The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Clinical significance and comparison with cyclosporine

Abstract

The histopathological changes in 51 renal allograft biopsies from patients immunosuppressed with FK506 were compared with those seen in 30 needle biopsies obtained from patients on cyclosporine. The frequency and severity of rejection episodes were similar in both groups. Tubular vacuolation and myocyte vacuolation were found to be useful morphological markers to monitor short-term drug toxicity associated with both drugs. Long-term administration of FK506 led to striped interstitial fibrosis and arteriolar hyalinosis, similar to that previously documented for cyclosporine. One case each of hemolytic uremic syndrome and necrotizing arteriopathy was noted in patients receiving FK506. FK506 and cyclosporine are structurally unrelated compounds; hence the parallelism observed in their nephrotoxicity profile suggests that the interactions of these drugs with renal tissue involves the operation of two different initial signal-transducing mechanisms, ultimately activating the same final metabolic pathways.

FIG. 1a,b

(a) The proximal and distal tubules in this patient with clinical FK506 toxicity show a fine cytoplasmic vacuolation. (b) In contrast, the vacuolation associated with ischemic injury, for example, acute tubular necrosis, is coarse and irregular. (Parts c and d shown on p. 64.)

FIG. 1c,d

(c) Panoramic electron micrographic view of FK506-induced tubular vacuolization (×3000). (d) At higher magnification, the vacuoles represent dilatations of the endoplasmic reticulum and lysosomal elements (×13,000).

FIG. 2

Acute FK506 toxicity resulted in prominent myocyte vacuolation in this interlobular artery. The patient clinically responded to a reduction in the dose of the drug.

FIG. 3

(a) A striped pattern of fibrosis with atrophy of the entrapped tubules develops on long-term administration of FK506, as has been reported for cyclosporine. (b) Focal calcifications in the tubular epithelium and interstitium accompany the fibrosis.

FIG. 4

Deposition of a hyaline material can be observed in arterioles in patients on FK506 therapy not known to be diabetic or hypertensive. These changes have also been described with cyclosporine therapy (Periodic acid Schiff stain).

FIG. 5

The interlobular artery shown has fibrin deposition, lymphocytes, and nuclear debris in its media. The renal function tests in the patients improved as the dosage of FK506 was lowered.

FIG. 6

The glomeruli in this case on FK506 therapy show capillary thrombosis and segmental necrosis. The patient presented clinically as a hemolytic syndrome for which no definite cause could be established.