PROTEIN AND ENZYME PROFILES IN TUBULOINTERSTITIAL NEPHRITIS

Abstract

When different compounds arc given to animals and humans, nephrotoxicity is a frequently observed toxic reaction, acting through a variety or biological mechanisms. An important avenue or research exists in the study of pre-existing renal insufficiency on chemical and drug-induced nephrotoxicity. Since nephrotoxicity is often unrecognised. a screening procedure by which adverse effects can be detected rapidly and reliably is needed. Early detection may allow the avoidance or these drugs or specific therapies and permit recovery from the toxic effects. Nephrotoxic renal damage is widespread and manifested usually by occupational exposure or therapeutic ingestion or drugs or toxins. In patients with drug hypersensitivity or infection leading to tubulointerstitial nephritis (TIN), abnormal tubular function or renal failure is present. In this study TIN of differing severity was induced in male Sprague Dawley rats using 40 mg/kg (Low dose) or 100 mg/kg (High dose) llcxachloro-13-hutadicne (HCBD). This model was further studied lo determine whether biochemical or histological markers could offer more sensitive markers and in the degree or pre-existing TIN would alter the site or subsequent effects or a second nephrotoxic insult. After five days, a period found to be adequate for tissue regeneration to become well established, the TIN kidney was exposed lo a secondary toxin. The secondary toxins were site specified and each asked a different question: • proximal tubule - 300 mg/kg maleic acid ( MAL) - How would a further tubulotoxic insult affect the response of a kidney with pre-existing TIN? • glomerulus – 100 mg/kg puromycin aminonucleoside (PAN) - Would the nephrotoxic protein overload or PAN exacerbate the pre-existing TIN? papilla - 50 mg/kg bromoethanamine (BEA) - This model was used to represent the renal papillary necrosis or analgesic abusers with an underlying TIN. Approach: 1. Classical markers (UTP, albumin, creatinine and NAG) using assays with improved sensitivity and specificity lo frequently published methodologies. 1 Profiles or some less commonly used analytes (RBP, kallikrein and laminin) 3. Grading or urine biochemistry and histology to determine which offered greater sensitivity. 4. Statistical evaluation using ANOVA or treatment groups, lime points as well as the combined assessment or treatment and time together. Findings: Low dose HCBD induced injury cannot be detected using routine biochemical parameters or light microscopy. • High dose HCBD induced TIN was detected with an early rise in UTP, albumin, RBP, laminin, creatinine, AAP, ALP and NAG, with a delayed decrease in kallikrein. • Tubular toxin on High dose HCBD induced TIN produced a significant reduction of biochemical and histological indices compared lo MAL alone. • Changes found in Low dose HCBD induced TIN after exposure to a second tubular toxin were severely attenuated. and within the limits of the Control group on light microscopy. • Protein overload on TIN enhanced damage of the tubulointerstitial injury. The damage was more severe, but did not prevent resolution. • Increased laminin execretion was evidenced earlier than traditional markers of UTP or albumin. •The electrophoretic blot of the PAN group probed with WGA showed changes in the banding pattern on day 4, occurring with the onset or gross proteinuria. • The biochemical markers were not useful in evaluating the RPN caused by BEA. • The electrophoretic blot of the BEA group probed with WGA showed additional hands on day 5 which could possibly he products or breakdown products of the regeneration process which was active al this lime. No one marker possesses the sensitivity and specificity to identify early damage in TIN or further injury mused by a second nephrotoxic event. However, a number of presently investigated parameters (RBP, Laminin and NAO) could be added to the arsenal or classical analytes currently in use in clinical laboratories for the early detection or renal injury.