Long-term studies of cisplatin-induced reductions in porcine renal functional reserve

Abstract

Mature Large White female pigs aged approx. 10 months received single intravenous doses of 1.5, 2, or 2.5 mg/kg cisplatin. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) in individual kidneys were measured prior to and at 4-week intervals for up to 24 weeks after cisplatin administration by renography using [99mTc]-diethylenetriamminepentaacetic acid (DTPA) and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated pig and that of three age-matched control pigs was then removed, and GFR and ERPF values were measured in the remaining kidney at 4-week intervals for a further 24 weeks after unilateral nephrectomy (UN). Pigs treated with cisplatin showed no significant reduction in GFR or ERPF for up to 24 weeks after drug infusion. As measured using inductively coupled plasma mass spectrometry, the mean renal platinum concentration in the left kidney removed at UN was 77.5 +/- 9.1 ng/g kidney per mg/kg cisplatin. Histological evaluation of these kidneys revealed narrow interconnecting rays of interstitial fibrosis in the deep cortex and medulla; in these areas, glomeruli exhibited thickened Bowman's capsules and occasionally shrunken sclerotic capillaries. In cisplatin-treated pigs, UN was associated with a marked reduction in the ability of the remaining kidney to increase its function in terms of GFR and, to a lesser extent, of ERPF. The increase seen in GFR following UN in the cisplatin-treated pigs was only ca. 50%-70% of that seen in age-matched UN controls. Histologically, these kidneys revealed resolution of the peritubular fibrosis observed at UN; occasional sclerotic glomeruli were also evident. Platinum remained detectable in these kidneys, the mean levels being 18.8 +/- 4.9 ng/g kidney per mg/kg cisplatin. These findings confirm previous observations and illustrate the need for caution in considering further treatment of patients who have previously received cisplatin along with a second potentially nephrotoxic agent.

Subclinical kidney injury induced by repeated cisplatin administration results in progressive chronic kidney disease

“…The development of interstitial fibrosis and glomerular pathologies after CDDP treatment recapitulates outcomes in a porcine model of CDDP treatment (45). Robbins et al found that 24 wk after an intravenous injection of low-dose CDDP, mature large white female pigs developed interstitial fibrosis in the deep cortex and medulla and that glomeruli had thickened Bowman's capsules and capillary changes (44,45). We saw a similar interstitial fibrosis pattern in the kidneys of mice treated with repeated CDDP treatment and aged out for 6 mo, as well as glomerular changes at this time point.…”

A clinically relevant mouse model of cisplatin-induced kidney injury.

“…The development of interstitial fibrosis and glomerular pathologies after cisplatin treatment recapitulates outcomes in a porcine model of cisplatin treatment (91). Mature, large white female pigs developed interstitial fibrosis in the deep cortex and medulla, and developed glomeruli with thickened Bowman's capsules and capillary changes 24 weeks after intravaneous injection of low dose cisplatin(91,92). We saw a similar interstitial fibrosis pattern in the kidneys of mice with repeated cisplatin treatment after 6 month age-out, as well as glomerular changes at this time point.…”

Sub-nephrotoxic cisplatin sensitizes rats to acute renal failure and increases urinary excretion of fumarylacetoacetase

“…However, it induces a reduction in RFR, which is manifested only when renal function is challenged, i.e. by unilateral nephrectomy (Robbins et al, 1990(Robbins et al, , 1992. In order to study the potential nephrotoxic effect of cisplatin, we evaluated RBF and RFR in our model.…”