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

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

6. 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

7. 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

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 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)

10. 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

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 Viral Fungal
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