Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?
We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell-related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group-namely, the tolerant recipients-were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross-validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.|UCB Celltech, UCB Pharma S.A., Slough, United Kingdom.
I
I
Rebollo-Mesa
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.
E
E
Nova-Lamperti
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.
P
P
Mobillo
National Institute for Health Research Biomedical Research Centre, Guy's and St. Thomas' National Health Service Foundation Trust, King's College London, London, United Kingdom.
M
M
Runglall
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
S
S
Christakoudi
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|University College London, London, United Kingdom.
S
S
Norris
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.
N
N
Smallcombe
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom.
Y
Y
Kamra
Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
R
0000-0001-5118-2017
R
Hilton
King's College London, London, United Kingdom.|Oxford University, Oxford, United Kingdom.|Imperial College London, London, United Kingdom.|Institute for Medical Immunology, Université Libre de Bruxelles, Bruxelles, Belgium.|Miltenyi Biotec, Bergisch Gladbach, Germany.|University of Nantes, Nantes, France.|Charité, Universitaatsmedizin Berlin, Berlin, Germany.
Hull and East Yorkshire Hospitals NHS Trust, Hull, United Kingdom.
S
S
Bhandari
St. James's University Hospital, Leeds, United Kingdom.
R
R
Baker
Uppsala University Hospital, Uppsala, Sweden.
D
D
Berglund
Leicester General Hospital, Leicester, United Kingdom.
S
S
Carr
Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
D
D
Game
Cardiff and Vale University Health Board, Cardiff, United Kingdom.
S
S
Griffin
Salford Royal Hospital, Salford, United Kingdom.
P A
PA
Kalra
Queen Alexandra Hospital, Portsmouth, United Kingdom.
R
R
Lewis
University of Glasgow, Glasgow, United Kingdom.
P B
PB
Mark
Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
S
S
Marks
St. George's Hospital, London, United Kingdom.
I
0000-0003-2322-7622
I
Macphee
Northern General Hospital, Sheffield, United Kingdom.
W
W
McKane
INSELSPITAL, Universitätsspital Bern, Klinik für Nephrologie/Hypertonie Abteilung für Hypertonie, Bern, Switzerland.
M G
MG
Mohaupt
Manchester Royal Infirmary, Manchester, United Kingdom.
R
R
Pararajasingam
King's College Hospital NHS Foundation Trust, London, United Kingdom.
S P
SP
Kon
Hospital Universitari Vall d'Hebr_on, Barcelona, Spain.
D
D
Serón
Evelina London Children's Hospital, London, United Kingdom.
M D
MD
Sinha
King's College Hospital NHS Foundation Trust, London, United Kingdom.
B
B
Tucker
Transplantační laboratoř IKEM, Prague, Czech Republic.
O
O
Viklický
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|King's Health Partners, London, United Kingdom.
R I
RI
Lechler
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|National Institute for Health Research Biomedical Research Centre, Guy's and St. Thomas' National Health Service Foundation Trust, King's College London, London, United Kingdom.|Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
G M
GM
Lord
Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.|National Institute for Health Research Biomedical Research Centre, Guy's and St. Thomas' National Health Service Foundation Trust, King's College London, London, United Kingdom.
M P
MP
Hernandez-Fuentes
D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors
D015415:Biomarkers; D007166:Immunosuppressive Agents
biomarker; immunobiology; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; molecular biology; tolerance; translational research/science