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Till the early 1990s there was no standardized international classification of renal allograft biopsies resulting in considerable heterogeneity in reporting among the various centers. A group of dedicated renal pathologists, nephrologists, and transplant surgeons developed a schema in Banff, Canada in 1991. Subsequently there have been updates at regular intervals. The following review presents the evolution of the Banff classification and its utility for clinicians.
Until the early 1990s, rejection of the renal allograft was classically classified into the following four types: 1) hyperacute, 2) acute, 3) accelerated acute, and 4) chronic. Hyperacute rejection was defined as immediate (minutes to hours) rejection of the graft due to the presence of preformed antibodies. Acute rejection was defined as rejection occurring after 5–7 days due to activated T cells. Accelerated acute was defined as an aggressive episode of rejection occurring within five days, due to formation of antibodies in a presensitized patient (history of blood transfusion, pregnancy, earlier transplant). Chronic rejection was defined as slow progressive graft dysfunction starting after three months. The pathophysiology of chronic rejection was considered to be both immune and nonimmune mediated. However, there was considerable heterogeneity among pathologists in characterization of renal allograft biopsies. Hence, it was felt that standardization of renal allograft biopsy was necessary to guide therapy and to help establish an objective end-point in clinical trials similar to that in heart and lung transplantation. Hence, a group of pathologists, nephrologists, and transplant surgeons met in Banff Canada from 2–4 August, 1991, to formulate a schema for nomenclature and classification of renal allograft pathology. The schema underwent considerable revision over the next couple years through follow-up meetings and correspondence including circulation of slides; and finally published in March 1993. Thereafter, the Banff group has been meeting at regular intervals. So far there have been a total of 10 Banff conferences, with publication of four updates of the original classification, the latest being in April 2008.[3–6] The Banff schema has undergone considerable evolution over the last 15 years. Besides Banff, other classification schemes have also been studied.[7,8] All these are somewhat confusing for the nephrologist. Hence, an attempt has been made to present the evolution of the various classification systems over the last 15 years in a form useful to nephrologists [Table 1].
As mentioned earlier, the aim of first Banff schema published in 1993 was to standardize the histopathological diagnosis of renal allograft biopsy. Specimen adequacy was taken as > 7 glomeruli with at least one artery. It was recommended to have seven slides:3 H and E, 3 PAS, and 1 trichrome. The novel features comprised introduction of the categories ‘Borderline Changes’ and ‘Chronic Allograft Nephropathy’ (CAN); and grading ‘acute rejection’ into mild, moderate, and severe. Banff also introduced a numerical grading system for each of the renal compartments-interstitium (i), tubules (t), vessels (v), and glomeruli (g) as: 0-absent, 1-mild, 2-moderate, and 3-severe. On histopathology, the renal allograft biopsies were classified into six categories viz., normal, hyperacute rejection, borderline, acute rejection, chronic allograft nephropathy, and other i.e. changes not due to rejection.
Hyperacute rejection occurs within 10 minutes to 1 hour after perfusion with the recipient's blood. This occurs since the recipient is presensitized to alloantigens on the surface of the graft endothelium. These alloantigens include:
During surgery, the initial pink kidney becomes soft, flabby, mottled purple or cyanotic and anuric. Subsequently, it swells with widespread interstitial hemorrhage and cortical necrosis. The histological features include the presence of thrombi in the microvasculature, interstitial hemorrhages, and prominence of neutrophils in the glomeruli. Currently, it is well known that C4d staining in peritubular capillaries is the diagnostic feature, which helps in differentiating it from vascular thrombosis. Hyperacute rejection is now rare, seen in nearly 0.5% of transplants. In addition, some cases of primary nonfunction of the graft may be due to hyperacute rejection. As it is well known that the treatment of hyperacute rejection is nephrectomy.
Borderline changes was characterized by infiltration of mononuclear cells (<25% of the parenchyma) or foci of mild tubulitis (1–4 mononuclear cells/tubular cross-section). Borderline changes might be considered suggestive of ‘very mild acute rejection’, but which were nondiagnostic. Banff opined that it was not mandatory to treat Borderline rejection. This has been somewhat controversial.
It was felt that tubulitis was a better measure of severity of rejection than the intensity or extent of interstitial lymphocytic infiltration. Thus, tubulitis (infiltration by > 4 mononuclear cells / tubular cross-section) and intimal arteritis (subendothelial infiltration by mononuclear cells) were taken as defining features for acute rejection. Glomerulitis, although included in the scoring system, was not taken for diagnosing or grading of acute rejection. Acute rejection was graded as follows:
Grade I acute rejection: Moderate (>25%) to severe mononuclear cell interstitial infiltrate (i2/i3) and moderate tubulitis (4 mononuclear cells/tubular cross section i.e., t2).
Grade II acute rejection: Severe tubulitis (t3) and/or intimal arteritis (v1/v2).
Grade III acute rejection: Transmural arteritis (v3).
Banff introduced the category ‘chronic allograft nephropathy’ (CAN) as a histopathological correlate of chronic allograft dysfunction. CAN was thought to include at least four entities at that period of time viz. chronic rejection, chronic cyclosporine toxicity, hypertensive changes, and chronic infection. The features suggestive of chronic rejection were: a) chronic transplant glomerulopathy: Glomerular basement membrane duplication and mesangial cell proliferation, and b) vasculopathy: Fibrous intimal thickening often with fragmentation of internal elastic lamina. Chronic changes in the interstitium (ci), tubules (ct), vessels (cv), and glomerulus (cg) were likewise graded into 0, 1, 2, and 3. The severity of interstitial fibrosis and tubular atrophy, as also chronic transplant glomerulopathy and vasculopathy were used to grade CAN into mild, moderate, and severe.Two other classification systems which developed around this time deserve mention.
Chronic allograft damage index (CADI) score was first developed in 1994. The CADI score was obtained by scoring each of the following from 0–3: Diffuse or focal inflammation, interstitial fibrosis, increase in mesangial matrix, glomeruloscerosis, intimal proliferation of vessels and tubular atrophy. CADI score < 2 is associated with a good graft survival, while high CADI score > 4 is associated with a poor outcome. This scoring system is still used occasionally both to study protocol and indication biopsies.
In 1997, pathologists in centers participating in the cooperative clinical trials in transplantation (CCTT) sponsored by the National Institutes of Health developed a scoring system (based on Banff) for the diagnosis of acute rejection. This was named as the CCTT system, which was more simple and objective. It replaced ‘grades of rejection’ in the Banff schema by ‘types of rejection’. There was no category of ‘borderline rejection’; and all cases of borderline rejection as per Banff met the criteria for type I rejection in the CCTT system. Type I rejection was defined by mononuclear interstitial infiltrate (>5% of parenchyma) and tubulitis. It recognized the importance of vasculitis per sec, as it has implications for response to therapy and graft survival. Type II rejection was defined by arterial or arteriolar endothelialitis and type III by fibrinoid necrosis or transmural inflammation. These criteria were subsequently incorporated in the Banff '97 schema. Currently, the CCTT system is no longer used independently.
Banff '97 constitutes a landmark document in the field of renal transplant pathology. It was developed using the First Banff schema and the CCTT modifications. The important changes introduced include:
As mentioned later, this classification of acute rejection still holds good, although it is now placed under acute T-cell-mediated rejection.
In the 2001 Banff meeting, published in 2003, it was recognized that antibodies play an important role in causing rejection. Studies presented at this Banff Conference showed that biopsies with C4d deposition had distinctly lower graft survival. Tubular HLA-DR expression was the morphologic feature most closely linked to deposition of C4d. Hence, C4d staining of the peritubular capillaries (ptc) was accepted as the marker of antibody-mediated rejection (AMR). Detailed pathological classification of AMR was outlined as follows:
The prior category of acute rejection was renamed as acute/active cellular rejection. Rest of the Banff '97 schema was left unchanged. More powerful immunosuppression was considered necessary in patients with AMR. Workers reported that use of plasmapheresis and IVIg was associated with good outcome. Use of anti-CD 20 therapy was also reported.
The 8th Banff Conference was held in July 2005 and published in 2007. The major revisions were: 1) change in the basic classification of rejection from acute and chronic to its pathophysiologic basis viz. antibody- mediated (AMR) and T-cell-mediated (TCR), either of which could be acute or chronic; and 2) Elimination of CAN, which had actually been introduced by the First Banff 12 years back.
CAN is not a homogenous entity. It is the end result of various injurious processes to the glomerulus, tubulointerstitium, and the microvascular compartments; resulting in interstitial fibrosis and tubular atrophy. The various such causes, which may be present either singly or in combination are shown in [Table 2]. During the last 12 years since the introduction of the term, researchers used ‘CAN’ indiscriminately as a diagnostic entity by itself rather than making attempts to pinpoint the exact disease causing CAN. Hence, in 2003, the Banff consensus conference decided to eliminate the term CAN from the Banff schema. Instead all efforts should be made to diagnose the etiology of the chronic allograft injury. If attempts to find the exact cause fail, then the biopsy report should be labelled as ‘interstitial fibrosis and tubular atrophy-not otherwise specified’ as discussed below.
The re-classified categories are as follows:
AMR may be super-imposed on acute T-cell-mediated rejection. AMR needs stronger immunosuppression. Plasmapheresis, IVIg, and ant-CD 20 antibody rituximab have all been tried with variable success.
Most cases of CHR are of insidious onset without past history of acute humoral rejection. CHR is present in about 10% of indication biopsies.
Although occasional eosinophils may be present, the presence of abundant eosinophils is associated with higher grades of rejection and a worse prognosis. The differential diagnosis consists of drug induced acute interstitial nephritis and infection. Plasma cells are associated with a poor graft survival. Similarly the presence of CD 20 + B cells in the interstitium is associated with a poor response to steroids. Neutrophils are suggestive of AMR or pyelonephritis. Mast cells correlate with interstitial edema.
The significant updates include the following:
The various categories remain unchanged.
Mueller et al. confirmed a significant association between the revised Banff '97 classification and graft outcome. Intimal arteritis was the only significant predictor of a poor survival probability. An area of some controversy is the ‘borderline change’. Although Banff recommends that treatment may not be indicated, studies have shown beneficial effect of treating this group with ant-rejection therapy.[18,19] Recently, SWOT (strengths, weaknesses, opportunities and threats) analysis of Banff was done. They found that Banff had universal impact on clinical practice and research. Currently, for routine clinical purposes, pathologists mention only the broad Banff category. Detailed scoring of the various compartments of the renal parenchyma is not mentioned in the report.
During rejection certain genes-g interferon inducible or cytotoxic T-cell associated are upregulated.[21,22] A study of the transcriptional profile of these genes is called transcriptomics, which can improve the biopsy diagnosis. One area in which it is especially useful is-the Banff ‘Borderline rejection’. These cases can be resolved into two distinct classes viz., rejection and nonrejection. It is expected that future Banff updates will integrate the histopathological and molecular parameters.
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Conflict of Interest: None declared.