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The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1

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Abstract

Glutathione-S-transferases (GST) play a central role in the inactivation of toxic drugs like cyclophosphamide (CP). These enzymes depict several polymorphisms with altered activity, and it has been shown that different polymorphisms influence the risk of malignancies and the outcome after chemotherapy. To prove the hypothesis that CP efficacy in children with nephrotic syndrome is influenced by polymorphic expression of GSTs, the genotype of 26 patients was analyzed and correlated with the outcome after CP treatment. All 26 children with steroid-sensitive nephrotic syndrome and frequent relapses or steroid dependency were treated with CP at a mean age of 6.7±4.0 years. CP was given in a dose of 2 mg/kg/day for 12±1 week. GST-M1, GST-P1 and GST-T1 polymorphisms were detected by PCR. In patients with GST-M1 null polymorphism, a significantly better rate of sustained remission was seen than in patients with the heterozygous or homozygous GST-M1 wildtype (0 versus 29%, P <0.01). In contrast, children with GST-P heterozygous or homozygous polymorphism had a significantly lower rate of sustained remission compared to homozygous wildtype (7 versus 38%, P <0.02). The GST-T1 genotype did not influence the outcome after CP treatment (P =0.32). Patients with the combination of GST-M1 null and GST-P1 wildtype did not relapse in 50%, compared to 6% in other children (P <0.01). We conclude that the polymorphic expression of GST-M1 and -P1 did significantly influence the long-term remission rate after CP treatment of steroid-sensitive nephrotic syndrome in children. Whereas GST-M1 null will increase cyclophosphamide efficacy, GST-P1 polymorphism seems to be related to enhanced susceptibility to further relapses.

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Acknowledgements

This study was supported by a grant from “Forschungsunterstützungskreis Kindernephrologie e.V.”

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Authors and Affiliations

  1. Clinic of Pediatric Nephrology, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

    Udo Vester, Birgitta Kranz, Rainer Büscher & Peter F. Hoyer

  2. Medical School, University of Hanover, Hanover, Germany

    Stephanie Zimmermann

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  1. Udo Vester
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  2. Birgitta Kranz
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  3. Stephanie Zimmermann
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  4. Rainer Büscher
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  5. Peter F. Hoyer
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Correspondence to Udo Vester.

Additional information

A part of this work was presented at the 31st meeting of the Arbeitsgemeinschaft Pädiatrische Nephrologie (APN), Vienna, Austria, 22–24 March 2001, and at the 12th congress of the International Pediatric Nephrology Association (IPNA), Seattle, Wash., 1–5 September 2001, and published in abstract form (Nieren- und Hochdruckkrankheiten 30:94, 2001, and Pediatric Nephrology 16:C123, 2001)

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Vester, U., Kranz, B., Zimmermann, S. et al. The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1. Pediatr Nephrol 20, 478–481 (2005). https://doi.org/10.1007/s00467-004-1759-7

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  • DOI: https://doi.org/10.1007/s00467-004-1759-7

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