Pathologic Findings

There are three pathologic forms of toxicity: acute nephrotoxicity, chronic nephrotoxicity, and thrombotic microangiopathy (hemolytic-uremic syndrome). Each can also arise in native kidneys in patients on CsA or tacro-limus for other reasons.

Acute Tubulopathy

The biopsy features of acute toxicity range from no morphologic abnormality to acute tubular injury or marked tubular vacuolization and vascular smooth muscle apoptosis (Fig. 21.1). The proximal tubules show loss of brush borders and isometric clear vacuolization (defined as cells filled with uniformly sized vacuoles). The vacuoles, much smaller than the nucleus, contain clear aqueous fluid rather than lipid, and are indistinguishable from those caused by osmotic diuretics. Immunofluorescence microscopy is negative. By electron microscopy, the vacuoles are dilated endoplasmic reticulum and appear empty (1). These lesions are reversible with decreased dosage.

Figure 21.1. Acute calcineurin inhibitor toxicity, showing isometric vacuolization of proximal tubules (H&E stain).

Arteriolopathy

A spectrum of acute and chronic arteriolopathy has been described by Mihatsch, ranging from acute, focal myocyte necrosis and mucoid intimal thickening to indolent nodular hyaline deposits (Fig. 21.2) (2). The characteristic features are individual smooth muscle cell degeneration, vacuol-ization, necrosis, and loss. The myocytes are replaced by hyaline deposits,

Figure 21.2. Chronic calcineurin inhibitor toxicity, peripheral nodules of hyaline are in an afferent arteriole, 2 years posttransplant (arrow; trichrome stain).

which are classically in a beaded pattern in the media. The usual hyaline deposits in hypertension or diabetes are subendothelial. The endothelial or smooth muscle cells may be vacuolated. Later biopsies show progressive scarring of arterioles, intimal fibrosis, and segmental glomerular obsolescence. Immunofluorescence of early lesions may show that the vessels have deposits of immunoglobulin M (IgM), C3, and fibrin. Electron microscopy shows apoptosis or necrosis of smooth muscle cells and replacement with hyaline material. Focal myocyte necrosis in the media of small arteries, in the absence of intimal changes, is regarded as a reliable indicator of CsA toxicity (3,4). The reversibility of the these lesions is debated.

Thrombotic Microangiopathy

Although more prevalent with higher doses of CsA in the 1980s, thrombotic microangiopathy (Fig. 21.3) still occurs under current regimens, even with careful attention to blood CsA levels. By 1994, the prevalence of CsA-associated thrombotic microangiopathy had decreased to 0.9%, accounting for 26% of the cases of thrombotic microangiopathy after renal transplantation (acute rejection, probably humoral, accounted for 53% and recurrent thrombotic microangiopathy 16%) (5). Patients typically present with acute renal failure, thrombocytopenia, microangiopathic hemolytic anemia, elevated lactic dehydrogenase, and hyperbilirubinemia. Despite these characteristic features, the clinical syndrome is not often recognized before biopsy. Those without systemic signs (thrombocytopenia, hemoly-sis) do considerably better (6).

The pathologic changes are the same as in thrombotic microangiopathy from other causes, although in the allograft the differential diagnosis with

Figure 21.3. Acute calcineurin inhibitor toxicity due to tacrolimus, with a pattern of thrombotic microangiopathy that resembles endarteritis [periodic acid-Schiff (PAS) stain].

endarteritis can be challenging. Loose intimal thickening and trapped red cells are useful discriminators.

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