Features and full reversibility of the renal toxicity of the ruthenium-based drug NAMI-A in mice

The ruthenium-based compound imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) is free of cytotoxicity up to 1 mM concentration after 1 h in vitro exposure of the LLC-PK1 renal tubule cells. In vivo, one cycle of i.p. administrations of 35 mg/kg/day NAMI-A (1 cycle = 6 consecutive days), is free of a measurable toxicity on mouse kidneys. After two cycles with a one-week drug-free washout between cycles, mitochondrial membrane potential of the renal cells drops by 37% (p < 0.05), serum creatinine increases by 30% (p < 0.05) and a significant decrease of body weight of 12% (p < 0.05) occurs. These parameters return to normal within 7 days after the end of treatment. A cycle-dependent alteration of glomeruli and a diffused swelling of renal tubules are also evident leading to a significant alteration of these structures after the third cycle. These effects are completely prevented if a 2-week drug free washout is used between two consecutive cycles. These data support the toxic accumulation of NAMI-A or of its products of transformation in the kidneys and stress the need of at least 14 days washout between two treatment cycles when the drug is given daily for 6 consecutive days.

Treatment of mice for three cycles, with doses of NAMI-A active on metastases, causes renal toxicity parallel to the increase of deposits of ruthenium in the basement membrane. This toxicity is fully reversed after 7-days and can be prevented with a two-week drug free interval between the cycles.Figure optionsDownload as PowerPoint slideHighlights
► NAMI-A is toxic to the kidney if treatment cycles are repeated at 7-day intervals.
► Renal toxicity follows Ruthenium accumulation in the kidney parenchyma.
► Toxicity consists of alterations of the tubular structure and of mitochondria.
► Renal toxicity is fully reversible after two weeks of drug-free washout.
► Renal toxicity is prevented with a 2-week washout period between cycles.