Myofibroblasts and the progression of crescentic glomerulonephritis

Background: The cellular and humoral factors involvedin the pathogenesis of glomerulosclerosis and renal fibrosis following acrescentic glomerulonephritis have not been fully elucidated.Myofibroblasts and transforming growth factor-{beta} (TGF-{beta})have been implicated in the development of experimental and clinical renalfibrosis. We have attempted to identify these mediators in crescenticglomerulonephritis and determine their role in the progression of thedisease. Patients and methods. We have studiedretrospectively 21 patients with crescentic and necrotizingglomerulonephritis (CNG) with emphasis on the renal expression (detected byimmunohistochemistry) of myofibroblasts (&agr;-smooth muscleactin⁺ cells), TGF-{beta} and collagen (III andIV) as well as their relationship with the clinical outcome of thesepatients. In situ hybridization histochemistry wasapplied to determine the site of synthesis of TGF-{beta}1 and collagenIII. All the patients were treated by immunosuppression and followed up fora median period of 14 months. Results: Myofibroblastsand TGF-{beta} were detected in the crescents as well as in theperiglomerular and tubulointerstitial areas in CNG biopsies. TGF-{beta}1was also detected within renal tubular cells. The percentage of glomeruliwith fibrotic and fibrocellular crescents was positively correlated withthe severity of Bowman's capsule disruption (r-0.631, P<0.01) andwith the intensity of myofibroblast expression in the interstitium(r-0.504, P<0.05). Strong interstitial immunostain formyofibroblasts and TGF-{beta} was also noted in association withinterstitial fibrosis. In situ hybridization revealedthe site of synthesis of TGF-{beta}1 to be the renal tubular cells ofpatients with CNG. By contrast, the site of synthesis of collagen IIIappeared to be confined to interstitial cells surrounding vessels, tubulesand the glomeruli in a distribution identical to that of myofibroblasts.There was a significant positive correlation between the number ofinterstitial &agr;-SMA⁺ cells and bothinterstitial TGF-{beta} (r=0.591, P<0.01) and interstitialcollagen IV (r=0.588, P<0.01). In addition, the number ofinterstitial &agr;-SMA⁺ cells and the extent ofimmunostain for collagen IV were positively correlated with the final serumcreatinine (r=0.517, P<0.05 and r=0.612, P<0.01 respectively)and partially predicted functional outcome (R²=26.7%and 37.5% respectively) as well as the response to treatment. Anassociation was observed between periglomerular myofibroblasts and thegeneration of fibrotin and fibrocellular crescents.Conclusion: These observations suggest a causal linkbetween myofibroblasts and fibrotic crescent formation. We also believethat interstitial myofibroblasts are actively involved in the pathogenesisof interstitial fibrosis in CNG.