1. Clinical Management of Kidney Transplants Dr. Michael Hadjigavriel Director Nephrology Larnaca General Hospital Cyprus - 2009 -Overview-

2. Pre-transplant Management Donors/Recipients

3. ABO compatibility A»A, A»AB B»B, B»AB AB»AB O»O, O»A, O»B, O»AB Rhesus compatibility not necessary (Blood group antigens that determine blood type are found on all cells while antigens for the rhesus are present only on the red blood cells)

4. Donors/Recipients Non ABO Compatible Donors –To increase graft availability some centers started to use non ABO compatible donors after specific treatment with rituximab (chimeric monoclonal antibody against the protein CD20) and plasmapheresis. –Results are comparable and very promising

5. Donors/Recipients HLA Compatibility more common HLA antigens between donor and recipient > better graft survival.

6. HLA Typing Process of identifying genetic markers (antigens) on leucocytes 3 general groups of HLA: A, B, DR Each group is inherited as part of a set from each parent and it’s known as Haplotype There are many HLA proteins: HLA –A 325, HLA-B 592, HLA-DR 451 220 genes coding MHC

7. Example Patient x has: -1 to 4 chances to have identical match with his brothers/sisters (i.e. to share the same 2 haplotypes) -1 to 2 chances to have partial compatibility with his brothers/sisters (i.e. to share 1 haplotype) -1 to 8 chances of compatibility with his cousins

8. Donors/Recipients Cross match –Positive: presence of antibodies against donor antigens. –Negative: No antibodies against donor antigens In normal practice to proceed to Tx cross match must be NEGATIVE

9. Donors /Recipients Kidney Transplantation with “Positive x-match” and “Sensitized patients” To increase number of transplants in positive x-match and/or sensitized patients (until lately non transplantable) some centers proceed to transplantation after removal of cytotoxic antibodies* from recipients with medications (rituximab, etc) and plasmapheresis (prior and after tx accordingly). Results are comparable and very promising (*These antibodies usually occur after pregnancy, blood transfusions or previous transplantations)

10. Donors/Recipients Donors Excluded Age >70 years: Special criteria applied Carriers of chronic infections: HIV, Hep. B, Hep C, etc.: Special criteria applied Carriers of chronic diseases: diabetes, cancer, amyloidosis, vascular patients, autoimmune diseases, renal dysfunction, etc.: Special criteria applied

11. Donors/Recipients Recipients excluded: Age >70: Special criteria applied High risk patients for major surgery: severe cardiovascular disease, etc High risk patients for: cancer, acute or chronic infections, etc Surgical impediments: calcified vessels, bladder diseases (neurogenic, BPH) etc.

12. Donor / Recipient preparation

13. Donor Preparation General biochemistry Hematology Viral studies (HBsAg, HCV, HIV, CMV, EBV, HSV) Ab’s or DNA accord. Hormones (PSA, CEA,CA 9-19, CA 125, AFP, etc) Urine (routine, culture, 24 hour protein, creatinine clearance) Imaging (US, IVP, MRA, chest x-ray) Specialized evaluation (ECG, cardiac echo, stress test, etc) Any other test or Specialized evaluation if indicated.

14. Recipient preparation General biochemistry Hematology Viral studies (HBsAg, HCV, HIV, CMV, EBV, HSV) Ab’s or DNA accordingly. Hormones (PSA, CEA, AFP,CA 9-19, CA 125, etc) Imaging (US abdomen,Plain Abdomen & pelvis, Chest x-ray) Specialized evaluation (ECG, cardiac echo, stress test, urodynamics, etc) Any other test or Specialized evaluation if indicated.

15. Recipient Preparation Pre-transplant immunosuppression: Protocol used: 24 hours before Tx: –Steroids (prednisone) 5mg/kg/bw (in divided doses) –MMF 500-1000 mg BD –1 hour before Tx: basiliximab (Simulect) 20mg iv (stat) (To be repeated on day 4 after tx). All recipients are started on Gancyclovir and Broad Spectrum Antibiotic Prophylaxis before surgery

16. Post-transplant Management Recipients

17. Post-transplant immunosuppression: Different Protocols in use: CyA+MMF+Pred CyA+SIR+Pred CyA+EVER+Pred TAC+MMF+Pred TAC+SIR+Pred SIR+MMF+Pred + Basiliximab or daclizumab : monoclonal antibodies anti inter leukin – 2 receptor antagonist (IL-2R)

18. Recipients Right after TX and or within 24 hrs: - Solumedrol 125-500 mg BD x 3 days and Accordingly (Initial Dose): - CyA: ~8mg/kg/bw/day in 2 doses - MMF ~1000-2000 mg/day in 2 doses - TAC ~0.1-0.2/kg/bw/day in 2 doses - EVER ~1.5mg/day in 2 doses - SIR ~5mg/day in 2 doses

19. Recipients Usually 7-10 days after initial dosing, doses of immunosuppressants are adjusted to obtain desired levels. Drug serum levels depend on protocol (combination of immunosuppressants) used. Special attention to other drugs influencing serum levels of immunosuppressants. Drug monitoring should be scheduled and performed periodically together with patient follow up.

20. Kidney Transplants Post-transplant complications Surgical Complications renal artery thrombosis / stenosis venous thrombosis / stenosis urinary leak (from UV anastomosis, ureter) UV stenosis lymphoceles

21. Kidney Transplants Post-transplant complications Medical (pathology) immediate or chronic Complications Rejection: Hyperacute/acute/chronic (CAN) Infection: viral/ bacterial/ mycotic/ opportunistic Cardiovascular: CAD/ CHF/ CVA/ HT Cancer: skin/ blood/ solid organs Diabetes / cataract/ hirsutism/ alopecia/ gum hypertrophy/ obesity/ impotence/ etc Drug toxicity (calcineurin inhibitors, etc.)

22. Kidney Transplants Follow up schedule for Tx patients: 1 st month: 3 times a week 1-3months: once a week 3-6months: once every 2 weeks 6 months-2 years: once a month 2 years and over: every 2 months

23. Follow up schedule should include : Haematology General biochemistry Urine (MSU, 24 hr collection) Drug level monitoring Detailed Clinical examination Diagnostic imaging (when necessary) Tx Biopsy (when necessary) Special attention to: cardiovascular disease, neoplastic disease, infection and parathyroid function

24. Specific and General Information on Kidney Tx

25. Specific Information Kidneys from LRD: Less cold ischemia time, less ATN, prompt diuresis, usually no need for HD after TX. Kidneys from CAD: longer cold ischemia time, more ATN, delayed diuresis, more frequent need for HD after TX.

26. Specific Information Treatment of Acute rejection: Steroid boluses: Methylprednisolone ATG: Polyclonal antibody, Rabbit antihuman activated T-Lymphocyte globulin. OKT3: murine monoclonal IgG2a antibody that specifically reacts with the T cell receptor-CD3 complex on the surface of circulating human T cells. ATGAM: lymphocyte immune globulin, anti- thymocyte globulin [equine]. Rituximab: Chimeric monoclonal antibody against the protein CD20. Plasmapheresis Irradiation of graft (abandoned method in majority of centers)

27. Specific Information CAN ( Chronic Allograft Nephropathy) Etiology: Cold Ischemia time Renal injury Degree of immunosuppression N° of acute rejections Drug toxicity Etc.

28. Specific Information CAN (Chronic Allograft nephropathy) Clinical signs and symptoms: Chronic reduction of renal function: rising creatinine, reduced GFR, etc. Biopsy: CAN (lymphomonocytic infiltration, sclerosis, etc) US: increased ecogenicity of graft Other signs and symptoms of progressive CRF (hypertension, proteinuria, etc).

29. Specific Information CAN (Chronic allograft nephropathy) Treatment: Change protocol of immunosuppression (?) Eliminate worsening cofactors (nephrotoxic drugs, stabilize hemodynamics, etc.) If acute on chronic rejection is suspected treat accordingly.

30. Thanks Any Questions?