Functional and histopathological changes in dog kidneys after administration of cisplatin.
The nephrotoxic effect of cisplatin (5 mg/kg i.v.) was evaluated in 8 dogs 48-72 h after administration. The lithium clearance method was used for assessing the absolute and fractional reabsorption rates of sodium and water in proximal as well as in more distal segments of the total nephron population, before and during saline loading (infusion of 5 ml/kg of isotonic saline i.v.). Histological examinations of the kidney biopsies were used to evaluate the degree of renal tissue injury. During 48-72 h after administration of cisplatin blood urea nitrogen and plasma creatinine increased significantly from 3.9 +/- 0.2 to 11.7 +/- 1.4 mmol/l and 96 +/- 3 to 178 +/- 10 mumol/l, respectively. Mean values of renal blood flow, glomerular filtration rate, filtration fraction and lithium clearance in cisplatin-treated animals (143 +/- 14 ml/min, 10.7 +/- 1.1. ml/min, 0.14 +/- 0.01 and 6.3 +/- 0.6 ml/min, respectively) were significantly lower than in 6 control animals (212 +/- 8 ml/min, 49.0 +/- 2.0 ml/min, 0.36 +/- 0.001 and 10.1 +/- 1.3 ml/min, respectively). In contrast, urinary excretion rates of sodium, potassium and water were significantly higher, while fractional as well as absolute proximal and distal reabsorption rates were significantly lower in cisplatin-treated animals compared to controls. Saline loading caused an increase in the output of tubular fluid from the proximal tubules (lithium clearance) in the cisplatin-treated animals, while the fractional distal reabsorption rate of sodium decreased significantly. The histological changes are in agreement with the physiological data which point to the proximal tubules as the more severely damaged segment. In conclusion, the depressed renal function 48-72 h after administration of cisplatin can be attributed to impairment of proximal as well as distal tubular reabsorptive capacities associated with increased renal vascular resistance. The polyuria seems to be due to impaired reabsorption rates in the distal nephron segments, which will affect the concentration mechanism.
Department Oncology, Finsen Institute, Copenhagen, Denmark.
G
G
Daugaard
U
U
Abildgaard
S
S
Larsen
N H
NH
Holstein-Rathlou
O
O
Amtorp
H P
HP
Olesen
P P
PP
Leyssac
D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D004285:Dogs; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D007677:Kidney Function Tests
D002945:Cisplatin