Acidifying defect induced by amphotericin B: Comparison of bicarbonate and hydrogen ion permeabilities

Abstract

The defect in urinary acidification induced by amphotericin B (AMB) was further characterized in turtle bladder. Since AMB has been shown to increase the hydrogen ion (H+) permeability of this epithelium in the absence of exogenous bicarbonate ions (HCO3-), we explored the permeability characteristics in the presence of imposed bicarbonate ion gradients, comparable to those occurring in vivo. With mucosal (M) pH lowered to the point of zero net hydrogen ion secretion, the transepithelial flow of bicarbonate ions (JHCO3) from serosa (S) to M was 0.91 +/- .06 y mole/hr in response to a 20 mM HCO3- gradient. After AMB addition to M, back diffusion of hydrogen ions from M to S (-JH) increased from zero to 0.36+/-0.05 micronmole/hr, whereas bicarbonate ion transport from S to M (JHCO3) failed to increase (0.91+/-0.06 before and 0.82+/-0.09 micronmole/hr after AMB). In contrast to M addition, S addition of AMB had no effect on either -JH or JHCO3. The defect in urinary acidification induced by AMB is characterized by a large increase in the permeability for hydrogen ions rather than that for bicarbonate ions and depends on direct exposure of the luminal cell membrane to AMB. The permeability increase is cation selective, not only for hydrogen ions but also, as shown previously, for potassium ions, and to a lesser extent, for sodium ions. The results are consistent with the formation by AMB of aqueous half pores in the luminal membrane. Although the passive permeabilities for bicarbonate and chloride ions are not affected primarily, they may increase after prolonged exposure, probably as a results of paracellular leaks that are not specific for AMB.

On the Mechanism of Toluene-Induced Renal Tubular Acidosis

“…In the turtle bladder, the addition of amphotericin B to the mucosal solution increased the mucosal pH required to nullify H+ secretion, a finding previously described by Steinmetz and associates [7,8]. In contrast, in bladders exposed to a high concentration of toluene the mucosal pH at which H+ secretion ceased completely was not different from that of controls (table IV).…”

“…It should also be noted that the concentration of various compounds employed to ex amine transport processes in vitro often exceed by sever alfold the levels of such substances in the body fluids. For instance, the concentration of amphotericin B used in this study and others [7][8][9] is 5-50 times higher than that measured in the urine of patients treated with this anti fungal drug [29]. Although extrapolation to the in vivo setting of the effects of high concentrations of toluene and amphotericin B upon in vitro acidification should be made with caution, we believe that the distinctive effects of either substance on the turtle bladder are relevant to the understanding of the defects in distal acidification caused by these drugs.…”

“…It has been suggested [5,6] that toluene could result in distal RTA by causing proton back-leak in the collecting tubule in a manner similar to that proposed to explain the distal acidification defect caused by amphotericin B [7][8][9], The urine pC 02 response to bicarbonate and neu tral phosphate infusions has been proposed as a way to distinguish a back-leak type of DRTA from a secretory type [10][11][12], It should be noted, however, that such a contention had not been directly validated and that whether urine pC 02 after bicarbonate loading would increase normally or not in a back-leak type of DRTA has been the subject of considerable debate [13][14][15][16][17][18]. Some authors felt that urine pC 02 in a highly alkaline urine should be subnormal because of back-difusion of car bonic acid [5,10,14] while others proposed that it should be normally high because of unimpaired proton secretion [15][16][17],…”

“…We therefore wanted to examine this parameter in toluene sniffers to gather insight into the mechanism of their defect in uri nary acidification. Since direct evidence for the existence of a back-leak type of DRTA is largely inferential from studies in urinary turtle bladders exposed to amphoteri cin B [7,8] we further studied the effect of toluene on acidification by this preparation under conditions simi lar to those employed using amphotericin B.…”

Nephrotoxic Mechanisms of Drugs and Environmental Toxins

“…Several studies in biologic membranes have shown that amphotericin B causes a marked increase in their cation permeability (Steinmetz and Lawson, 1970;Finn et al, 1977;Reuss et ai., 1978). The evidence that the primary event in the toxicity of amphotericin is such a permeability change is quite convincing.…”