Current problems in kidney transplantation: Clinical point of view

Stefan SchaubTransplantation Immunology and Nephrology

University Hospital Basel, Switzerlandschaubs@uhbs.ch

Allograft loss

Recipient deathwith functioning

allograft

Allograftfailure

50% 50%

Age!!Cardiovascular

InfectionMalignancy

Why do renal allograft fail?

Adapted from El-Zoghby. AJT, 2008

Acute rejection12%

„Chronic“ rejection24%

IF-TA: other, specified causes

8%PyVAN

7%

CNI-toxicity1%

(Recurrent) GN22%

Medical, surgical16%

Unknown10%

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

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

HLA-antibodies as a surrogate for memory

Pregnancy Transfusion Transplant

Naive B-cellIgM positiv

Plasma cellIgG positiv

Naive T-cell

Memory T-cell

Tn

Tm

Bn

PC

TaActivated T-cell

IgG HLA-Ab

Luminex Multiplex technology

bead

A1 A2 A3

A25A24A11

B7 B8 B27

B62B52B51

Color-coded beads Flow cytometer

Data

Clinical relevance of HLA-DSAdetected by Luminex

Author Year N DSA+ AMR Graft survival

Patel 2007 60 20 ↑ =

Gupta 2008 121 16 ↓

Berg Loonen

2008 34 13 =

Aubert 2009 114 11 = =

Amico 2009 334 67 ↑ ↓

Wahrmann 2009 338 39 ↑ ↓

Vlad 2009 325 27 ↑ =

Lefaucheur 2010 402 76 ↑ ↓

Willicombe 2011 480 45 ↑ ↓

Caro-Oleas 2012 892 50 ↑ ↓

Otten 2012 837 290 ↓

DonorHLA

anti-HLA-antibodies

Complement

Plasma cell

B-cell

T-cell

2. Binding strength of HLA-DSA to the target epitope3. Capacity of HLA-DSA to activate complement

5. Protective factors and ‚absorptive capacity‘ of endothelial cells

1. Magnitude and durability of the humoral memory response

4. Density of HLA-molecule expression

Amico P. Curr Opin Organ Transplant 2009

Complex biology…

Organ allocation

HLA-antibodies No HLA-antibodies

Try to transplant around DSA - Acceptable mismatch program - Living donor exchange program

Transplantation around DSAnot achievable - Adapt immunosuppression!!

Proceed with transplant

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

Subclinical allograft pathologies

- Rejection (AMR, TCMR)

- CNI-toxicity

- Polyomavirus nephropathy

„Clinical“ pathologies

„Subclinical“pathologies

Serum creatinine thresholdNickerson P. JASN 1998Rush D. AJT, 2007Loupy A. AJT, 2009

Nankivell B. NEJM, 2003

Schaub S. AJT, 2010

Clinical relevance of subclinical “TCMR”

Park WD. JASN, 2010

Interstitial fibrosis with inflammation at one yearpredicts decline of allograft function

Natural history of de novo DSA and AMR

Wiebe C. AJT 2012;12: 1157–1167

Hourmant. JASN 2005Moreso. Transplant 2012Wiebe. AJT 2012Liefeldt. AJT 2012

Screening for subclinical TCMR/AMR

Non-invasive rejection biomarkersto tailor surveillance allograft biopsy frequency to the individual needs of

every patient.

In which patients?When?How often?

Surveillance biopsies

De novo DSA as a non-invasive biomarkerfor subclinical AMR

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

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

Urinary CXCL10 chemokine as a biomarkerfor subclinical TCMR

CXCL10CXCL10

CXCL10

CXCL10

CXCL10

Jackson JA, AJT 2011Ho J, Transplantation 2011Schaub S, AJT 2009Hu H. Transplantation 2009Matz M, KI 2006Hauser IA, JASN 2005Hu H, AJT 2004

Demographic data – surveillance biopsies (n=362)

Acute score zero

(n=206)

Interstitial infiltrates

only(n=37)

Tubulitis t1+ any

i/v/g/ptc(n=86)

Tubulitis t2-3

+ any i/v/g/ptc(n=21)

Isolated vascular

compartment inflammation

(n=12)

P-level

Acute Scores - i - t - v - g - ptc

00000

1.2±0.40000

1.2±0.61

0.1±0.30.2±0.40.2±0.5

2.0±0.72.2±0.40.2±0.5

00

0.3±0.50

0.6±0.50.3±0.50.3±0.5

<0.0001

eGFR 47 (39-58) 51 (45-59) 47 (37-58) 43 (31-57) 48 (36-58) 0.57

Proteinuria - Prot/creat - a1m/creat

13 (8-21)4 (2.5-8.1)

13 (10-24)6 (3.7-8.5)

14 (9-24)5 (3.0-7.6)

12 (8-19)6 (3.2-10.8)

12 (8-15)5 (1.8-5.4)

0.400.21

Hirt-Minkowski P. AJT 2012

Urinary CXCL10 – subclinical pathologies

02468

10121416182022

≥24

CXCL10/creat[ng/mmol]

Interstitialinfiltrates

only(n=37)

Tubulitis t1+ any i/v/g/ptc

(n=86)

Tubulitis t2-3+ any i/v/g/ptc

(n=21)

Acute Banffscore zero

(n=206)

Isolated vascular

compartmentinflammation

(n=12)

p=0.07p<0.0001p<0.0001p=0.004

p=0.30

p=0.01

Urinary CXCL10 correlates with the extent ofsubclinical tubulo-interstitial inflammation

Hirt-Minkowski P. AJT 2012

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

SummaryCurrent 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…

Acknowledgement

Gideon HöngerPatrizia AmicoPatricia Hirt-MinkowskiFelix BurkhalterMichael DickenmannJürg SteigerDenise BielmannDoris LutzClaudia Petit

Transplant Immunologyand Nephrology

Institute of Pathology

Transplantation and NephrologyWinnipeg, Canada

Peter NickersonDavid RushJulie Ho

Helmut HopferMichael Mihatsch