Özdemir Bh

Tgf-β Expression In Renal Allograft Rejection And Cyclosporine Toxicity

Background. To assess short- and long-term influence of the TGF-β1 on renal allografts. Methods. Expression of TGF-β1 and TNF-α, and the proportion of macrophages and eosinophils in interstitium were evaluated in 64 cases including five cases with nonrejected kidneys (NRK), 18 cases with acute rejection (AR), 26 cases with chronic allograft nephropathy (CAN), and 15 cases with acute cyclosporine A (CsA) toxicity. Follow-up biopsies of all cases with AR and CsA toxicity were evaluated for development of interstitial fibrosis (IF) and graft atherosclerosis (GAS). Additionally, influence of tubular-TGF-β1 expression on graft function during 6 months after the diagnostic biopsy was evaluated. Results. A significant differences was seen between rejected kidneys and acute CsA toxicity in regards of tubular TGF-β1 expression that patients with CsA toxicity exhibited significantly higher grade of tubular TGF-β1 expression than patients with AR (P<0.05) and CAN (P<0.05). A significant difference was found between the grades of tubular TGF-β1 expression in regards to graft function of cases with AR and CsA toxicity (P< 0.05). Higher grade tubular TGF-β1 expression showed better graft function during 6 months. Besides the degree of renal TGF-β1 expression was positively correlated with development of diffuse IF and GAS (P<0.05) that the risk of the IF and GAS was higher in cases with grade 2 renal TGF-β1 expression. Conclusions. Despite the short-term posttransplantation tubule-repairing effects of TGF-β1, the overall effects of TGF-β1 in the kidney seem to be negative that increased expression of TGF-β1 promotes IF and vasculopathy associated with CAN.

Hypercholesterolemia Impairs Angiogenesis in Patients With Breast Carcinoma and, Therefore, Lowers the Risk of Metastases

Our aim was to study the effect of hypercholesterolemia on angiogenesis induced by breast carcinoma. Of 51 patients with invasive ductal carcinoma, 28 had hypercholesterolemia and 23 had normocholesterolemia. The intratumoral microvessel density (MVD) was evaluated by using anti-CD31 antibody. The expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on endothelial and tumor cells was examined and graded semiquantitatively. Patients with normocholesterolemia had a higher MVD (76.4 +/- 8.2) than those with hypercholesterolemia (54.6 +/- 5.1) (P < .01). The risks of recurrence and distant metastasis were higher in patients with normocholesterolemia than in patients with hypercholesterolemia (P < .01). Patients with hypercholesterolemia showed lower expression of endothelial VEGF and bFGF than patients with normocholesterolemia (P < .05 and P < .01, respectively). In addition, tumoral bFGF and VEGF expression showed negative correlation with the presence of hypercholesterolemia (P < .01). We suggest that hypercholesterolemia impairs angiogenesis by suppressing endothelial and tumoral bFGF and VEGF expression and, therefore, lowers the risk of metastases in cases of invasive breast carcinoma.

Diagnosing amyloid goitre with thyroid aspiration biopsy.

Objective:  The aim of the study was to evaluate the value of fine needle aspiration biopsy of the thyroid as a tool for diagnosing amyloid goitre and assess how amyloidosis affects thyroid tissue and thyroid function.

AMYLOID GOITER IN FAMILIAL MEDITERRANEAN FEVER (FMF): A CLINICOPATHOLOGIC STUDY OF 10 CASES

FMF Amyloidosis is an important etiological factor of end stage renal disease (ESRD) in Mediterranean Countries. Apart from major target organs as cardiovascular, respiratory and gastrointestinal system, endocrine organs can also be involved. We planned to investigate the thyroid involvement in our amyloidosis group. The aim of this study was to determine clinical characteristics of amyloid goiter in FMF patients and the abnormalities of thyroid function, as well as to identify pathologic characteristics. Twenty-two hemodialysis patients (mean age 34.1 ±14 years, range 17–68) whose ESRD secondary to FMF amyloidosis were evaluated with physical examination, serum levels of thyroid hormones, ultrasound examination of thyroid glands, thyroid syntigraphic studies. Goiter was found in 10 patients (4 male, 6 female) having enlarged neck mass (mean age 35 ± 14 years, range 23–64). The serum levels of thyroid hormones and TSH were normal in 4 patients. Other four cases had euthyroid sick syndrome. Only one patient developed tender enlarged neck mass with subacute thyroiditis symptoms and one had primary hyperthyroidism. Ultrasound examination showed; hypoecoic nodules in 6 patients diffuse multinodular enlargement in 4 patients. Thyroid syntigraphic studies revealed hypoactive nodules in 7 patients and hyperactive nodules in 3 patients. After the laboratory tests were completed, in 10 patients diagnosis were made with fine needle aspiration biopsy. Of 10 patients 5 underwent subtotal thyroidectomy. Immunohistochemical evaluation demonstrated the presence of amyloid AA immunoreactivity in all cases. In conclusion fine needle aspiration from the thyroid when enlarged is useful in the diagnosis of suspected amyloidosis, especially since it is a safe, easily performed procedure. With the help of amyloid goiter diagnosis the patients prognosis on hemodialysis and with renal transplantation can be predicted. Amyloid goiter must be searched in hemodialysis patients especially in Mediterranean Countries.

Influence of 1,25-Dihydroxyvitamin D3 on Human Leukocyte Antigen-DR Expression, Macrophage Infiltration, and Graft Survival in Renal Allografts

Vitamin D plays an important role in the regulation of cellular growth and cell proliferation as well as exerting immunoregulatory activities. We sought to show the influence of vitamin D on renal graft survival. Among 102 patients, 40 were treated with vitamin D (group D) and the remaining 62 cases were not, forming a control group (group C). We studied human leukocyte antigen (HLA)-DR expression on tubules, interstitial cells, peritubular capillaries (PTCs), and evaluated macrophage infiltration of the interstitium and the PTCs. Compared to group C, group D patients showed fewer acute rejection episodes. Compared to group C patients group D patients showed significantly lower degrees of tubular and interstitial HLA-DR expression as well as interstitial and PTC macrophage infiltration. In addition in the PTC, HLA-DR expression was greater and therefore PTC destruction less in group D patients (P<.001). Twenty-seven (43.5%) of 62 group C patients lost their grafts at 29.2±15 months, whereas only 7/40 (17.5%) group D patients lost their grafts at 43.2±13 months. A significant difference was noted between the two groups in regard to the time of graft loss (P<.01). Testing vitamin D therapy along with several other covariates showed an independent effect on 5-year graft survival (P<.001). These data confirmed that vitamin D therapy shows an independent positive impact on long-term graft survival, which may be explained by its immunosuppressive effects of to reduce renal HLA-DR expression and renal macrophage infiltration and in turn mitigate PTC destruction. In conclusion, these results highlighted the potential use of vitamin D in renal allograft patients.

A Six-Year Follow-Up After Interferon-Alpha Monotherapy for Chronic Hepatitis C Infection in Hemodialysis Patients

Interferon‐alpha (IFN) has been accepted as an effective treatment for chronic hepatitis C virus (HCV) infection in hemodialysis (HD) patients. We prospectively assess the long‐term clinical, biochemical, and virological effects of interferon in the treatment of HD patients with chronic HCV infection. This study was performed in 20 HCV‐RNA‐positive HD patients with evidence of chronic hepatitis on liver biopsy. The patients received IFN administered after HD sessions in doses ranging from 3 to 6 million units for 6 to 12 months. The patients were followed up for a period of 6 years with determinations of serial alanine aminotransferase (ALT) levels and serum HCV‐RNA. At the time of the final follow‐up, the patients had no cirrhosis or hepatocellular carcinoma. Among the nonresponder group, only 1 patient died due to sudden cardiac death. Sustained normal serum ALT levels occurred in 9 (45%) of the patients. Nine patients had variable ALT levels, and 2 patients had persistently elevated ALT levels. Eight (40%) patients were continuously HCV‐RNA negative, whereas 12 patients (60%) had variable HCV‐RNA results at the end of the 6‐year follow‐up. These findings show that the long‐term clinical, biochemical, and virological response to interferon monotherapy is good in HD patients with HCV infection.

Pauci-immune necrotizing crescentic glomerulonephritis with crescentic and full moon extracapillary proliferation: clinico-pathologic correlation and follow-up study.

The prognostic value of the type and extent of extracapillary proliferation (ECP) in pauci-immune necrotizing crescentic glomerulonephitis (PIGN) was evaluated in this study. In 141 PIGN cases, all glomeruli with ECP were grouped according to type (cellular, fibrocellular and fibrous) and extent of the lesions in Bowmans space; (segmental, semicircumferential and circumferential, which might be termed full moon-FM). Cases with cellular and fibrous lesions involving ≥ 50% of glomeruli with ECP were classified as cellular and fibrous groups, respectively, while the remaining cases were classified as fibrocellular. Cases with segmental and circumferential (FM glomerulus) lesions involving ≥ 50% of glomeruli with ECP were classified as ECPI and ECPIII (FM) groups, respectively, while the rest were classified as ECPII. All the cases were classified according to Berden et al. Significant results were only nearly obtained for the FM group, including the need for dialysis. The Cox regression model revealed a 2.6-fold risk for FM cases regarding dialysis requirement. We propose that the percentage of FM glomeruli should be noted in the pathology report, and cases with more than 50% of FM glomeruli (FM group) should be identified in the group with increased risk of dialysis requirement. Our series also suggests that classification according to Berden et al. is of clinical relevance.

Renal Fanconi syndrome and myopathy after liver transplantation: Drug-related mitochondrial cytopathy?

Abstract:  Advances in the field of transplantation provide a better quality of life and allow more favorable conditions for growth and development in children. However, combinations of different therapeutic regimens require consideration of potential adverse reactions. We describe a 15‐yr‐old girl who had orthotopic liver transplantation because of Wilson’s disease. Tacrolimus, MMF, and steroids were given as immunosuppressant. Lamivudine was added because of de nova hepatitis B infection during her follow‐up. Three yr after transplantation she developed renal Fanconi syndrome with severe metabolic acidosis, hypophosphatemia, glycosuria, and aminoaciduria. Although tacrolimus was suspected to be the cause of late post‐transplant renal acidosis and was replaced by sirolimus, acidosis, and electrolyte imbalance got worse. Proximal muscle weakness has developed during her follow‐up. Fanconi syndrome, as well as myopathy, is well recognized in patients with mitochondrial disorders and caused by depletion of mtDNA. We suggest that our patient’s tubular dysfunction and myopathy may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine.

Seronegative systemic lupus erythematosus: etiology of nephrotic syndrome and acute renal failure in early postpartum period

Systemic lupus erythematosus (SLE) is an autoimmune syndrome that occurs most commonly in women during their reproductive years. Nephritis is known to be one of the most serious complications of SLE. Lupus nephropathy is frequently associated with ANA and anti-dsDNA antibodies. Rarely, serological markers may be initially absent, and in many cases, they become positive after sometime. We present a 28-year old, otherwise healthy female who admitted to our clinic with edema, hypertension, proteinuria and acute renal failure following her fourth delivery. Serum immunological markers were negative and renal biopsy showed histopathological changes consistent with systemic lupus erythematosus as the etiology of nephrotic syndrome. A dramatic therapeutic response was achieved by pulse steroid and cyclophosphamide treatment following oral steroid therapy. In women with new onset nephrotic syndrome or renal function deterioration in postpartum period, even if the patient is asymptomatic or seronegative, it is crucial to exclude SLE for a rapid diagnosis and prompt treatment in the case of lupus nephritis. Renal biopsy is of diagnostic importance in such cases in which there is no other clinical, biochemical and serological evidence of the disease.

Destructive pulmonary effects of smoke inhalation and simultaneous alterations in circulating IL-6, TNF-α, and IFN-γ levels at different burn depths: an experimental study on rats

The current study sought to examine the interactions between inflammatory and immune events in the lung and circulating interleukin-6 (IL-6), tumor necrosis factor-&agr; (TNF-&agr;), and interferon-&ggr; (IFN-&ggr;) levels at different burn depths with concomitant smoke inhalation in the rat model. Forty-eight female Sprague-Dawley rats were divided into six groups: S, sham; P, partial-thickness burns; F, full-thickness burns; I, inhalation; Pi, partial-thickness burns + inhalation; and Fi, full-thickness burns + inhalation. Blood samples and lung biopsies were obtained 24 hours later. Blood levels of IL-6, TNF-&agr;, and IF-&ggr; were measured with enzyme-linked immunosorbent assay. The proportions of CD3(+) lymphocytes and CD68(+) macrophages in the biopsies were studied immunohistochemically. The most severe inflammatory changes, except the neutrophil sequestration, were observed in the Fi group. A dense amount of neutrophils was observed in the F group. Edema and massive alveolar bleeding were seen in the I, Pi, and Fi groups. The amount of CD3(+) lymphocytes were dense in the P, F, and Pi groups. The amount of CD68(+) macrophages were significantly dense in Pi, F, I, and Fi groups. IL-6, TNF-&agr;, and IF-&ggr; increased in all groups when compared to the S group. The highest IL-6 level was seen in the Fi group. TNF-&agr; significantly increased in the F, Pi, I, and Fi groups. Increase in IFN-&ggr; levels in the Pi and Fi groups was significantly higher than in the P and F groups. In concomitant smoke inhalation and skin burns, pulmonary damage and systemic inflammatory response are related and may be evaluated by blood levels of IL-6, TNF-&agr;, and IFN-&ggr; cytokines.