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1 Department of Medicine, University of Colorado at Denver, and Health Sciences Center, Denver, Colorado
Correspondence and requests for reprints should be addressed to Dennis M. Lyu, M.D., 1635 N. Ursula St. F749, Aurora, CO 80045. E-mail: dennis.lyu{at}uchsc.edu
ABSTRACT
As short- and long-term survival rates for lung transplantation continue to improve, and as more lung transplantations are occurring with each year, a multitude of medical complications are encountered by the clinician. This article reviews the long-term non-pulmonary noninfectious medical complications that arise beyond the postoperative period in patients who have undergone lung transplantation. This article reviews the development of renal failure, diabetes, cardiovascular complications of hypertension and atherosclerosis, osteoporosis and avascular necrosis, hematologic complications, thromboembolic disease, gastrointestinial complications, neurologic complications, and malignancy, including post-transplant lymphoproliferative disorder.
Key Words: medical complications • lung transplantation
Lung transplantation has emerged as an effective option in treating a variety of end-stage lung diseases by prolonging life expectancy and by substantially improving quality of life (1). Improvements in surgical techniques, lung preservation, immunosuppression, and management of infections have influenced the improvements in short-term mortality. Long-term survival rates have slightly improved with a 5-year estimated survival rate increasing from 47% in the 1995 through 1999 era to a 5-year survival rate of 52% in the 2000 through 2005 era (2). Bronchiolitis obliterans syndrome (BOS) and non-CMV infection account for the major causes of death after the first year (2). However, nonpulmonary, noninfectious medical complications that arise from lung transplantation also have significant effects on the morbidity and mortality of these patients, and better management of these medical complications may lead to improved long-term outcomes. With slight increases in long-term survival, and with more lung transplants being performed annually, and with a shift toward a larger proportion of older recipients undergoing lung transplantation (2), medical complications are expected to be encountered more frequently. This review article will focus on nonpulmonary, noninfectious medical complications that arise due to immunosuppressive therapy that impact the long-term management of lung transplant recipients.
RENAL FAILURE
Renal dysfunction is one of the most common long-term complications of lung transplant, with an incidence of 25.5% at 1 year after transplant and 37.8 at 5 years after transplant (2). By 6 months after transplant, 91% of lung transplant recipients undergo some degree of renal decline from their baseline pre-transplant level (3). Chronic renal failure with a creatinine greater than 2.5 mg/dl occurs at an incidence of 6.8% at 1 year after transplant and 11.0% at 5 years after transplant (2). The development of chronic renal failure increases the risk of death by four- to fivefold in patients who have undergone lung transplant (4). Long-term dialysis occurs in 1.7% of patients at 1 year and 3.2% of patients at 5 years.
The most common cause of renal failure is due to calcineurin inhibitor nephrotoxicity. In the acute setting, nephrotoxicity is caused by reversible vasoconstriction of afferent and efferent glomerular arterioles, resulting in increase of renovascular resistance by increased levels of the vasoconstrictor, endothelin, and impairing the production of the vasodilatory nitric oxide (5). These resulting adverse effects on the glomerular filtration rate are exacerbated by use of nonsteroidal anti-inflammatory drugs and by renin-angiotensin-aldosterone-system inhibiting drugs. The mechanisms of chronic calcineurin inhibitor nephrotoxicity are not well understood, but histologic features seen are (1) interstitial fibrosis with a striped appearance; (2) chronic arteriolopathy, with replacement of degenerated smooth-muscle cells in the tunica media vasorum with hyaline deposits in a beaded pattern; and (3) tubular atrophy with focal segmental glomerulonephritis (6). Focal segmental glomerulonephritis is seen in more then 50% of nonrenal solid-organ transplant recipients treated with cyclosporine in whom biopsies or autopsies were done (7, 8). Use of tacrolimus within the first 6 months after transplant is associated with less renal dysfunction than cyclosporine in patients who have undergone lung transplant (3).
Other factors that worsen the development of chronic renal failure, and which are in part caused by calcineurin inhibitor use, include hypertension, hyperlipidemia, and diabetes (3, 5, 9). Additional insults to the kidney at the time of transplant due to hypotension, hypoperfusion and aortic cross-clamp, and aggressive diuresis may also increase the likelihood of the development of chronic renal failure (5). Increased levels of calcineurin inhibitor dosing in patients who have undergone lung transplant versus those who have undergone other solid organ transplant can also lead to a higher risk of renal failure.
Management of kidney disease centers around lowering the levels of calcineurin inhibitor if the lower levels of immunosuppression can be tolerated. Associated comorbidities that can worsen renal failure such as hypertension, diabetes, and hyperlipidemia should be aggressively treated (5). The use of ACE inhibitors and angiotensin receptor blockers has been shown to slow the progression of renal disease in renal transplant recipients and in heart-transplant recipients (10, 11). Alternative immunosuppressive agents of mTOR inhibitors, sirolimus and everolimus, and/or mycofenolate mofetil (MMF) to replace or minimize calcineurin inhibitor use can be used to prevent renal failure or decrease the degree of renal failure as measured by BUN and creatinine (9, 12, 13). However, the mTOR inhibitors carry risks of hyperlipidemia and pulmonary toxicity and impairment of airway and wound healing (14, 15).
Other factors than calcineurin inhibitor toxicity should be considered in the setting of acute renal failure. Hemolytic uremia syndrome due to thrombotic microangioapathy secondary to calcineurin inhibitor use has been described (16). Drug toxicities, contrast nephropathy, obstructive nephropathy secondary to nephrolithiasis, and atheroembolism after invasive procedures should also be considered. The role of polyomavirus BK virus on the development of kidney failure is unclear in the nonrenal patient who has undergone transplant (5), although case reports of nephropathy in lung transplant recipients exist (17).
The progression of chronic renal failure ultimately leads to renal replacement therapy in the form of dialysis or renal transplantation. In nonrenal solid-organ transplants, kidney transplant is the treatment of choice as it is associated with a significantly lower mortality than dialysis (4). Given that patients who have not received previous transplants who receive primary kidney transplants have improved outcomes if they received the transplant before the establishment of dialysis, early referral of lung transplantation patients with chronic renal failure for subsequent kidney transplant is recommended (5).
DIABETES MELLITUS
The development of diabetes is a relatively common complication in patients who have undergone lung transplant, with a reported incidence of 24.3% at 1 year after transplant and 33.5% at 5 years after transplant (2). The presence of diabetes in the patient before transplantation confers an increased relative risk of mortality of 1.24 (95% confidence interval, 1.07–1.04). Risk factors leading to the development of diabetes are primarily due to glucocorticoid use and calcineurin inhibitor use, with tacrolimus having a much greater likelihood than cyclosporine of inducing diabetes (18–20). Other risk factors for the development of post-transplant diabetes in patients who have undergone lung transplant include older age of recipients, obesity as defined by BMI greater than 30, and frequent acute rejection episodes that are treated with high dose steroids (21). The development of diabetes has been demonstrated to correlate with an increased risk of infection and cardiovascular disease in other patients who have undergone solid organ transplant (22, 23). In patients who have undergone lung transplant, the development of diabetes has not been shown to correlate with worse outcomes, but this may be due to the relatively poor long-term outcomes of lung transplantation, as patients did not have enough time for the impact of diabetes on organ systems to develop (21). Guidelines for treatment of diabetes for solid organ transplants recommend intervention when patients have fasting glucose levels greater 126 mg/dl and hemoglobin A1C levels greater than 6.5% (24).
CARDIOVASCULAR COMPLICATIONS
The immunosuppressive medication of lung transplantation results in contributing to the development of cardiovascular comorbidities of hypertension, hyperlipidemia, diabetes, and renal disease. Hypertension is seen in 51.9% of patients who have undergone lung transplant at 1 year and in 85.6% of patients at 5 years (2). Hyperlipidemia is seen in 20.5% of patients who have undergone lung transplant at 1 year and in 52.2% of such patients at 5 years (2). Cardiovascular cause of death accounts for less than 5.3% of deaths in patients who survive longer than 1 year (2). This low percentage is in part likely due to standard pre-screening of lung transplant recipients with cardiac catheterization. However, with improving survival rates with each era, and an increasing recipient age, acute coronary syndromes are more likely to be encountered with increasing frequency.
Hyperlipidemia due to steroids and calcineurin inhibitor should be aggressively treated due to its well-established links to atherosclerosis. The use of HMG Co-A reductase inhibitor medications (statins) has been shown to effectively lower cholesterol levels while demonstrating decreased acute rejection episodes and prevention of bronchiolitis obliterans syndrome when the statins were started in the within the first year of transplant (25). Patients on statin medication had better spirometry readings and improved mortality. The effectiveness of statin medication in preventing acute rejection and BOS may be due to antiinflammatory mechanisms (26, 27). Goals of therapy should be for total cholesterol levels less than 200 mg/dl. Goals of hypertension control should follow standard recommendations for the general population regarding targets of systolic and diastolic blood pressure (28).
OSTEOPOROSIS
Osteoporosis is a complication of lung transplantation that can cause significant negative impact on quality of life and on morbidity due to related fractures. Solid organ transplantation has long been established to be associated with a high incidence of osteopenia and osteoporosis (29). The use of corticosteroids and other immunosuppressive medications are believed to have the largest impact of causing osteoporosis, although other factors are implicated as well (30). Osteopenia is defined by a bone mineral density (BMD) T-score of 1 to 2.5 standard deviations below the mean of a young healthy patient. Osteoporosis is defined by a T-score of less than 2.5 standard deviations below the mean of a young healthy patient (31). Patients with end-stage lung disease awaiting transplantation are already at higher risk of osteoporosis secondary to tobacco use, prior corticosteroid use, and diminished mobility (32). Patients with cystic fibrosis have additional risk factors of hypogonadism, malnutrition, impaired absorption of vitamin D and calcium, and increased levels of bone-resorbing cytokines (33, 34). The incidence of osteoporosis in patients awaiting lung transplantation is estimated to be between 32 and 54% (35–38).
Osteoporotic bone loss appears to be accelerated in the first 3 to 6 months after transplant for all solid-organ transplants as measured by decreases in BMD scores (36, 39–41). This accelerated bone loss in the early post-transplant months is also seen in patients who have undergone lung transplant (36, 42). Within the first year of lung transplant, the post–lung transplant fracture rate ranges from 6 to 18% and a loss in BMD of 4 to 12% is reported (35–38).
Therapy for prevention and treatment of osteoporosis begins with calcium and vitamin D supplementation with a minimum of 1,000 mg/day of calcium and 800 IU/day of vitamin D (29). Regular weight-bearing exercises may also be important for prevention and treatment of osteoporosis (43). Studies of calcium and vitamin D supplementation only in lung transplant recipients have shown no impact in preventing the development of osteoporosis (36–38, 44). Estrogen and hormone replacement therapy in combination with calcium and vitamin D supplementation in liver transplant and cardiac transplants have been shown to prevent decreases in BMD (45, 46). However, use of hormonal replacement therapy is not with out risk in the transplant population due to the increased risk of thromboembolic disease. Calcitriol has been demonstrated in patients who have undergone lung transplant to decrease the rate of bone loss within the first year after transplant (47, 48) when compared with historical control. However, calcium levels and urinary calcium levels need to be monitored in patients on calcitriol.
The most effective therapy in patients who have undergone lung transplant involves antiresorptive therapy with the use of bisphosphonate medication, either with intravenous administration of pamidronate, or oral bisphosphanate medication in decreasing the rate of BMD loss (48, 49). Reduction of fracture rate by bisphophonates in patients who have undergone transplant has not been proven (29, 49, 50). The greatest effect of bisphosphonates in reducing bone loss occurred when medication was started before transplantation when patients were on the waiting list (42). Guidelines for solid-organ transplants, which can be applied to patients who have undergone lung transplant, are to evaluate all pre-transplant candidates for osteoporosis by DEXA scan, and to begin bisphosphonate therapy on anyone with defined osteopenia or osteoporosis and to continue treatment for at least 6 to 12 months after transplantation (29, 51), with the possibility of indefinite therapy (42).
AVASCULAR NECROSIS
Avascular necrosis of the femoral head is a common occurrence in solid-organ transplant recipients, with an estimated prevalence of 3 to 22% (52, 53). In one study of 63 patients who had undergone lung transplant, an incidence of avascular necrosis of 10% was identified (54). The use of steroids is linked to the development of avascular necrosis (55). Early recognition of the possibility of avascular necrosis of the femoral head in the lung transplant patient presenting with hip and knee pain can be of utmost importance, as MRI scans have a sensitivity of 85 to 100% and early joint-sparing procedures such as core decompression and vascularized fibular grafting can obviate the need for full hip joint replacement (52).
HEMATOLOGIC COMPLICATIONS
Cytopenia is the most common hematologic complication of lung and other solid-organ transplants, and occurs due to bone marrow-suppressive immunosuppression medication, namely azathioprine and mycophenolate mofetil and cytoxan, as well as prophylactic antiinfectious medication such valganciclovir, acyclovir, and trimethoprim/sulfamethoxazole (56, 57). Renal failure that develops in patients who have undergone lung transplantmay also impact the development of anemia. Iron deficiency (57, 58) and low erythropoietin levels independent of renal disease (58) are also prevalent in patients who have undergone lung transplant. The use of erythropoietin with iron supplementation has been shown to improve hemoglobin levels in patients who have undergone lung transplant (59).
Infections such as parvovirus B19, CMV, EBV, and other viral infections must always be considered (60–62). Hemolytic anemias due to minor ABO-mismatch can occur, usually with formation of anti-ABO antibodies from graft donor lymphocytes against recipient erythrocytes (63, 64). Self-limited, idiopathic episodes of hemolytic anemia, usually within the first year after transplant and responsive to steroids, have been reported (65). Cyclosporine and tacrolimus have both been associated with thrombotic microangiopathy in which hemolytic anemia is associated with platelet aggregation, resulting in thrombosis of microvasculature and thus manifesting as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) (66). Graft-versus-host disease resulting in bone marrow aplasia has also been described (67).
THROMBOEMBOLIC DISEASE
Venous thromboembolism disease, which includes deep venous thrombosis and pulmonary embolism, has an increased incidence in lung transplant recipients, with a reported incidence of 8.6 to 29% (68–73). Patients that have undergone other solid-organ transplantation have a high incidence (6–8%) of venous thromboembolism as reported in kidney transplants and kidney-pancreas transplants (74–76).
The time of onset from transplantation to thromboembolic event varies from each study, with two studies reporting a median time of 47 to 69 days (73, 77), and another reporting a mean time of 11 months with the earliest event occurring at 3 months (69).
The etiology for the increased incidence of thromboembolism in patients who have undergone lung transplant is unclear, but risk factors may be advanced age, diabetes, concomitant pneumonia, greater immobility, and a higher incidence of indwelling cather placement with PICCs and central venous catheters (77). The possibility of acquired hypercoagulable state has also been raised (69).
Treatment consists of standard heparin followed by warfarin for long-term anticoagulation. Pulmonary embolism can cause significant morbidity to patients who have undergone lung transplant by placing them at high risk for pulmonary infarction, given that the dual blood supply from the bronchial artery is absent or poorly developed (70, 72). Due to this risk, thrombolytic therapy, either systemic or catheter directed, can be used as initial treatment for pulmonary embolism (68). Consideration of an IVC filter should be undertaken (68, 70). The length of long-term warfarin therapy has not been standardized in the lung transplant population. Some recommendations are for indefinite therapy so long as there are no adverse side effects (68).
GASTROINTESTINAL COMPLICATIONS
Long-term gastrointestinal complications are common in lung transplant recipients, likely due to higher doses of immunosuppressive medications. In the immediate postoperative transplant period, ileus and colonic perforation are the most commonly encountered gastrointestinal problems, and these can be life-threatening (78–80). Long-term common complaints are of nausea, vomiting, gastroesophageal reflux disease, diarrhea, constipation, and abdominal pain (81). It is estimated that over 60% of patients who have undergone lung transplant have at least one gastrointestinal complaint, and while mild, it can have significant impact on the quality of life of these patients (81).
Nausea is the most common gastrointestinal complaint, which is likely due to the medication side effects of calcineurin inhibitors and valgancyclovir (81). In cases of refractory nausea, gastroparesis should be excluded, as gastroparesis is estimated to occur in about 24% of lung transplant recipients, and usually responds to some degree to promotiltiy agents such as metoclopramide (82).
GERD has been demonstrated to have a high prevalence in patients with end-stage lung disease (83), and lung transplantation has been shown to increase the likelihood of GERD (84). GERD and aspiration have been linked to the development of BOS, and the use of Nissen fundoplication to curtail the development of BOS is becoming more widespread (78, 84, 85). This is discussed in detail in another article.
Severe gastrointestinal complications that occur include appendicitis, pancreatitis, cholecystitis, and diverticulitis (81). Gastrointestinal hemorrhage due to peptic ulcer disease can occur, and Barrett's esophagus and esophageal cancer should be evaluated for in cases of upper gastrointestinal hemorrhage. Hematochezia or melena should prompt imaging and colonoscopy to pursue ischemic colitis, colon cancer, pseudomembranous colitis, and cytomegalovirus colitis. PTLD in the gastrointestinal tract can manifest with gastrointestinal hemorrhage and pain. Patients with cystic fibrosis patients who undergo lung transplantation are at increased risk for additional gastrointestinal complications such as gastric bezoars and distal intestinal obstruction syndrome (DIOS), which can be a serious post-transplant complication (86).
NEUROLOGIC COMPLICATIONS
One study of 100 patients who had undergone lung transplant reported an incidence of 26% of patients having a neurologic complication in the form of severe headaches, seizures, strokes, and confusion (87). The majority of complications were due to calcineurin inhibitor toxicity or infections. The mechanism of calcineurin inhibitor toxicity is unknown, and is not necessarily related to elevated levels of cyclosporine or tacrolimus (87). Manifestations of calcineurin inhibitor toxicity include confusion, tremor, parasthesias of hand and feet seizure, blindness, and encephalopathy (88). Usually, the substitution of cyclosporine for tacrolimus, or vice versa, corrects the neurotoxicity. CT and MRI findings consist of bilateral white matter abnormalities suggestive of edema and without infarction in the posterior regions of the brain (89).
MALIGNANCY
Patients who have undergone solid-organ transplant are known to have a higher prevalence of malignancy than the general population (90). Some estimates place a three- to fourfold increase in the risk of malignancy in solid-organ transplants compared with the general population, while the relative risk of specific cancers may be increased by 100-fold (90–92). The incidence of malignancy may be even higher in patients who have undergone lung transplant than in those who have undergone other solid-organ transplants (93). The prevalence of malignancy in patients who have undergone lung transplant is reported to be 3.7% in 1-year survivors, 12.4% in 5-year survivors, and 25% in 10-year survivors (2). Beyond the first year, malignancy accounts for 9.3% of deaths. The highest incidence of malignancy in lung transplant is skin cancers and post-transplantation lymphoproliferative disorder (PTLD), with PTLD being the most common cancer in the first 2 years after transplantation, and skin cancers the most common malignancy after the second year (2, 93, 94).
Current guidelines absolutely exclude patients with malignancy within 2 years of candidacy for lung transplantation, and recommend excluding patients with malignancy within 5 years of candidacy (95). Even with this pre-screening bias, there is a higher incidence of cancer in patients who have undergone lung transplant than in the general population. There are currently no consensus guidelines for cancer screening and prevention for post-transplant guidelines, but general recommendations are for a minimum of adherence to general cancer screening guidelines (96). Given the high frequency of potentially aggressive skin cancers, patients should be evaluated by a dermatologist at least once a year.
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
PTLD comprises a spectrum of disorders that arise in post-transplant patients that are due to abnormal lymphoid proliferation. Histologically, PTLD ranges from benign polyclonal hyperplasia to malignant monoclonal lymphoma (97, 98). Clinical presentation of PTLD in patients who have undergone lung transplant widely varies from nodal local involvement to extranodal and disseminated involvement (99). The reported incidence of PTLD ranges from 1.3% to 20% depending on the center, with a typical range of 2 to 8% (100–103). In patients who have undergone lung transplant, PTLD usually involves the thorax in 69 to 89% of cases (104, 105), and usually involves the allograft (100, 106–108), with the abdomen being involved in 20 to 34% of cases (16, 100, 108). PTLD can also manifest in mucosal tissue of the gastrointestinal tract and bronchial airway and the skin (44, 109, 110). PTLD typically occurs within the first year after transplant (101, 107). Later-presenting PTLD in patients who have undergone lung tranplant is less likely to involve the allograft lung and usually incurs a worse prognosis (107).
The pathogenesis of PTLD is related to reactivation of the Epstein-Barr Virus (EBV), and usually involves B cells (76–95%) (100, 111–115), with T cell proliferation constituting 14% of PTLD (116, 117). Primary risk factors for the development of PTLD are pretransplant seronegative EBV status and intensity of immunosuppression (116, 118, 119).
Treatment is centered around lowering immunosuppression. Immunotherapy with rituximab, an anti-CD20 monoclonal antibody, has been used with success for PTLD in solid-organ transplants and in lung transplants (120, 121). Depending on the circumstance, surgery, radiation therapy, and/or chemotherapy are used in combination with lowering of immunosuppression and rituximab (101, 122).
CONCLUSIONS
As the overall expected survival in patients who have undergone lung transplant has improved, and as more patients live longer, long-term medical complications that arise as a consequence of immunosuppressive therapy are seen more frequently. These complications can have significant impact on the quality of life of lung transplant recipients, and can impact mortality as well. Early recognition of these complications, and therapy directed to prevent these complications, may lead to reduced morbidity and mortality in patients who have undergone lung transplant.
FOOTNOTES
Supported by Cardiovascular Medical Research and Education Fund for the Pulmonary Hypertension Breakthrough Initiative.
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 1, 2008; accepted in final form September 30, 2008)
REFERENCES
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