Non-immune factors in chronic rejection. Is there a role for hypolipemic drugs?
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Biomedical subjects
Publications and source records attributed to L Gradowska.
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Disturbances of lipid metabolism are considered to play a pathogenetic role in glomerulosclerosis. Since intraglomerular have been proposed to be involved in the pathogenesis of the glomerulosclerosis, we have investigated the influence of LDL on the activity of the cellular proteases. Cathepsins B and L were measured with the aid of fluorometry, and 7-amido-4-methylocoumarin derivates were used as substrates; Z-Arg-Arg-AMC for cathepsin B, Z-Phe-Arg-AMC for cathepsins B and L together. Rat mesangial cells cultured 24 h in medium supplemented with LDL revealed inhibition of cathepsin B activity at concentrations of 250 micrograms LDL/ml medium, lower LDL concentrations were without apparent effect. Since the glomerular accumulation of structural and nonstructural proteins plays an important role in glomerulosclerosis, we conclude that the augmented proteolytic activity of mesangial cells might be one of the pathways located by which hyperlipidemia causes an increased susceptibility to glomerular damage.
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The purpose of the study was to assess TGF-beta and IL-6 urinary excretion (measured with EIA) in 12 IDDM patients (7 F, 5 M, age 20-49 yrs, mean = 33.08) with albuminuria or microalbuminuria. Control group consists of 27 IDDM patients (12 F, 15 M, age 24-59 yrs. mean = 39.5) without albuminuria or microalbuminuria. Urinary excretion of IL-6 was significantly higher (p < 0.05) in IDDM patients with albuminuria (mean = 7.43 +/- 8.29 pg/mg creatinine) than in control group (mean = 3.74 +/- 2.64 pg/mg creatinine). Urinary excretion of TGF-beta was also higher (but not significantly in IDDM patients with albuminuria or microalbuminuria (mean = 42.0 +/- 30.0 pg/mg creatinine) than in control group (mean = 27.0 +/- 20.0 pg/mg creatinine). The data indicate that IL-6 and TGF-beta could be involved in the development of diabetic nephropathy.
Chronic rejection is primarily responsible for the late loss of allografted organs and remains an important clinical problem. Chronic rejection in the kidney is characterised by arteriolosclerosis and nephrosclerosis, glomerulonephritis and interstitial fibrosis. Recently, a large number of studies have indicated that proteolytic enzymes play important roles as mediators of glomerular injury. The aim of the study was to assess intraglomerular fibronectin and laminin contents as well as cysteine proteinases in activity chronically rejected human kidneys. We investigated kidney tissue from graftectomy specimens obtained from 11 patients with end-stage renal disease following chronic rejection. A group of 9 patients undergoing nephrectomy because of cancer served as a control group, but only not involved parts of the kidneys were used. When intraglomerular laminin contents were related to DNA content, significant accumulation in chronically rejected allografts was found in comparison to controls (382 +/- 171 micrograms per microgram DNA and 190 +/- 82 micrograms per microgram DNA, respectively, p < 0.01. The accumulation of fibronectin was higher than in controls, however the difference was not significant. When proteinase activity was related to intraglomerular DNA content, significantly enhanced cathepsin B and L activity was found in rejected kidney allografts (57 +/- 16 nmol AMC/min per mg DNA) in comparison to controls (15 +/- 2 nmol AMC/min per mg DNA). Summarizing, we observed accumulation of fibronectin and laminin in glomeruli and simultaneously an excess of proteolytic activity in human chronically rejected kidneys. The above phenomenon indicates that a very active metabolic process takes place in glomeruli during rejection.
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The major reason for late graft losses is chronic rejection. Recently, a large number of studies have indicated that proteolytic enzymes play an important role as mediators of glomerular injury. The cysteine proteinases cathepsins B and L degrade structural matrix proteins such as type I collagen and laminin. We investigated intraglomerular protease activities in 12 patients after kidney graftectomy because of end-stage renal disease following chronic rejection. A group of 12 patients undergoing nephrectomy because of cancer served as controls using only non-involved parts of the kidney. The activities of cathepsins B and L in homogenates of isolated glomeruli were measured fluorometrically methylcoumarylamide substrates and related to DNA content. In rejected kidney allografts we observed significantly enhanced intraglomerular cathepsin B activity and cathepsin B + L activity.
We evaluated the effects of treatment with interferon (IFN) on liver disease and renal allograft function in ten immunosuppressed cadaver kidney recipients. Two females and eight males (mean age 39 years) with biopsy-proven chronic active hepatitis (n = 8) or persistent hepatitis (n = 2) and serum positive for hepatitis B surface antigen (HBsAg) and HBe antigen (n = 5) or serum positive for anti-HCV antibodies (n = 3) or serum positive for HBsAg, anti-HCV and anti-HDV antibodies (n = 2) received 3 million units IFN thrice weekly of 6 months. All patients responded with a reduction in serum aminotransferase activity and in five of them liver function completely normalized. Three patients among five infected with HBV cleared HBeAg. During the follow-up period liver function remained stable in 9 patients after discontinuation of IFN therapy. Three patients lost their grafts due to rejection 1, 2, and 4 months after IFN therapy, respectively. In six patients renal function remained stable during and after IFN therapy. We conclude that in selected groups of renal allograft recipients IFN can be used safely and effectively for the treatment of chronic viral hepatitis.
Very low subcutaneous doses of standard and low molecular weight heparin inhibited the traffic of sensitized lymphocytes to a graft site, reduced in situ mononuclear cell infiltration and prolonged skin allograft survival in mice. Similar effects were caused by low doses of oral heparin, while higher oral doses prolonged graft survival. Our results suggest that oral heparin may have immunosuppressive properties applicable in clinical transplantation.