Tacrolimus (Fk506)-induced nephrotoxicity in spontaneous hypertensive rats.

Abstract

To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.

Tacrolimus in acute renal failure: does L-arginine-infusion prevent changes in renal hemodynamics?

“…In another in vivo-model, acute bolus Nielsen et al could demonstrate a predominantly preglomerular effect of tacrolimus with a marked reduction of inulinclearance as marker for GFR after a four-week administration in rats [16]. Experiments in spontaneous hypertensive rats have pointed out associated increases of plasma renin activity and urinary thromboxane excretion and decreased prostacyclin-metabolite-excretion together with a decrease in creatinine-clearance after CNI-administration [14]. Involvement of serotoninergic pathways has been suspected as one mediator of vasoconstriction and diminished renal blood flow [15].…”

Influence of hepatic ischemia-reperfusion injury on tacrolimus acute renal toxicity in pigs

“…15 These results suggest that the mechanism of kidney dysfunction is mainly vascular, although a toxic effect on the epithelial cells cannot be ruled out. 17 A direct effect of arteriolar vasoconstriction has been demonstrated, 17 which involves a reduction in PGI2 synthesis and an increase in endothelin production. 18,19 Tacrolimus has been shown to perturb the homeostasis of intracellular calcium in smooth muscle via the drug-calcineurin complex, encouraging arteriolar constriction; in fact, the administration of calcium antagonists (diltiazem and verapamil) may in reduce the vasoconstrictive effects and the degree of functional disturbance in animal models.…”

“…18,19 Tacrolimus has been shown to perturb the homeostasis of intracellular calcium in smooth muscle via the drug-calcineurin complex, encouraging arteriolar constriction; in fact, the administration of calcium antagonists (diltiazem and verapamil) may in reduce the vasoconstrictive effects and the degree of functional disturbance in animal models. [13][14][15][16][17][18][19][20][21] The loss of adrenergic balance due to a direct action of calcineurin on alpha receptors and the appearance of hypertrophy of the juxtaglomerular apparatus and other mechanisms that may produce a loss of renal vascular regulation causes by this drug. [13][14][15][16][17][18][19][20][21][22] The range of morphologic lesions is varied depending largely on the exposure time; vacuolization of the arterial tunica media (arteriolopathy), isometric vacuolization of the proximal tubule and hypertrophy of the juxtaglomerular apparatus are early lesions, whereas hypertrophy of the intima, mucoid deposits, glomerular hyalinosis and tubular atrophy with radial fibrosis have a later onset.…”

“…[13][14][15][16][17][18][19][20][21] The loss of adrenergic balance due to a direct action of calcineurin on alpha receptors and the appearance of hypertrophy of the juxtaglomerular apparatus and other mechanisms that may produce a loss of renal vascular regulation causes by this drug. [13][14][15][16][17][18][19][20][21][22] The range of morphologic lesions is varied depending largely on the exposure time; vacuolization of the arterial tunica media (arteriolopathy), isometric vacuolization of the proximal tubule and hypertrophy of the juxtaglomerular apparatus are early lesions, whereas hypertrophy of the intima, mucoid deposits, glomerular hyalinosis and tubular atrophy with radial fibrosis have a later onset. 23 In the clinical context, nephrotoxicity caused by tacrolimus follows two distinct pattern which have different pathogenesis and prognosis 6 : early dysfunction (during the first 30 days) and late dysfunction (from the second month after the transplant onward.…”

“…26 Patients with poorer hepatic function maintain higher, or on occasions extremely high, blood concentrations of tacrolimus. 9 A correlation between high drug concentrations and the occurrence of toxic episodes has been proven, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] but it is not essential to exceed the therapeutic range for nephrotoxicity to occur. 6,27,28 In two treatment groups (I and III), the blood concentration of tacrolimus remained within the therapeutic range (15.2 ± 2.4 compared with 12.3 ± 5.4 ng/mL; P = .4), even at the moment of death, and there were no significant differences between the two models.…”