Acute Rejection

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DIAGNOSTIC POSSIBILITIES IN TRANSPLANT-RELATED ACUTE RENAL FAILURE

FIGURE 10-1

Diagnostic possibilities in transplant-related acute renal failure.

1. Acute (cell-mediated) rejection

2. Delayed-appearing antibody-mediated rejection

3. Acute tubular necrosis

4. Cyclosporine or FK506 toxicity

5. Urine leak

6. Obstruction

7. Viral infection

8. Post-transplant lymphoproliferative disorder

9. Vascular thrombosis

10. Prerenal azotemia

FIGURE 10-2

Diagnosis of rejection in the Banff classification makes use of two basic lesions, tubulitis and intimal arteritis. The 1993-1995 Banff classification depicted in this figure is the standard in use in virtually all current clinical trials and in many individual transplant units. In this construct, rejection is regarded as a continuum of mild, moderate, and severe forms. The 1997 Banff classification is similar, having the same threshold for rejection diagnosis, but it recognizes three different histologic types of acute rejection: tubulointersititial, vascular, and transmural. The quotation marks emphasize the possible overlap of features of the various types (eg, the finding of tubulitis should not dissuade the pathologist from conducting a thorough search for intimal arteritis).

FIGURE 10-3

Tubulitis is not absolutely specific for acute rejection. It can be found in mild forms in acute tubular necrosis, normally functioning kidneys, and in cyclosporine toxicity and in conditions not related to rejection. Therefore, quantitation is necessary. The number of lymphocytes situated between and beneath tubular epithelial cells is compared with the number of tubular cells to determine the severity of tubulitis. Four lymphocytes per most inflamed tubule cross section or per ten tubular cells is required to reach the threshold for diagnosing rejection. In this figure, the two tubule cross sections in the center have eight mononuclear cells each. Rejection with intimal arteritis or transmural arteritis can occur without any tubulitis whatsoever, although usually in well-established rejection both tubulitis and intimal arteritis are observed.

FIGURE 10-4 (see Color Plate)

In this figure the tubules with lymphocytic invasion are atrophic with thickened tubular basement membranes. There are 13 or 14 lymphocytes per tubular cross section. This is an example of how a properly performed periodic acid-Schiff (PAS) stain should look. The Banff classification is critically dependent on proper performance of PAS staining. The invading lymphocytes are readily apparent and countable in the tubules. In the Banff 1997 classification one avoids counting lymphocytes in atrophic tubules, as tubulitis there is more "nonspecific" than in nonatrophed tubules. (From Solez et al. [1]; with permission.)

FIGURE 10-6

Artery in longitudinal section shows a more florid intimal arteritis than that in Figure 10-5. Aggregation of lymphocytes is also seen in the lumen, but this is a nonspecific change. The reporting for some clinical trials has involved counting lymphocytes in the most inflamed artery, but this has not been shown to correlate with clinical severity or outcome, whereas the presence or absence of the lesion has been shown to have such a correlation. (From Solez et al. [1]; with permission.)

Intimal arteritis in a case of acute rejection. Note that more than 20 lymphocytes are present in the thickened intima. With this lesion, however, even a single lymphocyte in this site is sufficient to make the diagnosis. Thus, the pathologist must search for subtle intimal arteritis lesions, which are highly reliable and specific for rejection. (From Solez et al. [1]; with permission.)

FIGURE 10-7

Transmural arteritis with fibrinoid change. In addition to the influx of inflammatory cells there has been proliferation of modified smooth muscle cells migrated from the media to the greatly thickened intima. Note the fibrinoid change at lower left and the penetration of the media by inflammatory cells at the upper right. Patients with these types of lesions have a less favorable prognosis, greater graft loss, and poorer long-term function as compared with patients with intimal arteritis alone. These sorts of lesions are also common in antibody-mediated rejection (see Fig. 10-9).

FIGURE 10-8

Diagram of arterial lesions of acute rejection. The initial changes (1-5) before intimal arteritis (6) occurs are completely nonspecific. These early changes are probably mechanistically related to the diagnostic lesions but can occur as a completely self-limiting phenomenon unrelated to clinical rejection. Lesions 7 to 10 are those characteristic of "transmural" rejection. Lesion 1 is perivascular inflammation; lesion 2, myocyte vacuolization; lesion 3, apoptosis; lesion 4, endothelial activation and prominence; lesion 5, leukocyte adherence to the endothelium; lesion 6 (specific), penetration of inflammatory cells under the endothelium (intimal arteritis); lesion 7, inflammatory cell penetration of the media; lesion 8, necrosis of medial smooth muscle cells; lesion 9, platelet aggregation; lesion 10, fibrinoid change; and lesion 11 is thrombosis.

FIGURE 10-9 (see Color Plate)

Antibody-mediated rejection with aggregates of polymorphonuclear leukocytes (polymorphs) in peritubular capillaries. This lesion is a feature of both classic hyperacute rejection and of later appearing antibody-mediated rejection, which is by far the more common entity. Antibody- and cell-mediated rejection can coexist, so one may find both tubulitis and intimal arteritis along with this lesion; however many cases of antibody-mediated rejection have a paucity of tubulitis [2]. The polymorph aggregates can be subtle, another reason for looking with care at the biopsy that appears to show "nothing."

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