Elizabeth A. Hooper, M.D., Edie Y. Chan, M.D., Edward F. Hollinger, M.D., Ph.D.
1 A 53-year-old African-American man with diabetic nephropathy receives a cadaveric renal transplant from a 30-year-old healthy donor. Which of the following statements is false.
A The 1-year graft survival rate is 90%.
B The patient’s life expectancy following transplantation more than doubles in diabetic patients.
C The primary cause of graft loss after 5 years is chronic rejection.
D Treatment of chronic rejection has improved significantly over the past 10 years.
E Treatment of renal failure with transplantation becomes cost-effective at the end of the second transplant year.
Ref.: 1-3
Comments
The graft survival rate is 89% for all deceased donor transplants. Grafts from extended-criteria donors have a decreased 1-year survival rate of 81%, whereas grafts from traditional-criteria donors have a 90% survival rate at 1 year. Recipients of living donor grafts have a 95% 1-year graft survival rate. For patients with diabetes, the average life expectancy is 8 years if no transplantation occurs. In contrast, patients receiving a transplant have an increase in average life expectancy of 19 years. Graft loss as a result of acute rejection has continued to follow a declining trend since the introduction of cyclosporine in the 1980s and tacrolimus in the 1990s. However, the incidence of graft loss because of chronic rejection has not changed significantly over the past 10 years. Despite improvements in immunosuppression and monitoring of opportunistic diseases, the 5-year survival rate after kidney transplantation is 70% for non–extended-criteria grafts, with most grafts being lost to chronic rejection. Transplantation becomes cost-effective when compared with dialysis at the end of the second year.
Answer
D
2 A 60-year-old woman has renal failure secondary to hypertension; she is undergoing hemodialysis and waiting for a cadaveric renal transplant. Which of the following statements regarding kidney transplantation is true?
A Crossmatching is performed before kidney transplantation to prevent graft loss from chronic cellular rejection.
B A positive crossmatch is an absolute contraindication to cadaveric renal transplantation.
C Hyperacute rejection is responsive to additional immunotherapy.
D Routine screening of potential recipients with the panel-reactive antibody (PRA) test can predict the presence of donor-specific antibodies.
E ABO incompatibility is an absolute contraindication to kidney transplantation.
Ref.: 4, 5
Comments
Hyperacute rejection of a transplanted kidney generally occurs within minutes of reperfusion and is due to the presence of preformed immunoglobulin G (IgG) antibodies in the recipient’s serum. These antibodies attach to major histocompatibility antigens (HLA-A, HLA-B, and HLA-DR) on the donor vascular endothelium. The test for donor-specific antibodies is called a crossmatch and is performed on all potential donors just before transplantation.
A positive crossmatch result is a relative contraindication to cadaveric renal transplantation. With cadaveric kidneys, there is insufficient time for preoperative plasmapheresis and intravenous immunoglobulin until a negative crossmatch is obtained. This increases the risk of immunologic graft loss. Patients undergoing living related renal transplantation with a positive crossmatch result can be treated to remove the antibody (through plasmapheresis, the administration of gamma globulin, or both) and agents such as Rituxamab (anti-CD-20) can be used to decrease antibody production. If a subsequent crossmatch result is negative following treatment, living related or unrelated renal transplantation can be performed with an acceptable success rate. Potential recipients of ABO-compatible renal allografts develop donor-specific HLA antibodies of the IgG class from antigen exposure because of transfusions, pregnancy, or previous transplants. The presence of donor-specific antibodies can be predicted by periodically testing the reactivity of the recipient’s serum to a panel of common A, B, and DR antigens and expressing the result as a percentage. This test is referred to as the panel-reactive antibody. The higher the PRA result at the time of transplantation, the more likely a patient is to have an episode of antibody mediated rejection. Previous recipients of ABO-incompatible allografts have had a high incidence of hyperacute rejection from preformed isoagglutinins, also of the IgG type, which attach to A and B antigens expressed by the vascular endothelium. However, success in Japan with ABO-incompatible donors and an increasing shortage of donors have resulted in recent evaluation of the use of ABO-incompatible renal allografts. The combination of modern immunosuppression and the use of plasmapheresis to remove isoagglutinins has resulted in acceptable graft survival rates. Recent studies have shown success with type A2 kidneys transplanted into type O recipients.
Answer
D
3 A 43-year-old woman undergoing dialysis for end-stage renal disease secondary to hypertension is placed on the transplantation waiting list. Allocation of cadaveric renal allografts is not dependent on which of the following?
A Number of prior kidney transplants
B HLA compatibility
C Previous living kidney donor status
D PRA test results
E Time spent on the waiting list
Ref.: 4
Comments
Allocation of cadaveric renal allografts is dependent on the length of time that the recipient has been maintained on hemodialysis, HLA compatibility, PRA results, and any previous history of kidney donation by the waiting recipient. Age is not a factor. HLA antigens are inherited on chromosome 6, and although multiple HLA antigens have been identified, kidney recipients and donors undergo tissue typing for only three antigens: HLA-A, HLA-B, and HLA-DR. Since these antigens are inherited from each parent, usually as a codominant allele, offspring have two HLA-A antigens, two HLA-B antigens, and two HLA-DR antigens. Siblings have a 25% chance of being HLA identical, a 50% chance of sharing one haplotype, and a 25% chance of being HLA dissimilar. HLA matching for all six antigens has resulted in improved long-term outcome in patients undergoing both living related and cadaveric renal transplantation. As a result, cadaveric organs that match for all six antigens are allocated nationwide. If no six-antigen matches can be found for a cadaveric renal allograft, the organ is placed locally, with points given for the number of HLA matches, PRA results, and time spent on the waiting list.
Answer
A
4 Which of the following best describes the preservation process for kidneys procured for transplantation?
A Continuous pulsatile perfusion with solutions that mimic intracellular electrolytes has proved to be superior to simple cold storage.
B Continuous pulsatile perfusion uses lactated Ringer solution for preservation.
C Simple cold storage allows longer preservation time because of its simplicity.
D University of Wisconsin (UW) solution contains lactobionate, which suppresses hypothermia-induced cell swelling.
E Simple cold storage is equivalent to continuous pulsatile perfusion when storage times are longer than 24 hours.
Ref.: 1
Comments
In 1987, University of Wisconsin solution was introduced at the University of Wisconsin by Belzer and Southard. This solution contains lactobionate, an osmotic agent that serves to inhibit calcium-dependent enzymes. This reduces hypothermia-related changes, including swelling of cells. Pulsatile perfusion is expensive and has been shown only to reduce delayed graft function. There is no difference in graft survival rates when comparing simple storage with pulsatile perfusion. For kidneys undergoing pulsatile perfusion, cryoprecipitated homologous plasma or other preservation solution is used, not crystalloid such as lactated Ringer solution.
Answer
D
5 A 30-year-old woman with lupus receives a kidney transplant. Two hours later she is anuric. Vital statistics about the kidney include a cold ischemia time of 10 hours, a 60-year-old donor, a negative crossmatch, and PRA of 80%. Select the best next step of management:
A Immediate angiogram to rule out arterial occlusion
B Immediate sonographic studies to verify vessel patency
C Immediate reexploration
D Immediate administration of high-dose steroids to treat rejection
E Magnetic resonance angiography to determine vessel patency
Ref.: 6
Comments
The most common cause of delayed graft function following kidney transplantation is acute tubular necrosis (ATN). However, ATN is usually characterized by urine production in the range of 10 to 30 mL/h, which generally declines to 0 to 5 mL/h over the first 24 hours. Although surgical complications such as vascular thrombosis and ureteral obstruction are rare, they must be excluded in patients who have anuria immediately after kidney transplantation. The initial test of choice is a Doppler ultrasound to verify vessel patency, exclude the presence of a fluid collection secondary to a hematoma or a urinoma that may be impinging on the graft, and rule out arterial or venous obstruction from kinking of one or both vessels. If no flow is seen in either the renal artery or vein, reexploration is indicated. Ultrasound is a quick, reliable, and noninvasive test to evaluate vessels and detect hydronephrosis and fluid collections; it should be performed before returning to the operating room.
Answer
B
6 A 30-year-old type 1 brittle diabetic patient with diabetic nephropathy receives a simultaneous pancreas and kidney (SPK) transplant. Which of the following statements is true?
A Elevation of plasma glucose levels in the early postoperative period is indicative of pancreas rejection.
B Bladder drainage is preferred because it is associated with fewer complications.
C Most surgeons prefer enteric drainage because the incidence of complications attributed to bladder drainage, such as acidosis and urinary tract infections, is decreased.
D Most surgeons prefer bladder drainage because the incidence of infections is reduced by avoiding contamination with enteric contents.
E The preferred enteric drainage of the pancreatic allograft is the cecum.
Ref.: 7
Comments
The first sign of renal rejection in an SPK transplant recipient may be elevated serum creatinine levels. Elevation of glucose in the immediate postoperative period can be a sign of vascular compromise. In long-term patients, elevated glucose is a late sign of rejection. Enteric drained pancreas transplants have a lower leak rate than those drained to the bladder, however a leak in an enteric anastamosis is more likely to result in graft loss. Long-term complications of bladder drainage include acidosis, infection, and cystitis from the loss of bicarbonate into the bladder. Bladder drainage is commonly converted to enteric drainage because of acidosis and recurrent urinary tract infections. Enteric drainage of the pancreas does not have a higher infection rate than bladder drainage. The preferred enteric drainage site is the small bowel.
Answer
C
7 Which of the following would exclude a patient from whole-organ pancreatic transplantation?
A History of hypoglycemic unawareness without end-organ damage
B History of coronary artery bypass grafting
C History of diabetic neuropathy
D History of lower extremity peripheral vascular disease
E None of the above
Ref.: 1
Comments
When considering pancreas transplantation, the benefits must be weighed against the risks of surgery and lifelong immunosuppression. Brittle diabetic patients are candidates for pancreatic transplantation regardless of the presence of end-organ damage. Pancreas transplantation may be lifesaving in patients with severe hypoglycemic unawareness. In patients with good glycemic control and no evidence of end-organ damage, the risks associated with lifelong immunosuppression may outweigh the benefits of insulin independence. There is good evidence that optimal glycemic control decreases the progression of microvascular complications of diabetes. This is significant for patients with diabetic nephropathy, neuropathy, and retinopathy. Vascular disease of the coronary arteries and peripheral vasculature is also common in diabetics and is a significant factor in the preoperative evaluation process. The cardiac status of a potential recipient must be fully evaluated. In those with significant coronary disease, cardiac revascularization may be required before transplantation. Peripheral vascular disease does not exclude a patient from transplantation but may change the operative planning regarding placement of.
Answer
E
8 In a uremic diabetic patient who undergoes SPK transplantation, which of the following statements regarding the secondary complications of diabetes and pancreatic transplantation is false?
A Diabetic retinopathy generally improves after pancreatic transplantation.
B Recurrence of diabetic nephropathy in renal allografts can be avoided.
C Diabetic neuropathy can improve after pancreatic transplantation.
D Patients with advanced diabetic neuropathy have an improved survival rate after pancreatic transplantation.
E Diabetic gastropathy may stabilize.
Ref.: 7
Comments
Retinopathy has not been shown to reverse with successful transplantation, but by 3 years after transplantation, there is often no further progression. In control groups including those with failed pancreatic transplantation, retinopathy usually progresses. With normoglycemia, nephropathy may not only be halted but also actually reversed. Comparisons of diabetics who have undergone kidney transplantation alone versus pancreas recipients have shown remodeling of the basement membrane in normoglycemic patients. This reversal is seen in patients with normoglycemia for at least 5 years. Patients with neuropathy have improvement in both motor and sensory indices following successful pancreatic transplantation. The combination of diabetes and severe neuropathy leads to a lower survival rate. Improvement in long-term glucose control results in improved neural function and subsequent improved survival rates. Like other neuropathies, diabetic gastropathy stabilizes.
Answer
A
9 Regarding liver transplantation for patients chronically infected with hepatitis C virus (HCV), which of the following statements is true?
A Posttransplant reinfection with HCV occurs in only 50% of patients.
B Combination interferon and ribavirin therapy is effective in treating recurrent hepatitis C.
C Posttransplant reinfection with HCV causes cirrhosis in approximately 80% of patients at 5 years after liver transplantation.
D The clinical course of hepatitis C after reinfection is less virulent than that of the original infection.
E Allograft failure secondary to recurrence of HCV infection is the most common cause of death and retransplantation in recipients with HCV infection.
Ref.: 8-10
Comments
The most common indication for liver transplantation worldwide is HCV infection. Most patients with chronic hepatitis C virus infection who develop cirrhosis have had the infection for more than 20 years. Patients chronically infected with HCV who undergo liver transplantation uniformly become reinfected within a matter of days. No therapy is effective in preventing reinfection. Cirrhosis develops much earlier in the transplanted allograft, with approximately 5% to 20% of patients exhibiting cirrhosis on biopsy at 5 years following transplantation. Combination therapy with interferon and ribavirin eradicates the recurrent infection in a small percentage of patients (approximately 25% to 36%) after transplantation. The most common cause of death and retransplantation in recipients with HCV infection is recurrence of hepatitis C.
Answer
E
10 Mr. Smith is a 58-year-old gentleman with hepatitis B–associated cirrhosis. Regarding liver transplantation in patients chronically infected with hepatitis B virus (HBV), which of the following statements is true?
A The frequency of de novo infection in patients with grafts from donors who are hepatitis B core antibody positive is 5%.
B The presence of HBV DNA or hepatitis Be antigen (HBeAg) in the serum of recipients before transplantation increases the risk for posttransplant recurrence.
C The frequency of recurrence is higher in patients with fulminant HBV infection.
D The risk for posttransplant HBV infection is 50% in patients who have detectable surface antigen.
E The risk for transmission through blood products is 1 in 500,000.
Ref.: 11
Comments
Before availability of the reverse transcriptase inhibitors lamivudine and adefovir, liver transplantation in patients chronically infected with HBV had an unacceptably high rate of recurrence. However, patients now undergoing transplantation for liver failure secondary to hepatitis B virus infection have excellent outcomes, with a negligible rate of recurrence of the native infection. Patients who test positive for e antigen or for HBV DNA have an increased risk for recurrent infection. Patients with fulminant hepatic failure secondary to HBV infection have the lowest risk for the development of recurrent infection. The frequency of de novo infection in patients who receive a hepatitis B core antibody–positive liver is approximately 50%. The risk for transmission of HBV from blood products is 1 in 200,000 per unit of screened packed red blood cells.
Answer
B
11 A 58-year-old man undergoes orthotopic liver transplantation (OLT) for cirrhosis secondary to HCV infection. At the time of transplantation he receives induction immunosuppression therapy. All of the following may be used as induction agents except:
A Alemtuzumab (Campath)
B Sirolimus (Rapamune)
C Basiliximab (Simulect)
D Rabbit antithymocyte globulin (Thymoglobulin)
E Steroids
Ref.: 12
Comments
Rabbit antithymocyte globulin is an antilymphocyte globulin commonly used for induction therapy. It has antibodies against CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and HLA class I. Clinical trials have shown it to be an effective drug for preventing acute rejection after transplantation. Basiliximab is a chimeric anti-CD25 monoclonal antibody that blocks IL-2 stimulation of T-cells by competitively binds to the interleukin-2 (IL-2) receptor without activating it. Alemtuzumab is a humanized monoclonal antibody against CD52 that is expressed on B cells, T cells, monocytes, and macrophages. Use of this drug leads to depletion of lymphocytes for approximately 2 to 6 months. Though rarely used alone, high-dose steroids may be used as an induction agent. Rapamycin is used only for maintenance immunosuppression.
Answer
B
12 Which of the following is the most commonly used primary maintenance immunosuppressive agent?
A Tacrolimus (Prograf)
B Azathioprine (Imuran)
C Mycophenolate (CellCept)
D Rapamycin (Sirolimus)
E Prednisone
Ref.: 12, 13
Comments
Tacrolimus was first isolated from Streptomyces tsukubaensis. It is approximately 100 times more potent than cyclosporine. A U.S. multicenter trial in 1994 randomized 478 liver transplant recipients to either tacrolimus- or cyclosporine-based immunosuppression. This trial demonstrated that tacrolimus was associated with significantly fewer episodes of acute steroid-resistant or refractory rejection. Mycophenolate mofetil, azathioprine, and sirolimus are not as potent as tacrolimus and are rarely used alone. Prednisone administered as monotherapy is not the standard of care. Steroids are used for their unique immunosuppressive qualities, such as reduction in the synthesis of IL-2 and interferon-γ (INF-γ). They also inhibit the secretion of IL-1 from macrophages.
Answer
A
13 After OLT 2 years earlier for autoimmune hepatitis, a 30-year-old woman is seen in the clinic for routine follow-up and complains of diarrhea. Which of the following statements is true regarding the toxicity of immunosuppressive agents?
A The calcineurin inhibitors cyclosporine, tacrolimus, and rapamycin are nephrotoxic.
B Mycophenolate and rapamycin are toxic to the gastrointestinal system.
C Tacrolimus has been associated with an increased incidence of posttransplant diabetes.
D Cyclosporine and tacrolimus can cause hirsutism and gingival hyperplasia.
E Cyclosporine and tacrolimus can cause thrombocytopenia.
Ref.: 12-14
Comments
All immunosuppressive agents have toxicities, but they can be minimized by using various combinations of the agents at lower dosages. Both tacrolimus and cyclosporine cause renal vasoconstriction, which leads to nephrotoxicity by reducing renal blood flow. Rapamycin is not nephrotoxic, but causes thrombocytopenia and hypercholesterolemia. After binding with the receptor, cyclosporine and tacrolimus each bind to calcineurin and form a larger complex. Calcineurin is a calcium-dependent protein that plays a crucial role in activation of transcription of the IL-2 gene. This signaling takes place in T cells. Inhibition prevents further phosphorylation and stops the second messenger cycle, thereby halting propagation of the immune response. Mycophenolate inhibits purine synthesis, which is essential for the proliferative responses of T and B cells to mitogens. However, it can also cause gastrointestinal side effects, such as diarrhea, flatulence, and bloating. Mycophenolate is the only immunosuppressive agent that frequently causes toxicity in the gastrointestinal system. Tacrolimus has been associated with an increase in posttransplant diabetes. Only cyclosporine is also associated with hirsutism, gingival hyperplasia, and thrombocytopenia.
Answer
C
14 A 35-year-old man with a body mass index of 22 underwent kidney transplantation 6 weeks earlier for focal segmental glomerular sclerosis. He has a sense of fullness in his pelvis and increased urinary frequency. On physical examination the ipsilateral lower extremity is painless but noticeably swollen. Ultrasound of the lower extremities is negative for deep venous thrombosis. An ultrasound of the transplanted kidney shows normal flow and a heterogenous a fluid collection adjacent to the bladder. A diagnosis of lymphocele is made. Treatment of a lymphocele after kidney transplantation may include all except which of the following?
A Percutaneous drainage regardless of symptoms
B Percutaneous drainage with sclerosis
C Prolonged external percutaneous drainage
D Observation if asymptomatic
E Laparoscopic internal marsupialization
Ref.: 6
Comments
Lymphoceles develop after kidney transplantation in up to 50% of recipients, usually as a result of inadequate ligation of the iliac lymphatics. They do not require intervention if asymptomatic. However, if they compress the kidney or obstruct the ureter intervention is necessary. Initial treatment usually involves percutaneous drainage. If the lymphocele recurs, most surgeons would place an external drain percutaneously under ultrasound or computed tomographic (CT) guidance. Percutaneous drainage with sclerosing agents such as povidone-iodine can be used, but such treatment can have a directly toxic effect on the transplanted kidney limiting there. If the lymphocele reaccumulates and becomes symptomatic after removal of the external drain, internal drainage by marsupialization is indicated. The marsupialization involves fenestrating the peritoneum to drain the lymphocele into the peritoneal cavity. This can be done as an open procedure or laparoscopically with ultrasound guidance.
Answer
A
15 Liver transplantation may be contraindicated for which of the following?
A Cirrhosis from prior alcohol use
B Stage II hepatocellular carcinoma (HCC) with cirrhosis
C A 30-year-old patient with liver failure and uncorrected pulmonary hypertension
D A 30-year-old patient with liver failure and hepatopulmonary syndrome
E A 30-year-old patient with liver failure and portal vein thrombosis
Ref.: 15-18
Comments
Patients with alcoholic liver disease who are abstinent for more than 6 months and have good psychosocial support are considered good candidates for liver transplantation because of the low risk for alcohol recidivism. As a group their long-term survival rate may be one of the highest because they are often not subject to viral hepatitis and other progressive diseases that may recur in the transplanted liver. Alcohol use is frequently encountered in patients who are evaluated for other diseases, and they too should be abstinent for a certain defined period. Patients awaiting liver transplantation are currently classified by the Model for End-Stage Liver Disease (MELD) system. The MELD system is based on points (0 to 40) calculated from a logarithmic formula that uses a patient’s bilirubin and creatinine levels and the prothrombin time. Patients also receive additional points for HCC and hepatopulmonary syndrome.
Hypoxemia from severe pulmonary hypertension is an absolute contraindication to transplantation. Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mmHg with normal pulmonary capillary wedge pressure. The overall right heart dysfunction in these patients will not withstand reperfusion. The overall prevalence of pulmonary hypertension in the general population is 0.13%, although in patients with portal hypertension it is significantly higher, 0.73%. For patients with liver failure, pulmonary hypertension can be classified as mild (mean pulmonary pressure of 25 to 35), moderate (mean pulmonary pressure of 35 to 45), or severe (mean pulmonary pressure >45). Pulmonary artery pressure higher than 50 mm Hg despite therapy correlates with a nearly 100% mortality rate. Patients with untreated severe pulmonary hypertension who undergo liver transplantation are at very high risk for cardiac death from right ventricular failure immediately following reperfusion. Fortunately, for moderate and severe pulmonary hypertension, treatment with epoprostenol or prostacyclin by constant infusion can reduce pulmonary pressure to a range at which liver transplantation can be successful. Liver transplantation may be contraindicated in patients with severe pulmonary hypertension unresponsive to prostacyclin. For patients who do respond, prostacyclin can be gradually weaned after transplantation and pulmonary pressure will remain normal.
Hepatopulmonary syndrome is essentially the opposite of pulmonary hypertension. Pulmonary capillaries serving unoxygenated areas of the lung respond to the liver disease by dialating, which causes a significant reduction in pulmonary systolic pressure and increases the shunt fraction to as high as 10% to 20% (normal shunt fraction is 7%). As a result, patients require increasing amounts of supplemental oxygen. However, transplantation is curative, and the shunt fraction is reduced to normal often within a few days, although complete resolution may take up to 15 months. Portal venous thrombosis can be corrected by thrombectomy at the time of transplantation or by superior mesenteric vein grafting.
Answer
C
16 A 62-year-old woman comes to the emergency department because of nausea and vomiting. She underwent OLT for alcoholic cirrhosis 5 weeks earlier. Her white blood cell count is 1.0 cell/mL. Which of the following is the most likely cause of her clinical symptoms.
A Wound infection
B Cytomegalovirus (CMV)
C Pneumonia
D Bowel obstruction
E Rejection
Ref.: 19
Comments
Cytomegalovirus has the highest incidence of infection in seronegative recipients who receive seropositive organs. Early CMV disease occurs most commonly between 3 and 8 weeks after transplantation. Late disease can also occur. Treatments for rejection such as antilymphocytic or antithymocyte globulin increase the incidence of CMV infection. The most common symptoms of CMV are malaise, anorexia, myalgia, and arthralgia. Laboratory abnormalities include thrombocytopenia, neutropenia, and elevated liver enzymes. CMV infection can have clinical manifestations that include gastrointestinal tract inflammation, hepatitis, and in severe cases, pneumonia. The mainstay of therapy is ganciclovir.
Answer
B
17 Which of the following statements regarding CMV infection is true?
A Infection with CMV following kidney transplantation is the strongest predictor of poor long-term survival.
B The incidence of symptomatic CMV infection is declining secondary to the use of screening tests.
C Patients at highest risk for the development of CMV infection are those who test seropositive for CMV IgG.
D CMV infection is more likely than infection with polyomavirus (BK) virus to cause chronic allograft nephropathy.
E CMV infection can be indistinguishable from acute Epstein-Barr virus (EBV) infection.
Ref.: 20
Comments
With development of the effective antiviral agent ganciclovir, acute rejection, not CMV infection, is now the strongest predictor of poor allograft survival. The incidence of CMV infection is declining, probably because of very effective tests for viral load in the serum, such as CMV pp65 antigen and CMV DNA testing and early prophylaxis. Patients who are at the highest risk for CMV are those who test seronegative for CMV IgG and receive an allograft from a donor seropositive for CMV IgG. CMV infection is usually an acute, systemic infection that can result in gastritis, hepatitis, pneumonitis, retinitis, and bone marrow suppression. CMV infection rarely involves only one organand seldom causes chronic nephropathy. Infection with polyomavirus is usually isolated to the kidney and the urinary system. BK infection can cause nephropathy in the transplanted kidney. Active infection is associated with progressive loss of graft function, a condition also known as polyomavirus-associated nephropathy. Acute infection with Epstein-Barr virus generally causes inflammation of the gastrointestinal tract in the form of gastritis, enteritis, or colitis and is thus clinically similar to CMV infection. The two can easily be distinguished by checking serum viral loads with quantitative CMV DNA and EBV DNA testing. In addition, biopsy specimens from inflamed gastrointestinal mucosa can be specifically stained for each virus.
Answer
B
18 A 40-year-old man is seen in the office with an enlarged groin lymph node. He underwent kidney transplantation 3 years ago. An excisional biopsy specimen is consistent with posttransplant lymphoproliferative disorder (PTLD). Which of the following statements is true?
A The use of antilymphocyte globulin is a risk factor for PTLD.
B The incidence of PTLD is elevated in patients with pretransplant seronegative EBV titers.
C PTLD is more common in recipients who seroconvert their CMV status.
D PTLD develops more commonly in children than in adults.
E All of the above.
Ref.: 20, 21
Comments
Posttransplant lymphoproliferative disorder represents a spectrum of diseases related to Epstein-Barr virus infection, including infectious mononucleosis, benign proliferation of B cells, and lymphoma. In a transplant recipient, clones of EBV-transformed B cells are generated as a result of infection with EBV from the donor or personal contact. Because of impaired immunity, transplant recipients are unable to control the clonal expansion of EBV-infected B cells, and may develop hyperplasia (an EBV-induced tumor) or neoplasia (lymphoma). Risk factors for the development of PTLD include the use of antilymphocytic globulin or polyclonal antibodies as induction agents. The risk for PTLD can be increased up to 75 times the standard risk in a previously seronegative EBV patient in whom a primary EBV infection develops after transplantation. Asymptomatic transplant recipients at risk or symptomatic recipients are surveyed for EBV infection by quantitative polymerase chain reaction analysis of peripheral blood. CMV infection in a negative recipient with a positive donor serum titer (CMV IgG) and CMV infection in a CMV-mismatched patient (donor positive for CMV IgG and recipient negative for CMV IgG) can also increase the risk for PTLD. The disease is more common in children than in adults. Patients with elevated serum levels of EBV are usually treated by decreasing the dosage of immunosuppressive agents and administering either acyclovir or ganciclovir. Patients with hyperplastic tumors are generally treated by terminating the administration of immunosuppressive agents and initiating treatment with acyclovir or ganciclovir. Patients with unresponsive hyperplastic tumors can be treated with the anti–B-cell (anti-CD20) antibody rituximab (Rituxan). CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin [vincristine], and prednisone) therapy is usually reserved for patients with lymphoma.
Answer
E
19 Which of the following does not predict a patient’s long-term survival rate following liver transplantation?
A Pretransplant MELD score
B Age of the recipient
C Prolonged warm ischemia time
D Use of antilymphocytic globulin
E Pretransplant intensive care unit admission
Ref.: 13, 22
Comments
The Model for End-Stage Liver Disease score can predict pretransplant mortality, but it does not predict posttransplant survival. MELD scores are derived from the continuous disease severity scale designed for patients after transjugular intrahepatic portosystemic shunting. Pretransplant functionality of the patient can relate to posttransplant outcomes. The survival rate for patients immediately after liver transplantation is related to the severity of the illness before transplantation. Statistics show that patients who are well enough to reside at home with liver disease at the time of transplantation have a 91.4% 1-year survival rate. In contrast, patients who had been hospitalized have an 84.5% survival rate. Those in an intensive care unit before transplantation have a 79.9% survival rate, and those on life support have a 69.7% survival rate. Increasing recipient age correlates with decreased long-term survival. The deleterious effects of increased warm ischemia time have been well established by analysis of the United Network for Organ Sharing (UNOS) database. In retrospective reviews, Rabbit antithymocyte globulin has been associated with decreased rates of acute rejection. It also may be given to limit the use of nephrotoxic agents (tacrolimus, cyclosporine) in patients with renal dysfunction after transplantation.
Answer
A
20 A 4-year-old child with hepatoblastoma requires a liver transplant. Which of the following would constitute an appropriate liver graft?
A Graft from a donor of similar size and habitus
B Split liver graft from an adult cadaveric donor and transplantation of the appropriate segment
C Left lobe or left lateral segment of a liver from an living adult donor
D All of the above
E None of the above
Ref.: 23-25
Comments
Over the past 10 years there has been a substantial expansion in the availability of donor grafts for pediatric liver transplantation. Previously, many children died while waiting for an appropriately sized donor to become available. Now, with the application of segmental liver resection techniques, full-size cadaveric liver grafts can be reduced to the appropriate volume for pediatric recipients. In addition, resection of the left lobe or the left lateral segment from a living adult donor can be performed, with comparable survival of the recipient and minimal risk to the donor.
Answer
D
21 Six months after renal transplantation, a 56-year-old woman is admitted to the hospital with high fever, an elevated serum creatinine level, disseminated varicella skin lesions, and bilateral pulmonary infiltrates. Which of the following statements is true?
A The treatment of choice is intravenous acyclovir with or without hyperimmunoglobulin.
B Bronchoscopic examination is unnecessary.
C The patient does not need to be placed in isolation.
D The immunosuppressive drug regimen should maintained to decrease the risk of rejection.
E The peak incidence of this disease is 3 years after transplantation.
Ref.: 26, 19
Comments
The incidence of herpes zoster (shingles) is 7.9% in renal transplant recipients, and it usually occurs during the first 9 months after transplantation. Intravenous, followed by oral acyclovir usually prevents systemic dissemination and leads to rapid healing of the skin lesions. The levels of immunosuppressive agents should be drastically reduced to prevent death. Respiratory isolation is necessary to prevent spread of infection to other patients. Bronchoscopic examination is advisable to rule out superinfection with bacterial, fungal, or other opportunistic organisms. Intravenous acyclovir with or without hyperimmunoglobulin (varicella-zoster immune globulin) is the therapy of choice. The peak incidence of herpes zoster occurs within the first posttransplant year as a result of high levels of immunosuppression.
Answer
A
22 With respect to de novo post–renal transplant diabetes mellitus, which of the following statements is false?
A It is more common in African-American recipients.
B Most patients do not require long-term insulin therapy.
C Risk factors include weight, age, and family history.
D It has become less common since the introduction of tacrolimus.
E Diabetes is more common with higher steroid doses.
Ref.: 27
Comments
New-onset diabetes after transplantation (NODAT) occurs at rates of 9.1%, 16%, and 24% at 12, 24, and 36 months after transplantation, respectively. Steroids, cyclosporine, and tacrolimus are diabetogenic. There is a direct relationship between steroid dosage and the incidence of NODAT. Tacrolimus-based immunosuppressive therapy was associated with a 15% incidence of NODAT. Rates are dose dependent and fall with decreased levels of tacrolimus. Cyclosporine-based immunosuppressive therapy resulted in only a 9% incidence of NODAT. Risk factors include age, obesity, family history of diabetes, and African-American race. The potential mechanisms include decreased insulin secretion, increased insulin resistance, and a toxic effect of tacrolimus and cyclosporine on pancreatic beta cells. In only 25% of patients with NODAT does persistent hyperglycemia develop, and 50% of patients in this group ultimately require insulin replacement therapy.
Answer
D
23 A 55-year-old is being evaluated for renal transplantation. His creatinine clearance is less than 10 mL/min. His past medical history is significant for hepatitis C following intravenous drug use 20 years ago. With respect to hepatitis and renal transplantation, which of the following statements is true?
A Hepatitis C is an absolute contraindication to organ donation.
B All hepatitis B surface antigen–positive patients are poor renal transplant candidates.
C The presence of HCV antibody is an independent risk factor for graft failure after transplantation.
D HCV-positive recipients have a poor prognosis.
E HCV-positive individuals should never be used as a donor.
Ref.: 26
Comments
Patients with preexisting hepatitis C who have a low viral load, normal liver function, and minimal chronic active hepatitis on liver biopsy are acceptable recipients for a renal transplant. Donors with a similar profile may be acceptable for such a patient but not for a recipient who does not have hepatitis C. Meta-analyses have shown hepatitis C has been shown to be an independent risk factor for death and graft failure after renal transplantation based on meta-analyses. Twenty-year survival rates are 88% for non-HCV patients versus 64% for HCV-positive recipients. Hepatitis B surface antigen–positive patients who have stable liver function and test negative for e antigen do fairly well after renal transplantation with low-dose immunosuppressive therapy. However, recipients who are HBV DNA positive and HBeAg positive have a much higher risk for mortality.
Answer
C
24 The incidence of primary nonfunction of a liver allograft following transplantation ranges from 2% to 10%. Immediately after the liver transplantation procedure, which of the following is not associated with this clinical syndrome?
A Metabolic alkalosis
B Hyperkalemia
C Reduced mental status
D Marked elevation in liver enzyme levels
E Minimal bile output (if a T-tube biliary drainage catheter is in place)
Ref.: 28
Comments
Primary nonfunction of a liver allograft is a poorly understood clinical syndrome associated with markedly abnormal function of the allograft (i.e., severe coagulopathy, acidosis, hyperkalemia, poor mental status, continued hyperdynamic cardiac function with high cardiac output, low systemic vascular resistance with liver failure, poor bile output, and usually renal failure). Recipients with normally functioning grafts have marked metabolic alkalosis secondary to metabolism of the citrate component of bicarbonate (from banked blood given during the transplant procedure) by the liver graft during the immediate posttransplant period. Within the first 24 hours after liver transplantation, patients with normally functioning grafts return to normal cardiac hemodynamics. The most specific pretransplant predictor of primary nonfunction is the amount of macrosteatosis (extracellular fat globules) in the liver allograft. Studies have shown that when greater than 30% of the cross-sectional area of a liver biopsy specimen exhibits macrosteatosis, the incidence of primary dysfunction may reach 13%. Other possible predictors of primary nonfunction include high levels of vasopressor support in the donor and cold ischemia time. Although a variety of strategies have been used in attempts to ameliorate this syndrome, the only treatment is prompt retransplantation.
Answer
A
25 Which of the following would exclude a patient with HCC from becoming a transplant candidate?
A A single 1-cm lesion in the liver with microvascular invasion
B Two lesions each less than 2 cm
C A solitary 1-cm HCC lesion in the lung
D A single 4.8-cm HCC lesion in segment VIII
E Portal vein thrombus
Ref.: 15, 29
Comments
Orthotopic liver transplantation is an excellent option for stage I and stage II HCC. It has an advantage over resection because of the multifactorial nature of Hepatocellular carcinoma. Approximately 80% to 90% of patients with HCC also have cirrhosis. OLT allows excision of the tumor and removal of the underlying disease, which should decrease the likelihood of recurrence. OLT can be considered for any stage I or stage II tumor. This limits OLT to patients without distant metastases, those with negative lymph nodes and either T1 or T2 disease. T1 disease is a solitary tumor without vascular invasion (regardless of size). T2 disease is a solitary tumor with vascular invasion or a combination of tumors all less than 5 cm in size. These groupings were developed on the basis of the way in which these tumors behave. Conventionally, OLT is an option for solitary tumors less than 5 cm in size or multiple tumors of up to three in number, all smaller than 3 cm. Distant metastasis is an absolute contraindication to transplantation. Portal vein thrombosis is a relative contraindication to transplantation.
Answer
C
26 A 32-year-old woman is seen in the emergency department with an acute onset of confusion. Her laboratory work reveals markedly elevated transaminase levels, hyperbilirubinemia, and coagulopathy. Which of the following is not a potential indication for transplantation in a patient with fulminant hepatic failure?
A A history of progressive jaundice over the past month
B Acute overdose of acetaminophen
C Acute infection with hepatitis A virus
D Prothrombin time greater than 100 seconds
E CMV affecting multiple organs
Ref.: 30, 31
Comments
Fulminant hepatic failure can be caused by a multitude of injuries to the liver, including but not limited to acetaminophen toxicity and infection with hepatitis A virus, HBV, EBV, parvovirus, CMV, varicella-zoster virus, and herpes simplex virus. Other causes include Bacillus cereus infection, other illicit drugs such as ecstasy, antiretroviral drugs, and pregnancy-related disorders (the syndrome of hemolysis, elevated liver enzymes, and low platelet count [HELLP] and acute fatty liver of pregnancy). Though not standardized, most centers follow the criteria established by the King’s College Hospital in London. Patients with acetaminophen overdose have a persistent acidosis (pH <7.30) or prothrombin time longer than 100 seconds plus serum creatinine levels greater than 300 µmol/L (>3.4 mg/dL) and grade 3 or 4 encephalopathy. In non–acetaminophen-caused fulminant hepatic failure the criteria are a prothrombin time longer than 100 seconds irrespective of encephalopathy or any three of the following: cryptogenic hepatitis or other drug toxicity, age younger than 10 years or older than 40 years, jaundice, duration of encephalopathy of less than 7 days, prothrombin time longer than 50 seconds, or serum bilirubin level greater than 300 µmol/L (17.5 mg/dL). By definition, jaundice progressing over more than a 7-day period would exclude a diagnosis of fulminant hepatic failure even though the encephalopathy may be acute in onset.
Answer
A
27 A 26-year-old man is found to be brain-dead after a gunshot wound to the head. His family consents to organ donation. Which of the following is a contraindication to organ donation?
A Positive hepatitis B core antibody
B Active hepatitis C
C History of basal cell carcinoma 5 years previously
D Donor liver biopsy with 10% steatosis
E Creutzfeldt-Jakob disease
Ref.: 32
Comments
There are both absolute and relative contraindications to organ donation. Absolute contraindications include transmissible agents that may cause death or severe disease in the recipient. These include Creutzfeldt-Jakob disease and other prion diseases such as kuru. Other contraindications include human immunodeficiency virus (HIV), disseminated or invasive viral infections, mycobacterial infections, fungal infections, or systemic bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA). Active malignancy is an absolute contraindication to donation. Low-grade skin cancers such as basal cell carcinoma do not exclude a donor. Five-year disease-free survival in the donor from any cancer is considered cure by UNOS. However, the type and the biologic behavior of the tumor should be considered. Late recurrence is seen with breast and lung cancer, and therefore additional caution is warranted even beyond the 5-year disease-free interval. Relative contraindications include age of the donor, hepatic steatosis, damaged organs, infection, and viral infection. Age older than 60 years places a donated organ in the extended-criteria category. Steatosis greater than 60% has a unacceptably high risk for primary nonfunction and is contraindicated; however, livers with steatosis of less than 30% have not been shown to have higher rates of nonfunction or lower graft survival rates than nonfatty livers. Liver transplantation from hepatitis B core antibody–positive donors results in a 22% to 100% seroconversion rate in hepatitis B core antibody–negative recipients. HBV-positive livers can be transplanted with concurrent postoperative treatment with hepatitis B immune globulin (HBIG) and lamivudine. The ideal recipient for a hepatitis B core antibody–positive donor is a patient who already has hepatitis B and would undergo treatment after transplantation regardless of donor status. Donors with hepatitis C should donate to only hepatitis C–positive recipients. The disease is transmitted universally. Recipients with hepatitis C will reinfect the new liver even if it is hepatitis C negative. Studies have shown no difference between patient survival, graft survival, or severity of recurrent hepatitis C disease.
Answer
E
28 Which of the following statements regarding the immune response is true?
A The primary immune response is more intense and rapid than the secondary immune response.
B A cell-mediated immune response consists primarily of T lymphocytes.
C T lymphocytes are the precursors of plasma cells, which produce antibodies.
D The immune response has three phases, the first being the establishment of memory.
E Immunoglobulins (IgG versus IgE versus IgM) are all identical except at the variable region.
Ref.: 12, 33
Comments
The immune response is characterized by a series of reactions triggered by an immunogen. Immunogens include substances recognized as foreign, or “nonself” (e.g., virus, bacteria, and histoincompatible tissues), as well as substances that are “altered self” or “modified self” (e.g., most tumor antigens). All immune responses, whether primary or secondary, are characterized by three phases: (1) cognitive phase(recognition of nonself antigen), (2) activation phase (proliferation of immunocompetent cells or lymphocytes), and (3) effector phase (development of immunologic memory). The primary immune response is the result of the first (or primary) exposure to a specific antigen. The secondary response results from a second (or subsequent) exposure to the same antigen. It is more rapid and more intense than the primary response and is a result of the phenomenon of immunologic memory.
There are two basic types of immune response: cell-mediated immune response (cellular immunity), mediated primarily by T lymphocytes, and humoral immune response, mediated primarily by B lymphocytes. B lymphocytes, or B cells, differentiate into antibody-producing plasma cells after activation. They develop in the fetal liver and the bone marrow. B lymphocytes are precursors of plasma cells and can be identified by specific antigen-binding sites on their surface. Plasma cells ultimately produce the antibodies that are found in serum and that may be transferred passively in serum. T lymphocytes, or T cells, mature in the thymus from multipotential cells derived from the bone marrow. Plasma cells produce immunoglobulins. Within a subgroup of immunoglobulins, IgG versus another IgG, the variable portions consist of both the light and heavy chains. The number of chains is constant. IgG has two heavy chains and two light chains joined by disulfide bonds that create a dimeric structure, whereas the IgM structure is made of multiple chains that create a pentamer.
Answer
B
29 Which of the following statements regarding T cells is true?
A T cells finish development in the thymus and then migrate to the bone marrow.
B The various types of T cells can be identified by the binding of specific monoclonal antibodies to antigens on the cell surface.
C Helper T cells can be activated to produce antibodies.
D Cytotoxic T cells can destroy target cells by recognizing foreign antigens at the target cell nucleus.
E Cell-mediated immunity can be transferred passively in serum.
Ref.: 12, 33
Comments
T lymphocytes (T cells) mature in the thymus, whereas B lymphocytes mature in the fetal liver and the bone marrow. The thymus, liver, and bone marrow are referred to as the primary lymphoid organs. The T lymphocytessubsequently migrate to the secondary lymphoid organs: the spleen, lymph nodes, and dispersed lymphoid tissues found in the bronchus, urogenital tract, and gut (i.e., Peyer patches). The T lymphocytes cycle through the bloodstream from these points in search of nonself antigens. Lymphocytes that differentiate into T cells and B cells express various clusters of antigens on their membranes. All T cells express the cell surface antigen–specific receptor designated CD3, whereas B cells express the cell surface antigen–specific receptors CD19 and CD20. CD3+ T cells can be distinguished and subdivided further by the expression of additional differentiation antigens on the T-cell surface (T-cell receptors): cytotoxic T cells (CD3/CD8), suppressor T cells (CD3/CD8), helper/inducer T cells (CD3/CD4), and delayed-type hypersensitivity T cells (CD3/CD4). Cytotoxic T cells are capable of destroying a target cell by recognizing a foreign or “modified-self” antigen and class I major histocompatibility complex (MHC) molecules on the target cell surface. Helper T cells consist of TH1 and TH2 cells. They appear to work together in a regulatory circuit with each having a negative effect on the other. TH1 cells are proinflammatory and release IFN-γ. TH2 cells release interleukins to promote B-cell differentiation and maturation. Delayed-type hypersensitivity T cells bring macrophages and other inflammatory cells to areas in which delayed-type hypersensitivity reactions occur through the production of various chemoattractant molecules known collectively as chemokines.
Answer
B
30 Which of the following statements regarding T-cell activation is true?
A Antigen recognition is not specific, which allows clonal expansion and differentiation.
B Antigen expression requires the T cell to be MHC compatible with the antigen-presenting cell.
C T cells produce IL-1 in response to antigen presentation.
D Plasma cells are responsible for the synthesis of IL-2.
E T cells recognize soluble antigen.
Ref.: 12, 33
Comments
When antigen enters a lymph node or the spleen, it may first be phagocytized by a macrophage, which processes the antigen and expresses it on the cell surface for presentation to B and T cells. Macrophages that do this are called antigen-presenting cells. Other antigen-presenting cells include dendritic cells (a macrophage-like cell found in the skin, lymph nodes, and other tissues) and a subset of B lymphocytes. Recognition of the antigen is highly specific and accomplished only by T-lymphocyte clones that have a receptor specific to that antigen. When antigen is presented to the T cell, macrophages produce IL-1, T cells produce IL-2, and T cells increase the expression of IL-2 receptor on the surface. This activation by IL-2 causes T cells to proliferate. Helper T cells interact with B cells to stimulate their differentiation into plasma cells that produce antibodies. Activated T cells, not plasma cells, produce IL-2. T cells require interaction with the MHC, and they do not directly recognize unbound circulating antigen.
Answer
B
31 Which of the following statements regarding interleukins is true?
A All interleukins will only upregulate the immune system.
B IL-8 is a neutrophil chemotactic factor.
C Interleukins are produced only by leukocytes.
D IL-10 produces fever and inflammation.
E Prednisone upregulates the effect of IL-1.
Ref.: 12, 33, 34
Comments
Interleukins are a group of cytokines that function in many various ways to upregulate and downregulate the immune system. IL-3 functions as a hematopoietic growth factor. IL-4, IL-6, and IL-10 are the interleukins that have known inhibitory functions. Interleukin-4 inhibits the secretion of cytokines by macrophages. IL-6 inhibits tumor necrosis factor (TNF). Interleukin-10 inhibits monocyte/macrophage function and counteracts the inflammatory cytokines. IL-4, IL-6, and IL-10 also have other stimulatory functions. IL-8 attracts neutrophils to the site of inflammation by movement through the vascular endothelium. Interleukin-1 is responsible for fever and inflammation and also leads to the proliferation of T and B cells. Interleukins are produced by a variety of cells, including macrophages and monocytes, T and B lymphocytes, mast cells, stromal cells of the thymus and bone marrow, fibroblasts, epithelial cells, and endothelial cells. Most of the interleukins stimulate a particular or just a few varieties of leukocytes. Glucocorticoid administration inhibits the synthesis of IL-1 (among others), thus downregulating the inflammatory and immune response.
Answer
B
32 Which of the following statements regarding the cytokine IL-1 is false?
A The major cells that produce IL-1 are monocytes and macrophages.
B IL-1 may induce fever.
C T-lymphocyte production of IL-2 is inhibited by IL-1.
D IL-1 may augment wound healing by increasing fibroblast proliferation and collagen synthesis.
E IL-1 binds to CD121.
Ref.: 33, 34
Comments
Cells of the immune system cells are regulated by a variety of cytokines that are, in general, categorized according to their cell of origin. One of these cytokines, interleukin-1, is a key regulator of inflammation, wound healing, and the immune response. It is produced primarily by macrophages but is also produced by neutrophils, fibroblasts, natural killer (NK) cells, keratinocytes, endothelial cells, and vascular smooth muscle cells. IL-1 can induce endothelial cells to produce prostaglandins, platelet-activating factor, and plasminogen activator, which can lead to vasodilation and hypotension by promoting endothelial leakage and intravascular thrombosis. IL-1 binds to CD121 receptors. It directly stimulates the thermoregulatory center of the hypothalamus, thereby inducing fever. IL-1 stimulates the liver to produce several acute phase proteins. It plays a key role in joint inflammation by inducing synovial cells to produce prostaglandin E2, collagenase, and phospholipase. IL-1 mediates wound healing by activating basophils and eosinophils, stimulating neutrophil and macrophage activity, and locally increasing fibroblast proliferation and collagen synthesis. Interleukin-1 induces the proliferation of T and B lymphocytes, IL-2 production, and expression of the IL-2 receptor. IL-1 stimulates the release of other cytokines, including interferon, IL-3, IL-6, and colony-stimulating factors. The effects of IL-1 on immunity are greatly amplified through the stimulation of other cytokines. IL-1 and TNF-α are currently being studied as therapeutic agents for autoimmune disease, such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis.
Answer
C
33 Which of the following statements regarding TNF is true?
A TNF is produced only by monocytes and macrophages.
B Release of TNF is stimulated by exotoxins.
C TNF is an anabolic stimulant to the host that results in the deposition of fat.
D TNF is responsible for the cachexia associated with metastatic disease.
E TNF-α expression increases in response to glucocorticoid exposure.
Ref.: 33, 34
Comments
Tumor necrosis factor is so named because of its ability to cause hemorrhagic necrosis in methylcholanthrene-induced sarcomas in mice. Tumor necrosis factor-α is produced primarily by monocytes and macrophages but also by neutrophils and NK cells. It stimulates the activity of neutrophils and induces endothelial cells to produce IL-1 and synovial cells and fibroblasts to produce prostaglandin E2 and collagenase. TNF-α enhances the procoagulant activity of endothelial surfaces, increases vascular permeability, degranulates neutrophils, and stimulates the release of superoxides and arachidonic acid metabolites. In gram-negative shock, endotoxin stimulates the release of TNF-α, which leads to hypotension, disseminated intravascular coagulation, and even death. TNF stimulates catabolism in muscle and fat cells, thereby leading to an increase in anaerobic glycolysis, protein breakdown, and lipolysis. It is largely responsible for the cachexia associated with metastatic disease. TNF-α also has a role in stimulating and mediating apoptosis. TNF-α is produced in lesser quantities when glucocorticoids are present. Glucocorticoidsdownregulate the signaling pathway that transcribes the TNF gene.
Answer
D
34 Which of the following statements regarding interferons is true?
A INF-γ is produced by macrophages.
B Interferon production is inhibited by infection.
C Interferons have a direct antiproliferative effect on TH2 cells.
D Cytokine production by macrophages is inhibited by interferons.
E Interferons have a direct antiproliferative effect on TH1 cells.
Ref.: 33, 34
Comments
Interferons are glycoproteins produced by a variety of cells in response to viral infection or other stimulants. Interferons block viruses in two ways: through signaling pathways and by inhibition of the translation machinery (protein synthesis). The three major classifications of interferons are based on their cells of origin: Interferon-α, produced mainly by macrophages; interferon-β, produced by epithelial cells, fibroblasts, and macrophages; and interferon-γ, produced by T lymphocytes and NK cells. Interferons have a direct antiproliferative effect on cells but can also induce differentiation. Interferons decrease the activity of TH2 cells but promote the differentiation of immature CD4+cells into committed TH1 cells. This explains their usefulness as anticancer agents, although some anticancer effects may also result from stimulation of the cytotoxic activity of macrophages, NK cells, and cytotoxic T cells. Interferons stimulate a variety of cells to release other mediators and cytokines.
Answer
C
35 Which of the following statements regarding rejection of solid organ transplants is true?
A Hyperacute rejection begins in the operating room with reperfusion of the transplanted organ.
B Liver transplants are especially susceptible to hyperacute rejection.
C Most immunosuppressive medications are used to prevent chronic rejection.
D The major cause of graft failure is acute rejection.
E Chronic rejection is characterized histologically by lymphocyte infiltration.
Ref.: 1
Comments
There are three types of solid organ rejection that are based on the timing of the rejection: hyperacute rejection, acute rejection, and chronic rejection. The immunologic mechanism varies among these types of rejection. Hyperacute rejection occurs immediately and is the result of preformed antibody binding to the allograft on reperfusion of the organ. Hyperacute rejection is due to ABO incompatibility or a high titer of antidonor HLA-I antibodies in the recipient. For kidney, heart, pancreas, and lung transplants, current protocols include preoperative testing for ABO incompatibility or HLA antibodies (or both). For reasons not completely elucidated, liver transplants are resistant to this process. Liver transplants are performed without HLA matching and can be performed without ABO typing, although the ABO type is usually matched. Acute rejection occurs days to weeks following transplantation. Since acute rejection is initiated by T-cell immunity, most medications for preventing and treating it are directed toward T-cell suppression. Microscopically, acute rejection is characterized by a lymphocytic infiltrate, with plasma cells and eosinophils being seen on tissue biopsy specimens. Chronic rejection occurs months to years after transplantation and is the major cause of graft failure and mortality with all organ transplants. There is loss of normal histologic structure, fibrosis, and atherosclerosis, with intergraft expression of certain cytokines. Chronic rejection is the final common pathway of various insults, including repeated bouts of acute rejection, drug toxicity, chronic mechanical obstruction, recurrent infections, noncompliance with immunosuppressive medications, and pretransplant organ issues such as ischemia time and older organ donors. There is no defined therapy for chronic rejection, but it is believed that a better understanding of cytokine-mediated atherosclerosis would help in the development of treatments and prevention of chronic rejection.
Answer
A
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