Cisplatin-induced reductions in renal functional reserve uncovered by unilateral nephrectomy: an experimental study in the pig.
Groups of mature Large White female pigs, approximately 10 months of age, received single intravenous infusions of 1.5, 2 or 2.5 mg/kg body weight (equivalent to approximately 90, approximately 120 and approximately 150 mg/m2) cisplatin. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured before and at 4 weeks after cisplatin infusion by renography using [99 mTc]-DTPA (diethylenetriamminepentaacetic acid and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated animal plus that of four age-matched control pigs was then removed surgically, and GFR and ERPF were measured in the remaining kidney at 4 weekly intervals for up to 24 weeks after unilateral nephrectomy (UN). The pigs treated with cisplatin exhibited no consistent change in either GFR or ERPF at 4 weeks after treatment. A histological evaluation of kidneys from animals treated with greater than or equal to 2 mg/kg cisplatin that had been removed at UN revealed both tubular and glomerular lesions. The latter consisted of cell proliferation on the parietal surface of the urinary space; damage to the S1 portion of the proximal convolution was also noted. Following UN there was a pronounced dose-dependent reduction in the functional status of the remaining kidney such that the increase in GFR and ERPF in pigs initially receiving 2.5 mg/kg cisplatin was less than 50% of that seen in age-matched UN controls. Moreover, the glomerular lesions observed at 4 weeks after cisplatin infusion had apparently progressed to glomerular hyalinisation by 24 weeks after UN. Thus, prior treatment with cisplatin may cause a permanent reduction in renal functional reserve that may be clinically "silent" until exposure to an additional nephrotoxic insult.
Robbins
M E
ME
Normal Tissue Radiobiology Research Group, Research Institute (University of Oxford), Churchill Hospital, UK.
Campling
D
D
Whitehouse
E
E
Hopewell
J W
JW
Michalowski
A
A
D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced; D006439:Hemodynamics; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009392:Nephrectomy; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine; D013997:Time Factors
D002945:Cisplatin