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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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Abstract: Acute humoral rejection (AHR) in kidney transplantation is associated with higher rates of allograft loss when compared with acute cellular rejection (ACR). Treatment with intravenous immunoglobulin (IVIG) combined with plasmapheresis (PP) has been used recently in many centers. We report the incidence, clinical characteristics, and outcome of patients with AHR treated with IVIG and PP. All patients (n = 519) at our institution who underwent kidney transplantation between January 1999 and August 2003 were retrospectively analyzed and classified according to biopsy results into three groups: AHR, ACR, and no rejection. AHR was diagnosed in 23 patients (4.5%) and ACR in 75 patients (15%). Mean follow-up was 844 ± 23 days. Female sex, black race, and high panel-reactive antibody were risk factors for AHR. Most AHR patients (22 of 23) were treated with IVIG and PP. Two-year graft survival was numerically worse in patients with AHR versus ACR (78% vs. 85%, p = 0.5) but the difference was not statistically significant. Graft survival after AHR treated with IVIG and PP is much better than it has been historically. IVIG in combination with PP is an effective treatment for AHR. Graft survival in this setting is similar to graft survival in patients with ACR. [Copyright &y& Elsevier]

Spectrum of disease in familial focal and segmental glomerulosclerosis. Background. Focal segmental glomerulosclerosis (FSGS) is the underlying pathologic entity in 5% of adults and 20% of children with end-stage renal disease (ESRD). FSGS is generally considered to be sporadic in origin. Methods. Recently, we identified 60 families involving 190 individuals with familial FSGS, providing evidence for a subset of families in which a genetic form is segregating. Each family had at least one member with renal biopsy-confirmed FSGS and at least one other member with either renal biopsy-confirmed FSGS or ESRD. Results. Twenty-six families had individuals affected in more than one generation [multigeneration (MG)], and the remaining 34 families had only a single generation (SG) affected. There was equal representation of males and females among affected individuals. Ten percent of MG families were African American, and 52% of SG families were African American. The mean age of presentation was significantly higher in the MG families (32.5 ± 14.6 years) compared with the SG families (20.1 ± 12.1 years, P = 0.0001). SG cases had higher levels of proteinuria at presentation (7.0 ± 5.6 g/24 hr, compared with 3.8 ± 3.4 g/24 hr, for the MG families, P = 0.002). On renal biopsy, tubulointerstitial damage was more severe in patients in the SG families than in the MG families; however, the level of glomerular damage did not differ between these groups. Fifty percent of the patients had progressed to ESRD by the age of 30 years. Variables measured at presentation that were independently associated with poor renal survival were decreased age, increased serum creatinine, and increased urinary protein excretion. Forty-one patients underwent successful renal transplantation, with a 10-year graft survival rate of 62%. One patient developed clinical and biopsy evidence of recurrence of FSGS in the allograft. Conclusion. These data confirm the existence of a... [ABSTRACT FROM AUTHOR]

Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. Background. Familial forms of focal segmental glomerulosclerosis (FFSGS) that exhibit autosomal dominant or recessive patterns of inheritance have been described. The genetic basis of these hereditary forms of FSGS is unknown. One recent study of a kindred from Oklahoma with an autosomal dominant form of FSGS linked this disease to a region of chromosome 19q. In addition, polymorphisms in a gene in this region on chromosome 19q13 have been linked to congenital nephrotic syndrome of the Finnish type. We have ascertained and characterized a large family with autosomal dominant FFSGS (Duke 6530). Methods. Families were compared for clinical and genetic heterogeneity. To test for linkage of our family to this portion of chromosome 19, genomic DNA was isolated from 102 family members, and polymerase chain reaction was performed using eight microsatellite markers that spanned the area of interest on chromosome 19. Data were evaluated using two-point linkage analysis, multipoint analysis, and an admixture test. Results. Linkage was excluded at a distance of ±5 to 10 cm for all markers tested with two-point log10 of the odds of linkage (LOD) scores and from an approximate 60 cm interval in this area of chromosome 19q via multipoint analysis. Conclusions. FSGS has been called the “final common pathway” of glomerular injury, as it is a frequent pathological manifestation with diverse etiologies. This diversity likely correlates with the genetic heterogeneity that we have established. Thus, our data demonstrate that there are at least two genes responsible for this disease, and there is genetic as well as clinical heterogeneity in autosomal dominant FSGS. [ABSTRACT FROM AUTHOR]