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Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens.

Kirby S, Satoskar A, Brodsky S, Pope-Harman A, Nunley D, Hitchcock C, Pelletier R, Ross P, Nadasdy T, Shilo K - Diagn Pathol (2012)

Bottom Line: While these new therapies lead to better graft survival, they can also cause a variety of complications.Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, The Ohio State University Medical Center, Columbus, USA.

ABSTRACT

Background: After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications.

Methods: A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications.

Results: The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.

Conclusions: Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.

Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395.

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Pathological findings in patients with sirolimus toxicity. In case 4, open lung biopsy shows diffuse alveolar hemorrhage represented by collections of hemosiderin laden alveolar macrophages (A, inset) and occasional hemosiderin granules within interstitium, (hematoxylin-eosin, original magnification x100 and x400, respectively). In case 10, open lung biopsy shows pulmonary hemorrhage in association with pulmonary alveolar proteinosis and organizing pneumonia: there are areas with hemosiderin deposition within interstitium (B) and cholesterol granulomas, finely granular proteinaceous material with cholesterol clefting (C) and foci of organizing pneumonia (D) in adjacent alveolar parenchyma, (hematoxylin-eosin, original magnification x100, x200 and × 40, respectively). Computed tomography of the chest at the time of open lung biopsy shows diffuse ground glass and "crazy pavement" opacities (E). Follow up computed tomography in 8 months (F) shows marked decrease in alveolar opacities; both scans are at the level of aortic arch for comparison. In case 16, open lung biopsy shows a combination of diffuse alveolar damage and pulmonary hemorrhage: there are edematous alveolar septae lined by hyaline membranes (G) and hemosiderin-laden macrophages (H) within alveolar spaces (H&E, original magnification x200 and x400, respectively).
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Figure 2: Pathological findings in patients with sirolimus toxicity. In case 4, open lung biopsy shows diffuse alveolar hemorrhage represented by collections of hemosiderin laden alveolar macrophages (A, inset) and occasional hemosiderin granules within interstitium, (hematoxylin-eosin, original magnification x100 and x400, respectively). In case 10, open lung biopsy shows pulmonary hemorrhage in association with pulmonary alveolar proteinosis and organizing pneumonia: there are areas with hemosiderin deposition within interstitium (B) and cholesterol granulomas, finely granular proteinaceous material with cholesterol clefting (C) and foci of organizing pneumonia (D) in adjacent alveolar parenchyma, (hematoxylin-eosin, original magnification x100, x200 and × 40, respectively). Computed tomography of the chest at the time of open lung biopsy shows diffuse ground glass and "crazy pavement" opacities (E). Follow up computed tomography in 8 months (F) shows marked decrease in alveolar opacities; both scans are at the level of aortic arch for comparison. In case 16, open lung biopsy shows a combination of diffuse alveolar damage and pulmonary hemorrhage: there are edematous alveolar septae lined by hyaline membranes (G) and hemosiderin-laden macrophages (H) within alveolar spaces (H&E, original magnification x200 and x400, respectively).

Mentions: In case 4, a 54 year old woman was admitted with recurrent shortness of breath for the fourth time in the five months following kidney transplant. The patient had a past medical history of chronic obstructive pulmonary disease and congestive heart failure with basic oxygen requirements of 3-4 l via nasal cannula. On her current admission she was in severe respiratory failure, requiring mechanical ventilation. Her trough sirolimus levels following transplantation were within range from 4.0 to 17.1, (mean, 8.8), normal 3-20 ng/ml. A chest CT on admission showed diffuse ground glass opacities and pleural effusions. Endobronchial biopsy was nondiagnostic, while a subsequent open lung biopsy showed collections of hemosiderin laden macrophages occupying alveolar spaces as well as hemosiderin granules within interstitium (Figure 2A). Evaluation for infectious organisms and vasculitis was negative. Since treatment for infection did not produce any significant improvement, sirolimus toxicity was suspected and sirolimus was discontinued. The patient returned to baseline respiratory status (3-4 l of oxygen) with improvements in bilateral opacities radiologically within 6 months. Following discharge, the patient required a single readmission for respiratory symptoms over the subsequent 33 months. At that time she was admitted for respiratory failure and subsequently expired. Postmortem examination revealed extensive hemosiderin deposition and a left upper lobe adenocarcinoma.


Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens.

Kirby S, Satoskar A, Brodsky S, Pope-Harman A, Nunley D, Hitchcock C, Pelletier R, Ross P, Nadasdy T, Shilo K - Diagn Pathol (2012)

Pathological findings in patients with sirolimus toxicity. In case 4, open lung biopsy shows diffuse alveolar hemorrhage represented by collections of hemosiderin laden alveolar macrophages (A, inset) and occasional hemosiderin granules within interstitium, (hematoxylin-eosin, original magnification x100 and x400, respectively). In case 10, open lung biopsy shows pulmonary hemorrhage in association with pulmonary alveolar proteinosis and organizing pneumonia: there are areas with hemosiderin deposition within interstitium (B) and cholesterol granulomas, finely granular proteinaceous material with cholesterol clefting (C) and foci of organizing pneumonia (D) in adjacent alveolar parenchyma, (hematoxylin-eosin, original magnification x100, x200 and × 40, respectively). Computed tomography of the chest at the time of open lung biopsy shows diffuse ground glass and "crazy pavement" opacities (E). Follow up computed tomography in 8 months (F) shows marked decrease in alveolar opacities; both scans are at the level of aortic arch for comparison. In case 16, open lung biopsy shows a combination of diffuse alveolar damage and pulmonary hemorrhage: there are edematous alveolar septae lined by hyaline membranes (G) and hemosiderin-laden macrophages (H) within alveolar spaces (H&E, original magnification x200 and x400, respectively).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3344684&req=5

Figure 2: Pathological findings in patients with sirolimus toxicity. In case 4, open lung biopsy shows diffuse alveolar hemorrhage represented by collections of hemosiderin laden alveolar macrophages (A, inset) and occasional hemosiderin granules within interstitium, (hematoxylin-eosin, original magnification x100 and x400, respectively). In case 10, open lung biopsy shows pulmonary hemorrhage in association with pulmonary alveolar proteinosis and organizing pneumonia: there are areas with hemosiderin deposition within interstitium (B) and cholesterol granulomas, finely granular proteinaceous material with cholesterol clefting (C) and foci of organizing pneumonia (D) in adjacent alveolar parenchyma, (hematoxylin-eosin, original magnification x100, x200 and × 40, respectively). Computed tomography of the chest at the time of open lung biopsy shows diffuse ground glass and "crazy pavement" opacities (E). Follow up computed tomography in 8 months (F) shows marked decrease in alveolar opacities; both scans are at the level of aortic arch for comparison. In case 16, open lung biopsy shows a combination of diffuse alveolar damage and pulmonary hemorrhage: there are edematous alveolar septae lined by hyaline membranes (G) and hemosiderin-laden macrophages (H) within alveolar spaces (H&E, original magnification x200 and x400, respectively).
Mentions: In case 4, a 54 year old woman was admitted with recurrent shortness of breath for the fourth time in the five months following kidney transplant. The patient had a past medical history of chronic obstructive pulmonary disease and congestive heart failure with basic oxygen requirements of 3-4 l via nasal cannula. On her current admission she was in severe respiratory failure, requiring mechanical ventilation. Her trough sirolimus levels following transplantation were within range from 4.0 to 17.1, (mean, 8.8), normal 3-20 ng/ml. A chest CT on admission showed diffuse ground glass opacities and pleural effusions. Endobronchial biopsy was nondiagnostic, while a subsequent open lung biopsy showed collections of hemosiderin laden macrophages occupying alveolar spaces as well as hemosiderin granules within interstitium (Figure 2A). Evaluation for infectious organisms and vasculitis was negative. Since treatment for infection did not produce any significant improvement, sirolimus toxicity was suspected and sirolimus was discontinued. The patient returned to baseline respiratory status (3-4 l of oxygen) with improvements in bilateral opacities radiologically within 6 months. Following discharge, the patient required a single readmission for respiratory symptoms over the subsequent 33 months. At that time she was admitted for respiratory failure and subsequently expired. Postmortem examination revealed extensive hemosiderin deposition and a left upper lobe adenocarcinoma.

Bottom Line: While these new therapies lead to better graft survival, they can also cause a variety of complications.Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, The Ohio State University Medical Center, Columbus, USA.

ABSTRACT

Background: After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications.

Methods: A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications.

Results: The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.

Conclusions: Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.

Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395.

Show MeSH
Related in: MedlinePlus