Noninvasive testing for mycophenolate exposure in children with renal transplant using urinary metabolomics
Khalid Taha
Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Search for more papers by this authorAtul Sharma
Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, Manitoba, Canada
Search for more papers by this authorKristine Kroeker
Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
Search for more papers by this authorColin Ross
Faculty of Pharmaceutical Sciences, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Search for more papers by this authorBruce Carleton
Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Search for more papers by this authorDavid Wishart
Departments of Computing Science and Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
Search for more papers by this authorMara Medeiros
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Search for more papers by this authorCorresponding Author
Tom D. Blydt-Hansen
Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Correspondence
Tom D. Blydt-Hansen, MDCM, FRCPC Associate Professor, University of British Columbia, K4-149, 4480 Oak Street, Vancouver, British Columbia V6H 3V4, Canada.
Email: [email protected]
Search for more papers by this authorKhalid Taha
Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Search for more papers by this authorAtul Sharma
Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, Manitoba, Canada
Search for more papers by this authorKristine Kroeker
Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
Search for more papers by this authorColin Ross
Faculty of Pharmaceutical Sciences, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Search for more papers by this authorBruce Carleton
Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Search for more papers by this authorDavid Wishart
Departments of Computing Science and Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
Search for more papers by this authorMara Medeiros
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Search for more papers by this authorCorresponding Author
Tom D. Blydt-Hansen
Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, Vancouver, British Columbia, Canada
Correspondence
Tom D. Blydt-Hansen, MDCM, FRCPC Associate Professor, University of British Columbia, K4-149, 4480 Oak Street, Vancouver, British Columbia V6H 3V4, Canada.
Email: [email protected]
Search for more papers by this authorAbstract
Background
Despite the common use of mycophenolate in pediatric renal transplantation, lack of effective therapeuic drug monitoring increases uncertainty over optimal drug exposure and risk for adverse reactions. This study aims to develop a novel urine test to estimate MPA exposure based using metabolomics.
Methods
Urine samples obtained on the same day of MPA pharmacokinetic testing from two prospective cohorts of pediatric kidney transplant recipients were assayed for 133 unique metabolites by mass spectrometry. Partial least squares (PLS) discriminate analysis was used to develop a top 10 urinary metabolite classifier that estimates MPA exposure. An independent cohort was used to test pharmacodynamic validity for allograft inflammation (urinary CXCL10 levels) and eGFR ratio (12mo/1mo eGFR) at 1 year.
Results
Fifty-two urine samples from separate children (36.5% female, 12.0 ± 5.3 years at transplant) were evaluated at 1.6 ± 2.5 years post-transplant. Using all detected metabolites (n = 90), the classifier exhibited strong association with MPA AUC by principal component regression (r = 0.56, p < .001) and PLS (r = 0.75, p < .001). A practical classifier (top 10 metabolites; r = 0.64, p < .001) retained similar accuracy after cross-validation (LOOCV; r = 0.52, p < .001). When applied to an independent cohort (n = 97 patients, 1053 samples), estimated mean MPA exposure over Year 1 was inversely associated with mean urinary CXCL10:Cr (r = −0.28, 95% CI −0.45, −0.08) and exhibited a trend for association with eGFR ratio (r = 0.35, p = .07), over the same time period.
Conclusions
This urinary metabolite classifier can estimate MPA exposure and correlates with allograft inflammation. Future studies with larger samples are required to validate and evaluate its clinical application.
Open Research
DATA AVAILABILITY STATEMENT
Patient level data are not publicly available. Secondary analysis or further validation of data used in the publication is available by contacting the corresponding author.
REFERENCES
- 1Blydt-Hansen TD, Sharma A, Gibson IW, Mandal R, Wishart DS. Urinary metabolomics for noninvasive detection of borderline and acute T cell-mediated rejection in children after kidney transplantation. Am J Transplant. 2014; 14(10): 2339-2349. doi:10.1111/ajt.12837
- 2Webster G, Wu J, Terner M, Ivis F, De Sa E, Hall N. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2004 to 2013. 2015.
- 3Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of De novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012; 12(5): 1157-1167. doi:10.1111/j.1600-6143.2012.04013.x
- 4Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Rates and determinants of progression to graft failure in kidney allograft recipients with De Novo donor-specific antibody. Am J Transplant. 2015; 15(11): 2921-2930. doi:10.1111/ajt.13347
- 5Hymes LC, Greenbaum L, Amaral SG, Warshaw BL. Surveillance renal transplant biopsies and subclinical rejection at three months post-transplant in pediatric recipients. Pediatr Transplant. 2007; 11(5): 536-539. doi:10.1111/j.1399-3046.2007.00705.x
- 6Hymes LC, Warshaw BL, Hennigar RA, Amaral SG, Greenbaum LA. Prevalence of clinical rejection after surveillance biopsies in pediatric renal transplants: does early subclinical rejection predispose to subsequent rejection episodes? Pediatr Transplant. 2009; 13(7): 823-826. doi:10.1111/j.1399-3046.2009.01200.x
- 7Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 annual data report: kidney. Am J Transplant. 2014; 14(S1): 44. doi:10.1111/ajt.12579
- 8Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007; 46(1): 13-58. doi:10.2165/00003088-200746010-00002
- 9Filler G, Bendrick-Peart J, Christians U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther Drug Monit. 2008; 30(2): 138-142. doi:10.1097/FTD.0b013e31816ba73a
- 10Arns W, Cibrik DM, Walker RG, et al. Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature. Transplantation. 2006; 82(8): 1004-1012. doi:10.1097/01.tp.0000232697.38021.9a
- 11Knorr JP, Sjeime M, Braitman LE, Jawa P, Zaki R, Ortiz J. Concomitant proton pump inhibitors with mycophenolate mofetil and the risk of rejection in kidney transplant recipients. Transplantation. 2014; 97(5): 518-524. doi:10.1097/01.tp.0000436100.65983.10
- 12Hesselink DA, van Hest RM, Mathot RAA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant. 2005; 5(5): 987-994. doi:10.1046/j.1600-6143.2005.00779.x
- 13Cattaneo D, Perico N, Gaspari F, Gotti E, Remuzzi G. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int. 2002; 62(3): 1060-1067. doi:10.1046/j.1523-1755.2002.00531.x
- 14van Gelder T, Tedesco Silva H, de Fijter JW, et al. Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid. Transplantation. 2010; 89(5): 595-599. doi:10.1097/TP.0b013e3181ca7d84
- 15van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008; 86(8): 1043-1051. doi:10.1097/TP.0b013e318186f98a
- 16Le Meur Y, Büchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007; 7(11): 2496-2503. doi:10.1111/j.1600-6143.2007.01983.x
- 17Daher Abdi Z, Prémaud A, Essig M, et al. Exposure to mycophenolic acid better predicts immunosuppressive efficacy than exposure to calcineurin inhibitors in renal transplant patients. Clin Pharmacol Ther. 2014; 96(4): 508-515. doi:10.1038/clpt.2014.140
- 18Daher Abdi Z, Essig M, Rizopoulos D, et al. Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach. Pharmacol Res. 2013; 72: 72-60. doi:10.1016/j.phrs.2013.03.009
- 19Wigger M, Armstrong VW, Shipkova M, et al. Atypical pharmacokinetics and metabolism of mycophenolic acid in a young kidney transplant recipient with impaired renal function. Ther Drug Monit. 2002; 24(3): 438-443. doi:10.1097/00007691-200206000-00019
- 20Weber LT, Hoecker B, Armstrong VW, Oellerich M, Tönshoff B. Long-term pharmacokinetics of mycophenolic acid in pediatric renal transplant recipients over 3 years posttransplant. Ther Drug Monit. 2008; 30(5): 570-575. doi:10.1097/FTD.0b013e31818752d9
- 21Tönshoff B, David-Neto E, Ettenger R, et al. Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev. 2011; 25(2): 78-89. doi:10.1016/j.trre.2011.01.001
- 22Oellerich M, Shipkova M, Schütz E, et al. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: implications for therapeutic drug monitoring. Ther Drug Monit. 2000; 22(1): 20-26. doi:10.1097/00007691-200002000-00004
- 23Martial LC, Jacobs BAW, Cornelissen EAM, et al. Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients. Pediatr Transplant. 2016; 20(4): 492-499. doi:10.1111/petr.12695
- 24Filler G, Alvarez-Elías AC, McIntyre C, Medeiros M. The compelling case for therapeutic drug monitoring of mycophenolate mofetil therapy. Pediatr Nephrol. 2017; 32(1): 21-29. doi:10.1007/s00467-016-3352-2
- 25Wishart DS. Metabolomics: the principles and potential applications to transplantation. Am J Transplant. 2005; 5(12): 2814-2820. doi:10.1111/j.1600-6143.2005.01119.x
- 26Spiga L, Atzori L, Noto A, et al. Metabolomics in paediatric oncology: a potential still to be exploited. J Matern Neonatal Med. 2013; 26(sup2): 23. doi:10.3109/14767058.2013.832062
- 27Posada-Ayala M, Zubiri I, Martin-Lorenzo M, et al. Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease. Kidney Int. 2014; 85(1): 103-111. doi:10.1038/ki.2013.328
- 28Nkuipou-Kenfack E, Duranton F, Gayrard N, et al. Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease. PLoS One. 2014; 9(5): e96955. doi:10.1371/journal.pone.0096955
- 29Boudonck KJ, Mitchell MW, Német L, et al. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol Pathol. 2009; 37(3): 280-292. doi:10.1177/0192623309332992
- 30Sieber M, Hoffmann D, Adler M, et al. Comparative analysis of novel noninvasive renal biomarkers and metabonomic changes in a rat model of gentamicin nephrotoxicity. Toxicol Sci. 2009; 109(2): 336-349. doi:10.1093/toxsci/kfp070
- 31Xu EY, Perlina A, Vu H, et al. Integrated pathway analysis of rat urine metabolic profiles and kidney transcriptomic profiles to elucidate the systems toxicology of model Nephrotoxicants. Chem Res Toxicol. 2008; 21(8): 1548-1561. doi:10.1021/tx800061w
- 32Schmitz V, Klawitter J, Bendrick-Peart J, et al. Metabolic profiles in urine reflect nephrotoxicity of sirolimus and cyclosporine following rat kidney transplantation. Nephron Exp Nephrol. 2009; 111(4): e80-e91. doi:10.1159/000209208
- 33Hauet T, Baumert H, Gibelin H, Godart C, Carretier M, Citrate EM. Acetate and renal medullary osmolyte excretion in urine as predictor of renal changes after cold Ischaemia and transplantation. Clin Chem Lab Med. 2000; 38(11): 1093-1098. doi:10.1515/CCLM.2000.162
- 34Hauet T, Gibelin H, Richer JP, Godart C, Eugene M, Carretier M. Influence of retrieval conditions on renal medulla injury: evaluation by proton NMR spectroscopy in an isolated perfused pig kidney model. J Surg Res. 2000; 93(1): 1-8. doi:10.1006/jsre.2000.5885
- 35Blydt-Hansen TD, Sharma A, Gibson IW, et al. Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients. Am J Transplant. 2020; 30: 1545-1555. doi:10.1111/ajt.16336
- 36Elnenaei MO, Chandra R, Mangion T, Moniz C. Genomic and metabolomic patterns segregate with responses to calcium and vitamin D supplementation. Br J Nutr. 2011; 105(1): 71-79. doi:10.1017/S0007114510003065
- 37Ji Y, Hebbring S, Zhu H, et al. Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: Pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther. 2011; 89(1): 97-104. doi:10.1038/clpt.2010.250
- 38Huang Q, Aa J, Jia H, et al. A Pharmacometabonomic approach to predicting metabolic phenotypes and pharmacokinetic parameters of atorvastatin in healthy volunteers. J Proteome Res. 2015; 14(9): 3970-3981. doi:10.1021/acs.jproteome.5b00440
- 39Wikoff WR, Frye RF, Zhu H, et al. Pharmacometabolomics reveals racial differences in response to atenolol treatment. PLoS One. 2013; 8(3):e57639. doi:10.1371/journal.pone.0057639
- 40Kaddurah-Daouk R, Weinshilboum RM. Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clin Pharmacol Ther. 2014; 95(2): 154-167. doi:10.1038/clpt.2013.217
- 41Lewis JP, Yerges-Armstrong LM, Ellero-Simatos S, Georgiades A, Kaddurah-Daouk R, Hankemeier T. Integration of pharmacometabolomic and pharmacogenomic approaches reveals novel insights into antiplatelet therapy. Clin Pharmacol Ther. 2013; 94(5): 570-573. doi:10.1038/clpt.2013.153
- 42Fernández-Ramos AA, Poindessous V, Marchetti-Laurent C, Pallet N, Loriot M-A. The effect of immunosuppressive molecules on T-cell metabolic reprogramming. Biochimie. 2016; 127: 127-136. doi:10.1016/j.biochi.2016.04.016
- 43Dun B, Sharma A, Xu H, Liu H, Bai S. Transcriptomic changes induced by mycophenolic acid in gastric cancer cells. Am J Transl Res. 2014; 6(1): 28-42.
- 44Dun B, Xu H, Sharma A, et al. Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid. Int J Clin Exp Pathol. 2013; 6(12): 2880-2886.
- 45Söllner J, Mayer P, Heinzel A, et al. Synthetic lethality for linking the mycophenolate mofetil mode of action with molecular disease and drug profiles. Mol Biosyst. 2012; 8(12): 3197-3207. doi:10.1039/c2mb25256b
- 46Filler G. Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int. 2004; 17(3): 120-125. doi:10.1007/s00147-003-0678-z
- 47Pawinski T, Luszczynska P, Durlik M, et al. Development and validation of limited sampling strategies for the estimation of mycophenolic acid area under the curve in adult kidney and liver transplant recipients receiving concomitant enteric-coated mycophenolate sodium and tacrolimus. Ther Drug Monit. 2013; 35(6): 760-769. doi:10.1097/FTD.0b013e31829b88f5
- 48Filler G, Todorova EK, Bax K, Alvarez-Elías AC, Huang S-HS, Kobrzynski MC. Minimum mycophenolic acid levels are associated with donor-specific antibody formation. Pediatr Transplant. 2016; 20(1): 34-38. doi:10.1111/petr.12637
- 49van Gelder T, Shaw LM. The rationale for and limitations of therapeutic drug monitoring for mycophenolate mofetil in transplantation. Transplantation. 2005; 80(Supplement):S253. doi:10.1097/01.tp.0000186380.61251.fc
- 50Molinaro M, Chiarelli LR, Biancone L, et al. Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients. Drug Metab Pharmacokinet. 2013; 28(2): 109-117. doi:10.2133/dmpk.DMPK-12-RG-048
- 51Li H, Mager DE, Sandmaier BM, et al. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil. Biol Blood Marrow Transplant. 2014; 20(8): 1121-1129. doi:10.1016/j.bbmt.2014.03.032
- 52McAdams-DeMarco MA, Law A, Tan J, et al. Frailty, mycophenolate reduction, and graft loss in kidney transplant recipients. Transplantation. 2015; 99(4): 805-810. doi:10.1097/TP.0000000000000444
- 53Ji S-M, Xie K-N, Chen J-S, et al. Retrospective evaluation of the effect of mycophenolate mofetil dosage on survival of kidney grafts based on biopsy results. Transplant Proc. 2014; 46(10): 3383-3389. doi:10.1016/j.transproceed.2014.09.107
- 54Weber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: a report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol. 2002; 13(3): 759-768. doi:10.1681/ASN.V133759
- 55Kuypers D. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004; 75(5): 434-447. doi:10.1016/j.clpt.2003.12.009
- 56Heller T, van Gelder T, Budde K, et al. Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients. Am J Transplant. 2007; 7(7): 1822-1831. doi:10.1111/j.1600-6143.2007.01859.x
- 57Borrows R, Chusney G, Loucaidou M, et al. Mycophenolic acid 12-h trough level monitoring in renal transplantation: association with acute rejection and toxicity. Am J Transplant. 2006; 6(1): 121-128. doi:10.1111/j.1600-6143.2005.01151.x
- 58Yang JW, Lee PH, Hutchinson IV, Pravica V, Shah T, Min DI. Genetic polymorphisms of MRP2 and UGT2B7 and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid. Ther Drug Monit. 2009; 31(5): 542-548. doi:10.1097/FTD.0b013e3181b1dd5e
- 59Kuypers DRJ, de Jonge H, Naesens M, et al. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients. Clin Ther. 2008; 30(4): 673-683. doi:10.1016/j.clinthera.2008.04.014
- 60Fu L, Huang Z, Song T, et al. Short-term therapeutic drug monitoring of mycophenolic acid reduces infection: a prospective, single-center cohort study in Chinese living-related kidney transplantation. Transpl Infect Dis. 2014; 16(5): 760-766. doi:10.1111/tid.12275
- 61Takemoto SK, Pinsky BW, Schnitzler MA, et al. A retrospective analysis of immunosuppression compliance, dose reduction and discontinuation in kidney transplant recipients. Am J Transplant. 2007; 7(12): 2704-2711. doi:10.1111/j.1600-6143.2007.01966.x
- 62Vanhove T, Kuypers D, Claes KJ, et al. Reasons for dose reduction of mycophenolate mofetil during the first year after renal transplantation and its impact on graft outcome. Transpl Int. 2013; 26(8): 813-821. doi:10.1111/tri.12133
Citing Literature
