Demonstration of the proliferation marker Ki-67 in renal biopsies: Correlation to clinical findings

Abstract

Assessment of cell proliferation in renal biopsy samples is a potentially promising analytical tool to evaluate disease activity. So far no information is available on the correlation between proliferative activity in different anatomic compartments of the kidney and clinical symptoms. To elucidate this issue, we examined renal biopsy specimens from 20 patients with systemic vasculitis (15 Wegener's granulomatosis, five microscopic polyangiitis), 20 patients with immunoglobulin (Ig) A nephropathy (IgAN), 13 patients with minimal-change disease (MCD), 11 patients with tubulointerstitial nephritis, and five patients with diabetes mellitus. The streptavidin-biotin-peroxidase complex technique was applied to autoclave-pretreated, formalin-fixed, paraffin-embedded tissue sections to label different cell types with the antibody MIB1 directed against the Ki-67 antigen. Proliferation index (PI) was estimated as the number of positively stained nuclei per glomerular cross-section or per square millimeter section area. The interstitial cells were discriminated by additional staining of Ki-67-processed samples with specific immune markers. In patients with vasculitis, PI was considerably elevated in the extracapillary glomerular compartment (0.86), in proximal tubules (6.24), and in the interstitium (8.62). High proliferative activity was also noted in interstitium (3.98) and proximal tubules (1.35) of patients with IgAN. Of particular interest was the increased interstitial proliferative activity (15.0) in diabetic patients. Resident renal cells, but not infiltrating cells, seemed to constitute the majority of the proliferating cell population in the interstitium. In systemic vasculitis, clinical disease activity was significantly correlated to endocapillary ( r s = 0.58), extracapillary ( r s = 0.67), proximal tubular ( r s = 0.67), and interstitial PI ( r s = 0.61). By multiple linear regression analysis, proximal tubular PI was correlated to the presence of hematuria (β = 0.72) and to interstitial fibrosis score (β = 0.59). Interstitial PI was independently correlated to antineutrophil cytoplasmic antibodies (ANCA) titer (β = 0.7) and interstitial fibrosis score (β = 0.55), and it was the only one PI correlated to serum creatinine concentration (β = 0.53). The independent association between interstitial PI and serum creatinine (β = 0.64) was also found in IgAN. Proximal tubular PI was correlated to interstitial fibrosis score (β = 0.59) and proteinuria (β = 0.54). In MCD, high PI values were noted in proximal tubular cells (1.42) but not in glomeruli and the interstitium. In conclusion, assessment of proliferation activity by immunohistology provides additional information beyond conventional pathological techniques to evaluate disease activity and prognosis in renal biopsies.