The study was aimed at investigating the association between MDR-1 genetic polymorphisms [C1236T, G2677T(A), C3435T] and parameters describing the clinical course and treatment response of childhood steroid-responsive nephrotic syndrome (SRNS). Three MDR-1 genetic markers were analyzed in 108 children diagnosed with SRNS and in 135 healthy controls with neither allergic nor renal disease. All subjects were genotyped by PCR-restriction fragment length polymorphism (RFLP) analysis, and an EM algorithm-based analysis was utilized to estimate haplotype frequencies. As expected, there was no difference in genotypic and allelic distribution between and among SRNS patients and healthy children. However, all individual polymorphisms were strongly associated with time to response to initial prednisone therapy. The frequencies of the mutated alleles were higher in late responders (time to remission: >7 days) to oral prednisone (0.53, 0.52,0.66) than in early responders (time to remission: <7 days; 0.24, 0.19, 0.32), with all p values <0.001 for positions 1236, 2677 and 3435, respectively). Odds ratios (ORs) reflecting the strength of the associations were as follows: 6.79 (95% CI:1.96- 23.54) for 1236 T/T, 13.7 (95% CI:2.78-67) for 2677 T/T and 9.92 (95% CI: 3.01-32.71) for 3435 T/T as compared to the respective-wild type homozygotes. The TTT haplotype was similarly found to be significantly associated with late oral steroid response (0.49 vs. 0.19, p=0.0003). Variants 1236T, 2677TA and 3435T identify patients that respond slower to oral prednisone. Although the functional properties of the substitutions investigated here are still to be determined, our findings may be a small step toward the optimization of immunosuppressive therapy in SRNS children.

The distribution of individual polymorphisms and three-marker haplotypes was similar in healthy children and SRNS patients (all p values >0.05). The GTA haplotype was associated with a higher GC sensitivity, as determined by TPR, and was found to be more prevalent in early (response 7 days) prednisone responders (27.7 vs. 14.5%, hap-score = -2.22, p = 0.05 adjusted for biopsy results). These results are in agreement with those reported earlier on an association of intron B haplotypes with GC sensitivity. The distribution of GC polymorphisms among the residents of north-eastern Poland was also determined.

The aim of this study was to examine the expression of P-glycoprotein (P-gp) in CD3 lymphocytes of children with nephrotic syndrome (NS) in relation to their clinical response to glucocorticoid (GC) treatment. The examinations were performed on two groups. The study group (I) consisted of 88 children aged 2.0-20.0 years with NS, divided according to their clinical response to GC: NFR-non-frequent relapse NS; FR-frequent relapse NS; SD-steroid-dependent NS. The control group (II) consisted of 18 healthy children never treated with GC. We measured P-gp expression on CD3 lymphocytes of patients with NS using a flow cytometry assay. The CD3/P-gp was significantly higher than in controls. The difference was higher in SD (P=0.0001) and FR - (P=0.0002) group. The difference in NFR was smaller. Mean CD3/P-gp (in percent) was twice as high in SD children than in NFR, and the difference, as between FR and NFR, was statistically significant (P<0.01). Worse response to GC or dependency may be due to overexpression of P-gp. Further examinations are necessary to establish whether increased P-gp activity is a result of MDR-1 polymorphism and to determine GC response, or to ascertain if such activity is only a result of GC therapy.

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