RenalRenal(Kidney) Transplantation(Kidney) Transplantation
Kidney TransplantKidney Transplant
Inserting a kidney of another live or dead person into a person.
The donor kidney is typically placed inferior of the normal anatomical location.
IndicationsIndications
The indication for kidney transplantation is end-stage renal disease (ESRD)
This is defined as a drop in the glomerular filtration rate (GFR) to 20-25% of normal
Majority of renal transplant recipients are on some form of dialysis – hemodialysis, peritoneal dialysis
Am J Kidney Dis 1999;34(Suppl1)
Cause of End Stage Renal Disease Cause of End Stage Renal Disease Among New Patients on Among New Patients on
Hemodialysis Hemodialysis
Diabeticnephropathy
Hypertension
Glomerulo-nephritis
Cystic KidneyDz
Other
38%
28%
13%
3%
18%
Kidney Int. 2009 May;75(10):1088-98. Epub 2009 Feb 18Kidney Int. 2009 May;75(10):1088-98. Epub 2009 Feb 18
According to a report in the Kidney International—the journal of the International Society of Nephrology—about 27,000 related and unrelated living kidney donor (LKD) transplants occur worldwide every year, of which 6,435 take place in the US with India figuring in between with about 3,200 transplants, a number which the authors said, doesn’t represent “reliable national data”.
In India the number of transplants per year can be in the range of 3,000-3,500, with barely 5% coming from the brain-dead. The annual requirement is about 150,000
Am J Kidney Dis 1999;34(Suppl 1)
Options in End Stage Renal Options in End Stage Renal DiseaseDisease
Options for patients with ESRD:– Peritoneal dialysis– Hemodialysis– Kidney transplantation
Living Donor (related and unrelated) Cadaveric Donor
Approximately 222,000 patients were receiving hemodialysis (1999 US Renal Data System Report)
Only 9000 cadaveric kidney transplants performed in 1999 Approximately 4000 living donor transplantations per year In the year 2000, more than 45,000 patients receiving
dialysis were awaiting cadaveric kidney transplantation
DialysisDialysisPeritoneal HemodialysisPeritoneal Hemodialysis
Allograft or allogeneic transplant when transplanted tissue or organs are sourced from a genetically non-identical member of the same species. Like between you and me !
Xenograft :transplant from another species like pig heart transplanted in human,
Isograft : transplanted organ or tissue from a genetically identical donor, i.e. an identical twin
Autograft: person’s own tissue transplanted in his own body. EX. Person’s bone marrow is taken and stored in laboratory. Then transplanted back into him after few days or few months when required.
TransplantationTransplantation
Kidney Transplant
Deceased donor(cadaveric transplant)Transplanting kidney of Person who had died recently
Living donor (Living donor transplant)Transplanting one kidney Of live person in anotherPerson.
Living –relatedBiological relationsExist between donor And recipientExample : mother and childBrother and sister etc.
Living –unrelatedNo biological relation existExample : you and me !
ContraindicationsContraindications of of TransplantTransplant
Malignancy with metastasis.Refractory cardiac failureChronic respiratory failureAdvanced hepatic diseaseExtensive vascular diseaseChronic infection , unresponsive to
treatmentHIV infectionSevere mental retardationPersistent coagulation disorder
Living donorsLiving donors
Donors are carefully evaluated on medical and psychological grounds
Overall, recipients of kidneys from live donors do relatively well, in comparison to deceased donors
Kidney is removed either laparoscopically or by incision.
Deceased DonorsDeceased Donors
can be divided in two groups:
Brain-dead (BD) donors Donation after Cardiac Death(DCD)
donors
Brain-dead (BD) donorsBrain-dead (BD) donors
Although brain-dead (or "heart-beating") donors are considered dead, the donor's heart continues to pump and maintain the circulation
This makes it possible for surgeons to start operating while the organs are still being perfused
Donation after Cardiac Donation after Cardiac DeathDeath
Donors are patients who have no chance of recovery whatsoever
Treatment is stopped - mechanical ventilation is shut off
After death has been declared, the patient is rushed to the operating theatre, where the organs are recovered
The transplant surgery lasts about three hours
The donor kidney will be placed in the lower abdomen and its blood vessels connected to arteries and veins in the recipient's body
Blood will be allowed to flow through the kidney again, so the ischemia time is minimized
In most cases, the kidney will soon start producing urine
Depending on its quality, the new kidney usually begins functioning immediately.
Living donor kidneys normally require 3-5 days to reach normal functioning levels.
Cadaveric donations strech that interval to 7-15 days.
Hospital stay is typically for four to seven days.
If complications arise, additional medicines or dialysis may be administered to help the kidney produce urine.
Medicines are used to suppress the immune system from rejecting the donor kidney.
These medicines must be taken for the rest of the patient's life.
The most common medication regimen today is : tacrolimus, mycophenolate, and prednisone.
Some patients may instead take cyclosporine, rapamycin, or azathioprine.
Basics of ImmunosuppressionBasics of Immunosuppression
Immune system distinguishes self from non-self Antigen: anything that can trigger an immune
response B-cell (lymphocyte) – secretes antibodies, presents
antigen to T-cell T-cell (lymphocyte), secretes cytokines (ex. IL-2),
directs and regulates immune responses, also attacks infected, cancerous or foreign cells
Basics of ImmunosuppressionBasics of Immunosuppression
Cytokines are chemical messengers – bind to target cells, encourage cell growth, trigger cell activity, direct cell traffic, destroy target cells, and activate phagocytes (“cell eaters”)
IL-2 activates T-cells and causes proliferation T-cell surface markers (CD3, CD25, CD52 and T-
cell receptor) CD=cluster of differentiation of T-cells
T- Lymphocyte ActivationT- Lymphocyte Activation
Three signals involved in T-cell activationCalcineurin is activated and induces
cytokine genes and T-cell activation genesIL-2 binds to IL-2 receptor which in turn
activates Target of Rapamycin (TOR) and promotes T-cell proliferation
De novo synthesis of purines is necessary for B and T cell proliferation
Management of a Transplant Management of a Transplant RecipientRecipient
Induction Therapy: administer medications that provide marked suppression prior to and during the first week post transplantation, some agents can also block B-cell mediated rejection
Maintenance Therapy: administer immunosuppressive agents continuously to prevent acute rejection
Administer medications to induce Tolerance?
What is Tolerance?What is Tolerance?
Immunologic unresponsiveness by the recipient to the kidney graft in the absence of maintenance immunosuppression.
Factors Determining Factors Determining Transplantation OutcomesTransplantation Outcomes
Type of donor (cadaveric vs. living) Matching and sensitization
– HLA match (0 antigen mismatch > 6 antigen mismatch)– Negative crossmatch
Racial Differences Recipient Age Donor Age Other Factors (delayed graft function, cold ischemia time, acute
rejection, chronic rejection, years on dialysis, diseases leading to ESRD)
ComplicationsComplications
Transplant rejection (hyperacute, acute or chronic)
Infections and sepsis Post-transplant lymphoproliferative
disorder Imbalances in electrolytes
What happens in What happens in transplantationtransplantation ? ?
Organ containing different HLA molecules is introduced in our body.
Immume system of our body recognizes these HLA as non self
immune system attacks on these organ containing different HLA and try to destroy them
This is called as rejection
What to do to prevent What to do to prevent rejection ?rejection ?
Matching
Blood type matching, Tissue type matching and Cross-matching
BLOOD TYPE MATCHINGBLOOD TYPE MATCHING
The basic donation pathways in kidney transplantation are very similar to those used in blood transfusions.
TISSUE MATCHINGTISSUE MATCHING
For tissue matching at least 6 specific antigens are matched between donor and recipient
These are HLA antigens on surface of kidney cell.
More matching means less chance of rejection
CROSSMATCHINGCROSSMATCHING
Very sensitive and final test performed on a kidney donor and a particular recipient.
Test involves a mixing of cells and serum (before transplantation) to determine whether or not the recipient of a kidney will respond to the transplanted organ by attempting to reject it
As many as 10 to 15 different or separate tests are done.
On balance, however, a well matched kidney is one in which
The blood type between the donor and recipient are compatible,
The tissue typing well defined and hopefully well matched and
All crossmatch studies are negative
Clinical phases of rejectionClinical phases of rejection
1.Hyperacute rejection (minutes to hours) Preexisting antibodies to donor HLA antigens Complement activation, macrophages
2. Acute rejection (around 10 days to 30 days) Cellular mechanism (CD4, CD8, NK,
Macrophages)
3. Chronic rejection (months to years !!) Mixed humoral and cellular mechanism
CHRONIC REJECTION IS STILL HARD TO MANAGE !
!
Treatment of kidney Treatment of kidney rejectionrejection
Hyperacute - Sometimes during the operation – No therapy, usually results in graft failure – kidney
should be removed
Acute (Most frequently in the first 4 weeks)– Dg.: BIOPSY !– Increase immunosuppression
Increase steroid dose Increase cyclosporin (monitor serum level !) ATG, ALG, OKT3
Chronic– ACE inhibitors, prostacyclin analog drugs– Steroid, Azathioprine, Mycophenolate
The average lifetime for a The average lifetime for a donor kidney is donor kidney is ten to fifteen ten to fifteen
yearsyearsWhen a transplant fails a When a transplant fails a
patient may opt for a second patient may opt for a second transplant, and may have to transplant, and may have to return to dialysis for some return to dialysis for some
intermediary time. intermediary time.
History of Kidney TransplantationHistory of Kidney Transplantation1950’s First successful kidney transplant Total body irradiation for immunosuppression Steroids
1960’s Azathioprine
1970’s Polyclonal anitbodies – anti-lymphocyte globulin
1980’s Cyclosporine , “triple drug therapy” Monoclonal antibody, OKT3 in 1985
Goals of Transplant ResearchGoals of Transplant Research
Prevent rejection and kidney graft loss Reduce the amount of immunosuppression
– Decrease side effects– Decrease toxicity and long term effects
Enhance long term patient and graft survival Provide reasonable cost effective therapy Improve patient adherence and quality of life Induce Tolerance (no long term medications, reduces
adverse effects, improves quality of life)
Immunosuppressant Discoveries Immunosuppressant Discoveries 1990-20001990-2000
Tacrolimus
Mycophenolate Mofetil
Basiliximab
Cyclosporine Microemulsion
Daclizumab
Rabbit Antithymocyte globulin
Sirolimus
Modes of Action of Currently Modes of Action of Currently Available ImmunosuppressantsAvailable Immunosuppressants
Calcineurin inhibitors– Cyclosporine– Tacrolimus
Purine synthesis inhibitors– Azathioprine– Mycophenolate mofetil
Nonspecific– prednisone
Target of Rapamycin inhibitor– Sirolimus
Polyclonal antibodies (bind several CD’s)
– Antithymocyte
globulin Monoclonal Antibodies
– Blocks Il-2 receptor Daclizumab Basilixmab
– OKT3 (anti-CD3)
Latest Agents Latest Agents
Campath 1H (anti-CD52) – lymphocyte and monocyte depleting agent
Deoxyspergualin – blocks maturation of T and B cells
Everolimus – TOR inhibitor like sirolimus FTY-720 – reversible depletion of lymphocytes
from peripheral blood (migration to spleen) CTLA4-Ig – blocks T-cell activation
Other New Developments in Other New Developments in Kidney TransplantationKidney Transplantation
Laparoscopic kidney donation– Advantages: less post operative pain, shorter hospital
stay, minimal scarring– Disadvantages: impaired early graft function, graft loss
or damage, longer operative time Improved surgical techniques and storage of the
kidney graft New antibiotics to treat and prevent opportunistic
infections (new antifungals, oral ganciclovir and valganciclovir)
Role of the Transplant SpecialistRole of the Transplant Specialist Disease state management
– Hypertension– Diabetes Mellitus– Osteoporosis– Hyperlipidemia– Electrolyte abnormalities
Patient understanding and adherence to the drug regimen
Pharmacokinetic drug level monitoring Drug interactions (esp. with immunosuppressants) Adverse drug reaction monitoring
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