Urinary lipid changes during the development of chemically-induced renal papillary necrosis: a study using mefenamic acid and N-phenylanthranilic acid

Acute renal papillary necrosis (RPN) in animals is characterized by increas ed renal lipid accumulation. The excretion of renal lipids into urine has b een determined to evaluate their possible use as sensitive early biomarkers for the diagnosis of RPN. This study investigates injury induced by two mo del nephrotoxins, mefenamic acid (MFA), a non-steroidal anti-inflammatory d rug (NSAID), and its analogue N-phenylanthranilic acid (NPAA). Oral NPAA wa s given repeatedly at doses of 100, 250 and 500 mg kg(1) daily for 5 days, followed by a 2 day respite over the weekend, and then four further daily d oses. The same dosing procedure was used with MFA, but at doses of 75, 150 and 300 mg kg(1). The control groups were given vehicle orally using the sa me volume given to the test groups. Urinary phospholipids (PLs), notably sp hingomyelin (SPM), phosphatidylcholine (PC) and phosphatidylethanolamine (P E), were measured and compared with other urinary parameters. Histopatholog ical investigations were also performed to confirm the presence or absence of RPN. Following MFA treatment, PC, PI and PE were raised significantly (p <0.001) on days 1 and 3 and for the remaining part of the experiment. Afte r NPAA treatment, PI showed a transient elevation, and PC and PE levels wer e significantly increased from day 2 onwards. Both drugs caused a dose-rela ted increase in PLs. There was no significant increase in the level of othe r urinary parameters. However, histopathological examination of the kidney on day 11 revealed lesions in the medulla and papilla following treatment w ith the two papillotoxins. These findings demonstrate the potential of urin ary PLs as diagnostic non-invasive biomarkers for early renal injury associ ated with RPN, which may provide an important improvement in the approach t o the therapeutic management of analgesic nephropathy.