Summary on Human Renal Transplantation

1. Human Renal transplantation
Dr. Edmond Wong
EAU 2010

2. History
• Carrel established the modern method of
vascular suturing at the turn of the 20th
century,
• Nobel Prize in 1912 for his work on organ
grafting
• 1933 : first human renal allograft by
Voronoy in the Ukraine
• Boston in 1954 :kidney from one twin was
transplanted into the other

3. History
• 1958 :first histocompatibility antigen described
• 1959 : Radiation for immunosuppression
• 1961: azathioprine became available
• 1962 : corticosteroids became part of a standard
immunosuppression regimen
• 1966: direct crossmatch between donor lymphocytes
and recipient serum
• 1960s : human renal preservation over 24 hours with
pulsatile machine perfusion or cold storage after flushing
with an ice-cold intracellular electrolyte solution
• Pretransplantation transfusion protocols are no longer
routinely prescribed because donor-specific sensitization
and the transmission of viral illnesses

4. History
• 1978 :first clinical trials of cyclosporine were reported by
Calne
• 1984, Congress passed the National Transplant Act
• late 1980s :The University of Wisconsin (UW) solution
• 1989 :Recombinant erythropoietin  reduce risk of the
development of anti-human leukocyte antigen (HLA)
antibodies
• 1990 : Joseph E. Murray received the Nobel Prize in
Medicine
• 1995: Laparoscopic donor nephrectomy was introduced
• Current development: novel immunosuppressive agents
and approaches to graft tolerance

5. Ethical issue in transplantation

6. Ethical issue in transplantation

7. Supply and use of decease donor
• Gap btw supply and demand of kidneys
tended to stabilized in countries with a
donation rate >40 kidneys per million
population (PMP)
• It is difficult to recommend specific ,
donor-promoting activities for countries
and organization

8. Ways to promote deceased donor
• Donor cards: opt in
• Computerized donor register: reduce refusal by
family
• Maintain adequate ICU bed & educational
program for ICU physicians
• Opt out (presume consent) legislation
• Non-heart beating donor (NHBD)
– With continuous perfusion machine for IA cold
perfusion until family arrived
• Elderly donors (>60): better 6m survival then pt
without transplant

10. How to enhance donation?

11. Enhanced living donation
Why living donor is suitable
• Living donor graft has better graft and
patient survival than deceased donors
• Kidney transplant results have improved
thus more patient with ESRD opt for
transplant rather than dialysis
• Lap donor nephrectomy is safe and
successful

13. 1. Accepting graft with anatomical
anomalies
• Anatomical anomalies: renal cyst, PUJO,
renal stone> 1cm, Duplex ureteral
system , multiple arteries & veins
• Graft with multiple a&v do not carry
increase risk of complication in experience
center

14. 2. ABO-incompatible donors
• Once a contraindication for renal transplantation
• New techniques: antibody adsorption columns & new
immunosuppressive tools (anti-CD20 monoclonal
antibody , rituximab)
• Adv: immediate availability of living donor
• Initial result show similar outcome, but lack long term
data
• Require more intense and most costly
immunosuppressive therapy
• Remains EXPERIMENTAL
• Other chose: cross-over transplantation

15. 3. Cross-match-positive living-
donor kidney transplant
• Once consider contraindication
• Plasmapheresis : extensive antibody elimination
strategies
• IVIG
• Intense immunosuppresion with antibody induction & use
of B-cell depleting agents(anti-CD20 AB rituximab)
• No long term result
• Remain EXPERIMENTAL

16. 4. Living unrelated kidney donation
• Altruistic non-consanguineous kidney
donation is allowed legally
• Provided checks are made for altruistic
motivation & financial gain excluded
• Result comparable to related living
donation

17. 5. non-direct living-donor
transplantation
• Between an altruistic donor and a recipient
unknown to the donor
• There are ethicial and legal concerns
• NOT recommended

18. 6. Payment to living donor from
central organization
• Payment of living donors to donate organs
is ethically unjustifiable
• All organ donors should have adequate
lifelong access to medical care for
prevention of renal failure and side effect
of organ donation

19. Ethical ways to show appreciation
for organ donation
• Donor “medal of honour”
• Cross-over transplantation or paired organ
exchange
• Medical leave for organ donation
• National insurance plan that provide life
and disability insurance for all living
donors

20. Kidney donor selection

21. Why is kidney transplant good?
• Prolongs life
• Reduce morbidity
• Improves quality of life
• Enable social and medical rehabilitation
• Reduce cost associated with medical care

22. Definition
• Isograft:
– A graft of tissue that is obtained from a donor
genetically identical to the recipient
• Xenograft:
– A type of tissue graft in which the donor and recipient
rare of different species
• Allograft:
– A graft of tissue obtained from a donor of same
species as , but with different genetic make up (e.g
transplatn btw two human being)

23. Basic immunology
• T cell :
– Detect processed Ag via T-cell receptor
– Produced cytokines
– Kills infected cells via interactions with cell surface
molecules
• B cell:
– Detect tertiary structures of antigens
– IgD & IgM antibodies act as receptors
– Need cytokine signals from T cell for activation
– Produce antibodies when activated
– Mediated complement fixation
– Responsible for Humoral immunity

24. MHC class
• MHC:
– Combination of various HLA haptotype create genetic variability
– Improve chance of population survival against few pathogens
• MHC Class I:
– HLA A, B, C
– Expressed by most nucleated cells
– Binds to CD8 on T lymphocytes
• MHC Class II:
– HLA DR, DP, DQ
– Expressed by specialized antigen-presenting cells (APCs):
dendritic cells, macrophages & endothelial cells

25. Kidney donor selection
• Diagnosis of brain death in deceased donor (refer to
HAHO 2007)
1. Any transmissible disease?
2. Any malignancy
3. Quality of organs for transplantation ?
• Vascular condition
• Renal function
1. Age?
– > 65 donor, similar short-term result but lower long term graft
survival
– But more on physical condition of donor rather than age
– Thus no absolute age limits to donation
– Living donor: 55 yr

26. Cadaver Donor
1. Normal renal function
2. HTN
3. Diabetes mellitus
4. No malignancy
5. No generalized viral or
bacterial infection
6. Age 6-45
7. Negative serologies(syphilis,
HIV, hepatitis, T-
lymphoproliferative virus)
• Resuscitation
– 90 mm Hg, UO 0.5
ml/kg/hr

27. Donor selection : Infection
• History of drug abuse?
• Serological test must be repeat, because
– Incubation period : HIV (2m), Hepatitis (6m)
– Fluid resuscitation with dilution effects

29. Donor selection: Malignancy
• Absolute contraindication as a donor:
1. Active cancer
2. Hx of metastatic cancer (except testicular
ca)
3. Cancer with high recurrence rate (breast ,
melanoma, leukaemia, lymphoma)
4. Brain hemorrhage of unknown etiology
(must exclude metastasis)
• Acceptable if 5yr absence of recurrence
after cure

30. Donor selection: vascular condition
and renal function
• Factors for excluding potential donors:
1. Previous MI
2. CABG or angina
3. Severe systemic vascular disease
4. Prolong hx of DM
5. Serious HT
6. Events of long-lasting hypotension
7. Oliguria
8. Long-lasting ICU stay
• Donor renal fxn : CrCl (Gockcroft-Gault formula): not
suitable if CrCl <50ml/min
• 24-hr Proteinuria
• USG kidney
• ARF is not itself a contraindication

31. Marginal donors
• Age:
– >70 yo without other risk factors
– 60-70: hx of DM , HT, proteinuria 1g/24h, or retinal
vascular changes
• Renal function:
– CrCl 50ml/min: still valuable for single graft
– CrCl <50ml/min: used as a dual graft or discarded if
histologically abnormal
– ~5-20% glomerulosclerosis at bx with >25 glomeruli
taken from both kidney: organs still valuable for a
single of double graft
– > 20% glomerulosclerosis : individual decision base
on renal function

32. One graft or two graft per patient?
• Two conflicting concepts:
– Single marginal kidney has reduced renal mass ,
which are further reduced by cold ischemic time,
transplant trauma and nephrotoxicity of
immunosuppressive therapy. Thus both kidney to
same recipient may increase nephron mass and
prevent kidney damage
– Marginal kidney have functional reserve which will
increase post-transplant. Dual transplantation is
redundant
• Double –kidney transplants: safe, well tolerated
and no more surgical complication than single-
graft operation

34. Explantation surgery

35. Explantation
• Deceased donor organ recovery:
– Each organ should be procured as quickly as
possible to minimise ischemic injury
– Heart, lungs, liver and pancrease, before
kidney retrieval
– Continuous machine perfusion reduces
injuries and improve post-op graft outcome

39. Living donor

40. Living donor
• Must not be coerced and paid for their donation
• Should be considered a gift of extraordinary
value

41. Living Related Renal Transplant
1. Improved graft survival
2. Less recipient morbidity
3. Limits time on dialysis
4. Partially alleviates supply problem of
cadaver kidneys
5. Timing of transplantation

43. Living donor assessment
• Complete history and PE
• Routine laboratory testing
• Serological evaluation:
– EBV, Herpes, CMV
– HIV
– Hep B& C
• Urinalysis and C/ST
• 24-h urine collection: CrCL , Protein
• Blood pressure measure: 3-10 x
• Imaging:
– CT scan with 3D reconstruction
– MRI angiography
– Renal angiography indicated if CT & MRI not available

44. Living Donor Selection
• Contraindications
– Mental disease
– Renal disease
– Morbidity, Mortality
Risk
– ABO incompatibility
– Crossmatch +
– Transmissible disease
• Evaluation
– Serology
– Three-dimensional
CT

46. Consent
• Mortality: 0.03%
• Major morbidity: 0.2%
• Minor morbidity: 8%
• Not associated with increase risk of renal
failure or HT
• Associated with asymptomatic proteinuria
• < 1% later regretted the donation

47. Choice of kidney
• Left kidney is preferred because of longer
length of the left renal vein
• Donor should always be left with the better
kidney
• Donor diuresis increase with mannitol :
0.5g/kg (usually 25g)
• Arterial spasm prevented by externally
applied papaverine

48. Choice of kidney: Number of RA
• CTA: provide both renal anatomy and vascular
road-map for the surgeon
• Right kidney selected if multiple left renal
artery and single Right renal artery
• Right kidney donor: 30%
• Question: in multiple left RA , is lap Rt donor
nephrectomy just as safe?

49. Problems of Right LLDN
• Technically much more challenging:
• Need retraction of the liver
• short right renal vein (RRV)
• further shortening of RRV after a stapled
transection
• presence of friable venous branches draining
into the IVC in proximity to the RRV
• Initial experience show almost 40% of graft loss
[Mandai 2001]

50. Modification of Rt LLDN
• Relocation of ports:
• make GIA stapler transects the RRV in a
plane parallel with the inferior venna cava
(IVC)
• more of the RRV length can be preserved
• Relocate the incision for kidney extraction
• Use of panel graft to lengthen the RRV
with great saphenous vein

51. How about using the left kidney
with vascular reconstruction?
•Close to each other:
•1. Conjoined anastomosis:
•2. End-to-side anastomosis:

52. •Far away:
•1. autogenous graft reconstruction
– Epigastric or hypogastric graft
•2. pseudo-Carrel patch technique
– segment of great saphenous vein

53. Results of vascular
reconstruction
• Many studies showed:
• 1-year graft survival rates: 91–98%
• Kuo PC et al. Am J Surg 1998;176: 559–63
• Hsu TH et al. Urology 2003;61:323–7
• no difference for single renal artery VS
MRAs
• However: more renal arteries are
associated with more ureteral
complications in the recipient

54. Left single
artery
Left LDN
Left multiple
arteries
Left LDN +
reconstruction
& Or
Right single
artery
Right LDN
Both multiple
arteries
Chose another
recipient
Left kidney
better
Right LDN
Recommendation for choice of
allograft

56. Lap living-donor nephrectomy
(LLDN)
• Good evidence base for LLDN
• Compare to OLDN: similar rate of
– graft fxn
– rejection rate,
– urological complication
– patient and graft survival
• Advantage: analgesic requirement, pain ,
hospital stay , time to return to work , cosmesis
• NO effect long term risk of ESRD
• Mortality rate: 0.03% (same as OLDN)

59. Organ preservation
• Euro-Collins is no longer recommended
• Celsior-solution
• UW solution (University of Wisconsin)
• HTK (histidine-tryptophane –ketoglutarate)

60. Methods of kidney preservation
2 motheds
• Initial flushing with cold preservation
solution followed by ice storage
• Continuous pulsatile hypothermic
machine-perfusion (relevance for non
heart-beating donors and marginal
donors)

61. Duration of organ preservation
• As short as possible
• Marginal and elderly (>55) donors are
more sensitive to ischemia
• Relies on hypothermia:
1. Lower metabolic rate
2. Conserves ATP
3. Prevents formation of oxygen-free radicals
during reperfusion phase

62. Kidney recipients

63. Cause of ESRF
• DM: 40%
• GN: 20%
– IgA nephropathy:60%
– Focal glomerulosclerosis : 10%
• Out of the total number of patients on renal
replacement therapy
– 50% on Peritoneal Dialysis
– 10% on Haemodialysis
– 40% have had renal transplantation
• Among the patients on dialysis treatment, 81.6%
were on PD.

64. ERRF: definition

65. ESRF (NKF-K/DOQI)
Am J Kidney Dis 2002 39 (Suppl 1: S1-S266)

66. RRT
• Dialysis
– Hemodialysis
• SCUF / CVVH / CVVHD / CVVHDF / SLEDD
– Peritoneal dialysis
• CAPD / CCPD / NPD / TPD
• Renal transplantation

67. Kidney recipient
• Careful pre-op workup of all transplant
candidates is mandatory to improve organ
and patient survival in the post-transplant
period
• The workup should be repeated regularly

69. Selection and preparation of
recipients
• Purpose: to diagnose the primary renal
disease and its risk of recurrence in the
kidney graft and to rule out active
invasive infection, a high probability of
operative mortality, noncompliance,
active malignancy, and unsuitable
conditions for technical success
( Barry, 2001 ; Kasiske et al, 2001 ).

70. Pre-transplant therapy
• Abnormal urogenital tract
• Urinary diversion
• Pre-transplant nephrectomy

71. 1. Abnormal urinary tract
• Urinary tract abnormali should be correct before
transplantation
• Congenital: PUV, Spina bifida, prune belly
syndrome, VUR, bladder extrophy , VATER
syndrome
• Acquire: Shrunken or neurogenic bladder
• Low-compliance bladder: CISC or bladder
augmentation or SP diversion
• Anatomical or functional disorder seems not to
change outcome of renal transplantation

72. 2. Urinary diversion
• Sphincter insufficiency or absent bladder:
conduits or continent catheterisable
pouches or artificial sphincters
• Low-compliance bladder with intact
sphincter: bladder augmentation +
continent pouches
• Urinary diversion at least 10-12 weeks
before transplantation
• Bladder augmentation after transplantation

73. 3. Pre-transplant nephrectomy

74. Indication for pre-transplant
nephrectomy:
1. Suspicious of malignancy
2. Large size (ADPKD)
3. Grade 4-5 VUR
4. Massive proteinuria
5. Intractable HT
6. Recurrent stones or UTI

75. Contraindication of transplant
recipient
• Malignancy: immunosuppresant may aggravate
underlying malignancy
• Infection
– Active infection: jeopardize immediate post-transplant outcome
– Chronic infection:
• Does not cause immediate post-op risk
• Repeat serology for CMV, HBV, HCV & HIV even if previous –ve
serology
• May have implications for allocation of organs
• Consult ENT, dentist, dermatologist, gynaecologist to firmly rule out
infection
• Short life expectancy
• Severe psychiatric disease

76. Infection screening
• HBV, HCV:
– hepatitis is the major cause of liver disease post renal transplant
– Liver bx to assess disease status
– Antiviral therapy before transplantation
• HIV: CI to transplant
• CMV: immunosuppressant asso with life-threatening
CMV disease, need prophylaxis
• EBV :
– in children and young adults
– Risk of EBV-related lymphoproliferative disease
• TB: need isoniazid prophylaxis
• Syphilis : TPHA-test (Treponema haemaglutination)

77. Other pre-transplant workup
• Cardiovascular workup
– Pt with cardiac disease have higher peri-op risk
– Indicated in: hx of CVD, PVD, stroke, CVA, long hx of
renal failure /dialysis, elderly or DM
– Investigation:
• ECHO : valvular disease, systolic / diastolic LV dysfxn
• Exercise ECHO/ thallium scan in pt with low exercise
capacity
• Coronary angiography
– Revascularisation should be performed in every
suitable transplant candidate before transplantation

78. Other pre-transplant workup
• Peripheral artery disease, CVA:
– Common in ureamic patients
– Significant cause of graft failure
– Pelvic radiography should routinely be done
– Duplex USG incase of vascular calcification
– Angiography and arterial repair as indicated
– Avoid contrast enhanced MRI with risk of
nephrogenic systemic fibrosis

79. Other pre-transplant workup
• DM
– Increase mortality and reduce long-term graft outcome
– Combine kidney –pancreas transplant in Type I DM  improve glucose control
and slow progression of CVD
– Watch out for CVD & bladder neuropathy
• Obesity:
– Higher surgical and non-surgical complication
– No recommend exclusion based on BMI
• Coagulopathies:
– Early graft thrombosis or post-transplant thrombotic complication
– Esp in pt with recurrent shunt thrombosis
– ATIII, protein C, activated protein C resistance (Factor V Leiden) , protein S, Anti-
phospholipid antibodies
• Other disease aggravated by immunosuppressant:
– Diverticulosis
– Cholecystolithiasis
– Hyperparathyrodism

80. Other consideration
• Age:
– Itself not a CI to transplantation
– Transplant reduced mortality in pt over 65
compare to pt on waiting list
– Attention for co-morbidities (esp cancer
/dementia)
– High fatality rate in the 1st
year

81. • Recurrence risk (original renal disease)
– < 10% graft loss due to recurrent disease after 10 yr
– Disease with high recurrence rate + immediate graft
loss
1. Light-chain deposit disease (LCDD): not recommended
2. Primary oxalosis : combined liver-kidney transplant
3. Anti-glomerular basement (anti-GBM) antibodies: can be
given after disappearance of anti-GBM Ab
4. Systemic disease (lupus, vasculitis, haemolytic
uraemic syndrome)
5. Focal and segmental glomerulosclerosis (FSGS) : txn
with plasmapheresis +/- rituximab
6. Renal amyloidosis / cystinosis / Fabry’s disease

82. Pt with previous transplant
• Look specially for malignancy , CVD &
development of antibodies against 1st
graft
• Gradual tail down immunosuppressant after graft
failure , as continue therapy increase risk of RRT
• Graft nephrectomy or embolisation if
symptomatic
• Prophylatic transplantectomy not beneficial
• Avoid repeat alloantigen mismatches

83. Transplantation in pregnancy
• Planning pregnancy
– Sex life and fertility improved after kidney
transplantation
– Pregnancy should be at a time of good general and
graft health : 1-2yr after transplant
– Similar outcome if stable graft fxn &
immunosuppressive therapy , no sign of rejection ,
HT, proteinuria, hydronephrosis or chronic infection
– Hydronephrosis increase risk of infection & stone
– Early adjustment of immunosuppresant

84. • Graft survival:
– Pregnancy rate increase to 5%

85. Care during pregnancy
• Control of proteinuria
• HT (pre-eclampsia)
• RFT
• Rejection
• Infection:
– Monthly MSU
– Treat bacteriuria always
– Antibiotics: penicillin & cephalosporine
– Antibiotic prophylaxis in all uro procedure
– Amniotic culture to screen for fetal infection

86. Immunosuppressive txn
• Cyclosporine , with or without azathioprine and
prednisone
• Pass placental barrier but not teratogenic
• Cyclosporine level decrease due to increase
volume distribution , thus should augment
dosage
• Tacrolimus may be safe
• MMF & sirolimus is CI : teratogenic

87. FU
• No increase rate of spontaneous (14%) or
therapeutic (20%) abortions
• Higher rate or pre-term and Caesarean section
due to high incidence of prematurity
• 20% babies are low birth rate
• No higher congenital abnormalities
• Breastfeeding is not recommended
• Weekly fetal RFT for 3 months
• Delay vaccination until infant is 6m old

88. Transplant technique

89. Transplantation Techniques

92. Renal vasculature
• Preserve lower pole artery to supply the
ureter if possible
• Use Carrel patch
• Small lower pole vessels may anastomose
end-to-ed to Inf epigastric artery

95. Lower urinary tract
• Extravesical ureteroneocystostomy is
normally performed

96. Complications
Early
1. Wound infection and abscesses (5%)
2. Hemorrhage
3. Hematuria
4. Incisional hernia (5%)
5. Urinary fistulae (5%)
6. Arterial thrombosis (0.5%)
7. Venous thrombosis (0.5% adult , 2.5% paed)

97. Complications
Late
1. Ureteral stenosis (5%)
2. Reflux (30-80%) and acute pyelonephritis
(10%)
3. Kidney stones (1%)
4. Renal artery stenosis (10%)
5. AVF & pseudo-aneurysm after renal biopsy
(10%)
6. Lymphocele (1-20%)

98. 1. Wound infection
• Risk factors:
– Obese, old, DM , hematoma, rejection or over-
immunosuppression
• Prevention:
– Minimise electro-coagulation
– SC aspiration drain
• Txn:
– Opening of wound
– Surgical drainage for deep abscess
– Rule out urinary fistulae

99. 2. Hemorrhage
• Risk factors:
– Acetylsalicylic acid (aspirin)
– Poorly prepared transplant hilus
– Multiple renal artery
– Renal biopsies
– Hyper-acute rejection (HAR)
• Treatment: surgical exploration & drainage
• Check uretero-vesical anastomosis &
insert double-J stent

100. 3. Hematuria
• After renal biopsy: look for AVF
• Txn: selective percutaneous embolisation

101. 4. Incisional hernia
• Risk factors:
– Obesity , DM , hematoma, rejection
– m-TOR inhibitor
• Treatment:
– Surgical with or without synthetic mesh

102. 5. Urinary fistula
• 3-5% without double J stent use
• Cause: ischaemic necrosis of the ureter
• Occur on the ureter, bladder or parenchyma
• Mx:
– Diversion: PCN, double-J, foley
– Reimplantation if distal necrosis and long ureter
– Uretero-ureteral anastomosis with native ureter
– Vesical fistula: SP or transurethral catheter
– Calyceal fistula: JJ stent + foley or polar nephrectomy & omental
plasty

103. 6. Arterial thrombosis
• 0.5% in 1st
week post-op
• Risk factor:
– Atherosclerosis
– Unidentified intimal rupture
– Poor suture technique
– Kinking of artery longer than vein
– Incorrect sited anastomosis
– Multiple arteries
– Paediatric transplant
• Presentation: primary non-fxn or sudden anuria
• Investigation: Doppler USG or technetium scan, CT
• Txn:
– Surgical exploration always necessary
– Radiological thrombectomy if within 1st
12 hours
– Graft nephrectomy

104. 7. Venous thrombosis
• Presentation: primary non-fxn , hematuria or
anuria
• Dx: Doppler USG or DTPA scan
• Treatment:
– Salvage thrombectomy  very poor success rate
– Graft nephrectomy

105. Late : 1. Ureteral stenosis
• 5% of transplant
• Dx: USG show hydronephrosis & derange RFT
• Most occur in 1st
yr, increase to 9% in 10yr
• Cause or hydronephrosis
1. High vesical pressure + ROU: bladder drainage
2. VUR: not obstruction
3. VU stenosis due to scar formation or poor surgical technique(80%)
• Risk factors: multiple A, age, delay graft fxn, CMV infection
• Treatment:
• PCN + monitor RFT
• AP to determine level of stenosis, degree & length
• Endoscopic or percutaneous treatment
• Outcome: better if early , distal & short
• Open surgery: uretero-ureteral ana or vesicopyelostomy

106. 2. Reflux & pyelonephritis
• Reflux is common
– Laedbetter (30%)
– Lich-Gregoire (80% short tunnel, 10% long tunnel)
• Acute pyelonephritis: 80% with reflux, 10%
without reflux
• Treatment:
– Endoscopic injection of deflux (40% success)
– Uretero-ureteral anas if native ureter not refluxive
– Ureterovesical re-implantation with long tunnel

107. 3. kidney stones
• Transplant with kidney or acquired
• Presentation: hematuria, infection or obstruction
• Dx: NCCT
• Treatment:
– Double J or PCN
– ESWL for calyceal or small renal stone
– PCNL or open nephrolithotomy for larger stone
– Ureteric stone: ESWL or URSL

108. 4. Renal artery stenosis
• Presentation:
– HT refractory to medical txn
– Deranges RFT without hydronephrosis
• Investigation: Doppler USG >2m/s
• Treatment:
– Medication with HT FU
– Intervention when stenosis > 70%
– Transluminal dilatation +/- stenting (70% success)
– Open surgery : resection with direction reimplantation with
higher success rate
– Repair with saphenous vein MUST be avoided

109. 5. AVF & pseudo aneurysm
• Presentation: repeated hematuria
• Investigation: Doppler USG /MRI / angiography
• Treatment:
– Regress spontaneously
– Indicated if persistent hematuria or diameter > 15mm
– Selective embolisation
– Pseudo aneurysm due to mycotic infection and can
be fetal

110. 6. Lymphocele
• Cause: insufficient lymphostasis of the iliac
vessels and/or of the transplant kidney
• Risk factor: obesity , m-TOR inhibitor
• Presentation: asymptomatic, pain cause by
ureter compression or infection
• Treatment:
– Mild with no compression on ureter or vessel: observe
– Laparoscopic marsupialisation
– Open surgery

112. Donor and recipient matching

113. Donor & Recipients matching
1. ABO compatible
2. HLA-A, B & DR phenotype
3. Lymphocyte cross-match test (avoid
hyper-acute rejection)

114. ABO compatibility
• Blood gp antigens can behave as strong
transplant antigens (i.e expression on
renal vascular endothelium)
• Incompatibility may cause early HAR
• Gp O donor theoretically can be transplant
to A, B or AB recipients
• Ways for ABO incompatible transplant:
– Antibody elimination: anti-B agents

115. Histocompatibility (HLA)matching
• Transplant outcome correlated with number of
HLA mismatch
• Remarkable polymorphism: must determine
HLA-A, HLA-B & HLA-DR phenotypes
• Less important in living- than decease donor
• HLA incompatibility:
– Proliferation & activation of recipients CD4+ & CD8+
T-cell
– Activation of B-cell allo-antibody
– Lead to cellular & humoral graft rejection

116. HLA testing
• HLA-testing and cross-matching must
follow the standard of e.g European
Federation of Immunogenetics

117. Cross matching
• Pt at risk: have HLA-specific allo-Ab or allo-
immunising events
– Pregnancy
– Blood transfusion
– Previous transplantation
• Cross match: detect preformed allo-antibodies in
recipient’s serum directed against lymphocytes
of the potential donor
• Complement-dependent lymphocytotoxicity
(CDC) assay is used
• Donor: obtain unseparated lymphocytes or T-
enriched lymphocytes

118. • T-lymphocytes: express only HLA class I Ag
• B- lymphocytes: express HLA class I & II Ag (from
spleen)
• Spleen have more B-lymphocyte than peripheral blood
• Thus, unseperately lymphocytes from spleen is more
sensitive than from peripheral blood
• +ve T-cell cross match: contraindication for
transplantation
• +ve B-cell cross match: may be due to
– Anti-HLA class I/II antibodies or allo-Ab
– Immune complexes
– Therapy with anti-B cell Ag (rituximab, alemtuzumab)
– Non-HLA allo-antibodies
– Thus decision depends on recipient’s antibody status &
immunological hx

119. • False +ve cross match result
– Autoimmune disease (IgM auto-Ab)
– IgM-anti-HLA allo-antibodies
• Ways to decrease false +ve:
– Txn with dithiothreitol (DTT)
– Flow cytometry cross-match
– Enzyme-linked immunosorbent assay (ELISA)
cross-match test: use solid-phase technology
to detect donor-specific anti-HLA antibodies

120. HLA-antibodies testing
• Potential recipients should be screened for HLA-
specific antibodies every 3 months or
• 2 & 4 weeks after every immunising event (blood
transfusion, transplantation , pregnancy and
graft explantation)
• Panel of lymphocytes use cover most of the
common HLA-alleles in the donor population,
and at least >50 different HLA-type cells
• Result is expressed as the percentage of panel
reactive antibodies (% PRA) and as the HLA
specificity against which these antibodies react

121. Immunosuppresion

122. Immunosuppression
• A balance of survival
• Dosage of drug high enough to suppress rejection
without endangering the recipient’s health
• Sensitized lymphocyte activity against a transplant
• Most important in initial post-transplant period to prevent
rejection
• Later stage: graft adaptation occurs, very low rejection
rates in maintenance patient
• Reduced over time by steroid tapering & gradual
lowering of calcineurin inhibitor (CNI)
• Common side effect: malignancy , opportunistic infection
• Synergistic regimen: dose reduction reduce side-effect
while maintaining efficacy

123. Standard initial immunosuppression
1. CNI (cyclosporine or tacrolimus)
2. Mycophenolate (MMF or enteric-coated
mycophenolate sodium, EC-MPS)
3. Steroids (prednisolone or
methylprednisolone)
4. With or without induction therapy

127. Calcineurin inhibitors (CNIs)
• Cyclosporin & tacrolimus
• Improve kidney survival
• Cornerstone of immunosuppresion
• Both are nephrotoxic
• Long term use is major cause of chronic allograft
dysfunction
• Both drug Similar outcome: overall patient &
graft survival (LE: 1a)
• Tacrolimus may provide better rejection
prophylaxis with better graft survival

128. Cyclosporine A
• Cyclosporine A micro-emulsion(CsA-ME;
Neoral)
• Use associated with reduced rejection rate 1 yr
post transplant (LE: 1b)
• “Critical-dose” drug: deviation from exposure
lead to severe toxicity or failure of efficacy
• Need close surveillance & drug level monitoring
• Drug level 2 hour after intake (C2 level)
• Major side effect: hypercholesterolaemic, HT,
Gum hypertrophy, constipation , hirsuitsm &
acne (LE : 1a)

129. Tacrolimus
• More powerful than cyclosporine
• More potent prophylaxis for transplant rejection
• Overall similar outcome vs cyclosporine (LE: 1a)
• Advagraf : allow once daily dose but need higher
dosage
• Monitor using trough level
• SE: DM, termor , headache, hair loss, GI ,
hypoMg
• Over-immunosuppression with MMF: polyoma
nephritis (LE: 1b)

130. • Complete CNI withdrawal in first 3 yr asso
with increase rejection risk & worse
outcome
• However, CNI withdrawal under MPA &
steroid is safe after 5 yr and resulted in
improved RFT

131. Mycophenolates
• MMF and EC-MPS
• Both base on Mycophenalic acid (MPA) inhibits
inosine monophosphate dehydrogenase (IMPDH)
• Decrease synthesis of guanosine monophosphate in
purine pathway
• Lymphocyte proliferation is more dependent on purine
nucleotide synthesis compare to other cell types
• Provide more specific lymphocyte-targeted
immunosuppression
• Not Nephrotoxic
• Main side effect: inhibits bone marrow fxn & GI
(diarrhoea)
• Both drug equally effective & identical safety profile

132. Effect
• MMF + prednisolone + CNI  profound
reduction of bx proven rejection (LE: 1b)
• MMF reduce chronic allograft rejection by
27% vs azathioprine
• MPA dose reduction are associated with
inferior outcome
• Regular monitoring for polyoma is
recommend when given with tacrolimus

133. Dosage
• With cyclosporine: MMF 1g BD or EC-MPS 720mg BD
• Not approved usage with tacrolimus but is use widely
worldwide
• Same initial dosage as with cyclosporine
• But dose reduction are frequent due to GI side effect
• After 6-12 months:
– MMF: 1000-1500mg QD
– EC-MPS: 720-1080 mg QD
• In maintenance: potency of MPA can be used for steroid
withdrawal (LE: 1a) or dose reduction of CNIs (better
RFT)
• MPA drug monitoring is not recommended

134. Side effect
• Bone marrow suppression
• GI toxicity : diarrhoea
• Over-immunosuppression: CMV infection
– Screening for CMV viraemia (LE: 1a)
– CMV prophylaxis : valganciclovir use in all CMV +ve recipient or
CMV +ve organ (proven to reduce CMV asso motality + long-
term graft survival )
• Polyoma virus nephropathy: esp when combine with
tacrolimus (LE: 1b)
• Progressive multifocal leukoencephalopathy is a
progressive and ultimately fatal white-matter disease of
the brain that is associated with polyomavirus infection

136. Azathioprine
• Replaced by MMF in most place
• Inferior to MPA in reduction of rejection rate
• Usually reserved for low-risk pt or who cannot
tolerate MPA
• No additional advantage in additional to
cyclosporine and steriod (LE : 1a)

137. Steroid
• Most still consider steroid as fundamental adj to
primary immunosuppression
• Many successful steroid withdrawal (LE: 1a)
• Potential benefit of steroid less prominent after
prolong treatment

138. m-TOR inhibitor
• Sirolimus and everolimus
• MOA: Suppress lymphocyte proliferation and
differentiation
• Inhibit both Ca-dependent & Ca-independent pathway,
block cytokine signals for T-cell proliferation
• Also affect B-cell, endothelial cell, fibroblasts and tumor
cells
• As effective as MPA when combine with CNIs in
preventing rejection (LE: 1b)
• Require monitoring of trough level due to narrow
therapeutic window & risk of drug-to-drug interaction

139. m-TOR inhibitor
• Side effects:
– Dose dependent bone marrow toxicity
– Hyperlipidemia
– Oedma
– Lymphoceles
– Wound healing problem
– Penumonitis (PCP): need septrin prophylaxis
– Proteinuria
– Impair fertility
– Aggravate nephrotoxicity with combine with CNIs (but itself not
nephrotoxic)
• CNI dosage should be reduce in combination therapy
with m-TORi

140. m-TORi
Sirolimus:
• ½ life: 60hr
• Once a day dose
• Kidney recipients only
• Should be given 4hr
after cyclosporine
• Use with steroid for
cyclosporine
withdrawal
Everolimus:
• ½ life: 24hr
• BD dose
• Kidney & heart
transplant
• Use with cyclosporine
simultaneously

141. Can m-TORi replace CNIs?
• NOT at initial phase: lower efficacy & problem with
wound healing & lymphocele (LE: 1a)
• NOT if proteinuria > 800mg/day / GFR <30ml/min
• YES at later stage (3m): improvement in RFT (LE: 1a)
• YES who are at risk of or develop malignancy after
transplantation
• Sirolimus +steroid vs Cyclosporine + steroid + sirolimus:
better long term survival, RFT & fewer malignancy (LE:
1b)
• Only few data on long term FU of m-TORi

143. T-cell depleting induction therapy
• “Induction” treatment with biological T-cell depleting
agents:
– Anti-thymocyte globulin (ATG)
– OKT3
– Anti-CD52 antibody (Campath1-H)
• Effective rejection prophylaxis while starting CNIs after
recovery of graft from ischemic injury (LE: 1b)
• Initial lower graft rejection rate, but no evidence of better
long-term graft outcome
• Side effect: increase risk of opportunistic infection &
cancer, post-transplant lymphoproliferative disease

144. Interleukin-2 receptor antibodies
• Daclizumab & basiliximab
• For rejection prophylaxis
• Given as short course post-transplant  reduce acute cellular
rejection by 40% (LE: 1a)
• No comparative study for both drug but appear similar efficacious
• No effect on patient or graft survival (LE: 1a)
• Study support quadruple therapy with these agents
• Allow early steroid withdrawal but with higher rejection rate
• Allow reduction of CNIs, with excellent renal fxn

150. Immunological complication
• Immunological rejection is a common cause of
early and late transplant dysfunction

152. Diagnosis
• Gold standard: transplant biopsy
• Banff criteria
• Class 1 is a "normal biopsy."
• Class 2 is "antibody-mediated changes." Ideally, both positive C4d staining and
circulating donor-specific antibodies are present in the setting of a rising creatinine to
make this diagnosis. Acute & chronic
• Class 3 refers to "Borderline Changes" which is essentially a mild form of T-cell-
mediated rejection..
• Class 4 is a more full-blown form of T-cell mediated rejection. As with humoral
rejection, there are both acute & chronic forms:
• The acute form of T-cell mediated rejection is furthermore subclassified
– Class IA: there is at least 25% of parenchymal showing interestitial infiltration and foci of
moderate tubulitis (defined as a certain number of immune cells present in tubular cross-
sections).
– Class IB: just like Class IA except there is more severe tubulitis.
– Class IIA: there is mild-to-moderate intimal arteritis.
– Class IIB: there is severe intimal arteritis comprising at least 25% of the lumenal area.
– Class III: there is transmural (e.g. the full vessel wall thickness) arteritis.
• Class 5 refers to interstitial fibrosis and tubular atrophy (IFTA), which is the new
preferred term for "chronic allograft nephropathy." Grade I refers to <25%>50% of
cortical area involved.
• Class 6 is a catch-all term describing changes not considered to be due to
rejection--for example, recurrent FSGS or CNI toxicity.

153. Hyper-acute rejection (HAR)
• MOA:
– Result of circulating , complement-fixing IgG Ab against incompatible
donor antigens
– Engage & destroy vascular endothelium
– ABO-incompatible grafts: pre-existing IgM iso-Ab against blood gp
antigents
– ABO compatible grafts: anti-donor HLA IgG antibodies
• Incidence: RARE
• Presentation:
– Seen at time of surgery
– Kidney becomes mottled , dark & flabby minutes of hours of
vascularisation
– Within 7 days: acute anuria , swollen graft
• Renal biopsy: generalized infarction of graft
• Treatment: Graft nephrectomy
• Prevention:
– Ensure ABO compatible
– CDC cross-match
– Screening for anti-HLA antibodies (pregnancy, previous transplant ,
blood transfusion)

154. Acute allograft rejection
• Classification (Banff criteria)
– T-cell mediated (acute cellular rejection ACR)
– Antibody mediated (acute humoral rejection
AHR)
• Acute cellular rejection
– Histo: tubulo-interstitial infiltrate of T-cell,
macrophages & neutrophils
• Diagnosis: renal biopsy or serum antibody
• Prognosis is poor with ACR + AHR

156. Txn of ACR
• IV methylprednisolone 500mg -1g QD for 3 day
• If anuria or raised Cr  another 3-day course
• Cyclosporine A level to ensure adequate
exposure
• Change CycA to Tacrolimus
• ALG or OKT-3 in severe steroid-refractory cases

157. Txn of AHR
• Similar to ACR
• Pulse steroid (500mg/day) x 3 days
• Conversion to tacrolimus with trough level > 10ng/ml
• Use of anti-CD20 Ab , rituximab (LE:1b)
• Remove antibodies with phasmapheresis or
immunoadsoprtion columns
• IVIG: 0.2-2.0g/kg (experimental)

158. Chronic allograft dysfunction /
Interstitial fibrosis and tublar atrophy (IF/TA)
• Take months to years to develop
• Presentation: Proteinuria, HT, rise Cr over
months
• Ddx: Chronic nephrotoxicity (CNIs) or
chronic kidney damage from marginal
donor kidney
• Histology: fibrosis, cortical atrophy, intimal
fibroplasia or larger artery , thickened
base membrane

159. • Diagnosis: Renal biopsy
• Treatment:
– Conversion to CNI-free regimen: m-TORi or
MPA
– To m-TORi if proteinuria < 800mg/day
– To MPA if beyond 3 years
– To azathioprine: need close monitoring
– ACE-I slow down renal decompensation
– Re-transplant or dialysis

161. Post-Transplant infection
• HSV:
– Acyclovir 400mg PO 5x/day for 5-10 days or
– Valacyclovir 1g PO TDS for 5-10 days
• CMV:
– Fever, pneumonia, GI ulcer, diarrhoea, retinitis
– Dx: shell viral culture, pp65 Antigenemia assay , PCR. RNA-DNA
hydridization assay
– Txn: Ganciclovir 5mg/kg IV Q12H x 2/52, then 1g TDS to complete 6
weeks
• EBV:
– Post-transplant lymphoproliferative disease
• Polyomavirus:
– BK virus, JC virus, SV40
– Asso with use of tacrolimus, MMF & sirolimus
– Polyomavirus nephropathy (PVAN)
– Dx: urine cytology
– Txn: reduction of immunosuppresion

162. Malignancy
Three cause of malignancy in recipients:
1. Transmitted malignancy from donor
2. Known or latent prior malignancy in the
recipients
3. “De-novo” malignancies in recipient after
transplantation

163. 1.Trasmitted malignancy from
donor
• Risk: 0.2% (increase in margin or elderly)
• Donor with pre-operative dx of cancer: (4.4%)
should not be donor if
– Active cancer
– History of metastatic cancer
– Cancer with high risk of recurrence (medulloblastoma
or glioblastoma multiform)
– Brain tumor of any grade with VP shunt
• Watch out for IC hemarrohage due to tumor
• Most common transmitted malignancy:
melanoma & choriocarcinoma

164. Tumor not CI to donation
• Basal cell carcinoma
• Non-metastatic spinocellular carcinoma of the
skin
• Cervical CIS
• Vocal cord CIS
• Low grade (1-2) brain tumor
• TaG1 TCC? Controversial
• Transplant of kidney with small RCC post PN?
Can be done with inform consent

166. What if donor was dx to have
cancer post-transplant?
• Graft nephrectomy or suspension of
immunosuppression are not always
necessary
• Discuss risk and benefit with patient

167. 2. Prior malignancy in the recipient
• Active tumor in recipient is absolute CI for kidney
transplantation
• But prior malignancy is not
• But WHO? When?
• Base on Cincinnati registry
– Consider type of tumor (TNM)
– Delay btw treatment and kidney transplantation
– Risk of recurrence
• 2 yr waiting period eliminate risk of recurrence in : CRS
(13%) , breast (19%) , Prostate (40%)
• 5 yr will eliminate most recurrence but not practical for
elderly pt
• No evidence of support fixed waiting time period before
transplantation
• Note: use of m-TORi associated with reduced incidence
of malignancy

169. 3. De-novo tumor in recipient
• Risk of malignancy after transplantation is
several times higher
• Most common: Skin (40%) or lymphatic
system (11%)

170. 1. Skin Cancer & Kaposi’s sarcoma
Skin cancer:
• Risk factor
– Age (>50)
– Sun & UV exposure
– HLA-B27 antigne exposure
– Cyclosporine, duration of immunosuppression (5% at
5yr)
• Incidence: 40% of post-transplant tumor
• 50% SCC, Male to female: 5 : 2
• Prevention: annual derma examination + sun
block

171. Kaposi’s sarcoma
• Incidence: 4%
• Risk factor: HHV8 +ve serology, CNIs
• Prevention: use m-TORi

172. 2. Post-transplantation lymphoproliferative
disease (PTLD)
• Extra-nodal dissemination & poor outcome
• Incidence: 1-5%
• Risk factor: cyclosporine, induction regimen (ALG, OKT3
& SIR)
• Presentation:
– Within 1st
year
– non-Hodgkin’s lymphoma
– EBV-iinfected B-lymphocytes
• Treatment: remission 60%
– Immunosuppressive therapy reduction or suspension
– Anti-CD20 Ab +/- chemotherapy + antiviral drug (acyclovir,
ganciclovir)

173. 3. Gyn cancer
• Cerival Ca : 3x higher
• CIS in 70%
• Risk: HPV infection , re-activation of latent
HPV
• Young recipients may benefit from HPV
immunization
• FU:
– annual cloposcopy + cytology
– USG + mammogram

174. 4. Ca prostate
• 1% of transplant population
• FU: annual PSA + DRE in Pt >50
• Most CaP are clinically localised disease

175. 5. Urothelial Ca
• 3x higher risk
• Patho: TCC, adeno , nephrogenic
adenoma
• FU: urine cytology, hematuria workup

176. 6. RCC
• In native or graft kidney
• Prevalence: 2% (100x higher)
• Risk factor:
– ACKD (main)
– Previous RCC
– VHL
• Patho: RCC & tubulopapillary ca
• FU: annual USG

177. Annual screening
• Renal fxn & SE of immunosuppressant
• Derma examination , tumor screening
– Nodal exam
– FOB
– CXR
– Gyn & Uro exam
• Investigation: Abd USG (graft+ native kidney)
• Detect cardiac risk
• Monitor BP, glucose , lipid profile

178. Graft & patient survival

180. Factors to consider
• Graft survival:
– Living-donor kidney better than deceased donor
(better selection ,shorter cold ischemic time)
– HLA-matched better than non-matched
– Number of mismatch
– Recipient’s age
– Time on dialysis
– Donor age: younger the better
– Cold ischemic time: marginal influence up to 24 hr
– Preservation soln: UW solution better
– Use of cyclosporine-A
– Number of previous transplantation