Banff borderline: where do we stand?

Banff borderline is a category 3 diagnostic entity in Banff classification scheme for histological diagnosis of kidney allografts. The biopsies with borderline changes have i score or percentage of interstitial mononuclear cell infiltrate in non-scarred area not more than 25% (i0 or i1) and any degree of tubulitis (t1, t2, t3). Becker et al. surveyed renal pathologists worldwide and found that the majority of them reserved the diagnosis for borderline changes for biopsies with i1 or 10-25% interstitial infiltrate. They did not consider biopsies with i0 to be in borderline category. Interestingly, many of them admitted to exaggerate i score in order to meet the diagnosis of borderline.

Beyond C4d: the ultrastructural appearances of endothelium in ABO-incompatible renal allografts

C4d is a marker of antibody-mediated rejection (ABMR). However, in ABO blood group incompatible (iABO) kidney transplants, the finding of positive C4d does not correlate with impaired graft function or histologic findings of antibody-mediated rejection by light microscopy. Brocker et al. looked further into ultrastructural findings of iABO grafts vs. ABO blood group compatible (cABO) grafts with positive C4d  vs. cABO grafts with negative C4d and no histologic findings of ABMR. iABO grafts had positive C4d in at least one of the biopsies. The authors did not find difference of ultrastructural findings between iABO and cABO group with negative C4d, in contrast to cABO with positive C4d in which more severe ultrastructural changes were seen and correlated with poor graft function/outcome. Accommodation was discussed as the reason for no deterioration of structure and function of iABO grafts with positive C4d.

Banff 2013 Meeting Report: Inclusion of C4d-Negative Antibody-Mediated Rejection and Antibody-Associated Arterial Lesions

Banff 2013 acknowledges C4d negative antibody-mediated rejection (ABMR). Positive C4d staining in graft biopsy was relegated to just 1 of 3 evidence of current/recent antibody interaction with vascular endothelium. The remaining 2 are moderate microvascular inflammation (g+ptc score at least 2) and the increased expression of gene transcripts related to endothelial injury. The other two criteria for acute/active and chronic active ABMR are intact with addition of intimal arteritis as one of histology evidence of acute tissue injury in acute ABMR.

The definition for glomerulitis (g) was changed. Now required complete or partial occlusion of glomerular capillary lumens and endothelial swelling in >1 capillary. The threshold for transplant glomerulopathy is modified. However, interstitial mononuclear cell infiltrate in scarred tissue (ti) is still not included in criteria for diagnosis of T cell-mediated rejection. Though it was recommended to included in the biopsy report.

Osmotic nephrosis

Tubular vacuolization in renal allografts can be related to calcineurin inhibitor toxicity, ischemic injury though other less commonly recognized conditions exist. Osmotic nephrosis is caused by administration of many

agents such as sucrose, dextran, maltose and contrast media. In renal allografts, it can occur as the result of IVIG administration in acute rejection because IVIG preparation may contain sucrose or maltose. The term seems to be a misnomer because the etiology is not the accumulation of water due to different osmotic gradient. The pathogenesis involves pinocytosis of the causative molecules by the proximal tubular cells, then the molecules fuse with lysosomes to form vacuoles. The high concentration of these agents administered to the patients with impaired renal function (impaired lysosomal clearing function) in a relatively short period of time results in massive accumulation of the vacuoles and further impairs renal function.
Histologically the proximal tubular cells show clear cell transformation due to accumulation of vacuoles. The vacuolated tubular cells are often seen side by side with the normal ones. This change is sometime difficult to differentiate with acute calcineurin inhibitor in allograft biopsy.

Problems with diagnosis of antibody-mediated rejection

Transplant glomerulopathy

It is now clear that the Banff criteria for diagnosis of antibody-mediated rejection (AMR) which include 1) presence of donor specific antibody (DSA) 2) microvascular injury (MVI) such as glomerulitis 3) positive C4d , though specific, are not sensitive to detect AMR. Papadimitriou et al. study of surveillance and for cause allograft biopsies wants to verify whether any of the AMR characteristics can be used reliably to indicate this type of rejection. The main findings are:

• DSA alone was not predictive of higher risk of graft dysfunction.
• C4d staining alone was associated with the risk of graft dysfunction, especially in diffuse and focal pattern.
• Any type of MVI lesions (glomerulitis, peritubular capillaritis, transplant glomerulopathy) were associated with the risk of graft dysfunction. The risk increased with the increasing combined Banff score for these lesions.
• Of all MVI, transplant glomerulopathy seemed to be the most ominous sign. This is probably the reflection of chronic, persistent injury. However the study did not describe multilayering of peritubular capillary basement membrane which is the other chronic lesion. It is interesting to see whether this lesion is correlated with graft dysfunction.
• The peritubular capillaritis was detected before glomerulitis (21.8 vs. 32.4 months).
• The authors suggested the use of combined MVI scores as the basis of AMR diagnosis.
• The authors argued for change in terms "acute" and "chronic active" used by Banff schema because AMR occurs insidiously in patients without hypersensitization, the use of term acute seems inappropriate.

Banff classification

The Banff classification revisited

Glomerulitis as a histologic feature indicating antibody-mediated rejection

Banff classification of renal allograft pathology started in 1991. Since then the classification has evolved considerably but still remains histology-based. Limitation of using traditional histology as the sole determination of allograft dysfunction is well known. The issues range from biopsy sampling error to interobserver variability in interpretation. In this minireview, Professor Solez, the founder of Banff classification, encourages the transplant community to adopt morphometry, genomics and molecular methods. The Banff classification will move toward these new technologies.

In my opinion, the incorporation of new techniques into traditional histopathology is not unique to renal allograft biopsy. We can see this trend in many field of surgical pathology.

Renal allografts with chronic lesions in early biopsies

Chronic Histological Damage in Early Indication Biopsies Is an Independent Risk Factor for Late Renal Allograft Failure

The study shows that chronic histological lesions are inherently bad for the kidney grafts biopsied for causes within 1 yr after transplant. On multivariate analysis arteriolar hyalinosis and transplant glomerulopathy were associated with graft survival while others such as interstitial fibrosis were not. However,all the chronic lesions occurred together and were collectively impacted graft survival. The study emphasizes the impact of chronic lesions on graft regardless of the etiology.

Diagnosing antibody-mediated rejection

Antibody-mediated rejection (ABMR) is a serious problem for kidney allografts. While T cell-mediated rejection (TCMR) can be treated effectively with immunosuppressive drugs, ABMR tends to be more refractory to treatment. On diagnostic front, there is a lack of test with sufficient sensitivity and specificity. Diagnostic criteria for ABMR was set by Banff include histologic changes, C4d in graft and donor specific antibody (DSA). The criteria have been proven to be too rigid with the increasingly-recognized C4d negative ABMR.

Banff 2011 Meeting Report

Every two years since 1991 Banff Meeting was held. It is a scientific gathering focusing on transplantation organ. The latest one was on 5-10 June 2011. Here are the topics related to kidney transplant being discussed.

C4d revisited

C4d is a byproduct of complement activation in classic and lectin pathway. It is non-functional but served as a robust evidence of antibody-mediated injury. It has been used as a tissue marker for antibody-mediated rejection (AMR) in kidney transplants for more than a decade. Its use has been extended to other transplant organs including heart, lung and pancreas though the liver grafts do not benefit from C4d yet.