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

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

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

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.

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 cushingoid facies and habitus acne increased appetite mood changes htn prox muscle weakness glucose intolerance poor wound healing

immunosuppression AZATHIOPRINE (IMURAN) MYCOPHENALATE MOFETIL 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

immunosuppression CYCLOSPORINE TACROLIMUS (FK-506, Prograf) SIROLIMUS 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 similar SEs to CSA but more GI and neurologic changes SIROLIMUS does not affect calcineurin activity

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

Monoclonal antibody immunosuppression used for prevention and treatment of acute (severe) rejection Muromonab-CD3 anti-CD25 mAbs (basiliximab and daclizumab) humanized anti-CD52 mAb alemtuzumab (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)

Types of rejection Hyperacute: Accelerated acute: Acute: Chronic: 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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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