Mempersiapkan transplantasi ginjal (resipien dan donor) Dr. Atma Gunawan SpPD.KGH

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1 Mempersiapkan transplantasi ginjal (resipien dan donor) Dr. Atma Gunawan SpPD.KGH

2 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

3 ALUR KIDNEY TRANSPLANT 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

4 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

5 Histocompatibility test Blood typing Tissue typing : HLA-A,B,DR Panel reactive antibody (PRA) Donor specific antibody Crossmatch testing

6 Blood typing 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 European guideline for kidney transplant 2000

7 40% Oag anti A Ab anti B Ab 45% 10% Aag (A 1 ~36%, A 2 ~9%) Bag anti A ab anti B Ab AagBag no Ab 5% The likelihood that two unrelated individuals are: - identical is 37.5% - compatible is 26.75% - incompatible is 35.75% 7

8 HLA TYPING (DONOR) No Class Locus HLA 1 Class I HLA-A A*11/A*24 HLA-B HLA-C HLA TYPING (luminex) B*27/B*44 C*03/C*07 2 Class II HLA-DR DRB1*12/ DRB1*12 HLA-DQA HLA-DQB HLA-DPA HLA-DPB DQA1*05:01/ DQA1*06:01 DQB1*02/ DQB1*03 DPA1*01:03/ DPA1*02:02 DPB1*02:01/ DPB1*13:01 HLA TYPING (RESIPIENT) No Class Locus HLA HLA typing mismatched: 13/16 HLA typing matched: 3/16 (A*11, /B*44, DPA*01) 1 Class I HLA-A A*03/A*11 HLA-B HLA-C B*35/B*44 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 HLA-DPB DPA1*01/ DPA1*01 DPB1*04/ DPB1*04 8

9 cpra 19% ; PRA class I 19%; class II 0%

10 Why less missmatch is better?

11 Influence of HLA mismatches on the outcome of deceased donor kidney transplants Craig J. Taylor et al. Phil. Trans. R. Soc. B 2011;366: by The Royal Society

12 A single sensitizing event can lead to multiple donor specific antibodies (DSA) Recipient HLA-typing: A1,A3 B8, B52 Donor HLAtyping: A1,A2 B7,B8 HLA-A2 antibody + HLA-B7 antibody

13 Detection Donor specific antibodies (DSA) by luminex HLA ANTIBODY RESIPIEN (TSANIA, 14 TH) Class Antigen Alele MFI I B8 HLA-B*08: II DR4 DRB1*04: DR4 DRB1*04: DR16 DRB1*16: DR16 DRB1*16: DR52 DRB3*02: DP11 DPA1*02:02 DPB1*11: DONOR HLA-ANTIBODI NEGATIVE, VIRTUAL CROSS MATCH NEGATIVE HLA TYPING DONOR (SANTI, 50 TH) No Class Locus HLA 1 Class I HLA-A A*11/A*24 2 Class II HLA-B HLA-C HLA-DR HLA- DQA HLA- DQB B*27/B*44 C*03/C*07 DRB1*12/ DRB1*12 DQA1*05:01 / DQA1*06:01 DQB1*02/ DQB1*03 HLA-DPA DPA1*01:03/ DPA1*02:03 HLA- DPB DPB1*02:01/ DPB1*13:01 13

14 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 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 January ; 28(1): Kelley M et al. British Medical Bulletin, 2014, 110: 23 34

15 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: , First published: 16 February 2010, DOI: ( /j x)

16 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

17 Graft injury and clinical presentation after development of de novo donor specific antibody American Journal of Transplantation 2014; 14:

18 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

19 Cross-match Scenario Cross-match negative proceed to Transplant Cross-match positive Contraindication

20 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

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

22 AHG-CDC Hasil Tn. Mujianto (AHG-CDC XM positif)

23 Flow Cytometric crossmatch

24 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

25 Interpretation of Crossmatch (CDC) result T-Cell XM -ve +ve -ve +ve B-Cell XM -ve +ve +ve -ve Interpretation No DSAb to HLA class I or II OR DSAb titre too low to cause positive reaction OR (DSAb that is not complementfixing relevance unclear) DSAb/s to HLA class I OR Multiple DSAbs to HLA class I +/- II DSAb/s to HLA class II OR Low level DSAb/s to HLA class I Technical error (possibly related to B-cell viability). The test should be repeated

26 Positive T-cell crossmatch is likely to generate hyperacute rejection

27 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

28 Interpretation Flow cytometric Crossmatch Results 1. Positive T-cell flow crossmatch suggests that there 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 other antibodies 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

29 Immunological risks Clinical Guidelines for Kidney Transplantation 2015

30 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

31 Immunological Risk Low risk Criteria Low-risk patients (DSA negative/xm negative, history sensitization negative) 0-1 DR mismatchs PRA < 20% Theraphy 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

32 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 livingdonor 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 operatingroom or immediately posttransplant and day 4. May receive one dose of tacrolimus immediate release + mycophenolate mofetil prior to surgery Start Tacrolimus when renal function is established

33 Donor evaluation steps Interested 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

34 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

35 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)

36 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

37 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

38 Relative or absolute contraindications to live kidney donations Age < or > years Low GFR (<70 ml/min) Hypertension (BP >140/90 mmhg) or on antihypertensive medications BMI > DM or abnormal glucose tolerance test History of gestasional DM Malignacy Microalbuminuria Recurrent kidney stones Trasmissable serious infections (HIV, hepatitis C, hepatitis B)

39 Acceptable GFR by donor age prior to donation Donor age (years) Acceptable corrected GFR prior to donation (ml/min/1.73 m 2 ) Up to

40 Impact Of Donor Old Age On Renal Transplant Outcome American Journal of Transplantation 2011; 11:

41 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 the majority 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 for hypertension) and if this is normal (see below) donor nephrectomy is not precluded. (B1) The presence of mild-moderate hypertension that is controlled with 1-2 antihypertensive 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)

42 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 ( mg/24 h) a high risk for donation. (Ungraded statement)

43 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)

44 Wassalam