Renal Transplantation

Terence Kee MBBS, MRCP, FAMS Consultant transplant nephrologist Renal transplant programme Singapore General Hospital

Objectives • • • • • • • • • • • • •

History of renal transplantation. Current status of renal transplantation in Singapore. Advantages and disadvantages of renal transplantation (RTX). Recipient evaluation. Deceased and living kidney donor evaluation. Histocompatibility testing. Immunobiology of RTX. Overview of drugs used for immunosuppression. (separate slides for self-study). Peri-transplant management. Transplant surgery. Surgical complications of RTX. Medical complications of RTX. Long term management of RTX.

History of renal transplantation

First animal kidney transplant Emerich Ulmann Vienna

First human kidney transplant using animal kidneys Mathieu Jaboulay Lyon

First human kidney transplant using human kidneys

Transplantation Immunology and use of nonchemical immunosuppression Sir Peter Medawar UK

Yu Yu Voronoy Ukraine

1902

1906

1933

1950s

First successful identical twin transplant Joseph Murray Boston

1954

History of renal transplantation

Chemical immunosuppression with 6-MP and the subsequent development of azathioprine

Use of tissue matching and acceptance of brain death criteria

Sir Roy Calne

Paul Terasaki

1960s

1970s

Introduction of cyclosporine and antilymphocyte serum

1980s

The era of modern immunosuppression

1990s onwards

History of renal transplantation in Singapore Human Organ Transplant Act Interpretation Act 1988

2000s 1990s

1980s

First living donor (unrelated) RTX 1991

1970 First deceased donor RTX 1970 Medical Therapy, Education and Research Act 1973 First living donor (related) RTX 1976

Human Organ Transplant Act Amendment 2004

Renal transplantation in Singapore Deceased donor Living donor

60 54

53

50

53

52

46 46 44

44

44

43

42

40 34 32 30

30

26

25

20

30

18

26

18 14

11

10 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

http://www.moh.com.sg

Renal transplantation in Singapore 800

Patients waiting for a renal transplant

700

639 607

600

553

574

650

666

673

661 625 557

500 400 300 200 100 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

http://www.moh.com.sg

Treatment options for end-stage renal failure

Kidney transplantation

Peritoneal dialysis

End stage kidney failure

Hemodialysis

Palliative care

Benefits of renal transplantation

Prolong life

Improve quality of life

Costeffective

Survival advantage of renal transplantation

Renal replacement therapy

1 year survival

5 year survival

Hemodialysis1

92%

65%

Peritoneal dialysis1

79%

27%

Living donor transplant2

99%

97%

Deceased donor Transplant2

97%

93%

1Singapore

renal registry 1999/2000 2 SGH renal transplant programme

Demographics of ESRD patients on dialysis or with RTX

Parameter

Dialysis

Transplant

Mean age, years

54.5 (38.3%≥ 60)

46.1

Diabetes mellitus

37.5%

23.2%

Ischemic heart disease

31.5%

10.2%

Cerebrovascular disease

11.4%

2.6%

Peripheral vascular disease

8.2%

1.7%

Causes of dialysis deaths

Cardiac events 29.3% Infection 23.2% Cerebrovascular disease 9.1%

1Data

refers to the prevalent population; Singapore renal registry 1999/2000

Renal transplantation is life-prolonging therapy

Wolfe RA, et al. N Eng J Med 1999;341:1725

Economic advantages of renal transplantation

Renal replacement therapy

Average annual costs

Hemodialysis

$42,000

Peritoneal dialysis

$35,000

Renal transplantation

$20,000

Includes costs of dialysis, medications, hospitalisation and consultation fees

Graft and Patient Survivals in Renal Transplant Recipients: SGH Modern era Of Immunosuppression Deceased Donor, n = 637

100

90

PERCENT SURVIVAL

90

PERCENT SURVIVAL

Living Donor, n =192

100

80

70

60

50

40

1yr 87.3% 97.1%

Graft Patient

80

70

60

50

40

5yr 10yr 79.5% 65.2% 92.8% 84.9%

Graft Patient

1yr 96.8% 98.9%

5yr 10yr 92.2% 81.8% 97.5% 95.1%

6

10

30

30 0

2

4

6

8

10 12 14 16 18 20 22

0

2

4

8

12

14

16

18

20

YEARS POST TRANSPLANT YEARS POST TRANSPLANT 1 Jan 2006,*Uncensored Courtesy of A/Professor Vathsala, Director of renal transplantation, SGH

Indications for kidney transplantation

• Irreversible and progressive (over 6-12m) chronic kidney disease. • Ideally before dialysis is initiated with GFR  20 ml/min (i.e preemptive transplantation). • Otherwise, as soon as stablilzed on dialysis. • No absolute contraindications to transplantation. Goldfarb-Rumyantzev A, et al. Nephrol Dial Transplant 2005;20: 167-175

Clinical phases of renal transplantation

1. Identification of the suitable recipient 2. Identification of the suitable donor

3. Tissue matching 4. Transplant surgery 5. Post-transplant care

Renal transplant candidate evaluation process Intial assessment for RTX

NO

Still a candidate ? YES

YES

Potential barrier ?

Evaluate

NO

NO YES

Proceed with evaluation

Barrier removed ?

Dialysis

Recipient evaluation

ESRD

Age

Nutritional status

Peripheral vascular assessment

No severe or active pulmonary disease

Bld group and HLA typing

Lifespan assessment

Cerebrovascular risks

No significant liver disease

Psychosocial assessment

Cardiac risks

Inactive systemic disease

Stable hematological condition

BMI assesment

Risks of recurrent renal disease

Infection risks

Wait out for cancer

No active gastrointestinal disease

Genitourinary assessment

Recipient evaluation Cardiovascular • • • • •

Assess risk factors Low risk: ECG High risk: Echocardiogram, stress testing, angiogram Revascularization if indicated Periodic revaluation if on the wait-list

Infections • • • •

Vaccinations No active bacterial or fungal infections No HIV Treat active HBV and HCV infections (must be HBV DNA and HCV RNA –ve)

Malignancy • Screen for malignancy as per general population • US and -fetoprotein surveillance for HBV and HCV • US native kidneys to r/o renal cell carcinoma

Recipient evaluation Pulmonary • CXR • Stop smoking • Referral to respiratory physician for pulmonary function testing of patients with suspected or known lung disease

Hepatobiliary and gastrointestinal • • • •

Baseline liver function tests and US Baseline Ba meal or upper GI endoscopy Exclusion of patients with cirrhosis Counselling of patients with gallstones and diverticular disease

Cerebrovascular and peripheral vascular disease • Carotid US snd neurologist assessment for patients with a past history of CVA and TIA • CTA for PCKD patients with past history of SAH or family history of intracranial aneurysms • Doppler screening for patients with history of PVD

Recipient evaluation Urological • • • •

Urodynamic studies to r/o neurogenic bladder Voiding cystourethrogram to r/o reflux Prostate examination ± PSA / biopsy in male recipients Pretransplant nephrectomy as indicated

Co-morbid conditions • Wait-out period for past history of cancer • Diabetics must have normal coronary angiogram • Inactive systemic disease e.g no clinical or laboratory evidence of active SLE; PRED dose must be  10 mg/d

Immunological risk assessment • • • •

ABO and HLA typing Panel reactive antibody (PRA) Cross-matching between recipient and donor Identification of anti-HLA antibodies if cross-match positive

Human leukocyte antigen

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/Transplants.html

Molecular HLA typing

http://www.bioinformatics

Human leukocyte antigen and its role in rejection Direct allorecognition Donor APC

HLA TCR

+

CD4 T cell

B cell

Indirect allorecognition Recipient APC Lymph node Donor peptide

Allograft cells

Antibodies

CD4 T cell

+

CD8 T cell

Complement

The importance of HLA matching

Terasaki PI, et al. N Eng J Med 1995; 333:333-336

Rejection

http://library.med.utah.edu

Rejection • Definition: Acute or subacute deterioration in allograft function associated with specific pathologic changes seen on biopsy

• Clinical diagnosis:  Incidence of rejection depends on intensity of immunosuppression  Can be early ( 60d) or late (>60d)  Classification is based on histological features e.g Banff system – tubulointerstitial, vascular or antibody mediated  May be subclinical (detected on protocol biopsies only)  Clinical symptoms and signs include reduced urine output, pain over the allograft, increased blood pressure, rising serum creatinine

• Negative impact of rejection:  Decreased allograft survival  Risks of infections and malignancy  Increased health-care costs

Rejection • Causes of rejection:    

Inadequate dosing of immunosuppressive drugs Overzealous weaning of immunosuppressive drugs Patient’s non-compliance Concurrent use of drugs that promote cytochrome P450 metabolism

• Treatment:  Increase baseline immunosuppression e.g increase dose or switch to more potent agents (CsA→TAC, AZA→MPA)  Pulse corticosteroids  Anti-T cell antibody e.g thymoglobulin, OKT3  Anti-B cell antibody e.g rituximab  Anti-T and B cell antibody e.g alemtuzumab (Campath-1H)  Intravenous immune globulin  Plasmaphresis

Pathogenetic antibodies in antibody mediated rejection • Anti-ABO  Anti-blood group A  Anti-blood group B

• Anti-major histocompatibility antigens  Anti-Class I HLA  Anti-Class II HLA

• Non-ABO, Non-HLA  Anti-minor histocompatibility antigens e.g MICA or MHC-class I-polypeptide-related sequence A  Anti-self proteins e.g angiotensin II type 1 receptor

Mixed acute cellular and antibody mediated rejection

Nickeleit V, et al. Kidney Int 2007; 71:7-11

Target donor cell-based detection of HLA antibody • Complement-dependent cytotoxic (CDC) assay

DTT

DTT treated XM +ve

T or B cell HLA antigen Recipient Ab DTT treated XM -ve

AHG Complement Colour reagent Lysed recipient IgM

Screening for anti-HLA antibodies

Newstead CG, et al. Chapter 91. Comprehensive Clinical Nephrology 3rd Edition

Target-donor cell based detection of HLA antibody Donor lymphocyte Recipient anti-HLA Ab Colored antihuman Ig

LASER

Target donor cell-based flow cytometry crossmatch

Types of kidney donors

Kidney donors

Deceased

Non-heart beating

Heart beating

Living

Related

Unrelated

Evaluation process for living kidney donor transplantation

Potential Live Donor

Medical history Establish relationship Social history

Step 1 Tests: ABO compatible Cytotoxic crossmatch (-) HLA Typing* Renal function tests Hep B, C, HIV (-)

Step 3 Tests: CT Angiogram Step 2 Tests: Full blood count Liver function tests Fasting Glucose,HbA1c Calcium, Uric acid Anti Nuclear Factor etc ECG, CXR

Psychiatric Review

Social Review Ethics Committee Approval Transplant

Criteria for LIVING kidney donor • • • • • • • • • • • • • •

Age ≥ 21 yrs Valid informed consent (educated and understands information) Voluntary decision; No coercion Ambulatory BP < 140/90 mmHg ( > 50 yr old donor with controlled BP, GFR > 80 ml/min and urinary albumin < 30 mg/d may be accepted for donation) CCT or GFR > 80ml/min 24h TUP < 150 mg/d Normal UFEME No diabetes No cardiovascular disease No significant lung disease No malignancy Normal LFT HBsAg, anti-HCV Ab, HIV –ve ANA and anti-dsDNA -ve

Adapted from the Amsterdam forum on the care of live kidney donor; Transplantation 2005; 79:S53-S66

Criteria for LIVING kidney donor • Asymptomatic stone formers with     

No hypercalciuria, hyperuricemia or metabolic acidosis No cystinuria or hyperoxaluria No urinary tract infections No evidence of multiple stones or nephrosclerosis on CT Any existing stone is < 1.5 cm or potentially removable during transplant

• Surgical acceptance of renal anatomy and vasculature on CTA

Adapted from the Amsterdam forum on the care of live kidney donor; Transplantation 2005; 79:S53-S66

Laparoscopic donor kidney nephrectomy (LDN)

http://www.surgery.usc.edu

Laparoscopic donor nephrectomy (LDN) • 10 hand assisted LDN • Mean operating time: 163.5 ± 32 minutes • Mean warm ischemia time: 2.16 ± 0.72 minutes • No conversion to open nephrectomy • No requirement for blood transfusion • Normal diet by 1.8 ± 0.8 days • Opioid analgesia up to 48 hrs • Ambulation by 2.1 ± 0.9 days • Discharge by 4 ± 1.5 days Chiong E, et al. Ann Acad Med Singapore 2004; 33: 294-297

Criteria for DECEASED kidney donor • Age 21-60 years if Singaporean citizen or PR, not opted out of HOTA and not a muslim or of unsound mind OR age 18 years and above if an organ pledger under MTERA • -ve HBsAg, -ve anti-HBcIgM (but total anti-HBc permitted) • -ve anti-HCV • -ve HIV • -ve VDRL • -ve Dengue PCR • No history of malignancy except certain brain tumors and skin cancers • No untreated, active bacterial infection • No active viral or fungal infection • No high-risk behaviour e.g IV drug abuse, commerical sex, malemale sexual intercourse, genital or perianal warts • No intrinsic renal disease (donors with HTN and DM permitted) Singapore Ministry of Health criteria

Criteria for receiving a DECEASED donor kidney • • • • • • • • • • • •

Age < 60 yrs No ischemic heart disease including EF < 50% No cerebrovascular disease No peripheral vascular disease No active liver disease in the last 6 months (implies also no cirrhosis) No history of malignancy regardless of time after diagnosis and treatment of malignancy No tuberculosis in the last 6 months No active psychiatric disorder HBsAg ±ve but HBeAg –ve and/or HBV DNA –ve Anti-HCV –ve and/or HCV RNA -ve HIV –ve Disease-specific requirements (DM, SLE) Singapore Ministry of Health criteria

Storage of kidneys after recovery

Static cold storage

Pulsatile machine perfusion

Halloran PF, et al. N Eng J Med 2004; 351:2715-2719

PRE-transplant phases Brain death certification ICU physician refers for organ donation and maintain donor stability

Referral to NOTU transplant coordinator Counselling, check for HOTA / METRA suitability, donor assessment tests, activate transplant team

Assessment by transplant team on donor organ suitability Identification of suitable organs, obtain clearance for recovery

Donor organ recovery Activate hospital transplant coordinator

Recipient selection and preparation

Implantation surgery

http://www.surgeryencyclopedia.com

POST-transplant phases Operating theatre

Recovery room Anaethetist Surgeon

Assessment of RTX perfusion by radionuclide study or doppler ulrasonography Radiologist

Transfer to high-dependency surgical ward Surgeon and physician

Transfer to general medical ward Physician

Discharge

Postoperative phase day 0 • Airway and breathing – Respiratory rate, depth and symmetry, pulse oximetry, stridor, wheeze, crepitations

• Circulation – Blood pressure, heart rate, rhythm (palpation and telemetry), JVP, skin colour, capillary refill, venous distension, skin turgor, skin temperature, CVP reading

• Vascular access – Extravasation, flow rate, flash-back, CVP position on CXR, bruit and thrill of AVF/AVG

• Wound dressing and surgical drain – Dressing seepage – Position, volume and content of drainage since OT

• Urinary catheter – Free flow, leakage, suprapubic or urethral pain, urine output (ideally > 30 ml/hr)

Postoperative phase day 0 • Blood investigations – Electrolytes, glucose, creatinine. calcium, phosphate, magnesium, full blood count

• Immunosuppression as per insitution’s protocol / physician • IV fluids – Gelofundin or SPPS if hypovolemic i.e CVP < 10, SBP < 100 mmHg, urine output < 30 ml/hr – ml to ml replacement of hourly urine output ± 15 ml with ½ NS (to a maximum of 500 ml/hr)

• IV dopamine 2.5 µg/kg/min if urine output < 50 ml/hr • Dialysis – Depends on fluid status, urine output and electrolytes

• Hypertension – Treat if systolic BP ≥ 180 mmHg ± diastolic BP ≥ 100 mmHg – Calcium channel blocker if can take orally – IV labetalol 5 mg; repeat every 5-10 mins till HR < 60 or 300 mg given if cannot take orally or systolic BP ≥ 200 mmHg

Postoperative phase day 0 • Pain control – – – –

Simple analgesia usually suffice. Investigate severe pain Percaution with opioids Avoid NSAIDs and COX-2 inhibitors

• Glucose control in diabetics – IV insulin infusion or SC insulin

• Monitoring – Hourly BP, HR, RR, Pulse oximetry, CVP, urine output

• Subsequent day orders – Follow protocol of insitution but generally includes:  Electrolytes, glucose, creatinine  Calcium, phosphate, magnesium (if polyuric > 500 ml/hr)  Full blood count ± CD cell subset count if on thymoglobulin  Immunosuppressive drug levels

Urological complications at SGH (7.7% incidence)

1Shum

CF, et al. Singapore Med J 2006; 47: 388-391

Common surgical complications (5-10% incidence) Complication

Cause

Diagnosis

Treatment

Renal artery thrombosis

Intimal dissection, kinking, torsion, rejection, hypercoagulability, tight renal artery stenosis

Anuria Perfusion scan or colour flow doppler

Reop for main vessel thrombectomy; Nothing for segmental vessels

Renal vein thrombosis

Angulation/kinking, external compression, stenosis, hypercoagulablity

Tender swollen graft, hematuria, colour flow doppler

Reop with thrombectomy

Hematoma

Bleeding from graft hilum or retroperitoneum

Clinical US or CT

Transfusion; Reop

HTN, renal dysfunction, peripheral edema

Angioplasty; surgery

Asymptomatic, hematuria, graft dysfunction

Monitor; embolization

Renal artery stenosis

Arteriovenous fistulas

Donor artery trauma, improper suturing, atherosclerosis

Renal biopsy

1Humar

A, et al. Seminars in dialysis 2005; 18: 505-510

Common surgical complications (5-10% incidence) Complication

Cause

Diagnosis

Treatment

Urine leak

Ischemia of the ureter, undue tension from a short ureter, direct surgical trauma to ureter

Fever, pain, swelling, increased Cr, reduced urine output, cutaneous urinary drainage, fluid Cr higher than serum Cr, radionuclide scan

Ureteric stent, drainage; reop with ureteric reimplantation

Obstruction

Edema, blood clots, hematoma, kinking

Elevated Cr, US, frusemide renogram

PCN, PTD, ureteric stent; ureteric reimplantation or bypass

Hematuria

Bleeding from anastomotic site or distal tip of ureter

Hematuria, blood clots, obstruction

Continuous bladder irrigation; cystoscopy

Leakage from cut lymphatic vessels

Asymptomatic, external compression, fluid Cr same as serum Cr, US or CT

Monitoring; percutaneous or surgical drainage and peritoneal window

Lymphocele

1Humar

A, et al. Seminars in dialysis 2005; 18: 505-510

Common medical complications Post-operative

Long-term

Ischemic heart disease

Cardiovascular disease

Delayed graft function

Infections

Pulmonary edema

Malignancy

Rejection

Rejection

Infection(s)

Tubular atrophy/interstitial fibrosis

Hypertension

Recurrent or de novo renal disease

Gastrointestinal bleeding

Diabetes mellitus

Cytopenias

Hypertension

Hemolytic uremic syndrome

Hyperlipidemia

Hepatitis

Hyperuricemia and gout

Drug toxicity e.g Nephrotoxicity from CNI Leukopenia from MPA

Osteporosis, osteonecrosis Anemia or polycynthemia Cataracts

Long-term management of RTX • Control cardiovascular risk factors     

• • • • • •

Hypertension Diabetes mellitus Obesity Hyperlipidemia Smoking

Prevent and treat infections Prevent and treat malignancy Monitor for recurrent / de-novo glomerulonephritis Treat anemia Prevent and treat post-transplant bone disease Adjust immunosuppressive therapy  Avoid over or under-immunosuppression  Adjust in response to drug toxicity and changes in RTX function

• Ensure compliance to treatment and continual education

Alternative career to nursing: Transplant coordinator

[email protected]