Alterations in the ubiquitin proteasome system in persistent but not reversible proteinuric diseases.

Podocytes are the key cells affected in nephrotic glomerular kidney diseases, and they respond uniformly to injury with cytoskeletal rearrangement. In nephrotic diseases, such as membranous nephropathy and FSGS, persistent injury often leads to irreversible structural damage, whereas in minimal change disease, structural alterations are mostly transient. The factors leading to persistent podocyte injury are currently unknown. Proteolysis is an irreversible process and could trigger persistent podocyte injury through degradation of podocyte-specific proteins. We, therefore, analyzed the expression and functional consequence of the two most prominent proteolytic systems, the ubiquitin proteasome system (UPS) and the autophagosomal/lysosomal system, in persistent and transient podocyte injuries. We show that differential upregulation of both proteolytic systems occurs in persistent human and rodent podocyte injury. The expression of specific UPS proteins in podocytes differentiated children with minimal change disease from children with FSGS and correlated with poor clinical outcome. Degradation of the podocyte-specific protein α-actinin-4 by the UPS depended on oxidative modification in membranous nephropathy. Notably, the UPS was overwhelmed in podocytes during experimental glomerular disease, resulting in abnormal protein accumulation and compensatory upregulation of the autophagosomal/lysosomal system. Accordingly, inhibition of both proteolytic systems enhanced proteinuria in persistent nephrotic disease. This study identifies altered proteolysis as a feature of persistent podocyte injury. In the future, specific UPS proteins may serve as new biomarkers or therapeutic targets in persistent nephrotic syndrome.

Association of linear ¹8F-sodium fluoride accumulation in femoral arteries as a measure of diffuse calcification with cardiovascular risk factors: a PET/CT study.

BACKGROUND: The aim of this study was to correlate linear (18)F-sodium fluoride accumulation in the femoral arteries as a measure of diffuse mineral deposition in medial elastocalcinosis with cardiovascular risk factors (RFs) and calcified plaque burden (CPB). METHODS AND RESULTS: In this study, 409 patients were examined by (18)F-sodium fluoride positron emission tomography/computed tomography (PET/CT). Tracer accumulation was analyzed both qualitatively and semiquantitatively by measuring the target-to-background ratio, and compared with cardiovascular RFs and CPB. Linear (18)F-sodium fluoride accumulation was observed in 159 (38.9%) patients and correlated significantly with age (P < .0001), hypertension (P < .0001), hypercholesterolemia (P = .0003), diabetes (P = .0003), history of smoking (P = .0007), prior cardiovascular events (P = .03), and CPB (P < .0001). The prevalence of linear tracer uptake increased as the number of cardiovascular RFs increased (P < .0001). CONCLUSIONS: Linear (18)F-sodium fluoride uptake in the femoral arteries (1) provides a measure of diffuse mineral deposition, (2) demonstrates a highly significant correlation with cardiovascular RFs and CPB, and (3) is found to accumulate more frequently in patients with a high-risk profile for cardiovascular events. (18)F-sodium fluoride PET/CT may become a unique tool for in vivo visualization and quantification of ongoing calcification in large arteries.

Atypical mycobacteriosis caused by Mycobacterium haemophilum in an immunocompromised patient: diagnosis by (18)F-FDG PET/CT.

We report a rare case of atypical mycobacteriosis diagnosed by F-FDG PET/CT. A 28-year-old man with a history of kidney transplantation presented with fever, painful nodular skin lesions, and elevated inflammatory markers. FDG PET/CT demonstrated multiple subcutaneous, cutaneous, and osseous areas of increased tracer uptake. Histopathologic and microbiological evaluation revealed disseminated infection with Mycobacterium haemophilum. FDG PET/CT is a valuable tool for early and correct diagnosis of occult sources of infection in immunocompromised patients.

Comparative diagnostic performance of ¹8F-FDG PET/CT versus whole-body MRI for determination of remission status in multiple myeloma after stem cell transplantation.

OBJECTIVES: To compare the diagnostic performance of whole-body magnetic resonance imaging (WBMRI) versus (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) for determination of remission status in patients with multiple myeloma (MM) after stem cell transplantation (SCT). METHODS: Thirty-one patients were examined by both WBMRI and PET/CT after SCT. Imaging results and clinical remission status as determined by the clinical gold standard (Uniform Response Criteria) were compared. RESULTS: One hundred four lesions were detected in 21 patients. PET/CT had a sensitivity of 50.0 %, a specificity of 85.7 %, a positive predictive value of 62.5 %, a negative predictive value of 78.3 %, and an overall accuracy of 74.2 % for determination of remission status. MRI had a sensitivity of 80.0 %, a specificity of 38.1 %, a positive predictive value of 38.1 %, a negative predictive value of 80 %, and an overall accuracy of 51.6 %. Concordant results were observed in only 12 (11.5 %) of the 104 lesions. CONCLUSIONS: In the post-treatment setting, both FDG PET/CT and WBMRI provide information about the extent of disease, allowing for a more comprehensive evaluation of persisting or recurrent myeloma. MRI may often be false positive because of persistent non-viable lesions. Therefore, PET/CT might be more suitable than MRI for determination of remission status.

Comparative effectiveness of 18F-FDG PET/CT versus whole-body MRI for detection of malignant peripheral nerve sheath tumors in neurofibromatosis type 1.

PURPOSE: The aim of this study was to compare the diagnostic performance of ¹8F-fluorodeoxyglucose (FDG) PET/CT and whole-body MRI for the detection of malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1, and to evaluate a panel of imaging-based criteria serving that purpose. PATIENTS AND METHODS: Thirty-one patients were examined by whole-body MRI and ¹8F-FDG PET/CT. A panel of imaging-based criteria including tumor region, size, shape, margin definition, contrast enhancement, heterogeneity before and after contrast, intratumoral lobulation, target sign, and mean and maximum standardized uptake values (SUVs) were evaluated. A SUVmax cut-off value of 3.5 was used for lesion analysis. Histopathologic evaluation and/or clinical follow-up served as the reference standard. RESULTS: ¹8F-FDG PET/CT had a sensitivity of 100%, whereas MRI had a sensitivity of 66.7%. On PET/CT, tumor size (P<0.005), SUVmax (P<0.0001), SUVmean (P<0.0001), and tracer uptake heterogeneity (P=0.002) were significantly associated with MPNSTs. On MRI, intratumoral lobulation (P<0.02), ill-defined margins (P=0.007), and irregular enhancement on T1-weighted imaging (P<0.001) were significantly associated with MPNSTs. CONCLUSIONS: Both PET/CT and whole-body MRI may distinguish benign and malignant PNSTs, but PET/CT has higher sensitivity for that purpose. Imaging-based criteria for identification of MPNSTs on both modalities were identified. False-positive results, requiring biopsy or clinical follow-up, may be reduced by using a combination of MRI and PET derived markers, but only at the price of reduced sensitivity.

Ubiquitin C-terminal hydrolase-l1 activity induces polyubiquitin accumulation in podocytes and increases proteinuria in rat membranous nephropathy.

Ubiquitin C-terminal hydrolase L1 (UCH-L1), a key protease of the ubiquitin-proteasome system (UPS), is associated with neurodegenerative diseases and cancer. Recently, de novo expression of UCH-L1 was described in podocytes in patients with membranous nephropathy (MN), in which UCH-L1 expression correlated with increased ubiquitin content. The objective of the present study was to investigate the role of UCH-L1 in ubiquitin homeostasis and proteasomal degradation in a rat model of MN. After disease induction, UCH-L1 expression increased in podocytes and coincided with decreased glomerular monoubiquitin content. After an initial increase in proteasomal activity, the UPS was impaired. In addition to an increase of ubiquitin in podocytes, aggregates were observed 1 year after disease induction, as in MN in human beings. Inhibition of UCH-L1 hydrolase function in MN reduced UPS impairment and ameliorated proteinuria. In contrast, inhibition of proteasomal activity enhanced UPS impairment, resulting in increased proteinuria. Stable UCH-L1 overexpression in cultured podocytes resulted in accumulation of monoubiquitin and polyubiquitin proteins. In contrast, stable knock-down of UCH-L1 reduced monoubiquitin and polyubiquitin proteins and significantly increased proteasomal activity, indicating that the observed effects in rat MN also occurred in cultured podocytes. These data demonstrate that UCH-L1 activity results in polyubiquitin accumulation, proteasome inhibition, and disease aggravation in experimental models of MN.