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Transforming growth factorbeta1 (TGF-beta1) is the main modulator of the healing process after tissue injury. In the kidney, if TGF-beta1 release is not switched off, extracellular matrix components (ECM) are accumulated and tissue fibrosis occurs. Urinary TGF-beta1 levels reflect its renal production and it has been determined in various types of glomerular disease. In this review, a critical analysis of the different immunoassays that have been used for the measurement of TGF-beta1 in the urine is presented and the importance of the serial determination of urinary TGF-beta1 levels in patients with various types of renal disease is discussed., (Copyright 2006 S. Karger AG, Basel)

Background: Endothelin-1 (ET-1), which acts via the specific receptors ET-A and ET-B, has been implicated in the development of renal scarring. The activation of the endothelin system was observed in experimental models of glomerular diseases and was attributed to the toxic action of proteinuria on the tubular epithelial cells. The aim of this study was to investigate whether the endothelin system in the kidney is altered in glomerular diseases and possibly related to proteinuria., Methods: Thirty-seven patients with different types of glomerulonephritis and 14 controls were included. Patients presented either nephrotic syndrome (n=25) or mild proteinuria (<1g/24h, n=12). The expression of ET-A and ET-B receptors in the renal tissue was examined immunohistochemically. At the time of biopsy, urinary ET-1 was determined., Results: Both receptors were mainly localized within tubular epithelial cells, and their expression was significantly higher in patients with glomerulonephritis compared to controls. The expression of ET-B was higher in nephrotic compared to non-nephrotic patients, while no difference was observed in the expression of ET-A receptors. A significant positive correlation of the degree of proteinuria with the excreted ET-1 (r= 0.487, p<0.05) and the extent of immunostaining for ET-B receptors (r=0.420, p<0.05) was observed. The expression of ET-B receptors and the excretion of ET-1 decreased significantly in patients with remission of nephrotic syndrome after therapy., Conclusion: This study provides evidence that the endothelin system is activated in human glomerular disease, confirming data from experimental studies. Proteinuria seems to be related to the activation of endothelin system, though further investigation is necessary to clarify this issue.

Background: Transforming growth factor-beta(1) (TGF-beta(1)) is the major fibrogenic growth factor implicated in the pathogenesis of renal scarring. Proteinuria is a poor prognostic feature for various types of glomerular disease and its toxic action may be related to the activation of tubular epithelial cells towards increased production of cytokines and chemoattractant peptides. In this work we studied the site of synthesis and expression profile of TGF-beta(1) in the renal tissue of patients with heavy proteinuria and examined the relation of this expression with the urinary excretion of TGF-beta(1)., Methods: Twenty-five patients with heavy proteinuria (8.4+/-3.0 g/24 h) were included in the study. All patients underwent a diagnostic kidney biopsy and were commenced on immunosuppressive therapy with corticosteroids and cyclosporin. The sites of synthesis and expression profile of TGF-beta(1) mRNA and protein in the kidney were examined by in situ hybridization and immunohistochemistry. Urinary and plasma TGF-beta(1) levels were determined by ELISA before the initiation of treatment and 6 months later and compared with those of normal subjects and of patients with IgA nephropathy and normal urinary protein excretion., Results: The site of synthesis and expression of TGF-beta(1) in the renal tissue of patients with heavy proteinuria was mainly localized within the cytoplasm of tubular epithelial cells. Interstitial expression was also present but glomerular TGF-beta(1) expression was found only in patients with mesangial proliferation. Urinary TGF-beta(1) excretion was significantly higher in nephrotic patients compared with normal subjects and with patients with IgA nephropathy and normal urinary protein excretion (783+/-280 vs 310+/-140 and 375+/-90 ng/24 h, respectively; P<0.01). In patients with remission of proteinuria after immunosuppressive therapy, urinary TGF-beta(1) excretion was significantly reduced (from 749+/-290 to 495+/-130 ng/24 h; P<0.01), while in patients with persistent nephrotic syndrome, it remained elevated., Conclusions: The localization of TGF-beta(1) mRNA and protein within tubular epithelial cells, along with its increased urinary excretion in patients with nephrotic syndrome, suggest the activation of these cells by filtered protein towards increased TGF-beta(1) production.

Transforming growth factorβ1 (TGF-β1) is the main modulator of the healing process after tissue injury. In the kidney, if TGF-β1 release is not switched off, extracellular matrix components (ECM) are accumulated and tissue fibrosis occurs. Urinary TGF-β1 levels reflect its renal production and it has been determined in various types of glomerular disease. In this review, a critical analysis of the different immunoassays that have been used for the measurement of TGF-β1 in the urine is presented and the importance of the serial determination of urinary TGF-β1 levels in patients with various types of renal disease is discussed. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β1 is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β1 levels in patients with crescentic nephritis could be used as a marker of response to treatment. Methods: Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β1 was estimated in biopsy sections by immunohistochemistry and urinary TGF-β1 levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β1 levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls. Results: Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β1 levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β1 was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β1 immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05). Conclusion: Increased TGF-β1 renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β1 levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis. [ABSTRACT FROM AUTHOR]

Background. Apoptosis, a gene-directed form of cell death, has been involved in the resolution of renal injury but also in the development of scarring. Bcl-2 and bax are proteins related to apoptotic process that either provides a survival advantage to rapidly proliferating cells(bcl-2) or promote cell death by apoptosis(bax). Various cytokines and growth factors are involved in this process. This study investigates the expression of bcl-2 and bax and the presence of apoptotic bodies in relation to the TGF-β1 expression at the time of diagnosis in the renal biopsies of patients with glomerulonephritis(GN). METHODS: Fifty patients with various types of GN and ten controls were included in the study. Bcl-2, bax and Transforming Growth Factor(TGF-β1) positive cells were detected in kidney biopsies by immunohistochemistry, while apoptotic cells were detected by in situ end labeling of fragmented DNA(ISEL). Morphometric analysis was used for quantitation of immunostaining. RESULTS: The intensity of bcl-2, bax and TGF-β1 immunostaining in the renal tissue of patients with GN was significantly more to the observed in the control biopsies. Bcl-2 and bax were expressed within the epithelial cells of proximal, distal and collecting tubules and in the renal interstitium. Bax and bcl-2 proteins were also identified within the glomeruli in a few patients but their distribution was not related to the type of GN. TGF-β1 was expressed in the cytoplasm of tubular epithelial cells and to a lesser extent in the renal interstitium and glomeruli. A positive correlation of TGF-β1 with the extent of bax immunostaining(r = 0.498, p < 0.05) and an inverse correlation with that of bcl-2(r = − 0.490, p < 0.05) were identified. Apoptotic bodies were identified only in the renal tissue of patients with GN and were mainly localized among tubular epithelial and interstitial cells. CONCLUSION: The intensity of bcl-2 and bax proteins expression and the presence of apoptotic bodies in the renal tissue of patients with GN suggest that apoptotic process is ongoing during the evolution of renal disease. The correlation of TGF-β1 expression with that of apoptosis-related proteins might represent an implication of this growth factor with apoptotic process in the human diseased kidney. [ABSTRACT FROM AUTHOR]