Time course of the change and amelioration of nedaplatin-induced nephrotoxicity in rats.

Nedaplatin (NDP) is a second-generation antineoplastic platinum complex, with reduced nephrotoxicity. Two experiments were conducted to characterize the time course of changes of its nephrotoxicity and to further evaluate whether hydration is useful for amelioration of nephrotoxicity. In the first experiment, 8-week-old male rats treated with 6 or 9 mg kg(-1) NDP at a single intravenous dose were killed 2, 4, 7 and 14 days after dosing. In the second experiment, nonhydrated (Nhyd) or hydrated (Hyd) rats, treated with a single intravenous dose of 20 mg kg(-1) NDP, were killed 7 days after dosing. Besides renal function and histopathological examinations, the urinary excretion of platinum was measured. Histopathologically, NDP-induced nephrotoxicity was initially characterized by single cell and/or focal necrosis in the epithelium of distal tubules and collecting ducts as well as proximal tubules. In the later stage, subsequent cystic dilatation and regeneration occurred in these affected tubules, but incomplete tissue repair was still observed in the kidney 14 days after dosing. However, NDP-induced nephrotoxicity was dramatically reduced by hydration, while it had no clear effects on myelotoxicity. Measurement of urinary platinum excretion revealed that the total amount of platinum excretion was significantly higher in Hyd-NDP rats than that in Nhyd-NDP rats. In terms of urinary concentration, Hyd-NDP rats showed a lower concentration compared with that in Nhyd-NDP rats. The current results suggest that NDP has the potential risk to cause nephrotoxicity at a human therapeutic dose without hydration and that pre- and post-hydration at dosing can ameliorate this nephrotoxicity.

Relationship between cisplatin or nedaplatin-induced nephrotoxicity and renal accumulation.

Nedaplatin is known to exhibit antitumor activity similar to that of cisplatin. However, concerning side effects, nedaplatin causes renal toxicity less frequently than cisplatin. In this study, we compared the incidence of renal toxicity between cisplatin and nedaplatin by investigating the difference in kidney tissue accumulation. Kidney tissue accumulation of cisplatin administered at 3.75 mg/kg was similar to that of nedaplatin administered at 24 mg/kg. At these doses, the plasma creatinine level and urinary excretion of glucose and N-acetyl-beta-D-glucosaminidase (NAG) similarly increased. There was a correlation between kidney accumulation of cisplatin and nedaplatin and the increases in plasma creatinine level and urinary excretion of NAG. Therefore, our results suggest that nedaplatin less frequently causes renal toxicity in comparison to cisplatin due to lower kidney accumulation.

Nephrotoxicity of a novel antineoplastic platinum complex, nedaplatin: a comparative study with cisplatin in rats.

The present study was designed to characterize the nephrotoxicity induced by the antineoplastic platinum complex nedaplatin (NDP) in rats of different ages in comparison with cisplatin (CDDP). A single dose of 15 mg/kg NDP or 7.5 mg/kg CDDP was administered intravenously to 8-, 11-, or 15-week-old male and female SD rats, which were then sacrificed after ten days. Body weight decreases were observed for both drugs, in direct relation to age. CDDP treatment markedly increased urinary excretion of NAG, gamma-GTP, LDH and protein, with peaks on day 4 and complete or partial recovery on day 7; NDP increased NAG, LDH and protein excretion, but to a lesser extent, and these elevations were generally more marked for females. CDDP increased plasma creatinine and BUN in males and females of all age groups at necropsy. No apparent changes were seen following NDP treatment except in the 15-week-old rats. These results also show that NDP is less nephrotoxic than CDDP. CDDP-treated rats showed remarkable proximal tubular lesions in the renal cortex and corticomedullary region, and the papillary lesions were minor. On the other hand, the NDP-induced nephrotoxicity was morphologically characterized by hyaline droplet changes (electron microscopically, hyperplasia of lysosomes), necrosis or hyperplasia of the collecting duct epithelium in the renal papilla and the epithelium covering the papilla. Cortical lesions, indicated by slight tubular dilatation, were found only in the animals with papillary lesions. In summary, NDP is a promising second-generation platinum complex with reduced nephrotoxicity.

Effects of efonidipine hydrochloride on renal arteriolar diameters in spontaneously hypertensive rats.

Efonidipine, a calcium antagonist, has been reported to dilate not only afferent but also efferent arterioles, thereby reducing glomerular hydrostatic pressure. We investigated the effect of chronic treatment with efonidipine or lisinopril on the afferent and efferent arteriolar diameters by the vascular cast technique. Four-week-old spontaneously hypertensive rats (SHR) were divided into three groups: untreated, efonidipine (25 mg/kg/day)-treated, and lisinopril (3 mg/kg/day)-treated. At 22 weeks of age, the renal vasculatures were fixed at the maximally dilated condition. The morphometrical measurements showed that the treatments with efonidipine and lisinopril caused structural alteration of the vasculature, resulting in significantly greater efferent arteriolar diameters than in untreated SHR. In addition, lisinopril-treated rats had wider afferent lumina. The renoprotective effect of efonidipine and lisinopril might be partly due to the structurally larger efferent arteriolar lumen.

Impaired urinary concentrating ability in genetically polyuric mice.

Newly recognized strain of mice with hereditary polyuria (PUS mice) was characterized. Polyuria was inherited as a single autosomal-recessive trait. At 15 weeks, PUS mice excreted hypotonic (urine osmolality: PUS;270.8 +/- 15.5 vs. cont.; 3,228.6 +/- 163.6 mosm/kg) polyuria (urine volume: PUS; 25.0 +/- 1.5 vs. cont.; 1.1 +/- 0.1 ml/day). In PUS mice, plasma osmolality was slightly elevated as well as urinary excretion of vasopressin (AVP). Although PUS mice could concentrate urine after 24 h water deprivation, urine osmolality remained low. Blunted response to continuous infusion of dDAVP, a synthetic V2 agonist, was also observed. These in vivo studies indicated renal resistance to AVP contributed to the polyuria in this strain of mice. Microanalysis of isolated tubular segments revealed that AVP-induced cAMP accumulation in cortical collecting ducts (CCD) of PUS mice was significantly lower (60%) with or without a phosphodiesterase inhibitor, IBMX. Vasopressin induced similar cAMP accumulation in medullary ascending limbs of Henle (MAL), and medullary collecting ducts (MCD) between PUS and control mice. In CCDs, PUS mice had low basal adenylate cyclase (AdC) activity and responded less to AVP and forskolin stimulation than control mice. No difference in cyclic AMP phosphodiesterase activity was detected between control and PUS mice. These results indicate that impaired cAMP accumulation due to low AdC activity may be related to the impaired renal concentrating ability observed in this new strain of mice.