Current problems in kidney transplantation: Clinical point of view

1. Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland schaubs@uhbs.ch

2. Allograft loss Allograft failure Recipient death with functioning allograft 50% 50% Age!! Cardiovascular Infection Malignancy

3. Why do renal allograft fail? Acute rejection Unknown 10% 12% Medical, surgical 16% „Chronic“ rejection 24% (Recurrent) GN IF-TA: other, 22% specified causes CNI-toxicity 8% 1% PyVAN 7% Adapted from El-Zoghby. AJT, 2008

4. How to prevent acute / chronic rejection? 1) Avoid transplantation in high risk constellations (e.g. preformed donor-specific memory) 2) Screening for early / subclinical rejection

5. How to prevent acute / chronic rejection? 1) Avoid transplantation in high risk constellations (e.g. preformed donor-specific memory) 2) Screening for early / subclinical rejection

6. Tn Tm HLA-antibodies as a surrogate for memory Transfusion Transplant Pregnancy Naive B-cell IgM positiv Naive T-cell Bn Ta Activated T-cell Plasma cell IgG positiv PC Memory T-cell IgG HLA-Ab

7. Luminex Multiplex technology Color-coded beads Flow cytometer A3 A2 A1 bead A24 A25 A11 Data B7 B27 B8 B62 B51 B52

8. Clinical relevance of HLA-DSA detected by Luminex

9. 1. Magnitude and durability of the humoral memory response 2. Binding strength of HLA-DSA to the target epitope 3. Capacity of HLA-DSA to activate complement 4. Density of HLA-molecule expression 5. Protective factors and ‚absorptive capacity‘ of endothelial cells Complex biology… T-cell B-cell Plasma cell Complement anti-HLA-antibodies Donor HLA Amico P. Curr Opin Organ Transplant 2009

10. Organ allocation HLA-antibodies No HLA-antibodies Proceed with transplant Try to transplant around DSA - Acceptable mismatch program - Living donor exchange program Transplantation around DSA not achievable - Adapt immunosuppression!!

11. How to prevent acute / chronic rejection? 1) Avoid transplantation in high risk constellations (e.g. preformed donor-specific memory) 2) Screening for early / subclinical rejection

12. Subclinical allograft pathologies „Clinical“ pathologies • Rejection (AMR, TCMR) • CNI-toxicity • Polyomavirus nephropathy Serum creatinine threshold Nickerson P. JASN 1998 Rush D. AJT, 2007 Loupy A. AJT, 2009 „Subclinical“ pathologies Nankivell B. NEJM, 2003 Schaub S. AJT, 2010

13. Clinical relevance of subclinical “TCMR” Interstitial fibrosis with inflammation at one year predicts decline of allograft function Park WD. JASN, 2010

14. Natural history of de novo DSA and AMR Hourmant. JASN 2005 Moreso. Transplant 2012 Wiebe. AJT 2012 Liefeldt. AJT 2012 Wiebe C. AJT 2012;12: 1157–1167

15. Screening for subclinical TCMR/AMR Surveillance biopsies In which patients? When? How often? Non-invasive rejection biomarkers to tailor surveillance allograft biopsy frequency to the individual needs of every patient.

16. De novo DSA as a non-invasive biomarker for subclinical AMR Not useful <1 year post-transplant (low prevalence) Annually beyond the 1st year. Restricted to patients at risk? Detection of de novo DSA should be followed by a biopsy Treatment options for chronic active AMR are very limited Prevention of development of de novo DSA is important: - Screen for and treat subclinical TCMR - Do not minimize IS in patients with repeated TCMR - Reinforce drug adherence and improve DR/DQ-matching

17. Urinary CXCL10 chemokine as a biomarker for subclinical TCMR CXCL10 CXCL10 CXCL10 CXCL10 Jackson JA, AJT 2011 Ho J, Transplantation 2011 Schaub S, AJT 2009 Hu H. Transplantation 2009 Matz M, KI 2006 Hauser IA, JASN 2005 Hu H, AJT 2004 CXCL10

18. Demographic data – surveillance biopsies (n=362) Hirt-Minkowski P. AJT 2012

19. Urinary CXCL10 – subclinical pathologies p=0.07 p<0.0001 p<0.0001 p=0.004 ≥24 p=0.01 22 20 18 p=0.30 16 14 12 CXCL10/creat [ng/mmol] 10 8 6 4 2 0 Acute Banff score zero (n=206) Tubulitis t1 + any i/v/g/ptc (n=86) Isolated vascular compartment inflammation (n=12) Tubulitis t2-3 + any i/v/g/ptc (n=21) Interstitial infiltrates only (n=37) Urinary CXCL10 correlates with the extent of subclinical tubulo-interstitial inflammation Hirt-Minkowski P. AJT 2012

20. Urinary CXCL10 as a non-invasive biomarker Urinary CXCL10 correlated with the extent of clinical and subclinical tubulointersitital inflammation. Moderate sensitivity (61-63%) and specificity (72-80%) - Problem 1: tubulitis t1 (=borderline changes)  clinical relevance of tubulitis t1? - Problem 2: Urinary CXCL10 does not reflect vascular compartment inflammation

21. Summary Current problems in kidney transplantation To adapt the immunosuppression to the individual needs of every patient - Surveillance biopsies - Non-invasive biomarker to guide performance of surveillance biopsies To accept the facts, that… - allograft recipients are getting older… - organ donors are getting older… - the deceased donor pool will not match the demand of the ever increasing waiting list…

22. Acknowledgement Transplant Immunology and Nephrology Transplantation and Nephrology Winnipeg, Canada Gideon Hönger Patrizia Amico Patricia Hirt-Minkowski Felix Burkhalter Michael Dickenmann Jürg Steiger Denise Bielmann Doris Lutz Claudia Petit Peter Nickerson David Rush Julie Ho Institute of Pathology Helmut Hopfer Michael Mihatsch