Mempersiapkan transplantasi ginjal (resipien dan donor)

Dr. Atma Gunawan SpPD.KGH

Who is recipient ?

• All patient ESRD • Absolute KI :

- Transplant candidate with cirrhosis - Active malignancy- Severe respiratory conditions - Severe Ischemic heart disease - Severe peripheral vascular disease - Severe cognitive impairment - Active drug or alcohol addiction - Patient non-adherence to therapy

Resipien memenuhi syarat

↓

Potential donor

↓

Edukasi dan aspek legal resipien dan donor

↓

Skreening awal resipien dan donor (gol darah, UL, kimia darah,virus

marker, kontraindikasi)

↓

Nephrologist team (skrening lanjutan) : ABO, HLA typing, CM, DSA, PRA,

CT angiografi Renal, MRI aortoiliaka

↓

Transplant team

↓

Approval, tanggal H0

↓

Final crossmatch dan evaluasi pre-operative

↓

Operation

↓

Follow up

ALUR KIDNEY TRANSPLANT

Skreening resipien

• Anamnesa

• Pemeriksaan fisik .

• Golongan darah, DL, UL,

LFT,elektrolit serum, gula darah,

profil lipid. Urine culture

• Serologi : hepatitis B dan C,

Syphilis, HIV, CMV, EBV,Herpes

• Radiologi : thoraks, BNO, USG

• Cardiologi : ECG, echo

• Dentis care , endoskopi

• MRI aortoiliaka resipien

• Crossmacth : CDC , luminex

(virtual CM) tes

• Tissue typing : HLA-A, B,C ;

DR,DP,DQ

• Mammografi ( >50 th), PRA (>45

th).

MRI aortoiliaca

Histocompatibility test

• Blood typing

• Tissue typing : HLA-A,B,DR

• Panel reactive antibody (PRA)

• Donor specific antibody

• Crossmatch testing

In cadaveric kidney transplantation,the donor should be ABO identical to

recipient, and ABO blood group compatiblity should be discouraged (level B).

In live donor kidney transplatation, ABO identity or compatibility are equally

accepted (level C)

Donor Resipient

A B AB O

A identical mismatched compatible mismatched

B mismatched identical compatible mismatched

AB mismatched mismatched identical mismatched

O compatible compatible compatible identical

Blood typing

European guideline for kidney transplant 2000

7

Oag

anti A Ab

anti B Ab

AagBag

no Ab

Aag

(A1 ~36%, A2 ~9%)

anti B Ab

Bag

anti A ab

40%

5%

45% 10%

The likelihood that two

unrelated individuals are:

- identical is 37.5%

- compatible is 26.75%

- incompatible is 35.75%

HLA TYPING (luminex)HLA TYPING (DONOR)

No Class Locus HLA

1 Class I HLA-A A*11/A*24

HLA-B B*27/B*44

HLA-C C*03/C*07

2 Class II HLA-DR DRB1*12/DRB1*12

HLA-DQA DQA1*05:01/DQA1*06:01

HLA-DQB DQB1*02/DQB1*03

HLA-DPA DPA1*01:03/DPA1*02:02

HLA-DPB DPB1*02:01/DPB1*13:01

HLA TYPING (RESIPIENT)

No Class Locus HLA

1 Class I HLA-A A*03/A*11

HLA-B B*35/B*44

HLA-C C*04/C*05

2 Class II HLA-DR DRB1*01/DRB1*08

HLA-DQA

DQA1*01/DQA1*04

HLA-DQB DQB1*04/DQB1*05

HLA-DPA DPA1*01/DPA1*01

HLA-DPB DPB1*04/DPB1*04

HLA typing mismatched: 13/16HLA typing matched: 3/16 (A*11, /B*44, DPA*01)

8

cPRA 19% ; PRA class I 19%; class II 0%

Why less missmatch is better ?

Influence of HLA mismatches on the outcome of deceased donor kidney transplants

Craig J. Taylor et al. Phil. Trans. R. Soc. B 2011;366:2312-2322

©2011 by The Royal Society

Donor HLA-

typing:

A1,A2

B7,B8

Recipient

HLA-typing:

A1,A3

B8, B52

+

HLA-A2 antibody

HLA-B7 antibody

A single sensitizing event can lead to

multiple donor specific antibodies (DSA)

Detection Donor specific antibodies (DSA) by luminex

HLA ANTIBODY RESIPIEN (TSANIA, 14 TH)

Class Antigen Alele MFI

I B8 HLA-B*08:01 735

II DR4 DRB1*04:01 360

DR4 DRB1*04:04 786

DR16 DRB1*16:01 881

DR16 DRB1*16:02 590

DR52 DRB3*02:02 350

DP11 DPA1*02:02DPB1*11:01

1065

HLA TYPING DONOR (SANTI, 50 TH)

13

No Class Locus HLA

1 Class I HLA-A A*11/A*24

HLA-B B*27/B*44

HLA-C C*03/C*07

2 Class II

HLA-DR DRB1*12/DRB1*12

HLA-DQA

DQA1*05:01/DQA1*06:01

HLA-DQB

DQB1*02/DQB1*03

HLA-DPA DPA1*01:03/DPA1*02:03

HLA-DPB

DPB1*02:01/DPB1*13:01

DONOR HLA-ANTIBODI NEGATIVE,

VIRTUAL CROSS MATCH NEGATIVE

Interpretation results of antibody detection assays

• These values can be further categorized into ranges of strength (i.e. strong, moderate or weak), or simply deemed as positive or negative.

• There is no consensus regarding positive cutoff values. Each transplant center currently sets its own MFI threshold for unacceptable antigens, with most centers selecting an MFI cutoff between 3000–5000. CTOT study, point to a positive cut off >1000 MFI for SPA data

• There is not an accepted cutoff for mean fluorescence index (MFI) of anti-HLA class I and class II antibodies detected by the SAB assays that has been validated to have clinical immunological relevance.

Peter S et al. Clin Transplant . 2014 January ; 28(1): 127–133Kelley M et al. British Medical Bulletin , 2014, 110: 23–34

Baseline Donor‐Specific Antibody Levels and Outcomes in Positive Crossmatch Kidney Transplantation

Baseline Donor‐Specific Antibody Levels and Outcomes in Positive Crossmatch Kidney Transplantation, Volume: 10, Issue: 3, Pages: 582-589, First published: 16 February

2010, DOI: (10.1111/j.1600-6143.2009.02985.x)

Interpretation results of antibody detection assays

• There is insufficient data to determine the meaning of a DSAb with a negative flow crossmatch

• The presence of a DSAb detected by Luminex in the setting of a negative CDC crossmatch appears to have inferior graft survival compared with no DSAb

• Recipients with third party anti-HLA Abs (antibodies against HLA antigens that are not donor-specific) have reduced graft survival compared with recipients without any anti-HLA antibodies

Graft injury and clinical presentationafter development of de novo donor specific antibody

American Journal of Transplantation 2014; 14: 255–271

Probability of graft loss within 3 years after de novo donor specific- human leukocyte antigens antibodies

appearance..

DSA:Donorspecific- human leukocyte antigens antibodies

World J Transplant 2014 March 24; 4(1): 1-17

Cross-match Scenario

• Cross-match negative → proceed to Transplant

• Cross-match positive → Contraindication

Method for crossmatching

1. Basic CDC (complement dependent cytotoxity crossmatch)

2. Isolated T and B cells CDC XM

3. AHG-CDC

4. DTT-CDC

5. Flow cytometry CM

6. Virtual crossmatch

Basic CDC

• First generation• Unable to distinguish between donor T cell and B cell populations • Unable to differentiate IgG from IgM• Low accuracy

AHG-CDC

Hasil Tn. Mujianto (AHG-CDC XM positif)

Flow Cytometric crossmatch

Flow cytometry XM (Tsania,14 th)

Sel T Sel B

Kontrol negatif(MCF 10,38)

Kontrol positif(MCF 20,93)

Donor resipien(MCF 11,19)

Kontrol negatif(MCF 33,38)

Kontrol positif(MCF 53,91)

Donor resipien(MCF 35,38

Interpretation of Crossmatch (CDC) result

T-CellXM

B-CellXM

Interpretation

-ve

+ve

-ve

+ve

-ve

+ve

+ve

-ve

No DSAb to HLA class I or II ORDSAb titre too low to cause positive reaction OR(DSAb that is not complement-fixing – relevance unclear)

DSAb/s to HLA class I ORMultiple DSAbs to HLA class I +/- II

DSAb/s to HLA class II ORLow level DSAb/s to HLA class I

Technical error (possibly related to B-cell viability).The test should be repeated

Positive T-cell crossmatch is likely togenerate hyperacute rejection

The relevance of a positive B-cell CDC crossmatch

• B-cell CDC crossmatching is not as predictive of HAR as the T-cell CDC crossmatch

• The major limitation is a rate of false positive results of up to 50%.• Antibodies to class II antigens are of less significance in generating

antibody-mediated rejection• B-cell CM + should be paired with Solid-Phase Immunoassays (ex

Luminex) to reveal presence of DSAbs• If a B-cell crossmatch is positive and there are no detectable

antibodies to class I or II antigens, the result may be falsely positive• If a positive result in the presence of detectable DSAbs signifies that

the identified DSAb may be functionally relevant in that it can activate complement

Interpretation Flow cytometric Crossmatch Results

1. Positive T-cell flow crossmatch suggests thatthere is a DSAb to a class I antigen

2. Positive B-cell crossmatch may be due to the same class I Ab or due to that and otherantibodies directed against either class I or II.

3. In case CDC XM T & B cell negative but Flow XM cell T&B positive :

- There is a low-level DSAb (or several antibodies)- There is/are one or more DSAb that are not

complement fixing- There is non-HLA antibody

Immunological risks

Clinical Guidelines for Kidney Transplantation 2015

Transplantation risk stratification

Transplantation risk stratification categories should be developed based on antibody identification and XM results

1. Very high risk patients (DSA positive/XM positive)2. High-risk patients (DSA positive/XM negative)3. Intermediate-risk patients: Includes history of

sensitization to donor antigen(s) by CDC and SPI but currently negative and history of sensitization with at least one positive test for HLA antibodies.

4. Low-risk patients (DSA negative/XM negative, history sensitization negative)

Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation

Transplantation & Volume 95, Number 1, January 15, 2013

Immunological

Risk

Criteria Theraphy

Low risk Low-risk patients (DSA negative/XM

negative, history sensitization negative)

0-1 DR mismatchs

PRA < 20%

Initial therapy: IL-2 receptor

blocker (basiliximab), a

calcineurin inhibitor,

mycophenolate

mofetil,steroids. Then a rapid

steroid elimination protocol

No basiliximab for identical

HLA match

Intermediate Risk Intermediate-risk patients :(DSA

negative/XM negative, history

sensitization positive : history of

sensitization to donor antigen(s) by CDC

and SPI but currently negative and

history of sensitization with at least one

positive test for HLA antibodies

PRA 20% - 80%

Quadriple therapy : IL-2

receptor blocker (basiliximab),

a calcineurin inhibitor ,

prednisone, and

mycophenolate mofetil (MMF)

High Risk Second transplant (1 or more rejection

within the first year post transplantation)

Any recipients PRA > 80%

DSA positive/XM negative

2 DR mismatch, 6 HLA mismatch

Quadriple therapy consisting

of an anti-thymocyte globulin

(Thymoglobulin®), a

calcineurin inhibitor ,

prednisone, and MMF

Immunological risk Criteria Theraphy

Sensitized patient DSA positive/XM positive IVIG ± rituximab ±

plasmapheresis or

immunoadsorption ±

induction with T-cell

depleting antibody

Sensitized patient ABO incompatible living-

donor transplants

Rituximab ± IVIG ±

plasmapheresis or

immunoadsorption

High Donor Risk Donors at high risk for

delayed graft function

Donor age greater than 60

years, acute kidney injury

and prolonged cold

ischemic time

Anti- thymocyte globulin 1.0

to 1.5 mg/kg begin as soon

as possible in operating-

room or immediately post-

transplant and day 4.

May receive one dose of

tacrolimus immediate

release + mycophenolate

mofetil prior to surgery

Start Tacrolimus when renal

function is established

Donor evaluation stepsInterested Donor

ABO Blood Type Compatible

HLA (Tissue Type) Compatibility

Full Nephrology Review Including Blood and X-Ray Test

Phsycology Review and legal aspect

CT angiography renal

Surgical Review

Final Cross Match

PROCEED TO TRANSPLANTATION

Medical Examination

Anamnesis

• Haematuria/proteinuria/urinary tract infection

• Gout, Nephrolithiasis

• Diabetes mellitus, including family history

• Hypertension, Ischaemic heart disease/peripheral vascular disease

• Weight change, Change in bowel habit

• Previous malignancy, Previous jaundice

• Systemic disease which may involve the kidney

• History transmissible infection

• Smoking, Current or prior alcohol or drug dependence

• Psychiatric history, sexual behaviour

• Obstetric history

• Results of national screening programme tests e.g. cervical smear, mammography,colorectal screening

Physical examanation

• Blood pressure measurement• Body mass index• Abdominal fat distribution• Examination of the cardiovascular

and respiratory systems• Examination for abdominal masses

or herniae• Examination for scars or previous

surgery• Examination for lymphadenopathy• Examination / history of regular

self-examination of the breasts• Examination / history of regular

self-examination of the testes

Laboratory screening for the potential donor

Blood • Haemoglobin and blood count

• Coagulation screen (PT and APTT)

• Creatinine, urea and electrolytes

• Measurement of GFR

• Liver function tests

• Bone profile (calcium, phosphate, albumin and alkaline phosphatase)

• Urate

• Fasting plasma glucose

• Glucose tolerance test (if family history of diabetes or fasting plasma glucose >5.6 mmol/l)

• Lipid profile

• Thyroid function tests (if strong family history)

• Pregnancy test (if indicated)

Urine

• Urinalysis (protein, blood and glucose ) at least twice)

• Microscopy, culture and sensitivity (at least twice)

• Measurement of protein excretion rate (ACR or PCR)

Additional screening

Virology and infection screen

• Hepatitis B and C

• HIV

• Cytomegalovirus

• Epstein-Barr virus

• Toxoplasma

• Syphilis

• Varicella zoster virus (where recipient seronegative)

• HTLV1 and 2 (if appropriate)

• HHV8 (where indicated)

• Malaria (where indicated)

• Trypanosoma cruzi (where indicated)

• Schistosomiasis (where indicated)

Imaging, psychosocial, cancer• Chest X-Ray and

Electrocardiogram (EKG)• Radiologic Testing: USG

urology, CT renal angiography ,IVP, MRI, and arteriogram

• Psychosocial and/or psychological evaluation

• Gynecological screening for female

• Cancer screening: may include a colonoscopy, mammogram, prostate exam, and skin cancer screening

CT renal angioraphy

Surgical Imaging aims :

- To choose the kidney

with single artery,

more lengthy artery,

absent pelvi-calyceal

and vessels anomalies,

lower split function

Relative or absolute contraindications to live kidney donations

• Age < 18-25 or > 70-75 years• Low GFR (<70 ml/min)• Hypertension (BP >140/90 mmHg) or on antihypertensive

medications• BMI > 30-35• DM or abnormal glucose tolerance test• History of gestasional DM• Malignacy• Microalbuminuria• Recurrent kidney stones• Trasmissable serious infections (HIV, hepatitis C, hepatitis B)

Acceptable GFR by donor age prior to donation www.bts.org

Donor age (years)

Acceptable corrected GFR

prior to donation

(ml/min/1.73 m2)

Up to 46 80

50 77

60 68

70 59

80 50

Impact Of Donor Old Age On Renal Transplant Outcome

American Journal of Transplantation 2011; 11: 1279–1286

HYPERTENSION IN THE DONOR

• Potential donors with blood pressure <140/90 mmHg should be considered as normotensive and therefore suitable for nephrectomy on the basis of blood pressure. (B1)

• Potential donors with ‘high normal’ blood pressure (>130/85 mmHg) should be warned about the greater future risk of developing hypertension and associated cardiovascular events (B1)

• Office blood pressure measurements are sufficient for the assessment of themajority of potential donors. Ambulatory blood pressure monitoring should be considered for potential donors who have hypertension (blood pressure greater than 140/90 mmHg or who are taking pharmacological treatment forhypertension) and if this is normal (see below) donor nephrectomy is notprecluded. (B1)

• The presence of mild-moderate hypertension that is controlled with 1-2antihypertensive agents is not a contraindication to kidney donation providing significant end organ damage has been excluded. (B1)

• Evidence of hypertensive end organ damage, poorly controlled hypertension, or hypertension that requires more than two drugs to achieve adequate control are relative contraindications to donor nephrectomy. (C2)

PROTEINURIA (ERBP 2013)

• We recommend quantifying urinary protein excretion in all potential living donors. (1C)

• We recommend overt proteinuria is a contraindication for living donation [24-h total protein >300 mg or spot urinary albumin to creatinine (mg/g) ratio >300 (>30 mg/mmol)]. (1C)

• We recommend further evaluating potential living donors with persistent (more than three measurements with 3 months interval) proteinuria <300 mg/24 h by the quantification of microalbuminuria to assess their risk of living donation. (Ungraded statement)

• We suggest considering persistent (more than three measurements with 3 months interval) micro-albuminuria (30– 300 mg/24 h) a high risk for donation. (Ungraded statement)

Hematuria (ERBP 2013)

• We recommend considering persistent haematuria of glomerular origin as a contraindication to living donation, because it may indicate kidney disease in the donor. (1B)

• Two or more positive tests, including trace positive, should be considered as persistent non-visible haematuria (PNVH). (B1)

• However, we acknowledge thin basement membrane disease might be an exception. (Ungraded statement)

Wassalam