Treatment of digoxin intoxication model by hybrid-kidney with hollowfibre module for clinical haemodialysis

Sir,

Although haemoperfusion is frequently used for the treatment of drug intoxication, this has some disadvantages and its use is limited [1]. We have previously reported a unique hybrid-type artificial kidney by culturing the immortalized renal proximal tubule cells with the introduction of multidrug resistance protein (MDR)-1 in the hollowfibre module for cell culture [2]. Moreover, we scaled up the system by connecting 10 modules in parallel and successfully treated dogs with digoxin intoxication, a substrate of MDR-1 [3]. Although this device was effective for the dog, we should further increase the number of modules connected for future clinical use. Here, we succeeded in scaling up the ‘hybrid-kidney’ by utilizing a single clinically used haemodialyzer and evaluated the efficacy for drug removal in vitro and in dogs with digoxin intoxication.

We used the same cell line, into which cDNA of human MDR-1 [4] was introduced. This clone, named PCTL-MDR, possesses about 100 times larger Km and Vmax values for digoxin than control cells, named PCTL [2]. A hollowfibre module available for clinical haemodialysis (APS-08S; Asahi Medical, Tokyo, Japan) made of polysulfone with a surface area of 0.8 m2 was purchased. We inoculated the cells onto the hollowfibre by an almost identical method to that reported previously [2,3]. Thus, 5.4 x 109 cells were injected on the pericapillary side of the module and cultured for 1 week in a CO2 incubator at 37°C. After incubation, transport of digoxin and inulin from the capillary to pericapillary side were evaluated in vitro. We found that >85% of perfused digoxin was transported from the capillary to pericapillary side by the system with PCTL-MDR, while such transport was only ~10% with PCTL and 20% without cells, respectively. Inulin concentration was not reduced on the venous side by the system with the cells, indicating that leakage did not occur. Next, we applied this to the dog model with digoxin intoxication [3,5]. Using PCTL-MDR, the digoxin concentration decreased to the therapeutic level at the end of a 3-h treatment. Although treatment with PCTL reduced digoxin concentration, the observed decrease was significantly smaller than with PCTL-MDR (Figure 1). Estimated digoxin clearance with PCTL-MDR was 31±2 ml/min. Slight leukocytopaenia and thrombocytopaenia, and elevated activity of circulating granulocyte elastase, was detected. However, the magnitude of these parameters was similar between three trials, and dogs tolerated this treatment well. Comparing digoxin clearance in the present experiments with that of adult [6], we propose to treat patients by increasing surface area of the single haemodialyzer to 2 m2, which is now commercially available. Thus, the present results suggest that our scaled-up module has sufficient capacity to treat digoxin-intoxicated patients, especially when complicated by renal failure. It might be useful to apply it to various types of artificial hybrid-kidneys with different types of cells for the treatment of patients in the future.



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Fig. 1. Change of serum digoxin concentration at just before (arterial) the hollowfibre module during treatment. Mean±SE, n = 6; closed circles, PCTL-MDR; open circles, PCTL; open squares, without cell; *P<0.05 vs. without cell.

 
Conflict of interest statement. None declared.

Shuichi Tsuruoka, Kenta Nishiki, Michi Wakaumi, Ning Wang, Hisashi Yamamoto, Hitoshi Ando, Masashi Imai and Akio Fujimura

Department of Pharmacology Division of Clinical Pharmacology Jichi Medical School Tochigi Japan Email: tsuru{at}jichi.ac.jp

References

  1. Gurland H, Samtleben W, Lysaght M et al. Hemoperfusion. In: Gurland H, ed. Replacement of Renal Function by Dialysis. Kluwer Academic, Dordrecht, The Netherlands, 1996; 485–500
  2. Tsuruoka S, Sugimoto KI, Ueda K et al. Removal of digoxin and doxorubicin by multidrug resistance protein-overexpressed cell culture in hollow fiber. Kidney Int 1999; 56: 154–163[CrossRef][ISI][Medline]
  3. Tsuruoka S, Nishiki K, Sugimoto K et al. Specific therapy of digoxin intoxication in dogs by hybrid kidney overexpressing multidrug resistance protein. Kidney Int 2002; 62: 1332–1337[CrossRef][ISI][Medline]
  4. Ueda K, Cardarelli C, Gottesman MM et al. Expression of a full-length cDNA for the human ‘MDR1’ gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 1987; 84: 3004–3008[Abstract]
  5. Tsuruoka S, Osono E, Nishiki K et al. Removal of digoxin by column for specific adsorption of beta(2)-microglobulin: a potential use for digoxin intoxication. Clin Pharmacol Ther 2001; 69: 422–430[CrossRef][ISI][Medline]
  6. Aronson J. Clinical pharmacokinetics of digoxin 1980. Clin Pharmacokinet 1980; 5: 137–149[ISI][Medline]




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