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Diagnosis: Chronic allograft glomerulopathy and changes suggesting chronic antibody-mediated rejection

In the past 10-15 years we have started to understand the spectrum of antibody effects on the allograft, which include hyperacute rejection, early and late acute rejection, and chronic rejection.

Several authors in 2004 (Takemoto SK, et al.Am J Transplant 2004;4:1033-41. [PubMed link]) suggested diagnostic criteria for chronic antibody-mediated rejection (AMR) in renal allografts, which like criteria for acute AMR include immunopathologic (C4d in PTC), serologic (anti-HLA or other antidonor antibody), and histologic components. The last requires three of the following four lesions to be present: Arterial intimal fibrosis, interstitial fibrosis/tubular atrophy, duplication of the glomerular basement membrane, and lamination of peritubular capillaries (PTC) basement membranes, although the first two of these are nonspecific findings and require comparison with a perioperative biopsy to ensure that these changes developed after transplantation. Furthermore, accurate demonstration of PTC basement membrane lamination requires electron microscopy, which is not routinely performed on renal allograft biopsies at most centers. In some cases PTC multilayering is so prominent that it can be seen with light microscopy (methenamine-silver stain). In our case PTC lamination is evidenced with light microscopy. To consider PTC multilayering suspicious for chronic AMR it must be prominent.

In some cases we can find PTC C4d deposition without clinical dysfunction nor histologic changes suggesting antibody-mediated rejection (AMR). This phenomenon has been calling "accommodation". In these cases is considered that the graft acquires resistance to humoral injury and continues to function well despite the continued presence of antibody against a target antigen expressed on graft endothelium. There are many well documented cases in ABO-incompatible kidney transplants. It has been proposed that in these cases, complement regulatory proteins and/or other control mechanisms may interrupt the complement cascade distal to the generation of C4d, so the persistence of C4d on graft endothelium represents a marker for the arrest of the complement cascade rather than ongoing complement-mediated graft injury. Whether accommodation also may occur in instances when there is circulating antibody against HLA antigens expressed on the graft remains to be determined, although studies of PTC C4d staining and neutrophil margination in initially HLA-incompatible renal allografts suggest that if this does occur, then it is considerably less common than with ABO-incompatible transplants. Careful histologic and immunohistologic study may help to answer this question and address any potential role of complement in the accommodation process Racusen LC, Haas M. Clin J Am Soc Nephrol. 2006;1:415-20. [PubMed link] [Free full text]).

The presence of C4d argues for an active, immunologic process, as C4d is transient, lasting days to weeks; so in the Banff Classification of the Renal Allograft Rejection the term "chronic active antibody-mediated rejection" is used to connote a process extending over some time, rather than a designation of inactivity (Takemoto SK, et al.Am J Transplant 2004;4:1033-41. [PubMed link]; Racusen LC, et al. Am J Transplant. 2003;3(6):708-14. [PubMed link]).

See the chapter Renal Transplantation Pathology, Part 2 (At present only there is Spanish version).

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Bibliography

• Arias LF, Arteta AA, Giraldo RD. Renal allograft rejection: difficulties in biopsy diagnosis in low-income countries. Am J Transplant. 2007 Dec;7(12):2835 [PubMed link] [Artículo completo]
• Racusen LC, Haas M.Antibody-mediated rejection in renal allografts: lessons from pathology. Clin J Am Soc Nephrol. 2006;1(3):415-20. [PubMed link] [Free full text]
• Takemoto SK, Zeevi A, Feng S, Colvin RB, Jordan S, Kobashigawa J, Kupiec-Weglinski J, Matas A, Montgomery RA, Nickerson P, Platt JL, Rabb H, Thistlethwaite R, Tyan D, Delmonico FL: National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004;4(7):1033-41. [PubMed link]
• Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant. 2003;3(6):708-14. [PubMed link]
• Solez K, Colvin RB, Racusen LC, et al. Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN'). Am J Transplant. 2007;7(3):518-26. [PubMed link]

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