Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions.
BACKGROUND
A major challenge in transplantation is improving long-term organ transplant and patient survival. Immunosuppressants protect the transplant organ from alloimmune reactions, but sometimes also exhibit limiting side effects. The key to improving long-term outcome following transplantation is the selection of the correct immunosuppressive regimen for an individual patient for minimizing toxicity while maintaining immunosuppressive efficacy.


METHODS
Proteomics and metabolomics have the potential to develop sensitive and specific diagnostic tools for monitoring early changes in cell signal transduction, regulation and biochemical pathways. Here, we review the steps required for the development of molecular markers from discovery, mechanistic and clinical qualification to regulatory approval, and present a critical discussion of the current status of molecular marker development as relevant for the management and individualization of immunosuppressive drug regimens.


CONCLUSIONS
Although metabolomics and proteomics-based studies have yielded several candidate molecular markers, most published studies are poorly designed, statistically underpowered and/or often have not gone beyond the discovery stage. Most molecular marker candidates are still at an early stage. Due to the high complexity of and the resources required for diagnostic marker development, initiatives and consortia organized and supported by funding agencies and regulatory agencies will be critical.
University of Colorado, Department of Anesthesiology, 1999 North Fitzsimons Parkway, Bioscience East, Suite 100, Aurora, CO 80045-7503, USA. uwe.christians@ucdenver.edu
Uwe
U
Christians
Jost
J
Klawitter
Jelena
J
Klawitter
Nina
N
Brunner
Volker
V
Schmitz
D015415:Biomarkers / Q000032:analysis* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D055442:Metabolome; D010641:Phenotype; D040901:Proteomics; D015398:Signal Transduction
D015415:Biomarkers; D007166:Immunosuppressive Agents
Nephron Exp Nephrol. 2009;111(4):e80-91
19293597
Kidney Int. 1993 Jan;43(1):234-45
8433564
J Clin Pathol. 1989 Jun;42(6):624-8
2738168
Transpl Immunol. 2008 Nov;20(1-2):3-5
18773959
Annu Rev Pharmacol Toxicol. 2001;41:347-66
11264461
Curr Opin Organ Transplant. 2010 Jun;15(3):349-56
20489630
Transpl Immunol. 2008 Nov;20(1-2):21-8
18775494
Am J Kidney Dis. 2009 Dec;54(6):1012-24
19850388
Transplantation. 2009 Dec 27;88(12):1323-31
20029328
Pediatr Nephrol. 2005 May;20(5):652-6
15782300
Transplantation. 1986 Oct;42(4):368-71
3020748
Circulation. 2006 May 16;113(19):2335-62
16702488
Bioessays. 2006 May;28(5):534-45
16615085
J Am Soc Nephrol. 2007 Mar;18(3):904-12
17267747
Am J Transplant. 2006 Sep;6(9):2006-12
16796717
Am J Kidney Dis. 2000 Feb;35(2):333-46
10676738
Transplant Proc. 2005 Dec;37(10):4254-8
16387092
Nat Biotechnol. 2010 May;28(5):478-85
20458318
Clin Pharmacol Ther. 2001 Mar;69(3):89-95
11240971
Am J Physiol Renal Physiol. 2006 Feb;290(2):F517-29
16174863
Drug Saf. 1997 Aug;17(2):75-92
9285199
Clin Chem. 1999 Dec;45(12):2243-9
10585359
Transplantation. 2006 Jul 15;82(1 Suppl):S41-6
16829796
Transplantation. 2005 Feb 27;79(4):419-26
15729167
J Neurol. 1999 May;246(5):339-46
10399863
Am J Transplant. 2004 Jul;4(7):1124-32
15196071
Curr Opin Crit Care. 2004 Dec;10(6):476-82
15616389
Transpl Int. 1994;7(1):17-21
8117397
J Am Soc Nephrol. 1998 Sep;9(9):1723-35
9727382
Pharmacol Toxicol. 1993 Apr-May;72(4-5):321-31
8372055
Curr Opin Mol Ther. 2004 Dec;6(6):600-7
15663324
Toxicology. 2008 Mar 20;245(3):219-23
18280028
Drugs. 2001;61(13):1957-2016
11708766
Kidney Int. 1988 Feb;33(2):571-7
3283401
Am J Transplant. 2006 Jan;6(1):41-9
16433755
Biol Pharm Bull. 2007 Jul;30(7):1254-9
17603163
Kidney Int. 1995 Mar;47(3):927-34
7752594
Transpl Int. 1991 Sep;4(3):146-50
1720317
Transplantation. 2010 Jul 27;90(2):189-97
20526237
Am J Cardiol. 1991 Apr 1;67(8):782-4
2006635
Transplantation. 2007 Feb 27;83(4):392-7
17318070
J Am Soc Nephrol. 2005 Oct;16(10):3015-26
16120819
J Lab Clin Med. 2005 Mar;145(3):125-33
15871303
Transplantation. 2006 Mar 15;81(5):643-54
16534463
Intensive Care Med. 2005 May;31(5):664-7
15812628
Can J Surg. 2010 Feb;53(1):57-63
20100415
Transplant Proc. 2009 Sep;41(7):2826-8
19765447
Ann Transplant. 2000;5(2):44-9
11217206
Nature. 2003 Mar 13;422(6928):198-207
12634793
Pediatr Nephrol. 2010 May;25(5):889-97
20072790
J Proteome Res. 2010 Feb 5;9(2):865-75
19994912
Transplantation. 2005 Dec 27;80(12):1660-6
16378057
Clin Nutr. 2008 Jun;27(3):328-39
18440672
Transplantation. 2007 Nov 15;84(9):1077-81
17998860
Expert Rev Mol Diagn. 2008 Sep;8(5):617-33
18785810
Curr Opin Organ Transplant. 2010 Feb;15(1):35-41
19935064
Nat Biotechnol. 2010 May;28(5):463-9
20458316
J Clin Invest. 2008 May;118(5):1657-68
18414680
Transplantation. 1999 Apr 15;67(7):1036-42
10221490
Am J Transplant. 2005 Dec;5(12):2814-20
16302993
J Proteome Res. 2005 Jul-Aug;4(4):1192-9
16083269
Transplant Proc. 2001 May;33(3):2129-31
11377474
Ann Surg. 2007 Aug;246(2):311-5
17667511
Lancet. 2001 Mar 17;357(9259):856-7
11265958
Am J Transplant. 2008 Feb;8(2):267-70
18093264
Transplantation. 2001 May 27;71(10):1400-6
11391226
Postgrad Med J. 2009 Oct;85(1008):538-45
19789193
Annu Rev Pharmacol Toxicol. 2008;48:463-93
17937594
Clin Chem. 2010 Feb;56(2):237-43
20007859
Am J Nephrol. 2005 May-Jun;25(3):250-5
15925859
Transplantation. 2001 Jun 15;71(11 Suppl):SS52-7
11583490
N Engl J Med. 1989 Dec 21;321(25):1725-38
2687689
Curr Opin Investig Drugs. 2003 Nov;4(11):1287-96
14758767
N Engl J Med. 2003 Dec 11;349(24):2326-33
14668458
Transpl Int. 2000;13(5):313-26
11052266
Kidney Int. 1998 Aug;54(2):482-91
9690215
Mol Cell Proteomics. 2004 Apr;3(4):311-26
14718574
Circulation. 2006 Jul 4;114(1 Suppl):I214-9
16820575
Transplantation. 2008 May 15;85(9):1281-6
18475184
Transplantation. 2005 Dec 15;80(11):1565-71
16371927
Biochem Pharmacol. 1997 Mar 7;53(5):723-31
9113092
Eur J Cardiothorac Surg. 2007 Jul;32(1):48-51
17482473
Int Urol Nephrol. 1999;31(5):727-34
10755366
Science. 2006 Apr 14;312(5771):212-7
16614208
Scand J Clin Lab Invest Suppl. 2008;241:73-7
18569970
Pediatr Surg Int. 2003 Nov;19(9-10):656-61
14574608
Biomark Insights. 2008 Feb 9;3:65-71
19578495
Nephron. 1994;67(3):308-16
7936021
Ther Drug Monit. 2008 Apr;30(2):151-8
18367974
Ren Fail. 2009;31(2):111-7
19212907
Expert Opin Med Diagn. 2008 Apr;2(4):387-398
19079800
J Am Soc Nephrol. 2003 Oct;14(10):2534-43
14514731
Transplantation. 2008 Aug 15;86(3):371-6
18698238
Appl Microbiol Biotechnol. 2007 Sep;76(3):495-511
17665194
Nephron. 1993;65(3):433-9
8289995
Uremia Invest. 1985-1986;9(2):277-80
3915928
J Am Soc Nephrol. 2005 May;16(5):1501-11
15772250
Clin Chem Lab Med. 2009;47(12):1553-6
19877765
J Mass Spectrom. 2001 Oct;36(10):1083-91
11747101
Mass Spectrom Rev. 2007 Jan-Feb;26(1):51-78
16921475
Br J Pharmacol. 2004 Oct;143(3):388-96
15339861
J Pharm Biomed Anal. 2004 May 28;35(3):599-608
15137985
J Proteome Res. 2008 Aug;7(8):3597-601
18620448
Clin Chem. 2005 Jan;51(1):3-5
15613702
Kidney Int. 2002 Jul;62(1):237-44
12081583
Expert Rev Mol Diagn. 2007 May;7(3):247-59
17489732
Transplant Proc. 2007 Jan-Feb;39(1):88-93
17275481
N Engl J Med. 2005 May 19;352(20):2049-60
15901858
Contrib Nephrol. 2008;160:76-87
18401163
Am J Kidney Dis. 1996 Jul;28(1):23-31
8712218
Nat Biotechnol. 2006 Aug;24(8):971-83
16900146
Mol Cell Proteomics. 2008 Oct;7(10):1850-62
18667409
Nephrol Dial Transplant. 2010 Jul;25(7):2150-8
20139407
Contrib Nephrol. 1984;42:123-9
6152415
Lancet. 2005 Apr 2-8;365(9466):1231-8
15811456
Transplant Proc. 2005 Sep;37(7):3119-20
16213325
Curr Opin Drug Discov Devel. 2009 Jan;12(1):40-52
19152212
Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1909-19
18669888
J Am Soc Nephrol. 2005 Jul;16(7):1886-903
15888557
Clin Lab Med. 1988 Sep;8(3):507-26
2901937
J Clin Pharmacol. 1997 Jul;37(7):575-86
9243350
Curr Opin Crit Care. 2002 Dec;8(6):509-14
12454534
Bone Marrow Transplant. 1999 Jul;24(1):35-9
10435732
Kidney Int. 1999 Jun;55(6):2407-14
10354289
Am J Transplant. 2009 Jun;9(6):1265-71
19459815
Clin Transplant. 2009 Mar-Apr;23(2):241-8
19402217
Clin Chem Lab Med. 2006;44(3):288-91
16519600
Electrophoresis. 1998 Aug;19(11):1998-2003
9740060
Contrib Nephrol. 1984;42:100-6
6152413
Mol Syst Biol. 2006;2:52
17016518
Curr Opin Nephrol Hypertens. 2007 Nov;16(6):506-11
18089962
Transpl Int. 2005 Feb;18(2):221-5
15691276
J Cardiovasc Pharmacol. 2005 Jan;45(1):81-7
15613984
Cancer Biomark. 2005;1(1):59-67
17192032
Ren Fail. 2009;31(8):765-72
19814648
Clin Chem. 1987 Jun;33(6):775-9
3297418
Transplant Proc. 2005 Apr;37(3):1428-30
15866626
J Hypertens. 2006 May;24(5):947-56
16612258
Cell Growth Differ. 1991 Jul;2(7):351-7
1782153
Transplantation. 2000 Apr 15;69(7):1252-60
10798738
Adv Cancer Res. 2007;96:269-98
17161683
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5330-5
19289845
Cell. 2008 Sep 5;134(5):714-7
18775301
J Proteome Res. 2007 Feb;6(2):459-68
17269703
Nat Biotechnol. 2010 May;28(5):446-54
20458314
Am J Physiol Renal Physiol. 2007 Jan;292(1):F131-9
16835406
Am J Transplant. 2006 Nov;6(11):2786-90
16952300
Pediatrics. 2009 Aug;124(2):620-6
19581263
Kidney Int. 2002 Nov;62(5):1601-10
12371960
Transplant Proc. 2006 Jul-Aug;38(6):1731-2
16908264
Expert Opin Drug Metab Toxicol. 2009 Sep;5(9):1023-38
19611406
Chem Res Toxicol. 2009 Jan;22(1):118-28
19099400
Pharm Res. 2005 Apr;22(4):499-511
15846456
Transplant Proc. 2010 Jan-Feb;42(1):54-6
20172280
Nat Biotechnol. 2010 May;28(5):436-40
20458311
Ther Drug Monit. 2005 Dec;27(6):733-7
16404806
Curr Opin Nephrol Hypertens. 2003 Sep;12(5):533-41
12920402
Transplantation. 2004 Aug 27;78(4):557-65
15446315
Nephron. 1996;72(3):402-6
8852487
Biochem J. 1992 Nov 15;288 ( Pt 1):285-90
1280113
Int Urol Nephrol. 2009;41(3):727-31
19115077
Drug Discov Today. 2005 Jun 1;10(11):781-8
15922936
Br J Clin Pharmacol. 2010 Aug;70(2):241-51
20653677
J Clin Chem Clin Biochem. 1982 Sep;20(9):615-9
6183389
Clin Pharmacol Ther. 2007 Jan;81(1):104-7
17186007
Contrib Nephrol. 2005;147:124-131
15604612
Clin Chim Acta. 1998 Aug 10;276(1):63-74
9760020
Am J Transplant. 2008 Nov;8(11):2360-7
18925903
Transplantation. 2001 Jun 15;71(11 Suppl):SS42-51
11583488
Annu Rev Genomics Hum Genet. 2004;5:267-93
15485350
Lancet. 2000 Jul 15;356(9225):194-202
10963197
Transplant Proc. 2010 Jan-Feb;42(1):57-61
20172281