Outline
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Basics of transplantation
Benefits of transplantation
Immunosuppressive medications
Common post-transplant problems
Basics of Transplantation
• Kidney transplantation is the most effective
therapy for end-stage renal disease.
• The transplanted organ can come from
either a live donor or deceased donor.
• Most deceased donor organs come from
brain dead donors.
• Non-standard criteria donors:
– Expanded criteria donors (ECD).
– Donation after cardiac death (DCD).
Anatomy of Renal Transplantation
Recipient Selection
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Very few contraindications.
General medical condition.
Cardiovascular screening.
Age-appropriate routine cancer screening (pap smear,
mammography, colonoscopy, PSA).
• Infection (HIV, Hepatitis, TB).
• Presence of preformed antibody (PRA).
– Pregnancy, prior transplant, blood transfusion
• Psychosocial evaluation, including compliance.
Benefits of Transplantation
• Life expectancy
• Cardiovascular benefits
• Quality of life
• Socioeconomic benefits
Life Expectancy
Ojo, J Am Soc Neph, 2001;12:589
Quality of Life
• Numerous studies have detailed improved
quality of life.
• Life satisfaction, physical and emotional
well-being and ability to return to work
higher in transplant recipients.
• Uremic complications more fully reversed.
• Fertility returns.
Immunosuppressive Medications
Slide courtesy of Dr. Meier-Kriesche
Immunosuppressive Medications
• Induction:
– Corticosteroids
– Anti-thymocyte globulin (ATG)
– IL-2 receptor antagonists
• Maintenance:
– Corticosteroids
– Calcineurin inhibitors (CNIs)
– mTOR inhibitors
– Antimetabolites
Immunosuppressive Medications
• Treatment of Rejection:
– Corticosteroids
– Anti-thymocyte globulin
– Intravenous Immunoglobulin (IVIG)
– Rituximab
– Plasmapheresis
Corticosteroids
• Used for induction, maintenance and
treatment of rejection.
• Mechanism of action:
– Inhibit function of dendritic cells.
– Inhibit translocation to nucleus of NF-κB.
– Suppress production of IL-1, IL-2, IL-3, IL-6,
TNF-α, and γ-IFN.
• Adverse effects numerous and well-known.
Corticosteroids
• Component of >80% of transplant protocols.
• Given IV at high doses (250-500 mg/day) for
induction or treatment of rejection.
• Tapered to maintenance dose of 5-10 mg/day in
early post-transplant phase.
• Should NOT be tapered off: increased risk of
rejection and graft loss!
• Steroid free regimen: overall some benefits but
graft survival likely worse.
Anti-thymocyte Globulin
(Thymoglobulin®)
• Used for induction and treatment of rejection.
• Prepared by immunization of rabbits with human
lymphoid tissue.
• Causes depletion of peripheral blood
lymphocytes.
• Administered generally via central line for 3-10
days.
• Premedication required: acetaminophen,
corticosteroids and antihistamine.
Anti-thymocyte Globulin: Adverse Effects
• Infusion-related reactions: chills, fevers,
arthralgias.
• Lymphopenia.
• Thrombocytopenia.
• Prolonged immunosuppression: increased
risk of opportunistic infections (PCP, CMV,
fungal).
• Possibly increased risk of BK virus
nephropathy.
IL-2 Receptor Blockers
• Basiliximab (Simulect®) and Daclizumab
(Xenapax®).
• Block CD25 (IL-2 receptor) on activated T
cells.
• Used for induction only.
• Almost no side effects, but also much less
potent.
Calcineurin Inhibitors
• Used for maintenance immunosuppression.
• Two agents in clinical practice:
– Cyclosporine (Sandimmune®, Gengraf®,
Neoral®, generic; CysA)
– Tacrolimus (Prograf®, generic; FK506).
• Generics NOT clinically therapeutically
equivalent.
• At present are key to maintenance
immunosuppression and a component of the
majority of transplant protocols.
Calcineurin Inhibitors: Dosing and
Monitoring
 Both medications are generally dosed twice per
day, 12 hrs apart.
 Trough levels monitored: check approximately 12
hrs after last dose.
 In some cases C2 levels might be checked 2 hrs
after administration.
 Cyclosporine is 35-40% bioavailable, tacrolimus
approximately 25%.
 Oral to IV conversion 3-4:1.
 Both are metabolized by cytochrome P450 3A4 &
3A5.
Calcineurin Inhibitors: Interactions
• Drugs to use with caution:
– NSAIDs—avoid.
– Amphotericin B & Aminoglycosides– worsened
nephrotoxicity.
– ACEi & ARBs– use with caution.
– Statins– avoid lovastatin, start others at lowest
possible dose.
mTOR Inhibitors
• Target site is the mammalian target of
rapamycin (mTOR), a key regulatory
kinase in cell division.
• Sirolimus (Rapamune®) only available
mTOR inhibitor in the US.
• Administered once daily, 24-hour trough
levels monitored.
• Also metabolized by P450 3A system, with
interactions similar to the CNIs.
Sirolimus: Adverse Effects
• Nephrotoxicity:
– Delays recovery from ATN.
– Potentiates cyclosporine Nephrotoxicity.
– Induces proteinuria.
– Tubulotoxic.
• Impairment of wound healing.
• Dyslipidemia (increased LDL and TGs).
• Pneumonitis.
• Cytopenias and anemia.
Antimetabolites
• Azathioprine (Imuran®, generic) is a purine
analogue that is incorporated into RNA and
inhibits cell replication.
• A mainstay of transplantation for 30 years, it has
largely been replaced by the below drugs.
• Mycophenolate mofetil (Cellcept®) and entericcoated mycophenolate sodium (Myfortic®) are
prodrugs of mycophenolic acid (MPA), an
inhibitor of inosine monophosphate
dehydrogenase (IMPDH).
Antimetabolites: Adverse Effects
• Azathioprine:
– Bone marrow suppression.
– Hepatitis.
– Azathioprine is inactivated by xanthine oxidase,
therefore should not be used in combination with
allopurinol.
• MPA prodrugs:
– GI toxicity: diarrhea, nausea, esophagitis.
– Leukopenia and anemia.
– Not different between formulations.
Intravenous Immune Globulin
• Used primarily for treatment of antibodymediated rejection.
• Mechanism of action:
– Reduction of alloantibodies through suppression
of antibody formation.
– Increased catabolism of circulating antibodies.
• Adverse effects:
– Infusion-related reactions (myalgias, headaches).
– Severe headache & aseptic meningitis.
– Autoimmine hemolytic anemia.
– Sucrose-based IVIG can cause ARF.
Common Complications of
Transplantation
 Early complications
 Surgical complications
 Delayed or slow graft function
 Lymphocele
 Acute rejection
 Acute cellular rejection
 Antibody-mediated rejection
 Infectious complications
 Cytomegalovirus
 BK virus
 Others
 Malignancy
 Chronic allograft dysfunction
Surgical Complications
 Graft thrombosis:
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Caused by thrombosis of donor renal artery or vein.
Usually happens in first week.
Diagnosed by ultrasound with doppler studies.
Almost always requires explant of kidney.
 Urine leak:
 Elevated creatinine.
 May or may not have abdominal pain.
 Diagnose with nuclear medicine scans (DTPA or
MAG3).
 Surgical repair and/or relief of obstruction.
Delayed Graft Function
• Need for dialysis in the first week after
transplantation.
• Causes:
– ATN from prolonged cold ischemia.
– Acute rejection.
– Recurrent disease.
• Usually requires biopsy for diagnosis and
management.
Acute Rejection
• May present with ARF or proteinuria.
• Diagnosis made by biopsy.
• Pathology is reported according to Banff
classification.
• Acute cellular rejection: treat with steroids or
ATG based on severity
• Antibody-mediated rejection: may require
steroids, ATG, rituximab, IVIG or plasmapheresis
based on severity and setting.
OUR EXPERIENCE @ KIMS
KIMS accrediteditations
Causes of ESRD
9%
3%3%
43%
18%
24%
DM
HTN
OTHER
GN
PCKD
IN
Hemodialysis
• Hemodialysis cleans and filters your blood
using a machine to temporarily rid your
body of harmful wastes, extra salt, and
excess water.
• Hemodialysis helps control blood
pressure and helps your body keep the
proper balance of important chemicals
such as potassium, sodium, calcium, and
bicarbonate.
Dialysis Machine
• At KIMS, Hemodialysis is carried out in a
room with polite and well-trained dialysis
technicians and nurses, round the clock, in
three 'shifts'.
• B'Braun & Fresenius Hemodialysis machines.
• Disposable artificial kidneys and tubing
ensure safe, predictable fluid removal and
dialysis.
• Separate areas for HCV + and HBV + Pts
Continuous Ambulatory Peritoneal
Dialysis (CAPD)
• Peritoneal Dialysis is another
procedure that removes extra water,
wastes and chemicals from your
body. This type of dialysis uses the
lining of your abdomen to filter your
blood. This lining is called the
peritoneal membrane and acts as the
artificial kidney.
• CAPD is the most common type of peritoneal
dialysis. It requires no machine and can be done
in any clean, well-lit place. With CAPD, your
blood is continually being cleaned. The dialysis
solution passes from a plastic bag through the
catheter and into your abdomen, where it stays
for several hours with the catheter sealed. The
period that dialysis solution is in your abdomen
is called the dwell time.
• Next, you drain the dialysis solution back
into the bag for disposal. You then use the
same catheter to refill your abdomen with
fresh dialysis solution so that the cleaning
process can begin again.
Tenckhoff Catheter
• KIMS also offers the option of CAPD.
Skilled surgeons insert the catheter and
dedicated staff train patients to dialyze
themselves at home.
• CAPD fluids by leading companies like
Baxter, Claris and J'Mitra are available for
individual needs for home delivery.
Renal Transplantation
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Treatment of choice
Improved quality of life
Prolonged survival
Free of dialysis &
dietary constraints
• Improvements in
anaemia & bone
disease
• Cheaper
Present Indian Scenario:
• About 100,000 patients needs kidney transplant each year
• Approximately 5000 transplants performed each year
• 95 percent living & 5 percent cadaver donors
• 60-70 % live donors are LRD
• 30-40% are LURD
(Varies from time to time and place to place)
LRD Source:
Parents 53%
 MOTHER - 76% FATHER - 24%
Siblings 25%
 SISTER- 66% BROTHER - 34%
Spouse 22%
 WIFE - 84% Husband 16%
Renal Transplant : 1985
Renal Transplant : 1984
Renal Transplant : 1987
Cadaver Transplantation in India
Renal Transplantation KIMS
Renal Transplant Programme started: 20th August 2004
First Cadaver transplant: 15th October 2006
60
57
60
LRRTx
CADAVER
51
50
40
34
30
19
20
10
0
16
12
19
16
9
5
4
0
0
2004
2005
2006
2007
2008
2009
2010
Percent Graft Survival
Graft Survival Rates at
One, Three and Five Years
100
90
80
70
60
50
40
30
20
10
0
94%
88%
78%
65%
1 Year
3 Year
5 Year
Time After Transplant
Deceased
donor
Living donor
Chief Transplant surgeon & Urologist
Dr. S.Sahariah MS, MAMS, FICS, FACS
• Dr. Sahariah, Chief of our kidney
transplantation team, is arguably the most
experienced transplant surgeon in the
country with more than 3000 successful
transplant surgeries to his credit.
• He has helped in starting Renal Transplant
Programme in 24 centers across the
country.
• The Renal transplant programme was started in 2005, so
far we have conducted more than 1,200(till Dec 2010)
renal transplant surgeries with excellent results.
• Well trained medical, paramedical & nursing staff is
associated with the programme who provide round the
clock services to the patients.
• The institute strictly follows the ethical guidelines as per
the Human Organ Transplantation Act, 1995 and
performs only living related donor kidney transplantation.
KIMS attributes…
• We have also developed a vibrant cadaver
donor transplantation programme since last
three years and performed more than 60
cadaver renal transplantations during this short
span which is one of the largest cadaver
transplant series in the country.
• We also have the distinction of performing
cadaver renal transplantation from the youngest
(18 months old) and oldest (79 years old)
cadaver donor in the country.
Cadaver Transplant at KIMS, Hyd
16 months
79 years old
Cadaver Transplantation in India