Evaluation of Fibrosis in Renal Allograft



Evaluation of Fibrosis in Renal Allograft


A. Brad Farris, III, MD








Collagen III immunohistochemistry stains fibrous tissue brown.






A positive pixel count algorithm is applied to the immunohistochemistry, and a markup image shows areas that are strongly positive (red), medium positive (orange), and negative (blue).


TERMINOLOGY



Synonyms



  • Scarring


  • Sclerosis


EPIDEMIOLOGY


Natural History



  • Extent of IF predicts renal allograft outcome & may be considered a surrogate marker



    • Studies show reciprocal correlation between kidney function & IF extent


    • IF & tubular atrophy (TA) have been associated with



      • Cold ischemia time


      • Clinical & subclinical acute rejection


      • Preexisting donor damage


      • Degree of sensitization


      • Cyclosporine exposure


      • Renal calcifications


  • IF shows prognostic value in renal donor biopsies



    • ↑ risk of adverse outcome at 6 months



      • 1.9x greater prediction from age alone with Banff index for IF (ci score > 0)


    • Morphometric interstitial volume: Correlates with graft function at 1 year


ETIOLOGY/PATHOGENESIS


Histogenesis



  • Molecular mediators



    • Transforming growth factor (TGF)-β


    • Bone morphogenetic protein (BMP)


    • Platelet-derived growth factor (PDGF)


    • Hepatocyte growth factor (HGF)


    • Recent genomic approaches show altered molecular factors in IF


  • Cellular mediators



    • Epithelial cells


    • Fibroblasts/myofibroblasts & fibrocytes


    • Inflammatory cells: Lymphocytes, monocyte/macrophages, dendritic cells, mast cells


    • Endothelial cells


Epithelial-to-Mesenchymal Phenotype (EMP)



  • Chronically injured epithelial cells may undergo transition to mesenchymal cells



    • Process termed “epithelial-to-mesenchymal transition (EMT)” in past literature


    • Injured epithelium may change morphology and express mesenchymal-like markers, but the actual EMT process has not been directly observed in vivo


    • So-called “EMT” may simply reflect a change in protein expression rather than a true transition


    • Mesenchymal markers are not entirely specific, making research questionable (per a recent Banff conference and other publications)



      • Thus, “EMP” may be more appropriate since changes may simply be the observation of altered phenotype


CLINICAL IMPLICATIONS


Clinical Presentation



  • IF contributes to functional deterioration


  • IF/TA associated with transplant vasculopathy, ↑ serum creatinine, or transplant glomerulopathy implies poorer prognosis than IF/TA without additional lesions


  • Protocol biopsies to assess IF progression can be useful in demonstrating the baseline state of the allograft as well as stepwise changes that are occurring




    • e.g., protocol biopsies can be helpful in clinical trials, investigation of drug effectiveness, etc.


MICROSCOPIC FINDINGS


Qualitative Visual Assessment



  • Not all fibrosis is “equal” or “the same” in quality & quantity



    • “Early,” “young,” or “active” IF may have greater potential for remodeling


    • Broad scars: Pyelonephritis & infarcts can produce severe focal injury & parenchymal destruction


    • Diffuse, fine IF: Diffuse disease of glomeruli, tubules, & vessels


  • IF patterns may have different implications



    • “Striped,” patchy fibrosis described with calcineurin inhibitor use, possibly due to preferential medullary ray involvement


    • Chronic obstructive pattern: Atubular glomeruli, dilated tubules, & intratubular Tamm-Horsfall protein casts with interstitial extravasation


  • Inflammation in areas of IF has been noted to be an adverse risk factor for renal disease progression


  • IF & TA typically correlate (i.e., IF/TA)



    • TA may be profound in renal artery stenosis, with little or no accompanying IF


    • IF/TA (graded I-III based on the same cutoffs as ci) has effectively replaced the term “chronic allograft nephropathy (CAN)”


  • Subcapsular, perivascular, & periglomerular IF are typically not counted, but objective exclusionary criteria are lacking


  • IF assessment typically focuses on the cortex, but many emphasize that medullary fibrosis is also important


Quantitative Visual Assessment

Jul 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Evaluation of Fibrosis in Renal Allograft

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