Protective effects of KW-3902, an adenosine A1-receptor antagonist, against cisplatin-induced acute renal failure in rats.

We investigated possible renal protective and therapeutic effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a novel and potent adenosine A1-receptor antagonist, on cisplatin-induced acute renal failure (ARF). ARF was induced in rats by a single injection of cisplatin-induced acute renal failure (ARF). ARF was induced in rats by a single injection of cisplatin (5 mg/kg, i.v.). Prophylactic treatment with KW-3902 (0.01-1 mg/kg, p.o., twice a day) significantly attenuated the increases of serum creatinine (S-CRE) and urea nitrogen (S-UN) induced by cisplatin. On the other hand, neither furosemide nor trichlormethiazide showed any ameliorating effects against the cisplatin-induced ARF. In the clearance study, the cisplatin-treatment induced marked decreases of glomerular filtration rate (GFR), renal plasma flow (RPF), and reabsorptions of water, sodium and potassium at tubular sites, in comparison with those in untreated normal rats. KW-3902 (0.1 mg/kg, p.o., twice a day) significantly improved these deteriorated glomerular and tubular functions. In the rats with established cisplatin-induced ARF, KW-3902 ameliorated the cisplatin-induced reductions of GFR, RPF, and reabsorptions of water, sodium and potassium at tubular sites. These results suggest that activation of adenosine A1-receptors is involved in the pathogenesis of cisplatin-induced ARF. The adenosine A1-receptor antagonist may be useful for the treatment of cisplatin-induced ARF.

Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria.

Circulating levels of immunoreactive parathyroid hormone (PTH) were measured in 40 patients with idiopathic hypercalciuria (IH) before and during reversal of hypercalciuria with thiazide, and in four normal subjects before and during induction of hypercalciuria with furosemide. 26 patients with IH had elevated serum PTH levels. The remaining patients had normal levels. Although the correlation was not complete, high PTH levels were generally found in patients who had more severe average urinary calcium losses. When initially elevated. PTH levels fell to normal or nearly normal values during periods of thiazide administration lasting up to 22 months. When initially normal, PTH levels were not altered by thiazide. Reversal of hyperparathyroidism by thiazide could not be ascribed to the induction of hypercalcemia, since serum calcium concentration failed to rise in a majority of patients. Renal hypercalciuria produced by furosemide administration elevated serum PTH to levels equivalent to those observed in patients with IH. The findings in this study help to distinguish between several current alternative views of IH and its relationship to hyperparathyroidism. Alimentary calcium hyperabsorption cannot be the major cause of IH with high PTH levels, because this mechanism could not elevate PTH. Idiopathic hypercalciuria cannot be a variety of primary hyperparathyroidism, as this disease is usually defined, because PTH levels are not elevated in all patients and, when high, are lowered by reversal of hypercalciuria. Primary renal loss of calcium could explain the variable occurrence of reversible hyperparathyroidism in IH, since renal hypercalciuria from furosemide elevates serum PTH in normal subjects. Consequently, a reasonable working hypothesis is that IH is often due to a primary renal defect of calcium handling that leads, by unknown pathways, to secondary hyperparathyroidism.