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 First human First Transplantation First

kidney kidney human Immunology and use successful
transplant transplant kidney identical
of nonchemical
using animal transplant
kidneys immunosuppression twin
using
Emerich Ulmann
human transplant
Vienna Mathieu Jaboulay
Lyon kidneys Sir Peter Medawar
UK Joseph Murray
Yu Yu Voronoy Boston
Ukraine

1902 1906 1933 1950s 1954

 History of renal transplantation

Chemical Use of tissue Introduction

immunosuppression with matching and of
6-MP and the acceptance cyclosporine
of brain death and anti- The era of modern
subsequent immunosuppression
development of criteria lymphocyte
azathioprine serum

Sir Roy Calne Paul Terasaki

1960s 1970s 1980s 1990s onwards

 History of renal transplantation in Singapore

Human Organ Human Organ

Transplant Act Transplant Act
Interpretation Act Amendment
1988 2000s 2004

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
 Renal transplantation in Singapore

60 Deceased donor
53
54 Living donor 53
52

50
46 46
44 44 44
43
42

40
34
32
30 30
30
26 26
25

20 18 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
700 650
666 673 661
639 625
607
600 553
574
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
Cost-
quality of
effective
life
Survival advantage of renal transplantation

Renal replacement 1 year 5 year

therapy survival survival
Hemodialysis1 92% 65%
Peritoneal dialysis1 79% 27%
Living donor
99% 97%
transplant2
Deceased donor
97% 93%
Transplant2

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%

1Datarefers 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

Living Donor, n =192
100

90 90
PERCENT SURVIVAL

PERCENT SURVIVAL
80 80

70 70

60 60

50 50

40 1yr 5yr 10yr 40 1yr 5yr 10yr

Graft 87.3% 79.5% 65.2% Graft 96.8% 92.2% 81.8%
Patient 97.1% 92.8% 84.9% Patient 98.9% 97.5% 95.1%
30 30
0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 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 Dialysis
YES
Proceed with
Barrier removed ?
evaluation
 Recipient evaluation

Nutritional Lifespan Cardiac Infection

ESRD Age
status assessment risks risks

Risks of
Peripheral Inactive Wait out
Cerebrovascular recurrent
vascular systemic for
risks renal
assessment disease cancer
disease

No severe or No
Stable No active
active significant
hematological gastrointestinal
pulmonary liver
condition disease
disease disease

Bld group and Psychosocial BMI Genitourinary

HLA typing assessment assesment 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
HLA TCR +
Donor CD4
APC T B cell
cell
Indirect allorecognition
CD4 Antibodies
Recipient T
APC cell

Lymph node
+ Complement
CD8 T
Donor peptide cell

Allograft cells
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 treated
XM +ve
DTT

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

Non-heart Related Unrelated

Heart beating
beating
 Evaluation process for living kidney donor transplantation

Potential Live Donor

Medical history Step 3 Tests:

Establish CT Angiogram
relationship
Psychiatric
Social history Review
Step 2 Tests:
Full blood count Social
Step 1 Tests: Liver function tests Review
ABO compatible Fasting Glucose,HbA1c Ethics
Cytotoxic crossmatch (-) Calcium, Uric acid Committee
HLA Typing* Anti Nuclear Factor etc Approval
Renal function tests ECG, CXR
Hep B, C, HIV (-) 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, male-
male 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 Recovery
theatre 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

Reop for main
Intimal dissection, kinking, Anuria
vessel
Renal artery torsion, rejection, Perfusion scan
thrombectomy;
thrombosis hypercoagulability, tight renal or colour flow
Nothing for
artery stenosis doppler
segmental vessels
Tender swollen
Angulation/kinking, external
Renal vein graft, hematuria, Reop with
compression, stenosis,
thrombosis colour flow thrombectomy
hypercoagulablity
doppler
Bleeding from graft hilum or Clinical Transfusion;
Hematoma
retroperitoneum US or CT Reop
HTN, renal
Donor artery trauma, improper
Renal artery dysfunction, Angioplasty;
suturing, atherosclerosis
stenosis peripheral surgery
edema
Asymptomatic,
Arteriovenous Monitor;
Renal biopsy hematuria, graft
fistulas embolization
dysfunction

1Humar A, et al. Seminars in dialysis 2005; 18: 505-510

 Common surgical complications (5-10% incidence)

Complication Cause Diagnosis Treatment

Fever, pain, swelling,
Ischemia of the ureter,
increased Cr, reduced Ureteric stent,
undue tension from a
urine output, cutaneous drainage; reop with
Urine leak short ureter, direct
urinary drainage, fluid Cr ureteric
surgical trauma to
higher than serum Cr, reimplantation
ureter
radionuclide scan
PCN, PTD, ureteric
Edema, blood clots, Elevated Cr, US, stent; ureteric
Obstruction
hematoma, kinking frusemide renogram reimplantation or
bypass
Bleeding from Continuous bladder
Hematuria, blood clots,
Hematuria anastomotic site or irrigation;
obstruction
distal tip of ureter cystoscopy
Monitoring;
Asymptomatic, external
percutaneous or
Leakage from cut compression, fluid Cr
Lymphocele surgical drainage
lymphatic vessels same as serum Cr, US or
and peritoneal
CT
window

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 Osteporosis, osteonecrosis
Nephrotoxicity from CNI Anemia or polycynthemia
Leukopenia from MPA
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]