Mechanisms of Toxic and Drug-Induced Injury
Iatrogenic renal injuries develop through several scenarios. The first is an acute interstitial immunologic reaction (a classic example is the response to methicillin). The second pathway involves the development of acute kidney injury (AKI). The third variant represents cumulative, progressive tubular injury. It is insidious because it becomes clinically apparent only after years of continuous toxin exposure and inevitably leads to chronic kidney disease (CKD). A classic example of this scenario is analgesic nephropathy, which is often diagnosed at the end-stage CKD stage.
Acute Drug-Induced Interstitial Nephritis
This condition presents as a hypersensitivity reaction. Triggers include synthetic penicillins (ampicillin, methicillin), other antibiotics (rifampin), diuretics (thiazides), nonsteroidal anti-inflammatory drugs (NSAIDs), and other medications such as cimetidine.
The pathogenesis involves two immune mechanisms:
- IgE-mediated mechanism: serum IgE levels rise, and basophils and plasma cells containing this immunoglobulin accumulate at the injury site.
- Type IV (delayed-type) hypersensitivity (DTH): a mononuclear or granulomatous infiltrate forms, and skin tests for haptens yield positive results.
Morphological features:
- Grossly: the kidneys appear slightly enlarged.
- Microscopically: marked interstitial edema is present. The inflammatory infiltrate consists predominantly of mononuclear cells (macrophages and lymphocytes), but the presence of eosinophils and numerous neutrophils is also highly characteristic of this pathology. Basophils and plasma cells are less common. Methicillin or thiazides may induce the formation of interstitial granulomas with giant cells. Tubules show varying degrees of necrosis and regeneration. Glomeruli are typically spared, with the exception of cases triggered by NSAIDs, where minimal change disease with nephrotic syndrome may develop concurrently.
Analgesic Nephropathy
This condition is associated with excessive and prolonged use of analgesics and is one of the leading causes of CKD, particularly in Western Europe. Morphologically, the process presents as chronic tubulointerstitial nephritis accompanied by renal papillary necrosis (necrosis of the renal pyramid apices).
Grossly, the kidneys retain normal size or are slightly reduced. The cortical surface shows alternating areas of bulges and depressions. Depressions correspond to zones of cortical atrophy located directly over necrotic papillae. The pyramids themselves are at various stages of destruction: from fresh necrosis to calcification, fragmentation, and complete sloughing.
Histological features:
- Papillae: areas of necrosis are visible. In severe cases, the papilla undergoes total necrosis, transforming into amorphous masses where only the outlines of former tubules can be discerned. Foci of dystrophic calcification appear. Segments of papillae may slough off and pass into the urine.
- Cortex: tubules disappear or undergo marked atrophy. Interstitial fibrosis and chronic inflammation develop. The primary mechanism driving these changes is obstructive atrophy, resulting from tubular destruction in the underlying papillae. Secondary pyelonephritis frequently complicates the process.
- Blood vessels: a characteristic analgesic microangiopathy develops, affecting small blood vessels of the papillae and the submucosa of the urinary tract. Its hallmark is thickening of the basement membrane, which is PAS-positive.