Pulmonary considerations of organ transplantation. Part I.

State of the Art Pulmonary Considerations of Organ Transplantation Part 11 •2

NEIL A. ETTINGER and ELBERT P. TRULOCK Contents

Introduction Liver Transplantation Pretransplant Considerations Hypoxemia Pulmonary Hypertension Liver-Lung Disorders Lung Function Abnormalities Pulmonary Edema Pleural Effusions Malignancy Intraoperative Considerations Stage 1 Stage 2 Stage 3 Pulmonary Embolism Posttransplant Considerations Noninfectious Complications Atelectasis Pleural Effusions ARDS Airway Complications Pulmonary Calcification Infectious Complications Bacterial Pneumonia CMV Pneumonia Pneumocystis Pneumonia Renal Transplantation Pretransplant Considerations Lung Function in Chronic Renal Failure Pulmonary Edema Uremic Pleural Disease Pulmonary Calcification Renal-Pulmonary Syndromes Pulmonary Vascular Disease Tuberculosis Posttransplant Considerations Noninfectious Complications Immediate Postoperative Complications Pulmonary Edema Thromboembolic Disease Posttransplant Malignancies Recurrence of Renal-Pulmonary Syndromes Infectious Complications CMV Pneumonia Bacterial Pneumonia Pneumocystis carinii Pneumonia Fungal Pneumonia Mycobacterial Pneumonia

Introduction

T he last decade has seen unprecedent1386

ed success in organ transplantation. One year survival among recipients of livers, kidneys, hearts, and lungs now reaches 70 to 80% in many transplant centers, largely as a result of improvements in immunosuppressive therapy and refinements in surgical techniques. In 1990, it was estimated that 9,560kidney,2,656liver, 2,085 heart, 262 lung, 50 heart-lung, and 2,200 allogeneic bone marrow transplants were performed in the United States alone (1, 2). Although the l-yr survival statistics are impressive, transplantation of any organ is often followed by a variety of complications that may cause significant morbidity and mortality. Prominent among these complications are pulmonary disorders, which may range from opportunistic pulmonary infections to rejection of a lung allograft. The diagnosis and management of these disorders are often difficult and require specific expertise and insight into those problems that are unique to transplantation. The proliferation of organ transplant programs has also had considerable impact upon the practice of pulmonary medicine. The diagnosis of unexplained pulmonary infiltrates or symptoms, interpretation of abnormal pulmonary function, and assessment of surgical risk have become important parts of the preoperative evaluation of organ transplant candidates. Likewise, the management of pulmonary disease posttransplantation requires a significant amount of consultative time and attention. The return of organ transplant patients to their communities also requires referring physicians to be awareof those issues that are germane to transplantation. The emerging role of the "transplant pulmonologist" warrants reviewof those topics that are relevant to both the pretransplant and the posttransplant pulmonary evaluation. Issues that are important in the evaluation and management of pulmonary disorders in liver,kid-

ney,bone marrow, heart, and heart-lung transplant candidates and recipients are discussed. Special Considerations

The cumulative experience gained from the management of organ transplant recipients has led to a better understanding of the clinical patterns and temporal evolution of a variety of opportunistic infections; however, despite their relative predictability, any type of infection can occur at almost any time in a given recipient. Moreover, rejection of the transplanted organ, particularly the lung, can resemble infection. For these reasons, an early, aggressive approach to the diagnosis of unexplained pulmonary infiltrates is warranted.

Diagnostic Methods Bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) have proven extremely helpful in the diagnosis of infectious complications in organ transplant recipients. BAL has proved useful in the diagnosis of Pneumocystis carinii pneumonia, fungal, and mycobacterial infections (3, 4), whereas TBLB is effective in the diagnosis of lung allograft rejection and CMV pneumonitis (5). BAL and TBLB may be complementary in their ability to diagnose or exclude infectious and noninfectious complications

(Received in original form October 5, 1990, and in revised form February 14, 1991) (This is Part I of three parts; the second part will appear in the next issue of the Review) 1 From the Respiratory and Critical Care Division, Washington University School of Medicine, St. Louis, Missouri. 2 Correspondence and requests for reprints should be addressed to Neil A. Ettinger, M.D., Respiratory and Critical Care Division, Washington University School of Medicine, Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110.

1387

STATE OF THE ART: PULMONARY CONSIDERATIONS OF ORGAN TRANSPLANTATION

(6) following transplantation, and they may obviate the need for open lung biopsy. Also, improved radiologic imaging with computed tomography or magnetic resonance imaging permits better localization and diagnosis of pulmonary lesions (7). The aggressive use of these diagnostic modalities allows earlier diagnosis of pulmonary processes that may favorably impact upon patient outcome. A detailed discussion of these methodologies, however, is beyond the scope of this article. One of the more important diagnostic advances of the last decade has been the development of rapid methods for detecting cytomegalovirus (CMV) infection. The introduction of the shell-vial assay, which utilizes commercially available, monoclonal reagents to detect the presence of immediate early CMV antigens in infected cells, has permitted the diagnosis of CMV infection in samples of tissue or body fluids within 24 and 40 h (8). This technique represents a dramatic improvement over the 2- to 6-wk delay that is typically required for conventional cultures to turn positive.

Cytomegalovirus Injections Other than allograft rejection, the most significant problem facing the organ transplant recipient is cytomegalovirus infection. Referred to as the "troll of transplantation" by Balfour (9), CMV infection is ubiquitous among organ transplant recipients and has been associated with increased susceptibility to bacterial, fungal, and protozoal superinfection; increased risk of chronic rejection; and increased overall mortality (10). CMV seronegative recipients of organs from seropositive donors (primary infection) are at the greatest risk of developing serious CMV disease. Seropositive recipients of organs from seronegative or seropositive donors also have a very high rate of CMV infection (reactivation or reinfection), but fewer patients experience a serious CMV illness. As a result, a number of approaches have been developed to prevent or ameliorate primary CMV infection. Matching of donors and recipients by CMV serologic status has also been advocated in an effort to avoid primary CMV infections (11); however, limited organ availability may preclude this approach. In general, when several patients are reasonable candidates for an available organ, CMV considerations might then be used to match the donor organ with a recipient if the organ allocation program permits. The detection of CMV in lavage fluid

is of uncertain significance, as no method short of biopsy has been shown to unequivocally distinguish pneumonitis from noninvasive infection. Cytologic analysis has proved to be a specific but insensitive marker of tissue invasion, whereas immunoperoxidase staining is sensitive but not specific (12). Recent applications of molecular biologic methods, such as the polymerase chain reaction, offer the ability to detect CMV at earlier stages of infection but do not address the issue of pathogenicity (13). The detection of CMV in lavage fluid should be placed in its proper clinical context. The presence of suspicious symptoms or radiographic or clinical signs should prompt further investigation by either transbronchial or open lung biopsy.

Unanswered Questions For all the improvements and refinements made in the management of organ transplant recipients, many questions remain unanswered. It is unclear whether recipients of different types of organs develop infectious or noninfectious complications with a similar frequency and timing. Also, the effectiveness of treatment and prophylactic strategies may vary between different patient populations. Thus, the experience gained in one transplant population might not alwaysbe applicable to another. For this reason, the infectious and noninfectious pulmonary considerations of each type of organ transplant recipient are reviewed. Liver Transplantation

Since the first orthotopic liver transplant (OLT) was performed by Starzl in 1963, improvements in surgical technique, anesthesia, and immunosuppression have resulted in a l-yr survival rate that approaches or exceeds 70010 (14-18). This ~ figure compares favorably with the less than 30% l-yr survival observed when medical therapy is applied to patients who might otherwise be considered candidates for liver transplantation (15). Accordingly, OLT is now considered an established therapeutic modality for the treatment of end-stage liver disease, and it is no longer considered experimental (16, 18). The list of indications for OLT is long and is outlined in several recent reviews (15, 16, 18). Because both surgical technique and patient survival haveimproved, many previously absolute contraindications to OLT are now considered relative, reflecting the recent success of the procedure as well as the willingness of trans-

plant surgeons to extend the operation to high-risk patients (15). Pretransplant Considerations

The pulmonary evaluation of the liver transplant candidate focuses on the detection of severe arterial hypoxemia and pulmonary hypertension, two pulmonary manifestations of chronic liver disease that may significantly affect the intraoperative or postoperative course. In addition, the cause of unexplained pleural effusions and pulmonary infiltratesshould be identified,

Hypoxemia Arterial hypoxemia of varying severity is present in 30 to 50% of patients with cirrhosis, even with the absence of an underlying cardiopulmonary illness(19, 20). In a recent review from the Mayo clinic, 11% of patients undergoing OLT had a room air arterial Pao, < 70 mm Hg prior to transplantation (21). A variety of mechanisms may be invoked to explain hypoxemia in this setting including aspiration, pleural effusions, diaphragmatic dysfunction, atelectasis, or ascites (21). Hypoxemia, however, may also be related to the underlying liver disorder and, under these circumstances, may be caused by ventilation-perfusion (VA/Q) mismatching or by intrapulmonary vascular dilatations (lPVD) located at the capillary level. Patients can usually be separated into two groups based upon the underlying pathophysiology, severity of hypoxemia, and clinical symptoms (21). Mild Hypoxemia Most patients with hypoxemia and liver disease have mild hypoxemia with few or no pulmonary symptoms or signs. Spirometry, lung volumes, and chest radiographs are usually normal in these patients although measurements of closing volume are often increased. Diminished ventilation of the lung bases with early airway closure may be responsible for the abnormal ventilation-perfusion relationships that are reported in cirrhotic patients (19, 22). Severalhypotheses regarding the mechanisms of mild hypoxemia have been advanced. Hypoxic pulmonary vasoconstriction (HPV) was absent in 9 of 10cirrhotics studied by Daoud and colleagues (23), and failure of this autoregulatory mechanism was postulated as the cause of hypoxemia. Naeije and coworkers (24), however, found that HPV was preserved although reduced in intensity. It appears that abnormal VA/Q relationships are of primary importance in the

1388

pathophysiology of mild hypoxemia, and significant disturbances of regional lung ventilation have been documented in both smoking and nonsmoking cirrhotics (19,25). Recent studies using the multiple inert gas technique confirm that cirrhotics with mild hypoxemia have increased perfusion of lowVA/Q lung units. Rodriguez-Roisin and coworkers (26) linked the abnormal VA/Q matching with the severity of the underlying hepatic disease. Melot and colleagues (27), however, failed to corroborate this observation but found that the characteristic hyperventilation seen in the majority of patients with cirrhosis reduced the impact of VA/Q mismatching on arterial oxygenation. In addition to VA/Q abnormalities, IPVD have also been documented in patients with mild hypoxemia, but the contribution of these vascular changes to mild gas exchange abnormalities is unknown (21). Overall, mild hypoxemia does not appear to result in excessive morbidity during the intraoperative or postoperative period.

Severe Hypoxemia A small number of patients with liverdisease are severelyhypoxemic and have significant respiratory limitation (24). Dyspnea is a prominent symptom; cyanosis, clubbing, orthodeoxia, and exercise desaturation are often present. The chest radiograph frequently demonstrates reticulonodular infiltrates predominantly in the lower lung fields (28, 29). The arterial Pao2 is usually lessthan 60 mm Hg, particularly in the standing position (orthodeoxia), but may partially correct with the administration of 100070 oxygen. This degree of hypoxemia has proved refractory to pharmacologic manipulation with almitrine bismylate (30) and, until recently, was considered an absolute contraindication to OLT (18). Severe hypoxemia in liver disease appears to be caused primarily by IPVD, although direct arteriovenous communications are occasionally seen. Abnormal dilatation of pulmonary capillaries increases diffusion distance and results in inadequate transfer of oxygen from the alveoli to red cells moving through the center of the abnormal vessels(diffusion disequilibrium). Support for this hypothesis includes histopathologic demonstration of these abnormally dilated vessels (31), partial but not complete improvement in the widened alveolar-arterial oxygen gradient with the administration of 100% oxygen(28), and early,systemicappearance of technetium-labeled macroaggregrated albumin during radionuclide

ETTINGER AND TRULOCK

lung scanning (32). In addition, contrastenhanced echocardiography and pulmonary angiography (21) have confirmed both the intrapulmonary location of the shunt and the existence of these abnormal vessels (figure 1). The recommendation that severehypoxemia be considered an absolute contraindication to livertransplantation was based on limited experience with patients who had severe hypoxemia and who required prolonged mechanical ventilation after transplantation. (21, 33). There is evidence, however, that intrapulmonary shunt may reverse after resolution of he-

patic disease or in selected patients following OLT. Silverman and colleagues (20)observed complete reversal of severe hypoxemia, clubbing, and cyanosis in a child who experienced spontaneous resolution of hepatitis; Krumpe and coworkers (34) observed similar findings in a cirrhotic patient with hypoxemia who recovered from hepatic failure. Starzl and colleagues (35) observed a dramatic reduction in calculated shunt fraction within 10days of transplantation in 3 infants with arterial hypoxemia. A recent report by Stoller and coworkers (36) describes complete resolution ofclubbing

Fig. 1. Contrast 2D-echocardiography of a 51-yr-old woman with primary biliary cirrhosis who was considered for OLT. Screening arterial blood gases were 7.42/27/62 on room air. On administration of 100% inspired oxygen, supine Pa02 was 272, standing Pao2 was 224; (A) cardiac anatomy seen from the apical four-chamber view (B) immediately following contrast (saline microbubbles) injection, appearance of contrast is seen in the right atrium and right ventricle, but not in the left-sided chambers, thereby excluding an intracardiac shunt; (C) subsequent appearance of contrast in the left atrium and left ventricle is consistent with the presence of an intrapulmonary shunt.


and hypoxemia in a single patient after OLT and carefully documents normalization of intrapulmonary shunt previously detected by contrast echocardiography and perfusion lung scanning. These findings suggest that intrapulmonary shunt is reversible in certain patients with liver disease, although which patients are likely to improve following transplantation cannot presently be predicted. Recently, Salem and coworkers (37) used a somatostatin analogue to close intrapulmonary shunts in a patient with severe hypoxemia, thereby allowing successful OLT. This pharmacologic approach, if confirmed in larger numbers of patients, warrants further consideration in patients who are otherwise good transplant candidates. The evaluation of candidate with hypoxemia for liver transplantation should include contrast-enhanced echocardiography as well as determination of shunt fraction with the administration of 1000/0 oxygen, particularly in those patients with a Pa02 < 70 mm Hg. Patients who improve with small amounts of supplemental oxygen might reasonably be considered for OLT (21).

Pulmonary Hypertension The development of pulmonary hypertension in patients with liver disease is rare although well recognized (38). The exact prevalence of this clinical syndrome is unknown, but the incidencein autopsy series ranges from 0.25 to 0.73% of patients with cirrhosis, much higher than the incidence expected in the general population (39). Thus, pulmonary hypertension in liver disease appears to be a distinct clinical entity rather than the coincidental occurrence of two different diseases. Portal hypertension nearly always precedes the discovery of pulmonary vascular disease by several years, although rare exceptions have been described (38, 40). At first, the disorder is usually silent with subclinical elevation of pulmonary artery pressures preceding overt, symptomatic disease. The clinical features usually evolveinsidiously, but the onset of symptoms or signs may occasionally be abrupt. Exertional dyspnea is the most common symptom, occurring in all reported cases. Chest pain, syncope, and hemoptysis occur less frequently (39). Physical findings are indicative of pulmonary hypertension or right ventricular dysfunction; the electrocardiogram usually shows evidence of right ventricular hypertrophy or right axis deviation, and the chest radiograph nearly always reveals prominent pulmonary arteries. Although these patients occa-

sionally survive for prolonged periods, fatal hemodynamic decompensation is the rule in the majority (38). Most cases of pulmonary hypertension in liver disease have been reported in patients with cirrhosis; however, hepatic parenchymal disease or failure is not necessary for its development. Rather, the strongest association appears to be with portal hypertension, regardless of its etiology (40, 41). Patients with surgical portacaval shunts appear to be at high risk for the development of this disorder, suggesting that bypassing the liver, either surgicallyor functionally, predisposes patients to the development of this syndrome (40). These observations suggest that humoral mediators that are produced or normally inactivated by the liver may directly injure or constrict the pulmonary vascular tree. The histopathologic features of this syndrome are typical of primary pulmonary vascular disease. Medial hypertrophy, concentric intimal proliferation, and plexogenic arteriopathy involving small pulmonary arteries are the principal findings (40). A recent autopsy series also revealed a high incidence of intravascular thrombosis in association with the plexiform lesions (41). Despite early conclusions to the contrary, thromboembolization does not appear to be an important contributing factor to the development of pulmonary hypertension in the majority of these patients (42, 43). During the pretransplant evaluation, careful attention should be paid to clinicalor electrocardiographic evidence of pulmonary hypertension or right ventricular dysfunction. Abnormal clinical findings or prominence of the pulmonary vas-

Fig. 2. A 35-yr-old man with cryptogenic cirrhosis and portal hypertension who had unsuspected pulmonary hypertension discovered at the time of OLT. Chest radiograph taken immediately prior to transplantation revealed prominent pulmonary arteries (right pulmonary artery diameter = 17 mm) and mild cardiomegaly. Pulmonary artery pressures prior to induction of anesthesia were 55/25 mm Hg (mean = 35 mm Hg). Intraoperative and postoperative course was complicated by severe pulmonary hypertension and required intravenous prostaglandin E2 and nitroglycerin. Patient SUbsequently did 'well and was discharged on postoperative Day 37. Repeat right heart catheterization 1 yr later revealed a reduction in the pulmonary artery pressures to 41/16 (mean = 23) and a decrease in the size of the right pulmonary artery to 13 mm.

1389

culature on the chest radiograph should prompt further study by either Doppler echocardiography or right heart catheterization. The impact of OLT on the natural history of this disorder is not known, although the hemodynamic abnormality clearly results in a more complicated perioperative course. Precedent for successful completion of the surgical procedure exists, with mild reduction of pulmonary artery pressures seen after 1yr of followup (figure 2). The ultimate reversibility of the pulmonary vascular changes in these patients is.unknown and awaits further study.

Liver-Lung Disorders A variety of chronic liver diseases is associated with pulmonary dysfunction, either as a direct manifestation of the underlying disease process or as an indirect consequence of hepatic insufficiency. The effects of portal hypertension and cirrhosis on gas exchange and pulmonary vascular architecture are examples of the indirect consequences of liver injury. Diseases such as primary biliary cirrhosis and chronic active hepatitis, however,are thought to be autoimmune disorders that have both hepatic and pulmonary manifestations (44). These disorders, as well as sclerosing cholangitis, have been associatedwith specific changes in pulmonary pathology and lung function. Primary biliary cirrhosis (PBC) is one of the most common indications for 0 LT. Despite its known association with pulmonaryabnormalities, overt, symptomatic pulmonary disease is uncommon (45, 46). The occurrence of pulmonary disease in PBC may instead be related to its association with Sjogren's syndrome


1390

or scleroderma, two autoimmune disorders which have well-known pulmonary complications and which concur with PBC in up to 50070 and 20% of cases respectively (44, 47). Patients with PBC and Sjogren's syndrome have a high frequency of respiratory complaints, particularly dyspnea and productive cough (47). These symptoms appear to be related to a lymphocytic bronchitis that causes atrophy of bronchial glands and inspissation of secretions. Pulmonary function testing may reveal either obstructive or restrictive ventilatory changes, but a reduction in DLcois the most common abnormality reported (47, 48). More than one lung function abnormality occurs in up to 50070 of patients, particularly those with symptomatic liver disease (48). Interstitial lung disease is rare in patients with PBC, but, when present, may be characterized by parenchymal granulomatous inflammation. Overlap with sarcoidosis is suggested, but current evidence does not support a direct association (49). Based on BAL fluid analysis, 50% of all PBC patients may have a subclinical lymphocytic alveolitis that is not related to the activity of the underlying liver disease (46). Although usually indolent, rapidly-progressive, fatal pulmonary disease is described (45). The combined presentation of scleroderma and PBC has been associated with both a reduction in diffusing capacity and airway obstruction (50). Although interstitial inflammation, fibrosis, and pulmonary vascular disease are observed in scleroderma and are considered characteristic features of this disorder (51), these findings are not well documented in patients with combined scleroderma and PBC. The association between chronic active hepatitis (CAR) and lung disease is weaker than with PBC, but pleural effusions, pleurisy, and pulmonary fibrosis have all been reported. In a review of 35 OLT candidates with CAH, the majority of patients had normal spirometry and lung volumes, but 53 % had diffusing capacities < 80% of predicted (44). Sclerosing cholangitis is associated with bronchitis and bronchiectasis, but these abnormalities may instead be related to coexistent ulcerative colitis (44).

Lung Function Abnormalities Pretransplant assessment of pulmonary function in patients with chronic liver disease usually reveals one or more abnormalities. Although these abnormalities

rarely preclude or contraindicate OLT, they may identify patients with an increased risk of intraoperative and/or postoperative complications. In a review of lung function in 67 0 LT candidates, the most frequent abnormality was a decrease in DLCO, occurring in nearly 60% of all patients with nonmalignant liver disease. However, nearly 80% of the patients with a decreased DLCO were smokers. A variety of spirometric abnormalities, including restrictive and obstructive ventilatory defects, were also found. As expected, obstructive abnormalities were associated with cigarette smoking and restrictive changes with ascites. The type and the frequency of the pulmonary function changes did not appear to be related to the specific underlying liver disorder (52). Ascites also influences pulmonary function and can cause significant respiratory embarrassment. Intraabdominal hydrostatic pressure increases after the accumulation of large amounts of ascites, causing pressure to be exerted from the peritoneal cavity upon the undersurface of the diaphragm. The increase in hydrostatic pressure results in restriction of diaphragmatic excursion and decreased thoracic gas volume despite expansion of the thoracic cage and abdomen (53). Intrapleural pressure also increases, and chest wall compliance decreases (54). These changes increase the work of breathing and (55) predispose the patient with ascites to atelectasis, retained secretions, and pulmonary infections. These complications are particularly common in the immediate postoperative period (56), and the development of pleural effusions in the setting of ascites only magnifies these alterations. Paracentesis results in little change in FRC as removal of ascites causes both diaphragmatic descent and rib cage deflation, changes that have offsetting effects upon FRC (53).

Pulmonary Edema Acute hypoxemic respiratory failure is a common manifestation of acute hepatic insufficiency or decompensated chronic liver disease. The most common cause of respiratory failure in this setting is noncardiogenic pulmonary edema, which has been reported in 37 to 79% of critically ill patients with hepatic failure. Although sepsis is a common predisposing factor (57), some episodes have no identifiable cause and are presumably a direct Of, indirect result of liver failure (44). Neurogenic mechanisms have been implicated because of the frequent association be-

tween respiratory failure and cerebral edema (58). Although the precise mechanisms have not been determined, the impact on survival is clear. In a study by Matuschak and coworkers (57) of 29 patients with end-stage liver failure, no patient with noncardiogenic pulmonary edema survived to transplantation.

Pleural Effusions Pleural fluid accumulation occurs in approximately 5% of patients with cirrhosis and, in the absence of intrinsic cardiopulmonary disease, is generally referred to as hepatic hydrothorax (59). The effusions occur most often on the right side but can involve both hemithoraces; the fluid is a transudate in uncomplicated cases (55). Hepatic hydrothorax occurs most often in the presence of ascites, but effusions may occur in the absence of clinically detectable ascitic fluid. This situation may lead to the erroneous conclusion that the pleural fluid is related to an intrathoracic process (60). Diaphragmatic defects that serve as pleuro-peritoneal communications have been implicated as the cause of these effusions, and the normal fluctuation of intrathoracic pressure with respiration is thought to explain the unidirectional movement of fluid (44). In the absence of clinically detectable ascites, radionuelide scanning with 99mTc-DTPA can confirm peritoneal to pleural transfer of fluid (60). Exclusion of other intrathoracic causes of pleural fluid accumulation (i.e., infection, thromboembolic disease, and metastatic carcinoma) is important in the pretransplant evaluation process, particularly when exudative or hemorrhagic effusions are identified.

Malignancy Investigation of unexplained nodules or intrathoracic adenopathy is important in the pretransplant evaluation because the presence of metastatic hepatocellular carcinoma may exclude the patient from further transplant consideration. The lung is the most common site of spread and pulmonary metastases are found in 23 to 70% of patients with hepatocellular carcinoma at postmortem. However, only 8 to 28% of patients have premortem chest radiographs that suggest the presence of metastatic disease, emphasizing that intrathoracic metastases often go undetected (44). The most common radiographic manifestation is multiple pulmonary nodules, although as many as 25% may have nodules and effusions (61). Ef-

1391


fusions as well as hilar node involvement may be indicative of lymphangitic pulmonary spread. Intraoperative Considerations

A variety of cardiopulmonary changes occur during OLT that may have considerable impact on the intraoperative and early postoperative course. Marked changes in intravascular volume, lung compliance, and cardiac function are consistently described, and these may affect the duration of mechanical ventilation postoperatively. Life-threatening intraoperative embolism of air, thrombus, or tumor fragments have also been reported. OLT is divided into three distinct stages each of which is accompanied by predictable metabolic and hemodynamic changes.

Stage 1 Anesthesia is induced and recipient hepatectomy is performed during the first phase of OLT (62). Bilateral subcostal incisions are utilized but superior extension with a xyphoidectomy or a sternotomy is often required (16). Previous abdominal surgery, particularly a surgical portal shunt procedure, increases the difficulty of this dissection as does the complex venous anatomy commonly found with portal hypertension. Both of these factors can result in extensive intraoperative bleeding, particularly in the setting of a coagulopathy (18). Accordingly, large volumes of blood, plasma, and colloid are usually administered during this stage of the procedure. In patients who have impaired free water excretion, the large volume of infused fluid increases extravascular lung water. Oxygen requirements usually increase during this stage of the operation, and positive end-expiratory pressure is often used to improve gas exchange and to minimize the concentration of inspired oxygen (63). Stage II During the second stage of the procedure, the donor liver is inserted, and the vascular anastamoses are completed. Before 1982,this stage of the operation was performed by cross-clamping the inferior vena cava and portal vein. This approach resulted in decreased venous return, a fall in cardiac output, and frequent systemic hypotension. The introduction of venovenous bypass, whereby blood from the portal vein and inferior vena cava is drained by large bore cannulae through a centrifugal pump into the superior vena cava, has resulted in decreased intraoperative blood loss, improved hemody-

namic stability, and lower morbidity and mortality (64). Despite the use of venovenous bypass, cardiac output and wedge pressures still fall to some degree during this stage, but these changes usually resolve with reperfusion of the liver (62).

Stage III Reperfusion of the donor liver occurs during the third and final stage of OLT. This phase of the procedure is characterized by marked hemodynamic instability with decreased systemic vascular resistance and increased cardiac output (62). Hypotension occurs frequently, and vasopressors are often needed. The most commonly advanced hypothesis for the hemodynamic instability seen during reperfusion is the release of vasoactive substances from the preserved donor liver. Intracardiac filling pressures are elevated early in stage 3, reflecting increased venous return, increased circulating blood volume, or mild left ventricular dysfunction (65, 66). However, measurements ef filling pressure during reperfusion may be misleading as transesophageal echocardiography, performed during stage 3, suggests that a decrease in left ventricular compliance may occur. In addition, right ventricular wall motion abnormalities have also been observed along with intracardiac air and thrombus. These findings suggest that right coronary embolization of air or thrombus could also explain the occurrence of hypotension during stage 3 (65, 66). Pulmonary Embolism Air embolism is common during OLT although there are usually few clinical sequelae (67). The reported frequency of this complication varies and appears to depend on the method used to detect venous air. Life threatening air embolism has been reported within minutes of the institution of veno-venous bypass (68). Improperly secured connections at the portal vein and inferior vena caval cannulae may allow entrainment of ambient air that can be difficult to detect, particularly when opaque, heparin-bonded tubing is used (68, 69). The intraoperative use of mass spectroscopy, transesophageal echocardiography or precordial doppler monitoring may enable detection of venous air before serious complications develop (65, 67, 70). Hemodynamically significant venous air embolism not associated with venovenous bypass has also been reported (71). Treatment of massive air embolism in this setting has been uniformly unsuccessful in all reported cases (68, 71).

Presently, efforts are directed toward improved detection of air as well as improved connections in the veno-venous bypass device. Pulmonary thromboembolism is not mentioned in the recent reviews of the pulmonary complications related to OLT (55, 72, 73) although it is reported (74). Tumor emboli from a primary hepatic malignancy have also been described. Growth of tumor into the hepatic vein or inferior vena cava increases the risk of this complication (75). Postransplant Considerations

The early postoperative course is marked by the development of pleural effusions and atelectasis, both of which may act independently or in concert to prolong mechanical ventilation. Diaphragmatic dysfunction is common but is usually reversible. The adult respiratory distress syndrome (ARDS), although infrequent, is consistently reported and has devastating consequences. Infection is the most important postoperative pulmonary complication, and it is the principal source of morbidity and mortality from pulmonary disease in OLT recipients. Noninfectious Complications

The noninfectious complications that arise after OLT are most commonly a reflection of prolonged general anesthesia, extensive upper abdominal surgery, and massive administration of blood products and colloid (44). These factors are characteristic of major hepatic surgery, which itself is associated with an incidence of pulmonary complications that approaches 25070 (76). In a review of the first 100 OLT recipients at the Mayo clinic, Plevak and colleagues (77) reported that the mean duration of mechanical ventilation was 26 hours (median = 83 h) and that 22070 of patients had diffuse infiltrates either at the initial or at a subsequent intensive care unit admission. Half of these patients had noninfectious etiologies. In addition, 23% of readmissions to the intensive care unit were for respiratory failure.

Atelectasis Atelectasis is common during the immediate postoperative period and is generally attributed to a variety of factors that occur both during and after the transplant procedure. Extensive right upper quadrant dissection along with retraction of the right hemidiaphragm causes diaphragmatic irritation or injury resulting in abnormal diaphragmatic function


1392

that may last for months (56, 72). In addition, decreased lung compliance as a result of intravascular volume expansion, respiratory muscle atrophy caused by poor nutrition, or impaired postoperative mental status may all contribute to inadequate expansion of the lung (63, 77). Pleural effusions, which are nearly universal following OLT, further predispose to the development of atelectasis. In general, aggressive chest physiotherapy is usually sufficient treatment although bronchoscopy may be required in up to 20070 of cases. Prolonged atelectasis, although rare, is also observed (44).

Pleural Effusions Pleural effusions occur in nearly all OLT recipients within the first week of transplantation. Effusions are almost exclusively right-sided in location; they are often large and are nearly always transudative. Left-sided effusions may also occur, but these are lesscommon and of smaller volume (78).The accumulation of pleural fluid may be related to preoperative ascites or to reactive fluid formation as a result of the extensive subdiaphragmatic dissection (77, 78). Hemothorax is rare and is usually observed after procedures known to cause hemorrhage (liver biopsy or open lung biopsy) or during anticoagulation for deep venous thrombosis (72). Empyemas occur infrequently but are consistently cited. Pleural space infections with gram-negative enteric pathogens as well as fungi and protozoa have been described (79, 80). The management of pleural effusions after OLT may be difficult. Most effusions resolve spontaneously within the first several weeks following transplantation. The effusions, however, are occasionally large and can reaccumulate rapidly after drainage. Approximately one-third of effusions require definitive treatment with either thoracentesis or tube thoracostomy (44). These procedures, while reasonable as initial therapeutic approaches, may be associated with an increased risk of bleeding in patients with persistent coagulopathies. The use of a small pigtail catheter appears to be an appropriate and safe method of draining large, recurrent effusions under these circumstances (81).

ARDS ARDS has been reported in 4.5% to 17.5% of 0 LTrecipients and is associated with a mortality that approaches 80% (72, 73, 82). The onset is usually within the first postoperative week, although late occurring episodes (> 2 wk) are

reported (72, 82-84). The etiologic factors that may initiate lung injury after o LT are variable, reflecting the complex medical and surgical setting. Hypotension, hemorrhage, and sepsis occur alone or in combination in many OLT recipients during or after transplantation and may precipitate acute lung injury. Sepsis, however, appears to be the most common cause of ARDS in these patients (72, 83). In a review of 193 patient undergoing OLT by Takaoka and coworkers (82), ARDS was observed in 4.5070 of patients, and sepsis was the precipitating factor in each case. Retransplantation also appears to place the OLT recipient at great risk of developing acute lung injury. ARDS occurred in 21% of patients receiving two or more grafts compared with 2.7% of patients receiving a single graft. Other, more unusual causes of ARDS have also been postulated. Powell-Jackson and coworkers (84) observed two cases of ARDS in 21 OLT recipients and attributed them to the administration of cyclosporine through a central venous catheter. Matuschak and colleagues (57) described rapid improvement in a patient with ARDS and disseminated intravascular coagulation after retransplantation for hepatic rejection and they postulated that rejection may play an etiologic role. Further evidence supporting these observations, however, has not been reported.

Pulmonary Calcification Pulmonary calcification has been described in OLT recipients (56, 72, 85). This complication is often asymptomatic although respiratory failure has been reported. Those patients with symptomatic disease usually develop nonproductive cough and dyspnea within several months of transplantation. Depending upon the severity of the process, lung function testing may be normal or restrictive, and the chest radiograph may reveal focal nodular or alveolar infiltrates that remain stable or slowlyprogress (56). The diagnosis of pulmonary calcification can be made by transbronchial lung biopsy, but 99mTc pyrophosphate bone scanning has proved useful as a noninvasive diagnostic modality in this setting (86). Histologically, fine microcrystals are found in the interstitium or perialveolar space, with occasional intra-alveolar deposits. In the more severe cases, dense calcific deposits are accompanied by interstitial fibrosis (85). The mechanism of pulmonary calcium deposition following OLT is not precisely known, but several risk factors,

such as ARDS or viral pneumonia, have been identified. Patients who developthis complication typically have postoperative renal failure; received large quantities of plasma, blood, and elemental calcium; and have high levels of circulating mid-molecule parathormone (85). In addition, the use of citrate containing blood products may indirectly cause secondary hyperparathyroidism, which may be aggravated by the administration of exogenous elemental calcium. Treatment focuses on the correction of underlying metabolic abnormalities by replacing Vitamin D and keeping exogenous calcium deposition to a minimum. Reversal of respiratory failure using this treatment outline has been reported (85). Infectious Complications

In the largest review from the mid-1970s, Schroter and coworkers (79)reported that the incidence of bacteremia and fungemia in OLT recipients exceeded 70%. Although the standardization of surgical methods and the introduction of more selective immunosuppression has reduced the mortality from infections, the incidence of infection in recent series still approaches or exceeds this figure (80, 8789). Risk factors for post-OLT infection have been identified. Prolonged operative time, prolonged postoperative antibiotic therapy, renal failure, and gastrointestinal or vascular complications are factors that are associated with the development of infection in OLT recipients (87, 88). Bacterial or fungal infections that occur after OLT usually arise from the liver or biliary system itself and are typically caused by aerobic, gram-negative enteric bacteria or Candida (79). Injury to the liver by rejection, vascular insult, or defectivebiliary drainage enhances the penetration of microorganisms into the recipient's blood or peritoneum. Consequently, bacteremia, abdominal abscesses, and peritonitis constitute a significant proportion of infections. The critical period for the development of infection after OLT is the first two months after the procedure. After the first six months, infections are less frequent but may be caused by either bacteria or opportunistic pathogens (80, 88). The recent introduction of selective bowel decontamination appears to have reduced the morbidity and mortality associated with infection and deserves further consideration (87, 88).

Bacterial Pneumonia Bacterial pneumonia is reported in 2 to


1393

TABLE 1 PNEUMONIA FOLLOWING OLT

Study

Year

Schroeter (69) Dummer (80) Jensen (62) Kusne (79) Thompson (63) Colonna t (78) Payat (70)

1976 1983 1983 1988 1988 1988 1989

Causative Pathogens'

n

Patients with Pneumonia

(%)

G (-)

G (+)

CMV

PCP

ASP

CAN

HSV

ANAER

Other

93 24 18 101 46 35 83

40 6 6 14 15 5 14

(43) (25) (33) (14) (33) (14) (17)

15 2 1 11 NR 4 1

1 0 1 5 2 0 3

7 1 4 5 7 1 2

11 0 1 11 NR 0 5

8 2 2 3 NR 0 1

7 0 0 0 NR 0

4 0 1 0 2 0 0

1 1 0 0 NR 0 0

3 (Toxo. Nocardia) 0 0 0 NR 0 2 (Crypto)

0

De/inition 0/ abbreviations: NR = not reported; G (-) = gram negative; G (+) = gram positive; CMV = cytomegalovirus; PCP = Pneumocystis cerini. pneumonia; ASP CAN = Candida albicans; HSV = herpes simplex virus; ANAER = anaerobe; Taxa = Toxoplasma gandii; Crypto = Cryptococcus neoformans . • Multiple pathogens often present. t Used selective bowel decontamination.

25070 of OLT recipients and accounts for 12to 50% of pulmonary infections (44); however, comparison of current published reports with the largest reviewfrom the precyclosporine era reveals a general decline in the incidence of pneumonia, particularly when selective bowel decontamination is used (table 1). The majority of bacterial pneumonias develop in intubated patients and are not usually associated with bacteremia (44). Postoperative atelectasis, aspiration, and prolonged mechanical ventilation are common predisposing factors (90), and gram-negative enteric organisms are the predominant pathogens. Gram-positive organisms, however, are more frequent when selective bowel decontamination is employed (91). Although the overall incidence of pneumonia has decreased, the case fatality rate remained as high as 40% in a recent reviewof infections in 101 OLT recipients (88).

CMV Pneumonia CMV infection is a substantial source of morbidity following OLT and is the most common infection in this patient population (90). The incidence of CMV infection approaches or exceeds 60% in most large series, and invasive or symptomatic disease occurs in 20 to 70% of infected patients (80, 89, 92, 93). CMV pneumonia typically occurs during the fourth to sixth postoperative week although cases have been observed as early as the second week. Fever, malaise, myalgias, and arthralgias often precede the appearance of pneumonitis, and hepatitis is a frequent accompanying feature (80, 88). Coinfection with other opportunistic pathogens, particularly Pneumocystis carinii, is common (72, 94). Augmentation of immunosuppression for treatment of allograft rejection often precedes the onset of CMV-related illness followingOLT.In particular, treat-

= Aspergillus /umigatus;

ment of allograft rejection with OKT3 tive bowel decontamination all appear to has been associated with a high incidence have contributed to the observed decline of disseminated disease in patients at risk in incidence (88, 99). The majority of for primary infection. The same has not fungal pneumonias occur within the first been observed in OLT recipients at risk month oftransplantation and are usualfor reactivation infection (93). Although ly caused by Candida species or Asperthe association between OKT3 therapy gillus. Disseminated infection with these and CMV disease appears strong, it is organisms are associated with mortality not statistically significant and warrants rates in the range of 70 to 100% (44). further study with larger numbers of paPneumocystis Pneumonia tients (88, 94). Ganciclovir appears to be effective for Pneumocystiscariniipneumonia (PCP) the treatment of CMV pneumonia after usually occurs three to five months after OLT. Reversal of clinical, biochemical, OLT, but episodes occurring within the and radiographic abnormalities soon af- first few weeks of transplantation have ter institution of therapy is common, and also been described. The radiographic complete clearing of virus occurs in 75 presentation may be atypical in these to 100% of patients. The most common cases, with focal instead of diffuse inadverse effect is reversible neutropenia, filtrates (88). Coinfection with CMV is and the incidence of relapse is low. Suc- common and is associated with particucessful treatment of patients requiring larly high mortality. Prophylaxis with mechanical ventilation is also described trimethoprim-sulfamethoxazole (TMP(88, 94-96). The efficacy of the combined SMX) has not been studied in a ranuse of ganciclovir- and CMV-specificim- domized, controlled manner in OLT munoglobulin in the treatment of CMV recipients; however, its effectiveness pneumonia has not been established in among other organ transplant recipients recommends its use after OLT. OLT recipients. The use of passive immunization with Renal Transplantation CMV-specific immunoglobulin has not reduced the incidence of primary CMV . Both patient and renal allograft survival infection after OLT. Its role in prevent- have improved over the past decade and ing viral dissemination or ameliorating transplantation compares quite favorably the severity of CMV disease is also un- to dialysis as a therapeutic modality for certain. Conflicting conclusions were end stage renal disease (l00, 101). Over reached by two studies that addressed 95% of recipients are still alive at 1 yr, these issues (97, 98). and graft survival exceeds 70% for cadaver organs and 90% for living related Fungal Pneumonia organs (loo). The pulmonary considerations of renal A 1983 report by Dummer and coworkers (89) observed a 42% incidence of in- transplantation encompass a variety of vasive fungal infections after OLl'; how- infectious and noninfectious disorders. ever, more recent observations suggest a Unlike liver transplantation in which the marked decrease in the frequency of in- surgical procedure itself predisposes vasive fungal disease (80, 99). Improve- the patient to pulmonary complications, ments in surgical technique, decreased to- the intraoperative pulmonary consideratal operative time, better regulation of tions of renal transplantation are relativeimmunosuppression, and the use of selec- ly fewand primarily related to anesthesia.


1394

Pretransplant Considerations

Renal transplantation is often performed without first obtaining preoperative pulmonary evaluation. The lower abdominallocation of the incision as well as the elective nature of the surgery results in a comparatively low incidence of perioperative pulmonary problems (102). Renal failure, however, may produce alterations in gas exchange and lung volumes, and the lung may be involved in a number of systemic disorders that affect the kidney.

Lung Function in Chronic Renal Failure Uremia is associated with a reduction in diffusing capacity that is not readily attributable to other factors such as anemia, decreased lung volumes, elevated lung water, or cigarette smoking (103). The reduction in OLeo appears to be related to a decrease in the membrane component of diffusion, and it often persists after renal transplantation (104). The degree of reduction may be directly proportional to the severity of renal insufficiency. In practical terms, however, the diffusion abnormality does not usually cause hypoxemia. If impaired oxygenation is found, other causes of hypoxemia should be sought. Restrictive ventilatory changes may also occur as a result of increased lung water, pulmonary calcification, or interstitial pulmonary fibrosis. Interstitial fibrosis is found in nearly 50070 of chronic hemodialysis patients at autopsy and best explains the reduction in lung volumes and OLeo. The stimulus for fibrosis in this setting is unknown but may be related to chronic fluctuations in interstitial fluid or to recurrent episodes of subclinical pulmonary hemorrhage during dialysis (104, 105).

Pulmonary Edema Uremic pulmonary edema has remained controversial since the early descriptions of the disorder. Occurring in patients with acute or chronic uremia, it has been reported in as many as 60% of uremic patients at the time of death (106). Early reports described remarkably similar clinical, radiographic, and histopathologic features, which supported the hypothesis that the disorder was a direct result of uremia. Dyspnea and mild hemoptysis were prominent symptoms, and the presence of perihilar infiltrates was pathognomonic and portended a poor prognosis (107). Early histopathologic studies of uremic pulmonary edema revealed diffusely

indurated lungs filled with protein rich edema fluid, hyaline membranes, and small amounts of alveolar hemorrhage. Occasional infiltration of the alveolar septae with mononuclear cells supported the hypothesis that the disorder was an immunologic complication of uremia (106, 108). Although these findings were nonspecific, they did suggest that hypervolemia, left ventricular failure, or abnormal pulmonary capillary permeability could playa role (107, 109). The relative contributions of the heart and lungs to uremic pulmonary edema are unknown. The clinical and radiographic features are indistinguishable from those of hypervolemia or congestive heart failure, and resolution is clearly documented after reduction of intravascular volume (108, 109). Cardiac disorders are common in end-stage renal disease, and a variety of factors such as anemia, hypervolemia, surgical arteriovenous shunts, hypertension, and ischemic heart disease may adversely affect left ventricular function (110, 111). The existence of a specific uremic cardiomyopathy is also supported by the high incidence of left ventricular dysfunction in patients with uremia that is not explained by other factors and that may be reversed following hemodialysis or renal transplantation (111-115). Recent evidence has also suggested that the severity of left ventricular dysfunction may parallel the degree of renal insufficiency (115). Although cardiac factors may be necessary for the development of uremic pulmonary edema, experimental evidence suggests that increases in both pulmonary capillary and epithelial permeability also occur. This conclusion is supported by studies demonstrating increased sodium permeability across the alveolarcapillary membrane in dialysis patients with uremic edema and increased clearance of 99ffiTc-OTPA that is reversed by hemodialysis (116, 117). The mechanism of uremic pulmonary edema appears to be multifactorial, involving both cardiac and pulmonary mechanisms.

Uremic Pleural Disease Pleural effusions are common in patients on chronic hemodialysis and are usually attributed to interdialysis hypervolemia or congestive heart failure (118). Inflammatory pleural disease, however, may also occur and cause confusion regarding the etiology of pleural effusions found on the pretransplant chest radiograph. Fibrinous pleuritis is found in 20 to 39% of uremic patients at autopsy (105, 106), and its association with pleural fric-

tion rubs, exudative effusions, and pleuritic chest pain has led to the use of the descriptive term, uremic pleuritis (119). Pleuritis is now a well-recognized complication of uremia, and its incidence is probably underestimated (120). Pleural inflammation occurs even in well-dialyzed patients and is not related to the duration of dialysis, the interdialysis period, or the magnitude of the elevation of the blood urea nitrogen (119, 120). The clinical features are nonspecific. Pleural friction rubs are frequent, are usually transient, and may be associated with pleuritic chest pain. Effusions may involve one or both hemithoraces, tend to be moderately large in size, and are often hemorrhagic. The pleural fluid is usually exudative and lymphocytic although the protein content may be diluted in patients on peritoneal dialysis (119-121). Pleural biopsy is nonspecific and typically reveals an organized fibrinous exudate or granulation tissue (120). The high frequency of hemorrhagic pleural fluid may be explained by the presence of abundant granulation tissue in the pleural space, the intrinsic coagulation defect of uremia, or the use of heparin during hemodialysis (118, 120). Uremiceffusions often disappear spontaneously within several weeks of their appearance (120). Intensification of dialysis will not usually speed resolution but may provide symptomatic relief (121). Fibrothorax and empyema may complicate these effusions (118, 121-123), and decortication has been required in patients with progressive pleural fibrosis. Restrictive ventilatory changes often accompany the development of significant fibrotic pleural disease. The pretransplant evaluation of pleural effusions should exclude other disease entities that may cause significant morbidity, particularly tuberculosis, empyema, pulmonary infarction, and malignancy (120). If hypervolemia is suspected, aggressive dialysis with extra fluid removal may resolve the issue. If not, pleural fluid and tissue should be obtained for histologic and cytologicexamination as well as culture. Thromboembolic disease, although rare (124), should be ruled out, and lung function testing should be performed both for diagnostic purposes and to provide a baseline for future follow-up.

Pulmonary Calcification Metastatic calcification is a well-known complication of chronic renal failure and may involveboth visceral and nonvisceral sites (124). Although the lung is the most


commonly affected organ, pulmonary involvement is often clinically and radi ographically silent. In a prospective stud y by Conger and coworkers (125) of 31 chronically hemodialyzed patients, 60070 of patients who died during follow-up had pulmonary calcification at autopsy. Radiographic changes werepresent in only one patient and no patient had respiratory symptoms during life. Symptomatic patients fare worse, however. Seven of 13 symptomatic patients reviewed by Justrabo and coworkers (124) ultimately died of respiratory failure, but these cases appear to represent the extreme in the spectrum of this disorder (124-126). Pulmonary calcification is not related to the patients' age, underlying renal disease, or the duration of dialysis (125). A variety of mechanisms have been proposed, including elevation of parathyroid hormone and/or increases in the Ca-P04 product above the solubility constant for these ions (125, 127). The phenomenon is best explained by calciphylaxis, a process whereby soft tissues respond to a variety of chemical sensitizers with deposition of calcium. Pulmonary calcification has also been observed following renal transplantation, although these patients almost uniformly have experienced a period of graft failure prior to significant calcium deposition (124,

1395

Fig. 3. A 47-yr-old patient with endstage renal disease. (A) The patient presented with low-grade fever and biapical pulmonary infiltrates. Antituberculous therapy was started , but transbronchial lung biopsy subsequentlyconfirmed pulmonary calcification . (B) The patient subsequently developed progressive metastatic calcificat ion in the chest as well as soft tissues over the ensuing 18 months.

126, 127).

The radiographic pattern of pulmonary calcification is variable. Both diffuse and localized infiltrates are described and the calcific nature of the infiltrates may not be recognized (figure 3). The individual opacities are usually less than 2 mm in diameter, but larger nodular infiltrates have also been reported. The most characteristic radiographic feature is the unchanging nature of the infiltrates over time (128). Pulmonary function testing is often normal although restrictive changes or a reduction in DLeo may occur. Changes in lung function may parallel the severityof the histologic process with reductions in lung volumes and Pao, occurring in patients with the greatest degree of fibrosis. These observations suggest that it is the fibrotic response and not the calcium itself that accounts for abnormal respiratory function (125). The diagnosis of pulmonary calcification may be suggested by 99mTc_DPTA scanning or by density measurements with computed tomography (129, 130). The sensitivity and specificity of radionuclide scanning in detecting this process is controversial, and it should not be the sole method of diagnosis, partie-

ularly when fever is present (127). Treatment is often unsatisfactory. Spontaneous resolution is occasionally observed, and reduction of vitamin D and/ or calcium intake has been successful in a fewpatients (127, 129,131). Renal transplantation has been suggested as a therapeutic modality; however, acute progression of prexisting pulmonary calcification has also been observed following transplantation (124, 132). Pulmonary Vascular Disease A high incidence of pulmonary atherosclerosis is observed among dialysis patients at post mortem. These findings suggest chronic elevations of pulmonary artery pressures during life and probably reflect the numerous pulmonary in-

suIts that may occur as a result of endstage renal disease or hemodialysis (105). Presently, there is no evidence to suggest that primary pulmonary vascular disease is associated with uremia or chronic hemodialysis. TUberculosis Tuberculosis occurs more frequently in patients with chronic renal failure than in the general population and should be considered when evaluating pulmonary disease in patients before renal transplantation. The incidence of active infection ranged from 3.7 to 6.0070 of patients followedlongitudinally while on dialysis, an infection rate that is 12 to 15 times higher than normal (133, 134). These figures, however, may reflect some geographic

1396

bias or high background rates of infec- up to 10% (141). Recent evidence suggests that the presence of anti-GBM alone is tions in the populations studied. Heightened susceptibility to mycobac- not sufficient to cause alveolar hemorterial infection is most likely related to rhage and that some additional pulmoimpaired cell-mediated immunity, a well- nary insult is required. Cigarette smoking known consequence of the uremic state and upper respiratory infections are well(135). Numerous studies have document- recognized predisposing factors (139). In ed abnormal lymphocyte responsiveness addition, high inspired oxygen concenand have shown that impaired lympho- tration is an aggravating factor and cyte function may be transmitted in vitro should be avoided if the clinical status by uremic serum and reversed by dialy- permits. The impact of Goodpasture's syndrome sis. These functional abnormalities improve in stable patients on long-term on the lung is variable. Pulmonary inhemodialysis. The time of greatest im- volvement ranges from mild hemoptysis munologic impairment appears to be to fulminant alveolar hemorrhage with from several months prior to 6 months respiratory failure. Hemoptysis is comafter the institution of dialysis. This mon and occurs in nearly all patients at interval coincides with the period of some point in the course of their illness; greatest risk for developing active tuber- however, pulmonary symptoms may be completely absent and the diagnosis sugculosis (134). The clinical features of tuberculosis in gested by an otherwise inexplicable fall in hemoglobin, by the presence of flucend-stage renal disease are nonspecific. Prolonged fever, anorexia, and weight tuating pulmonary infiltrates or by an inloss are common. The chest radiograph crease in DLco above baseline (136, 142). may show infiltrates, effusions, or ade- Renal biopsy is usually performed for dinopathy in a variety of patterns and com- agnosis because demonstration of antibinations and may not be suggestive of GBM deposition is more consistent in remycobacterial disease. Tuberculin skin nal tissue than in the lung (141). Antitesting may be misleading as a high fre- GBM deposition, however, has been quency of false negative results have been demonstrated in both open lung and observed. In general, the diagnosis may transbronchial biopsy specimens (139). Treatment ofGoodpasture's syndrome be difficult to make as the clinical findings are similar to those commonly seen is directed toward removal of circulating in many chronically ill patients on long- anti-GBM antibody by plasmapheresis and by suppression of further antibody term hemodialysis (133, 134). If active mycobacterial disease is dis- production with steroids and cytotoxic agents. covered, treatment should be completed, if possible, prior to transplantation. StanIntervention before development of olidard therapy with unmodified doses of guric renal failure is associated with exisoniazid or rifampin or short-course cellent results; treatment failures occur therapy with modified doses of pyrizina- predominantly in patients whose serum mide Or ethambutol may be used (134). creatinines exceed 7 mg/dL The pulmonary lesion appears to be more responsive Renal-Pulmonary Syndromes to therapeutic intervention than the reSuccessful transplantation of renal al- nal insult; over 90% of pulmonary lelografts into patients with pulmonary sions, but only 40% of renal lesions immanifestations of either Goodpasture's prove with therapy (139). syndrome or Wegener's granulomatosis Renal transplantation is effective theris well documented (136-138). The pul- apy for renal failure that develops as a monary evaluation of these patients must result of Goodpasture's syndrome. Beconsider the impact of these disorders on cause the risk of recurrence is higher both lung function and surgical risk. when anti-GBM antibody is present, transplantation is usually deferred 4 to 6 months after the anti-GBM antibody Goodpasture's Syndrome titer is reduced to very low levels or is Goodpasture's syndrome is a rare cause undetectable (137, 143). of chronic renal insufficiency (139). The diagnostic triad of glomerulonephritis, Wegener's Granulomatosis intraalveolar hemorrhage, and antibody directed toward glomerular basement The lung is the most commonly affected membrane (anti-GBM) is useful, but all organ in Wegener's granulomatosis, with of these findings are not consistently over 90% of patients having eitherrapresent (140). Isolated renal involvement diographic or histologic evidence of puloccurs in 20 to 40070 of patients and ex- monary involvement. The disease is charclusive pulmonary involvement occurs in acterized by a necrotizing granulomatous

ETTiNGER AND TRUL.OCK

vasculitis involving both the upper and lower respiratory tract and the kidneys. Limited involvement of the lungs is also described (144). Pulmonary involvement typically precedesthe onset of renal disease and symptoms referable to the sinuses and upper airway predominate. Unlike Goodpasture's syndrome, hemoptysis is rare, and massive pulmonary hemorrhage is unusual. Constitutional symptoms, however, are often prominent and atypical pulmonary features, such as endobronchial involvement and subglottic stenosis, may also occur (145). The impact of this disorder on lung function is variable. A significant percentage of patients have obstructive physiology, but the majority have normal pulmonary function (146). Multiple, bilateral nodular infiltrates are the most common radiographic findings, but diffuse infiltrates, solitary nodules, and pleural effusions are also observed. Cavitation occurs frequently within the pulmonary nodules, but this finding is often not apparent on the plain chest radiograph. The diagnosis of Wegener's granulomatosis is usually made by biopsy of upper airway lesions or by open lung biopsy. The presence of antineutrophil cytoplasmic antibodies in the serum is specific but not sensitive for the diagnosis of this disorder (139). Renal transplantation in patients with Wegener's granulomatosis is often successful, particularly in patients with inactive or controlled disease (147). Its effectivenessin patients with active disease is not well documented (138). Posttransplant Considerations

An original report of "transplant pneumonia" by Rifkind and colleagues (148) in 1964 described a pulmonary disorder characterized by fever, pulmonary infiltrates, and hypoxemia that developed in the setting of renal allograft rejection. In the absence of a clear infectious etiology, they and others proposed that these episodes were caused by immunologic cross-reactivitybetween the lung and kidney. Subsequently, Uranga and coworkers correctly observed that the most likely etiology was pulmonary edema and suggested instead that a variety of causes of transplant pneumonia are possible (149). Based on three major reviews of over 855 patients (150-152), pulmonary complications occur in 18 to 24% of renal allograft recipients. Furthermore, Ramsey and coworkers (150) observed that 50% of these complications directly contributed to the patient's death and that 50% of all fatalities were directly related


to a pulmonary process. Transplant pneumonia encompasses a broad range of infectious and noninfectious processes, the majority of which occur early in the posttransplant period. If identified early, a significant reduction in mortality may be achieved (150). Noninfectious Complications

Approximately 30 to 40010 of pulmonary complications after renal transplantation are noninfectious in nature. However, these complications are difficult to distinguish from infection. They are frequently accompanied by fever and pulmonary infiltrates, and therefore, are often not considered until infectious etiologies are excluded. Pulmonary complications that develop in the immediate postoperative period are usually related to underlying lung disease or to complications of anesthesia. Pulmonary edema and thromboembolic disease are examples of noninfectious pulmonary complications that occur early and often go unrecognized during the initial evaluation. Transplant-related malignancies and recurrence of renal-pulmonary disorders, although rare, are necessary considerations.

Immediate Postoperative Complications The vast majority of renal allograft recipients are extubated in the operating room at the end of general anesthesia. A small proportion require ventilatory support because of the prolonged effects of muscle relaxants that are seen in uremic surgical patients (102); however, the use of newer anesthetic agents that are not metabolized or excreted by the kidneys has reduced the incidence of this problem. In a review of over 500 consecutive renal transplants, Heino and colleagues (102)observed that the incidence of pneumonia within the first postoperative week was 2.2%, similar to that observed in other general surgical patients. The incidence of postoperative atelectasis approached 25% and was only marginally related to prolonged need for ventilatory assistance. In general, the early postoperative course is uneventful from the pulmonary perspective, except in patients with underlying obstructive lung disease that may otherwise be managed in the usual fashion. Pulmonary Edema The most frequent noninfectious pulmonary complication in the renal allograft recipient is pulmonary edema (150-152). Unlike pulmonary edema that occurs in

1397

the setting of cardiac decompensation or marked decline in the frequency of this ischemia, the majority of these patients complication, largely as a result of imhave normal or marginally impaired left proved surgical technique and earlier ventricular function. Impaired salt and postoperative mobilization (156). water excretion, which is common periThe incidence of deep venous thromoperatively (149), or progressive renal bosis after renal transplantation is greater dysfunction associated with allograft re- than in age-matched patients undergojection are the usual physiologic mecha- ing other types of major operations (156). nisms (150-152). Intracardiac filling pres- Manipulation of the pelvic veins during sures (PaOP) are typically high and the surgical procedure and the use of the patient usually responds to diuresis, high-dose steroids for treatment of alhemodialysis, or augmentation of im- lograft rejection may be significant munosuppression (151-153). Also, non- predisposing factors (150, 157).The types cardiogenic pulmonary edema following of immunosuppressive agents used may the use of antilymphocyte globulin may also be important. Brunkwall and cobe a problem during treatment of early workers (156) observed a striking degraft rejection (154). crease in the incidence of deep venous Pulmonary edema usually develops thrombosis (24.1 to 9.3%) in patients within the first month following renal treated with cyclosporine and low-dose transplantation. Those episodes related prednisone versus those treated with azato early graft dysfunction usually occur thioprine and prednisone. It is not clear within the first few days after surgery, if this difference is attributable to a whereas those related to rejection may smoother postoperative course in paoccur at any point after transplantation. tients treated with cyclosporine, The clinical presentation often resembles The clinical presentation of throminfection; fever, dyspnea, and diffuse pul- boembolic disease following renal transmonary infiltrates are typical manifesta- plantation is often atypical. A minority tions. The presence of fever is most like- of patients complain of pleuritic pain, ly related to allograft rejection and is a dyspnea, or cough and less than 50% manifestation of the immunologic re- have obvious thrombophlebitis (150,151). sponse directed to the transplanted kid- The majority of emboli appear in the first ney. Weight gain, elevated serum creati- few weeks after transplant, although nine, cardiomegaly, and diastolic hyper- cases occurring months to years after surtension are common clinical findings that gery are described. The source of clot may also help distinguish this process varies, with thromboemboli arising from the lower extremities, the inferior vena from infection (150). Although the majority of patients re- cava, or the iliac vein-renal vein anastaspond to therapy aimed at correcting mosis (151, 152). A syndrome consisting hypervolemia or suppressing graft rejec- of fever, declining renal function, baction, mortality from pulmonary edema teriuria, thrombophlebitis, and pain over may be significant, particularly when the the renal allograft was observed in two diagnosis is delayed or superimposed in- patients in Simmons' study (151). In fection develops. In Ramsey's review of general, this diagnosis should be consid227 patients, 50% of those with pulmo- eredin renal transplant patients with unnary edema died of pulmonary superin- explained effusions, pulmonary nodules, , or peripheral lung infiltrates (157). fection (150). Thromboembolism following renal transplantation was formerly associated Thromboembolic Disease with an extremely high mortality, largeAlthough the incidence of pulmonary ly as a result of superinfection developthromboembolism is markedly reduced ing in areas of infarcted lung. In the rein uremic patients (155), renal transplan- port by Ramsey and coworkers (150) 8 tation clearly reestablishes the risk of this of 9 patients with pulmonary emboli died complication. In Ramsey's review of 227 as a result of pulmonary superinfection. patients, thromboembolic disease was the In uncomplicated cases, however, antimost frequent noninfectious pulmonary coagulation is usually effective (151). Vecomplication, occurring in 60% of pa- na caval filters are recommended when tients with a noninfectious pulmonary appropriate and are not generally asprocess (150)!Similarly, observations by sociated with injury to the allograft as Simmons and coworkers (151) showed long as vena caval potency is maintained that 16% of all pulmonary complications (158). in his series were a result of pulmonary emboli. Although these early reports Posttransplant Malignancies document a relatively high incidence, contemporary experience has shown a Pulmonary malignancies are among the


1398

more unusual diagnostic possibilities when considering the cause of pulmonary infiltrates in the renal transplant recipient. A variety of tumors, however, have been observed in these patients, and they should be considered when the radiographic features and the rate of progression of a pulmonary process are thought to be atypical for infection. Lymphoma, Kaposi's sarcoma, and metastatic renal-cell carcinoma have all been described.

Lymphoma Lymphomas are the most common posttransplant malignancy after exclusion of skin and cervical cancers, and they are frequently described in renal transplant recipients. They account for 26% of tumors reported to the Cincinnati Transplant Thmor Registry (CTTR) prior to the introduction of cyclosporineand 810,10 of those reported after the drug's introduction into clinical practice (159). They also occurred in 2.50,10 of renal transplant recipients reported by Starzl and co-workers (160). The tumors are typically B-cell non-Hodgkin's lymphomas and have a high incidence of extranodal involvement and dissemination (161, 162). A number of pathogenetic mechanisms have been proposed to explain the high frequency of these tumors in the transplant population. Chronic allogeneic stimulation by the allograft, Epstein-Barr virus (EBV)infection, and the high intensity of immunosuppression have all been invoked (161-163). There is clear evidence supporting a role for EBV in the genesis of some of these tumors (162). No single immunosuppressive agent can be blamed, although they have been observed to occur earlier and more frequently with cyclosporine. Pulmonary involvement with transplant lymphomas is well documented although unusual (159-164). Gastrointestinal presentations or a mononucleosistype syndrome are the predominant clinical features in the majority of patients. When the lung is involved,focal, nodular infiltrates are the most common radiographic pattern. Lung involvement may be subradiographic, however,and detected only at autopsy. Treatment is controversial and depends upon the clonal nature of the tumor. High dose, intravenous acyclovir or alpha interferon have met with success in some subsets of patients; however, reduction or discontinuation of immunosuppression is usually advocated, given the poor prognosis of these tumors (159, 160).

Kaposi's Sarcoma The incidence of Kaposi's sarcoma (KS) in the renal transplant population is estimated to be increased 400- to 500-fold over the general population, and it may affect as many as 4% of renal transplant patients of Mediterranean or Jewish ancestry (165). The behavior of this tumor in the renal transplant recipient is more aggressive, with nearly half of patients having visceral organ involvement (166). The natural history is similar to Kaposi's sarcoma occurring in patients with acquired immunodeficiency syndrome (AIDS) (167). Pulmonary involvementwith KSis rare in the renal transplant patient (168-170). Cough, dyspnea, and low-grade fever are common clinical features, and isolated pleural effusions, nodules, and diffuse reticulonodular infiltrates are described. Pleural fluid, when present, is often serosanguinous or hemorrhagic, and pleural biopsy is usually unrevealing. Restrictive ventilatory changes and mild hypoxemia have been reported in patients with diffuse involvement. Although open lung biopsy is often required, successful diagnosis has been made by transbronchial biopsy or by biopsy of endobronchial tumor (169, 170). Discontinuation of immunosuppression has resulted in complete resolution of pulmonary KS within several months, even in patients with extensive disease (170). Although a reduction in immunosuppression may be effective in localized disease, visceral involvement should be considered sufficiently life threatening to consider complete discontinuation ofimmunosuppressive drugs. Chemotherapy, radiotherapy, and surgical excision have met with mixed results. Metastatic Tumors In general, neoplasms that commonly occur in the general population, such as those derived from lung, colon, or breast, do not occur more frequently in transplant recipients (161). Occult renal-cell carcinoma, however, has been documented in 6.5% of chronically dialyzed patients at autopsy (105), underscoring the potential for transplanting a kidney into a patient who has an underlying malignancy (figure 4). Over 90 cases have been documented where a donor organ bearing malignant cells has been transplanted into. a renal transplant recipient. Forty-one percent of these patients subsequently developed malignancies, the majority of which were metastatic. In one-third of these patients, the tumor was a primary renal tumor

unknowingly inserted into a recipient. The majority of patients died although several patients had dramatic resolution of metastatic disease after discontinuation of immunosuppression and removal of the allograft (161).

Recurrence of Renal-Pulmonary Syndromes Results of renal transplantation in patients with Goodpasture's syndrome are generally excellent with a recurrence rate of < 5% (143); however, recurrence of both renal and pulmonary disease has been documented despite waiting an appropriate interval and documenting the absence of anti-GBM antibody (171, 172). Alveolar hemorrhage has been documented as early as 24 h after transplantation but may occur at any point in association with any flare of disease activity. Recurrent hemorrhage following transplantation may also be associated with intercurrent infection and may not be accompanied by rising anti-OBM titers (171). Recurrence of Wegener's granulomatosis is documented in both the upper and lower respiratory tract after renal transplantation (147, 173).Pulmonary lesions have been reported as early as 6 wk and as late as 4 yr(147, 174). Transient focal infiltrates or cavitary lesions are the most frequently described radiographic findings. In the majority of patients, both renal and pulmonary lesions developed while the patients were on standard immunosuppresive regimens containing prednisone and azathioprine. Substitution of cyclophosphamide for azathioprine was effective in nearly all cases (147, 173). Infectious Complications

Infections account for 65% of all pulmonary complications after renal transplantation (150, 151). There has been a marked decline in the incidence of these infections over the last 15 years, largely as a result of improved surgical technique and better immunosuppression. Whereas 42% of patients transplanted at the University of Colorado from 1962through 1968had at least one episode of pneumonia (175), the incidence of pneumonia has ranged from 8 to 16% in more recent surveys (150, 176-178). Bacterial pathogens and CMV are the most frequent causes of pneumonia following renal transplantation, although pulmonary disease caused by Pneumocystis carinii, Aspergillus, endemically restricted fungi, and mycobacteria are also described.


Fig. 4. Chest radiograph of a sz-yr-old man with metastatic renal cell carcinoma arising following renal transptantation. The patient had received a kidney from a living related donor 8 yr earlier. Five years follow ing transplantation , bilateral nephrectomies of the native kid· neys wasperfonned for refractory hypertension . An unsuspected renal cell carcinoma was discovered on microscopic sections. Four years later, the patient presented with extensive metastatic dis· ease to the lungs and mediast inum.

Cytomegalovirus Pneumonia CMV infection is the most common infectious complication after renal transplantation and is a significant cause of morbidity, mortality, and graft loss (179). Although the incidence of infection has ranged from 43 to 920/0, recent studies consistently report an incidence of 75% (10); however, the incidence of both CMYinfection and disease has declined since the introduction of cyclosporine (180). Overall, 20 to 40% of infected patients develop symptomatic disease (10, 180, 181).

The frequencyand the severityof CMVrelated illnesses in the renal transplant patient depends upon the source ofthe virus, the CMV serologic status of the recipient and the use of steroids or antilymphocyte globulins for the treatment of rejection (10, 180, 181). The majority of patients have either asymptomatic infection or mildly symptomatic disease, usually appearing within the first 2 months of transplantation. Fever is present in over 90%, is frequently prolonged, and may be the only clinical sign that appears. Headache, fatigue, arthralgias, myalgias, and diarrhea are also reported, and hematologic abnormalities, including neutropenia and anemia, occur most frequently in patients with severe disease (10, 181). In the renal transplant recipient, symptoms of mild CMV disease are usually present for 1 to 2 wk prior to the onset of CMV pneumonitis. Hypoxemia may also develop before radiographic changes occur. Diffuse interstitial and/or alveolar infiltrates are the most common radiographic findings although focal infiltrates, nodules, discoid atelectasis, and

normal chest radiographs have been reported (10, 181). The finding of a reduced DLeo in patients who have seroconverted but who have no radiographic changes or symptoms has led some authors to suggest that most if not all renal transplant patients with CMV infection have some degree of pneumonitis (182). Whether these findings reflect a direct effect of the virus on the lung or represent early, subradiographic pulmonary inflammation is unclear. Coinfection with multiple pathogens, particularly Pneumocystis carinii and Pseudomonas aeruginosa, is common and is associated with high mortality (1981, unpublished studies). In addition, failure to seroconvert in the face of a symptomatic infection is associated with a poor outcome and is reported in 50% of fatal cases of CMV disease (10). The morbidity of severe CMV disease in renal transplant recipients has led to the development of a variety of prophylactic strategies. Snydman and coworkers (183) found substantial reduction in the incidence of mild CMV syndromes, CMV pneumonitis, and other life-threatening opportunistic infections in patients at risk for primary CMV disease who weretreated with CMV-specific hyperimmune globulin. Similar results were obtained by Kokado and colleagues (184) in patients who received globulin after administration of antilymphocyte globulin or OJ(T3. The effectiveness of nonspecific immune globulin, however, is not well documented. No reduction in the incidence of infection or disease has been detected, although a reduction in the severity of illness is suggested by several investigators (185-187). Recently,

1399

Balfour and coworkers (188) demonstrated that high-dose acyclovir reduced the incidence of CMV infection and disease, particularly in patients at risk for primary illness. The incidence of CMV pneumonia was markedly reduced, and the drug regimen was welltolerated. These studies are encouraging and suggest that some form of prophylaxis is appropriate, particularly in renal transplant patients at risk for primary disease. Before the availability of ganciclovir, CMV pneumonia in the renal transplant recipient carried a 48% overall mortality, and over 900,0 of those patients who required mechanical ventilation died of respiratory failure or its complications (181). Treatment consisted of either rapid withdrawal of immunosuppression, with its attendant risk of graft rejection or transplant nephrectomy. These strategies allowed some degree of immune reconstitution but were often unsuccessful (189). Ganciclovir is effective therapy for the treatment of CMV pneumonitis in renal transplant recipients. Based on data obtained from eight studies, survival approaches 78 % of treated patients (range = 33 to 100%), including 39% of patients who required mechanical ventilation (180,189-195). The drug is welltolerated and achieves complete virologic clearing in 70 to 90% of patients. A 20 to 40% incidence of reversible neutropenia rarely limits the drug's utility (194-196). Treatment failure is associated with persistent isolation of the virus from cultured sites and the presence of copathogens in the lung (189, 194). Early institution of treatment results in a more favorable clinical outcome (189, 196). Recent evidence suggests (hat the use of CMV hyperimmune globulin may also be effectivein the treatment of CMV pneumonitis in this pa.tient population. The number of patients treated, however, has been small, and the severity of illness has not been well documented (197). The usefulness of this treatment strategy in renal transplant recipients awaits further verification. Bacterial Pneumonia Bacterial pulmonary infections are less common in the renal transplant recipient than previously reported. Nosocomial pneumonias usually develop within the first month of transplantation and community-acquired pneumonias at any point in the posttransplant course. The clinical presentation of bacterial pneumonia in this patient population may be fulminant (150), with the sudden onset

1400


Fig. 5. Sequential chestradiographs of a 58-yr-oldman who had receiveda renal transplant 3 months earlier; (A) at presentation withthe acuteonsetof high fever and neutropenia(8) 8 h later after the developmentof dense right upper lobe consolidation. The patient died of Pseudomonas sepsis the same day.

of fever and/or pulmonary symptoms over 12 to 24 h (figure 5). Nosocomial pneumonia is caused predominantly by gram-negative organisms, although outbreaks of more unusual pathogens such as Legionella have been documented (176, 198). Malnutrition, a previous pulmonary complication, or multiple renal transplants enhance the risk of pneumonia (151). In addition, Ramsey and coworkers (150) observed a temporal relationship between the incidence of hospital-acquired pneumonia and the administration of steroid boluses for the treatment of allograft rejection. Although the etiologic agent may not be identified, the response to broad spectrum antibacterial therapy is generally good if instituted early (178, 199). However, superinfection with nonbaeterial or-

ganisms, particularly fungi, is associated with an extremely poor prognosis (152). As expected, gram-positive organisms and Haemophilus influenzae are the most common etiologic agents ofcommunityacquired pneumonias in the renal transplant recipient. These infections usually respond well to treatment and have a prognosis that is similar to nonimmunosuppressed patients with the same infection (150). Pneumocystis Carinii Pneumonia The early experience with renal transplantation indicated that the incidence of PCP was less than 5070, even withoutthe use of prophylaxis (150-152, 176,' 178). After the introduction of cyclosporine, however, a striking increase in the incidence of this infection was report-

ed by several centers (150-152, 176, 178, 200-203). The epidemiology surrounding these infections strongly suggested that the use of cyclosporine was the single most likely factor responsible for the increased incidence of PCP. Unlike PCP in patients with the acquired immune deficiency syndrome (AIDS), the onset of infection tends to be acute in renal transplant recipients. Fever and respiratory symptoms typically develop over several days, 2 to 4 months after transplantation; however, later onset cases have also been reported (200, 201, 203, 204). Mortality varies, ranging from 8 to 80%. As expected, those patients with concurrent CMV pneumonitis usually fared the worst. The use of prophylactic TMP-SMX has markedly reduced the incidence of PCP in those centers that had previously reported significant outbreaks (200203). The duration of'prophylaxis that is required is unclear, but a 12-month regimen is appropriate given the clustering of cases at 2 to 4 months, with occasional cases occurring at close to 1 yr (202). Some authors have advocated indefinite prophylaxis given the salutary effect on posttransplant bacterial infections and its relatively low cost (205). The use of trimethoprim may competitively inhibit creatinine secretion, resulting in an increase in serum creatinine without a concomitant decrease in measured glomerular filtration (201). The rise in creatinine may make it difficult to distinguish allograft rejection 'from drug toxicity,particularly in patients in whom the drug is started late after transplant. Starting the drug immediately following surgery or decreasing the frequency or the dose of the drug may be helpful. Given the risk of PCP with current immunosuppressive regimens, monthly treatments with aerosolized pentamidine may be warranted in patients who are sulfa allergic. However,the effectivenessof this regimen has not been documented in this patient population. Fungal Pneumonia The incidence of fungal pneumonia following renal transplantation may be directly related to the number of treated rejection episodes. Survival appears best in those patients whose pneumonia is de- . tected and treated early (150, 206). Fungal infections that are superimposed upon another infectious process, particularly CMV infection, have a particularly poor prognosis (207). A variety of species of fungi have been documented to


cause pneumonia in the renal transplant recipient, including Aspergillus, Candida, Cryptococcus, Histoplasma, and Coccidioides. Aspergillosis is the most frequent and the most serious pulmonary mycosis described. This infection usually occurs within the first 4 months of transplantation, but it may also occur sporadically within the first year (207). The clinical presentation of this infection is usually subacute, with fever, productive cough, and mild dyspnea evolving over several days to weeks (150). In a review of 25 cases in renal transplant patients over an 8-yr period, Weiland and coworkers (207) observed both focal cavitary infiltrates and diffuse pulmonary involvement as the predominant radiographic patterns. The diagnosis was made antemortem in only 56070 of the patients, emphasizing the difficulty in detecting invasivedisease despite culture of both sputum and bronchoscopy specimens. The presence of multiple positive sputum cultures for aspergillus or a positive protected specimen brush culture was highly predictive of invasive pulmonary infection in this series. In addition, the combined use of transbronchial biopsy and protected catheter culture demonstrated reasonable sensitivity and specificity in the detection of invasive disease. The response to therapy with amphotericin is variable. Weiland and coworkers (207) observed 16% survival, although the presence of copathogens significantly affected outcome. Eighty percent of those with primary aspergillus infection responded to combined amphotericin and 5-flucytosine, whereas none of those with aspergillus infection superimposed on another pulmonary infection survived. Surgical resection of localized cavitary disease with or without combined antifungal therapy has also been successful in a few patients (150, 207). Isolation of Coccidioides immitis and Histoplasma capsulatum from respiratory secretions has proved highly suggestive of invasive disease (176). Dissemination has been observed in up to 75% of renal allograft recipients with either infection and may occur without radiographic evidence of pulmonary involvement (208, 209). The radiographic features of pulmonary involvement in both of these fungal infections are not predictable. Interstitial, alveolar, and miliary infiltrates are described (208-210). The response to therapy is also unpredictable. H. capsulatum is associated with a good response to amphotericin, but pulmo-

nary infection with C. immitis is not as responsive and is associated with appreciable mortality (210).

Mycobacterial Pneumonia The incidence of mycobacteriafinfections in renal transplant patients is several times higher than in the general population, occurring in 0.65to 2.3% of patients in recently published reports (211, 212). They also have been reported in as high as 9.5% of patients who live in areas where tuberculosis is prevalent (213). The clinical presentation of mycobacterial disease may be unpredictable following renal transplantation (214). Although pulmonary involvement is the most frequent clinical manifestation (213), there is a high incidence of joint and skin involvement (211). The onset of infection is usually late, with the majority of patients developing the disease close to a year or more after transplantation; however,cases occurring as early as 2 wk have been reported (211, 212, 214, 215). Respiratory symptoms are often minimal and an unexplained, prolonged fever or an abnormal chest radiograph may be the only clue to the infection (214,216). The radiographic manifestations can involve the upper or lower lobes or appear as miliary infiltrates (214). Systemic symptoms such as fever, malaise, and weight loss are particularly prominent in patients with pulmonary disease (211). Dissemination is common and is associated with significant mortality (212,215). The adult respiratory distress syndrome has also been described (217). The majority of infections are caused by tuberculous mycobacteria, but infections with atypical organisms occur in 24 to 42% of patients (211, 218). The pathogenesis is presumed to be reactivation, although primary infection has been suggested on the basis of negative tuberculin skin testing prior to transplantation (218); however, the high incidence of cutaneous anergy in patients with end-stage renal disease makes this unlikely (211, 214). The use of bronchoscopy with transbronchial biopsy is often required for diagnosis; routine sputum smears and cultures are frequently negative. Mycobacterial disease in this patient population usually responds to standard antituberculous chemotherapy (90, 216). Short-course therapy with three drugs is usually effective (216),but some authors recommend 18-month treatment regimens with two or three drug regimens (213,218). The possibility of drug toxicity is enhanced because of the renal ex-

1401

cretion of isoniazid, streptomycin, and ethambutol (214). Toxicity may also be potentiated during periods of renal dysfunction. Rifampin induces hepatic microsomal enzymes, increases steroid catabolism, and reduces the bioavailability of cyclosporine. These effects may precipitate acute allograft rejection (219). Reduction of immunosuppression is generally not recommended unless lifethreatening disease is present. The issue of prophylaxis in patients with positive tuberculin skin tests is controversial. One year of prophylaxis has been recommended for immunocompromised patients with previously untreated disease or positive tuberculin skin tests (211, 218); however, fatal isoniazidinduced hepatitis has been reported in a renal transplant patient, and the potential toxicity of the drug is not trivial (211). In addition, Rubin and coworkers (90) observed only one case of reactivation tuberculosis among 47 renal transplant recipients who were tuberculin positive prior to transplant, suggesting that the incidence of reactivation is low and not worth the risk of chemoprophylaxis. In general, the use of prophylaxis is probably not warranted except in areas where tuberculosis is endemic or where recent skin test conversion can be documented. References 1. Bortin MM, Rimm AA. Increasing utilization of bone marrow transplantation: results of the 1985-1987 survey.Transplantation 1989; 48:453-8. 2. Freitag A. United Network for Organ Sharing, 1990; Transplantation statistics. 3. Stover DE, Zaman MB, Hajdu SI, Lange M, Gold J, Armstrong D. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med 1984; 101:1-7. 4. Martin WJ, Smith TF, Brutinel WM, Cockerill FR, Douglas Ww. Role of bronchoalveolar lavage in the assessment of opportunistic pulmonary infections: utility and complications. Mayo Clin Proc 1987; 62:549-57. 5. Higenbottam T, Stewart S, Penketh A, Wallwork J. The diagnosis of lung rejection and opportunistic infection by trans bronchial lung biopsy. Transplant Proc 1987; 19:3777-8. 6. Broaddus C, Dake MD, Stulbarg MS, et al. Bronchoalveolar lavage and transbronchial biopsy for the diagnosis of pulmonary infections in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 102:747-52. 7. Horn JE, Bartlett JG. Infectious complications following heart transplantation. In: Baumgartner WA, Reitz BA, Achuff SC, eds. Heart and heartlung transplantation. Philadelphia: w.a Saunders, 1990; 220-36. 8. Martin WJ, Smith TF. Rapid detection of cytomegalovirus in bronchoalveolar lavagespecimens by a monoclonal antibody method. J Clin Microbiol 1986; 23:1006-8. 9. Balfour HH. Cytomegalovirus: the troll of transplantation (editorial). Arch Intern Med 1979;


1402

139:279-80. 10. Glenn J. Cytomegalovirus infections following renal transplantation. Rev Infect Dis 1981; 3:1151-78. 11. Hutter JA, Scott J, Wreghitt T, Higenbottam T, Wallwork J. The importance of cytomegalovirus in heart-lung transplant recipients. Chest 1989; 95:627-31. 12. Paradis IL, Grgurich WF, Drummer JS, Dekker A, Dauber JH. Rapid detection of cytomegalovirus pneumonia by evaluation of bronchoalveolar cells. Am Rev Respir Dis 1988; 138:697-702. 13. Shibata 0, Martin WJ, Appleman MD, Causey OM, Leedom JM, Arnheim N. Detection of cytomegalovirus DNA in peripheral blood of patients infected with human immunodeficiency virus. J Infect Dis 1988; 158:1185-91. 14. Krom RAF, Wiesner RH, Rettke SR, et al. The first 100liver transplantations at the Mayo Clinic. Mayo Clin Proc 1989; 64:84-94. 15. MaddreyWC, VanThielDH. Livertransplantation: an overview. Hepatology 1988; 8:948-59. 16. Wood RP, Rikkers LF, Shaw BW, Williams L. A review of liver transplantation for gastroenterologist. Am J Gastroenterol 1987; 92:593-606. 17. Iwatsuki S, Starzl T, Gordon RD, et al. Liver transplantation: selection of patients and results. Transplant Proc 1987; 19:2373-7. 18. Busuttil RW, Goldstein L, Danovitch GM, Ament ME, Memsic LD. Liver transplantation today. Ann Intern Med 1986; 104:377-89. 19. Furukawa T, Hara N, Yasumoto K, Inokuchi K. Arterial hypoxemia in patients with hepatic cirrhosis. Am J Med Sci 1984; 287:10-3. 20. Silverman A, Cooper MD, Moller JH, Good RA. Syndrome of cyanosis, digital clubbing, and hepatic disease in siblings. J Pediatr 1968;72:70-80. 21. Krowka MJ, Cortese DA. Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation (editorial). Hepatology 1990; 11:138-41. 22. Ruff F, Hughes JBM, Stanley N, et al. Regionallung function in patients with hepatic cirrhosis. J Clin Invest 1971; 50:2403-13. 23. Daoud FS, Reeves JT, Schaefer Jw. Failure of hypoxic pulmonary vasoconstriction in patients with liver cirrhosis. J Clin Invest 1972;51:1072-80. 24. Naeije R, Hallemans R, Mols P, Melot C. Hypoxic pulmonary vasoconstriction in liver cirrhosis. Chest 1981; 80:570-4. 25. Funahashi A, Kutty AVP,Prater SL. Hypoxaemia and cirrhosis of the liver. Thorax 1976; 31:303-8. 26. Rodriguez-Roisin R, Roca J, Augsti AG, Mastai R, Wagner PO, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis 1987; 135:1085-92. 27. Melot C, Naeije R, Dechamps P, Hallemans R, Lejeune P. Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis. Am Rev Respir Dis 1989; 139:632-40. 28. Davis HH, Schwartz OJ, Lefrak SS, Susman N, Schainker BA. Alveolar-capillary oxygen disequilibrium in hepatic cirrhosis. Chest 1978; 73: 507-11. 29. Kennedy TC, Knudson RJ. Exercise-aggravated hypoxemia and orthodeoxia in cirrhosis. Chest 1977; 72:305-9. 30. Krowka MJ, Cortese DA. Severe hypoxemia associated with liverdisease;Mayo clinicexperience and the experimental use of almitrine bismesylate. Mayo Clin Proc 1987; 62:1648-73. 31. Williams A, TrewbyP, Williams R. Structural alterations to the pulmonary circulation in fulminant hepatic failure. Thorax 1979; 34:447-53. 32. Bank ER, Thrall JH, Dantzker DR. Radionuclide demonstration of intrapulmonary shunting in cirrhosis. AJR 1983; 140:967-9.

33. Van Thiel DH, Schade RR, Gavaler JS, Shaw BW, Iwatsuki S, Starzl TE. Medical aspects of liver transplantation. Hepatology 1984; 4(Suppl: 79-83). 34. Krumpe PE, Cummiskey JM, Lillington GA. Alcohol and the respiratory tract. Med Clin North Am 1984; 68:201-19. 35. Starzl TE, Grothy CG, Brettschneider L, et al. Extended survival in 3 cases of orthotopic homotransplantation of the human liver. Surgery 1968; 63:549-63. 36. Stoller JK, Moodie 0, Schiavone WA, et al. Reduction of intrapulmonary shunt and resolution ofdigitalclubbing after livertransplantation. Hepatology 1990; 11:138-41. 37. Salem 0, Dindzans V, Freeman J, O'Doriso T, Ruthardt F, Van Theil D. Liver transplantation following pre-operative closure of intrapulmonary shunts. Hepatology 1989; 10:569. 38. Lebrec 0, Capron JP, Dhumeaux 0, Benhamou JP. Pulmonary hypertension complicating portal hypertension. Am Rev Respir Dis 1979; 120:849-56. 39. McDonnell PJ, ToyePA, Hutchins GM. Primary pulmonary hypertension in cirrhosis: are they related? Am Rev Respir Dis 1983; 127:437-41. 40. Lockhart A. Pulmonary arterial hypertension in portal hypertension. Clin Gastroenterol 1985; 14:123-38. 41. Edwards BS, Weir EK, Edwards WD, Ludwig J, Dykoski RK, Edwards JE. Coexistent pulmonary and portal hypertension: morphologic and clinicalfeatures. J Am Coli Cardio11987; 10:1233-8. 42. Naeye RL. "Primary" pulmonary hypertension with co-existing portal hypertension: a retrospective study of six cases. Circulation 1960; 22:376-84. 43. Senior RM, Britton AC, Turino GM, Wood JA, Lauper GA, Fishman AP. Pulmonary hypertension associated with cirrhosis of the liver and with portacaval shunts. Circulation 1968;37:88-96. 44. Krowka MJ, Cortese DA. Pulmonary aspects of liverdisease and livertransplantation. Clin Chest Med 1989; 10:593-616. 45. Wallace JG, Tong MJ, Ueki BH, Quismorio FP. Pulmonary involvement in primary biliary cirrhosis. J Clin Gastroenterol 1987; 9:431-45. 46. Wallaert B, Bonniere P, Prin L, Cortot A, Tonnel AB, Voisin C. Primary biliary cirrhosis: subclinicalinflammatory alveolitisin patients with normal chest roentgenograms. Chest 1986;90:842-8. 47. Rodriguez-Roisin R, Pares A, Bruguera M, et al. Pulmonary involvement in primary biliary cirrhosis. Thorax 1981; 36:208-12. 48. Uddenfeldt P, Bjerle P, Danielsson A, Nystrom L, Stjernberg N. Lung function abnormalities in patients with primary biliary cirrhosis. Acta Med Scand 1988; 223:549-55. 49. Maddrey WC. Sarcoidosisand primary biliary cirrhosis: associated disorders? N Engl J Med 1983; 308:588-90. 50. Clarke AK, Galbraith RM, Hamilton ERD, Williams R. Rheumatic disorders in primary biliary cirrhosis. Ann Rheum Dis 1978; 37:42-7. 51. Hunninghake GW, Fauci AS. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 1979; 119:471-94. 52. Hourani J, Bellamy P, Batra P, Busuttil R, Simmons M, Taskin D. Lung function and chest radiographic abnormalities in patients with severe liver failure. Chest 1988; 94(Suppl:54). 53. Hanson CA, Ritter AB, Duran W, Lavietes MH. Ascites: its effect upon static inflation of the respiratory system. Am Rev Respir Dis 1990; 142:39-42. 54. Abelmann WH, Frank NR, Gaensler EA, Cugell OW. Effects of abdominal distension by ascites on lung volumes and ventilation. Arch Intern

Med 1954; 93:528-40. 55. Krowka MJ, Cortese DA. Pulmonary aspects of chronic liver disease and liver transplantation. Mayo Clin Proc 1985; 60:407-16. 56. Costello P, Williams CR, Jenkins RW, Jensen WA, Rose RM. The incidence and implications of chest radiographic abnormalities following orthotopic liver transplantation. Can Assoc Radiol J 1987; 38:90-5. 57. Matuschak GM, Shaw BW. Adult respiratory distress syndrome associated with acute liver allograft rejection: resolution following hepatic retransplantation. Crit Care Med 1987;15:878-81. 58. TrewbyPN, Warren R, Contini S, et al. Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure. Gastroenterology 1978; 74:859-65. 59. Johnston RF, Loo RV. Hepatic hydrothorax: studies to determine the source of the fluid and report of thirteen cases. Ann Intern Med 1964; 61:385. 60. Albin RJ, Johnston GS. External accumulation of radionuclide in hepatic hydrothorax. Clin Nucl Med 1989; 14:341-3. 61. TsaiG, Liu J, Siauw C, Chen P. Thoracic roentgenologic manifestations in primary carcinoma of the liver. Chest 1984; 86:430-4. 62. Rettke SR, J anossy TA, Chantigian RC, et al. Hemodynamic and metabolic changes in hepatic transplantation. Mayo Clin Proc 1989;64:232-40. 63. Tuman KM, Speiss BD, McCarthy RJ, Logas WG, Williams JW, Sankary HN. Effects of continuous arteriovenous hemofiltration in cardiopulmonary abnormalities during anesthesia for orthotopic liver transplantation. Anesth Analg 1988; 67:363-9. 64. Shaw BW,Martin OJ, Marquez JM, et at. Venous bypass in clinica11iver transplantation. Ann Surg 1984; 200:524-34. 65. Ellis JE, Lichtor JL, Chung MR, et al. Mechanism of myocardial dysfunction during livertransplantation: the role of isolated right ventricular failure (abstract). Anesthesiology 1987; 67:A82. 66. Lichtor JL, Ellis JE, Uitvlugt A, et al. Transesophageal echocardiography during liver transplantation. Anesth Analg 1987; 66(Suppl:104). 67. Rettke S, Chantigian R, Janossy T, et al. Anesthesia approach to hepatic transplantation. Mayo Clin Proc 1989; 64:224-31. 68. Khoury GF, Mann ME, Porot MJ, AbdulRasool IH, Busuttil RW. Air embolism associated with veno-venous bypass during orthotopic liver transplantation. Anesthesiology 1987; 67:848-51. 69. Ramsey MA, Klintmalm G, Brajtbord D, Swygert TH. Air embolism during liver transplantation. Anesthesiology 1988; 68:829. 70. Gibby GL. Precordial doppler is not obsolete for venous air embolism monitoring. Anesthesiology 1988; 68:829. 71. Kutt JL, Gelb AW.Air embolism during liver transplantation. Can Anaesth Soc J 1984; 31:713. 72. Jensen WA, Rose RM, Hammer SM, et a/. Pulmonary complications of orthotopic livertransplantation. Transplantation 1986; 42:484-90. 73. Thompson AB, Rickard KA, Shaw BW, et al. Pulmonary complications and disease severity in adult liver transplant recipients. Transplant Proc 1988; 20:646S-9S. 74. Navalgund AA, Kang Y, Sarner JB, Jahr JS, Gieraerts R. Massivepulmonary thromboembolism during liver transplantation. Anesth Analg 1988; 67:400-2. 75. Vigouroux D, Bornet JL, Delacroix M, Conil C, Coni! JM. Fatal neoplastic embolism during liver transplantation. Cah Anesthesiol1986; 34:423-4. 76. Ekberg H, Tranberg KG, Anderson R, Jeppsson B, Bengmark S. Major liverresection: perioperative course and management. Surgery 1986;


100:1-7. 77. Plevak DJ, Southorn PA, Narr BJ, Peters SG. Intensive care unit experience in the Mayo liver transplantation program: the first 100cases. Mayo Clin Proc 1989; 64:433-45. 78. Olutola PS, Hutton L, Wall WJ. Pleural effusion following liver transplantation. Radiology 1985; 157:594. 79. Schroter GPJ, Hoelscher M, Putnam CW, Porter KA, Hansbrough JF, Starzl TE. Infections complicating orthotopic liver transplantation: a study emphasizing graft-related septicemia. Arch Surg 1976; 1l1:1337-47. 80. Paya CV, Hermans PE, Washington JA, et 01. Incidence, distribution, and outcome of episodes of infection in 100orthotopic livertransplantations. Mayo Clin Proc 1989; 64:555-64. 81. Wood RP, Tzakis A, Shaw BW, Starzl TE. A simplified technique for the treatment of simple pleural effusions. Surg Gynecol Obstet 1987; 164:283-4. 82. Takaoka F, Brown MR, Paulsen W, Ramsay MAE, Lintmalm GB.Adult respiratory distress syndrome following orthotopic liver transplantation. Clin Transplant 1989; 3:294-9. 83. Howell RSC, Bayley S, CaIne RY. Respiratory failure after liver transplantation. Eur J Intensive Care Med 1975; 1:137-40. 84. Powell-Jackson PR, Carmichael FJL, Calne RY, Williams R. Adult respiratory distress syndrome and convulsions associated with administration of cyclosporin in liver transplant recipients. Transplantation 1985; 38:341-3. 85. Munoz SJ, Nagelberg SB, Green PJ, etal. Ectopic soft tissue calcium deposition following liver transplantation. Hepatology 1988; 8:476-83. 86. Raisis IP, Park CH, Yang SL, Maddrey W. Lung uptake of technetium-99m phosphate compounds after liver transplantation. Clin Nucl Med 1989; 13:188-9. 87. Colonna JD, Winston DJ, Brill JE, et 01. Infectious complications in livertransplantation. Arch Surg 1988; 123:360-4. 88. Kusne S, Dummer JS, Singh N, et al. Infections after liver transplantation: an analysis of 101 consecutive cases. Medicine 1988; 63:132-43. 89. Dummer JS, Hardy A, Ho M. Early infections in kidney, heart and liver transplant recipients on cyclosporine. Transplantation 1983; 36:259-67. 90. Rubin RH. Infection in the renal and liver transplant recipient. In: Rubin R, Young L, eds. Clinical approach to infection in the compromised host. New York: Plenum, 1988; 657-81. 91. Wiesner RH, Hermans PE, Rakela J, et al. Selective bowel decontamination to decrease gram negative aerobic bacterial and candida colonization and prevent infection after orthotopic liver transplantation. Transplantation 1988; 45:570-4. 92. Haagsma EB, Klompmaker 11, Grond J, et al. Herpes virus infections after orthotopic liver transplantation. Transplantation 1987; 19:4054-6. 93. Singh N, Dummer JS, Kusne S, et al. Infections with cytomegalovirus and other herpes viruses in 121 liver transplant recipients: transmission by donated organ and the effect of OKT3 antibodies. J Infect Dis 1988; 158:124-31. 94. Harbison MA, DeGirolami PC, Jenkins RL, Hammer SM. Ganciclovir therapy of severe cytomegalovirus infections in solid organ transplant recipients. Transplantation 1988; 46:82-8. 95. Paya CV, Hermans PE, Smith TF, et al. Efficacy of ganciclovir in liver and kidney transplant recipients with severe cytomegalovirus infection. Transplantation 1988; 46:229-34. 96. deHemptinne B, Lamy ME, Salizzoni M, et al. Successful treatment of cytomegalovirus disease with 9(l,3-dihydroxy-2-propoxymethyl guanine). Transplant Proc 1988; 20:652-5.

97. Saliba F, Gugenheim J, Bismuth SA, Mathieu D, Serres C, Bismuth H. Incidence of cytomegalovirus infection and effects of cytomegalovirus immune globulin prophylaxis after orthotopic liver transplantation. Transplant Proc 1987; 19:4081-2. 98. Rakela J, Wiesner RH, ThswellHF, et al. Incidence of cytomegalovirus infection and its relationship to donor-recipient serologic status in liver transplantation. Transplantation 1987;19:2399-402. 99. Kusne S, Dummer JS, Singh N, et al. Fungal infections after liver transplantation. Transplantation 1988; 20:650-1. 100. Monaco AP. Clinical kidney transplantation in 1984. Transplantation 1985; 17:5-11. 101. RlyeMW. Renal transplantation. In: Flye W, ed. Principles of organ transplantation. Philadelphia: W.B. Saunders, 1989; 264-93. 102. Heino A, Orko R, Rosenberg PH. Anaesthesiological complications in renal transplantation: a retrospective study of 500 transplantations. Acta Anesthesiol Scand 1986; 30:574-80. 103. Forman JW, Ayers LN, Miller WC. Pulmonary diffusing capacity in chronic renal failure. Br J Dis Chest 1981; 75:81-7. 104. Lee HY, Stretton TB, Barnes AM. The lungs in renal failure. Thorax 1975; 30:46-53. 105. Fairshter RD, Vaziri ND, Mirahmadi MK. Lung pathology in chronic hemodialysis patients. Int J Artif Organs 1982; 5:97-100. 106. Hopps HC, Wissler RW.Uremic pneumonitis. Am J Pathol 1953; 31:261-73. • 107. Bass HE, Greenberg D, Singer E, Miller M. Pulmonary changes in uremia. JAMA 1952; 148: 724-6. 108. Henkin RI, Maxwell MH, Murray JE Uremic pneumonitis: a clinical, physiological study. Ann Intern Med 1962; 57:1001-8. 109. DePass SW, Stein J, Poppel MH, Jacobson HG. Pulmonary congestion and edema in uremia. JAMA 1956; 162:5-9. 11O. Scharf S, Wexler J, Longnecker RE, Blaufox MD. Cardiovascular disease in patients on chronic hemodialytic therapy. Prog Cardiovasc Dis 1980; 22:343-56. 111. Hung J, Harris PJ, Uren RF, Tiller DJ, Kelly Dr. Uremic cardiomyopathy-effect of hemodialysis on left ventricular function in end-stage renal failure. N Engl J Med 1980; 302:547-51. 112. Burt RK, Gupta-Burt S, Suki WN, Barcenas CG, Ferguson 11, Van Buren CT. Reversal of left ventricular dysfunction after renal transplantation. Ann Intern Med 1989; 111:635-40. 113. Lai KN, Barneden L, Mathew TH. Effect of renal transplantation on left ventricular function in hemodialysis patients. Clin Nephrol 1982; 16:74-8. 114. Capelli JP, Kasparian H. Cardiac work demands and left ventricular function in end-stage renal disease. Ann Intern Med 1977; 86:261-7. 115. Pehrsson SK, Jonasson R, Lins L. Cardiac performance in various stages of renal failure. Br Heart J 1984; 52:667-73. . 116. Crosbie WA, Snowden S, Parsons V.Changes in lung capillary permeability in renal failure. BMJ 1972; 4:388-90. 117. Belcher NG, Rees PJ. Changes in pulmonary clearance of technitium labelled DrPA during hemodialysis. Thorax 1986; 41:381-5. 118. Rodelas P, Rakowski TA, Argy WP, Schreiner GE. Fibrosing uremic pleuritis during hemodialysis. JAMA 1?80; 243:2424-5. 119. Nidus BO, Matalon R, Cantacuzino D, Eisinger RP. Uremic pleuritis: a clinicopathologic entity. N Eng1 J Med 1969; 281:255-7. 120. Berger HW, Rammohan G, Neff MS, Buhian WJ. Uremic pleural effusion. Ann Intern Med 1975; 82:362-4. 121. Galen MA, Steinberg SM, Lowrie EG, Laza-

1403 rus JM, Hampers CL, Merrill JP. Hemorrhagic pleural effusion in patients undergoing chronic hemodialysis. Ann Intern Med 1975; 82:359-61. 122. Gilbert L, Seymour R, Frankel H, Jacobs M, Mankowitz BJ. Fibrinous uremic pleuritis: a surgical entity. Chest 1975; 67:53-6. 123. McCabe TA, Rakowski TA, Argy WP, Reilly MJ. Fibrosing uremic pleuritis complicated by thoracicempyema. Arch Intern Med 1982;142:1369-70. 124. Justrabo E, Genin R, Rifle G. Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis. Thorax 1979; 34:384-8. 125. Conger JD, Hammond WS, Alfrey AC, Contiguglia SR, Stanford RE, Huffer WE. Pulmonary calcification in chronic dialysis patients. Ann Intern Med 1975; 83:330-6. 126. Giacobetti R: Feldman SA, Ivanovich P, Huang CM, Levin ML. Sudden fatal pulmonary calcification following renal transplantation. Nephron 1977; 19:295-300. 127. Gilman M, Nissm J, Terry P, Whelton A. Metastatic pulmonary calcification in the renal transplant recipient. Am Rev Respir Dis 1980; 121:415-9. 128. Mootz JR, Sagel SS, Roberts TH. Roentgenographic manifestations of pulmonary calcifications. Radiology 1973; 107:55-60. 129. Evans TW, Collins M, Adams JE, et al. Pulmonary calcification in a renal transplant recipient. Br J Dis Chest 1983; 77:202-5. 130. Faubert PF, Shapiro WB, Porush JG, et al. Pulmonary calcification in hemodialyzed patients detected by technetium-99m diphosphonate scanning. Kidney Int 1980; 18:95-102. 131. Smith JC, Stanton LW,Kramer NC, Parrish AE. Nodular pulmonary calcification in renal failure. Am Rev Respir Dis 1969; 100:723-8. 132. Alfrey AC, Jenkins D, Groth CG, Schorr WS, Gecelter L, Ogden DA. Resolution of hyperparathyroidism, renal osteodystrophy and metastatic calcification after renal homotransplantation. N Engl J Med 1968; 279:1349-56. 133. Pradhan RP, Katz LA, Nidus BD, Matalon R, Eisinger RP. Tuberculosis in dialyzed patients. JAMA 1974; 229:798-800. 134. Andrew QT, Schonfeld PY, Hopewell PC, Humphreys MH. Tuberculosis in patients with endstage renal disease. Am J Med 1980; 68:59-64. 135. Raska K, Raskova J, Shea SM, et al. T cell subsets and cellular immunity in end stage renal disease. Am J Med 1983; 75:734-40. 136.,Bergrem H, Jervell J, Brodwall EK, Flatmark A. Mellbye O. Goodpasture's syndrome: a report of seven patients including long term follow-up of three who received a kidney transplant. Am J Med 1980; 68:54-8. 137. Cameron JS. Glomerulonephritis in renal transplants. Transplantation 1982; 34:237-45. 138. van YperseleC, Pirson Y, Vandenbroucke J, Alexandre GP. Haemodialysis and transplantation in Wegener's granulomatosis. BMJ 1979; 2:93-4. 139. YoungKR. Pulmonary-renal syndromes. Clin Chest Med 1989; 10:655-76. 140. Proskey AJ, Weatherbee L, Easterling RE, Greene JA, Weller JM. Goodpasture's syndrome: a report of five cases and a review of the literature. Am J Med 1970; 48:162-73. 141. Rees AJ. Pulmonary injury caused by antibasement membrane antibodies. Semin Respir Med 1984; 5:264-72. 142. Ewan PW, Jones HA, Rhodes CG, Hughes JMB. Detection of intrapulmonary hemorrhage with carbon monoxide uptake: application in Goodpasture's syndrome. N Eng! J Med 1976; 295:1391-6. 143. Cameron JS, Turner DR. Recurrent glomerulonephritis in allografted kidneys. Clin Nephrol 1977; 7:47-54.

1404 144. Carrington CB, Liebow AA. Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med 1966; 41:497-527. 145. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98:76-85. 146. Rosenberg DM, Weinberger SE, Fulmer JD. Functional correlates of lung involvement in Wegener's granulomatosis: use of pulmonary function testing in staging and follow-up. Am J Med 1980; 69:387-94. 147. Steinman TI, Jaffe BF, Monaco AP, Wolff SM, Fauci AS. Recurrence of Wegener's granulomatosis after kidney transplantation: successful reinduction of remission with cyclophosphamide. Am J Med 1980; 68:458-60. 148. Rifkind D, Starzl TE, Marchioro TL, Waddell WR, Rowlands OJ, Hill RB. Transplantation pneumonia. JAMA 1964; 189:808-14. 149. Uranga VM, Simmons RL, Kjellstrand CM, Buselmeier T, Najarian JS. Pathogenesis of "transplant lung": interstitial pulmonary edema. Ann Surg 1973; 178:573-7. 150. Ramsey PG, Rubin RH, Tokoff-Rubin N, Cosimi AB, Russell PS, Greene R. The renal transplant patient with fever and pulmonary infiltrates: etiology, clinical manifestations, and management. Medicine 1980; 59:206-22. 151. Simmons RL, Uranga VM, laPlante ES, Buselmeier TJ, Kjellstrand CM, Najarian JS. Pulmonary complications in transplant recipients. Arch Surg 1972; 105:260-8. 152. Webb WR, Gamsu G, Rohlfing BM, et al. Pulmonary complications of renal transplantation: a survey of patients treated by low-doseimmunosuppression. Radiology 1978; 126:1-8. 153. Boyes R, Puri VK, Toledo L, Schneider F. Pulmonary edema in renal transplant patients. Am Surg 1987; 53:647-51. 154. Dean NC, Amend WC, Matthay MA. Adult respiratory distress syndrome related to antithymocyte globulin therapy. Chest 1987; 91:619-20. 155. Mossey RI, Kasabian AA, Wilkes BM, Mailloux LU, Susin M, Bluestone PA. Pulmonaryembolism: low incidence in chronic renal failure. Arch Intern Med 1982; 142:1646-8. 156. Brunkwall J, Bergqvist D, Bergentz SE, Bornmyr S, Husberg B. Postoperative deep venous thrombosis after renal transplantation. Transplantation 1987; 43:647-9. 157. Rubin RH. Case 13-1985. N Engl J Med 1985; 312:843-50. 158. Milano S, Niccoli L, Cristinelli L, Mombelloni G. Vena cava filter and renal transplant. Ann Thorac Surg 1988; 45:350-2. 159. Penn I. Lymphomas complicating organ transplantation. Transplant Proc 1983; 15:2790-7. 160. Starzl TE, Porter KA, Iwatsuki S, et al. Reversibility of lymphomas and Iymphoproliferative lesions developing under cyclosporine-steroid therapy. Lancet 1984; i:583-7. 161. Penn I. Risk of cancer in the transplant patient. In: Flye M, ed. Principles of organ transplantation. Philadelphia: w.B. Saunders, 1989;634-43. 162. Hanto DW, Gajl-Peczalska KJ, Frizzera G, et al. Epstein-Barr virus induced polyclonal and monoclonal B-celllymphoproliferative diseases occurring after renal transplantation. Ann Surg 1983; 198:356-69. 163. Thiru S, Caine RY, Nagington J. Lymphoma in renal allograft patients treated with cyclosporin-Aas one of the immunosuppressive agents. Transplant Proc 1981; 13:359-64. 164. Bia MJ, Flye MW. Immunoblastic lymphoma in a cyclosporine treated renal transplant recipient. Transplantation 1985; 39:673-5. 165. Harwood AR, Osoba D, Hofstader SL, et


al. Kaposi's sarcoma in recipients of renal transplants. Am J Med 1979; 67:759-65. 166. Penn I. Kaposi's sarcoma in organ transplant recipients. Transplantation 1979; 27:8-11. 167. Pitchenik AE, Fischl MA, Saldana MJ. Kaposi's sarcoma of the tracheobronchial tree. Chest 1985; 87:122-4. 168. AI-Suleiman M, Haleen A, Al-Khader A. Kaposi's sarcoma after renal transplantation. Transplant Proc 1987; 2243-4. 169. Chanez P, Mourad G, Aubas P, et al. Kaposi's sarcoma of the bronchial tree in a renal transplant recipient. Respiration 1988; 53:259-61. 170. Gunawardena KA, AI-Hasani MK, Haleem A, AI-Suleiman M. Pulmonary Kaposi's sarcoma in two recipients of renal transplants. Thorax 1988; 43:653-6. 171. Almkuist RD, Buckalew VM, Hirszel P, Maher JF, James PM, Wilson CB. Recurrence of antiglomerular basement membrane antibody mediated glomerulonephritis in an isograft. Clin Immunol Immunopathol 1981; 18:54-60. 172. Morzycka M, Croker B, Seigler H, Tisher C. Evaluation of recurrent glomerulonephritis in kidhey allografts. Am J Med 1982; 72:588-98. 173. Salaman R, Cole GA, Saltissi D. Haemodialysis and transplantation in Wegener's granulomatosis (letter). British J Med 1980; 280:254. 174. Curtis J J, Diethelm AG, Crowell WT, Whelchel JD. Recurrence of Wegener's granulomatosis in a cadaver renal allograft. Transplantation 1983; 36:452-4. 175. Eickoff TC. Infectious complications in renal transplant recipients. Transplant Proc 1973; 5:1233-8. 176. Peterson PK, Ferguson R, Fryd DS, Balfour HH, Rynasiewicz J, Simmons RL. Infectious diseases in hospitalized renal transplant recipients: a prospective study of a complex and evolving problem. Medicine 1982; 61:360-72. 177. Hesse UJ, Fryd DS, Chatterjee SN, Simmons RL, Sutherland DER, Najarian JS. Pulmonary infections: the Minnesota randomized prospective trial of cyclosporine vs azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Arch Surg 1986; 121:1056-60. 178. Masur H, Cheigh JS, Stubenbord WT. Infection following renal transplantation: a changing pattern. Rev Infect Dis 1982; 4:1208-19. 179. Hill RB, Dahrling BE, Starzl TE, Rifkind D. Death after transplantation (editorial). Am J Med 1967; 42:327-34. 180. Metselaar H, Weimar W. Cytomegalovirus infection and renal transplantation. J Antimicrob Chemother 1989; 23:37-47. 181. Peterson PK, Balfour HH, Marker SC, Fryd DS, Howard RJ, Simmons RL. Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine 1980; 59:283-300. 182. van Son WJ, TegzessA, Hauw T, et al. Pulmonary dysfunction is common during a cytomegalovirus infection after renal transplantation even in asymptomatic patients. Am Rev Respir Dis 1987; 136:580-5. 183. Snydman DR, Werner BG, Heinze-Lacey B, et a/. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal transplant recipients. N Engl J Med 1987; 317:1049-54. 184. Kokado Y, Ishibashi M, Tanaka K, Baba K, Yabuuchi M, Sonado T. Cytomegalovirus infection after renal transplantation: effect of prophylactic hyperimmune globulin. -Cfin Transplant 1989; 3:223-7. 185. Steinmuller DR, Graneto D, Swift C, et a/. Use of intravenous immunoglobulin prophylaxis for primary cytomegalovirus infection post living

related donor renal transplantation. Transplant Proc 1989; 21:2069-71. 186. KasiskeBL, Heim-DuthoyKL, TortoriceKL, Ney AL, Odland MD, Rao V. Polyvalent immune globulin and cytomegalovirus infection after renal transplantation. Arch Intern Med 1989;149:2733-6. 187. Khawand N, Light JA, Brems W, Aquino A, Ali A. Does intravenous immunoglobulin prevent primary cytomegalovirus disease in kidney transplant recipients? Transplant Proc 1989;21:2072-4. 188. Balfour HH, Chace BA, Stapleton JT, Simmons RL, Fryd DS. Randomized, placebo controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989; 320:1381-7. 189. Hecht DW, Snydman DR, Crumpacker CS, Werner BG, Heinze-Lacey B. Ganciclovir for treatment of renal-transplant associated primary cytomegalovirus pneumonia. J Infect Dis 1988; 157:187-90. 190. Creasy TS, Flower AJE, Veitch PS. Lifethreatening cytomegalovirus infection treated with dihydropropoxymethylguanine (letter). Lancet 1986; 1:675. 191. Thomson MH, Jeffries DJ. Ganciclovir therapy in iatrogenically immunosuppressed patients with cytomegalovirus disease. J Antimicrob Chemother 1989; 23:61-70. 192. Winston DJ, Ho WG, Bartoni K, et a/. Ganciclovir therapy for cytomegalovirus infections in recipients of bone marrow transplants and other immunosuppressed patients. Rev Infect Dis 1988; IO(Suppl:547-53). 193. Lang PH, Buisson G, Rostoker A, et a/. DHPG treatment of kidney transplant recipients with severe CMV infection. Transplant Proc 1989; 21:2084-6. 194. Snydman DR. Ganciclovir therapy for cytomegalovirus disease associated with renal transplantation. Rev Infect Dis 1988; IO(Suppl:554-62). 195. Erice A, Jordan MC, Chace BA, Fletcher C, Chinnock BJ, Balfour HH. Ganciclovir treatment of cytomegalovirus disease in transplant recipients and other immunocornpromised hosts. JAMA 1987; 257:3082-7. 196. Crumpacker C, Marlowe S, Zhang JL, Abrams S, Watkins P. Treatment of cytomegalovirus pneumonia. Rev Infect Dis 1988; IO(Suppl: 538-46). 197. Lautenschlager I, Ahonen J, Eklund B, et a/. Hyperimmune globulin therapy of clinical cytomegalovirus infection in renal allograft recipients. Scan J Infect Dis 1989; 21:139-43. 198. Wilczek H, Kallings I, Nystrom B, Hoffner S. Nosocomial Legionnaires' disease following renal transplantation. Transplantation 1987; 43: 847-51. 199. Peterson PK, Anderson RC. Infection in renal transplant recipients. Am J Med 1986;81:2-10. 200. Hardy AM, Wajszczuk CP, Suffredini AF, Hakala TR, Ho M. Pneumocystis carinii pneumonia in renal-transplant recipients treated with cyclosporine and steroids. J Infect Dis 1984;149:143-7. 201. Franson TR, Kauffman M, Adams MB, Lemann J, Caberera E, Hanacik L. Cyclosporine therapy and refractory Pneumocystis carinii pneumonia. Arch Surg 1987; 122:1034-5. 202. Santiago-Delpin EA, Mora E, Gonzalez ZA, Morales-Oretero LA, Bermudez R. Factors in an outbreak of Pneumocystis carinii in a transplant unit. Transplant Proc 1988; 20:462-5. 203. Talseth T, Holdaas H, Albrechtsen D, et al. Increasing incidence of Pneumocystis carinii pneumonia in renal transplant patients. Transplant Proc 1988; 20:400-1. 204. Sterling RP, Bradley BB, Kahlil KG, Kerman RH, Conklin RH. Comparison of biopsy-proven Pneumocystis carinii pneumonia in acquired im-


mune deficiency syndrome patients and renal allograft recipients. Ann Thorac Surg 1984; 38:494-9. 205. Fox BC, Sollinger HW, Belzer FO, Maki DG. A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med 1990; 89:255-73. 206. Bach MC, Adler JL, Breman J, et at. Influence of rejection therapy on fungal and nocardial infections in renal transplant recipients. Lancet 1973; 1:180-4. 207. Weiland D, Ferguson RM, Peterson PK, Snover DC, Simmons RL, Najarian JS. Aspergillosis in 25 renal transplant patients. Ann Surg 1983; 198:622-9. 208. Wheat LJ, Smith EJ, Sathapatayavongs B, et at. Histoplasmosis in renal allograft recipients. Arch Intern Med 1983; 143:703-7.

209. Yoshino MT, Hillman BJ, Galgiani IN. Coccidioidomycosis in renal dialysis and transplant patients: radiologic findings in 30 patients. AJR 1987; 149:989-92. 210. Cohen 1M, Galgiani IN, Potter D, Ogden DA. Coccidioidomycosis in renal replacement therapy. Arch Intern Med 1982; 142:489-94. • 211. Lloveras J, Peterson PK, Simmons RL, Najarian JS. Mycobacterial infections in renal transplant recipients. Arch Intern Med 1982; 142:888-92. 212. Riska H, Gronhagen-Riska C, Ahonen J. Tuberculosis and renal allograft transplantation. Transplant Proc 1987; 19:4096-7. 213. Malhotra KK, Dash SC, Dhawan IK, Bhuyan UN, Gupta A. Tuberculosis and renal transplantation-observations from an endemic area of tuberculosis. Postgrad Med J 1986; 62:359-62. 214. Coutts II, J egarajah S, Stark JE. Tuberculosis in renal transplant recipients. Br J Dis Chest 1979; 73:141-8.

1405 215. Samhan M, Panjwani DD, Dadah SK, Kumar MSA, Araj G, Abouna GM. Is tuberculosis a contraindication for renal transplantation. Transplant Proc 1989; 2036-7. 216. Dautzenberg B, Grosset J, Fechner J, et at. The management of thirty immunocompromised patients with tuberculosis. Am Rev Respir Dis 1984; 129:494-5. 217. Vaz AJ. Miliary tuberculosis and the adult respiratory distress syndrome in a renal transplant recipient (letter). Chest 1979; 75:412. 218. Spence RK, Dafoe DC, Rabin G, et at. Mycobacterial infections in renal allograft recipients. Arch Surg 1983; 118:356-9. 219. Offerman G, Keller F, Molzahn M. Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am J Nephrol 1985; 5:385-7.

Pulmonary considerations of organ transplantation. Part 3.

Pulmonary considerations of organ transplantation. Part 2.

Organ culture of the postnatal mouse Crista ampullaris. Part I.

All about Dowels - A Review Part I. Considerations before Cementation.

Understanding depression in medical patients. Part I: Diagnostic considerations.

The Intersection of Pulmonary Hypertension and Solid Organ Transplantation.

Pulmonary infectious complications of human immunodeficiency virus infection. Part I.

Pulmonary Neuroendocrine Tumors: Part I. Spectrum and Characteristics of Tumors.

ATS Core Curriculum 2014: part I. Adult pulmonary medicine.

Pulmonary infection in the compromised host: part I.

Bioethics of organ transplantation.

Ethics of organ transplantation.

Hepatitis B reactivation and rituximab: a new boxed warning and considerations for solid organ transplantation.

Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs.

Pulmonary endarterectomy: part I. Pathophysiology, clinical manifestations, and diagnostic evaluation of chronic thromboembolic pulmonary hypertension.

Brain protection: physiological and pharmacological considerations. Part I: The physiology of brain injury.

Laryngeal transplantation: ethical considerations.

Mechanical properties of tissue conditioners. Part I: theoretical considerations, behavioral characteristics, and tensile properties.

Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I).

Organ Transplantation in China.

Facebook and organ transplantation.

Immunosuppression in organ transplantation.

Current status of organ transplantation.

Cancers complicating organ transplantation.