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Abstract
Background:
Steroid pulse therapy has been used for patients with acute rejection after kidney transplantation. The ABCB1 gene codes for P-glycoprotein, a transporter that is involved in the metabolism of steroids. However, the role of ABCB1 polymorphisms has not been investigated in patients with acute rejection after kidney transplantation.
Methods:
Among 763 patients that received kidney or simultaneous pancreas-kidney transplantation at Seoul National University Hospital between May 1996 and July 2009, 684 patients agreed to genetic sampling for polymorphisms. Acute rejection was defined as biopsy-proven, acute cellular rejection with increased serum creatinine, or in the context of delayed or slow graft function. Steroid-resistance was defined as no improvement in serum creatinine, need for additional OKT3 or ATG treatment, or repeated acute rejection within 30 days. Three polymorphisms of ABCB1 gene (C1236T, C3435T, G2677T/A) were assessed.
Results:
C allele frequency of C3435T was 59.3% and of C1236T 40.1%. Patients who were steroid-resistant (n=37) had higher serum creatinine at kidney biopsy compared to those who were steroid-sensitive (n=49, P＜0.001). The frequency of ABCB1 gene polymorphisms (C1236T and C3435T) did not differ significantly between patients who were steroid-sensitive and those who were resistant. An association with G2677T/A could not be analyzed due to a high failure rate of genotyping.
REFERENCES
1). Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004; 351:2715–29.
2). Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000; 342:605–12.
3). Petrie JJ, Rigby RJ, Hawley CM, Suranyi MG, Whitby M, Wall D, et al. Effect of OKT3 in steroid-resistant renal transplant rejection. Transplantation. 1995; 59:347–52.
4). Madden RL, Mulhern JG, Benedetto BJ, O'Shea MH, Germain MJ, Braden GL, et al. Completely reversed acute rejection is not a significant risk factor for the de-velopment of chronic rejection in renal allograft recipients. Transpl Int. 2000; 13:344–50.
5). Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002; 346:580–90.
6). Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in nor-mal human tissues. Proc Natl Acad Sci USA. 1987; 84:7735–8.
7). Siegsmund M, Brinkmann U, Scháffeler E, Weirich G, Schwab M, Eichelbaum M, et al. Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol. 2002; 13:1847–54.
8). Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003; 43:285–307.
9). Sakaeda T. MDR1 genotype-related pharmacokinetics: fact or fiction? Drug Metab Pharmacokinet. 2005; 20:391–414.
10). Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, et al. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007; 315:525–8.
11). Choi HJ, Cho HY, Ro H, Lee SH, Han KH, Lee H, et al. Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome. Pediatr Nephrol. 2011; 26:1981–8.
12). Coto E, Tavira B. Pharmacogenetics of calcineurin inhibitors in renal transplantation. Transplantation. 2009; 88(3 Suppl):S62–7.
13). Tavira B, Coto E, Díaz-Corte C, Ortega F, Arias M, Torres A, et al. Pharmacogenetics of tacrolimus after renal transplantation: analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes. Clin Chem Lab Med. 2011; 49:825–33.
14). Cattaneo D, Ruggenenti P, Baldelli S, Motterlini N, Gotti E, Sandrini S, et al. ABCB1 genotypes predict cy-closporine-related adverse events and kidney allograft outcome. J Am Soc Nephrol. 2009; 20:1404–15.
15). Bandur S, Petrasek J, Hribova P, Novotna E, Brabcova I, Viklicky O. Haplotypic structure of ABCB1/MDR1 gene modifies the risk of the acute allograft rejection in renal transplant recipients. Transplantation. 2008; 86:1206–13.
16). De Meyer M, Haufroid V, Elens L, Fusaro F, Patrono D, De Pauw L, et al. Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation. J Surg Res. 2012; 178:988–95.
17). Moore J, McKnight AJ, Döhler B, Simmonds MJ, Courtney AE, Brand OJ, et al. Donor ABCB1 variant as-sociates with increased risk for kidney allograft failure. J Am Soc Nephrol. 2012; 23:1891–9.
18). Gendzekhadze K, Rivas-Vetencourt P, Montano RF. Risk of adverse posttransplant events after kidney allograft transplantation as predicted by CTLA-4 +49 and TNF- alpha -308 single nucleotide polymorphisms: a prelimi-nary study. Transpl Immunol. 2006; 16:194–9.
19). Min SI, Kim SY, Ahn SH, Min SK, Kim SH, Kim YS, et al. CYP3A5 ∗1 allele: impacts on early acute rejection and graft function in tacrolimus-based renal transplant recipients. Transplantation. 2010; 90:1394–400.
20). Dilger K, Schwab M, Fromm MF. Identification of bu-desonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein. Inflamm Bowel Dis. 2004; 10:578–83.
21). Elens L, Capron A, Kerckhove VV, Lerut J, Mourad M, Lison D, et al. 1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation. Pharmacogenet Genomics. 2007; 17:873–83.
22). Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T, et al. Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients. Steroids. 2008; 73:1052–9.
23). Wasilewska A, Zoch-Zwierz W, Pietruczuk M, Zalewski G. Expression of P-glycoprotein in lymphocytes from children with nephrotic syndrome, depending on their steroid response. Pediatr Nephrol. 2006; 21:1274–80.
24). Funaki S, Takahashi S, Wada N, Murakami H, Harada K. Multiple drug-resistant gene 1 in children with ste-roid-sensitive nephrotic syndrome. Pediatr Int. 2008; 50:159–61.
25). Jafar T, Prasad N, Agarwal V, Mahdi A, Gupta A, Sharma RK, et al. MDR-1 gene polymorphisms in steroid-re-sponsive versus steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant. 2011; 26:3968–74.
26). Krupoves A, Mack D, Seidman E, Deslandres C, Amre D. Associations between variants in the ABCB1 (MDR1) gene and corticosteroid dependence in children with Crohn's disease. Inflamm Bowel Dis. 2011; 17:2308–17.
27). Mourad M, Wallemacq P, De Meyer M, Malaise J, De Pauw L, Eddour DC, et al. Biotransformation enzymes and drug transporters pharmacogenetics in relation to im-munosuppressive drugs: impact on pharmacokinetics and clinical outcome. Transplantation. 2008; 85(7 Suppl):S19–24.
28). Woodahl EL, Yang Z, Bui T, Shen DD, Ho RJ. Multi-drug resistance gene G1199A polymorphism alters efflux transport activity of P-glycoprotein. J Pharmacol Exp Ther. 2004; 310:1199–207.
29). Kuwano M, Uchiumi T, Hayakawa H, Ono M, Wada M, Izumi H, et al. The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignancies. Cancer Sci. 2003; 94:9–14.
Table 1.
Distribution of ABCB1 single nucleotide polymorphisms
| Present study |
Healthy control |
|||||||
|---|---|---|---|---|---|---|---|---|
| Previous study | Hapmap data | |||||||
| Genotype | Patients (n=86) | HWE (P value) | Korean a (n=100) | Indian b (n=216) | European (n=226) | Chinese (n=84) | Japanese (n=172) | |
| C3435T | C | 59.3 | 0.58 | 58.5 | 50.5 | 42.9 | 58.3 | 54.1 |
| T | 40.7 | 41.5 | 49.5 | 57.1 | 45.9 | 45.9 | ||
| C1236T | C | 40.1 | 0.41 | 35.5 | 67.4 | 54.8 | 29.1 | 41.3 |
| T | 59.9 | 64.5 | 32.6 | 45.1 | 70.9 | 58.7 | ||
| G2677T/A | G | 52.7 | Genotyping | 37.0 | 72.7 | 38.4 | 53.1 | 44.8 |
| T | 33.9 | failure (n=30) | 43.0 | 27.3 | 61.6 | 46.9 | 55.2 | |
| A | 13.4 | 20.0 | - | - | - | - | ||
Table 2.
Comparison of baseline characteristics according to steroid resistance
Table 3.
Association of ABCB1 genotypes with steroid resistant rejection episodes
Table 4.
Comparison of baseline characteristics according to steroid resistance (excluding delayed graft function/slow graft function status)
Table 5.
Association of ABCB1 genotypes with steroid resistant rejection episodes (excluding delayed graft function/slow graft function status)
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