Kidney podocyte-associated gene polymorphisms affect tacrolimus concentration in pediatric patients with refractory nephrotic syndrome

Abstract

Few studies have investigated the correlation between pharmacogenomics and tacrolimus pharmacokinetics in patients with nephrotic syndrome (NS). This study evaluated the influences of genetic polymorphisms of metabolic enzymes, transporters, and podocyte-associated proteins on tacrolimus concentration in Chinese pediatric patients with refractory NS. A total of 167 pediatric patients with refractory NS were included from July 2013 to December 2017. Age of onset was restricted to <14 years of age. Dose-adjusted tacrolimus trough concentration (C0/D) on the third month was calculated, and 20 single-nucleotide polymorphisms in sixteen genes were genotyped. Age was correlated with tacrolimus C0/D (p = 0.006, r = 0.213). Tacrolimus C0/D was higher in CYP3A5 nonexpressers than in CYP3A5 expressers (p = 0.003). ACTN4 rs62121818, MYH9 rs2239781, CYP3A5*3, and age explained 20.5% interindividual variability of tacrolimus concentration in the total cohort. In CYP3A5 nonexpressers, ACTN4 rs62121818 and MYH9 rs2239781 together explained 14.6% variation of tacrolimus C0/D. MYH9 rs2239781, LAMB2 rs62119873 and age together explained 22.3% variability of tacrolimus level in CYP3A5 expressers. CYP3A5*3 was still an important factor affecting tacrolimus concentration in patients with NS. Podocyte-associated gene polymorphisms, especially ACTN4 rs62121818 and MYH9 rs2239781, were the other most important biomarkers for tacrolimus whole blood levels. Genotyping of CYP3A5, ACTN4, and MYH9 polymorphisms may be helpful for better guiding tacrolimus dosing in pediatric patients with refractory NS.

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Fig. 1: The correlation between age and tacrolimus C0/D.
Fig. 2: Influence of CYP3A5*3 and other podocyte-associated genotypes on dose-adjusted tacrolimus trough concentration (C0/D) in whole patients (n  =  167, *p  <  0.05; **p  <  0.001).
Fig. 3: Influence of ACTN4 genotypes and diplotype on dose-adjusted tacrolimus trough concentration (C0/D) in whole patients (n  =  167, *p  <  0.05).
Fig. 4: Influence of ACTN4 genotypes and diplotype on dose-adjusted tacrolimus trough concentration (C0/D) in CYP3A5 nonexpressers (n  =  82, **p  <  0.001).
Fig. 5: Influence of some podocyte-associated genotypes on dose-adjusted tacrolimus trough concentration (C0/D) in CYP3A5 expressers (n  =  85, *p  <  0.05).

References

  1. 1.

    Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629–39.

    PubMed  Google Scholar 

  2. 2.

    Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013;62:403–41.

    PubMed  Google Scholar 

  3. 3.

    Nishi S, Ubara Y, Utsunomiya Y, Okada K, Obata Y, Kai H, et al. Evidence-based clinical practice guidelines for nephrotic syndrome 2014. Clin Exp Nephrol. 2016;20:342–70.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet. 2001;40:283–95.

    CAS  PubMed  Google Scholar 

  5. 5.

    Evans WE, McLeod HL. Pharmacogenomics-drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538–49.

    CAS  PubMed  Google Scholar 

  6. 6.

    Rojas L, Neumann I, Herrero MJ, Boso V, Reig J, Poveda JL, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015;15:38–48.

    CAS  PubMed  Google Scholar 

  7. 7.

    Khaled SK, Palmer JM, Herzog J, Stiller T, Tsai NC, Senitzer D, et al. Influence of absorption, distribution, metabolism, and excretion genomic variants on tacrolimus/sirolimus blood levels and graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:268–76.

    CAS  PubMed  Google Scholar 

  8. 8.

    Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharm Ther. 2015;98:19–24.

    CAS  Google Scholar 

  9. 9.

    Birdwell KA, Chung CP. The potential of pharmacogenomics to advance kidney disease treatment. Clin J Am Soc Nephrol. 2017;12:1035–7.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hao GX, Huang X, Zhang DF, Zheng Y, Shi HY, Li Y, et al. Population pharmacokinetics of tacrolimus in children with nephrotic syndrome. Br J Clin Pharm. 2018;84:1748–56.

    CAS  Google Scholar 

  11. 11.

    Li JL, Liu S, Fu Q, Zhang Y, Wang XD, Liu XM, et al. Interactive effects of CYP3A4, CYP3A5, MDR1 and NR1I2 polymorphisms on tracrolimus trough concentrations in early postrenal transplant recipients. Pharmacogenomics. 2015;16:1355–65.

    CAS  PubMed  Google Scholar 

  12. 12.

    Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007;17:428–37.

    CAS  PubMed  Google Scholar 

  13. 13.

    Tryggvason K, Pikkarainen T, Patrakka J. Nck links nephrin to actin in kidney podocytes. Cell. 2006;125:221–4.

    CAS  PubMed  Google Scholar 

  14. 14.

    Warejko JK, Tan W, Daga A, Schapiro D, Lawson JA, Shril S, et al. Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2018;13:53–62.

    CAS  PubMed  Google Scholar 

  15. 15.

    Cheng W, Zhou X, Zhu L, Shi S, Lv J, Liu L, et al. Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese. Nephrol Dial Transplant. 2011;26:2544–9.

    CAS  PubMed  Google Scholar 

  16. 16.

    Dandapani SV, Sugimoto H, Matthews BD, Kolb RJ, Sinha S, Gerszten RE, et al. Alpha-actinin-4 is required for normal podocyte adhesion. J Biol Chem. 2007;282:467–77.

    CAS  PubMed  Google Scholar 

  17. 17.

    Feng D, DuMontier C, Pollak MR. The role of alpha-actinin-4 in human kidney disease. Cell Biosci. 2015;5:44.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008;14:931–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zhang Q, Shi SF, Zhu L, Lv JC, Liu LJ, Chen YQ, et al. Tacrolimus improves the proteinuria remission in patients with refractory IgA nephropathy. Am J Nephrol. 2012;35:312–20.

    CAS  PubMed  Google Scholar 

  20. 20.

    Li JL, Wang XD, Chen SY, Liu LS, Fu Q, Chen X, et al. Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective. Pharmacogenomics J. 2011;11:300–6.

    CAS  PubMed  Google Scholar 

  21. 21.

    Zhang Y, Li JL, Fu Q, Wang XD, Liu LS, Wang CX, et al. Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients. Acta Pharm Sin. 2013;34:555–60.

    CAS  Google Scholar 

  22. 22.

    Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928–9.

    CAS  PubMed  Google Scholar 

  23. 23.

    Wallemacq PE, Furlan V, Moller A, Schafer A, Stadler P, Firdaous I, et al. Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients. Eur J Drug Metab Pharmacokinet. 1998;23:367–70.

    CAS  PubMed  Google Scholar 

  24. 24.

    Sun JY, Xu ZJ, Sun F, Guo HL, Ding XS, Chen F, et al. Individualized tacrolimus therapy for pediatric nephrotic syndrome: considerations for ontogeny and pharmacogenetics of CYP3A. Curr Pharm Des. 2018;24:2765–73.

    CAS  PubMed  Google Scholar 

  25. 25.

    Terrazzino S, Quaglia M, Stratta P, Canonico PL, Genazzani AA. The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis. Pharmacogenet Genomics. 2012;22:642–5.

    CAS  PubMed  Google Scholar 

  26. 26.

    Kamdem LK, Streit F, Zanger UM, Brockmoller J, Oellerich M, Armstrong VW, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005;51:1374–81.

    CAS  PubMed  Google Scholar 

  27. 27.

    Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005;15:693–704.

    CAS  PubMed  Google Scholar 

  28. 28.

    Brambila-Tapia AJ. MDR1 (ABCB1) polymorphisms: functional effects and clinical implications. Rev Investig Clin. 2013;65:445–54.

    Google Scholar 

  29. 29.

    Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet. 2018;392:61–74.

    PubMed  Google Scholar 

  30. 30.

    Liao R, Liu Q, Zheng Z, Fan J, Peng W, Kong Q, et al. Tacrolimus protects podocytes from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting podocyte apoptosis. PLoS ONE. 2015;10:e0132724.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Shen X, Jiang H, Ying M, Xie Z, Li X, Wang H, et al. Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models. Sci Rep. 2016;6:32087.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Critchley DR. Focal adhesions—the cytoskeletal connection. Curr Opin Cell Biol. 2000;12:133–9.

    CAS  PubMed  Google Scholar 

  33. 33.

    Zhao X, Hsu KS, Lim JH, Bruggeman LA, Kao HY. alpha-Actinin 4 potentiates nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-kappaB) activity in podocytes independent of its cytoplasmic actin binding function. J Biol Chem. 2015;290:338–49.

    CAS  PubMed  Google Scholar 

  34. 34.

    Khurana S, Chakraborty S, Zhao X, Liu Y, Guan D, Lam M, et al. Identification of a novel LXXLL motif in alpha-actinin 4-spliced isoform that is critical for its interaction with estrogen receptor alpha and co-activators. J Biol Chem. 2012;287:35418–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Wakamatsu A, Fukusumi Y, Hasegawa E, Tomita M, Watanabe T, Narita I, et al. Role of calcineurin (CN) in kidney glomerular podocyte: CN inhibitor ameliorated proteinuria by inhibiting the redistribution of CN at the slit diaphragm. Physiol Rep. 2016;4:e12679.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Zangar RC, Bollinger N, Verma S, Karin NJ, Lu Y. The nuclear factor-kappa B pathway regulates cytochrome P450 3A4 protein stability. Mol Pharm. 2008;73:1652–8.

    CAS  Google Scholar 

  37. 37.

    Gu X, Ke S, Liu D, Sheng T, Thomas PE, Rabson AB, et al. Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. J Biol Chem. 2006;281:17882–9.

    CAS  PubMed  Google Scholar 

  38. 38.

    Kim SJ, Lee S, Park HJ, Kang TH, Sagong B, Baek JI, et al. Genetic association of MYH genes with hereditary hearing loss in Korea. Gene. 2016;591:177–82.

    CAS  PubMed  Google Scholar 

  39. 39.

    Franceschini N, Voruganti VS, Haack K, Almasy L, Laston S, Goring HH, et al. The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study. Hum Genet. 2010;127:295–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Lin MH, Miller JB, Kikkawa Y, Suleiman HY, Tryggvason K, Hodges BL, et al. Laminin-521 protein therapy for glomerular basement membrane and podocyte abnormalities in a model of Pierson syndrome. J Am Soc Nephrol. 2018;29:1426–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Funk SD, Bayer RH, Malone AF, McKee KK, Yurchenco PD, Miner JH. Pathogenicity of a human laminin beta2 mutation revealed in models of Alport syndrome. J Am Soc Nephrol. 2018;29:949–60.

    CAS  PubMed  Google Scholar 

  42. 42.

    Rood IM, Deegens JKJ, Lugtenberg D, Bongers E, Wetzels JFM. Nephrotic syndrome with mutations in NPHS2: the role of R229Q and implications for genetic counseling. Am J Kidney Dis. 2019;73:400–3.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by grants from the National Natural Science Foundation of China (grant no. 81603203), the National Key Research and Development Program (grant no. 2017YFC0909303), the National Key Research and Development Program (grant no. 2016YFC0905001), Health Commission of Guangdong Province (grant no. 2016–568), Guangzhou Women and Children’s Medical Center/Guangzhou Institute of Pediatrics (grant no. YIP-2018–020). We thank the physicians (Fazhan Zhong, Huiying Deng, Fu Zhong, Ye Chen, Huabin Yang, and Zichuan Xu) and nurses (Hui Deng, Yuru Liao) from the division of nephrology for their contribution to patients’ recruitment and sample collection. Thank Caijiao Guo for her concentration determining assistance from the clinical laboratory. Thanks for the help of Fangling Zeng, Bing Zhu, and Yinghua Li from the central lab and Xiaojun Cao and Xu Lin from the department of science and education. Yanling He, Yingjie Li, and Min Huang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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The study was performed according to the Declaration of Helsinki and guidelines on good clinical practice, and ethical approval was obtained from the ethics committee of Guangzhou Women and Children’s Medical Center (no. 201509). Written informed consent was obtained from all patients or their guardians before participation. This study was a part of a large clinical trial (NCT02602873), aiming to achieve individualized administration of tacrolimus in patients with pediatric NS.

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Mo, X., Li, J., Liu, Y. et al. Kidney podocyte-associated gene polymorphisms affect tacrolimus concentration in pediatric patients with refractory nephrotic syndrome. Pharmacogenomics J 20, 543–552 (2020). https://doi.org/10.1038/s41397-019-0141-x

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