In Press, 1995, Transplantation Proceedings copyright by Appleton and Lange.

The Banff Schema Four Years Later

Kim Solez, M.D.*, Lorraine C. Racusen, M.D. **, David C. Rayner, M.D.*, Steen Olsen, M.C.*** and Philip F. Halloran, M.D.****

*Department of Laboratory Medicine and Pathology
Faculty of Medicine, University of Alberta
Edmonton, Canada T6G 2R7

**Department of Pathology,
Johns Hopkins Medical Institutions,
Baltimore Maryland 21205, USA

***University Institute Of Pathology,
University of Aarhus,
Aarhus, Denmark

****Division of Nephrology and Immunology Department of Medicine,
Faculty of Medicine, University of Alberta
Edmonton, Canada T6G 2A9

 


On the occasion of the Third Banff Conference on Allograft Pathology to be held July 20-24, 1995 in Banff, Canada, it is useful to reflect on the progress since the first such meeting four years ago and the work that still remains to be done. First, the successes: The original Banff Classification of Renal Allograft Pathology [1] is in wide use and there have been extensive studies showing its clinical validity and reproducibility [2-10]. Extrapolating from these studies, it is likely that the classification has resulted in improvement in patient care. The Banff classification has been endorsed by the FDA and other regulatory agencies and has enabled the use of objective histologic endpoints for international clinical trials of new antirejection agents and other scientific studies.

Concepts which grew out of the development of the Banff classification are now being applied to liver allograft pathology and pathology of the native kidney.

As a background for deliberations at the Banff Conference ten problems warrant discussion:

  1. Underdiagnosis of rejection in patients biopsied in the setting of suspected rejection, an outcome of the original design of the classification [1] which was based on the idea that false negative diagnoses of histologic rejection were less harmful to the patient than false positive diagnoses.

    There will always be some inaccuracy in rejection diagnosis based on the inevitable sampling error problems inherent in percutaneous biopsies [1].

    Any attempt to make more stringent the criteria for rejection diagnosis [see below] will increase this problem of underdiagnosis in patients with suspected rejection.

     

  2. Overdiagnosis of rejection on the basis of tubulitis in protocol biopsies obtained in normally functioning grafts or those biopsied because of proteinuria.

    This overdiagnosis of rejection is particularly a feature of late graft biopsies, in which additional criteria should probably be established to raise the threshold for rejection diagnosis.

     

  3. The presence of bona fide rejection which deserves treatment in a proportion of patients with "normally functioning" grafts.

    The work of Rush et al. [8, 9] clearly indicates that the phenomenon of treatable subclinical rejection exists. The difficulty is in establishing a reasonable dividing line between a true false positive diagnosis and the identification of subclinical rejection in which treatment should be considered.

     

  4. Occasional difficulty in unequivocal identification of lymphocytes in tubulitis, glomerulitis, and intimal arteritis lesions.

    We have written previously about the need to use well-performed PAS stains [11] to identify the key lesions of the Banff classification. For laboratories with routine access to immunoperoxidase procedures staining for common leukocyte antigen (anti CD-45) may add precision to lymphocyte identification. However we have observed that the Dako reagent which gives the crispest specific staining in paraffin sections does not stain all lymphocytes, whereas the Becton Dickinson antibody does stain all lymphocytes but also gives nonspecific reactivity in tubular cells. So presently it appears that there is no reagent which is ideal for this purpose.

     

  5. Tendency to undervalue clinical data in application of the Banff classification.

    In this regard we have become a victim of our own success. It was never intended that treatment decisions would be based entirely on biopsy findings divorced from clinical data. This is why the far right column in Table 5 (p. 417) of the original Banff classification paper is labeled "Possible clinical approach" [1]. Any attempt to regard this column as a strong treatment recommendation certainly should be opposed. As a consequence of the false negatives due to sampling error mentioned above there frequently are patients with biopsies in the "borderline changes" category who deserve antirejection treatment. The strength of clinical suspicion of rejection should be the guide for therapy in such instances.

     

  6. Need to avoid disruption of ongoing clinical trails which use Banff classification endpoints by making arbitrary changes in the schema.

    Pharmaceutical companies running international clinical trials of new anti-rejection agents represent very important "consumers" of the pathology diagnoses rendered using the Banff schema. Central slide review for such trials has been conducted thus far without knowledge of clinical history.

    If the classification is modified to allow for different interpretation in renal failure and protocol-normal function biopsies, clinical trails could accommodate to this is one of two ways:

    First, one could differentiate between biopsies on the basis of time. It could be assumed that all biopsies before one year are taken for renal failure indications and all biopsies one year and after are protocol biopsies in normally functioning grafts.
    As a preferable alternative, one could indicate to the central pathologist whether the indication for the biopsy was renal failure, proteinuria, or protocol requirement. Such information would not invalidate the blindness of the central review but would allow for more accurate interpretation.

     

  7. Need for a more rigorous approach to the specific diagnosis of chronic rejection.

    As an initial approach the recommendations of Paul et al [14] and Mihatsch et al [15] for defining chronic rejection will be followed but with additional incorporation of peritubular capillary changes as described by Monga et al. [16]. There is a strong need to decide whether any estimation of peritubular capillary changes can be made by light microscopy or whether the diagnostic changes can only be revealed using electron microscopy.

     

  8. Need to identify the specific morphologic features suggesting antibody-mediated rejection.

    Consideration needs to be given to the diagnosis of late-appearing antibody-mediated rejection in which glomerulitis, peritubular capillary accumulation of polymorphs, and severe vasculitic and thrombotic vascular lesions are three of the defining features [17, 18] (See Abstract below). An important decision to be made at the upcoming Banff meeting is whether to incorporate this entity into the classification in 1995 or wait until 1997 when it is better understood.

     

  9. Need more information about the natural history of hyaline arteriolar thickening in cyclosporine toxicity and means of assessing this lesion in a reproducible manner.

    More data is needed on the rapidity of onset of hyaline arteriolar change [19] and the relative significance of "specific" and "nonspecific" arteriolar thickening as described by Mihatsch [13]. Since the studies of both Mihatsch et al [13] and Marcussen et al. [7] show poor reproducibility in assessment of this lesion an alternative approach to quantitation should be sought. Location of the lesions within the arteriolar tree may be helpful in differential diagnosis [19, 20].

     

  10. Need for a balanced approach to implantation or preimplantation (donor) biopsies.

    Experience with central slide review in international clinical trials clearly shows the great value of a baseline implantation biopsy [21-23].

    Many more such biopsies should be performed to improve the accuracy of assessment of vascular lesions in later biopsies, but moderate degrees of scarring and vascular disease should not be interpreted as contraindications to use of the kidney. In the studies of Curschellas et al [23] 62% of implantation biopsies showed significant morphologic changes, most commonly fibrous intimal thickening or hyaline arteriolar thickening. Despite these changes 82% of transplant recipients had a good initial and long term function. The authors suggest that since age-related vascular disease does not seem to compromise renal function after transplantation, a more liberal choice of donors should be considered.

    "One size fits all" not the best approach to classification.

    After three months post-transplant we are considering differentiating biopsies obtained at time of suspected rejection from those obtained in grafts with stable function, and applying different histologic thresholds for diagnosis of rejection in these two settings. In normally functioning grafts with tubulitis but no intimal arteritis the proposal is that two further criteria must be met before a diagnosis of rejection can be made:

    1) the presence of two out of three of the additional lesions cited by Colvin [12] and
    2) the presence of tubulitis in tubules not satisfying the criteria for tubular atrophy described by Mihatsch et al [13].

    Incorporating the Colvin criteria would mean that to diagnose rejection in the presence of tubulitis without arteritis, two of the following three lesions would have to be present: edema, tubular injury (in association with the inflammatory infiltrate), or activated lymphocytes (judged on size and appearance on PAS and H&E).

    Excluding tubulitis in atrophic tubules as defined by Mihatsch [13] would mean not counting lymphocytic invasion in tubules with (p. 27) thickened tubular basement membranes and reduced diameter. In the absence of thickened basement membranes atrophy would be regarded as present when tubular diameter was reduced to less than 50% of normal values, as determined by comparison with adjacent tubules." Tubulitis in atrophic tubules would also not be counted as evidence of acute rejection in biopsies obtained after one year post-transplant. However, for biopsies obtained in the setting of suspected rejection in the early post-transplant period the basic construct of the Banff Schema would remain the same, thus maintaining the integrity of ongoing clinical trials.

 

References

  1. Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, Croker BP, Droz D, Dunnill MS, Halloran PF, Hayry P, Jennette JC, Keown PA, Marcussen N, Mihatsch MJ, Morozumi K, Myers BD, Nast CC, Olsen S, Racusen LC, Ramos EL, Rosen S, Sachs DH, Salomon DR, Sanfilippo F, Verani R, von Willebrand E, Yamaguchi Y: International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int 44:411-422, 1993.

     

  2. Solez K, Hansen HE, Kornerup HJ, Madsen S, Sørensen AWS, Pedersen EB, Marcussen N, Benediktsson H, Racusen LC, Olsen S: Clinical validation and reproducibility of the Banff classification of renal allograft pathology. Trans Proc 27:1009-1011, 1995.

     

  3. Gaber LW, Moore LW, Alloway RR, Flax S, Gaber AO: Correlation between Banff classification, acute renal rejection scores and reversal of rejection. Trans Proc 27:1019, 1995.

     

  4. Kupin W, Venkat KK, Mozes M, Wiener Y, Escobar F, Goggins M: Clinical and renal histologic predictors of response to OKT3 therapy using the Banff classification in renal transplant recipients. JASN 5:1019, 1994.

     

  5. Abbi R, Tomasulla, Butt K, Delaney V: Can the Banff classification of kidney transplant pathology predict irreversible, early acute rejection? JASN 5:992, 1994.

     

  6. Gaber LW, Schroeder T, Moore LW, Gaber AO: Predictive value of Banff scoring in recurring acute allograft rejection. JASN 5:1005, 1994.

     

  7. Marcussen N, Olsen TS, Benediktsson H, Racusen L, Solez K: Reproducibility of the Banff classification of renal allograft pathology: Inter- and intra-observer variation. Transplantation (in press, 1995).

     

  8. Rush DN; Jeffery JR; Gough J: Sequential protocol biopsies in renal transplant patients. Clinico-pathological correlations using the Banff schema. Transplantation 59(4):511-4, 1995.

     

  9. Rush DN, Jeffery JR, Gough J: Sequential protocol biopsies in renal transplant patients: Repeated inflammation is associated with impaired graft function at one year. Trans. Proc. 27:1017-1018, 1995.

     

  10. Dooper PMM, Hoitsma AJ, Koene RAP, Bogman MJJT: Evaluation of the Banff Criteria for the histologic diagnosis of rejection in renal allograft biopsies. Trans. Proc. 27:1005-1006, 1995.

     

  11. L.C. Racusen, D.C. Rayner, K. Trpkov, S. Olsen, and K. Solez: The Banff classification of renal allograft pathology: Where do we go from here? Trans Proc (in press, 1995). (View Copy on WWW server.)

     

  12. Colvin RB: Kidney, in R.B. Colvin, A.K. Bhan, and R.T. McCluskey, eds. _Diagnostic Immunopathology_, Raven Press, 1995, p. 346.

     

  13. Mihatsch MJ; Antonovych T; Bohman SO; Habib R; Helmchen U; Noel LH; Olsen S; Sibley RK; Kemeny E; Feutren G: Cyclosporin A nephropathy: standardization of the evaluation of kidney biopsies. Clin Nephrol 1994 Jan;41(1):23-32

     

  14. Paul LC; Häyry P; Foegh M; Dennis MJ; Mihatsch MJ; Larsson E; Fellstrom B: Diagnostic criteria for chronic rejection/accelerated graft atherosclerosis in heart and kidney transplants: joint proposal from the Fourth Alexis Carrel Conference on Chronic Rejection and Accelerated Arteriosclerosis in Transplanted Organs. Transplant Proc 1993 Apr;25(2):2022-3

     

  15. Mihatsch MJ; Ryffel B; Gudat F: Morphological criteria of chronic rejection: differential diagnosis, including cyclosporine nephropathy. Transplant Proc 1993 Apr;25(2):2031-7

     

  16. Monga G, Mazzucco G, Messina M, Motta M, Quaranta S, Novara R: Intertubular capillary changes in kidney allografts: a morphologic investigation on 61 renal specimens. Mod Pathol 5:125-130, 1992.

     

  17. Trpkov K, Campbell P, Pazderka F, Cockfield S, Solez, K, Halloran PF: Pathology and clinical outcome in anti-class I antibody mediated acute renal allograft rejection (1995 ASTP and ISN oral presentation, submitted). [Abstract below.]

     

  18. Olsen S, Spencer E, Cockfield S, Marcussen N, Solez K: Endocapillary glomerulitis in the renal allograft. Transplantation (in press, 1995).

     

  19. Morozumi K, Thiel G, Albert FW, Banfi G, Gudet F, Mihatsch MJ: Studies on morphological outcome of cyclosporine-associated arteriolopathy after discontinuation of cyclosporine in renal allografts. Clin Nephrol 38:1-8, 1992.

     

  20. Ström EH, Epper R, Mihatsch MJ: Cyclosporine-associated arteriolopathy: The renin-producing vascular smooth muscle cells are more sensitive to cyclosporine toxicity. Clin Nephrol 43:226-2312, 1995.

     

  21. Racusen LC, Solez K, Olsen S: The pathology of kidney transplantation: A standardized approach to histologic rejection diagnosis in Solez K, Racusen LC, and Billingham M, eds., Solid Organ Transplant Rejection: Pathology and Diagnosis, Marcel Dekker Inc., New York (in press, 1995).

     

  22. Solez K: International standardization of criteria for histologic diagnosis of chronic rejection in renal allografts. Clin Transpl 8:345-350, 1994.

     

  23. Curschellas E; Landmann J; Durig M; Huser B; Kyo M; Basler V; Thiel G; Mihatsch MJ: Morphologic findings in "zero-hour" biopsies of renal transplants. Clin Nephrol 1991 Nov;36(5):215-22

Abstract from Reference 17, Trpkov et al.

Pathology and clinical outcome in anti-class I antibody mediated acute renal allograft rejection:

 


Alloantibody frequently appears during the immune response to alloantigens in renal transplant recipients. We studied whether the presence of antibody against donor class I antigens correlated with clinical and pathologic features of acute rejection episodes. We identified patients who had (i) clinical evidence of acute rejection; (ii) a renal biopsy showing pathologic features of acute rejection, defined by the Banff criteria; and (iii) pre- and post-transplant sera screened against donor T cells. We divided these patients into those with or without donor specific alloantibody reactive with donor T cells, presumed to be anti class I. Of 44 patients meeting these criteria, 20 were antibody negative (Ab-R) and 24 were antibody positive (Ab+R). In patients with multiple rejections only the first episode meeting these criteria was tested. The Ab+R patients had a higher incidence of severe vasculitis (V3) (p<.0009) and glomerulitis (p<.02). Ab-R patients more often had tubulitis than Ab+R patients: Moderate (T2) and severe(T3) tubulitis was present in 19/20 (95%) of Ab-R patients, versus 12/24 (50%) of Ab+R patients (p<.003). No renal biopsies in the Ab-R group had infarction, compared with 9/24 in the Ab+R group (p<.003). Polymorphs in peritubular capillaries were more frequent in Ab+R patients (p<.003). Fibrin thrombi in glomeruli and/or vessels, fibrinoid necrosis, and dilatation of peritubular capillaries were also more frequent in the AB+R group. Graft loss was increased in the Ab+R patients, particularly graft loss before 3 months (12/24 compared with 3/20, p<.025).

These results indicate that, during biopsy proven acute rejection episodes, the presence of anti-class I antibody in the early post-transplant period correlates with and probably causes severe vascular lesions, glomerulitis, infarction, and early graft loss. Thus the findings of fibrin thrombi in small blood vessels, fibrinoid necrosis in vessel walls, glomerulitis, and polymorphs in peritubular capillaries in renal transplant biopsies should suggest that the rejection is associated with anti class I antibody.

 


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Last Modified: January 20, 1997 9:32:59 AM