Plasmacytoid urothelial carcinoma: a rapid autopsy case report with unique clinicopathologic and genomic profile.

BACKGROUND: Rapid ("warm") autopsies of patients with advanced metastatic cancer provide important insight into the natural history, pathobiology and histomorphology of disease in treatment-resistant tumors. Plasmacytoid urothelial carcinoma (PUC) is a rare variant of urothelial carcinoma characterized by neoplastic cells morphologically resembling plasma cells. PUC is typically aggressive, high-stage at presentation, and associated with poor outcomes. Recurrence is common in PUC, with the majority of recurrences occurring in the peritoneum. CASE PRESENTATION: Here, we report rapid autopsy findings from a patient with recurrent PUC. The patient had persistent pain after cystoprostatectomy, although initial post-operative imaging showed no evidence of disease. Imaging obtained shortly before his death showed only subtle growth along vascular tissue planes; however, extensive disease was seen on autopsy. Plasmacytoid tumor cells formed sheets involving many serosal surfaces. Molecular interrogation confirmed a mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein in the tumor cells. CONCLUSIONS: The sheet-like growth pattern of PUC makes early phases of disease spread much more difficult to capture on cross-sectional imaging. Alternative forms of surveillance may be required for detection of recurrent PUC, and providers may need to treat based on symptoms and clinical suspicion.

Complications and adequacy of transplant kidney biopsies: A comparison of techniques.

INTRODUCTION: Kidney biopsies are an essential tool in the diagnosis and management of kidney diseases, particularly in kidney transplant recipients. Biopsies carry a risk for serious complications and not all biopsies achieve adequate tissue. We examined the impact of kidney biopsy technique on complications and biopsy adequacy. METHODS: The cohort consisted of consecutive kidney transplant patients undergoing biopsy by one of three techniques: ultrasound localization, real-time ultrasound guidance, and ultrasound-guided trocar placement. Variables of interest included patient characteristics and procedural characteristics. The primary outcome was serious complication attributable to kidney biopsy, and the secondary outcome was biopsy adequacy as defined by Banff criteria. RESULTS: Among 263 patients undergoing biopsy, 27 (10.3%) had a complication (14 with gross hematuria, 10 requiring blood transfusion, 3 requiring an unplanned interventional radiology procedure, 1 kidney loss; no deaths). Complications were more common among patients biopsied using ultrasound-guided trocar compared to real-time ultrasound and ultrasound localization (21.4% vs 7.9% vs 7.1%, respectively, p = 0.008). After adjusting for patient and procedure characteristics, technique was no longer significantly associated with complication. Biopsy adequacy was significantly higher when using ultrasound localization and real-time ultrasound compared to ultrasound-guided trocar (84.6% vs 86.8% vs 69.6%, p = 0.029), and this finding persisted in adjusted analysis. CONCLUSION: Kidney biopsy complications appear to be similar when using any of the three techniques examined in our study. However, ultrasound-guided trocar technique may yield lower biopsy adequacy when compared to non-trocar techniques.

Beyond Criteria and Definitions: Outcome of a Standardized Antibody-Mediated Rejection Protocol with a Diagnostic Schema Different from the Banff 2009 Criteria.

A new clinical diagnostic schema is needed for the diagnosis of antibody-mediated rejection (AMR) in kidney transplant recipients due to the limited utility of C4d staining, lack of standardized quantitative tests for donor specific antibodies, and potential new diagnostic markers. The treatment of AMR remains controversial because previous studies included heterogeneous treatment modalities, small sample sizes, and short follow-up time. At the University of Michigan Transplant Center, 26 patients were diagnosed with AMR based on our diagnostic protocol including C4d-negative AMR in thesetting of graft dysfunction and Banff tissue injury type II (capillaritis) or type III (arteritis). After diagnosis, these patients received six sessions of plasmapheresis (PP) and IVIG (100 mg/kg after the first to fifth PP and 500 mg/kg with the last PP). Our novel finding in this analysis was the association between persistent C1q detection and graft loss. We confirmed that C4d positivity at diagnosis is associated with worse outcomes. Also, we found that response to our treatment protocol is dependent on C4d staining and Banff tissue injury type.

An unusual case of membranous nephropathy associated with an ovarian tumor.

Secondary membranous nephropathy (MN) associated with malignancy is not uncommon in adults, but it is rare in children. We report a 6-year-old girl who developed nephrotic-range proteinuria following diagnosis of a Sertoli-Leydig ovarian tumor. A renal biopsy was performed, which led to the diagnosis of MN. The patient maintained normal renal function and gradually showed improvement in proteinuria over several months without the use of corticosteroids or angiotensin-converting enzyme inhibitors. Our case highlights the importance of performing screening urinalyses in children with tumors to recognize the presence of clinically significant, but potentially asymptomatic kidney disease.

The role of aldosterone blockade in murine lupus nephritis.

BACKGROUND: The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x NZW) F1 murine lupus model. METHODS: Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes. RESULTS: Treatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 microg/ml versus 1,036 microg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 microg/ml versus 614 microg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-gamma, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand. CONCLUSION: Aldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis.

Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus.

Increased monocyte/macrophage (Mphi) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4(+) T cell subset. Furthermore, autoreactive murine CD4(+) T cells that kill syngeneic Mphi in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased Mphi apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased Mphi apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB x SWR (SNF(1)) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c x DBA1 (DBF(1)) non-lupus-prone mice. Lupus-prone mice SNF(1) mice that were treated with clodronate liposomes, but not mice treated with vehicle, developed significant increases in autoantibodies to dsDNA, nucleosomes, and the idiotypically related family of nephritic Abs Id(LN)F(1), when compared with untreated SNF(1) mice. Furthermore, clodronate treatment hastened the onset of proteinuria and worsened SNF(1) lupus nephritis. When compared with vehicle-treated controls, clodronate-treated non-lupus-prone DBF(1) mice developed significantly higher levels of anti-nucleosome and Id(LN)F(1) Abs but did not develop lupus nephritis. We propose that Mphi apoptosis contributes to the pathogenesis of autoantibody formation and organ damage through both an increase in the apoptotic load and impairment in the clearance of apoptotic material. This study suggests that mechanisms that induce scavenger cell apoptosis, such as death induced by autoreactive cytotoxic T cells observed in SLE, could play a pathogenic role and contribute to the severity of the disease.

Regulation of the human taurine transporter by oxidative stress in retinal pigment epithelial cells stably transformed to overexpress aldose reductase.

In diabetes, overexpression of aldose reductase (AR) and consequent glucose-induced impairment of antioxidant defense systems may predispose to oxidative stress and the development of diabetic complications, but the mechanisms are poorly understood. Taurine (2-aminoethanesulfonic acid) functions as an antioxidant, osmolyte, and calcium modulator such that its intracellular depletion could promote cytotoxicity in diabetes. The relationships of oxidative stress and basal AR gene expression to Na+-taurine cotransporter (TT) gene expression, protein abundance, and TT activity were therefore explored in low AR-expressing human retinal pigment epithelial (RPE) 47 cells and RPE 47 cells stably transformed to overexpress AR (RPE 75). Changes in TT gene expression were determined using a 4.6-kb TT promoter-luciferase fusion gene. Compared with RPE 47 cells, in high AR-expressing RPE 75 cells, TT promoter activity was decreased by 46%, which was prevented by an AR inhibitor. TT promoter activity increased up to 900% by prooxidant exposure, which was associated with increased TT peptide abundance and taurine transport. However, induction of TT promoter activity by oxidative stress was attenuated in high AR-expressing cells and partially corrected by AR inhibitor. Finally, exposure of RPE 75 cells to high glucose increased oxidative stress, but down-regulated TT expression. These studies demonstrate for the first time that the TT is regulated by oxidative stress and that overexpression of AR and high glucose impair this response. Abnormal expression of AR may therefore impair antioxidant defense, which may determine tissue susceptibility to chronic diabetic complications.