Transplantation

1. Transplantation Junior Basic Science Carla Fisher, MD 12-15-09

2. Transplant immunology • Major antigens responsible for rejection are the genes known as the major histocompatibility complex (MHC) • In humans MHC is known as human leukocyte antigen (HLA) • Class I (-A, -B, -C) are found on all nucleated cells • Class II (-DR, -DP, -DQ) are expressed on antigen presenting cells (B lymphocytes, monocytes, dendritic cells) • Can get humoral or cellular (more common) rejection

3. Transplant Immunology • Allorecognition • recognition of foreign HLA molecules by recipient T cells • Panel reactive antibody (PRA) • Detects presence of donor-specific antibodies by testing reactivity of the recipient’s serum to a panel of common A, B, and DR antigens • Results expressed as a percentage • Higher PRA indicates patient more likely to have an episode of acute cellular rejection

4. Immunosuppression • Induction: administered immediately post operatively to induce immunosuppression (biologic) • Maintenance: to maintain immunosuppression once recovered from OR (non-biologic) • In 1960s, 2 drugs were available. Currently there are 15+ available.

5. Immunosuppression • CORTICOSTEROIDS • historically first used • proven benefits however many side effects, esp in long term • for this reason steroids have been removed from many newer immunosuppressive protocols • first line therapy for acute rejection • common side effects: • mild cushingoidfacies and habitus • acne • increased appetite • mood changes • htn • prox muscle weakness • glucose intolerance • poor wound healing

6. immunosuppression • AZATHIOPRINE (IMURAN) • inhibits purine synthesis which inhibits T cells • 6-mercaptopurine is active metabolite • side effect is myelosuppression • MYCOPHENALATE MOFETIL • similar to azathioprine as an anti-metabolite but is more selective

7. immunosuppression • CYCLOSPORINE • binds cyclophilllin and inhibits genes for cytokine synthesis (IL-2) decreases T cell activation • calcineurin inhibitor • side effects include nephrotoxicity, hepatotoxicity, tremors, seizures, hirsuitism • TACROLIMUS (FK-506, Prograf) • actions similar to CSA but much more potent • calcineurin inhibitor • similar SEs to CSA but more GI and neurologic changes • SIROLIMUS • does not affect calcineurin activity

8. Biologic Immunosuppression • ANTITHYMOCYTE GLOBULIN (ATGAM) • equine polyclonal antibodies directed against antigens on T cells • must be infused via central line, premedication with steroids/benadryl • induction therapy • THYMOGLOBULIN • rabbit polyclonal antibodies • similar to ATGAM, may be more effective

9. Monoclonal antibody immunosuppression • used for prevention and treatment of acute (severe) rejection • Muromonab-CD3 • anti-CD25 mAbs (basiliximab and daclizumab) • humanized anti-CD52 mAbalemtuzumab (Campath-1H) • anti-CD20 (rituximab) • anti–lymphocyte function-associated antigen-1 (anti–LFA-1) • anti–intercellular adhesion molecule-1 (anti–ICAM-1) • anti–tumor necrosis factor alpha (TNF-α) (infliximab)

10. Types of rejection • Hyperacute: • occurs within minutes • caused by preformed abs that should be picked up by crossmatch • Accelerated acute: • occurs within first few days • cellular and antibody mediated response • caused by sensitized T cells to donor antigens • Acute: • less common with modern immunosuppression • within days to months after transplantation • predominantly a cell mediated process, lymphocytes • usually manifested with abnormal laboratory values but pt asymptomatic • Chronic: • months to years after transplant • increasingly common problem • multifactorial

11. Which of the following statements regarding kidney transplantation is/are true? • The one year actuarial survival rate for all patients is greater than 95% • The survival rate following transplantation appears to be improved only in diabetic patients • The primary cause of graft loss after 5 years is chronic rejection • Treatment of chronic refection has improved significantly over the past 10 years • Treatment of renal failure with transplantation becomes cost effective at the end of the second transplant year

12. Kidney Transplantation • currently approx 70,000 patients awaiting kidney transplant • mortality usually related to stroke/MI • attach to iliac vessels, usually on the R • post op UOP impt to assess graft (must know pre operative UOP) • decreased UOP post kidney transplant? • hypovolemia • vascular thrombosis • bladder outlet obstruction • ureter obstruction • drug toxicity • acute rejection

13. Kidney Transplantation - Complications • Urologic • can be due to poor blood supply to ureter • drainage and stenting usually 1st line treatment • Vascular complications • renal artery (1%) or vein thrombosis • renal artery stenosis • Lymphocele • incidence 0.6% -18% • Rejection • Usually represented by ↑ Cr • w/u includes US and biopsy • 5 year graft survival 65% cadaveric, 75% living

14. Allocation of cadaveric renal allografts is dependent on which of the following? • Time on hemodialysis • HLA compatibility • Recipient’s age • PRA results • Region of transplant center

15. Pancreas Transplantation • commonly done simultaneously with kidney tx • do pancreas tx alone when pt’s diabetes severe enough to warrant immunosuppression • need donor celiac, SMA, portal vein

16. Pancreas/Kidney Transplantation • Successful tx results in: • Stabilization of retinopathy • ↓ neuropathy • ↑ nerve conduction velocity • ↓ autonomic dysfunction (gastroparesis) • ↓ orthostatic hypotension • No reversal of vascular disease

17. Pancreas Transplantation - complications • *common • Thrombosis (6%) • Hemorrhage • Infection • Pancreatitis • Rejection

18. Islet Cell Transplantation • Utilizes islets of Langerhans • Still requires immunosuppression • In 1995, a report of the International Islet Transplant Registry indicated that of 270 recipients, only 5% were insulin independent at 1 year posttransplant.

19. Liver Transplantation • Used for acute and chronic liver disease • Hepatitis (most common indication) • ETOH (must be abstinent x 6 mos) • Primary biliary cirrhosis, primary sclerosing cholangitis • Biliary atresia • Hepatocellular CA • Single tumor < 5cm • Up to 3 tumors < 3cm • APACHE score – best predictor of 1 year survival • Model for End stage Liver Disease

20. Liver Transplantation – Postoperative care • Serial laboratory check • Coags • Bilirubin • Glucose • LFTs

21. Liver Transplantation - complications • Bile leak (#1) – PTC, stent • Primary nonfunction – requires retransplantation • Hepatic artery thrombosis • Abscesses • IVC stenosis • cholangitis

22. Regarding liver tx for patients chronically infected with hepatitis C virus, which of the following statements is/are true? • Post-transplant re-infection with hepatitis C virus occurs in all patients • Post-transplant re-infection with hepatitis C virus can be prevented with combination therapy with interferon and ribavirin and hyperimmunoglobulin • Post-transplant re-infection with hepatitis C virus causes cirrhosis in approximately 30% of patients at 5 years after liver transplantation • The clinical course of hepatitis C after re-infection is more virulent than that of the original infection

23. Infections • Bacterial • More likely to occur immediately post transplant • Prevention of pneumocystis pneumonia with Bactrim • Viral • CMV • Fungal • Mortality 20%

24. Which of the following statements is/are true regarding CMV infection? • infection with CMV following kidney transplantation is the strongest predictor of poor long-term survival • The incidence of symptomatic CMV infection is declining owing to the utilization of screening tests • Patients at highest risk for developing CMV infection are those who test seropositive for CMV IgG • CMV infection is more likely to cause chronic allograft nephropathy than infection with BK virus • CMV infection can be indistinguishable from acute EBV infection

25. Malignancy • Non-melanomatous skin cancers – 3-7x more likely • Post transplant lymphoproliferative disorder – 2-3x more likely • EBV • Gynecologic/urologic cancers • Kaposi’s sarcoma