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Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from January 1, 2000 to November 1, 2017 using the text "transplant transbronchial." The diagnosis field for all cases retrieved was then searched for the text "cellulose." These cases were queried for patient demographics and outcomes. Between January 1, 2000 and November 1, 2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in 2 of our cases was favored to be donor derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.

Rationale: The main hindrance to long-term success of lung transplantation is bronchiolitis obliterans syndrome (BOS), generally thought to be a manifestation of chronic allograft rejection. BOS is associated histologically with epithelial injury, bronchocentric mononuclear inflammation, and fibrosis of small airways known as bronchiolitis obliterans (BO). Few studies have directly compared clinical, radiographic, and histologic findings of BOS and BO, particularly in the era of improved immunosuppression and infection prophylaxis. Patients undergoing pulmonary retransplantation for BOS provide a unique opportunity to investigate these relationships., Methods: All patients who underwent pulmonary retransplantation for BOS from 1992 to 2004 at Duke University Medical Center were reviewed. Pathology findings in explanted lung allografts were compared with clinical, radiographic, and transbronchial biopsy data., Results: Over the 12-year study period, 12 patients underwent pulmonary retransplantation for BOS. The median time to BOS was 517 days (intraquartile range, 396 to 819.8 days). BOS scores prior to retransplantation were 2 in 2 patients and 3 in 10 patients. We developed a semiquantitative scoring system for epithelial, inflammatory, and fibrotic changes in affected airways to permit better comparison between BO and BOS. Somewhat surprisingly, only 50% (6 of 12 patients) had severe fibrotic changes, although all had some degree of epithelial injury, fibrosis, or inflammation centered around the bronchi and bronchioles. Furthermore, pathology findings other than BO were present in most explanted allografts and included cholesterol clefts (n = 4), focal invasive aspergillosis (n = 1), interstitial fibrosis (n = 2), and chronic vascular rejection (n = 1)., Conclusions: In this series of patients with advanced BOS undergoing retransplantation, at least some degree of BO was present in all explanted allografts. However, the degree of epithelial changes, fibrosis, and inflammation present among affected bronchi varied considerably. Furthermore, a wide range of pathologic processes of potential clinical significance were evident in half of the patients. We conclude that significant histologic heterogeneity exists among patients undergoing retransplantation for BOS, potentially contributing to the variability of patient responses to treatment.

Background: Cytomegalovirus (CMV) is the most important opportunistic pathogen in lung transplant recipients and is associated with direct and indirect morbidity. Infection or disease with CMV is often diagnosed through detection of the virus in the blood, culture of bronchoalveolar lavage fluid, or histologic examination of lung tissue obtained on transbronchial biopsy. Endobronchial lesions involving the virus have received little attention, however., Methods: We reviewed the records of 76 endobronchial biopsies obtained at our institution from January 1999 through October 2004 and performed a detailed examination of the specimens and clinical histories for all patients with biopsy evidence of bronchial CMV infection., Results: We identified three patients with endobronchial CMV infection, manifested in each case as an endobronchial polyp. On histologic examination of the endobronchial biopsy specimens, cells with cytopathic effects characteristic or suggestive of CMV infection were present in two cases, and immunohistochemical staining confirmed the presence of CMV in all three. All patients were clinically well with normal chest X-rays before biopsy. Two of three patients had multiple subsequent episodes of CMV disease., Conclusions: To our knowledge, this is the first report of endobronchial polypoid CMV disease in lung transplant recipients. Our results suggest that biopsy of endobronchial lesions in pulmonary allografts should be pursued to establish a definitive etiology.

Background: Lung transplantation is an established treatment modality for a number of chronic lung diseases. Long-term survival after lung transplantation is limited by chronic allograft dysfunction, usually manifested by bronchiolitis obliterans syndrome. We describe a case series with upper lobe fibrosis, a novel presentation of chronic allograft dysfunction., Methods: We reviewed lung transplants at the Toronto General Hospital and Duke University Hospital from 1990 to 2002 and identified patients with upper lobe fibrosis., Results: Thirteen of 686 patients (6 women) developed upper lobe fibrosis (Toronto, 9; Duke, 4); 12 of 13 had bilateral transplants. The median age at diagnosis was 42 years (range, 19-70). Primary diagnoses were cystic fibrosis, 6; emphysema, 4; sarcoidosis, 1; and pulmonary fibrosis, 2 patients. Radiographic diagnosis was made at a median of 700 days post-transplant (range, 150-2,920). Pulmonary function tests demonstrated predominantly a progressively worsening restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of obliterative bronchitis, bronchiolitis obliterans obstructive pneumonia, and aspiration. Nine patients died at a median follow-up of 2,310 days (range, 266-3,740), 8 due to respiratory failure., Conclusion: Upper lobe fibrosis is a novel presentation of chronic allograft dysfunction in lung transplant recipients and is differentiated from bronchiolitis obliterans syndrome on the basis of physiologic and radiologic findings.

Intravenous injection of drugs that contain insoluble foreign material can lead to pulmonary embolization of the material and can have devastating results, including pulmonary hypertension and death. Most cases are detected after the onset of extensive, irreversible damage, precluding potentially life-saving intervention, or are detected at autopsy. We report here a case of microcrystalline cellulose embolization in a lung transplant recipient detected at routine transbronchial biopsy, and we describe the circumstances associated with the development of this condition and its clinical outcome.

Introduction: Posttransplant lymphoproliferative disorder (PTLD) is a relatively infrequent but devastating complication that occurs after solid-organ transplantation. Although the optimal treatment for this condition is unknown, rituximab, a murine/human chimeric monoclonal antibody, has shown promise in the treatment of PTLD. In this report, we define the incidence, clinical features at presentation, and response to treatment of all cases of PTLD observed at our institution over a 10-year period, including four patients who received treatment with rituximab., Methods: A review of all patients who underwent lung or heart-lung transplant at Duke University from 1992 to 2002 was performed (n = 400), and demographic and clinical outcome data were extracted., Results: PTLD was observed in 10 of 400 patients (2.5%). Patients who acquired PTLD were predominantly > 55 years old (8 of 10 patients) and with a native disease of COPD (7 of 10 patients). Diagnosis of PTLD was made a median of 343 days after transplant. The type of transplant and Epstein-Barr virus (EBV) status prior to transplant did not appear to influence the risk for PTLD. Patients presented with thoracic organ involvement (7 of 10 patients), extrapulmonary disease (2 of 10 patients), or both (1 of 10 patients). Histologic subtypes included polymorphic B cell (n = 4), monomorphic B cell (n = 3), B cell without further classification (n = 2), and anaplastic T cell (n = 1). Only one patient responded to reduced immunosuppression alone. Patients treated with surgery or radiation (n = 2) or rituximab (n = 4) had favorable responses to therapy. Both patients treated with chemotherapy died related to complications of treatment and PTLD., Conclusions: Presentation and histologic appearance of PTLD varies considerably among lung transplant recipients. PTLD was more frequent among older patients with COPD, regardless of pretransplant EBV serology. Rituximab appears effective as a first-line therapy for PTLD, but additional studies are needed in order to define its efficacy and side effect profile in this population of patients.