Protocol Core Needle Biopsy and Histologic Chronic Allograft Damage Index (CADI) as Surrogate End Point for Long-Term Graft Survival in Multicenter Studies

Abstract

Abstract. This study is an investigation of whether a protocol biopsy may be used as surrogate to late graft survival in multicenter renal transplantation trials. During two mycophenolate mofetil trials, 621 representative protocol biopsies were obtained at baseline, 1 yr, and 3 yr. The samples were coded and evaluated blindly by two pathologists, and Chronic Allograft Damage Index (CADI) score was constructed. At 1 yr, only 20% of patients had elevated (Ͼl.5 mg/100 ml) serum creatinine, whereas 60% of the biopsies demonstrated an elevated (Ͼ2.0) CADI score. The mean CADI score at baseline, 1.3 Ϯ 1

Correlation of Quantitative Digital Image Analysis with the Glomerular Filtration Rate in Chronic Allograft Nephropathy

“…Despite this association with late graft injury, it is clear that histopathologic alterations of CAN are present in up to two-thirds of kidneys transplants as early as 2 years after transplantation (20) and may occur in the absence of discernible alterations in renal function (5,23,24). Furthermore, lesions similar to those of CAN may be identified in the aging kidney (10,25), implying that some renal allografts fulfill diagnostic criteria for CAN at the time of transplant.…”

“…These considerations have raised the possibility that early histologic detection of CAN may be used to predict risk for subsequent loss of graft function and, potentially, to determine the efficacy of specific therapeutic interventions. In support of this concept, a number of recent studies have provided evidence that the degree of tubulointerstitial fibrosis (TIF) accurately predicts the subsequent clinical course of renal allografts whether present in surveillance ('protocol') or clinically indicated biopsies (5,8,9,12,23,26,27).…”

“…Although the mechanisms underlying this fibrogenic response -the characteristic morphologic manifestation of chronic allograft nephropathy (CAN) -remain incompletely defined, the role of renal biopsy in the classification of chronic lesions, in excluding other forms of renal injury (such as acute rejection and recurrent glomerular disease), and, to some degree, in guiding therapy is well established (4,5). The extent of chronic tubulointerstitial alterations has been reported to correlate well with declining renal function in CAN as well in kidneys of nonallograft patients with parenchymal renal disease (5)(6)(7)(8)(9). Fibrotic/sclerotic abnormalities involving the glomerular and vascular compartments are less uniformly present in CAN but may define clinically important patient subgroups (10,11).…”

“…For this reason, there is interest in developing methods to accurately and reproducibly quantify the histologic abnormalities of CAN, particularly tubulointerstitial fibrosis (TIF), and in determining how these measurements correlate with renal function and graft survival. The use of automated or semi-automated computerized digital analysis of biopsy sections, stained by various methodologies, to reveal fibrotic tissue or specific components of fibrotic tissue (such as collagen), has been reported by a number of groups (5,6,15,16). These studies clearly demonstrate the value of quantification of TIF in predicting subsequent graft loss but also raise concerns regarding variability between different methods and lack of correlation with conventional histologic analyses (5).…”

“…The use of automated or semi-automated computerized digital analysis of biopsy sections, stained by various methodologies, to reveal fibrotic tissue or specific components of fibrotic tissue (such as collagen), has been reported by a number of groups (5,6,15,16). These studies clearly demonstrate the value of quantification of TIF in predicting subsequent graft loss but also raise concerns regarding variability between different methods and lack of correlation with conventional histologic analyses (5). Many cross-sectional or longitudinal studies of CAN do not incorporate accurately measured graft function.…”