary to antigen-antibody complexing from antibody directed against the antisera itself, or the complexing of the sera with circulating lymphocytes (ie, OKT3 with circulating lymphocytes). Hammond71 also observed that a rejection episode may involve pure cellular, pure humoral, or both cellular and humoral mechanisms simultaneously. Humoral rejection, whether hyperacute or occurring sometime later, may require aggressive therapy directed primarily at B cells with modalities such as plasmapheresis58*76 to reduce the antibody titer, cytotoxic agents (such as cyclophosphamide),75-76 mechanical assist devices,65’76aor, potentially, retransplantation.76ax77 Humoral or vascular rejection may provide some explanation for those patients who present with hemodynamic compromise but do not show significant histologic evidence of typical cellular rejection on biopsy, and why use of anti-T-cell-mediated therapies, including OKT3 and ATG, may not be very effective in reversing systolic dysfunction. Recently, however, Schroeder7’ observed a good response in renal transplant patients with vascular rejection in using OKT3, presumably by altering the effect of helper T lymphocytes on amplification and proliferation of B cells. Another potential endothelial target of cytotoxic antibody is the vascular endothelial cell antigen system described by Cerelli.79-so These antigens occurred in over 10% of patients with

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peripheral vascular disease and have been shown to be present in cardiac transplant recipients who developed hyperacute rejection.81 Noninvasive Diagnosis

Although endomyocardial biopsy remains the gold standard for the evaluation of allograft rejection in cardiac transplant patients, this procedure is invasive, both time and personnel intensive, and is usually performed in areas of high demand, such as the cardiac catheterization laboratory or the operating room. In addition, as noted above, endocardial biopsy has a potential for both sampling error47-49 (falsenegative) and misinterpretation.38-@ For these reasons and others, a large number of investigators have evaluated a variety of noninvasive markers of rejection. One technique recently revieweds2 to noninvasively diagnose rejection is echocardiography, which is frequently performed serially in the follow-up of cardiac transplant recipients. Echocardiography provides evaluation of chamber size, contractility, presence of pericardial effusion, or cardiac valvular incompetence. Dawkins,“” Valantine,s3 and other investigators84-87have shown that although systolic dysfunction is a late, uncommon finding in cardiac allograft rejection, diastolic dysfunction is much more sensitive and may in fact precede histologic evidence of rejection.83 Using Doppler echocardiography, these investigators have shown that measured intervals, such as the pressure halftime and isovolumic relaxation time decrease, whereas early mitral flow velocity increases during rejection, all of which return to baseline with adequate treatment. Some difficulties can occur using this modality to diagnose rejection as the previously mentioned measurements are influenced by both heart rate and variable loading conditions. Other echocardiographic findings noted with rejection include systolic anterior motion of the mitral valve,88 insufficiency of the mitral valve,89 and increased posterior wall thickness.“@‘87 In neonatal and pediatric patients, echocardiography is the primary tool to diagnose rejection” and, unlike adults, systolic rather than diastolic dysfunction (particularly posterior wall thickening) is more sensitive, perhaps due to the marked tachycardia and fluctuations in heart rate commonly

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observed in this age group. Although nearly uniformly available and commonly performed on transplant patients, echocardiography has not yet been proven sensitive or specific enough to alter biopsy frequency by most centers. Cardiac transplant physicians have continued to focus on immunologic monitoring to detect allograft rejection since the initial transplants.‘3.28.29 Parameters evaluated have included preoperative response to phytohemaglutin (PHA) and concanavalin A,28 as well as postoperative total lymphocyte count, T lymphocyte fraction of total lymphocyte count,14 T4/T8 ratios,” and, recently, the analysis of cellsurface markers.q2,93 Activation of the immune system by alloantigens results in the production of a number of receptors on the surface of activated lymphocytes including one for IL-2, the major lymphokine responsible for helper T cell function.94.95 Fluorescent antibodies can be used to detect the presence of the IL-2 receptor and quantitate the number of circulating lymphocytes expressing this receptor.‘3.96 Although expression of this receptor is nonspecific (ie, infection may also cause activation of the immune system with resultant appearance of this receptor) in the absence of signs of overt infection, serial measurements of IL-2 receptor may be very sensitive and predictive of developing allograft rejection especially early posttransplant.93’96 Roodman and Miller93 have shown an 89% sensitivity and 82% specificity of IL-2 receptor assays with allograft rejection during the first 6 weeks following transplantation, although the sensitivity and specificity decreased significantly after that time due in part to infrequent IL-2 determinations and decreasing frequency of rejection with time. However, the number of IL-2 positive T4 lymphocytes reached a diagnostic level at an average of 4.8 days prior to histologic evidence of rejection. Use of newer antibodies directed against the larger, more functional 75KD subunit of the receptor,97 or the soluble moiety? may significantly enhance the sensitivity and specificity of this test. Other forms of immunologic monitoring include analysis of the peripheral blood smear for evidence of lymphoblasts, so-called cytoimmunologic monitoring.99-‘03 Despite these reports and ease of performance, this test is not widely used in the United States. Electrocardiographic correlates of allograft

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rejection beyond summated R-wave amplitude used with azathioprine therapy include analysis of the oscillations and amplitude of abnormal spikes in the late diastolic portion of the surface electrocardiogram, so-called late potentials.‘““05 These electrical potentials have been shown to be fairly predictive of significant ventricular arrhythmia in nontransplant ischemic patients.‘06-‘0* Other investigators have shown that electrodes placed on the surface of the right and left ventricle at the time of transplantation can be very sensitive for the detection of rejection,“’ and in fact have been used clinically to obviate the need for a number of biopsies, especially in pediatric and neonatal transplant recipients.“’ The summated voltage is obtained at night while the patient is asleep using telemetric pacemaker probes located on each ventricle. Decreases of as little as 10% may herald a rejection episode. This technique offers great potential for pediatric heart transplant patients in whom endomyocardial biopsy is difficult to obtain. The detection of cardiac allograft rejection by radionuclide techniques has been recently reviewed by Addonizio.“’ A number of nuclear tracers have been investigated including indiumlabeled antimyosin antibody,‘11a-113and lymphocytes,‘14 phosphorus nuclear magnetic resonance,“5.“6 thallium-201,“‘~“* technisium-99M, and gallium-67 imaging.‘lg Although all of these techniques have shown some promise, in general they require an advanced degree of rejection to detect a positive result, thereby minimizing their use as a screening test in their current form, as well as possibly exposing the recipient to additional radiation. In addition, several chemical substances have shown some correlation with rejection including prolactin,120.‘21 which may competitively share a receptor with cyclosporine and interact directly, so that levels of prolactin may go up with inadequate cyclosporine. In addition, neopterin,‘” pz-microglobulin,“3 and urinary thromboxane levels’” have been used with some success and may be used to help corroborate the diagnosis of rejection. Finally, several investigators are now evaluating the effect of rejection on the coronary microvasculature as evidenced by alterations in coronary flow reserve.‘2s~‘26Unfortunately, this requires invasive testing, again limiting its appli-

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cation as a noninvasive screening test for rejection. There have been a number of risk factors identified following cardiac transplantation for the development of allograft rejection. Crandall”’ and MillerSO have observed as much as a twofold to fourfold increased risk of rejection in female (especially multiparous women) transplant recipients compared with age-matched male recipients, potentially due to undetected circulating antibodies formed during pregnancy. In addition, patients with high-titer PRA screens63’64 and positive donor-specific crossmatches,‘28’1” as well as patients who received a transplant for myocarditis13’ are at increased risk. A number of investigators131-133 have noted decreased rejection in patients older than 55 years of age, presumably due to the decrease in immunologic responsiveness that has been observed and documented with increasing age.‘34 The importance of these observations is that the treatment for transplant recipients can and should be modified and tailored for the individual so as not to overimmunosuppress (eg, stable male patients over 55 years of age with a negative PRA) or underimmunosuppress (eg, younger female patients or those with a positive PRA or donor-specific crossmatch) those who are at greater risk for rejection. Treatment of allograft rejection has also evolved over time and varies with the severity and type of rejection as well as local institutional bias or preference. There is an increasing amount of data now becoming available (unfortunately none from randomized-controlled trials) that offers some insight into the possible results using different forms of therapy. Corticosteroids, which are the oldest form of rejection therapy, have a number of effects on the immune system including impaired release of IL-l, decreased chemotaxis, lymphocytotoxicity, and retardation of the inflammatory response.‘35”35a’136 The choice of intravenous or oral steroids remains somewhat arbitrary, as there have been no randomized trials in cardiac transplantation comparing the efficacy of the two routes of administration. Miller” has reported as high as 85% efficacy in reversing rejection with one course of 3 g of intravenous methylprednisolone (1 g/d times 3 days) for all grades of severity, although severe rejection was less likely to respond to methylprednisolone alone. Although

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the dose of 3 g of methylprednisolone is perhaps the most conventional dose used for intravenous administration, a recent randomized trial from Germany13’ has shown equal efficacy with a 1.5 g total dose compared with the usual 3 g dose suggesting that the suprapharmacological dose of 3 g of methylprednisolone may in fact be unnecessary. Further investigation is needed to determine the merits of adjusting the dose based on a number of parameters, including patient weight (rather than a fixed dose per rejection in all patients), time posttransplant (ie, do rejections occurring after 6 months require smaller doses for resolution of rejection), and presence or absence of hemodynamic compromise. Development and adoption of a uniform biopsy grading scale is mandatory before a comparison of various therapies can be performed. Fortunately, a uniform grading scale has recently been developed.‘38 Due to the decreased severity of rejection observed with cyclosporine and the potential morbidity associated with high-dose intravenous steroids,139”40 several groups have evaluated the use of oral steroids in “bolus” dosages (100 mg/d) for 3 to 5 days followed by a taper of variable rapidity. Micheler14’ has shown 90% successful resolution of rejection using a prednisone dosage of 100 mg/d for 3 days with rapid taper to baseline maintenance dose over 1 week. More recently, Hosenpud142 has shown less efficacy in rejections occurring both before and one month after transplantation (52% and 65%, respectively) using somewhat lower doses of oral steroids. The comparative advantages or disadvantages of the route of administration are difficult to assess, as both can be given in the outpatient setting with no significant difference in cost,‘43 and the comparative risk of complications such as peptic ulcer, infection, hypertension, insomnia, gIucose intolerance, and osteoporosis by route of administration has not been investigated in cardiac transplantation. However, Gray and Morris’” reported an equal efficacy (60%) with both routes of administration, but higher fluid retention, infection, and hypertension with oral steroids in a series of 100 renal transplant patients. Both oral and intravenous cyclosporine have been used to treat acute cardiac allograft rejection, although this agent’s mechanism of action145*146would suggest that it would not be

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effective once rejection has been fully established by histological criteria. However, Kobashigawa14’ has reported an 85% success rate in reversing mild to moderate allograft rejection at variable times posttransplant with doubling of the oral cyclosporine dose. Investigators at the Texas Heart Institute’48,149 have shown that intravenous cyclosporine, in dosages as high as 4 mg/kg/d, was equally effective in resolving rejection and not associated with significant nephrotoxicity or infection. Only 8% to 10% of cardiac allograft rejection episodes are associated with hemodynamic compromise,5’ but these rejections, as well as those that are refractory to one or two courses of corticosteroids, can usually be effectively treated with lymphocyte antibody therapy. Although polyclonal agents such as antithymocyte globulin (A~G)2’.28,15fl and antilymphocyte globulin (ALG)50.‘51 have been used successfully, the largest experience in treatment of refractory renaj152-154 or cardiac’55-‘59 allograft rejection has been with the monoclonal preparation OKT3, which has been successful in nearly 90% of the cases.152-159 The mechanism of action16’-‘@ and clinical ro1e165of this agent have been extensively reviewed. Although OKT3 can induce idiotypic antibody formation, it has been used successfully to “retreat” a number of patients who initially received it as prophylaxis, including those with demonstrated human antimouse antibodies after treatment.1”6-‘68 Although there have been no randomized clinical trials comparing the efficacy of different dosages for acute rejection therapy, this agent is routinely given in a fixed dosage of 5 mg/d regardless of age or body size. However, Norman169 has recently reported equal efficacy with a lower dose of OKT3 when used as an early postoperative prophylaxis (22 mg v usual 70 mg total dose), raising the question of possible use of lower doses for the treatment of rejection. The Utah program”’ has reported superior efficacy of 14 days versus 10 days of treatment, but there was an increase in anti-OKT3 antibody formation and subsequent vascular rejection with administration for greater than 14 days. Unfortunately, there have also been no randomized prospective trials to confirm the widely held opinion that OKT3 is the most potent agent available for severe or refractory rejection. Some programs use large doses of methylprednisolone

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(1.5 to 2.0 g) in addition to OKT3 for the treatment of moderate or severe rejection associated with hemodynamic compromise.171 The need for and risk-benefit ratio of adjunctive high-dose corticosteroids in this setting has not been evaluated, but hemodynamic compromise may be associated with humoral as well as cellular rejection and steroids would be additionally helpful. A number of drugs used primarily for cancer chemotherapy, such as methotrexate,‘72,173 have been used for the management of recalcitrant mild to moderate rejection. Methotrexate is a potent inhibitor of both cellular and humoral immunity and targets rapidly proliferating cells. It is typically substituted for azathioprine in dosages ranging from 2.5 to 7.5 mg either every 8 hours for 4 consecutive doses once a week, or daily for 2 consecutive days per week, with the dose being adjusted to maintain white blood cells (WBC) greater than 4,500 cells/mL3. Other chemotherapeutic agents that have been investigated include vincristine73 and cyclophosphamide, 75*174~175 the former primarily used in an attempt to block the “rebound” rejection seen after OKT3 prophylaxis, and the latter used primarily for humoral or antibody-mediated rejection. A final modality recently reported for the treatment of refractory cardiac allograft rejection is total-lymphoid irradiation (TLI).17’,“’ In limited trials for patients refractory to multiple courses of several agents including OKT3, TLI has been successful in reversing rejection. Although there has clearly been an evolution in the agents used to treat acute allograft rejection, there has also been an equal amount of attention focused on various regimens to prevent its long-term development ie, maintenance immunosuppression. The initial type of maintenance immunosuppression was based on the demonstrated efficacy in the laboratory of the purine antagonist azathioprine in conjunction with corticosteroids.178,‘79 This regimen, now called “conventional therapy,” was the sole type of maintenance immunosuppression used until the introduction of cyclosporine in the early 1980s.‘80,‘B’ Cyclosporine was powerful enough to also allow a significant reduction (up to 30% to 40%) in the dose of corticosteroids used in many programs and was associated with a significant increase in survival rate and a reduction in the severity and mortality from both rejection

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and infection.lsGlE6 However, the dosage of 16 to 18 mg/kg/d initially used was associated with a number of significant complications, such as hypertension,ls7 nephrotoxicity,“’ and malignancy,lEg which questioned its long term use. These complications were significantly reduced, without loss of immunosuppressive efficacy, by the development of a third basic immunosuppressive regimen, “so-called” triple therapy by Bolman,16 which was simply the reinclusion of azathioprine in combination with cyclosporine and prednisone. The addition of azathioprine (at a conventional dosage of 2 mg/kg/d) allowed a 30% to 40% reduction in cyclosporine dose, thereby significantly reducing its side effects as well as allowing another 20% to 40% reduction in the average dose of corticosteroids. This was a critical development in the field of cardiac transplantation because it renewed enthusiasm for the use of cyclosporine by showing that complications thought to be inescapable and irreversible were quite manageable by dose reduction without loss of immunosuppressive efficacy. Long-term follow-up studies have shown sustained immunosuppressive efficacy and reduced complications with the exception of graft coronary artery disease.lEga Although corticosteroids have been a component of every immunosuppressive regimen to date, this agent has a significant number of dose-related side effects that are cumulative and associated with significant morbidity. These complications have stimulated a number of centers to investigate the latest type of maintenance immunosuppressive regimen, “steroidfree,” using only azathioprine and cyclosporine. Yacoublgo was the first to demonstrate success with a regimen consisting of only azathioprine and cyclosporine and compared those results with previous reports on azathioprine, cyclosporine, and prednisone. A number of centers’g1-‘g3 have subsequently shown that as many as 60% of patients could be totally withdrawn from corticosteroid therapy using criteria of allowing three isolated episodes of allograft rejection before considering the patient steroid dependent. All of the above series were initiated within the first 1 to 3 weeks posttransplant, and following a 10 to 14 day course of lymphocyte antibody therapy. Recently, Miller194 reported an 85% success rate in weaning patients from steroids without the use of lymphocyte antibody

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therapy, using a more conservative criteria of allowing only two allograft rejections before returning the patient to steroids. Unlike the other series, steroid withdrawal was not initiated until an average of 10.2 months (range 4 to 60 months) posttransplant. One important observation in that investigation was although both patients with and without previous rejection underwent steroid withdrawal, rejection while off steroids occurred primarily in patients who had had previous rejection while on steroids (4 of 12 with previous rejection v 2 of 26 without previous rejection). Initiating the taper of steroids at this later date may help identify those patients who have “relative” graft tolerance and who may therefore be able to avoid the attendant complications of long-term corticosteroid therapy without risk of subsequent rejection. These results, in the absence of antibody therapy, are now being investigated with an earlier withdrawal of steroids. However, unlike Renlund,19’ who demonstrated significant reductions in weight, cholesterol, triglycerides, and infection in those patients who were able to be weaned from the steroids (compared with those who remained on maintenance steroids because of recurrent rejection), Miller’94 was unable to show any significant improvement in any of these parameters, possibly due to the low dose of maintenance steroids used in that program (5 mg/d) at the time of initiating steroid withdrawal. The induction of allograft unresponsiveness, or selective tolerance, has been the goal of organ transplantation since the initial work of Medawar.“* However, there has never been a clear demonstration that the number of treated rejection episodes is directly correlated with or predictive of ventricular dysfunction or transplantation coronary disease. In addition, Mason has shown that the treatment of rejection may result in increased infections or adverse consequences.196 The first 7 to 10 days following allograft implantation represents a peak time for potential sensitization of the recipient to the allograft during clearance of donor dendritic and endothelial cells that bear class II antigens on their surface. Suboptimal immunosuppression during this time period can result in permanent immunization. One approach for preventing this occurrence is the prophylactic use of antilymphocyte-antibody therapy for 7 to 14

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days posttransplant. This form of therapy has been referred to as “induction” therapy-an attempt to induce a state of allograft unresponsiveness-but there is little data to support an actual reduction in the incidence of rejection with the use of these agents. Several polyclonal agents, ALG, ALS, ATG, which represent pooled gamma globulin produced by immunization of rabbits, horses, goats, mice, and other animals by cultured spleen cells have been developed, and recently a monoclonal preparation (OKT-3) has been developed against the T3-cell-surface antigen found on mature T cells. Once OKT3 is attached and occupies the CD-3 receptor, the CD-3 cells undergo opsonization and rapid removal from the circulation by the reticuloendothelial system.1m’64 This rapid reduction in CD-3 cell population is evidenced not only in the peripheral circulation”’ but also in the myocardium, usually with an associated improvement in diastolic compliance and systolic function. However, the rapid clearance of nearly all CD-3 cells from the circulation may also predispose them to infection due to both a loss of suppressor cell function and potentially altering the contribution of T cells to B-cellclonal amplification and antibody response to infection. OKT3 has a number of potential side effects including hypotension,‘97 fever, and systemic reactions that have recently been shown to be due to cell lysis and release of lymphokines.198 Many of these “first dose” effects can be obviated by administration of the first dose intraoperatively199 with pretreatment use of highdose methylprednisolone. Unlike the dose of ALG that is adjusted daily by the number of circulating lymphocytes, OKT3 is given in a fixed dose regardless of patient age or size or the time posttransplant. Investigations need to be undertaken to establish the need or benefit of near total ablation of all circulating T3 lymphocytes and the potential efficacy of smaller doses. There have been a number of trials comparing the relative efficacy of monoclonal induction versus polyclonal induction agents in cardiac transplantation.2W”05 OKT3 was found to be associated with a lower incidence of rejection in comparison with ATG administration in the Utah program,‘@’ but ATG was found to be superior to OKT3 in investigations performed at the University of Pittsburgh,‘0’,20’ Loyola,203 and University of Michigan,2M although no two

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protocols were exactly the same. Although the concept of providing enhanced immunosuppression at a time of high-risk of sensitization to the donor allograft is attractive, these agents have never been studied in a randomized, prospective trial between “induction” and “noninduction” therapy to demonstrate evidence of their superiority or address the question posed by Renlund in a recent editorial-is cytolytic therapy necessary ?206These agents to date have never shown results superior to those achieved without their use and may be associated with an increased risk of infection.207.20xMost centers are deeply committed to either “induction” or “noninduction” immunosuppressive therapy, although it usually represents institutional bias with little or no experience with both forms of therapy. The few nonrandomized, uncontrolled single-institution comparative experiences that have been reported209 or performed’10.2” between OKT3 and triple drug therapy only involve approximately 50 patients each and usually bias the data by selecting OKT3 for those patients at high risk of nephrotoxicity posttransplant. However, these comparisons’08-“o have failed to demonstrate a reduction in rejection frequency or severity with induction therapy. They only demonstrate a delay in time to first rejection. In addition, recent data from the WGTC” shows essentially identical survival rates at one year (90%) both with and without “induction” therapy despite multiple variations in dose and duration of these agents. Many centers have used this form of therapy successfully, but until randomized, prospective multicenter trials can be conducted comparing induction with noninduction therapy, the importance and added benefit of this form of therapy remains unproven in cardiac transplantation. However, these agents offer very potent immunosuppression, and experience with their use will help identify patients most suited for their use. There are a large number of new immunosuppressive drugs for maintenance therapy currently being tested including rapamycin,“* RS61443,*13 FK-506,*14-*19 deoxyspergualin,“’ and donarubicin.22’,222 One unique agent given for prophylaxis of rejection is the prostaglandin E, analogue misoprostol.2’3 Its use was associated with a significant reduction in the incidence of rejection in a randomized, double-blind, placebo-controlled trial in 77 renal transplant pa-

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tients. Patients who received misoprostol also had fewer infections and hospital days-two important parameters in cost-efficiency analysis. This observation of a beneficial effect of prostaglandins of the E, series in preventing rejection has also been shown in laboratory animals.‘” One final new approach is the use of a platelet-activating factor (PAP) receptor antagonist.“’ PAP has been shown to be a key component in the cascade of events involved in acute humoral vascular rejection. Blockade of the PAP receptor alone is not able to prevent graft destruction but may be given pretransplant to highly sensitized patients who are at high risk for hyperacute rejection.225 Other new agents for acute-rejection therapy include several monoclonal antibodies, one of which is directed against the IL-2 receptor.226-229 The initial IL-2 receptor antibody preparations only occupied the receptor on the surface of the celI,22~229but newer formulations, coupled with agents such as diphtheria toxin,230 make it cytotoxic. In addition, OKT4A,231 a monoclonal antibody against CD4 lymphocytes, offers more selective immunosuppression than achieved with OKT3 and possibly donor-specific unresponsiveness.232These so-called “designer” antibodies233 and other approaches offer great promise for improved, more selective immunosuppression, but their toxicity (eg, idiotypic antibody formation-sensitization) need to be studied. Several of the agents have received unwarranted public attention despite the modest number of patients treated and the limited follow-up. Hopefully, they will all undergo controlled, randomized, multicentered trials before being released so that the deficiencies in our knowledge of induction-therapy agents will not be compounded by a nonscientific embrace of the next generation of agents. INFECTION

Infection has been the nemesis of cardiac transplantation since its inception and remains the leading cause of posttransplant death in and has been the subject many programs, 14~20~181 ‘*‘~.3~~ However, the incidence of many reviews, of death due to infection in cardiac transplantation has decreased over time due to a number of factors including (1) improvements in the recognition and treatment of allograft rejection, (2) increased sophistication and sensitivity of diag-

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nostic techniques, particularly computed tomography (CT) and magnetic resonance imaging (MRI) scanning, (3) new antimicrobials for both prophylaxis and primary treatment of all types of infection, (4) improved patient selection, (5) improved detection and treatment of rejection, and (6) importantly, more specific maintenance immunosuppression, especially cyclosporine. As a result, the types of organisms and overall trends of morbidity and mortality have changed greatly and results are more variable and more related to type and amount of immunosuppression. This review will focus on the current incidence, timing, and response to infection and addresses many of the observations and impressions about infection previously held that may no longer be valid. Like several other areas of transplantation, the reporting of infection data has been variable. It is often difficult to ascribe the exact cause of death, ie, to separate out those infections that were the pure and only cause of death from those occurring in the setting of multiorgan system failure, or more commonly, an infection that occurs during or shortly after intensive treatment of a rejection episode. One approach is to report and tabulate all treated infections whether verified by positive culture identification or not. Others believe that infections such as presumed viral upper-respiratory-tract infection, urinary-tract infection, and culture-negative infections may occur independent of the type or level of immunosuppression used and should not be tabulated. The WGTC” have recently reported data on over 700 patients transplanted in 1989, using the definition of only those infections treated with intravenous antibiotics, or any therapy (topical, oral, or intravenous) of a viral, fungal, or protozoa1 infection. At 1 year posttransplant the average number of infections per patient was 0.68, with the majority occurring within the first 6 months. All patients in this series were treated with triple-drug-maintenance immunosuppression (cyclosporine, azathioprine, and prednisone) and roughly equal percentages did or did not receive perioperative-antilymphocyte-antibody therapy (eg, OKT3, ATG). The effect of the type of immunosuppression used on the incidence of infection has never been studied in a controlled manner, but data from the WGTC,‘l using the criteria described previously, showed

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no difference between the two types of immunosuppression when evaluated by infections per patient month of follow-up (0.12 antibody therapy v 0.09 no antibody). The percent of patients free of infection has also decreased from the early reports of Stanford234-23’ where less than 20% of patients were free of infection compared with a recent report from BolmarP in 1988 showing over 56% of patients experienced no infection episodes. There are two peak incidences of infection following cardiac transplantation244.‘47.‘4R and are due to different types of organisms. The “early” period (within the first month of transplantation), is dominated by nosocomial infections,24” predominantly gram-negative organisms and staphylococcus species, whereas the “late” period (more than 1 to 5 months posttransplantation) is dominated by opportunistic infections such as cytomegalovirus, pneumocystis, and fungal infections.‘43.245Dummer245 has recently described the temporal occurrence of each class of infectious agent at various times posttransplant. Bacteria were most common from postoperative days 3 to 28, and viruses were common usually after 30 days with the exception of herpes simplex mucocutaneous infections which are often present within the first 7 to 14 days posttransplant. Important opportunistic infections such as cytomegalovirus (CMV), fungi, and Pneumoqstis carinii were all uncommon within the first month, with a peak incidence at 45 to 50 days for CMV, 30 to 60 days for fungi, and 60 to 150 days for pneumocystis. Toxoplasmosis may be found within the first 14 to 20 days, but usually occurs within the first 3 months posttransplant.24y,“‘0 However, Dummer24s has also noted that there is an increasing risk of bacterial infection after 6 months, such that infections occurring greater than 2 years posttransplant had a lo- to 20-fold increased likelihood of being bacterial than any other type of infection. The types of organisms in either time period that occur have been variably reported and reviewed51,245~24R,249 and reflect differences in type and amount of immunosuppression as well as local nosocomial infection trends, A number of investigators’8h.‘40.24” have reported a nearly 3 to 1 prevalence of bacterial over viral infection, whereas Andreone14’ reported the opposite (viral, 72%; bacterial, 22%) in patients who received transplants at a similar time. This was reconfirmed by

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Olivari in a 5-year follow-up of the same cohort.l”ya More recently, the WGTC” have reported an equal incidence of viral and bacterial infections (42% v 43%, respectively), with fungus accounting for 10% and protozoa approximately 5% in over 1,400 patients who received transplantations in 1988 and 1989. However, the type of virus infection was influenced by the type of immunosuppressionsl with herpes simplex virus being more common in the “noninduction” group (61% v 37%) and CMV more common in the “induction” therapy group (63% v 39%). Similar observations of increased CMV infection with induction therapy have been reported in rena1207,Zoand liver208.‘5’ transplantation recipients using either antithymocyte globuIin”‘or OKT3. The lung has been consistently shown to be the most common site of infection in cardiac transplantation patients24’.‘4’,2’2-‘Shsince the initial reports by Stinson’34 and Remington23h at Stanford. A number of explanations have been offered for this observation including (1) chronic congestive heart failure in the recipient with increased risk of hypostatic lung and subclinical infection, (2) prolonged intubation, (3) cardiac cachexia with poor nutrition and immunologic competence, and (4) microaspiration.247.253.?54The predominance of lung infection in heart transplantation is consistent with the experience in other transplanted organs, where infection seems to dominate at the site of the transplant,‘5” although lung infection has been very common with solid-organ transplantation.‘56~‘59 Two main risk factors identified by Merme1’53 for pneumonia after solid-organ transplantation include patients intubated for longer than 1 day, especially those who had to be reintubated postoperatively and those on high-dose corticosteroids or receiving rejection therapy with corticosteroids within the first 2 weeks posttransplant. The chest x-ray appearance and the tempo of the illness may provide clues to the etiolofl with diffuse infiltrates being suggestive of CMV, pneumocystis, or herpes virus infection, and focal infiltrates suggestive of bacteria, Nocardia or Aspergillus. Infections that manifest quickly (less than 24 to 48 hours) suggest a bacterial origin or occasionally CMV, whereas a more subclinical presentation suggests viral organisms, and indolent infections more typical of cryptococcus.

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The incidence and types of extrapulmonary infections in heart transplant recipients duplicate data obtained from nontransplant intensivecare-unit patients, with intravenous catheterrelated bacteremia and urinary tract infections being extremely common complications.245 Intraabdominal sources of infection include peptic ulcer, diverticulitis, and cholecystis.260-263 These complications can be especially challenging in the early postoperative period as patients are frequently on high doses of corticosteroids, which may significantly impair the inflammatory response and associated signs and symptoms. Intracranial infections occur at variable times posttransplant2&2,2 and often involve opportunistic organisms such as Aspergillus, Cryptococcus, or Toxoplasma. Mediastinitis has been a variable complication, with incidence ranging as high as 8%‘” to as low as 0% in a series of 110 patients reported by Bolman’82 with the use of vancomycin chest irrigation at the time of the transplant procedure. The drug cyclosporine has had a significant impact on infection in cardiac7,‘86~239~240’243 as well as renalz6’ and live?@ transplantation beyond increased survival. Hofflinls6 has shown that cyclosporine has also been associated with a number of favorable changes in the incidence and type of infection seen in comparison to azathioprine-based therapy including (1) decreased mortality due to infection (39% to ll%), (2) decreased number of bacterial infections, particularly bacterial pneumonias and bacteremia, (3) decreased incidence of viral infections, particularly CMV and especially the visceral involvement of these infections, (4) decrease in the incidence of fungal infection, particularly aspergillus, and (5) a decrease in the incidence of pneumocystis infection. The contribution to the above observations of a reduced steroid dosage during cyclosporine therapy is difficult to assess, but is probably positive. Andreonez4’ has also reviewed the incidence of infection with two different cyclosporine regimens in comparison with azathioprine-treated patients. In his series the incidence of infection per patient in the first year posttransplant was 1.3 with azathioprine plus prednisone, reached a high of 1.6 with cyclosporine and prednisone alone, but decreased to 0.6 infections per patient with the three-drug combination of cyclosporine, azathioprine, and prednisone. Unlike

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most previous data, he observed an evolving increase in the percentage due to viral infections (54% Aza + Pred, 57% cyclosporine (CyA) + Pred, and 72% CyA + Aza + Pred). These data may have been influenced by increased use of antimicrobial prophylaxis with agents such as acyclovir and trimethoprim sulfa in the most current triple-drug group. There have been a variety of therapies used as prophylaxis for specific infections including a number of antimicrobial agents that have been used in the early months posttransplant or following treatment of rejection including (1) trimethoprim sulfa243.269 and/or inhaled pentamidine*” for prevention of P carinii, (2) trimethoprim sulfa also for Nocardia, Toxoplasma, or Listeria infection,%* (3) acyclovir for all herpes virus infections including herpes simPled”,*‘* and zoster,273 Epstein-Barr virus, and CMV,274-277 and (4) nystatin or clotrimozole troches for Candida species. Acyclovir (Burroughs Wellcome Co, Research Triangle Park, NC) has been used as prophylaxis for CMV infection274-276and although use of this agent has not reduced the overall incidence of CMV infection (detected by serologic conversion), its use has been associated with a decrease in the severity of infection especially for patients who are CMV-negative recipients that receive a CMV-positive donor. Due to significant morbidity associated with CMV278 and the relatively high incidence of this infection following perioperative administration of lymphocyte antibody therapy,2m”79 a randomized trial is now ongoing to evaluate the prophylactic use of 9-(1,3 dihydroxy-2-propoxymethyl) quanine (DHPG), Gancyclovir, which has been shown to be very effective in the management of CMV infection.280-282Superinfections are fairly common with each of these infections especially with CMV and P carinii.283 Several centers have noted a relative decrease in the incidence of superinfections with these two organisms with the use of either a single agent, trimethoprimsulfa, or trimethoprimsulfa plus acyclovir. Other measures used as prophylaxis against infection include use of hyperimmune globulins284-286and vaccines287 that have been shown to be effective in renal transplant patients. Infection surveillance288 has been another approach to prospective management of infection. One method is to obtain serologic titers of

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CMV, herpes simplex, Epstein-Barr virus, and Toxoplasma as well as hepatitis and human immunodeficiency virus (HIV) on each candidate at the time of listing for transplantation to assess previous exposure and antibody status. As more patients are waiting for a longer period of time before transplantation, it may be appropriate to repeat these titers at the time the patient is admitted for transplantation so that the diagnosis of sero conversion or diagnostic change in titer can be based on the most recent titers. A fourfold increase in titers is required to document evidence of infection. Although a number of centers have noted a lag time between evidence of viral shedding (especially herpes viruses) and the development of clinical infection, the cost efficiency of surveillance cultures posttransplant is unclear. The need for protective isolation also seems unfounded. Isolation techniques for cardiac transplant patients have varied from laminar flow rooms and sterile sheetsa to the more common approach of “reverse” isolation with disposable mask and glove. Strict isolation has never been shown to have any impact on reducing the incidence of infections2wx291 and reverse isolation and attention to prevention of common nosocomial infections292 seem adequate during the initial hospitalization. Several infections deserve more detailed discussion. First, CMV, which has been associated with significant morbidity and mortality in cardiac transplantation patients.278 The actual incidence of CMV in cardiac transplant recipients has been variably reported from 30% to 100%243.“9’-295 (depending on use of surveillance cultures) due in large part to there being a significant overlap between the terms CMV infection (a documented fourfold rise in serologic titer), CMV syndrome (a mild self-limiting febrile illness), and CMV disease (an overt infection associated with positive cultures from several possible locations including the gut, heart, butfy coat of the blood, urine, and lung). This infection is rarely seen before 5 to 6 weeks posttransplant, usually occurring at 40 to 50 or following intensive antirejection days2452247 therapy.Z07,279The type of immunosuppression used has an impact on the incidence of this disease, being more common in patients treated with prophylactic antilymphocyte antibody therapy.” Invasive infection, especially pneumonia,

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is uncommon in programs that do not use this therapy293 and acyclovir or gancylovir prophylaxis may also play a role in reducing the incidence of this infection.276*277The incidence of primary (seroconversion) or secondary (reactivation) types of infection also vary.294,295 The diagnosis of CMV infection has been aided by the development of a number of techniques including the shell vial assay,296monoclonal antibodies to early antigens297 or CMV IgM antibody,298 bronchoalveolar lavage culture,299 and nucleic acid hybridization techniques.296.300Due to the number of serotypes of CMV, demonstration of CMV antibody in the recipient’s serum pretransplant may not prevent subsequent “reinfection” with another serotype, especially when receiving immunosuppressive therapy. A number of centers have noted that the most critical risk factor for the development of clinical CMV infection is use of a CMV-positive donOr,2’3.29~.3~lespecially into a CMV-negative recipient (no evidence of measurable CMV antibody). Currently, however, the limited number of donors available prohibits the matching of donor and recipient by CMV serology. Due to the morbidity and mortality associated with this infection, several alternative management strategies have been used in an attempt to decrease the incidence of postoperative CMV infection including use of CMV-negative blood products302-3”4 or leukocyte-poor or -filtered blood, as the leukocyte is the presumed vector for this disease. Clinical involvement is primarily in the gastrointestinal tract293,305.306 with fever, malaise, cramping, and diarrhea as the most common manifestations, although ulceration with bleeding may also occur.305.306The highest morbidity and mortality from CMV infection is with pulmonary invo1vement.27s.2x’ The treatment of CMV has evo1ved3” and includes acyclovir and the acyclic nucleoside analogue, gancyclovir,‘81,308 which is now approved for clinical use and recently, trisodium phosphonoformate.309 Whether or not CMV can ever be prevented using hyperimmune globulin or vaccines remains to be demonstrated.3’0 One unique approach in laboratory animals has been to radiate the allograft prior to implantation.31’ Pneumoqstis carinii31*~3’2has also been a significant clinical infection in cardiac transplant recipients since the initial reports by Stinson233 and Baumgartner.’ This infection has endemic

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features in that several centers report a relatively high incidence (8% to lo%), whereas others report no cases of this infection?l Like CMV, it occurs most commonly in association with lymphocyte antibody therapy, but prophylaxis with trimethoprim sulphamethoxozole, which can now be given intermittently with equal efficacy to daily therapy,312 is effective in preventing clinical infection.2429268This infection can be observed alone or coexisting with CMV,282 typically occurring 30 to 60 days posttransplant as well as following treatment of rejection. It occurs almost exclusively in the lung and frequently presents with a nonproductive cough and a normal chest x-ray that may evolve quickly to show changes of diffuse infiltration. Transbronchial biopsy and lavage culture may establish the diagnosis, but open lung biopsy is frequently required.313 Treatment of &eumocystis pneumonia is primarily using trimethoprimsulfamethoxazole314-316 or pentamidine in patients allergic to sulfa.316 Other unusual or problematic infections include Toxoplasma,3172318 Cryptococcus,319 Aspergillus,320 and Nocardia321S22; the latter two being common inhalational infections often related to construction and disruption of old heating/air conditioning ducts.3239324 In addition, ListeriaTZ Legionella,3% and mycobacteria327 may be noted on rare occasions. The role of various immunosuppressive regimens in developing these infections is unclear. One of the difficult clinical decisions at the time of development of a significant infection is how to manage the immunosuppression. Each of the currently used immunosuppressive agents have unique mechanisms of action that may predispose patients to certain types of infection. Corticosteroids, which cause a decrease in the release of IL-l, an inflammatory response mediator, as well as neutrophil chemotaxis are commonly associated with fungal infections. Azathioprine, which is myelotoxic and suppresses both the function and total number of neutrophils, may also predispose to fungal infections as well as gram-negative organisms. It is perhaps the one agent that should be decreased when a significant clinical infection occurs, especially CMV, which is commonly associated with neutropenia. In therapeutic levels CyA does not effect suppressor cells, but high or toxic levels may decrease suppressor cell function and pre-

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dispose to viral infection. Reduction of this drug, especially when high blood levels are found, may help in the recovery from viral infection. However, CyA levels that are allowed to go too low may result in coexisting or subsequent rejection, as infection can cause a nonspecific activation of the immune system and patients with sensitized lymphocytes will exhibit rejection in concert with the infection. It is obvious that infection plays a major role in the morbidity and mortality associated with cardiac transplantation. A reliable and sophisticated microbiological laboratory and infectious disease consultant are critical for the success of any transplant program. An aggressive approach is mandated for any suggestion of infection in transplant recipients at any time after the procedure.3z7 Attention to common local nosocomial infections and their local sensitivities as well as intravenous catheter care329 is critical, particularly early posttransplant. Broadspectrum, empiric antibiotics are to be discouraged, with more attention paid to gram stains, history, physical examination, and diagnostic testing, with therapy directed using the evidence accumulated. More aggressive diagnostic procedures such as bronchoscopy, lavage, CT scans and even open-lung biopsy are frequently successful in achieving an early diagnosis and instituting therapy, especially when the above routine diagnostic tests are unrewarding. Development of infection should always suggest an excessive amount of immunosuppression. The persistence of infection as the leading cause of death over the past decade strongly suggests that there is more attention given to concerns about possible sequelae of rejection than the higher morbidity and mortality associated with infection. CORONARY

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DISEASE

Although infection and rejection remain the overall leading causes of death in heart transplantation recipients,3 it is clear that the risk of death from those two factors is centered within the first year posttransplant. The leading cause of death after that period is an unusual and accelerated form of coronary artery disease that has been referred to by a number of terms including spontaneous arteriosclerosis, accelerated graft atherosclerosis (AGAS), coronary occlusive disease, and, with recent observation

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of involvement of coronary venules,330 the term transplant coronary vasculopathy has been suggested. The term allograft arteriopathy is perhaps most appropriate, as the very same process has been described in rena1,331heart-lung,332 and liver3”’ allografts. This entity differs significantly from the coronary atherosclerosis seen in nontransplant patients, not only in natural history but in disease mechanisms; therefore, the term atherosclerosis will be avoided. Although reluctant to use another name for this disease, the term transplantation coronary disease (TCD), which avoids reference to atherosclerosis and arterial disease, will be used in this review. This entity has been recognized since the initial transplants performed at Stanford University, where the incidence was as high as 40% at 2 years posttransplant in the first 18 patients and was present in all survivors by 3 years.’ Although it is unusual to occur in the first year, the average incidence of developing this disease is approximately 10% per year thereafter, or approximately 40% to 50% by year 5,334-338 etfecting children as frequently as adults.33y The definition of this entity is based on its angiographic appearance, although there is little data comparing the angiographic estimate of luminal narrowing with precise autopsy measurement in cardiac transplant patients. However, there are a number of anecdotal reports describing coronary angiograms in cardiac transplant patients that have been interpreted as “normal” within as little as 2 months of autopsy confirmation of extensive three-vessel disease.340,34’There are also numerous reports of the discrepancy between these two techniques in nontransplant patients.34’“44 One possible explanation for these discrepant findings is the current use of the angiogram obtained at 1 year posttransplant as the “gold standard” for the subsequent interpretation of the presence or absence of TCD. This disease process apparently begins to develop almost immediately after transplantation as McManus” observed evidence of a T-cell mediated intimitis in 100% of 15 cardiac allografts studied as early as 2 weeks posttransplant. Other more anecdotal reports have described significant intimal changes by 3 months347 and autopsy series have showed that all patients examined after 12 months posttransplant have significant diffuse evidence of this disease.34RIt is clear from the previous reports that a great

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deal of this disease process may occur within the first year; therefore, the use of the angiogram obtained at 1 year after transplant as the baseline reference can be potentially misleading and may help explain the finding of a “normal” angiogram but pathological evidence of diffuse disease. As a result, a number of centers have begun performing the first coronary angiogram within 2 to 4 weeks of the transplant procedure in an attempt to obtain true baseline measurements of luminal diameter, as well as assess the incidence of preexisting disease in the donor that may also potentially be erroneously ascribed to TCD later on. Gao34y has recently documented that a highly significant (P = .002) reduction occurred in epicardial coronaries from baseline (mean 5.1 weeks posttransplant) to the first yearly examination. However, only 2 of the patients in a series of 43 patients had detectable TCD. In addition, Alderman349a has noted the unusual clockwise rotation of the transplanted heart and the need to perform angiograms in a uniform reproducible manner so that the films can then undergo side-by-side comparison in subsequent years. Gao350 has provided the best classification scheme of this disease to date, as well as making some critical comparisons and contrasts between the angiographic appearance of this disease and nontransplant coronary disease. Although TCD may exhibit proximal, focal, epicardial stenoses typical of non-TCD, the unique hallmark of this disease is the diffuse obliterative disease of the distal vessels. Although the number of lesions per patient were nearly identical (5.5 nontransplant v 5.7 transplant), Gao5’ noted there were a number of differences in patients with TCD in comparison with a series of nontransplant patients with coronary artery disease including (1) a smaller percentage of proximal stenoses in TCD (76% v 100%) of which few occurred in primary epicardial vessels (57% v 75%) and more occurred in secondary branch vessels (43% v 25%) (2) the point of total occlusion was located in the distal vasculature in 49% of transplant patients versus only 4% in nontransplant patients, and (3) the distal disease, which is not observed at all in nontransplant patients, was located in distal epicardial vessels in 25%, secondary branch vessels in 41%, and in third- and fourth-order vessels in over 33% where the characteristic

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rapid pruning and obliteration is most obvious. Perhaps the greatest evidence of the rapidity with which this disease develops is the fact that 92% of the transplant patients had what was graded as minimal to no collateral vessels in contrast to only 7% of the nontransplant patients. The histopathology of this disease has been reviewed by Billingham351~3s2 and others3”“” and is as unique and different from standard coronary disease as is the angiographic appearance. The initial gross appearance reflects the angiographic findings in that the disease is concentric and tubular, in contrast to the eccentric, focal stenosis of non-TCD, and is located diffusely throughout the entire coronary tree involving the distal vessels in equal proportion to the proximal vessels. Microscopically, the cardinal features of TCD include a marked hyperplasia of smooth muscle cells and macrophages and accumulation of collagen and ground substance in the endothelium. The migration of these smooth muscle cells from the media into the intima takes place without the typical disruption of the internal elastic membrane seen in nonTCD. A unique finding characteristic of this disease is the so-called “foam cell” which is located in the intima of these vessels and is the result of phagocytosis of the migrated smooth muscle cells and cholesterol by the macrophages, with resultant vacuolization and foamy appearance. Atheromatous plaques do appear in TCD, but unlike non-TCD, they are minimally calcified, more cellular, and contain a higher quantity of lipids (especially cholesterol). Ulceration and thrombus formations are distinctly unusual until very late in the disease. This difference may be related to cyclosporine or higher doses of steroids. Pucci and Billingham358have recently reported that the coronary disease found in a series of early transplant recipients who were treated with azathioprinebased immunosuppression (and an average prednisone dosage of 20 mg/d) and followed for a mean of 8.4 years appeared more like typical nontransplant atherosclerosis with marked calcification of the plaque and thrombus formation. However, most of the other features of TCD previously noted were also present, implying little direct effect of cyclosporine on the development of this disease. The sequence of events leading to the development of this dis-

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ease seems to be initiated by an intimitis or inflammation of the intimal cells by T lymphocytes,346followed by a proliferation of smooth muscle cells and macrophages that then migrate into the arterial intima. This is followed by collagen deposition with actual fibrosis and scarring of the intima and subsequent luminal compromise. Further cholesterol infiltration of the wall with resultant foam-cell formation causes the major compromise of the internal lumen. The pathophysiological mechanisms responsible or involved in this disease may be multiple, but they are basically either immune-mediated or “environmental” (eg, lipids and hypertension). The role of hyperlipidemia and other risk factors in non-TCD has been controversial. Early laboratory investigations by Alonzo,359 Lurie,360 and other investigators361-364have shown that any type of immunologic endothelial injury could result in the development of this disease process but when this injury occurred in the setting of a high-cholesterol level, the disease was accelerated. The role of elevated plasma lipids was initially thought to be clinically important as Stinson365 found fasting triglycerides to be one of the two variables correlated with this disease. Although this has not been a uniform observation with cyclosporine-based therapy,337,338 most series now report either a consistent trend or statistically significant correlation between TCD and elevated cholesterol and/or triglycerides.366,367 The effect of other factors known to increase the risk for coronary artery disease in nontransplant patients368 have not been consistently correlated and may reflect different mechanisms involved with TCD. However, one nonimmune risk factor thought to be important for the development of TCD is obesity.“’ In an analysis of explanted hearts, Winters and colleagues from Loyo1a369have recently shown that postoperative body mass was the strongest independent risk factor for developing TCD, with a correlation coefficient with percent luminal narrowing equal to 0.77 (P = .0009). In addition, they showed that the luminal narrowing was progressive over time and that the impact of other risk factors such as total cholesterol, triglycerides, and infection were additive. Other contributing factors for development of TCD may include donor age?’ although there have

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been only a limited number of “older” donors (>45 years of age) used to date. Donor ischemic time3” also tends to be higher in those who develop this disease, supporting the observations of the independent ability of cryopreservation to result in endothelial injuryj72 as temperature is not controlled between procurement and implantation and temperatures below 4°C are perhaps not uncommon. It has long been believed that primary disease etiology in the recipient (ischemic or nonischemic) was not predictive of the development of TCD,335,337,339 but this data may have been biased in that the majority of patients undergoing transplants until 1986 were less than 40 years of age with a nonischemic origin. However, more recent data from the Registry of the International Society for Heart Transplantation3 suggests that average patient age has increased over time to the current 44 years of age, and data from the WGTC” has shown that as of 2 to 3 years ago more patients are being transplanted because of underlying ischemic heart disease. With time and the increased number of such patients being transplanted, etiology of the disease mandating the need for transplantation may become an independent risk factor. Support for the immune-mediated hypothesis for TCD was based largely on the observation that it was limited to the coronary vascular bed (ie, the allograft) and that involvement was diffuse, thereby implying a local, direct endothelial injury. Presuming that this was an immunologically mediated disease, attention was initially directed at the number of mismatches of HLA class I antigens between donor and recipient. Stinson373 initially found that mismatch at the HLA-A2 and A3 loci were correlated with development of TCD, but only A2 was an independent risk factor. However, Frist374 has subsequently disproved that initial observation in a longer follow-up of patients at Stanford. In contrast to the extraordinary lengths pursued in renal transplantation in an attempt to achieve a complete six-antigen match between the donor/ recipient, the field of cardiac transplantation essentially ignores HLA matching with the exception of patients with high preformed HLA antibody titers, as most crossmatches are performed retrospectively, eg, after implantation. Investigation needs to be directed at the role not only of HLA class I antigens but also HLA

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class II antigens (eg, DR and DQ) which are also known to be immunogenic.375,376 The initial report by Hess3” on the appearance of circulating cytotoxic antibodies against donor class I and class II antigens on the surface of the graft endothelium was direct evidence in support of an immune-mediated mechanism of this disease. In a small series of 12 patients, Hess noted the appearance of circulating donorspecific cytotoxic antibodies (in association with hypercholesterolemia) was strongly correlated with the development of TCD and an increased mortality. This observation of the negative prognostic value of donor-specific cytotoxic antibodies has subsequently been confirmed by Rosej” and other investigators.379.380 Another target for immune-mediated injury is the vascular endothelial cell (VEC) antigen as described by Cerilli.79,80 This unique antigen system was present in over 10% of patients with demonstrable peripheral vascular disease and has been found in some cardiac transplant patients with early severe rejection who subsequently developed TCD.“’ The antibody to this endothelial antigen is able to fix complement and is therefore cytotoxic and may be present more frequently than anticipated, as Cerrilli’s lab is the only center currently able to screen for presence of this potential source of endothelial injury. A logical extension of the immune-mediated theme is the belief that cellular rejection would be highly correlated with development of TCD, a hypothesis that has led to use of the term “chronic rejection” for this disease. However, this theory was not substantiated by Gao367in his review of the large series from Stanford, in which neither time to first rejection nor the incidence of early, late, or total number of rejection episodes were correlated with the subsequent development of TCD. In contrast, Uretsw7 found that patients who had more than two rejections within the first year of transplant did have a statistically significant increased probability of developing this disease. Other series have failed to show any statistical correlation,336 but the analysis of rejection as a risk factor for TCD is severely impaired by the lack of a standard biopsy grading system. In addition, whether antibody-mediated (vascular) rejection with immunoglobulin and complement deposition on the vascular endothelium is

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more predictive of subsequent TCD remains to be demonstrated. Dequesenoy and coinvestigators at the University of Pittsburgh3” have made a unique observation on the correlation between rejection and TCD. They had previously shown that although histological examination of endomyocardial biopsies may show no evidence of rejection, a percentage of the biopsies will show cell growth when the biopsy cells are cultured.54 Using this observation, they retrospectively analyzed the correlation of cell growth with the development of coronary disease.381 They found that those patients who had the highest amount of steroid exposure as a treatment for rejection had the lowest incidence of coronary disease of the subpopulation of “growers.” This implied that the demonstration of cell growth represented smoldering rejection and that those patients whose biopsies reached a histological grade sufficient to warrant bolus therapy perhaps had the greatest retardation of the disease process. These observations have very compelling implications as the question of whether corticosteroids are more atherogenic or more protective of immune-(antibody) mediated endothelial injury in cardiac transplant patients remains unanswered. Craemer38’a,3*1bhas offered support for the role of rejection in the development of TCD using both donor lymphocytes3”” as well as skin grafts and donor spleen lymphocytes. Use of cyclosporine or FKS06 resulted in increased group survival but worsening arteriosclerotic coronary lesions similar to TCD in humans.381b These preliminary data suggest that more patients should be managed more aggressively to achieve a grade 0 biopsy, but few conclusions can be drawn for the clinical management of patients at this time. However, this addresses two fundamental question in cardiac transplantation-what is the goal of immunosuppression (ie, a grade 0 biopsy) and what is the associated risk to benefit ratio. There are a number of other potential causes of endothelial injury other than immune mediators including cyclosporine,382 cryopreservation of the donor heart,3702383and recently, cellular rejection itself was shown to be associated with endothelial injury.384 Infection has also recently been shown to have a compelling correlation with subsequent development of coronary disease. In the laboratory, Minick,385 Vere11a,386

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Fabricant, and Hajjar3” have demonstrated that various viruses, especially herpes viruses, could induce coronary atherosclerosis identical to that seen clinically in heart transplant patients. For example, cytomegalovirus infection in animals is associated with increased cholesterol incorporation into the arterial intima, denovo synthesis of cholesterol by endothelial cells, as well as impaired metabolism of cholesterol in the liver.389 These laboratory observations have been supported by clinical reports from Stanford;% Minnesota,391 and Papworth showing that patients who had clinical or subclinical cytomegalovirus infection had a significant increased risk of developing TCD. The significant morbidity and mortality associated with the development of TCD and the observation made recently of the critical role of donor/recipient cytomegalovirus serology mismatch297.305may now warrant consideration of using cytomegalovirus serology in matching cardiac transplant recipients if this long-term correlation is substantiated by others. To date, the use of noninvasive techniques to establish the diagnosis of TCD has been disappointing. Nitkin and subsequently McKil10p~~~ and Young have demonstrated the lack of sensitivity of standard thallium exercise in predicting or identifying the presence of this disease, perhaps due to the small-vessel nature of this disease. However, newer techniques, such as single-photon-emission-CT (SPECT) thallium scans3” have shown significant correlation with the presence of this disease in transplant patients394 as well as nontransplant patients and may serve as a fairly reliable screening test and decrease the need for yearly coronary angiograPhY-

Studies of TCD have focused on comparing the importance of critical risk factors and histological and angiographic features in populations with TCD versus conventional atherosclerotic coronary disease in nontransplant patients. Although there are a number of differences, endothelial injury seems to play a critical role in the development of atherosclerosis in both transplant and nontransplant patients.396 The mechanism(s) by which endothelial injury results in smooth muscle cell and macrophage proliferation in TCD suggests that it may be a nonspecific response possibly under gene control. Support for this observation is the marked

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histological similarity between TCD and nontransplant patients who develop early restenosis following percutaneous transluminal coronary angioplasty (PTCA).397.398This procedure results in rupture of the endothelium, and although the vast majority of patients seem to heal with a retardation and scarring of the intima, a number of patients will develop rapid restenosis within the first 6 months after the procedure.399 This may represent another nonspecific endothelial injury that induces a regulator gene that results in the same myointimal proliferative process characteristic of TCD. Support for this unifying hypothesis includes work by FroeghmO who has reported a beneficial effect of the peptide angiopeptin, which inhibits smoothmuscle-cell proliferation in both angioplasty and transplant models. At the cellular level, a number of investigations have focused on the role of vascular wall cells in not only antigen expression and production of lymphokines,4”“.401 but development of transplant coronary disease.4n1-404 In addition, other possible mediators in&de platelet-derived growth factors,405 prostaglandins,406.4”7and estradiol.40R Recently, several investigators have evaluated the role of coronary artery flow reserve as a measurement of small-vessel or obliterative disease in cardiac transplant recipients409.410Nitinberg409was able to demonstrate consistent and statistically significant reductions in coronarysinus blood flow in patients during allograft rejection. However, they did not evaluate any patients with documented TCV. In contrast, McGinn4”’ and coinvestigators at the University of Minnesota investigated 25 patients from 6 to 57 months after transplant with no evidence of allograft rejection and compared them with 20 nontransplant normaI subjects using a coronary Doppler catheter and papaverine as the vasodilating agent. Although there were only five transplant patients with coronary atherosclerosis, the severity of which ranged from 25% to 38% at maximal stenosis, they were unable to demonstrate any significant decrease in vasodilater reserve compared with controls. The results of this technique have been inconsistent with the use of different provocative agents including acetylcholine,41’ papaverine,4’2 and adenosine413 and the validity of this technique in transplantation patients remains to be proven. Control of variables such as diastolic pressure

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and heart rate are critical aspects of interpreting coronary flow data in normal patients.414 Marcus414 has noted that over 50% of the resistance alterations in coronary flow are achieved in the large vessels of greater than 100 km in diameter and, therefore, coronary flow reserve may not be a sensitive indicator of microvascular disease in this population. Other new agents, such as endotheIin,4’s~4’h an endogenous vasoconstrictor substance of vascular endothelium or a combination of the above agents, may offer further potential for this technique. Therapies used in an attempt to retard or inhibit this disease have also evolved from initial reports of the importance of the combination of antiplatelet agents, aspirin, and dipyridamole plus warfarin417 to antiplatelet agents a~one~417-4?l More recently, agents such as heparin42’ and fish oil have been shown to be of potential benefit.4’3 These earlier observations have not stood the test of time and presently most centers use only aspirin as prophylaxis for coronary artery disease.5’ There is some suggestion that the pIateIet aggregation seen in transplantation patients is significantly greater than that in non-TCD patients, and therefore may require two- to fourfold greater amounts of aspirin-like compounds to impair the platelet aggregation seen in TCV.4’4 One other interesting observation regarding drug therapy of this disease is that calcium channel blockers have been shown to actually retard the development and progression of atherosclerosis.425-42yRecently, Schroeder4’” has shown a significant inhibition of the development of transplant coronary disease with the use of diltiazem in a series of 134 recipients at Stanford. This observation and the role of calcium channel bIockers in decreasing the development of this disease merits verification and focused investigation. One palliative approach to TCD has been the use of PTCA as initially reported by Hastillo43” and Vetrovec.431 A multicenter registry has been formed432 that will greatly advance our understanding of the role of this technique in transplant patients, although preIiminary results have been discouraging, perhaps due to the extensive distal and diffuse involvement of this disease. The only definitive form of treatment for TCD is retransplantation. A recent review of 20 patients undergoing retransplantation for graft

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atherosclerosis at Stanford3@ showed that the survival rate was 55% in 1 year and only 25% in 2 years. Although several patients have survived more than 5 years after retransplantation for this entity, the overall success was only 10% at 5 years and 5 of the 11 patients who survived more than 1 year had developed AGAS in the second allograft as well. These very discouraging results have caused a number of centers to no longer offer retransplantation to patients who develop critical graft coronary artery disease in light of the increasing number of candidates now on waiting lists who may have significantly superior l- and 2-year-survival rates. Although it has been widely believed that cardiac transplant patients do not experience angina pectoris due to the denervation produced by the procedure, there have been several case reports of anginal-like pain with documented coronary artery disease.434-436 Gao435 has also reported two patients who had anginal-like chest pain, and three patients who had leftarm pain in association with exertion. All five developed subsequent myocardial infarction. Recently viable intrinsic nerves have been demonstrated by immunohistochemical markers posttransplant and, importantly, Wilson438 has shown evidence of reinnervation in a patient who had anginal-like pain posttransplant by use of the provocative agent tyrosine. Gao436recently reviewed the experience with cardiac transplantation patients who sustained myocardial infarction and found that they had a higher risk of congestive heart failure, shock, and death than reported in most series for nontransplant coronary disease,439@0as well as sudden death in those who survived the hospitalization.436 Although all patients were known to have atherosclerotic coronary disease prior to the myocardial infarction and were closely followed, at explantation or autopsy nearly 20% of the patients had evidence of multiple diffuse nontransmural infarctions. In summary, this unusual form of coronary disease has become the leading limitation to long-term survival in heart transplant recipients with an incidence of nearly 50% at 5 years. The disease is characterized by diffuse obliterative small-vessel disease as well as proximal epicardial stenosis. Research is ongoing as to the role of rejection and perhaps more importantly, a

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definition of both the optimal threshold for initiating antirejection therapy and of acceptable chronic histological scores. Molecular approaches to search for the controlling gene that may be responsible for this extraordinary, nonspecific proliferative process and substances that can blunt this proliferation, may offer our greatest hope for truly limiting the progression of this disease. MALIGNANCY

The de novo development of malignant neoplasms has been one of the major side effects of every immunosuppressive regimen used to date for solid organ transplantation and is considered by many to be an inescapable problem.441 However, the incidence and type of malignancy, as well as its response to therapy, differ with the type of immunosuppression used.441-449 Penn44’-444 has shown that tumors in transplant recipients receiving immunosuppression occur much earlier than in age-matched-nontransplant patients and interestingly, do not represent an increase in the most common malignancies reported in the nontransplant population, ie, lung, breast, colon. In the precyclosporine era, malignancy accounted for over 11% of the deaths in cardiac transplant patients who survived greater than 3 months posttransplant,5”4X15 but this has decreased to a current estimate of 4% to 6%. However, with 90% l-year and 70% to 75% 5-year-survival rates reported today,3 malignancy may become an increasing long-term risk for cardiac transplantation recipients. The heart seems relatively privileged with regard to invasion of the primary allograft by tumor. Incidences have been reported44z-ti as high as 60% in a small series of heart-lung recipients and 30% to 40% in renal transplant patients in comparison with no reported cases in cardiac transplant recipients. Unlike the vast registry of more than 3,600 tumors in transplant patients that has been compiled by Israel Penn441-M4in the Cincinnati Transplant Tumor Registry (CTTR), primarily from renal transplant patients treated with azathioprine-based immunosuppression, there has been sparse and variable reporting of the incidence and nature of malignancy associated with cardiac transplantation. Although the ClTR does not suggest that there is a different malignant potential

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between renal and nonrenal transplant recipients, it unfortunately includes only approximately 100 cardiac transplant recipients and only 450 total patients who have received cyclosporine. Nonetheless, it represents the largest collection of tumors in patients managed with cyclosporine and allows comparisons and contrasts with the vast experience with azathioprinebased (AZA) immunosuppression. Cutaneous malignancy is the most common tumor associated with azathioprine-based immunosuppression accounting for 40% of all malignancies reported with that form of immunosuppression.441M One possible mechanism to explain this unusually high incidence of skin cancer is that the azathioprine metabolite, nitromidazole, causes significant photosensitivity with potential resultant skin cancers.44”a However, unlike nontransplant patients where basal cell cancers are the most common type of cutaneous malignancy, azathioprine therapy is associated with a 2 to 1 predominance of squamous cell over basal cell carcinomas. Squamous cell carcinoma in azathioprine-treated patients is also associated with more metastatic disease, and in fact cutaneous malignancy accounts for 6% of all deaths in azathioprine-treated patients versus less than 1% with cyclosporine.443 In contrast, the predominant malignant tumor seen in association with cyclosporine therapy is a unique type of lymphoma.U’-443.448.449 Data from Penn449 suggests that the incidence of this type of malignancy, as a percent of the total number of malignancies, has decreased over time from 41% in 1983 to 29% in 1983. This is in contrast to azathioprine patients in whom lymphoma accounts for approximately 12% of all tumors, with no change in incidence over time. The natural history of this malignancy has been quite varied, leading Hanto and others to use the term “lymphoproliferative disease” (LPD) instead of lymphoma to describe this entity. The LPD observed in association with cyclosporine has several significant differences from those that develop in azathioprine-treated patients including”’ (1) cyclosporine-associated LPD occurs much earlier (mean, 12 months v 45 months for azathioprine-treated patients), (2) central nervous system involvement is less common, 14% in cyclosporine, typically with diffuse involvement in 75% cases

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versus 39% in azathioprine-treated patients, where it was localized in 3 of 4 patients, (3) cyclosporine LPD occurred more commonly intraabdominally (22% v 12%) and was more localized to the bowel (32% v 19%) (4) the involvement of LPD syndrome with cyclosporine parallels the equal distribution between nodal and extranodal tissues seen in the normal population versus 75% extranodal involvement with azathioprine, and (5) cyclosporine LPD was more responsive to reduction in immunotherapy. The clinical presentation of CyA LPD has been described by Hanto45’ to occur in two basic forms in renal transplant patients: either in young patients (usually 45 years old), usually presenting with solid tumors often involving the central nervous system at an average of 12 months posttransplant, and although their course is slower, it is still progressively fatal. These two modes of presentation are not uniform and overlap occurs in cardiac transplant recipients. The etiology of this tumor has been shown to be due to the Epstein-Barr virus.450-454The Epstein-Barr viral genome has been demonstrated within the malignant B cell proliferations. Fluorescent staining within monoclonal antibodies directed against the virus have also frequently demonstrated the virus within the B cells. In addition, this type of lymphoproliferative disorder can be reproduced in the laboratory with Epstein-Barr virus infection, especially in the presence of cyclosporine.4s4 Yousem45” has offered a nice model of the role of Epstein-Barr virus in this lymphoproliferative disorder. Although Epstein-Barr virus infection triggers the production of a humoral response, with antibody directed against the virus, the actual clearance of the virus is due to the cellular-mediated defense, specifically cytotoxic, suppressor, and natural killer cells. These important T cell functions are blocked by adequate and particularly high doses of cyclosporine. Stimulation and/or activation of Epstein-Barr virus in the setting of impaired T cell function then allows an unregulated proliferation of the Epstein-

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Barr virus infected B cells, which results in the B cell hyperplasia. In the absence of adequate T cell surveillance, a monoclonal population of B cells may develop, perhaps in part due to actual chromosomal translocations that can be induced by the virus. This may also result in stimulation of host cell oncogenes and eventual malignant transformation.456 Data on whether primary or secondary infection are more likely to result in or induce this disease is inconsistent, but most data suggest that primary infection results in higher morbidity.456” Armitage457 has recently reported that 17 of 18 cardiac transplant recipients who developed LPD had evidence of a primary Epstein-Barr virus infection. This would suggest transfer of the virus by the donor graft or transfused blood products. Although over 80% of transplant patients develop evidence of viral shedding, clinical infection or sequelae, such as LPD, are poorly correlated. The role of hyperimmune globulin and/or vaccinations against Epstein-Barr virus in preventing development of LPD is under investigation. Defining the histological appearance of this tumor has been a difficult and controversial area. Frizzera458 initially described four basic types of histological findings including (1) hyperplastic lymph nodes, (2) polymorphous B cell hyperplasia, (3) polymorphous B cell lymphoma, and (4) an immunoblastic B cell sarcoma. Criteria used included the presence of necrosis, cytologic atypia, and binucleate ReedSternberg cells, (thought to be the hallmark of Hodgkin’+type lymphoma). However, Randhawa459 and Nalesnik4w and coinvestigators at the University of Pittsburgh have pointed out that these features, including necrosis, can also be seen in typical cases of infectious mononucleosis occurring in immunologically competent patients. In their experience, architectural features were of little help in discerning whether a proliferation was from a monoclonal or polyclonal source. They believed the finding of cellular monotony and uniformity with failed maturation of immunoblasts into plasma cells predicted the response of the LPD. They reported three patients with malignant lymphoma as defined by the criteria of Frizzera,458 who recovered with reduction in immunotherapy a1one.45v Hantoe has subsequently simplified

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the histological classification to either nonmalignant diffuse B cell hyperplasia or polyclonal B cell lymphoma, using clonal analysis as well as malignant transformation to separate the two forms. To the untrained eye, almost all of these proliferations appear to have undergone malignant transformation, and consultation with a trained expert in this field is recommended prior to initiating aggressive therapy for malignancy. One of the newest techniques used to predict the natural history or malignant potential of a lymphoproliferative tumor is based on clonal analysis of immunoglobulin chains of the B cells involved using DNA probes.6’465 Cells that show only one immunoglobulin class are believed to be due to a single clone and have already undergone malignant transformation, in contrast to those that demonstrate multiple chains of immunoglobulin, which are referred to as polyclonal. In general, only polyclonal tumors have been responsive to reduced immunosuppression. There has been some debate in cardiac transplantation regarding the accuracy of clonal analysis of these tumors to predict the patient’s clinical course. Clearye reviewed 10 cases from Stanford in 1982 and believed that all patients with LPD had monoclonal tumors and therefore should all be treated as malignancies. However, Hantoe has shown that cyclosporine associated LPD tumors can evolve and transform from polyclonal proliferation to a monoclonal malignancy. Nalesnike5 has noted less of a predictive accuracy, citing three patients who had a monoclonal tumor shown by DNA probes and supportive histology, which have demonstrated regression of the tumor with simple reduction in immunotherapy. One aspect of LPD that differentiates it from all other types of malignancy is the critical role of the amount of immunosuppression. Starz14@ was one of the first to report the responsiveness of these tumors to a significant reduction (often in excess of 50%) in all immunosuppressive agents used. Data from Penn and the CTTR44’.442 suggests that in excess of 40% of patients with cyclosporine-associated LPD will respond to reduction in immunotherapy, although no protocol or uniform amount or percent reduction has been attempted. This tumor has a predilection for gut-associated lymphoid tissues, particularly

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the small bowel, where surgical excision of the tumor is often required in addition to reduction in immunosuppression. There is little data to support the use of chemotherapy or radiation therapy as first line treatment for this disease, as these tumors have been minimally responsive to these manipulations and their use may in fact only hasten clinical demise. Swinnen and Costanzo-Nordin467 have recently reported the development of LPD in 6 of 35 patients who received transplants at Loyola in 1988. Using multivariant analysis of greater than 30 risk factors, only the use of lymphocyte antibody (OKT3) therapy was found to be an independent risk factor. All patients received perioperative administration of OKT3 at the usual dosage of 5 mg/d for 14 days, or 70 mg. Four of the nine patients who received retreatment with OKT3, ie, total dose more than 7.5 mg, developed LPD, in contrast to only 2 of 26 patients who had a cumulative dose below 75 mg. This is in concert with the findings of Brumbaugh46X at Stanford who noted that cumulative dose of antithymocyte globulin was the only statistically correlated risk factor for the development of LPD in a series of 77 cardiac transplant recipients. Neither seroconversion nor a fourfold rise in titer of EpsteinBarr virus antibody were correlated with the development of tumor in this series. However, in the setting of high cyclosporine levels, seroconversion was an independent risk factor, although high cyclosporine levels alone were not correlated. Additional evidence for the direct causal role of ATG in the development of this tumor was the finding of the LPD tumor in the soft tissue of the thigh at the sites of previous intramuscular injections of the agent. However, the number of rejection episodes, and therefore the cumulative amount of immunosuppressive therapy, has not been analyzed thoroughly as a risk factor for developing LPD. These observations underscore the importance of withholding aggressive chemotherapy or radiation therapy until a trial of reduced immunosuppression is attempted to evaluate the responsiveness of the tumor. Intravenous acyclovir, a well-described therapy for both herpes simplex virus and EpsteinBarr virus infection,469.470has been thought to be an important part of the armamentarium for the treatment of this tumor although no controlled

trials have been conducted. Dummer4” has reported a seemingly paradoxic case in which acyclovir therapy was associated with clearance of Epstein-Barr virus from the oral pharynx but a progression of the B cell lymphoma in the gut. Sullivan4’* and coinvestigators have elegantly described the probable explanation for this observation in that the epithelial cells of the oral pharynx possess a linear form of DNA for which acyclovir is very effective, but this drug has no effect on cells possessing a circular form of DNA, the form present in B lymphocytes. They described the differences between a “permissive” infection, in which the cells possess the viral genome and the infectious virus is actively replicated within the cell and have linear Epstein-Barr virus DNA, and “nonpermissive” infection, in which cells have the viral genome present and replicate, but infectious virus particles are not produced. Nonpermissive infection occurs in cells with circular Epstein-Barr virus DNA. Their relatively simple gel technique for the discrimination of circular or linear EpsteinBarr virus DNA can help identify those cells for which acyclovir will be of no additive value. Their data would suggest that acyclovir may play little role in resolution or regression of typical B cell LPD tumors. One recent innovative form of therapy for this disease has been reported in mismatched bone marrow transplantation by Blanche.473 Lymphoproliferative tumors occurred in two patients within 60 days following bone marrow infusion with a clone of B cells containing the Epstein-Barr virus nuclear antigen in both blood and bone marrow cells. Each patient was treated for 10 days intravenously with both a mouse monoclonal anti-B cell antibody directed against the CR,-receptor on the surface of B cells and a CD,,-specific antibody that binds B cells at all steps of differentiation. Both patients demonstrated clinical resolution of all clinical and biological manifestations of disease within 3 weeks of treatment and recurrence has not been observed at 15 and 18 months follow-up. T cell function developed fairly normally in these patients following transplantation, although B cell function was partly abnormal nearly 2 years posttransplant. This isolated report offers hope for further use of monoclonal antibodies directed against this proliferation as adjunctive

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therapy, but its role in treatment of solid organ transplant recipients is only anecdotal at present. The mechanism(s) by which there is a preponderance of certain types of unusual tumors in transplant recipients, as well as the unusual location, clinical behavior, and histology of the lymphoproliferative tumors, suggest that the pathogenesis may not be related exclusively to drug-induced loss of suppressor-cell function. Matas et al, from the University of Minnesota, questioned the role of chronic antigenic stimulation in the development of this tumor. In one animal model, oncogenic bioactivation occurred when mice were given allogeneic skin grafts and simultaneous immunosuppression.475 However, neither skin grafts nor use of azathioprinebased immunosuppression alone resulted in viral activation. Although RNA viruses are known to be oncogenic? the herpes virus family, which are DNA-type viruses, have also been shown to be oncogenic in a number of animal models477 and were first reported to be associated with human neoplasia with the Burkitt lymphoma.478 Epstein-Barr virus has been shown to be capable of transforming cultures of proliferating lymphocytes and cause chromosomal alterations.479 This observation does not prove direct causality, but the role of viral oncogenes and immunostimulation (either by infection or rejection) in the development of this tumor merits further investigation. Cyclosporine itself has been shown to have carcinogenic properties,47g especially in previously reported animal models of malignancy.4B09481 In summary, evidence to date suggests that the development of cyclosporine-associated lymphoproliferative disease indicates a state of overimmunosuppression. The risk to benefit ratio of additional immunosuppression in the form of prophylactic use of lymphocytotoxic antisera requires further investigation and review as it may in fact predispose to this problem 467,468 although cumulative maintenance doses of these agents are perhaps more critical. These data also raise questions about the use of so-called “target levels” to guide cyclosporine therapy. Markers of lymphocyte activation such as the IL-2 receptor may be a better assessment of the relative “adequacy” of any level of cyclosporine and allow more individualized tailoring of immunotherapy in conjunction with

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endomyocardial biopsy. The goal of immunosuppressive therapy today should not be the attainment of arbitrary target levels but to identify the minimum effective level of immunosuppressive therapy and thereby hopefully minimize the risk of malignancy and other complications. HYPERTENSION

Hypertension is perhaps the most common complication associated with the use of cyclosporine,482-484having been reported not only in transplantation recipients but also in patients receiving the drug for other indications such as autoimmune disease.485-489There is an abundance of evidence available to support the observation that cyclosporine plays the primary role in this form of hypertension.490-4g6For example, Loughrin490 noted a 57% incidence of hypertension in bone marrow transplantation recipients treated with cyclosporine, compared with 4% of those treated with methotrexate. However, the incidence, onset, severity, and natural history vary considerably between patient populations and indications for its use. Perhaps the largest and most direct body of evidence for the primary role of cyclosporine is the comparison of the incidence of hypertension in patients treated with cyclosporine versus azathioprinebased therapy. Several prospective randomized trials in renal transplant patients493-4g5have shown a two- to threefold increased incidence of hypertension with use of cyclosporine and historical comparisons in cardiac transplant recipients have shown similar results.498-500 The incidence of cyclosporine-associated hypertension (CAH) in cardiac transplant recipients ranges from 50% to 100%,4g6-506 but comparisons are somewhat limited by the lack of uniform criteria for the initiation of therapy and the definition of adequate control. The earliest reports using much higher dosages of cyclosporine than are used today (16 to 18 mg/kg/d v 5 to 6 mgikg/d), suggested that the incidence was between 80% to 100%.497~502 These investigators also noted that CAH was often difficult to control, usually requiring multiple-drug therapy including diuretics, vasodilators, and B-blockers. There is controversy about the exact role of the cyclosporine dose in reducing the incidence of hypertension. Many programs have reduced the dose of cyclosporine both preoperatively as

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well as long term. Miller503 observed a decreased incidence of hypertension to a low of 37% associated with a reduction in cyclosporine dosage in patients who received transplants in 1989 (n = 22) where the cyclosporine dose averaged 3.4 mg/kg/d at 1 year posttransplant versus 78% in 1984 (n = 22) when the cycIosporine dose averaged 6.1 mg/kg/d. However, this reduced incidence with lower cyclosporine dosages has not been a uniform finding as Olivari504 and Starlingso reported a 90% incidence of CAH at 1 year posttransplant using doses of cyclosporine that were slightly higher than reported by Miller:03 5 to 6 mg/kg/d in a three-drug regimen of cyclosporine, azathioprine, and prednisone. There are very few factors that correlate with or predict the development of CAH. It develops independent of race, sex, age, or prior history of hypertension48’-4X4; in fact, an incidence as high as 40% to 60% has been reported in pediatric recipients.s07-5w Some investigators have noted an increased trend in Afro-Americans especially those with a previous history of hypertension.503 Interestingly, this form of hypertension seems to be independent of renal function often developing in patients with normal serum creatinine, although similar to nontransplant patients not receiving cyclosporine,510 hypertension is fairly uniform in those patients who develop renal insufficiency. There are several other unusual features of CAH, including very early onset-almost uniformly evident within 4 to 6 weeks of transplant498.so2-?04 and persistance with little alteration over time. This is in contrast to a large series of renal transplant patients reported by Jarwenko and Kahan5” where the percent of patients requiring antihypertensive therapy actually decreased from 72% at one month to only 36% at 1 year and less than 20% at 2 years posttransplant. One of the most atypicaI features of CAH is the lack of usual or normal nocturnal decrease in blood pressure.498,4y”This phenomenon was observed by Reeves”’ to be due to a lack of the normal 15% decrease in heart rate that occurs at night.51’,5’3 There is commonly an expansion of vascular volume at night due to retrieval of extracellular fluid from peripheral pooling that occurs during the day with a resultant mild increase in ejection fraction and stroke volume at night. This increase is

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typically more than offset by a decrease in heart rate due to decreased sympathetic stimulation with sleep. Transplant patients do not demonstrate this nocturnal decrease in heart rate. This coupled with the normal or possibly enhanced cardiac output associated with increased volume that occurs at night and elevated systemic resistance results in either an elevation or a lack of decline in nocturnal blood pressure. The transplant ventricle contracts normally and due to denervation does not “see” a sustained increase in systemic vascular resistance found in this condition and, therefore, does not reflexively decrease ejection fraction or cardiac output. This mechanism may be important early posttransplant when a normal donor ventricle is inserted into patients who often have dramatically elevated systemic vascular resistance. Further investigation is needed to examine the incidence and severity of hypertension as a function of the systemic vascular resistance at the time of transplantation. In addition, the blood pressure response to exercise is variable and phase-shifted due to the denervated state.5’4.5’5 If there is not an adequate warm-up period, there is a time delay in heart rate and blood pressure response for several minutes after the onset of exercise, and blood pressure elevation will persist for several minutes after the cessation of exercise, until there is a decrease in circulating catecholamines. This can return to nearly a normal pattern with sustained conditioning posttransplant.5’” There have been a number of causes proposed for cyclosporine-associated hypertension. Cyclosporine appears to cause a sodium-avid statesI as fractional excretion of sodium is decreased, particularly in association with progressive nephrotoxicity. The exact role and status of intravascular volume is controversial. Data indicating a lack of intravascular vohtme overload includes hemodynamic studies that have shown normal cardiac filling pressures and generally normal ejection fraction.5’7-5’9 However, Bantle”’ has shown a volume-dependent mechanism in salt-depleted patients who demonstrated a decrease in blood pressure and an increasing plasma-renin activity indicating normal glomerular function and an intact reninangiotensin mechanism. He believed that this extracellular fluid volume expansion would be

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responsive to diuretics. In addition, Bellets21 found a 15% increase in plasma volume (686 mL in cardiac transplant patients v 445 mL in controls) at an average of 288 days posttransplant. Although the role of volume may be significant in the early postoperative phase, long term use of diuretics often result in a disproportionately increased azotemia with only modest improvements in blood pressure. Another controversial issue is the role of corticosteroids in CAH. Patients initially managed with azathioprine and prednisone received doses of corticosteroids as high as two to four times that currently used in cyclosporine-based therapy with one third the incidence of hypertension.498.SO0 This would suggest a minimal role of corticosteroids in cyclosporine-associated hypertension. However, the Utah programs2* has recently reported a significant decrease in the incidence of hypertension in patients that were able to be totally withdrawn from corticosteroids early posttransplant compared with those patients who remained on maintenance steroids. The hemodynamics associated with this form of hypertension are unique and seem to be mediated by an increase in systemic vascular resistance.519-521Although cardiac output and ejection fraction remain normal, systemic vascular resistance is elevated with a resultant increase in systemic arterial pressure. The denervation produced by the procedure uncouples the heart from the peripheral vasculature eliminating the reflex fall in systemic resistance with normal or increased cardiac output. A number of possible etiologic explanations in CAH have been explored including the sympathetic nervous system.5u High sympathetic tone is a common finding in patients with chronic congestive heart failure prior to transplantation,‘” but Olivaris2’ has reported normalization of norepinephrine levels within 6 months of transplant. These data seemingly minimize the long-term importance of the sympathetic nervous system, although it is potentially a factor early posttransplant when normal functioning hearts are implanted in series with an elevated systemic resistance. In contrast, there has been an increased sensitivity shown to neural and hormonal stimulation in association with cyclosporine use that may promote an

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exaggerated response to both neural and sympathetic stimuli.S26 Scherer et als2’ have recently shown a two- to sevenfold higher rate of sympathetic nerve firing in heart transplant recipients treated with cyclosporine as compared with patients with myasthenia gravis who were treated with cyclosporine versus azathioprine-treated or control patients. A local renal effect of the sympathetic nervous system has been suggested by investigations demonstrating that a-blockade as well as renal sympathectomy have ameliorated the development of this form of hypertension 528s29leading investigators to suggest that cycl&porine acts as an a-agonist. Although the denervated state causes a loss of typical reflexes, normal baroreceptor function is the rule and in fact, loss of normal baroreceptor function has been associated with the development of hypertension.530,53’ Finally, circulating catecholamines have been shown by a number of investigators not to be elevated.504352’ Stagerwalt526has shown little evidence of sympathetic stimulation as he measured low circulating catecholamine levels and increased receptor density, which were the exact opposite predicted if catecholamines were elevated in this setting. A great deal of attention has been focused on the renin-angiotensin-axis as a mechanism for found signifyCAH. 498,5W,SM,521,532-535 Thompson498 cant elevation in plasma-renin levels in most of the initial cardiac transplant patients at the University of Pittsburgh. However, Myers535 has demonstrated an apparent block in the conversion of inactive prorenin to the active moiety by cyclosporine. Total renin (the sum of inactive and active renin) is therefore elevated with cyclosporine, but this is due predominantly to an increase in inactive renin. Myers535 showed an almost twofold increase in the ratio of inactive to active renin in patients receiving cyclosporine compared with azathioprine-based therapy. This observation may explain some of the disparity in the literature where acute intravenous administration in humans or any cyclosporine administration in animals has resulted in an increase in renin levels.5wX529 Ballet521 has investigated this thoroughly in a series of 15 cardiac transplant recipients who became hypertensive following surgery. He showed that there was no elevation in plasma-renin activity, aldosterone, or angiotensin-converting enzyme lev-

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els. Further evidence for the lack of a role of the renin-angiotensin system is the fact that angiotensin-converting inhibitors cannot block the development of this form of hypertension in the laboratoryT5 One alternative mechanism for CAH is an imbalance between vasodilator and vasoconstrictor prostaglandins.536-541 Cyclosporine has been shown to increase thromboxane production and thromboxane A receptor blockers can in fact diminish the development of hypertension.536-538 This hypothesis of enhanced vasoconstrictor prostaglandins in CAH is consistent with the known hemodynamic effects of cyclosporine on the kidney, namely a decrease in renal blood flow and an increase in renal vascular resistance.5’7-51y Nield”36 has demonstrated a decreased prostacycline stimulating factor in response to cyclosporine and suggested that either this decrease in the vasodilator stimulating factor or the release of these vasodilating prostaglandins contributes to the relative imbalance between vasoconstrictor and vasodilator prostaglandins with the net effect of cyclosporine being enhanced vasoconstriction. In addition, the use of both omega-3 fatty acids and fish oil,5J’ which inhibit thromboxane synthesis, have also been shown to be beneficial in preventing CAH. Recently, the synthetic prostaglandin E, analogue, misoprostol,S42 has been shown to diminish the development of hypertension when given to renal transplant patients for the first 4 weeks posttransplant, although it did not alter the nephrotoxic properties and did not offer enhanced immunosuppression. One interesting additional concept relates to a possible role for hypomagnesemia in this form of hypertension. Junes43 observed in bone-marrow-transplant recipients that although all patients had an identical baseline magnesium level, those patients who became hypertensive had a significantly lower magnesium level at the time hypertension was documented and responded to supplementation. Treatment of this form of hypertension has varied, but may offer some insight into its mechanism. Thompson4y8-500 and other investigators50’.5”“.504 have described the nearly refractory nature of this condition using diuretics, vasodilators, and P-blockers. A more optimistic view has been observed with the use of calcium

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channel blockers,503,544often used as monotherapy. Cyclosporine action at the cellular level is at least partially mediated through cyclophylin, 545,546 thus affecting intracellular calcium. This could explain the superior response to calcium channel blocker agents reported previously. The response to various types of calcium blockers is not uniform. Use of diltiazem may result in significant increases in cyclosporine levels547.548 by inhibiting the hepatic metabolism of cyclosporine via the cytochrome P450 enzymatic pathway, with a resultant increase in renal toxicity and secondary worsening of the hypertension. Reduction in cyclosporine dosage at the time of starting diltiazem can minimize this problem. Angiotensin converting enzyme (ACE) inhibitor drugs have been used by a number of investigators with variable results. Laboratory data have shown an inability of these agents to block the development of this form of hypertension, probably due to cyclosporine’s effect of blocking the conversion of prorenin to renin.535 This would suggest that ACE inhibitors would not be very effective, although as noted many centers report using ACE inhibitor drugs with reasonable efficacy. A trial by the WGTC to test the comparative efficacy of calcium channel blockers and ACE inhibitors in cardiac transplant recipients has been initiated. Hypertension remains the most common complication associated with cyclosporine administration, although its incidence and severity have decreased to a variable degree with continual reductions in dosages of this drug. Further investigation is needed into the mechanism(s) of cyclosporine’s effect on systemic vascular resistance and possible mediators such as prostaglandins and/or endothelin. NEPHROTOXICITY

The nephrotoxicity associated with cyclosporine use has been the topic of investigation and interest since its clinical introduction over a decade ago and is considered by many to be its major side effect.54”-55’Like hypertension, cyclosporine-associated nephrotoxicity (CAN) occurs with equal frequency in nontransplant patients as we11.48x.55’ The comparatively toxic maintenance doses used initially (16 to 18 mg/ kg/d) in cardiac transplant recipients were asso-

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ciated with an average doubling of serum creatinine within 1 year posttransplant, a significant increase compared with azathioprine-treated patients.550’552The severity of the nephrotoxicity caused significant alarm and concern about the safety of cyclosporine in long-term use. Several early heart transplant recipients in fact were withdrawn from cyclosporine and converted back to azathioprine-based therapy due to progressive deterioration of renal function which required dialysis in a few patients.535,553,554 However, with time and the understanding of the immunosuppressive efficacy of much lower doses of cyclosporine, there has been a gradual reduction in the acute and long-term nephrotoxicity reported today.555-559 The natural history of CAN is undefined, but it seems to be both time- and therefore cumulative-dose dependent. Patients withdrawn from cyclosporine within 3 months of initiation almost uniformly regain 100% of renal function, and those withdrawn before 12 months have a near total recovery.56o One highly controversial question regarding CAN is its potential for reversibility. Based on histological and functional examination, Myers has felt that CAN is progressive and irreversible.535~5sz~553 This view has not been shared by a number of OtherS,556-558,561.56Z including Greenber$* who has reported the majority of change in creatinine occurred by the first year with little change at 3 to 4 years. Many patients555W558 have had a gradual decrease in their cyclosporine dose over time which may have contributed to the lack of progression seen in long-term follow-up. However, a recent update of the series from the University of Pittsburgh by Greenberg562 suggested a further worsening occurs in patients followed up to 7 years, but there are very few patients included in the longer follow-up (4 to 8 years) and conclusions based on this sample size are hazardous. In a group of 355 patients treated with various combinations of cyclosporine and other agents at Stanford University,556 the mean creatinine was 1.1 mg/dL at 1 month posttransplant, 1.6 mg/dL at 6 months, and 1.8 mg/dL at 12 months and remained essentially unchanged up to 5 years. Mille?58 reported a mean creatinine of 1.0 mg/dL at 1 month posttransplant, 1.5 mg/dL at 1 year, and 1.6 mg/dL at 5 years. NordinSs7 has reported almost

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identical results in creatinine levels over time, but noted a decrease in glomerular filtration rate during this time from 74 cm3/min in the preoperative period to 62 cm3/min at 1 year and 56 cm3/min at 3 years. However, Radovancevic559 and Frazier from the Texas Heart Institute have reported levels as high as 1.9 at 12 months posttransplant that increased to a mean of 2.4 at 5 years posttransplant despite a decrease in mean cyclosporine dose from 6.5 mg at 1 year to 3.8 mg at 5 years. Clearly the greatest percentage change occurs within the first 6 months of exposure to cyclosporine and further attention needs to be focused on risk-factor analysis and results of protocols that withhold cyclosporine for the first 5 to 10 days posttransplant. The laboratory findings associated with cyclosporine nephrotoxicity535.56O include (1) a decrease in glomerular filtration rate, (2) an increase in serum creatinine, (3) a decrease in urea secretion with a disproportionate increase in azotemia, (4) elevated potassium and urate due to decreased fractional excretion, and (5) type four renal tubular acidosis with decreased reabsorption of bicarbonate. However, most patients maintain normal urine volumes and proteinuria is very uncommon. One of the hallmarks that distinguishes cyclosporine from almost all other nephrotoxins is that cyclosporine is associated with an unusually low fractional excretion of sodium, hence the term “a sodium avid state.” The alterations in tubular function are nonspecific and occur independent of glomerular filtration rate.570 Although creatinine clearance has been a reliable estimate of glomerular filtration rate in normal patients,564 its use has been questioned in nontransplant patients with glomerular disease.565566 Tomalovich567 and coinvestigators from Stanford found that creatinine clearance was also poorly correlated with the severity of renal injury in renal and heart transplant patients treated with cyclosporine. Progressive toxicity causes renal tubules to hypersecrete creatinine with a resultant increase in urinary creatinine, relative decrease in serum creatinine, and potential falsely elevated creatinine clearance. They have suggested that inulin clearance is perhaps the simplest and most closely correlated test of glomerular filtration rate in cyclosporine-treated patients. However, Nordin5’j8 found no differ-

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ence between inulin and creatinine clearance in a group of 10 cardiac transplant patients observed at 6 and 12 months posttransplant. The inverse of serum creatinine that has also been shown to correlate closely with glomerular filtration rate in nontransplant patientss35.5”~565may also be reliable in cyclosporine-treated patients. A number of hemodynamic findings in the kidney associated with this form of cyclosporinea decrease in renal induced injury include 535s60.569 plasma flow, an increase in renal vascular resistance, and a decrease in renal blood flow as a percentage of cardiac output. MyersSj5 has shown that cyclosporine in comparison with azathioprine-treated cardiac transplant patients is associated with highly significant reductions in glomerular filtration rate (94 cm3 v 47 cm3 per minute), renal plasma flow (440 mL v 284 mL), renal blood flow as a percent of cardiac output (15.9% v 8.8%), and an increase in renal vascular resistance (272% v 126%). However, he did not believe the fall in glomerular filtration rate was solely due to decreased renal plasma flow as the filtration fraction was also significantly depressed. In addition, as mean arterial pressure in these patients was either normal or elevated, the decrease in renal plasma flow was thought to be secondary to a primary increase in resistance. The histological picture of cyclosporineassociated renal injury has been reviewed by a number of authors.s35~55’~570-572 Most of the early investigation has been in renal transplant recipients in whom the coexistence of chronic renal allograft rejection may create difficulty in defining the changes due to cyclosporine alone. Myers535 has reviewed autopsy and renal biopsy tissue from cyclosporine-treated cardiac transplant recipients at Stanford and compared them with a similar group of age-matched, livingrelated renal transplant patients in an attempt to discern changes unique to cyclosporine. The effect of cyclosporine can be observed at a11 levels of the nephron, beginning in the preglomerular afferent arteriole where arteriolar sclerosis and eosinophilic proteinaceous deposits with hyalinosis of the arterial wall are noted with secondary luminal narrowing. These deposits replace the pericytes to a variable degree, but fibrinoid necrosis is not noted early on. Myerss3’ has elegantly analyzed the distribution of the

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cross-sectional area of these glomeruli and categorized them into small, medium, and large. The total number of glomeruli were reduced in CAN (730 control v 665 CAN). In normal patients, there is a bell-shaped distribution of glomerular size, but cyclosporine results in a bimodal distribution with an increase in the percentage of small glomeruli (56%), a marked decrease in medium-sized glomeruli, and perhaps, as a means of compensation, an increase in the large glomeruli. Further analysis has shown that this increase in large glomeruli is due to an increase in the mesangial matrix as well as hyperplasia of the juxtaglomerular apparatus. Cyclosporine injury seems to occur in the straight portion of the proximal tubule in the juxtamedullary region of the kidney, where tubular atrophy is characteristic. In addition, the proximal tubule cells exhibit vacuolization, although similar vacuolization can be noted in association with exposure to the suspension vehicle of cyclosporine and therefore is also nonspecific.574 Finally, one of the most characteristic features of cyclosporine-associated nephrotoxicity (CAN) is interstitial fibrosis. Microscopically this has a unique striped appearance with alternating fibrosis and atrophy. This observation raises interesting speculation about possible periodic “toxic” amounts of cyclosporine in the kidney, but it seems to be a consistent finding in most patients examined, regardless of cyclosporine levels reported. Inflammatory changes are not typically prominent but radiolabeling studies have demonstrated cyclosporine and its metabolites to be actually deposited in the interstitium.575 This may result in a nonspecific inflammatory response and secondary fibrosis. Fibrosis has also been reported in cardiac biopsies in association with the use of cyclosporine and may also be a nonspecific but common response.s76 The mechanism(s) involved in CAN has been the subject of several reviews?49*560,577 Demonstration of the exact mechanism(s) responsible for cyclosporine-associated renal injury has been hampered because animals are manyfold more sensitive to the effects of cyclosporine and there are no animal models available to reproduce the response in humans.577~579 KaharP’ has proposed two basic pathophysiologic mechanisms. The first involves an increase in proximal tubular

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pressure as a result of injury to proximal tubular risk factors for CAN. As the preoperative dose cells with resultant back pressure in the glomerwas decreased from 15 to 18 mg/kg to the ulus and a subsequent decrease in glomerular current dose of 3 to 5 mg/kg, nephrotoxicity has filtration rate, so-called glomerulotubular feedvirtually been eliminated. In addition, the peak back. The second and more widely agreed upon perioperative creatinine in the patients who mechanism is that of arteriolar vasoconstriction developed nephrotoxicity was 2.4 mg/dL in comand secondary ischemia. Possible effecters of parison with 1.6 mg/dL in those who did not, this vasoconstriction include (1) cyclosporine, despite both groups returning to an identical with a unique and direct effect on the smooth average serum creatinine Ievel of 0.9 mgidL at 1 renal muscle arteriolesS74 (predominantly the month posttransplant. This observation implies afferent arteriole), (2) the sympathetic nervous some type of injury occurring at the time of system, (3) the renin-angiotensin aldosterone initial exposure to cyclosporine that predissystem, or most likely (4) an imbalance in posed the kidney to long-term progressive dysvasoconstrictor and vasodilator prostaglandins function. Macris593 has shown that hospitalized resulting in net vasoconstriction. patients, especially those requiring intravenous Data to support the role of prostaglandins in inotropes or mechanical assistance (status l), CAN are both direct and circumstantial. Direct patients with an increase in creatinine at the evidence includes the observation that cyclospotime of transplant, or those with perioperative rine can increase synthesis of the vasoconstrichemodynamic instability, are at greatest risk for tor prostaglandin thromboxane537,538 and that the enhanced nephrotoxic effects of cyclospoblockade of the thromboxane receptor or use of rine. In addition, a number of drugs can have an additive nephrotoxic effect when used concomiagents such as fish oi1,541which can decrease tantly with cyclosporine via various mechathromboxane synthesis, may retard the progression of this injury. In addition, Misoprostol,S4’ a nisms. Such drugs include aminoglycosides, amprostaglandin E, analogue, has been shown to photericin, trimethoprine sulpha, aketocomizol, blunt the development of this injury when given erythromycin, cimetidine, acyclovir, and nonsteroid antiinflammatory agents.594 to renal transplant recipients for the first 4 weeks nephrotoxicity ocfollowing transplantation. Other data536,537,581.582 Cyclosporine-associated support the role of prostaglandins in CAN. curs in both an early and late phase form. Circumstantial evidence includes the enhanced Impaired or worsened renal function in the first nephrotoxicity observed with the use of nonstepostoperative days, which is typically unresponsive to diuretics, presents significant problems roidal antiinflammatory drugs583,584which are to the clinician. There are several approaches to known to also inhibit prostaglandin synthesis. More recently, Bunchman and other invesminimize this problem including a delay in initiation of cyclosporine until good renal functigators585-5sshave observed that cyclosporinetion is established (1 to 4 days)595 or total induced or -associated vasoconstriction may be avoidance of cyclosporine for the first 4 to 10 mediated by the endothelial vasoconstrictor, days posttransplant. Intravenous lymphocyte endothelin. Cyclosporine exposure resulted in an increase in endothelin levels and vasoconstricantibody therapy (eg, OKT3 or ATG) is used or substituted to maintain adequate immunotion which could then be blocked by antiendosuppression in the absence of cyclosporine. thelin antibody.“’ This area of investigation may Another alternative is the use of intravenous identify another critical component or mediator cyclosporine either in the pre- or immediateof CAN. Finally, direct infusion of atria1 napost operative period or both to avoid unexpectturetic factor (ANF) has been able to prevent edly high-peak levels in cyclosporine level. Bolacute CAN,588 although ANF has been reported man5% and others597*598 have reported no increase to be elevated in cardiac transplant patients.589 The risk factors associated with the developin short- or long-term nephrotoxicity and equal immunosuppressive efficacy with the use of ment of this injury have been reviewed by intravenous cyclosporine. The approach to CAN several investigators. 591-593 Milleti91 has observed occuring months to years after transplant is that the preoperative dose of cyclosporine and either reduced dose599@’or conversion to azathipeak perioperative creatinine were two major

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oprine-based immunosuppression. This conversion has resulted in increased rejection and even graft loss in both rena1600aand cardiac transplantation.6”b Although it is clear that cyclosporine has a toxic effect on the kidney, the use of lower doses of this agent both preoperative and in long-term maintenance therapy have been associated with a reduction in its toxic properties. The mechanism involved in this toxicity is primarily arteriolar vasoconstriction with secondary ischemia. Continued investigation into the mediators of the vasoconstriction is ongoing and multicenter trials, which are needed to assess the long-term nephrotoxicity of variable immunosuppressive regimens, may help minimize this complication in the future. HYPERLIPIDEMIA

Elevation of plasma lipids has been associated with the use of both corticosteroids and cyclosporine, whether for transplantation recipients,601-606nontransplantation diseases, such as asthma,607 nephrotic syndrome,ho8 or in healthy control patients.h07-609Interestingly, there is a disparity regarding the lipid fraction(s) elevated between organs transplanted. The primary lipids increased in renal transplant recipients are triglycerides and HDL cholesterol,“lO~hl’ whereas most reports on cyclosporine-treated heart transplantation recipientsm’-m6 have shown that the major lipid elevation occurs with LDL cholesterol. The HDL fraction is usually normal or occasionally elevated and therefore total cholesterol is typically elevated. These elevations in plasma lipids vary with time, but are frequently evident as early as 2 weeks posttransplant and often peak between 3 to 6 months.601mh06 Interestingly, Becker6W noted further elevations in all lipid fractions at 16 months, which subsequently decreased again by 20 months posttransplant. The response of triglycerides to immunosuppressive medications has also varied with a twofold increase in triglycerides in comparison with cholesterol (90% v 45%) reported by Ballantyne,605whereas Becker and Keogh have demonstrated essentially no change in triglycerides within the first 12 months. Another way to observe lipid response in transplant patients is to compare them with established norms from the Lipid Research

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Group.6’” Becker6” has shown that in contrast to nontransplant patients with coronary disease, cyclosporine-treated heart transplant recipients show a higher percentage of patients with total serum cholesterol levels greater than the 75th percentile (52% v 25%) and nearly four times as many had levels greater than the 90th percentile (38% v 10%). In addition, patients who receive transplants for ischemic heart disease seem to have a greater degree of hyperlipidemia than nontransplant counterparts,604 a finding also noted by Ballantyne.6’9 The major controversy is whether prednisone or cyclosporine is the primary cause of lipid elevation. Several studies have demonstrated that prednisone seems to be the primary cause. Blumh14 has shown in an interesting computerassisted model that a regression equation could be developed that could predict the levels of cholesterol expected with various doses of corticosteroids. The cumulative amount of corticosteroids was the strongest predictor of both LDL and total cholesterol in Becker’sho detailed analysis of 92 heart transplant patients from three different centers treated with variable doses of immunosuppression. Cumulative prednisone dose was correlated with both total cholesterol (P < .OOOl) and also with LDL cholesterol, but not triglycerides, and was independent of age, sex, or time posttransplant. Cumulative cyclosporine dose also correlated with LDL cholesterol but was a much weaker predictor (P = .04). Renlundhls has recently demonstrated that patients withdrawn entirely from corticosteroids have had a significantly lower plasma cholesterol than patients who are unable to be weaned from corticosteroids due to recurrent rejection. Similar results were obtained by TayloP” in patients withdrawn from steroids early posttransplant. However, this beneficial effect of steroid withdrawal on plasma lipids was not demonstrated in the series by Miller,194 where patients were withdrawn at a much later time (mean 8.5 months v 1.2 months) and had been receiving only 5 mg average per day maintenance therapy at the time the steroids were withdrawn. Stamler,“* in a series of 20 heart transplant patients with a mean age of 41 years has suggested that the hyperlipidemia noted was due possibly to the hepatotoxicity resulting from

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cyclosporine therapy. The possible mechanism for a cyclosporine-induced hyperlipidemia was thought to be a toxic effect on the hepatocyte with resultant impaired cellular clearance of LDL by the liver. However, the effect of cyclosporine may be via indirect effects on steroid metabolism,616-617 especially diabetics.616 Harris,616 showed that the total cholesterol and triglycerides decreased significantly when they were converted from cyclosporine- to azathioprine-based immunosuppression in a series of 13 nondiabetic renal transplant patients who were receiving an average of 30 mg prednisone every other day. Keogh603 has shown a strong correlation (r = .90) between hyperlipidemia and obesity, a finding reported by other observers.610s619 The mechanism postulated for the corticosteroidmediated hyperlipidemia is via a weight-related increase in insulin resistance, with subsequent increase in hepatic synthesis of low-density cholesterol and finally triglyceride and LDL cholesterol. Several observations can therefore be made regarding the hyperlipidemia associated with cardiac transplantation: (1) total cholesterol is the most commonly elevated lipid fraction and is due predominantly to increases in the LDL fraction, (2) hyperlipidemia occurs as early as 2 weeks and peaks between 3 to 6 months, but is somewhat variable, and (3) hyperlipidemia may be due to a variety of factors, but most important are obesity and the primary effects of corticosteroids. Several problems exist with interpreting the data available regarding the incidence and type of hyperlipidemia following cardiac transplantation: (1) lack of control of variables such as exercise, diet, and weight gain between the studies reported, (2) a majority of patients were relatively young (mean age 40-44) with a significant predominance of nonischemic etiology,6°1-606and (3) variable thresholds were used to initiate treatment during the course of follow-up. The treatment of hyperlipidemia has varied and there are no controlled randomized trials reported to date comparing the various agents available. However, the WGTC is about to initiate a trial comparing lovastatin with gemfibrozo1.633 Despite initial reports of the rhabdomyolysis and toxicity associated with the use of lovastatin in conjunction with cyclosporine,629-631

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a number of investigators have reported the beneficial effects on hyperlipidemia with reduced dosages.632 Finally, alternate-day steroid use has been suggested to have a favorable effect on lipid levels,612 especially triglycerides, in renal transplant patients. This is not a uniform finding but needs to be evaluated in cardiac transplant recipients. It is unclear whether improved control of plasma lipids will favorably affect subsequent graft coronary disease to the degree that has been noted in nontransplant patients.613@3-6B HEMODYNAMIC

ALTERATIONS

There are a number of posttransplantation complications that can be diagnosed by hemodynamic measurements. The first is pericardial effusion, which occurs following standard cardiac surgery in about 4% to 5% of patients, usually due to bleeding or inflammation (Dressler’s syndrome). Effusions have also been reported by a number of investigators following cardiac transplantation.633-636 Stevenson634 noted bleeding to be the most common cause of pericardial effusion in a large series of cardiac transplant recipients at UCLA, perhaps due to transplantation of a normal-sized heart into an often greatly distended pericardium creating a large potential space for fluid accumulation. However, Hastillo’j3’ and coinvestigators at the University of Virginia have suggested that cyclosporine may play a causal role, as only 1 of 15 transplants receiving azathioprine-based therapy developed a pericardial effusion versus 14 of 29 initially treated with cyclosporine. This has not been verified by other investigators.634.6” A variable, but usually small number of these efhtsions may develop tamponade physiology and require pericardiocentesis. An important observation has been reported by Valantine636 in a series of 189 patients from Stanford. Twelve of the 189 transplant recipients developed significant pericardial effusions, 10 of which occurred within the 1st month posttransplant and 8 of 12 required pericardiocentesis due to tamponade physiology. The pericardial fluid was sterile in seven of the eight patients. However, there was a high correlation between pericardial effusion and allograft rejection. At the time the effusion was found, 5 of 12 patients exhibited moderate acute rejection (re-

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quiring bolus therapy), 3 patients had mild rejection (no therapy), and 4 patients had no histological evidence of rejection. However, all three patients graded as mild rejection showed progression to moderate acute rejection requiring bolus therapy within 7 days. In addition, two of the four patients with no histological evidence of rejection showed moderate rejection on biopsy within 5 days and another exhibited treatable rejection within 14 days. Therefore, in the absence of bleeding in excess of 500 mL634 the development of a significant pericardial effusion within the first month is strongly correlated with cellular or antibody-mediated rejection and several follow-up biopsies are warranted to rule out this phenomenon. Another cyclosporine-associated complication that can occur at various times posttransplant is the development of restrictive physiology in the transplanted heart.637m646 This may be manifest as equalization of diastolic pressures and/or the characteristic dip and plateau appearance on pressure tracings of the ventricle. Volume loading may be required to demonstrate the occult forms of this problem.“’ A form of this restrictive physiology can occur as early as 2 to 3 weeks posttransplantM0-64Z with elevated right heart pressures and diastolic equalization and may be due to either rejection63R or preoperative volume overload that has not resolved. These findings frequently normalize within 1 month posttransplant if due to volume alone. However, Valantine637 has reported the development of a restrictive/constrictive physiology evidenced by a dip and plateau appearance on pressure tracings and Doppler echocardiography but not diastolic equalization in 10 of 64 patients who underwent annual hemodynamic evaluation and Doppler echocardiography at a mean of 5 years posttransplant (range of 1 to 13 years). In addition to characteristic wave forms, there was evidence of impaired systolic function with decreased left ventricular dP/dt (delta pressure/delta time) and stroke volume. Clinically, 8 of these 10 patients with restrictive physiology exhibited some degree of heart failure at the time of the study, with 4 in New York Hospital Association class 3 or 4. Doppler examination showed a decrease in isovolumic relaxation time and pressure half-time, as well as earlier peak mitral valve flow and reduced

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aortic flow, all consistent with impaired systolic and diastolic function. One interesting observation is that the patients who exhibited signs of restrictive physiology had nearly twice as many rejection episodes as those who had no evidence of this physiology (6.7 ), 3.6 rejections per patient). Although there was a trend toward more fibrosis in the endocardial biopsies of those with restrictive physiology, this did not achieve statistical significance nor did other risk factors, such as age of the donor or recipient, cold ischemic time, time posttransplant, or systolic blood pressure. The development of this restrictive physiology may be a consequence of the inflammation associated with rejection, as suggested by Valantine, or perhaps a manifestation of the fibrotic reaction described in most transplanted organs in response to cyclosporine therapy.576 One additional cause of high right atria1 pressures in the first several weeks posttransplant, especially when accompanied by low or normal left atria1 or wedge pressures, is pulmonary hypertension which was present in the recipient.M9 An unconditioned donor right ventricle frequently cannot adapt to this high afterload and can fail to such severity as to require mechanical assistance. The use of prostaglandins in the immediate postoperative period has been of significant benefit in most patients to lower pulmonary artery pressures.6so Intravenous amrinone has also been reported to lower pulmonary pressures.651 One misleading potential finding is a high-normal cardiac index. This is frequently due to severe tricuspid regurgitation with over half of the cardiac output injectate solution being regurgitated back into the right atrium, thereby causing a falsely high flow estimate by the thermodilution catheter. Recently, several investigators have questioned the role of “oversizing” a donor for a patient with high pulmonary artery pressures as this may result in relative restriction.652 Another cause of acute right heart failure is torsion of the pulmonary artery anastomosis.653 Although abnormal hemodynamics and elevations in cardiac chamber pressures have been reported in long-term follow-up,h39-647 Frist,646 reporting on the 5-year follow-up at Stanford, has demonstrated that with the exception of higher aortic left ventricular end diastolic and

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pulmonary artery pressures, cardiac allograft function in cyclosporine-treated patients remains essentially normal and well preserved over the 5-year follow-up. However, one question that has not been resolved is the correlation of the number and severity of episodes of allograft rejection with long-term ventricular function. Although both mitra1654 and tricuspid65S.656valvular competence of varying severity have been reported, they are frequently due to effects of the double-sized atrium created by transplantation. The distorted ventricular geometry often produced by the transplant procedure, with previous operations and scarring of the posterior atria1 surface may independently alter left atria1 geometry, and contribute to mitral insufficiency. Lewe#’ noted moderately severe tricuspid regurgitation to be present within 1 month of transplantation in 14 of 20 transplant patients. Right ventricular volume overload was noted in 13 of 14 of these patients in comparison with none of 6 patients with no tricuspid regurgitation. He found that pulmonary artery systolic pressures greater than 55 mm Hg prior to surgery were highly correlated with the development of significant tricuspid regurgitation posttransplant. In contrast, elevated pulmonary vascular resistance (PVR) pretransplant did not correlate with development of tricuspid regurgitation, but PVR greater than 3 Wood units in the postoperative setting correlated in a positive manner. Tricuspid regurgitation may also be a consequence of the size of the atria1 chamber, right ventricular dysfunction from elevated pulmonary artery pressures, early allograft rejection, or chordal injury from endomyocardial biopsy. This high incidence of tricuspid regurgitation has not been validated in other series.656 COMPLICATIONS

A number of general surgical complications may occur in cardiac transplant recipients,2N-263 due in part to both the increasing age of the average recipient as well as the increasing length of survival posttransplant. The incidence of general surgical complications following cardiac transplantation has ranged from 15% to 30%. Many of these complications including peptic ulcer disease, cholecystitis, diverticulitis, and pancreatitis present within the first 2 to 6

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weeks following transplantation when the doses of corticosteroids are high. As a result, patients are often not diagnosed (having only modest signs of infection/inflammation) until advanced complications have occurred which often require surgical intervention. The largest series reported to date is from the University of Pittsburgh where Steed263 reported that general surgical complications occurred in 40 of 143 patients (28%) undergoing heart, heart/lung, and heart/liver transplantation over a 5 year period. Seventeen of the 40 patients (42%) required surgery, including 10 that required laparotomy. One area of uncertainty is the management of the patient with asymptomatic biliary disease.657 Evidence of cholecystitis preoperatively may warrant diagnostic evaluation to define the need for consideration of elective surgery prior to undergoing transplantation or heightened awareness of symptoms of gallbladder disease referable in the posttransplant period. Finally, there are a number of drug-related side effects/complications that have been reported with each of the immunosuppressive agents currently used. 658The incidence of these complications is variable but often relate to the cumulative dose of each agent. Cyclosporine has been associated with a number of benign often dose-related side effects, such as hirsutism, gingival hyperplasia (which may be related to injection of cyclosporine undiluted into the mouth503), gout,265,659,661 and neurotoxicity.662-672 The manifestations of neurotoxicity include seizures, paresthesia, tremor (which is often a manifestation of high-cyclosporine levels), altered mental status, and central nervous sytem infection264.270 ( et‘th er encephalitis or meningitis). Seizures often occur in younger patients within the first 1 to 2 weeks posttransplant.670-672 Hypomagnesemia is a common finding in these patients673-676who usually have a negative diagnostic work-up and is due to high glomerular filtration rates and increased renal magnesium wasting associated with cyclosporine use. Repletion of magnesium with oral or intravenous therapy is often all that is needed to manage this problem, and antiepileptics such as diphenylhydantoin are usually not required.503 Other neurological side effects of cyclosporine include complaints of decreased mental status, especially

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cortical function. Many of these neurological manifestations will improve with magnesium repletion, and a trial of magnesium is warranted before embarking upon an expensive neurological work-up if these symptoms develop after reduction in cyclosporine dose. Magnesium supplementation may be required for more than 6 to 9 months and may not be correlated with cyclosporine dose or preoperative diuretic use.‘03 An unusually severe depression of mental status, often to the point of coma, has been reported in patients with low serum cholesterol, usually after liver transplantation677 but it may also occur in cardiac transplant recipients. The major side effects of azathioprine are hematologic and gastrointestinal.678-tio The drug is myelotoxic and may result in suppression of all three cell lines in the bone marrow, especially white blood cells. The neutropenia is often somewhat idiosyncratic, occurring early after the initiation of azathioprine therapy, even in low doses. Anemia is typically megaloblastic, is common with chronic administration, and is not usually responsive to B,, or folate administration. Thrombocytopenia is less frequent and of variable severity. In addition, hepatotoxicity may be noted with azathioprine therapy679.68” and is manifest by an elevation in both bilirubin and heptocellular enzymes. Biopsy reflects a cholestatic jaundice. Dose reduction will generally result in improvement of this problem but occasionally necessitates cessation of the drug.

The complications associated with chronic corticosteroid administration are dose related and cumulative.68’3682The incidence of osteoporosis with secondary necrosis of the femoral head varies and may be idiosyncratic and not correlated with total steroid exposure. The use of vitamin D and calcium supplements in this setting has never been evaluated in a controlled trial. Other complications of steroids have been widely reported but are often ameliorated by low-dose or steroid-free regimens. Finally, other less serious complications involving the skinbR3,bX4 and oropharynx685 have been reported. In conclusion, although a number of complications may occur with long-term use of cyclosporine-based immunosuppressive therapy in cardiac transplant recipients, enormous progress has been made in this field in the past decade. A majority of recipients now enjoy a class 1 functional status and a 5year actuarial survival rate that may exceed 7.5%.3 Clearly, cardiac transplantation has become the optimal therapy for end-stage heart failure. The goal of the next decade will be to identify strategies and therapies to minimize these potential complications and identify potentially better ways to guide cyclosporine use and define the minimal effective immunosuppression. ACKNOWLEDGMENT The author is indebted to Mrs. Gloria Skelton secretarial help in the preparation of this manuscript.

for her

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8. Hunt SA: Complications of heart transplantation. Heart Transplant 3:70-74, 1983 9. Hunt SA, Stinson EB: Cardiac transplantation. Annu Rev Med 32:213-220,198l 10. Hastillo A, Hess ML, Lower RR: Cardiac transplantation: Expectation and limitation. Mod Concept Cardiovast Dis 50:13-24, 1981 11. Stinson EB, Dong E, Bieber CP, et al: Cardiac transplantation in man. I. Early rejection. JAMA 207:22332242,1969 12. Greipp RB, Stinson EB, Dong E Jr, et al: Acute rejection of the allografted human heart: Diagnosis and treatment. Ann Thorac Surg 12:113-126,197l 13. Oyer PE, Stinson EB, Bieber CP, et al: Diagnosis and treatment of acute cardiac allograft rejection. Transplant Proc 11:296-303, 1979 14. Oyer PE, Stinson EB, Jamieson SW, et al: One year experience with cyclosporine A in clinical heart transplantation. J Heart Transplant 1:285-290, 1982 15. Copeland JG, Mammana RB, Fuller JK. et al: Heart

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transplantation. Four years experience with conventional immunosuppression. JAMA 251:1563-1566,1984 16. Wallwork J, Cory-Pearc R, English TA: Cyclosporine for cardiac transplantation: U.K. trial. Transplant Proc 15:2559-2566,1983 17. Griffith BP, Hardesty RL, Bahnson HT: Powerful but limited immune suppression for cardiac transplantation with cyclosporine A and low-dose steroid. J Thorac Cardiovast Surg 87:35-42,1984 18. Bolman RM, Elick B, Olivari MT, et al: Improved immunosuppression for heart transplantation. Heart Transplantation 4:315-318,1985 19. Kahan BD: Immunosuppressive therapy with cyclosporine for cardiac transplantation. Circulation 75:40-56, 1987 20. Grattan MT, Moreno-Cabral CE, Stames VA, et al: Eight-year results of cyclosporine-treated patients with cardiac transplants. J Thorac Cardiovasc Surg 99500-509, 1990 21. Marboe CC, Buffaloe A, Fenoglio JJ Jr: Immunologic aspects of rejection. Prog Cardiovasc Dis 32:419-432,199O 22. Krensky AM, Weiss A, Crabtree G, et al: T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med 322:510-517,199O 23. Lower RR, Dong E Jr, Shumway NE: Suppression of rejection crisis in the cardiac homograft. Ann Thorac Surg 1:645,1965 (abstr) 24. Lower RR, Dong E Jr, Glazener FS: Electrocardiogram of dogs with heart homografts. Circulation 33:455-460, 1966 25. Cooper DK, Charles RG, Rose AG, et al: Does the electrocardiogram detect early acute heart rejection? J Heart Transplant 4:546-549,1985 26. Popp RL, Schroeder JS, Stinson EB, et al: Ultrasonic studies for the early detection of acute cardiac rejection. Transplantation 11:543-550,197l 27. Bieber CP, Griepp RB, Oyer PE, et al: Relationship of rabbit ATG serum clearance rate to circulating T-cell level, rejection onset, and survival in cardiac transplantation. Transplant Proc 9:1031-1036,1977 28. Bieber CP, Griepp RB, Oyer PE, et al: Use of rabbit antithymocyte globulin in cardiac transplantation. Relationship of serum clearance rates to clinical outcome. Transplantation 22:478-488,1976 29. Bieber CP, Shumway NE: Cardiac transplantation 1979. Ann Thorac Surg 28:205-207,1979 30. Caves PK, Stinson EB, Billingham ME, et al: Diagnosis of human cardiac allograft rejection by serial cardiac biopsy. J Thorac Cardiovasc Surg 66:461-466,1973 (abstr) 31. Caves PK, Stinson EB, Billingham ME, et al: Serial transvenous biopsy of the transplanted human heart. Improved management of acute rejection episodes. Lancet 821-826,1974 32. Billingham ME: Diagnosis of cardiac rejection by endomyocardial biopsy. J Heart Transplant 1:25-30,198l 33. McAllister HA Jr, Schnee MJ, Frazier OH, et al: A system for grading cardiac allograft rejection. Texas Heart Inst J 13:1-2,1986 34. McAllister HA Jr: Histologic grading of cardiac allograft rejection: A quantitative approach. J Heart Transplant 9:277-281,199O

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35. Kemnitz J, Cohner T, Schaeffers HJ, et al: A classification of cardiac allograft rejection. Am J Surg Path01 7:503-515,1987 36. Hutchins GM: The pathology of heart transplantation, in Baumgartner WA, Reitz BA, Achuff SC (eds): Heart and Heart-Lung Transplantation. Philadelphia, PA, Saunders, 1990, pp 183-210 37. Winters GL, Kendall TJ, Radio SJ, et al: Posttransplant obesity and hyperlipidemia: Major predictors of severity of coronary arteriopathy in failed human heart allografts. J Heart Transplant 9:364-372,199O 38. Billingham ME: Dilemma of variety of histopathologic grading systemsfor acute cardiac allograft rejection by endomyocardial biopsy. J Heart Transplant 9:272-276, 1990 39. Billingham ME: Endomyocardial biopsy interpretation in cyclosporine-treated cardiac recipients. Cardiac Surg 2:641-646,198s 40. Billingham ME: Endomyocardial biopsy detection of acute rejection in cardiac allograft recipients. Heart Vessels 1:86-90,1986 (suppl 1) 41. Billingham ME: Endomyocardial biopsy diagnosis of acute rejection in cardiac allografts. Prog Cardiovasc Dis 33:11-18,199O 42. Sibley RK, Olivari MT, Bolman RM, et al: Endomyocardial biopsy in the cardiac allograft recipient. Ann Surg 203:177-187,1986 43. Carrier M, Pelletier LC: Characteristics and diagnosis of acute rejection after cardiac transplantation. Cardiac Surg 2:631-639,198s 44. Tazelaar HD: Spectrum and diagnosis of myocardial rejection. Cardiol Clin 8:119-140,199O 45. Chomette G, Auriol M, Delcourt A, et al: Human cardiac transplants. Diagnosis of rejection by endomyocardial biopsy. Causes of death (about 30 autopsies). Virchows Arch (Pathol Anat) 407:295-307,1985 46. Kottke-Marchant K, Ratliff NB: Endomyocardial biopsy: Pathologic findings in cardiac transplant recipients. Arch Path01 Lab Med 120:211-244,199O 47. Zerbe TR, Arena V: Diagnostic reliability of endomyocardial biopsy for assessment of cardiac allograft rejection. Hum Path01 19:1307-1314,198s 48. Spiegelhalter DJ, Stovin PG: An analysis of repeated biopsies following cardiac transplantation. Stat Med 2:33, 1983 (abstr) 49. Kemnitz J, Choritz H, Cohnert TR, et al: Predictive implications of bioptic diagnosis in cardiac allografts. J Heart Transplant 8:315-329,1989 50. Miller LW: Treatment of cardiac allograft rejection with intravenous steroids. J Heart Transplant 9:283-287, 1990 51. A report of the Working Group of Transplant Cardiologists. J Heart Transplant 9:61,1990 52. Herskowitz A, Soule LM, Mellits ED, et al: Histologic predictors of acute cardiac rejection in human endomyocardial biopsies: A multivariate analysis. J Am Co11 Cardiol9:802-810,1987 53. Imakita M, Tazelaar HD, Billingham ME: Heart allograft rejection under varying immunosuppressive protocols as evaluated by endomyocardial biopsy. J Heart Transplant 5:279-285,1986 54. Weber T, Kaufman C, Zeevi A, et al: Lymphocyte

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growth from cardiac allograft biopsy specimens with no or minimal cellular infiltrates: Association with subsequent rejection episode. J Heart Transplant 8:233-240,1989 55. Carlquist JF, Hammond EH, Anderson JL: Propagation and characterization of lymphocytes from rejecting human cardiac allografts. J Heart Transplant 7:397-406, 1988 56. Pfeffer PF, Foerster A, Tveter AK, et al: Donorspecific cytotoxic T cells recovered from transvenous biopsies after clinical heart transplantation. Transplant Proc 20:306-307, 1988 57. Weil R III, Clark DR, lwaki Y, et al: Hyperacute rejection of the transplanted human heart. Transplantation 32:71-72,198l 58. Minakuchi J, Takahashi K, Toma H, et al: Removal of preformed antibodies of plasmapheresis prior to kidney transplantation. Transplant Proc 18:1083-1086, 1986 59. O’Connell JB, Renlund DG: Diagnosis and treatment of cardiac allograft rejection, in Thompson ME, Brest AN (eds): CardiacTransplantation. Philadelphia, PA, Davis, 1990, pp 147-162 60. Roy R, Belles-Isles M, Pare M, et al: The importance of serum dithiothreiotol treatment in crossmatching selection of presensitized kidney transplant recipients. Transplantation 50:532-534, 1990 61. Braun WE: Laboratory and clinical management of the highly sensitized organ transplant recipient. Hum lmmunol26:245-260, 1989 62. Ting A: Positive crossmatches-When is it safe to transplant? Transplant lnt 2:2-7,1989 63. O’Connell JB, Renlund DG, Dewitt CW, et al: Cardiac transplantation in sensitized recipients without a prospective crossmatch. J Heart Transplant 7:74A, 1988 (abstr) 64. Lavel J, Kormos RL, Duquesnoy R: Influence of high panel reactive antibody and positive lymphocytotoxic crossmatch on survival after cardiac transplantation. J Heart Transplant 9:56A, 1990 (abstr) 65. Miller LW: Cardiac transplantation as therapy for heart failure. Curr Prob Cardiol (in press, April 1991) 66. Busch GJ, Reynolds ES, Gavinek EG, et al: Human renal allografts. The role of vascular injury in early graft failure. Medicine 50:29-84, 1971 67. Herskowitz A, Soule LM, Ueda K, et al: Arteriolar vasculitis on endomyocardial biopsy: A histologic predictor of poor outcome in cyclosporine-treated heart transplant recipients. J Heart Transplant 6:127-136, 1987 68. Smith SH, Kirklin JK, Geer JC, et al: Arteritis in cardiac rejection after transplantation. Am J Cardiol59:11711173,1987 69. Schuurman HJ, Jambroes G, Borleffs JC, et al: Acute humoral rejection in a heart transplant recipient. Transplant Proc 21:2529-2530,1989 70. Jambroes G, Borleffs JC, Slootweg PJ, et al: Acute humoral rejection after heart transplantation. Transplantation 46:603-605, 1988 71. Hammond EH, Yowell RL, Nunoda S, et al: Vascular (humoral) rejection in heart transplantation: Pathologic observations and clinical implications. J Heart Transplant 8:430-433, 1989 72. Slootweg PJ, Schuurman HJ, Jambroes G: Myocytol-

265 ysis as a result of vascular rejection: biopsy and autopsy findings-A case report. J Heart Transplant 8:450-453,1989 73. Crandall BG, Gilbert EM, Renlund AG, et al: A randomized trial of the immunosuppressive efficacy of vincristine in cardiac transplantation. Transplantation 50:3437,199o 74. Ensley R, Hammond E, Yowell R, et al: Clinical manifestations of vascular rejection in heart transplantation. Symposium and Poster Abstracts of the XIII lnternational Congress of the Transplantation Society, San Francisco, CA, August 1990 75. Zhu LP, Cupps TR, Whalen G, et al: Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells. J Clin Invest 79:1082, 1987 (abstr) 76. Evrard HM, Miller C, Schwartz M, et al: Resistant hepatic allograft rejection successfully treated with Cyclophosphamide and plasmapheresis. Transplantation 50:702720,199O 76a. Jurmann MJ, Wahlers T, Coppola R, et al: Early graft failure after heart transplantation: Management by extracorporeal circulatory assist and retransplantation. J Heart Transplant 8:474-478, 1989 77. Miller LW, Phelan D, Seacord L, et al: Multiparous women--Is routine antibody screening enough in cardiac transplantation? Symposium and Poster Abstracts of the XIII International Congress of the Transplantation Society, San Francisco, CA, August 1990, pp 383A 78. Schroeder T, Weiss M, Smith R, et al: The efficacy of OKT3 in acute vascular rejection. Symposium and Poster Abstracts of the XIII International Congress of the Transplantation Society, San Francisco, CA, August 1990 79. Cerelli J, Brasile, Galouzis T, et al: The vascular endothelial antigen system. Transplantation 39:286-289, 1985 80. Brasile L, Zerbe T, Rabin B, et al: Identification of the antibody to vascular endothelial cells in patients undergoing cardiac transplantation. Transplantation 40:672-675. 1985 81. Trento A, Hardesty RL, Griffith BP, et al: Role of the antibody to vascular endothelial cells in hyperacute rejection in patients undergoing cardiac transplantation. J Thorat Cardiovasc Surg 95:37-41,1988 82. Hsu DT, Spotnitz HM: Echocardiographic diagnosis of cardiac allograft rejection. Prog Cardiovasc Dis 33:149160,199O 82a. Dawkins KD, Oldershaw PJ, Billingham ME, et al: Changes in diastolic function as a noninvasive marker of cardiac allograft rejection. J Heart Transplant 3:286-290, 1984 83. Valantine HA, Fowler MB, Hunt SA, et al: Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute rejection. Circulation 76:V86-V92,1987 (suppl V) 84. Paulsen W, Magid N, Sagar K, et al: Left ventricular function of heart allografts during acute rejection: An echocardiographic assessment. Heart Transplant 4:525-529, 1985 85. Desruennes M, Corcos T, Cabrol C, et al: Doppler echocardiography for the diagnosis of acute cardiac allograft rejection. J Am Co11 Cardiol 12:63-70, 1988

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86. Forster T, McGhie J, Rijsterborgh H, et al: Can we assessthe changes of ventricular filling resulting from acute allograft rejection with Doppler echocardiography? J Heart Transplant 7:430-434,1988 87. Wear K, Schnittger I, Director BA, et al: Ultrasonic characterization of acute cardiac rejection from temporal evolution of echocardiograms. J Heart Transplant 5:425429,1986 (abstr) 88. Johnson DE, Gollub SB, Wilson DB, et al: Systolic anterior motion of the mitral valve as a manifestation of heart transplant rejection. J Heart Transplant 7:289-291, 1988 89. Stevenson LW, Dadourian BJ, Kobashigawa J, et al: Mitral regurgitation after cardiac transplantation. Am J Cardiol60:119-122, 1987 90. Boucek MM, Hodgkin DD, Matthis CM, et al: Accuracy of echocardiographic rejection surveillance in infant cardiac transplantation. J Heart Transplant 9:63A, 1990 (abstr) 91. Kawaguchi A, Mohanakumar T, Lee HM, et al: T-lymphocyte analysis in cardiac allograft recipients treated with cyclosporine. Ann Thorac Surg 42:517-522,1986 92. Mohanakumar T, Hoshinaga K, Wood NL, et al: Enumeration of transferrin-receptor-expressing lymphocytes as a potential marker for rejection in human cardiac transplant recipients. Transplantation 42:691-694,1986 (abstr) 93. Roodman ST, Miller LW, Tsai CC: Role of interleukin-2 receptors in immunologic monitoring following cardiac transplantation. Transplantation 45:1050-1056,1988 94. Smith KA: Interleukin-2: Inception, impact, and implications. Science 240:1169-1176,1988 95. Waldmann TA: The structure, function, and expression of interleukin-2 receptors on normal and malignant lymphocytes. Science 232:727-732,1986 96. Fieguth HG, Haverich A, Hadam M, et al: Correlation of interleukin-2 receptor positive circulating lymphocytes and acute cardiac rejection. Transplant Proc 21:25172518,1989 97. Colvin RB, Preffer FI, Fuller TC, et al: A critical analysis of serum and urine interleukin-2 receptor assay in renal allograft recipients. Transplantation 48:800-805, 1989 98. Young JB, Lloyd KS, Windsor NT, et al: Elevated soluble interleukin-2 receptor levels early after heart transplantation and long-term survival and development of coronary arteriopathy. J Heart Transplant 1990 (in press) 99. Borleffs JC, Jambroes G, Pringer KB: Cytoimmunologic monitoring and endomyocardial biopsies in patients after heart transplantation. J Heart Transplant 5:370, 1986 (abstr) 100. Reichenspurner H, Ertel W, Hammer C, et al: Immunologic monitoring of heart transplant patients under Cyclosporine immunosuppression. Transplant Proc 16: 1251,1984 (abstr) 101. Hanson CA, Bolling SF, Stoolman LM, et al: Cytoimmunologic monitoring and heart transplantation. J Heart Transplant 7:424-429,1988 102. Fieguth HG, et al: Cytoimmunologic monitoring in early and late acute cardiac rejection. J Heart Transplant 5:371,1986 (abstr) 103. Klanke D, Hammer C, Schubel C, et al: Reproduc-

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ibility and reliability of cytoimmunological monitoring (CIM) of heart transplant patients (HTP). Transplantation 21:25122513,1989 104. Keren A, Gillis AM, Freedman RA, et al: Heart transplant rejection monitored by signal-averaged electrocardiography in patients receiving cyclosporine. Circulation 70:1124-1129,1984 (suppl I) 105. Haberl R, Weber M, Reichenspurner H, et al: Frequency analysis of the surface electrocardiogram for recognition of acute rejection after orthotopic cardiac transplantation in man. Circulation 76:101-108,1987 106. Simpson MB: Use of signals in the terminal QRS complex to identify patients with ventricular tachycardia after myocardial infarction. Circulation 64:235-242,198l 107. Denes P, Santorelli P, Howser RG: Quantitative analysis of the high frequency components of the terminal portion of the body QRS in normal subjects and in patients with ventricular tachycardia. Circulation 67:1129-1138,1983 108. Brithar G, Becker R, Cypil L: Noninvasive detection of the late potentials in man-A new marker for ventricular tachycardia. Eur Heart J 109. Warnecke H, Schuler S, Goetze HJ, et al: Noninvasive monitoring of cardiac allograft rejection by intramyocardial electrogram recordings. Circulation 76:72-76, 1986 (suppl III) 110. Muller J, Warnecke H, Schuler S, et al: Continuous remote control of rejection after heart transplantationpresent state or the technique. Symposium and Poster Abstracts of the XIII International Congress of the Transplantation Society, San Francisco, CA, August 1990, p 53 111. Addonizio LJ: Detection of cardiac allograft rejection using radionuclide techniques. Prog Cardiovasc Dis 33:73-83,199O llla. Frist W, Yasuda T, Segall G, et al: Noninvasive detection of human cardiac transplant rejection with indium111 antimyosin (Fab) imaging. Circulation 76:81-85, 1987 (suppl V) 112. Hall TS, Baumgartner WA, Borkon AM, et al: Diagnosis of acute cardiac rejection with antimyosin monoclonal antibody, phosphorous nuclear magnetic resonance imaging, two-dimensional echocardiography, and endocardial biopsy. J Heart Transplant 5:419-424,1986 113. DeNardo D, Scibilia G, Macchiarelli AG, et al: The role of indium-111 antimyosin (Fab) imaging as a noninvasive surveillance method of human heart transplant rejection. J Heart Transplant 8:407-412,1989 114. Eisen HJ, Eisenerg SB, Saffitz JE, et al: Noninvasive detection of rejection of transplanted hearts with indiumIll-labeled lymphocytes. Circulation 75:868-876,1987 115. Revel D, Chapelon C, Mathieu D, et al: Magnetic resonance imaging of human orthotopic heart transplantation: correlation with endomyocardial biopsy. J Heart Transplant 8:139-146,1989 116. Aherne T, Tscholakoff D, Finkbeiner W, et al: Magnetic resonance imaging of cardiac transplants: The evaluation of rejection of cardiac allografts with and without immunosuppression. Circulation 74:145-156,1986 117. Barak JH, Laraia PJ, Bolcher CA, et al: Thallium kinetics in rat cardiac transplant rejection. Transplantation 45:687-692,1988 118. McKillop JH, Goris ML: Thallium-201 myocardial

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