Renal Concentration Defect Induced by Cisplatin

Abstract

The effects of cisplatin (5 mg/kg BW given intraperitoneal^) on renal concentration mechanism were evaluated initially by clearance studies in rats 5–7 days after cisplatin administration and compared to normal rats. During hypotonic saline infusion, cisplatin rats showed a lower inulin clearance (0.56 ± 0.07 vs. 1.12 ± 0.09 ml/min/100gBW, p < 0.01), a higher fractional distal delivery (CNa + CH₂0/Cin) (36.3 ± 4.4 vs. 22.8 ± 4.5%, p < 0.05), and lower CH₂0/CNa + CH₂0 (33.6 ± 5.8 vs. 56.5 ± 5.0%, p < 0.01). During hypertonic saline infusion the TcH₂0/Cosm was lower in cisplatin (18.3 ± 1.1%) than in normal rats (33.4 ± 3.5%, p < 0.01). These results suggest a defect in NaCl transport in the thick ascending limb of Henle and proximal tubule. In order to characterize these tubular defects, we measured Na-K-ATPase activity {\iM Pi/mg protein/h). In the renal cortex of cisplatin rats the ATPase activity was lower (18.1 ± 3.2) than in normal rats (33.4 ± 6.4, p < 0.05), also in the inner strip of the outer medulla of cisplatin rats Na-K-ATPase was reduced (26.0 ± 5.7) when compared with normal rats (67.3 ± 9.2, p < 0.01), presumably representing a decrease in enzyme activity in the thick ascending limb. In vitro measurements of diffusional water permeability (Pdw) and urea permeability (P_urea) of the perfused papillary collecting duct isolated from polyuric cisplatin rats showed that vasopressin (200 uU/ml) added to the bath increased the P_Dw from 65.4 ± 11.2 to 104.4 ± 12.7 X 10^-5cm/s(p < 0.01) and the P_urea from 20.1 ± 5.7 to 30.3 ± 8.2 X 10”⁵cm/s(p < 0.05), as observed in the papillary collecting duct of normal rats. These findings suggest that the polyuric effect of cisplatin is due, at least in part, to impaired NaCl transport of the proximal tubule and thick ascending limb of Henle’s loop. The data rule out the possibility of ADH resistance in the papillary collecting duct.

Butein Ameliorates Renal Concentrating Ability in Cisplatin-Induced Acute Renal Failure in Rats

“…These findings are not different from previously published data in which the marked polyuria has been identified in the cisplatin-induced ARF. [1][2][3][4] Clearance study indicated that GFR was decreased following cisplatin-treatment in rats. Moreover, the urinary creatinine excretion was attenuated in rats with cisplatin-in- A. B.…”

“…ARF, when caused by cisplatin, is typically characterized by a nonoliguria, a severe reduction in glomerular filtration rate (GFR), a variable fall in renal blood flow, and a decrease in the urinary concentrating ability. [1][2][3][4] Certain pathophysiologic conditions associated with an altered urinary concentration have been related causally to an altered regulation of aquaporin (AQP) water channel in the kidney. [5][6][7][8] Several recent studies have provided convincing of reducing expression of renal aquaporin 2 (AQP 2) in rats with cisplatin-induced ARF.…”

Progression of Cisplatin-Induced Nephrotoxicity in a Carnitine-Depleted Rat Model

“…It has been reported that cisplatin elicited oxidative stress in and around mitochondria, thereby inducing apoptosis of renal proximal tubule cells and dysfunction of the kidney [4, 5, 6]. Cisplatin is a well-known renal tubular toxin, leading to increased excretion of a number of substances, including amino acids, glucose, phosphate, sodium, magnesium and L -carnitine [7, 8]. The mechanisms of this toxic effect may involve direct inhibition of specific membrane transport systems, mitochondrial toxicity and depletion of glutathione, finally leading to loss of specific functions and/or necrosis of renal tubular cells [9, 10, 11].…”

L-Carnitine Ameliorates the Decrease of Aquaporin 2 Levels in Rats with Cisplatin-Induced Kidney Injury

“…Cisplatin is known to induce AKI in rats, which then exhibit oliguria, severe reduction in glomerular filtration rate (GFR), reduced renal blood flow, and damage to the renal urinary concentrating ability [17,18]. Several recent studies have indicated that L-carnitine is capable of preventing renal proximal tubular cell apoptosis, inhibiting mitochondrial respiration dysfunction and DNA injury, improving renal function, and elevating the GFR in rats with cisplatin-induced renal dysfunction [19].…”