Renal accumulation of biglycan and lipid retention accelerates diabetic nephropathy.

Hyperlipidemia worsens diabetic nephropathy, although the mechanism by which renal lipids accumulate is unknown. We previously demonstrated that renal proteoglycans have high low-density lipoprotein (LDL) binding affinity, suggesting that proteoglycan-mediated LDL retention may contribute to renal lipid accumulation. The aim of this study was to determine the relative effect of diabetes and hyperlipidemia on renal proteoglycan content. Diabetic and non-diabetic LDL receptor-deficient mice were fed diets containing 0% or 0.12% cholesterol for 26 weeks, and then kidneys were analyzed for renal lipid and proteoglycan content. Diabetic mice on the high-cholesterol diet had accelerated development of diabetic nephropathy with elevations in urine albumin excretion, glomerular and renal hypertrophy, and mesangial matrix expansion. Renal lipid accumulation was significantly increased by consumption of the 0.12% cholesterol diet, diabetes, and especially by both. The renal proteoglycans biglycan and decorin were detectable in glomeruli, with a significant increase in renal biglycan content in diabetic mice on the high-cholesterol diet. Renal biglycan and renal apolipoprotein B were colocalized, and regression analyses showed a significant relation between renal biglycan and renal apolipoprotein B content. The increased renal biglycan content in diabetic nephropathy probably contributes to renal lipid accumulation and the development of diabetic nephropathy.

Reversibility of renal injury with cholesterol lowering in hyperlipidemic diabetic mice.

Hyperlipidemia is a risk factor for development and progression of diabetic nephropathy. However, it is not known if reduction of hyperlipidemia is protective against progression of disease. The goal of this study was to determine if reduction of hypercholesterolemia could limit progression of diabetic nephropathy. Diabetic and nondiabetic LDL receptor deficient (LDLR(-/-)) mice were fed diets containing either no cholesterol (0%) or high cholesterol (0.12%) for 36 weeks. One group each of diabetic and nondiabetic mice were fed the high-cholesterol diet for 26 weeks then changed to the 0% cholesterol diet for the last 10 weeks. Consumption of the high-cholesterol diet exacerbated the development of diabetic nephropathy with elevations in urine albumin excretion, glomerular and renal hypertrophy, and mesangial matrix expansion. Increased glomerular lipid and apolipoprotein B accumulation was found in diabetic mice that consumed the 0.12% cholesterol diet compared with other groups. However, diabetic mice that changed from the high-cholesterol diet to the 0% cholesterol diet for the last 10 weeks had lower urine albumin excretion and mesangial matrix expansion compared with mice that consumed the 0.12% cholesterol diet throughout. This suggests that hyperlipidemia causes continuous renal injury, and that lowering cholesterol levels by dietary means can improve renal function in diabetic LDLR(-/-) mice.

Dysfunctional transforming growth factor-beta receptor II accelerates prostate tumorigenesis in the TRAMP mouse model.

The contribution of a dysfunctional transforming growth factor-beta type II receptor (TGF beta RII) to prostate cancer initiation and progression was investigated in an in vivo mouse model. Transgenic mice harboring the dominant-negative mutant TGF-beta type II receptor (DNTGF beta RII) in mouse epithelial cell were crossed with the TRAMP prostate cancer transgenic mouse to characterize the in vivo consequences of inactivated TGF-beta signaling on prostate tumor initiation and progression. Histopathologic diagnosis of prostate specimens from the TRAMP+/DNTGF beta RII double transgenic mice revealed the appearance of early malignant changes and subsequently highly aggressive prostate tumors at a younger age, compared with littermates TRAMP+/Wt TGF beta RII mice. Immunohistochemical and Western blotting analysis revealed significantly increased proliferative and apoptotic activities, as well as vascularity and macrophage infiltration that correlated with an elevated vascular endothelial growth factor and MCP-1 protein levels in prostates from TRAMP+/DNTGF beta RII+ mice. An epithelial-mesenchymal transition (EMT) effect was also detected in prostates of TRAMP+/DNTGF beta RII mice, as documented by the loss of epithelial markers (E-cadherin and beta-catenin) and up-regulation of mesenchymal markers (N-cadherin) and EMT-transcription factor Snail. A significant increase in the androgen receptor mRNA and protein levels was associated with the early onset of prostate tumorigenesis in TRAMP+/DNTGF beta RII mice. Our results indicate that in vivo disruption of TGF-beta signaling accelerates the pathologic malignant changes in the prostate by altering the kinetics of prostate growth and inducing EMT. The study also suggests that a dysfunctional TGF beta RII augments androgen receptor expression and promotes inflammation in early stage tumor growth, thus conferring a significant contribution by TGF-beta to prostate cancer progression.

BK virus nephropathy after allogeneic stem cell transplantation: a case report and literature review.

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.

Photon-deficient Mass on FDG-PET Scan in Renal Cell Carcinoma: A Case Report.

F-18 Fluorodeoxyglucose Positron Emission Tomography imaging (F-18 FDG PET) detects malignancies depending on the uptake profile of glycolysis of tumors; however, the role of FDG PET is limited in the evaluation of primary renal malignancy because of low FDG uptake by renal cell carcinoma and also because normal urinary excretion of FDG seen in the images. A patient with renal cell carcinoma whose FDG PET imaging study incidentally shows a photon-deficient mass in the upper pole of the right kidney is present here. The diagnosis is also validated by the histopathological findings of tumor necrosis, hemorrhage, and scars.

2-Deoxy-2-[F-18]fluoro-D-glucose positron emission tomography illustrates two visceral tumors in a post kidney transplant patient with multiple cutaneous malignancies.

The success of renal transplantation brings with it the dilemma of managing patients with complications from lifelong immunosuppressive therapy. Immunosuppressed transplant recipients are a special population with significantly increased risk for development of skin cancers. Because malignant tumors are increasing as demonstrated on 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) positron emission tomography (PET) image, we report the unusual coincidence of multiple cutaneous cancers and two visceral malignancies 20 years after renal transplantation. The malignancies include basal cell and squamous cell carcinomas and malignant fibrous histiocytoma. FDG-PET images show, in this case, visceral masses with increased metabolism: one in the left upper lung and one in the abdomen, corresponding to individual mass lesions observed on computed tomography (CT) images of the chest and abdomen. A fine-needle biopsy of the nodule of the left upper lung lobe yielded a diagnosis of a sarcoma. The mass lesion of the abdomen had caused bowel obstruction, requiring exploratory laparotomy; histopathological findings from the resected mass from the abdomen confirmed the diagnosis malignant fibrous histiocytoma. This long-term immune suppressed transplant recipient developed viscerally located malignant lesions demonstrated by FDG-PET imaging and three types of cutaneous malignancies (skin cancers).

Effect of terazosin on tissue vascularity and apoptosis in transitional cell carcinoma of bladder.

OBJECTIVES: To present a pilot study to determine whether the alpha1-adrenoceptor antagonist terazosin can induce apoptosis in transitional cell carcinoma (TCC) of the bladder, similar to the effect seen with prostate cancer. The alpha1-adrenoceptor antagonist terazosin has recently been shown to induce apoptosis in prostate cancer cells both in vitro and in vivo and to reduce prostatic tissue vascularity by potentially affecting endothelial cell adhesion. METHODS: The records of 24 men who underwent radical cystectomy for TCC of the bladder at the Lexington Veterans Affairs Medical Center were reviewed. The control group consisted of 15 men who were never exposed to terazosin. The study group consisted of 9 men who were treated with terazosin before cystectomy. Sections of the bladder tumor and normal trigone were subjected to immunohistochemical analysis for microvessel density, endothelial cell CD31 expression, and apoptosis detection (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling), as well as high-molecular-weight cytokeratin staining. RESULTS: A significant reduction in tissue vascularity (14.0 versus 19.2, P <0.05) and a significant increase in the apoptotic index (3.0% versus 1.7%, P <0.05) was detected in terazosin-treated bladder tumors compared with untreated bladder tumors. Most TCC specimens (80%) exhibited strong and consistently uniform immunostaining for high-molecular-weight cytokeratin staining. CONCLUSIONS: These results suggest that terazosin reduces tumor vascularity and induces apoptosis in TCC of the bladder. Additional studies with more patients are necessary to reach definitive conclusions. However, considering the proven apoptotic action of terazosin in prostatic tissue, this study may have implications for the use of terazosin in the treatment of bladder TCC.

Scarred atrophic thyroid after I-131 therapy for Graves' disease documented at autopsy.

Radioiodine is used as the definitive treatment of choice in most patients with Graves' hyperthyroidism. Most patients with Graves' disease eventually develop hypothyroidism following I-131 therapy and require thyroid hormone replacement therapy. We present a patient with aortic stenotic cardiac disease and coronary artery disease who suffered from fatigue, weight loss and atrial fibrillation. The patient's radionuclide study, as well as the T4 and TSH, confirmed Graves' disease and he received I-131 therapy. Our patient's development of hypothyroidism following 5 mCi I-131 therapy after seven days later was considered as unusual; in addition, our patient, at autopsy, had documented histopathologic changes confirming atrophy and fibrosis of the thyroid gland.

Angiotensin-converting enzyme genotype and outcome in pediatric IgA nephropathy.

Angiotensin-converting enzyme (ACE) I/D polymorphism has been implicated as a genetic marker for progression of glomerular disease. Studies of ACE genotypes in adults with IgA nephropathy (IgAN) have yielded conflicting results. We performed ACE genotyping on 79 patients with IgAN diagnosed prior to age 18 years who had either progressed to end-stage renal disease (ESRD) or are now more than 5 years post biopsy. Mean follow-up was 14.8 years for those with normal renal function. Forty-three (54.4%) subjects had normal renal function and a normal urinalysis at last evaluation. Sixteen (20%) progressed to ESRD and 1 has chronic renal insufficiency. Kaplan-Meier survival curves for progression to ESRD did not differ significantly for the ACE DD, ID, and II genotype groups (P=0.095, log-rank test). By univariate analysis, presence of hypertension and degree of proteinuria at diagnosis, and unfavorable histology but not ACE genotype, was significantly associated with progression to ESRD. In the Cox proportional hazards model that included grade of proteinuria, the ACE D allele was a significant independent predictor of outcome with a hazard ratio of 2.37 (P=0.031). Our data, while inconclusive, suggest that the ACE D allele may associate with poor outcome in pediatric IgAN.