Low‐Density Lipoprotein Adsorption Therapy Can Restore Drug Sensitivity for Immunosuppressants Via Inhibitory Effects Upon MDR‐1 Gene Expression

In two patients with steroid‐resistant nephrotic syndrome (SRNS), we investigated the relationship between clinical findings during immunosuppressive therapy and multiple drug resistant gene‐1 (MDR‐1) expression. MDR‐1 was detected by real‐time polymerase chain reaction (PCR). In a boy who initially developed SRNS at 3 years, we observed MDR‐1 expression over 3 years. Maximal and minimal MDR‐1 expression were 90 000 and 7800 copies/µg RNA, respectively. In a 4‐year‐old boy who initially developed SRNS at 3 years, we determined MDR‐1 expression over 2 years. Maximal and minimal MDR‐1 expression were 42 000 and 6900, respectively. MDR‐1 evaluation requires determination of MDR‐1 expression at several time points in a clinical course. Establishment of a normal expression may be needed for each individual patient. Increasing MDR‐1 during remission was followed soon by recurrences, an observation that may be a guide for therapeutic choice. LDL influences a humoral factor involved in MDR‐1 expression. Both patients responded to LDL adsorption therapy because of elevated LDL levels. While cyclosporine A therapy gradually decreased MDR‐1 expression, LDL adsorption therapy decreased expression sharply. Based on the results of the present study, LDL adsorption therapy could contribute to the amelioration of drug sensitivity for immunosuppressants including corticosteroids via inhibitory effects on MDR‐1 expression.

[1]  J. Li,et al.  Influence of the MDR1 haplotype and CYP3A5 genotypes on cyclosporine blood level in Chinese renal transplant recipients , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[2]  Shori Takahashi,et al.  Multiple drug‐resistant gene 1 in children with steroid‐sensitive nephrotic syndrome , 2008, Pediatrics international : official journal of the Japan Pediatric Society.

[3]  N. Yorioka,et al.  Beneficial effect of low-density lipoprotein apheresis (LDL-A) on refractory nephrotic syndrome (NS) due to focal glomerulosclerosis (FGS). , 2007, Clinical nephrology.

[4]  L. Chyczewskî,et al.  MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children , 2007, Pediatric Nephrology.

[5]  K. Kohno,et al.  Transcriptional regulation of multidrug resistance‐1 gene by interleukin‐2 in lymphocytes , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[6]  A. Yoshioka,et al.  Up-regulation of interleukin-2 mRNA in children with idiopathic nephrotic syndrome , 2004, Pediatric Nephrology.

[7]  M. Zaniew,et al.  [Resistance to therapy in primary nephrotic syndrome: effect of MDR1 gene activity]. , 2000, Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego.

[8]  D. Daret,et al.  Effect of VLDL on the inhibition of arachidonic acid transformation by dexamethasone in cultured smooth muscle cells. , 1993, Biochimica et biophysica acta.

[9]  E. Ingulli,et al.  Severe hypercholesterolemia inhibits cyclosporin A efficacy in a dose-dependent manner in children with nephrotic syndrome. , 1992, Journal of the American Society of Nephrology : JASN.

[10]  B. Sikic,et al.  Reversal by cefoperazone of resistance to etoposide, doxorubicin, and vinblastine in multidrug resistant human sarcoma cells. , 1989, Cancer research.