2. Renal (Kidney) Transplantation

3. Kidney 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.

5. Indications Indications 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

6. Am J Kidney Dis 1999;34(Suppl1) Cause of End Stage Renal Disease Among New Patients on Hemodialysis 28% 13% 3% 18%

7. Kidney 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

8. Am J Kidney Dis 1999;34(Suppl 1) Options in End Stage Renal Disease 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

9. Dialysis Peritoneal Hemodialysis

10. 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. Transplantation

11. 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 another Person. Living –related Biological relations Exist between donor And recipient Example : mother and child Brother and sister etc. Living –unrelated No biological relation exist Example : you and me !

12. Contraindications of Transplant Malignancy with metastasis. Refractory cardiac failure Chronic respiratory failure Advanced hepatic disease Extensive vascular disease Chronic infection, unresponsive to treatment HIV infection Severe mental retardation Persistent coagulation disorder

13. Living 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.

14. Deceased Donors can be divided in two groups: Brain-dead (BD) donors Donation after Cardiac Death(DCD) donors

15. Brain-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

16. Donation after Cardiac Death 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

17. 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

18. 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.

19. 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.

20. Basics 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

21. Basics 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

22. T- Lymphocyte Activation Three signals involved in T-cell activation Calcineurin is activated and induces cytokine genes and T-cell activation genes IL-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

23. Management of a Transplant Recipient 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?

24. What is Tolerance? Immunologic unresponsiveness by the recipient to the kidney graft in the absence of maintenance immunosuppression.

25. Factors Determining Transplantation 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)

26. Complications Transplant rejection (hyperacute, acute or chronic) Infections and sepsis Post-transplant lymphoproliferative disorder Imbalances in electrolytes

27. What happens in transplantation ? 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

28. What to do to prevent rejection ? Matching Blood type matching, Tissue type matching and Cross-matching

29. BLOOD TYPE MATCHING BLOOD TYPE MATCHING The basic donation pathways in kidney transplantation are very similar to those used in blood transfusions.

30. TISSUE MATCHING TISSUE 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

31. CROSSMATCHING 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.

32. 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

33. Clinical 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 ! !

34. Treatment of kidney rejection 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

35. The average lifetime for a donor kidney is ten to fifteen years When a transplant fails a patient may opt for a second transplant, and may have to return to dialysis for some intermediary time.

36. History of Kidney Transplantation 1950’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

37. Goals 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)

38. Immunosuppressant Discoveries 1990-2000 Tacrolimus Mycophenolate Mofetil Basiliximab Cyclosporine Microemulsion Daclizumab Rabbit Antithymocyte globulin Sirolimus

39. Modes of Action of Currently Available 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)

40. 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

41. Other New Developments in Kidney 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)

42. Role 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