As mentioned earlier, the aim of first Banff schema published in 1993[2
] 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.[9
] These alloantigens include:
- ABO incompatibility: Primarily IgM antibodies.
- Anti-HLA class I antibodies: Primarily IgG3.
- Anti-HLA class II antibodies: IgG/IgM antibodies in glomeruli and peritubular capillaries (where class II is prominent).
- Anti-endothelial-monocyte antibodies.
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).
Chronic allograft nephropathy
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
Chronic allograft damage index (CADI) score was first developed in 1994.[7
] 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.[10
] This scoring system is still used occasionally both to study protocol and indication biopsies.
Cooperative clinical trials in transplantation system
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,[8
] 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.