Expression of cyclooxygenase-1 and cyclooxygenase-2 in human renal allograft rejection-- a prospective study.

Cyclooxygenases (COX) are known to be involved in inflammatory kidney diseases. However, there are no data available about the expression of COX-1 and only preliminary reports about the expression of COX-2 in biopsies of patients undergoing acute renal allograft rejection. We conducted this prospective study to analyze the expression, distribution, and cellular localization of COX-1 and -2 and thus to elucidate the role of COX in human kidney transplantation. One hundred forty-four biopsies were included from patients without rejection and unaltered morphology (n = 60), with acute interstitial rejection (n = 7), with acute vascular rejection (n = 21), with chronic allograft nephropathy (n = 16), without rejection but with various other lesions (n = 40). COX-1 and -2 expression was localized in each biopsy by immunohistochemistry. We found a highly significant up-regulation of COX-1 in vessels and in infiltrating interstitial cells of patients with acute allograft rejection compared with biopsies with well-preserved tissue. Also, COX-2 expression was significantly elevated in infiltrating interstitial cells of biopsies with acute rejection. This is the first prospective study demonstrating a significant induction of both COX-1 and -2 in human allograft biopsies with acute rejection after renal transplantation.

Expression of the chemokine receptor CXCR3 in human renal allografts--a prospective study.

BACKGROUND: Mechanisms involved in the recruitment and activation of inflammatory cells during renal allograft injury are still incompletely understood. Since chemokines play pivotal roles in this process, our prospective study was performed to evaluate further the role of the chemokine receptor CXCR3. METHODS: A total of 138 biopsies were included from patients without rejection and unaltered morphology (according to Banff 97 classification grade 1, n = 49), with acute interstitial rejection (Banff grade 4 type I, n = 8), with acute vascular rejection (Banff grade 4 type II, n = 23), with chronic allograft nephropathy (Banff grade 5, n = 16), without rejection but with various other lesions (Banff grade 6, n = 36) and from pre-transplant kidneys (n = 6). The expression of CXCR3-, CD4- and CD8-positive cells was localized by immunohistochemistry and quantified by image analysis. RESULTS: CXCR3 was expressed by infiltrating inflammatory cells, but not by intrinsic renal structures. CXCR3-positive cells were found to be involved in tubulitis and vascular rejection. The area of CXCR3-positive staining was significantly larger in biopsies with acute interstitial rejection (P<0.001) and acute vascular rejection (P<0.001) as compared with normal renal graft biopsies. There was a strong morphological and numerical correlation between CXCR3 and both CD4- and CD8-positive T cells, respectively. CONCLUSIONS: A significant part of both CD4- and CD8-positive T cells express the chemokine receptor CXCR3. During renal allograft rejection, the number of these cells increases significantly at the site of injury and might be targeted by CXCR3 blocking agents.

Clinical management of large adrenal cystic lesions.

The widespread use of ultrasonography and computed tomography has resulted in an increased diagnosis of large sized adrenal cysts with diameters of more than 5 cm. Most of these adrenal cystic lesions are clinically silent and are therefore often diagnosed incidentally. Since up to 7% of adrenal cysts are malignant, a careful hormonal, morpho-functional and instrumental evaluation is mandatory. In particular, functioning adrenal carcinomas or pheochromocytomas have to be ruled out. Fine needle aspiration cytology as well as examination of a punch biopsy specimen of the cystic wall are of limited value, as there is considerable overlap in cytologic and histologic features of benign and malignant adrenal cystic lesions. Immediate surgical excision is indicated in the presence of symptoms, suspicion of malignancy, increase in the size or detection of a functioning adrenal cyst. En bloc adrenalectomy, preferably by a laparoscopic approach, has become the treatment of choice.

Solid-organ transplantation in HBsAg-negative patients with antibodies to HBV core antigen: low risk of HBV reactivation.

Hepatitis B virus (HBV) reactivation is a well-described event in HBV surface antigen (HbsAg)-positive patients undergoing immunosuppression. There are only few data about the risk of HBV reactivation in HBsAg-negative solid-organ transplant recipients with resolved HBV infection. We conducted a systematic screening of serum and liver samples from 38 HBsAg-negative and anti-HBV core antigen (anti-HBc)-positive patients for the presence of HBV-DNA and for serologic HBV markers before and after solid-organ transplantation (kidney, n=23; liver, n=9; heart, n=6). Pretransplant prevalence of HBV-DNA was 24% (6/25) in serum and 33% (3/9) in liver samples. Forty-four percent (15/34) of the recipients were viremic after transplantation; this finding was more common in patients coinfected with hepatitis C (P=0.011) and in patients negative for anti-HBs (P=0.001). Two recipients became antigenemic (HBsAg-positive), but none developed clinical signs of hepatitis. In conclusion, subclinical reactivation of HBV infection was detected in a significant proportion of HBsAg-negative solid-organ-transplant recipients.

Binding of the chemokine SLC/CCL21 to its receptor CCR7 increases adhesive properties of human mesangial cells.

BACKGROUND: Adherence of human mesangial cells to the surrounding matrix contributes to glomerular homeostasis and is important for the maintenance of glomerular architecture and function in normal adult human kidney. The expression of chemokines and corresponding chemokine receptors on adjacent intrinsic renal cells indicates a novel chemokine/chemokine receptor function on nonimmune cells important for glomerular homeostasis. A constitutive expression of the chemokine SLC/CCL21 on human podocytes and of its corresponding receptor CCR7 on mesangial cells was shown before. SLC/CCL21 has a positive effect on proliferation and migration of mesangial cells and leads to increased cell survival in Fas-induced apoptosis. In leukocytes chemokines mediate integrin-dependent firm adhesion. Therefore, we examined the influence of chemokine receptor CCR7 activation by SLC/CCL21 on adhesive properties of human mesangial cells to matrix molecules. METHODS: Adhesion assays, mechanical detachment assays, and evaluation of integrin activation by integrin-linked kinase activity were performed. Changes in the cytoskeletal F-actin were illustrated by phalloidin immunofluorescence staining. RESULTS: SLC/CCL21 stimulation enhanced adhesiveness to fibronectin in a time- and concentration-dependent manner. SLC/CCL21 also increased the firmness of mesangial cells adhesion as judged by detachment assays. Furthermore activation of integrin-linked kinase occurred with SLC/CCL21 addition to mesangial cells, resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and protein kinase B (PKB/Akt). Exposure of mesangial cells to SLC/CCL21 also resulted in F-actin rearrangements with membrane ruffling and extensions leading to bridging between mesangial cells. CONCLUSION: Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts. This includes integrin-linked kinase activation and F-actin rearrangements. Thus, local chemokine generation and chemokine receptor expression on mesangial cells may play an important role in the maintenance of glomerular homeostasis and in local remodeling processes.