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- 30. References • Racusen, L.C., Solez, K., Colvin, R.B., Bonsib, S.M., Castro, M.C., Cavallo, T., Croker, B.P., Jake Demetrius, A., Drachenberg, C.B., Fogo, A.B., Furness, P., Gaber, L.W., Gibson, I.W., Glotz, D., Goldberg, J.C., Grande, J., Halloran, P.F., Hansen, H.E., Hartley, B., Hayry, P.J., Hill, C.M., Hoffman, E.O., Hunsicker, L.G., Lindblad, A.S., Marcussen, N., Mihatsch, M.J., Nadasdy, T., Nickerson, P., Steen Olsen, T., Papadimitriou, J.C., Randhawa, P.S., Rayner, D.C., Roberts, I., Rose, S., Rush, D., Salinas-Madrigal, L., Salomon, D.R., Sund, S., Taskinen, E., Trpkov, K., Yamaguchi, Y. (1999) The Banff 97 working classification of renal allograft pathology. Kidney International 55:713-23. • • • Solez, K., Colvin, R.B., Racusen, L.C., Haas, M., Sis, B., Mengel, M., Halloran, P.F., Baldwin, W., Banfi, G., Collins, A.B., Cosio, F., David, D.S.R., Drachenberg, C., Einecke, G., Fogo, A.B., Gibson, I.W., Glotz, D., Iskandar, S.S., Kraus, E., Lerut, E., Mannon, R.B., Mihatsch, M., Nankivell, B.J., Nickeleit, V., Papadimitriou, J.C., Randhawa, P., Regele, H., Renaudin, K., Roberts, I., Seron, D., Smith, R.N., Valente, M. (2008) Banff 07 Classification of renal allograft pathology: Updates and future directions. American Journal of Transplantation 8:753-60. • • Sis, B., Mengel, M., Haas, M., Colvin, R.B., Halloran, P.F., Racusen, L.C., Solez, K., Baldwin III, W.M., Bracamonte, E.R., Broecker, V., Cosio, F., Demetris, A.J., Drachenberg, C., Einecke, G., Gloor, J., Glotz, D., Kraus, E., Legendre, C., Liapis, H., Mannon, R.B., Nankivell, B.J., Nickeleit, V., Papadimitriou, J.C., Randhawa, P., Regele, H., Renaudin, K., Rodriguez, E.R., Seron, D., Seshan, S., Suthanthiran, M., Wasowska, B.A., Zachary, A., and Zeevi, A. (2010) Banff ’09 Meeting Report: Antibody mediated graft deterioration and implementation of Banff working groups. American Journal of Transplantation 10:464-71. • • Mengel, M., Sis, B., Haas, M., Colvin, R.B., Halloran, P.F., Racusen, L.C., Solez, K., Cendales, L., Demetris, A.J., Drachenberg, C.B., Farver, C.F., Rodriguez, E.R., Wallace, W.D., Glotz, D. (2012) Banff 2011 Meeting Report: New concepts in antibody-mediated rejection. American Journal of Transplantation 12:563-70.
Notes de l'éditeur
- Normal tubules, intralobar artery and peritubular capillaries. The proximal tubules have cells with abundant eosinophilic cytoplasm and a brush border on the luminal surface. The distal tubules are smaller, with no brush border. Peritubular capillaries are found in between the tubules. The artery is composed of 3 layers, the intima, media and the adventitia, from inner most to outer most.
- Edema. Edema can be seen in acute rejection as well as in ATN. It is no longer used in the grading of acute rejection (Sis,B., et al (2010) Banff ‘09 Meeting Report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. Transplantation 10:464-71.)
- Fibrous Intimal Thickening (“cv”). Fibrous intimal thickening is a non-specific indicator of chronic rejection, both cell and antibody mediated. Fibrous intimal thickening would be suspicious for antibody-mediated rejection if accompanied by the presence of donor specific antibodies and C4d capillary deposition. Cell mediated rejection would be suggested by the presence of interstitial fibosis. Cell and antibody mediated rejection can co-exist. Criteria for the grading of fibrous intimal thickening were presented at the 1997 Banff conference (Racusen, L.C., et al. 1999, The Banff working classification of renal allograft pathology, Kidney International 55:713-23). The most affected artery is to be chosen for grading. A grade of cv0 indicates no intimal fibrosis; cv1 is assigned to biopsies with arterial lumen narrowing of up to 25%; biopsies with arterial narrowing of 26-50% earn a cv2 grade; more than 50% narrowing is scored as cv3. The additional findings of disruption of the internal elastic lamina, formation of a neo-intima (new lumen within the fibrosis), or mononuclear inflammatory cells within the intima, increase the specificity of a diagnosis of chronic rejection.
- “ptc”. This picture shows peritubular capillaritis (ptc), increased neutrophils in the capillaries surrounding the proximal and distal tubules in the cortex. In the presence of C4d capillary deposition and circulating anti-donor specific antibodies, the extent of ptc is used to grade antibody mediated acute rejection. Biopsies with less than 10% capillaritis are scored as ptc0, regardless of the extent of focal involvement. Beyond the 10% minimum, ptc scoring is determined by the maximum number of inflammatory cells per luminal cross section. The presence of 3-4 inflammatory cells in the most severely affected capillary cross section corresponds to ptc 1. The presence of 5-10 inflammatory cells per capillary cross section rates ptc 2, and more than 10 inflammatory cells is scored as ptc3. The type of inflammatory cell is noted in the report, specifically whether mononuclear versus neutrophil, and the approximate percentage. The nature of the inflammatory cell infiltrate, either focal or diffuse, is also included. Ptc is not scored in the medulla, to avoid false positives associated with ATN in the vasa recta. ptc is not scored in areas close to lymphoid aggregates, in another effort to avoid false positives. The definition for ptc grading is given in Solez, K., et al (2008) Banff 07 classification of renal allograft pathology: update and future directions. Am. J. Transplantation 8:753-60.
- PAS stain of normal tissue. The PAS stain can be used to highlight the basement membrane of renal tubules and glomeruli. The thinned brush border and epitheium seen in tubules in ATN is better shown with PAS. Glomerular lesions highlighted by PAS include the collagenous deposits seen in focal segmental glomerulosclerosis and the mesangial expansion characteristic of Kimmelstiel Wilson nodules in diabetic patients.
- Normal arteriole. The inner most layer of the artery is the intima, the thickest layer is the media, and the outer most layer is the adventitia. Changes in arteries serve as indicators of rejection. Arteritis can suggest acute rejection, either cell or antibody mediated. Intimal fibrosis can be seen in cell mediated or antibody mediated chronic rejection. Examples of these changes are presented in subsequent slides.
- Arteriole with hyalinosis. Hyaline deposition in the arterial wall, with replacement of muscle, is shown here. Arteriolar hyalinization can correlate with cyclosporine toxicity, although it is non-specific, and can be seen with increasing donor age as well. Preliminary studies presented at Banff 07 suggested that arteriole hyalinization is predictive of graft function (Sis, B., et al, 2006, Reproducibility studies on arteriolar hyaline thickening scoring in calcineurin inhibitor-treated recipients. Am. J. Transplant 6:1444-50. ). Although not yet part of the Banff criteria, arteriolar hyalinization is graded as follows: aah0 indicates no arteriolar hyalinization, aah1 indicates hyalinization of only one arteriole, without circumferential involvement. aah2 indicates hyalinization in multiple arterioles, without circumfernetial involvement. aah3 is reserved for cases with circumferential hyalinization, regardless of the number of arterioloes affected. The picture illustrates an aah1 lesion. This grading system is optional, and currently under evaluation (Solez, K., et al (2008) Banff 07 classification of renal allograft pathology: updates and future directions, Am. J. Transplantation 8:753-60.)
- Thrombosis . The picture shows a thrombus, an aggregate of platelets and fibrin, adherent to an arteriole wall. When accompanied by C4d capillary deposition and anti donor antibodies, thrombosis is an important indicator of acute antibody-mediated rejection, with a score of II (Sis, B., et al (2010) Banff ‘09 Meeting Report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. Transplantation 10:464-71.)
- Normal proximal and distal tubules. The proximal tubules are larger, have cells with abundant cytoplasm, and a brush border is present on the luminal surface. Most absorption is performed in the proximal tubules, including water, sodium, potassium, glucose and amino acids. The distal tubules are smaller, the cytoplasm of the cells is less eosinophilic, and there is no brush border. Sodium and Chloride are co transported across the distal tubules via a thiazide-sensitive carrier.
- Acute Tubular Necrosis. The picture shows sloughing of cells from the tubules into the lumen. Individual cells are necrotic, with fading nuclei. Many of the tubules have thinned epithelium and proximal tubules with flattened brush borders are seen. The presence of acute tubular necrosis is used in the Banff grading of rejection, and is scored as grade I antibody mediated rejection, when accompanied by C4d capillary deposition and the presence of anti donor antibodies (Sis, B., et al (2010) Banff ‘09 Meeting Report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. transplantation 10:464-71.) ATN can also result from ischemia, drug exposure and other insults unrelated to rejection.
- Tubulitis (“t1”). The picture shows mononuclear inflammatory cells within the tubules, having traversed the tubule basement membrane. Inflammatory cells also lie between the tubules. Tubulitis is assessed in the grading of cell-mediated acute rejection, if seen along with interstitial inflammation involving at least 25% of the biopsy parenchyma. In addition, multiple foci of tubulitis must be identified. If these requirements are met, tubulitis is graded as follows, based upon the most inflamed part of the biopsy: t0 is the absence of tubulitis, t1 is the grade assigned when 1-4 mononuclear inflammatory cells per luminal cross section are identified. t2 indicates foci with 5-10 mononuclear inflammatory cells per cross section. t3 indicates > 10 mononuclear inflammatory cells per cross section, or a minimum of 2 areas of tubule basement membrane destruction in the presence of either t2 tubulitis at another focus of the biopsy, or moderate/severe (i2/i3) parenchymal inflammation. Tubulitis is not evaluated in areas with tubule atrophy, since these areas can have non-specific inflammation. This picture illustrates t1 tubulitis. Descriptions of parenchymal inflammation and its grading are presented subsequently. The definition and scoring of tubulitis is given in Racusen, L.C., et al. (1999) The Banff ‘97 working classification of renal allograft pathology, Kidney International 55:713-23. Tubulitis and parenchymal inflammation are used together in the determination of the borderline category of the Banff criteria. A biopsy is graded as borderline when tubulitis (t1, t2, or t3) is present along with mild interstitial inflammation (i1), or when mild tubulitis is present (t1) along with moderate to severe interstitial inflammation (i2, i3) (Racusen, L.C., et al. 1999, The Banff 97 working classification of renal allograft pathology, Kidney International 55:713-23.)
- Tubulitis (“t2”). This picture shows up to 9 mononuclear cells per tubule cross section, qualifying for the grade of t2, assuming multiple foci of tubulitis are identified, and that moderate/severe (i2/i3) interstitial inflammation is also present.
- Tubulitis (“t3”) with accompanying interstitial lymphocytic inflammation. This picture illustrates t3 tubulitis, with more than 10 mononuclear inflammatory cells per tubule cross section. This would qualify as t3 tubulitis if multiple foci of inflammation are identified, along with the presence of moderate/severe (i2/i3) interstitial inflammation. The drawing shows a mononuclear inflammatory infiltrate, suggesting that the second requirement is met.
- Mononuclear Cell Interstitial Inflammation (“i1”). The illustration shows a mononuclear infiltrate in the renal interstitium, occupying 10-25% of the parenchyma, qualifying for a grade of i1. Interstitial inflammation is graded as follows: i0 indicates inflammatory infiltrates in <10% of the renal parenchyma; a grade of i1 is given when the inflammatory infiltrate occupies between 10-25% of the parenchyma; i2 indicates that 26-50% of the parenchyma shows inflammation, and i3 is used when the inflammatory infiltrate covers more than half of the parenchyma (Racusen, L.C., et al., 1999, The Banff working classification of renal allograft pathology, Kidney International, 55:713-23. ) The infiltrate is typically composed of T lymphocytes. If more than 5-10% of the infiltrate consists of eosinophils or neutrophils, this is noted in the report as i*, and the differential diagnosis must be expanded to include a hypersensitivity reaction (eosinophils) or infection (neutrophils), as well as rejection. Alone, interstitial inflammation is not diagnostic of rejection, but when accompanied by tubulitis, it indicates acute cell-mediated rejection. Acute cell mediated rejection is graded as IA when there is moderate/severe interstitial inflammation (i2/i3) and moderate tubulitis (t2). The grade is IB if moderate/severe interstitial inflammation is seen with severe tubulitis (t3). According to the 1997 Banff classification, interstitial inflammation was not evaluated in sub capsular areas or in areas of scarring (Racusen, L.C., et al , 1999, The Banff 97 working classification of renal allograft pathology, Kidney International, 55:713-23. ) A new method for evaluation of interstitial inflammation was introduced at the 2007 Banff Conference, with a plan to test its performance over several years (Solez, K., et al. 2008, Banff 07 classification of renal allograft pathology: updates and future direction, Am. J. Transplantation, 8:753-60.) The new method assesses all cortical interstitial inflammation, including sub-capsular areas. The grading is based on the 1997 Banff criteria, but is designated as ti rather than i. Data presented at the 2009 Banff conference suggests that the new total inflammation (ti) scoring method correlates better with prognosis than the i score used in the current Banff criteria (Sis, B., et al 2010, Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. Transplantation 10:464-71.) The total inflammation ti scoring method is to be tested at multiple study centers, before changes are made to the current Banff criteria, as discussed at the 2009 Banff Conference (Sis, B., et al., Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. transplantation, 10:464-71).
- Mononuclear Cell Interstitial Inflammation (“i2”). The illustration shows grade i2 interstitial inflammation, with mononuclear inflammatory cells occupying 26-50% of the renal parenchyma.
- Mononuclear Cell Interstitial Inflammation (“i3”). The picture illustrates grade i3 interstitial inflammation, with mononuclear cells occupying more than 50% of the parenchyma.
- Interstitial Fibrosis (“ci3”). The illustration shows interstitial fibrosis occupying more than half of the parenchyma (ci3) as well as severe tubule atrophy (ct3). Interstitial fibrosis is graded as follows, ci0 indicates fibrosis in up to 5% of the cortical renal parenchyma. A grade of ci1 is assigned when 6-25% of the cortical parenchyma shows fibrosis. ci2 indicates fibrosis in 26-50% of the cortical area, and ci3 is the grade assigned when more than 50% of the area is affected by fibrosis (Racusen, L.C., et al. 1999, The Banff working classification of renal allograft pathology, Kidney International 55:713-23). The grading of interstitial fibrosis is based on the interstitium, even if vascular areas show fibrosis as well. Since the interstitium comprises the majority of the biopsy, grading based on the interstitium results in less sampling error (Racusen, L.C., et al. 1999, The Banff 97 working classification of renal allograft pathology, Kidney International 55:713-23). Tubule atrophy is graded as described at the 97 Banff conference, as follows, ct0 is no atrophy, ct1 indicates atrophy in up to 25% of the cortical tubules, ct2 is assigned to biopsies showing atrophy affecting between 26-50% of tubules, and ct3 is used for those biopsies with atrophy in more than 50% of the cortical tubules. Interstitial fibrosis and tubule atrophy are incorporated into one score, as described at the 09 Banff Conference (Sis, B., et al, 2010, Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. Transplantation, 10:464-71.) Grade I indicates interstitial fibrosis and tubular atrophy affecting less than 25% of the cortical area of the biopsy, grade II is assigned to biopsies with 26-50% involvement, and grade III is used for those biopsies with more than 50% involvement. When seen with C4d capillary deposition and anti donor antibodies, cortical fibrosis and tubular atrophy support a diagnosis of chronic antibody mediated rejection. When seen in the absence of C4d deposition and anti donor antibodies, interstitial fibrosis and tubule atrophy support a diagnosis of chronic T-cell mediated rejection.
- Normal glomerulus. This illustration shows the afferent and efferent arterioles, the proximal tubule entering Bowman’s capsule, a cross section of the distal convoluted tubule, and the glomerular components themselves, the capillaries, glomerular epithelial cells, and the mesangium. All parts of the glomerular apparatus can be affected by medical renal diseases. Diabetes, for example, can lead to expansion of the mesangium, resulting in structures known as Kimmelstiel Wilson nodules, as well as thickening and hyalinosis of the arterioles.
- Glomerulitis (“g”). The illustration shows neutrophils in the glomerular mesangium. When accompanied by C4d capillary deposition and anti donor antibodies, glomerulitis supports a diagnosis of acute antibody-mediated rejection (Racusen, L.C., et al. 1999, The Banff 97 working classification of renal allograft pathology, Kidney International 55:713-23). Glomerulitis is graded according to whether it affects portions of glomeruli (segmental) or entire glomeruli (global). The percentage of glomeruli affected is also a factor. A grade of g0 indicates no glomerulitis; g1 is assigned if neutrophil infiltrates (segmental or global) are seen in less than 25% of glomeruli; g2 is the grade assigned if there is global or segmental glomerulitis in 25-75% of glomeruli; grade g3 indicates primarily global glomerulitis in more than 75% of glomeruli. Any glomerulitis (g>0) earns an acute antibody mediated rejection grade of II (Sis, B., et al. 2010, Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. Transplantation 10:464-71). Glomerulitis is not specific for antibody rejection, and can be seen in the early stages of thrombotic microangiopathy.
- Mesangial Matrix Increase (“mm”). A normal glomerulus has no more than mesangial cells between each capillary. This illustration shows an increased number of mesangial cells between capillaries. Mesangial matrix increase supports a diagnosis of chronic antibody-mediated rejection when seen in association with C4d capillary deposition and anti donor antibodies (Racusen, L.C., et al. 1999, the Banff 97 working classification of renal allograft pathology, Kidney International 55:713-23). Mesangial matrix increase alone however, is not specific for chronic rejection, and can be seen in diabetes and memebranoproliferative glomerulonephritis for example. It is less specific for chronic antibody-mediated rejection than double conours in glomerular capillary loops, illustrated subsequently. The minimum requirement for mesangial matirx increase is more than 2 mesangial cells between capillaries in at least two lobules in a non-sclerosed glomerulus. A lobule is defined as a glomerular capillary and its associated connective tissue, or mesangium. Mesangial matrix increase is defined as follows, mm0 indicates no increase; mm1 is defined as increased mesangium in up to 25% of non-sclerosed glomeruli, the mm2 grade is assigned when 26-50% of non-sclerosed glomeruli show mesangial expansion, mm3 is the grade given if more than 50% of non-sclerotic glomeruli are affected.
- chronic transplant glomerulopathy needs to have reduplication of glomerular basement membranes The illustration shows glomerular capillaries with a “double contour”, with basement membrane material in between the endothelial and epithelial cells. When seen in association with capillary C4d deposition and anti donor antibodies, this finding is specific for chronic antibody-mediated rejection
- A portion of the glomerulus (normal). The illustration shows normal glomerular capillaries with associated endothelial and mesangial cells. The foot processes of the enothelial cells form tight junctions with the capillary basement membrane, allowing filtration regulation.
- Mesangial Matrix Increase (“mm”) A normal glomerulus has no more than mesangial cells between each capillary. This illustration shows an increased number of mesangial cells between capillaries. Mesangial matrix increase supports a diagnosis of chronic antibody-mediated rejection when seen in association with C4d capillary deposition and anti donor antibodies (Racusen, L.C., et al. 1999, the Banff 97 working classification of renal allograft pathology, Kidney International 55:713-23). Mesangial matrix increase alone however, is not specific for chronic rejection, and can be seen in diabetes and memebranoproliferative glomerulonephritis for example. It is less specific for chronic antibody-mediated rejection than double conours in glomerular capillary loops, illustrated subsequently. The minimum requirement for mesangial matirx increase is more than 2 mesangial cells between capillaries in at least two lobules in a non-sclerosed glomerulus. A lobule is defined as a glomerular capillary and its associated connective tissue, or mesangium. Mesangial matrix increase is defined as follows, mm0 indicates no increase; mm1 is defined as increased mesangium in up to 25% of non-sclerosed glomeruli, the mm2 grade is assigned when 26-50% of non-sclerosed glomeruli show mesangial expansion, mm3 is the grade given if more than 50% of non-sclerotic glomeruli are affected.
- chronic transplant glomerulopathy . The illustration shows glomerular capillaries with a “double contour”, with mesangium in between the endothelial and epithelial cell basement membranes. When seen in association with capillary C4d deposition and anti donor antibodies, this finding is specific for chronic antibody-mediated rejection (Racusen, L.C., et al. 1999, The Banff 97 working classification of renal allograft pathology, Kidney International 55:713-23). Double contours can also been seen in membranoproliferative glomerulonephritis, but clinical history along with electron microscopy and immunofluorescence assays can give definitive identification.
- Immunohistochemistry for C4d is positive in the peritubular capillaries. Positive capillary staining for C4d is evidence for binding of antibody to endothelial cells, since C4d is the inactivated form of C4 complement. The 1997 Banff conference recommended that there must be morphologic evidence of tissue damage, in addition to C4d staining and circulating anti donor antibodies, to support a diagnosis of antibody mediated rejection (Racusen, L.C., et al. 1999, The Banff working classification of renal allograft pathology, Kidney International 55:713-23). The 2009 Banff conference however, concluded that even without morphologic damage, capillary C4d deposition in the presence of circulating anti donor antibodies can indicate antibody mediated rejection (Sis,B., et al. 2010, Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups, Am. J. Transplantation 10:464-71). At the 2011 Banff conference, patients with C4d negative antibody-mediated rejection were presented (Mengel, M., et al. 2012, Banff 2011 Meeting Report: new concepts in antibody-mediated rejection, Am. J. Transplantation 12:563-70). These patients had circulating donor specific antibodies along with morphologic evidence of damage, including glomerulitis. A working group was established with the goal of defining C4d independent antibody mediated rejection.