Abstract
Renal papillary necrosis (RPN) in humans may be a consequence of analgesic abuse. The development of the lesion manifests very few symptoms, but the sequelae may include disruption of normal homoestasis and chronic renal failure. Attempts to define the molecular pathogenesis of the analgesic associated lesion in experimental animals has not been successful. The lesion can only be induced over many weeks, not all of the test animals are equally affected and experiments are notoriously irreproducible. 2-Bromoethanamine (BEA) hydrobromide has been used as a model papillotoxin in this study on rats. A single dose of BEA caused RPN within 24 to 48h in all treated animals. The lesion could be varied limited focal papillary necrosis (50mg/kg po) to total medullary ablation (>150mg/kg ip). Pretreating rats with mixed functional oxidase inducers (henobarbitone, 3-methylcholanthrene) or inhibitors (cobaltous chloride); thiol protectors (acetylcysteine, methionine) and free radical scavengers (zinc sulphate); reserpine or dexamethasone cause no change in the magnitude of the lesion. Antirheumatic compounds and their analogues (given before BEA) and dehydration exacerbated the lesion. Some degree of protection against BEA-induced RPN was afforded by anti-oxidants and ethanolamine pretreatment. Animals with a steptozotocin-induced diabetes were refractory to BEA. Microscopically the earliest changes following BEA insult were a hydropic degeneration (4h) reverting to an apparently normal architecture (8h), followed by necrotic change. The histochemical staining intensity of the medullary proteoglycan (PoG)-glycosaminoglycan (GAG) interstitial matrix increased dramatically within hours of BEA treatment. The staining was lost only from those parts of the papilla which were necrosed. A marked perturbation of the papillary ground substance was confirmed biochemically by an altered pattern of PoG-GAG polydispersion in urine and by loss of [35]S from the papilla, but not from the cortex or from extra-renal tissue. Carbon-14 labelled BEA was synthesised. About 70% of the administered dose was excreted in urine, 4% as CO[2], 2% as a volatile base, up to 11% in bile, but only 4% in faeces. The BEA-derived products in urine and bile could each be separated into 6-8 components. The bile products were, in general, of higher molecular weight than those in urine. A model is proposed in which a primary effect on renal interstitial cell function or a perturbation of the medullary PoG-GAG ground substance leads to necrosis and contributes to the sequelae associated with the lesion.