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EFFECT OF WR-2721 ON FUROSEMIDE-INDUCED NEPHROCALCINOSIS † 1632

We previously demonstrated in the rat that parathyroidectomy protects from development of furosemide-induced nephrocalcinosis (NC) (Pediatr. Res. 1996;39:375A). In the present study we investigated the effect of WR-2721(WR), a PTH - blocking agent, on NC in the young rat. Five groups of 4-week old Sprague-Dawley male rats were studied (each n=6): (a) control (b) furosemide 40 mg/kg (c) furosemide + WR 20 mg/kg (d) furosemide + WR 30 mg/kg(e) furosemide + WR 40 mg/kg. Furosemide and WR were given each in a single daily dose simultaneously for 2 wks. At the last 4 days of the study animals were placed in metabolic cages and at the end anesthetized and exsanguinated by aortic puncture. One kidney was studied histologically and the other ashed for Ca analysis. Results: Furosemide effect was noticed in groups (b)-(e) by increased urine output, fluid intake and urine Cl. Histologic scores (0-4) of NC: (a) 0.0±0.0 (b) 3.3±0.7 (c) 2.8±1.5 (d) 0.8±0.8 (e) 0.5±0.8 and kidney Ca content (μgm/gm dry tissue): (a) 188±128 (b) 2118±1120 (c) 1708±841 (d) 519±417 (e) 326±243 both showed development of NC with furosemide and a gradual decrease in the magnitude of NC with increasing doses of WR, with no difference between groups (a) and (e). There were no differences among the groups in their creatinine clearance, urine pH, Ca or P excretion, however serum ionized Ca++ in (d) 5.80±0.13 and (e) 5.70±0.10 were significantly lower than in (b) 5.97±0.07. These results provide further support for the role of PTH in furosemide-induced NC and demonstrate the feasibility of medically protecting the kidney from developing furosemide-induced NC by blocking the effect of PTH.