Renal (Kidney) Transplantation Kidney Transplant Inserting a kidney of another live or dead person into a person. The donor kidney is typically placed.

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