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Hemoptysis in Renal Transplant Recipients

Background: Hemoptysis is the expectoration of blood from respiratory system. Clinical entities associated with hemoptysis in renal transplant recipients differ from those causing hemoptysis in common population. This review summarizes all reported clinical conditions related to hemoptysis in renal transplant patients, their causes, diagnostic approach and management. Methods and Materials: Primary literature was researched through MEDLINE/PubMed database and Google Scholar without restrictions. Relevant and current literatures related to hemoptysis in renal transplant recipients were used. Results: Overall 23 articles were included, since they report clinical conditions associated with hemoptysis in renal transplant recipients. Opportunistic lung infections, pulmonary hemorrhage associated with drugs and malignancies are usual causes of hemoptysis in these patients, sometimes with a fatal outcome. Conclusions: Hemoptysis is an important manifestation in renal transplant patients, caused frequently by rare clinical entities, different from those in common population.


Introduction
Hemoptysis is the expectorating of blοod or blood-stained mucus from the respiratory system. Common causes of hemoptysis in developed countries include lung cancer, bronchiectasis and acute bronchitis, while in developing countries Mycobacterium tuberculosis and Paragonimus westermani lung infections and noncystic fibrosis (CF) related bronchiectasis are more frequent causes [1]. In addition, bleeding disorders such as thrombocytopenia, disseminated intravascular anticoagulation, platelet dysfunction syndromes and von Willebrand disease) and use of anticoagulant or antiplatelet medications may lead to non-life-threatening or life-threatening hemoptysis [2][3][4].
The lung parenchyma is mostly supplied by the low-pressure pulmonary artery circulation, from which most episodes of hemoptysis are originated. In contrast, the bronchial artery circulation is a high-pressure circulation, originating from the systemic circulation, that supplies mostly the endobronchial tree. Hemorrhage from a bronchial artery is the cause of life-threatening hemoptysis in the most of the cases, although the bronchial artery circulation is responsible for only 2% of the total lung supply [5].
Renal transplant recipients, as immunocompromised hosts, present pulmonary complications, mostly infections, like invasive aspergillosis, with hemoptysis as a characteristic manifestation, sometimes with a fatal outcome. In addition, medications and localized causes of lung hemorrhage like malignancies must also be considered in differential diagnosis of hemoptysis in these patients [6]. This review summarizes all reported clinical conditions associated with hemoptysis in renal transplant patients. It also summarizes their causes, that differ frequently from common causes of hemoptysis and their diagnostic approach.

Methods and Materials
An electronic search in MEDLINE/PubMed and Google Scholar was conducted with the keywords "Hemoptysis" AND "Renal Transplant Recipients" OR "Kidney Transplant Recipients" OR "Renal Transplant Patients" OR "Kidney Transplant Patients" with English language limitation. All articles were accurately screened by two authors, and those reporting data on hemoptysis in renal transplant recipients were included. The reference list of each document that could be identified with our criteria was also hand-searched for detecting other eligible studies.

Results
Overall, 100 articles were originally identified using our search criteria and from the reference list of the previously identified documents. Following elimination of duplicates, 77 were excluded after screening of title, abstract or full text, since they did not report the occurrence of hemoptysis in renal transplant recipients or they were not written in English language. Table 1 summarizes the studies describing clinical conditions associated with hemoptysis in renal transplant recipients, their causes, diagnostic approach, and management. Lung infections, pulmonary hemorrhage associated with drugs and malignancies are usual causes of hemoptysis in these patients. Imaging with chest X-ray and computed tomography (CT), bronchoscopy and microbiological evaluation of body fluids are important diagnostic tools.  [6].
Mucormycosis is an increasingly emerging life-threatening invasive fungal infection, especially in immunocompromised hosts [10]. This infection has been reported as a cause of hemoptysis in renal transplant recipients [11][12][13].
Additionally, other unusual pathogens have been demonstrated as causative factors of hemoptysis in renal transplant recipients. Legionella pneumophila has been mentioned as a causative agent of lower respiratory tract infection in renal transplant recipients complicated with hemoptysis [14,15].
Rhodococcus equi, a gram-positive coccobacillus bacterium, is another unusual microorganism associated with lung mass and endobronchial malakoplakia leading to hemoptysis in renal transplant recipients [16,17].
Besides, parasites have been described to cause pulmonary infection with hemoptysis in renal transplant recipients, especially in endemic countries. Strongyloides stercoralis pulmonary infection has been described to cause dyspnea, bilateral infiltrates and hemoptysis in renal transplant recipients [18,19] Kwon et al. presented a case of renal transplant recipient who was admitted because of hemoptysis, a pulmonary cavity and right adrenal gland mass. Infection due to Paragonimus westermani was confirmed from biopsy specimens of wedge resection of the lung and adrenalectomy [20].

Drug-Induced Pulmonary Hemorrhage
Therapeutic agents have been associated with pulmonary hemorrhage presenting with the symptom of hemoptysis in kidney transplant patients. Nitrofurantoin has been reported to cause diffuse infiltrates and worsening hemoptysis in a renal transplant recipient [21]. The immunosuppressive agent azathioprine has also been described as cause of pulmonary hemorrhage and hemoptysis in a renal transplant patient [22].
Sirolimus, also called as rapamycin, which is a macrolide compound that is utilized for preventing organ transplant rejection, has been associated with alveolar hemorrhage, lung infiltrates and hemoptysis in kidney transplant recipients [23,24].
Alemtuzumab, a monoclonal antibody that binds to CD52 protein on the surface of mature lymphocytes, is another drug related to pulmonary hemorrhage leading to hemoptysis in renal transplant recipients. Pulmonary hemorrhage associated with alemtuzumab induction therapy has been reported in two patients with Alport syndrome who developed acute dyspnea and hemoptysis after renal transplantation [25,26]. Anandh et al. described a 46-year-old man, renal transplant recipient, who presented with cough and hemoptysis on 1st posttransplant day. Mycophenolate sodium was thought the potential cause of hemoptysis. The withdrawal of the drug resulted in patient's improvement [27].

Malignancies
Rare types of malignancies have been reported as underlying causes of hemoptysis in renal transplant patients. Kaposi sarcoma is a well established human herpesvirus-8 (HHV-8) driven complication of renal transplantation and immunosuppression with lung involvement. It is an uncommon malignancy thought to arise from precursor endothelial cells in a multicentric pattern resulting in tumor of mixed vascular and fibroblastic origin [28]. Kaposi sarcoma of the lung has been described to cause pulmonary hemorrhage, bilateral pulmonary infiltrates and hemoptysis [28] and acute hypoxic respiratory failure and hemoptysis [29] in renal transplant recipients.
Pulmonary metastatic angiosarcoma is a rare cause of hemorrhage, traditionally showing multiple nodules on chest CT. Pulmonary metastatic angiosarcoma leading to hemoptysis has been diagnosed in two cases of renal transplant recipients [30].

Investigations for hemoptysis
Imaging Chest X-ray is the initial diagnostic modality for the investigation of underlying cause of hemoptysis in renal transplant recipients providing useful information about the location and characteristics of the lung lesions [6-8, 9, 11-13, 15-17, 19-122, 24-27, 29]. In several cases, chest X-ray guides the physicians to possible diagnoses without the need of chest CT [5, 8, 11-13, 19, 22]. Chest CT is a more sensitive imaging tool for the detection of pulmonary abnormalities responsible for hemoptysis in renal transplant patients, facilitating the identification of the area for bronchoscopic approach and narrowing the differential diagnosis of hemoptysis [8-9, 12-13, 16, 18, 21, 24-29]. In addition, chest CT allows the image-guided needle aspiration biopsy of thoracic lesions, establishing the final cause of hemoptysis [8,12].
Positron Emission Tomography (PET) has been used to differentiate benign lung lesions from nonbenign abnormalities in cases that the suspicion of malignancy is high [21,31]. Transesophageal echocardiogram is another imaging tool that has been utilized in a case of an angiosarcoma of the right atrium, metastatic to bones and lungs, causing hemoptysis in a kidney transplant recipient [30].

Bronchoscopy
The role of traditional methods to diagnose lung infections is limited in immunocompromised renal transplant recipients [31]. Suspected lung infection is the most common indication for bronchoscopy among solid organ recipients. Bronchoscopy has been used in the diagnostic approach of hemoptysis in renal transplant recipients in order to provide inspection of bronchial tree for discovering potential site of active bleeding and to obtain bronchoalveolar lavage (BAL), bronchial washings, bronchial brushings, bronchial biopsies, endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) biopsies of mediastinal lesions and transbronchial biopsy (TBB) for histological and microbiological examination [7-13, 11, 13, 15-16, 18, 22, 24-30].

Thoracentesis and Pleural Drainage
Thoracentesis and drainage of pleural fluid have been performed in some cases of hemoptysis, that pulmonary lesions are accompanied by pleural effusion, in order to examine the fluid for pathogenic microorganisms or abnormal cytology [15,30].

Microbiological Evaluation-Serological Testing
Microbiological evaluation of different specimens and body fluids, with microscopic examination, culture and evaluation with polymerase chain reaction (PCR), has an important role in the investigation of hemoptysis in renal transplant recipients, confirming or excluding specific infections [6-9, 12, 14-16, 18-20, 22, 24-26, 28-29]. Serological testing for antibodies (IgG and IgM) to specific microorganisms has also been used for the diagnosis of underlining lung infections in renal transplant recipients with hemoptysis [15,21].

Surgical Procedures
Surgical procedures have been utilized for the diagnostic approach of hemoptysis in renal transplant recipients in cases when investigation with imaging, bronchoscopic techniques and microbiology/ serology testing did not reveal a diagnosis or in order to confirm a controversial diagnosis. Thoracotomy with lobectomy, thoracotomy with lung biopsy and video assisted thoracoscopic wedge resection of the lung have been used for obtaining lung tissue and establish the underlying diagnosis of hemoptysis [8,13,[20][21].

Discussion
Ηemoptysis in renal transplant recipients, as immunocompromised patients, can occur in the context of infections (tuberculosis, mycetoma, invasive pulmonary aspergillosis, necrotizing parenchymal pneumonia, parasitic infection) [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]32]. Hemoptysis can also occur in the context of post-transplant malignancy due to immunosuppression (bronchial cancer, pulmonary metastases from other primary site) [28][29][30]33], in the context of potential drug toxicity [21][22][23][24][25][26]34], use of anticoagulants or antiplatelet agents [34], pulmonary embolism [35] or bronchiectasis due to recurrent pulmonary infections [36]. According to the existing literature, it cannot be concluded whether one or another reasons could lead to better or worse outcomes. Table 2 shows potential conditions leading to hemoptysis in renal transplant recipients. Physicians should keep in mind that the course of hemoptysis is unpredictable. Thus, the management is standardized, including several steps. The first steps include confirming the diagnosis of hemoptysis and assessment of its severity. The next step should focus to localize the site and find the cause of hemoptysis. Finally, the most appropriate therapeutic approach should be decided. It is of great importance, in case of severe hemoptysis, locating the site of bleeding and administering specific treatment including maintenance of free airways, to be performed simultaneously with identifying the cause of bleeding. Therefore, chest-X-ray, chest CT scan and bronchoscopy are essential procedures in the diagnostic algorithm. Coagulation tests are also useful in case of suspection of coagulation disorder [37]. This review has some limitations. Our results are limited by the quality and extent of the data in the reports. More specifically, case reports are unchecked, and while they can recommend hypotheses, they are not able to confirm robust conclusions. However, clinicians should be aware of even the few number of cases reported in the literature suggesting rare cases of hemoptysis in renal transplant recipients.

Conclusions
In conclusion, hemoptysis is an important respiratory symptom in renal transplant patients. Clinical entities related to hemoptysis in renal transplant patients are different from these in common population. Opportunistic lung infections, drug-induced pulmonary hemorrhage and rare types of malignancy should be taken into account in the differential diagnosis of hemoptysis in these patients. Imaging with chest X-ray and CT, bronchoscopic techniques and microbiological evaluation of body fluids are important diagnostic modalities. Surgical procedures are used less frequently for diagnosis and management, especially when hemoptysis persists or becomes severe despite conservative management.

Declarations of interest
None.

Funding resources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.