title: 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.
authors.affiliation: Research Institute (University of Oxford), Churchill Hospital, U.K.
authors.forename: M E
authors.initials: ME
authors.lastname: Robbins
authors.forename: T B
authors.initials: TB
authors.lastname: Bywaters
authors.forename: R S
authors.initials: RS
authors.lastname: Jaenke
authors.forename: J W
authors.initials: JW
authors.lastname: Hopewell
authors.forename: L M
authors.initials: LM
authors.lastname: Matheson
authors.forename: P
authors.initials: P
authors.lastname: Tothill
authors.forename: E
authors.initials: E
authors.lastname: Whitehouse
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D009392:Nephrectomy; D010984:Platinum / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine; D013997:Time Factors
chemical_list: D010984:Platinum; D002945:Cisplatin