Pathologic Findings Light Microscopy

The sites of acute cellular rejection are the interstitium, tubules, endothe-lium, and glomeruli. They may be involved separately or in combination.

The characteristic microscopic feature of type I rejection is a pleomor-phic interstitial infiltrate of activated lymphocytes and monocytes, accompanied by interstitial edema and tubular injury. The cells invade tubules ("tubulitis") and infiltrate the cortex (10-25% in the Banff system is considered suspicious for rejection and >25% is rejection) (Fig. 20.1).

Table 20.1. Pathologic classification of renal allograft lesions

I. Immunologic rejection

A. Acute cellular rejection (ACR)

1. Tubulo-interstitial (CCTT/Banff type I + Banff suspicious)

2. Vascular (endothelialitis) (CCTT/Banff type II)

3. Glomerular (acute allograft glomerulopathy) (No CCTT/Banff type)

B. Acute humoral rejection (AHR) (termed hyperacute rejection when in first 24 hours)

1. Acute tubular injury [C4d+ peritubular capillaries PTCs; new category]

2. Capillary inflammation (C4d+ PTCs; new category)

3. Arterial fibrinoid necrosis (previously CCTT/Banff type III)

C. Chronic allograft rejection: Arterial intimal thickening, glomerulopathy and/or interstitial fibrosis and tubular atrophy with immunologic activity a. Chronic active humoral rejection (C4d+)

b. Chronic active cellular rejection (T cells in lesions)

D. Non-human leukocyte antigen (HLA) alloantibody-mediated renal diseases

1. De novo membranous glomerulonephritis

2. Anti-glomerular basement membrane (GBM) disease (in Alport's syndrome)

3. Anti-tubular basement membrane (TBM) disease II. Nonrejection injury

A. Acute ischemic injury (ATN)

B. Perfusion injury

C. Calcineurin inhibitor nephrotoxicity (cyclosporine, tacrolimus)

1. Acute a. Functional b. Tubular c. Vascular

2. Thrombotic microangiopathy

3. Chronic a. Tubulo-interstitial b. Vascular (hyalinosis)

D. Other Drug Toxicity

1. OKT3

2. Rapamycin

E. Major artery/vein thrombosis

F. Renal artery stenosis

G. Obstruction

H. Infection (viral, bacterial, fungal)

I. Acute tubulo-interstitial nephritis (drug allergy) J. De novo glomerular disease

1. Focal segmental glomerular sclerosis (hyperfiltration/ collapsing)

2. Diabetic nephropathy

3. Other specific types

K. Posttransplant lymphoproliferative disease

III. Idiopathic

A. Chronic allograft nephropathy:

Arterial intimal thickening, glomerulopathy and/or interstitial fibrosis and tubular atrophy without immunologic activity (no C4d or T cells)

IV. Recurrent primary disease

A. Immunologic (e.g., IgA nephropathy, lupus nephritis, anti-GBM disease)

B. Metabolic (e.g., amyloidosis, diabetes, oxalosis)

C. Unknown (e.g., dense deposit disease, focal segmental glomerular sclerosis)

Modified from Colvin (2).

Figure 20.1. Acute cellular rejection (type I). A diffuse mononuclear infiltrate is present with edema and tubulitis [arrows; periodic acid-Schiff (PAS) stain].

The infiltrating mononuclear cells typically include lymphoblasts, with cytoplasmic basophilia, nucleoli, and occasional mitotic figures, indicative of increased synthetic and proliferative activity. The infiltrate consists of T cells (CD4 and CD8) macrophages and sometimes B cells.

Infiltration of mononuclear cells under arterial and arteriolar endothelium is the pathognomic lesion of type II acute cellular rejection ("endarteritis" or "endothelialitis") (Fig. 20.2). When lymphocytes are only on the surface of the endothelium, their significance is less certain. Lymphocytes also commonly surround vessels, a nonspecific feature, unless the cells invade the media. Endotheliitis has been reported in 48% to 54% of the renal biopsies with acute cellular rejection in three series (4-6). Some do

Figure 20.2. Acute cellular rejection with endarteritis (type II). A small artery has subendothelial infiltration of mononuclear cells 7 days after transplantation (H&E stain).
Figure 20.3. Acute cellular rejection, type III. Transmural inflammation of an artery is shown. The C4d stain was negative.

not find the lesion as often, which may possibly be ascribed to inadequate sampling, overdiagnosis of rejection, or timing of the biopsy with respect to antirejection therapy. These lesions are more frequent in the larger arteries (6). In our experience, about 20% of the arteries are involved, so that several arteries in the sample are almost essential for its detection (6). Rarely, the lymphocytes invade through the media, so-called transmural endarteritis (Fig. 20.3).

In most cases of acute cellular rejection, the glomeruli are spared or show minor changes, typically a few scattered mononuclear cells (T cells and monocytes) and occasionally segmental endothelial damage, termed "glomerulitis" (7-9). In a minority of cases, a severe, diffuse form of glomerular injury is evident and dominates the histologic pattern (Fig. 20.4).

Figure 20.4. Acute allograft glomerulopathy. This pattern of glomerular injury can occur as a feature of cellular or humoral rejection (PAS stain).

In 1981 Richardson and his colleagues (10) drew attention to a distinctive, acute allograft glomerulopathy, characterized by hypercellularity, injury and enlargement of endothelial cells, infiltration of glomeruli by mononuclear cells, and by webs of periodic acid-Schiff (PAS)-positive material. The glomeruli contain numerous CD3+ and CD8 + T cells and monocytes (9,11). This severe form of glomerulopathy has been observed in 4% to 7% of biopsies taken for allograft dysfunction, typically 1 to 4 months after transplantation (10,12-14). Acute allograft glomerulopathy is believed to be an unusual variant of cellular rejection, sometimes promoted by cyto-megalovirus (CMV) infection. T cells, not antibodies, are regularly detected in glomeruli immunohistochemically (9,11), and OKT3 can reverse the lesion (15). For unknown reasons, rejection becomes focused on glomerular components; florid glomerulopathy may occur with little interstitial inflammation, although cellular endarteritis is common.

Interstitial mononuclear inflammation and tubulitis occur in a variety of diseases other than acute rejection, such as drug-induced allergic tubulo-interstitial nephritis, and therefore cannot be considered proof that rejection is present. The presence of systemic infection is another well-known cause of tubulo-interstitial nephritis and tubulitis. Tubulitis has been documented in renal transplants with dysfunction due to lymphocele (obstruction) and to pneumonia (15). Tubulitis is often present in atrophic tubules from any cause and does not indicate acute rejection. Posttreatment with anti-T-cell antibodies, the inflammation diminishes in most patients and this is correlated with successful response to therapy. This type of rejection often responds to steroid pulses and rarely causes graft loss (6,16-19).

Cellular arteritis must not be confused with necrotizing arteritis, characteristic of humoral rejection (type III). Rarely, transmural cellular inflammation causes frank medial necrosis, but this complication of cellular arteritis can be distinguished from necrotizing arteritis by the heavy mononuclear infiltrate. Regrettably, many still do not distinguish these lesions, regarding all "vascular rejection" as predominately humoral. Cellular arteritis has a much better rate of reversal than necrotizing arteritis (61% vs. 29% 1-year graft survival) (20), which alone justifies their separation.

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