Fibrosis proximal

Cyclosporine is a macrolide antibiotic and has been used as an immunosuppressive agent. Cyclosporine can cause both renal and nonrenal toxicity. Clinically renal toxicity consists of four discrete syndromes which include acute reversible renal functional impairment, delayed renal allograft function, acute vasculopathy, and chronic nephropathy with interstitial fibrosis. Proximal tubular epithelium is uniquely sensitive to the toxic effect. The toxic effect is characterized by isometric cytoplasmic vacuolations (several small equally sized vacuoles in cytoplasm), necrosis with or without subsequent mineralization, inclusion bodies (giant mitochondria), and giant lysosomes. Acute vasculopathy consists of vacuolization of the arteriolar smooth muscles and endothelial cells leading to necrosis. In some cases, thrombotic microangiopathy develops, characterized by thrombosis of the renal micro vasculature. Long-term treatment with cyclosporine results in chronic nephropathy with interstitial fibrosis (Chamey et al., 2004). 

Renal Effects. The characteristics of early or acute lead-induced nephropathy in humans include nuclear inclusion bodies, mitochondrial changes, and cytomegaly of the proximal tubular epithelial cells dysfunction of the proximal tubules (Fanconi s syndrome) manifested as aminoaciduria, glucosuria, and phosphaturia with hypophosphatemia and increased sodium and decreased uric acid excretion. These effects appear to be reversible. Characteristics of chronic lead nephropathy include progressive interstitial fibrosis, dilation of tubules and atrophy or hyperplasia of the tubular epithelial cells, and few or no nuclear inclusion bodies, reduction in glomerular filtration rate, and azotemia. These effects are irreversible. The acute form is reported in lead-intoxicated children, whose primary exposure is via the oral route, and sometimes in lead workers. The chronic form is reported mainly in lead workers, whose primary exposure is via inhalation. Animal studies provide evidence of nephropathy similar to that which occurs in humans, particularly the acute form (see Section 2.2.3.2). 

Histopathological evidence of renal damage has been observed in lead-exposed workers. Renal ultrastructure and function were examined in five men with heavy occupational exposure to lead (Cramer et al. 1974). In addition, renal function was evaluated in two men from whom renal biopsies were not obtained. PbB levels ranged from 71 to 138 pg/dL. Renal function tests were normal in all except for a reduced glomerular filtration rate in one worker. Two subjects with relatively short exposure to lead (6 weeks and 8 months) and PbB levels of 89-129 pg/dL had intranuclear inclusions in the proximal tubules. Renal biopsies from workers with longer periods of lead exposure (4-20 years, PbB levels of 71-138 pg/dL) had diffuse interstitial or peritubular fibrosis. Glomeruli were normal in all subjects. 

Crohn s disease is granulomatous and in most cases it is a simultaneous disease of the ileum and colon. The primarily inflamed region is the distal ileum, and all intestinal layers are thickened. The mucosal surface is reddened, nodular, and cobblestone-Uke, with mnltiple linear ulcerations. The mucosal layer is thickened by inflammatory infiltrate, the submucosa and serosa by fibrosis, and the serosa by hypertrophy. Chronic nlcerative colitis is a systemic disease that starts at the rectum or the sigmoid colon and progresses proximally to involve the entire left side of the colon. The colonic crypts are the first sites of cell damage and death, and the disease primarily involves the mucosal layer of the intestine. 

Acute exposure to inorganic lead can cause reversible damage to the kidneys, manifested as tubular dysfunction. Chronic exposure to lead, however, causes permanent interstitial nephropathy, which involves tubular cell atrophy, pathological changes in the vasculature, and fibrosis. The most pronounced changes occur in the proximal tubules. Indeed, lead-protein complexes are seen as inclusion bodies in tubular cells, and the mitochondria in such cells have been shown to be altered with impaired oxidative phosphorylation. Clearly, this will influence the function of the proximal tubular cells in reabsorption and secretion of solutes and metabolites. Consequently, one indication of renal dysfunction is amino aciduria, glycosuria, and impairment of sodium reabsorption. 

Oosporein, which is produced primarily by Oospora colo-rans and Caetomium trilaterale, is observed in feed stuffs, cereals and peanuts. It has been reported to be toxic in poultry resulting in nephrotoxicity, and visceral and articular gout. The pathological observations in oosporein toxicity include necrosis of the tubular epithelial cells in the proximal tubules with basophilic casts, hyaline casts in the distal tubules with fibrosis and interstitial pyogranuloma-tous inflammation, urate deposits in various tissues, and proventricular enlargement with mucosal necrosis (Pegram and Wyatt, 1981 Brown et al, 1987). 

The mechanism of action of talc in pleurodesis has not been fully elucidated, although it is thought to stimulate a typical local inflammatory response, with reduced fibrinolytic activity, mesothelial cell injury, and fibroblast proliferation. Pneumonitis or respiratory failure can be secondary to downstream inflammatory mediators from more proximal talc injury (7). This acute-phase inflammatory response is dose-related (8,9) and is inhibited by glucocorticoids (10). Talc may also have an adhesion stimulating quality, since empyema alone stimulates a typical inflammatory response but does not lead to pleurodesis (11). In fact, talc stimulates intercellular adhesion molecule-1 in mesothelial cells (12). The mechanism of chronic fibrosis may involve continuous fibroblast activation by foreign body giant cell released mediators or macrophages. 

Extensive expression of KlM-1 has been found in proximal tubule cells in biopsies from patients with acute tubular necrosis [302]. KlM-1 is also expressed in other conditions where proximal tubules are dedifferentiated, including renal cell carcinoma [303, 304], chronic cyclosporine nephrotoxicity [305], a protein-overload model of tubulointerstitial disease [306], polycystic kidney disease [307], and contrast nephropathy. In several chronic conditions, KlM-1 has been found primarily expressed at the luminal side of dedifferentiated proximal tubules, in areas with fibrosis and inflammation. Independent of the specific disease, renal KIM-1 correlated positively with the extent of renal damage and negatively with renal function. In these patients, urinary levels of KIM-1 were and correlated positively with tissue KIM-1 and negatively with renal function. Thus, KIM-1 is upregulated in renal disease and is associated with renal fibrosis and inflammation. Urinary KIM-1 is also associated with inflammation and renal function, and reflects tissue KIM-1. 

Schwerdt G, Flolzinger FI, Sauvant C, Konigs M, Flumpf FlU, and Gekle M. Long-term effects of ochratoxin A on fibrosis and cell death in human proximal tubule or fibroblast cells In primary culture.Toxicology 232 57-67, 2007. 

Figure 3. Sequential renal biopsies, separated by 10 years, in a patient with hypokalemia related to chronic diuretic abuse. Initial biopsy (on the left) shows proximal tubular cell vacuolization and mild interstitial inflammation. The subsequen t examination (on the right) demonstrates marked interstitial fibrosis, tubular atrophy and dropout.

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