Proteinuria and tubulointerstitial lesions in lupus nephritis

Background. Response of the renal tubules to proteinuria is implicated in p rogression of renal disease. Experimentally, proteinuria causes increased t ubular synthesis of macrophagic and other chemokines, with increased tubula r cellular proliferation and apoptosis, leading to interstitial inflammatio n and fibrosis. Clinically, diminution of proteinuria leads to the slowing of progression, but whether this leads to reduction in tubular lesions has not been directly demonstrated in humans. Methods. Initial (Bx1) and systematic six-month biopsies (Bx2) from 71 pati ents with lupus nephritis were studied, with a subset of 34 biopsies also s tained for proliferating cell nuclear antigen (PCNA), the macrophage marker PGM1, and cytokeratins (AE1/AE3), and morphometric cell and tubular profil e counts performed. Results. Positive correlations were found between increasing levels of prot einuria and the following light microscopic parameters: tubular epithelial pyknosis, tubular epithelial nuclear "activation," tubular lumenal macropha ges, interstitial inflammation and fibrosis, but not with tubulointerstitia l immunofluorescence. Significant positive correlations also were found wit h the following immunohistochemical parameters: PCNA in epithelial cells (r = 0.74) and tubular luminal cells (r = 0.47); tubular lumenal macrophages (r = 0.63) and tubular epithelial cells with acquired PGM1 staining (r = 0. 36); and pyknotic tubular epithelial cells (r = 0.47). All showed strong co rrelations with serum creatinine (Sc,) as well. All were reduced at Bx2, ge nerally in parallel to the reduction in proteinuria. Tubulointerstitial imm une deposits appear to play only a minor role in the development of tubular epithelial lesions and the progression of renal disease in lupus. They sho w only limited correlation with Sc, and no correlation with proteinuria. By multiple regression, they are not associated with tubular epithelial lesio ns, interstitial inflammation or interstitial fibrosis at either biopsy, wh ereas tubular epithelial lesions are strongly associated with interstitial inflammation at Bx1 and with interstitial fibrosis at Bx2. Cytokeratin corr elated strongly with S-Cr (r = 0.53, P = 0.002) but not with proteinuria (r = 0.27, NS), and was the sole immunohistochemical parameter to increase at Bx2. It appears to be a sensitive marker for tubular atrophy. Conclusions. In this study both proteinuria and S-Cr showed a hierarchy of correlations with morphologic variables: Tubular epithelial cell changes > tubular macrophages > interstitial inflammation > interstitial fibrosis, co rresponding to current experimental models, but not previously demonstrated in humans.