1. The “father of experimental surgery” who performed pioneering research, including several transplantation procedures, was:
A. Homer, the Greek who described the Chimaera in his Iliad.
B. Gasparo Tagliacozzi, the Italian who described a method of reconstructing the nose.
C. John Hunter, the Scot who performed autografts and xenografts.
D. Emrick Ullmann, the Austrian who performed the first successful renal allograft.
E. Alexis Carrel, the Franco-American who described a successful technique for vascular anastomosis.
Answer: C
DISCUSSION: All of the descriptions are correct and represent important contributions to the history of transplantation. However, the Scottish surgeon John Hunter (1728–1793), is rightfully known as the father of experimental surgery because of his pioneering research. Several of his experimental procedures involved
transplantation, including autografting of a cock's spur to its comb and xenografting of a human tooth to the comb of a cock.
2. Transplantation terminology contains terms to describe the relationship of the graft donor to the graft recipient. Historical terms such as “homograft” and “heterograft” have been replaced by less ambiguous terms. The correct modern terminology for a graft between genetically nonidentical members of the same species is:
A. Allogeneic graft.
B. Autogeneic graft.
C. Isogeneic graft.
D. Syngeneic graft.
E. Xenogeneic graft.
Answer: A
3. The modern era of clinical organ transplantation began with the advent of chemical immunosuppression. The important drug discovery that produced the initial success of cadaveric transplantation was:
A. Cyclophosphamide.
B. Azathioprine.
C. Cyclosporine.
D. Antilymphocyte serum.
E. Monoclonal antibody OKT3.
Answer: B
DISCUSSION: All of the listed drugs have immunosuppressive activity that has proved useful in transplant recipients. However, the discovery in 1959 by Schwartz and Dameshek that 6-mercaptopurine blocked antibody production and the subsequent creation by Hitchings in 1961 of its safe, convenient imidazole derivative named azathioprine produced the first consistently effective immunosuppression for successful cadaveric renal transplantation.
4. Which of the following statements correctly characterize the genetic basis of histocompatibility?
A. Histocompatibility is determined by a series of genes inherited as a complex and subject to the mendelian rules that characterize recessive traits.
B. Histocompatibility depends in part on the inheritance of histocompatibility genes and in part on the inheritance of T-cell receptor genes.
C. Major histocompatibility genes are polymorphic.
D. Histocompatibility genes are independently segregating and co-dominant.
E. Histocompatibility is learned.
Answer: CDE
DISCUSSION: Histocompatibility refers to the genetic determinants of graft rejection. The determinants of overwhelming importance consist of a series of histocompatibility genes that segregate independently during meiosis. Each gene has multiple, dominant alleles. Histocompatibility genes and the proteins they encode are highly polymorphic (i.e., they exist in multiple forms).
5. The major histocompatibility complex (MHC) includes genes that encode which of the following proteins?
A. HLA-A.
B. HLA-DR.
C. TAP-1.
D. 21-Hydroxylase.
E. HLA-L.
Answer: ABCD
DISCUSSION: The major histocompatibility complex (MHC) includes genes encoding histocompatibility antigens, some other proteins, and a number of pseudogenes that do not encode proteins. The class I region encodes more than 15 genes, including the classical transplant genes A, B, and C as well as HLA-E, F, and G and four pseudogenes, H, J, K, and L. The class II region contains more than 25 genes, including those for the transplantation antigens HLA-DR, DQ, and DP. The region also includes two alpha genes, DMA and DNA, and two beta genes, DMB and DOB, genes for the low-molecular-weight proteins (LMPs) LMP2 and LMP3 and for the transporter molecules TAP1 and TAP2. The class III region, lying between class II and class I, contains more than 30 genes, among which are the genes encoding the complement components factor B, C2, and both C4 molecules, both tumor necrosis factor genes alpha and beta, and the heat shock proteins Hsp 1H and Hsp 70 2, and 21-hydroxylase.
6. Which of the following distinguish MHC class I from MHC class II antigens?
A. MHC class I and class II antigens are encoded in different regions of the MHC complex.
B. MHC class I antigens are expressed on specialized antigen-presenting cells, whereas MHC class II antigens are expressed on all cells.
C. MHC class I and class II are members of different supergene families.
D. MHC class I are considered to be the major histocompatibility antigens and MHC class II the minor histocompatibility antigens.
E. MHC class I is recognized by the CD8 glycoprotein, whereas MHC class II is recognized by the CD4 glycoprotein.
Answer: AE
DISCUSSION: MHC class I and class II antigens are encoded by genes in different regions of the MHC. The genes and the proteins they encode are homologous to immunoglobulins and thus are members of the immunoglobulin supergene family. MHC class I antigens are expressed on the surface of all cells, whereas MHC class II antigens are largely restricted in expression to antigen-presenting cells and endothelial cells. Both MHC class I and class II antigens are major histocompatibility antigens because their incompatibility in the donor and recipient can lead to very rapid and vigorous rejection of an allograft. The T cells that have antigen receptors specific for MHC class I plus peptide express CD8, a co-receptor that binds to the MHC class I molecules. The T cells that have antigen preceptors specific for MHC class II plus peptide express CD4, a co-receptor that binds to MHC class II molecules.
7. Which of the following characterize the role of the major histocompatibility antigens in immune responses?
A. The major histocompatibility antigens are critical in antigen processing and presentation.
B. Major histocompatibility antigens contribute to the maturation of T cells in the thymus.
C. T cells recognize only foreign antigens that are complexed with major histocompatibility antigens.
D. Expression of major histocompatibility antigens is increased in inflammation.
E. Recognition of major histocompatibility antigens is critical to the development of tolerance.
Answer: ABCDE
DISCUSSION: Once thought to be solely markers of individuality, MHC antigens are crucial to cell-mediated immune responses. Foreign antigens taken up by antigen-presenting cells are degraded and then become complexed with MHC molecules and expressed on the cell surface, and these events are enhanced in inflammation. Since T cells recognize only foreign antigens expressed as peptides in association with MHC antigens, the possibility for recognition is increased as a consequence of inflammation. Since T cells recognize only antigens expressed in association with MHC antigens, recognition of these antigens is critical to the development of tolerance to “self.”
8. The unusual intensity of alloimmune responses reflects which of the following characteristics?
A. The presence of a peptide-binding groove in the MHC molecule.
B. Recognition of the native structure of allogeneic MHC molecules.
C. The high frequency of T cells able to recognize directly allogeneic MHC antigens.
D. Stimulation of many T-cell receptors during the interaction of a T cell with an antigen-presenting cell.
E. The high frequency of antigen-presenting cells able to be recognized by T cells.
Answer: BCDE
DISCUSSION: Allotransplantation evokes an unusually intense and rapid cellular immune response. In contrast to conventional cellular immune responses, in which foreign antigens are recognized only as peptides in the groove of self MHC antigens, allogeneic MHC antigens are recognized directly as native proteins on the surface of allogeneic antigen-presenting cells. Thus, a large fraction of antigen-presenting cells is able to present alloantigen in this fashion, and a large fraction (up to 10%) of T cells is able to respond.
9. Which of the following statements correctly characterize the role of histocompatibility typing in transplantation?
A. Histocompatibility typing must be carried out before transplantation can safely be undertaken.
B. The “rules” of histocompatibility were established shortly after the advent of immunosuppressive therapy made transplantation feasible.
C. Histocompatibility typing may involve serologic, cellular, and molecular procedures for typing.
D. The role of histocompatibility matching in transplantation is controversial.
E. The cross-match test is carried out to determine whether a potential graft recipient has antibodies against the donor.
Answer: CDE
DISCUSSION: The concept of histocompatibility and the rules governing the susceptibility to rejection were deduced early in this century by such investigators as Jensen, Little, and Tyzzer, who were interested in the inherited resistance or susceptibility to transplanted tumors. The application of histocompatibility to clinical transplantation, however, had to await the advent of immunosuppressive therapy. Despite the practice of organ transplantation for more than 30 years, the role of histocompatibility typing in transplantation is controversial. Although grafts between HLA-matched donors and recipients exhibit better survival than HLA-mismatched grafts, matching is not routinely performed before transplantation of the heart or liver, and the outcome of these grafts may be very good. Histocompatibility typing involves the use of a variety of techniques—serologic, cellular, and molecular—to identify the antigens carried by the donor and the recipient. In addition to formal typing, the recipient is tested via cross-match for antibodies against the donor.
10. Activation of T cells requires:
A. Stimulation of the antigen receptor.
B. Stimulation of the MHC antigen.
C. Co-stimulation.
D. Anergy.
E. CD3.
Answer: ACE
DISCUSSION: The activation of T cells generally involves the delivery of two types of signals. One signal is initiated when the T-cell antigen receptor binds in a cognate manner to an MHC antigen bearing an antigenic peptide expressed on the surface of an antigen-presenting cell. This interaction is enhanced by the co-ordinate binding of CD4 or CD8 to the MHC antigen complex. This interaction initiates signaling through CD3, as well as through CD4 or CD8, both of which are associated with tyrosine kinases. Full activation of the T cell also requires the delivery of “co-stimulatory” signals. These signals may arise through the interaction of CD28 expressed by the T cell with B7-1 or B7-2 expressed on antigen-presenting cells. If only the T-cell antigen receptor is stimulated (and co-stimulation is not provided) the T-cell becomes anergic, that is, resistant to further stimulation. Anergy may be an important mechanism contributing to tolerance.
11. Which of the following statements characterize the biology of allotransplantation?
A. The rejection response is systemic.
B. The rejection response is learned.
C. The rejection response involves a constellation of immunologic and environmental factors.
D. Allotransplantation evokes a cellular immune response.
E. Allotransplantation evokes a humoral immune response.
Answer: ABDE
DISCUSSION: Medawar and Gibson elucidated some of the basic principles of transplantation biology. Rejection of a second skin graft from the donor of a first graft is very much hastened, indicating that the response is learned and that the second response evokes “memory.” The second graft is rejected rapidly, regardless of its location, indicating that the response is systemic. The major immune reaction causing rejection of a first graft is a cellular immune response; however, the recipient exposed to allogeneic cells develops antibodies against alloantigens, indicating that a humoral response has also occurred.
12. Allograft rejection may involve which of the following?
A. Helper T cells.
B. Veto cells.
C. Cytotoxicity.
D. Cytokines.
E. The Arthus reaction.
Answer: ACD
DISCUSSION: The effector mechanisms that underlie the pathogenesis of allograft rejection remain the subject of controversy. Rejection, like delayed-type hypersensitivity, may be mediated by helper T cells, which release cytokines that activate other cells such as macrophages and directly alter endothelial cell functions. On the other hand, rejection may be mediated by cytotoxic T cells, which kill or injure target cells through direct interactions. Both types of cells can be found in grafts undergoing rejection, and there is experimental evidence suggesting that both may be involved. Veto cells kill T cells, which recognize MHC antigens on the veto cell surface; this action is thought to contribute to tolerance and not to rejection. The Arthus reaction is an immune response that, in contrast to allograft rejection, is mediated primarily by antibodies and not by cells.
13. Which of the following statements about allograft rejection are true?
A. In the absence of immunosuppression, the time and intensity of rejection of transplants between unrelated donors and recipients is highly variable.
B. Allograft rejection may be mediated by antibodies or by cells.
C. Allograft rejection is thought to be caused by Th2 cells.
D. Acute cellular rejection is the major cause for loss of clinical organ transplants.
E. An individual with “tolerance” is unable to reject an allograft.
Answer: B
DISCUSSION: In the absence of immunosuppression, allografts from randomly selected donors are always rejected, and the rate of rejection is rapid as compared with the rate of development of most immune responses. Although allograft rejection in naive recipients is mediated predominantly by cells, antidonor antibodies can cause very severe types of rejection, including hyperacute and acute vascular rejection. Antidonor antibodies or cellular responses may contribute to the development of chronic rejection, which is now the most common cause of graft loss. Recent studies demonstrate that helper T cells may differentiate along one of two pathways. The Th1 pathway leads to secretion of interferon-gamma and other cytokines and is associated with delayed-type hypersensitivity and allograft rejection. The Th2 pathway is associated with secretion of interleukin-10 (IL-10) and IL-4 and may actually inhibit alloimmune responses. The development of Th2 responses may thus contribute to tolerance. Like allograft rejection, tolerance is highly specific. Thus, a person who is tolerant to one antigen or one individual is still able to mount an immune response against other antigens and other individuals.
14. The presence of donor-reactive lymphocytotoxic antibodies in the serum of a potential kidney transplant recipient:
A. Can be detected by in vitro testing with recipient leukocytes and donor serum.
B. Is a contraindication to kidney transplantation.
C. Can be found in all male patients older than 20 years.
Answer: B
DISCUSSION: The presence of donor-reactive antibodies, detected by incubation of the recipient's serum with donor lymphocytes in the presence of complement, results in a “positive crossmatch,” and is a contraindication to renal transplantation. They occur as a result of pregnancy, blood transfusions, or previous organ transplants.
15. Utilization of a living related donor instead of a cadaver donor is no longer an advantage in renal transplantation because:
A. Public recognition of transplantation as a successful therapy has facilitated obtaining family permission for recovery of transplantable organs. Thus, because sufficient kidneys are available from “brain-dead” accident victims, there is no need to use related donors.
B. Cyclosporine therapy after cadaveric renal transplants has improved their outcome, which is now comparable to related-donor transplants.
C. Modern preservation techniques can maintain viability of kidneys from cadaver donors for many hours, consistently allowing their early function to be as good as that of kidneys from living donors.
D. None of the above.
Answer: D
DISCUSSION: It is generally accepted that transplantation is a useful therapy; however, the number of recipients continues to greatly exceed the number of suitable cadaver donors whose families grant permission for organ recovery. Thus, availability of a living donor may shorten the waiting period for a transplant by several years. Cyclosporine has improved the short-term results of cadaveric transplantation, but the attrition of these grafts is greater than that for living-donor transplants, especially those with close histocompatibility. The predicted 10-year survival of grafts from HLA-identical siblings is 80%, whereas for cadaver grafts it is only 40%. Although preservation techniques can maintain viability of kidneys for 36 to 48 hours, cadaver kidneys suffer a much higher rate of posttransplant acute tubular necrosis than those from related donors. Acute tubular necrosis has been shown to have a definite detrimental effect on long-term graft survival.
16. Large volumes of urine in the early postoperative course of renal transplant patients:
A. Result from osmotic stimuli to diuresis.
B. May signify reversible polyuric acute tubular necrosis.
C. Should be replaced by administration of equal volumes of crystalloid.
D. Facilitate the diagnosis of rejection and obstruction of the renal artery and/or collecting system.
Answer: ABCD
DISCUSSION: Factors responsible for the brisk diuresis following renal transplantation include osmotic stimuli secondary to high urea and/or glucose concentrations in the serum, and mild proximal tubular damage resulting from allograft ischemia. To avoid severe dehydration in the early postoperative period, an attempt should be made to replace urine losses with equal volumes of 0.45% NaCl solution to which 20 to 30 mEq. NaHCO 3 per liter may be added. The diagnosis of rejection and/or obstruction to urine flow is made easier when a transplanted kidney is undergoing voluminous diuresis rather than demonstrating oliguria or anuria secondary to severe acute tubular necrosis.
17. As compared with the early immunosuppressive drugs (azathioprine, steroids, antilymphocyte serum) some newer agents have the following specific advantages:
A. Cyclosporine, which interferes with lymphokine production, exhibits neither bone marrow nor renal toxicity.
B. Monoclonal antibody (OKT3) is more available and has greater specificity and fewer side effects than antilymphocyte serum.
C. Tacrolimus (FK506) has properties similar to those of cyclosporine but is especially valuable for rescue of grafts that are failing on cyclosporine therapy.
D. None of the above.
Answer: C
DISCUSSION: Cyclosporine interferes with production of cytokines and lacks the bone marrow toxicity of azathioprine. Unfortunately its chief toxicity is renal. Although OKT3 is more available, more uniform, and more specific than antilymphocyte serum, some of its side effects are even greater, such as fever, chills, nausea, vomiting, diarrhea, and pulmonary edema. Tacrolimus has been used most extensively for liver grafts. It has been found especially valuable in reversing rejection of failing grafts.
18. Survival rates for patients on dialysis are better than those for patients receiving renal allografts in the following circumstances:
A. A living related donor is available.
B. A cadaver donor must be used.
C. The recipient's renal failure is secondary to diabetes.
D. None of the above.
Answer: D
DISCUSSION: Patients receiving chronic dialysis have a mortality rate of 6% to 20% per year, every year. The mortality rate is as high as 11% to 25% per year in diabetic dialysis patients. Patients undergoing renal transplantation have an operative mortality rate of less than 2%, and the 1-year survival for recipients of living related kidneys is better than 95%. Survival is greater than 90% for recipients of cadaver kidneys. The 5-year patient survivals are approximately 80% for nondiabetic recipients of living related and cadaver kidneys, and 60% to 70% for diabetic recipients. Thus, a well-functioning renal allograft provides a greater chance for a longer life than does chronic dialysis.
19. Posttransplantation hypertension can be caused by:
A. Rejection.
B. Cyclosporine nephrotoxicity.
C. Renal transplant artery stenosis (RTAS).
D. Recurrent disease in the allograft.
Answer: ABCD
DISCUSSION: Both acute and chronic rejection may result in hypertension. The former causes acute fluid retention and plugging of peritubular capillaries with inflammatory cells. This may progress to intimal swelling and medial necrosis and eventuate in ischemia secondary to endothelial proliferation and obliteration of small vessels. Chronic rejection, thought to be related to protracted humoral injury, results in obliteration of capillaries via the development of intimal hyperplasia. Cyclosporine has a vasoconstrictive effect which, through activation of the renin-angiotensin system, may lead to hypertension. RTAS is responsible for hypertension in 4% to 12% of renal allograft recipients. It responds well to percutaneous angioplasty. A careful trial of angiotensin-converting enzyme inhibitors may be diagnostic of RTAS. Recurrent disease such as membranoproliferative glomerulonephritis and focal glomerular sclerosis may result in significant hypertension in renal allograft recipients.
20. Which of the following statements about posttransplantation malignancy is correct?
A. Certain immunosuppressive agents increase the incidence of malignancy in transplant recipients, whereas others do not.
B. Those malignancies most commonly seen in the general population (breast, colon) are substantially more common in transplant recipients.
C. Lymphoproliferative states and B-cell lymphomas are associated with Epstein-Barr virus.
D. None of the above.
Answer: C
DISCUSSION: Both naturally occurring and iatrogenic states of immune deficiency are associated with an increased rate of de novo malignancy. Transplant recipients have a rate of malignancy approximately 100 times that of the normal population. The degree of immunosuppression, rather than a specific immunosuppressive agent, appears to be responsible. Squamous and basal cell carcinomas of the skin are most common; however other tumors that are common in the general population, such as breast and colon cancers, do not appear to be increased in incidence. Lymphomas, which occur at a rate that is 350 times normal, and the lymphoproliferative states that often precede them appear to be associated with Epstein-Barr virus. Possible explanations for these high malignancy rates include defective immunosurveillance, chronic stimulation of the reticuloendothelial system by the allograft, the carcinogenic effect of immunosuppressive drugs, and viral oncogenesis.
21. One week after receiving a cadaver renal allograft, the recipient remains oliguric and dialysis dependent. Ultrasonography reveals a larger perigraft fluid collection. Your next step in management includes:
A. No further investigations (since perigraft collections are fairly common after renal transplantation).
B. Aspiration of the perigraft fluid collection and instillation of a fibrosis-inducing agent to obliterate the dead space.
C. Angiography for localization of a bleeding site in the renal allograft.
D. Aspiration of the perigraft fluid collection for chemical analysis.
Answer: D
DISCUSSION: Urine leaks usually occur early after transplantation, and the most frequent site of leakage is from the ureteroneocystostomy or ischemic ureter. The clinical signs are pain, swelling, and deterioration of renal function before leakage from the wound is observed. Aspiration of the perigraft fluid collection for chemical analysis of blood urea nitrogen (BUN) and creatinine would aid the differentiating urinoma from lymphocele. The composition of urinoma reveals BUN and creatinine concentrations several orders of magnitude higher than those of a lymphocele, which are comparable to the values in blood.
22. Regarding access for hemodialysis, which of the following statements is/are incorrect?
A. Some patients are not candidates for hemodialysis.
B. Some complications can lead to exsanguination.
C. The best access to place for a patient beginning dialysis is a leg polytetrafluoroethylene (PTFE) graft from the femoral artery to the saphenous vein.
D. First of all one should attempt to create a Brescia-Cimino fistula.
E. The leading complication of PTFE grafts is infection.
Answer: CE
DISCUSSION: Some patients do not tolerate hemodialysis because of cardiac difficulties or because they cannot be heparinized for hemodialysis. If a peripheral shunt becomes disconnected, the patient can exsanguinate. This can occur if a cap or clamp is inadvertently removed from a central dialysis catheter. The ideal location for a dialysis fistula or graft is in the upper extremity as far distal as possible, such as with a Brescia-Cimino fistula or a forearm loop graft. The leading complication of PTFE grafts is thrombosis caused by intimal hyperplasia in the venous limb. Infection is the second leading complication with these grafts.
23. Access to the peritoneal cavity for peritoneal dialysis can be gained:
A. Percutaneously.
B. Surgically.
C. Using laparoscopy.
D. Only using general anesthesia.
Answer: ABC
DISCUSSION: Chronic ambulatory peritoneal dialysis (CAPD) catheters may be placed at the bedside with a straight Tenckhoff catheter under local anesthesia. They can be placed laparoscopically or by making a small perimedian incision and placing the catheter through the rectus muscle. All of the techniques can be performed using local anesthesia; however, use of the laparoscopy commonly calls for general anesthesia.
24. Which of the following are true concerning immunosuppression?
A. Current immunosuppressive agents function in a nonspecific manner to suppress rejection.
B. The use of immunosuppressive agents is associated with an increased rate of opportunistic infections.
C. An increased rate of malignancy is not associated with the use of immunosuppressive agents.
D. In almost all cases, the graft is rejected if immunosuppression is discontinued.
Answer: ABD
DISCUSSION: At the present time, clinical immunosuppression involves the use of agents that function in a nonspecific manner to prevent rejection. These agents suppress almost all aspects of the immune response. Because of their mechanism of action, they have associated toxicities and side effects, such as an increased rate of opportunistic infections. An increase in certain malignancies is also associated with use of these agents. In almost all cases, the graft is rejected if the immunosuppression is discontinued. Therefore, immunosuppression must be continued for the life of the graft.
25. Which of the following is true for hyperacute rejection?
A. It is mediated by preformed cytotoxic antibody.
B. It occurs late in the life of the graft.
C. It is usually reversible with a bolus of steroids.
D. None of the above.
Answer: A
DISCUSSION: Hyperacute rejection is mediated by preformed cytotoxic antibody. It can be screened for by cross-matching procedures. It usually occurs immediately after graft placement or within the first 24 to 48 hours after graft placement. It is almost never reversible.
26. The major components of the immune system include which of the following?
A. T lymphocytes.
B. B lymphocytes.
C. Cytokines.
D. Macrophages.
Answer: ABCD
DISCUSSION: The development of the lymphoid system begins with a pluripotent stem cell in the liver and bone marrow of the fetus. With maturation of the fetus toward term, the bone marrow becomes the primary site for lymphopoiesis. It produces the T lymphocytes, B lymphocytes, and macrophages that are critical to the immune response. These cells then produce cytokines or soluble growth factors, which amplify the immune response.
27. The most common types of immunosuppressive agents used clinically include which of the following?
A. Antimetabolites.
B. Alkylating agents.
C. Inhibitors of helper T-cell activation.
D. Irradiation.
E. Lymphocyte depletion compounds.
Answer: ABCDE
DISCUSSION: Much of the susceptibility of lymphocytes to immunosuppression is due to the vast cellular changes that follow immune stimulation. The biosynthetic events that take place make the lymphocytes vulnerable to inhibition at various stages of the cell cycle. Cyclosporine inhibits cytokine gene expression, whereas alkylating agents and radiation produce cross-linkages and breaks in DNA strands that interfere with cell differentiation and division. Agents that produce depletion of lymphocytes include antilymphocyte globulin (ALG) and monoclonal antibodies (OKT3).
28. Which of the following is/are true of the antiproliferative agents?
A. They act by preventing the differentiation and division of the immunocompetent lymphocyte after it encounters antigen.
B. The antimetabolites in this group have a structural similarity to cell metabolites and either inhibit enzymes of a metabolic pathway or are incorporated during synthesis to produce faulty molecules.
C. The most frequently used antiproliferative agent is azathioprine.
Answer: ABC
DISCUSSION: Antiproliferative agents inhibit the full expression of the immune response by preventing the differentiation of the immunocompetent lymphocyte after it encounters antigen. They act in one of two ways: they either structurally resemble necessary metabolites, or they combine with certain cellular components, such as DNA, and thereby interfere with function. Until recently, azathioprine was the most widely used immunosuppressive drug in transplantation, and it still has a major clinical role in preventing rejection.
29. Which of the following is the one true statement about acute rejection.
A. Acute rejection is mediated by T lymphocytes.
B. Acute rejection is mediated by preformed cytotoxic antibody.
C. Acute rejection most frequently occurs over months.
Answer: A
DISCUSSION: Acute rejection is mediated primarily by T lymphocytes. It occurs over 1 to 3 weeks after placement of an allograft. Hyperacute rejection is mediated by preformed cytotoxic antibody. It occurs within 48 hours of placement of a graft. Chronic rejection is mediated by both T cells and B cells and occurs over months.
30. Which of the following are true of cyclosporine?
A. It was the first immunosuppressive agent to be used clinically.
B. It acts selectively on T cells to suppress rejection.
C. Toxic effects include hirsutism, hypertension, nephrotoxicity, and increased risk of opportunistic infections.
Answer: BC
DISCUSSION: Cyclosporine is a product of a fungus and was discovered in 1972. It has contributed very significantly to the development of the field of transplantation. The mechanism of action is relatively specific for T lymphocytes. Other inflammatory cells are much less sensitive to its immunosuppressive effects. It inhibits activated T lymphocytes and prevents the cells from manufacturing and releasing interleukin 2 (IL-2). Toxicities include hirsutism, hypertension, nephrotoxicity, and increased risk of opportunistic infections (because it still functions as a nonspecific immunosuppressive agent).
31. Which of the following are true of OKT3?
A. It is not a monoclonal antibody.
B. It binds to the T-cell receptor and inactivates T-cell function.
C. It is the monoclonal antibody most frequently used in clinical transplantation.
Answer: BC
DISCUSSION: OKT3 is a monoclonal antibody produced in limitless supply by a hybridoma. It binds to a site associated with the T-cell receptor complex to inactivate the T cell. It is the most widely used monoclonal antibody in clinical transplantation.
32. Hypothermia (0؛ to 4؛ C) is a critical component of successful organ cold storage because:
A. Oxygen is more soluble in cold solutions and provides a continual supply for energy metabolism.
B. There is no way to suppress microbial growth except by cooling and slowing the growth rate.
C. Hypothermia diminishes energy requirements and allows the limited energy reserve to keep the organ alive.
D. It slows metabolism and the enzymic processes that would destroy the cell.
Answer: D
DISCUSSION: Hypothermia in simple organ cold storage serves one primary function but secondary ones as well. The primary function is to slow metabolism. Metabolic rates decrease about twofold for every 10؛ C drop in temperature. Cooling an organ from 37؛ to 0؛ to 4؛ C drops metabolism about 12- to 13-fold. This is related to the activation energy of enzymatic processes as expressed by Arrhenius and van't Hoff. Thus, catabolism of structural and functional cellular element is retarded for a long period—up to 3 days for some organs. The cold also suppresses microbial growth, but this can be accomplished by other means as well. The cold also allows time for the transplantation operation, and during this time it is important to be quick or to keep cooling the organ.
33. Is the following statement true or false? Organs should be preserved only for short periods of time (4 to 8 hours) because longer periods lead to too many complications, and even loss of the organ.
Answer: FALSE
DISCUSSION: The logistics of organ transplantation make it very difficult to use all available cadaver organs within 4 to 8 hours. To use all the organs requires the capability to preserve them for at least 24 hours. It has been shown that most organs can be matched to a recipient within about 17 to 24 hours. For all but the heart and lung, most intra-abdominal organs tolerate preservation for 20 to 30 hours and perform as well as those preserved for 4 to 8 hours. Although undue delay should not be purposefully used, certainly, most organ transplants do not need to be done on an emergency basis. However, this is not true for hearts and lungs, which should be transplanted as quickly as possible.
34. Which of the following statements about hepatic artery thrombosis following liver transplantation is/are correct?
A. Thrombosis of the hepatic artery following liver transplantation is more common in children than in adult patients.
B. Thrombosis of the hepatic artery usually occurs several weeks after transplant as a result of arteriosclerosis.
C. Thrombosis of the hepatic artery in the early days following transplantation is a serious complication leading to death unless retransplantation can be performed within 36 to 72 hours.
D. Late thrombosis of the hepatic artery may present as biliary complication or intrahepatic abscesses.
E. Thrombosis of the portal vein is more frequent than hepatic artery thrombosis following liver transplantation.
Answer: ACE
DISCUSSION: Thrombosis of the hepatic artery remains one of the most serious early complications of liver transplantation. This complication is three to five times more common in children than in adults. The major cause of this complication is related to technical error, although the hypercoagulable state may play a significant role in some situations. Early thrombosis of the hepatic artery leads to rapid liver failure with a fatal outcome unless a transplant can be performed within 36 to 72 hours. Although thrombolytic therapy through percutaneous or surgical access can be successful, most of these patients require retransplantation. Stenosis of the hepatic artery or late thrombosis of the hepatic artery can lead to multiple intrahepatic strictures of the bile duct and/or hepatic abscesses. This complication also often requires retransplantation. Portal vein thrombosis is a rarer complication. It is a devastating condition when it occurs early, but can be tolerated well if it develops after several months. Portal hypertension due to late portal vein thrombosis can often be treated successfully by a shunt procedure.
35. Which of the following statements about fulminant hepatic failure (FHF) is/are correct?
A. Fulminant hepatic failure can occur in the setting of pre-existing chronic liver disease.
B. Coagulopathy and coma are important findings in patients with FHF.
C. Liver transplant should not be attempted in patients with FHF because of the high mortality rate, regardless of the treatment used.
D. The main cause of death in these patients is cerebral edema.
E. One of the most important factors in prognosis of FHF is the cause of liver disease.
Answer: BDE
DISCUSSION: FHF corresponds to the rapid loss of hepatic function in the absence of pre-existing liver disease, causing jaundice, coagulopathy, and coma. One of the major prognostic factors is the cause of the liver disease. Early admission to an intensive care unit and management by physicians experienced in liver transplantation are mandatory. The major cause of death in these patients is cerebral edema. In patients who rapidly develop coma, subdural intracerebral pressure monitoring is mandatory for optimal management as well as for identification of patients who can benefit from liver transplantation. The survival rate for patients with FHF who underwent liver transplantation is currently above 65%. This is the only cure in most patients with FHF.
36. Which of the following statements about immunology in liver transplantation is/are correct?
A. Good human leukocyte antigen (HLA) matching between recipient and donor is mandatory for a good outcome for liver transplantation.
B. Hyperacute rejection is almost nonexistent following liver transplantation.
C. Acute rejection occurs in more than 50% of patients and is reversible in most patients with large doses of steroids.
D. Acute rejection is very rare later than 2 months after liver transplantation unless the patient is inadequately immunosuppressed.
E. Chronic rejection is different from acute rejection, is usually irreversible, and often requires retransplantation.
Answer: BCDE
DISCUSSION: Immune-mediated reactions following liver transplantation are clearly different from those that follow other solid organ transplants. The liver is tolerated quite well, and currently donors and recipients are matched only for their ABO group. Even when the ABO barrier is not respected, survival is still over 60%. T cell–mediated acute rejection occurs in about half of the patients within 6 weeks after liver transplantation, and acute rejection is reversed by large doses of steroids in most cases. Chronic rejection, on the other hand, is a different entity that is ill-understood and corresponds to destruction of small arteries and bile ducts. Change in the immunosuppression regimen sometimes may hinder the progression of this disease, but often retransplantation is required.
37. An elevated serum amylase level following pancreas-kidney transplantation may be due to:
A. Preservation/procurement injury.
B. Rejection.
C. Reflux pancreatitis.
D. Duodenal segment leak or bladder leak.
E. Native pancreatitis.
F. Constipation.
Answer: ABDEF
DISCUSSION: During the immediate postoperative period, an elevated serum amylase is usually due to preservation or procurement injury to the transplanted pancreas. If UW (University of Wisconsin) solution and a good flushout technique is used in an acceptable donor, amylase is usually elevated only several hundred points and will decline in a day or two. Rejection of the pancreas can also cause elevated serum amylase and is usually accompanied by a rise in the creatinine value due to concomitant renal transplant rejection. Reflux pancreatitis is generally caused by bladder dysfunction: increased pressure transmitted back through the pancreatic ducts causes pancreatitis. It is generally relieved by bladder decompression with a Foley catheter. Naturally, leakage from the anastomosis of the pancreas transplant to the bladder causes absorption of amylase from the peritoneal cavity and an elevated serum amylase value. Constipation causes a rise in the amylase level of pancreas-kidney transplant recipients, for reasons that remain unclear. Native pancreatitis has to be borne in mind in the differential diagnosis of hyperamylasemia in transplant patients. Contributing factors may include underlying gallbladder disease, as well as side effects of steroids and Imuran.
38. Complications of a pancreas transplant drained into the bladder include:
A. Duodenal segment leak.
B. Recurrent urinary tract infections.
C. Recurrent hematuria.
D. Urethritis.
E. Refractory loss of bicarbonate.
Answer: ABCDE
DISCUSSION: All of the listed problems are potential complications of bladder drainage. The most useful diagnostic tests for a duodenal segment leak include CT cystogram and technetium-based nuclear cystogram. Cystoscopy should be performed in patients with recurrent urinary tract infections to evaluate the presence of sutures or foreign bodies acting as a nidus for infection. Severe recurrent hematuria, as well as urethritis (most commonly affecting males), may occur with bladder drainage. Finally, severe bicarbonate loss may be associated with bladder drainage, and some patients may have difficulty keeping up with the loss by oral bicarbonate replacement. All of the above situations can be effectively treated with enteric conversion
39. Patient selection criteria for simultaneous pancreas-kidney transplantation should include:
A. Type I diabetes mellitus.
B. Type II diabetes mellitus.
C. Dialysis dependence.
D. Renal dysfunction with a creatinine value greater than 3.0.
E. Minimal extrarenal morbidity related to diabetes.
Answer: ADE
DISCUSSION: Simultaneous pancreas-kidney transplantation should be reserved for patients with Type I, juvenile, insulin-dependent diabetes mellitus. Although patients with Type II diabetes could potentially be helped, these older patients generally are not in good condition for simultaneous pancreas-kidney transplantation, nor are they reliably cured. In order to reliably monitor renal transplant function, the pretransplant creatinine value should be above 3, but the patient must not necessarily be on dialysis. To achieve good long-term results with pancreas-kidney transplantation it is appropriate to select patients with minimal extrarenal morbidity related to their diabetes.
40. Criteria for a pancreas donor include:
A. No history of diabetes.
B. No liver donation.
C. No replaced hepatic artery vessels arising from the superior mesenteric artery (SMA).
D. No previous splenectomy.
E. No pancreatitis.
Answer: AE
DISCUSSION: Combined liver-pancreas procurement should be routine, even if the right hepatic artery arises from the superior mesenteric artery. In this situation, since the transplanted liver is the life-saving organ, the proximal superior mesenteric artery should remain with the liver and the distal superior mesenteric artery supplying the head of the pancreas can be reconstructed on a Y-graft of iliac artery with the splenic artery. Successful pancreas transplantation can be performed using donors who have previously undergone splenectomy; however, there should be no significant pancreatitis and no history of diabetes in the donor.
41. For which of the following clinical scenarios would cardiac transplantation be an appropriate therapeutic modality?
A. A 50-year-old man with angina pectoris, three-vessel coronary artery disease, and a left ventricular ejection fraction of 25%.
B. A 75-year-old woman with irremediable heart failure secondary to critical aortic stenosis.
C. A 25-year-old male athlete with insidious onset of heart failure secondary to idiopathic dilated cardiomyopathy.
D. A 55-year-old woman who is status post two previous surgeries for coronary artery revascularization, now presenting with heart failure in the absence of angina, left ventricular ejection fraction of 15%, and insufficient target coronary arteries for a third bypass procedure.
E. A newborn infant with hypoplastic left heart syndrome and no other congenital anomalies.
F. A 30-year-old woman who develops irremediable heart failure due to postpartum cardiomyopathy after giving birth.
Answer: CDEF
DISCUSSION: Scenarios A and B are not appropriate for cardiac transplantation. The patient in example A would be far better served by a conventional revascularization procedure such as coronary artery bypass grafting. The risk might be somewhat greater than normal because of his depressed left ventricular ejection fraction; however, cardiac transplantation is a therapy that is necessarily reserved for persons for whom no other procedure is available. That clearly is not the case in this example. In example B, despite the fact that this patient's disease might be benefited by cardiac transplantation, she is too old to withstand the rigors of this procedure and its attendant therapies. Examples, C, D, E, and F, all represent situations in which cardiac transplantation would be appropriate. In all these cases there is end-stage heart disease, and no other therapies are available that are likely to have any substantial benefit. Therefore, it is appropriate to consider cardiac transplantation for these patients, as a last resort.
42. Suitable donors for heart transplantation have which of the following characteristics?
A. Normal electrocardiogram (ECG).
B. Normal echocardiogram.
C. Positive serology for HIV or hepatitis B or C.
D. Patient requiring high-dose epinephrine to maintain a systolic blood pressure of 90 mm. Hg.
E. Age over 70 years.
Answer: AB
DISCUSSION: To be suitable for cardiac donation, individuals must have a normal ECG and a normal echocardiogram. Clearly, positive serologic tests for HIV or hepatitis B or C would render donors unsuitable for solid organ transplantation. Similarly, high-dose pressor support and age greater than 60 years, in most programs, contraindicate cardiac donation.
43. Heart-lung transplant is currently the therapy of choice for which of the following conditions?
A. Primary pulmonary hypertension with reasonably well-preserved right ventricular function.
B. Eisenmenger's syndrome due to single ventricle and truncus arteriosus.
C. Validated cardiomyopathy in a patient with cystic fibrosis and end-stage lung disease.
D. Cystic fibrosis and end-stage lung failure with normal heart function.
E. Eisenmenger's syndrome due to an atrial septal defect.
F. End-stage lung disease secondary to emphysema.
Answer: BC
DISCUSSION: Heart-lung transplantation is now properly used only for persons with end-stage disease of the heart and lungs. Therefore, a patient with primary pulmonary hypertension and reasonably wellpreserved right ventricular function is best treated with a single or bilateral lung transplant. A person with complex congenital heart disease and Eisenmenger's syndrome or one who has end-stage disease of the heart and lungs would be better treated with combined heart-lung transplantation. Patients with Eisenmenger's syndrome secondary to relatively straightforward defects (e.g., atrial septal defect, ventricular septal defect) are best treated with concomitant correction of the congenital defect and single or bilateral lung transplantation. Similarly, the patient with end-stage emphysema with normal heart function can be treated very well with single or bilateral lung transplantation, preserving the donor heart for someone who truly has heart failure.
44. Both single and bilateral lung transplantation are suitable technical alternatives for which of the following conditions?
A. Obstructive lung disease (chronic obstructive pulmonary disease, emphysema).
B. Restrictive lung disease (pulmonary fibrosis).
C. Primary pulmonary hypertension.
D. Cystic fibrosis.
Answer: ABC
DISCUSSION: Single-lung transplantation is inappropriate for cystic fibrosis or for any patient with chronic bilateral pulmonary sepsis. Leaving a septic native lung in situ in an immunocompromised patient would leave the patient at risk for local and systemic septic complications. Single-lung transplantation with contralateral pneumonectomy would be associated with a high risk of empyema in the pneumonectomy space and also disruption of the bronchial stump. Both single- and bilateral lung transplantation have been applied successfully in all of the other disease categories listed here.
45. Which of the following are contraindications to lung transplantation?
A. Age 65 years or older.
B. Current corticosteroid therapy.
C. History of thoracotomy.
D. Ventilator-dependent respiratory failure.
Answer: D
DISCUSSION: Single-lung transplantation is still offered up to age 65 years. Current low-dose corticosteroid therapy has not been demonstrated to lead to a higher risk of airway complications after lung transplantation. Advancements in operative technique have lessened the risk of surgery, so prior thoracotomy is no longer a contraindication to lung transplantation. However, patients with chronic ventilator-dependent respiratory failure who have no potential for cardiopulmonary rehabilitation currently are not accepted for evaluation for potential lung transplantation.
46. Which of the following is the single most useful approach for diagnosing acute lung allograft rejection?
A. Clinical diagnosis.
B. Decline in spirometry and oxygenation.
C. Chest radiographic abnormalities.
D. Fiberoptic bronchoscopy with transbronchial lung biopsy.
Answer: D
DISCUSSION: Virtually all lung transplant patients experience at least one episode of acute rejection during their postoperative recovery in hospital. All of the approaches mentioned above are useful in leading to the diagnosis. Clinically, the patient experiences malaise and fever. There is also typically a slight decline in spirometry and arterial oxygenation. The chest radiograph typically shows a hilar or basal shadow; however, although these findings all suggest acute rejection, they are not specific. The one test with high specificity for detection of acute rejection is bronchoscopy with transbronchial lung biopsy.
47. Advantages of split-thickness skin grafts over full-thickness skin grafts include:
A. Split-thickness grafts include only part of the epidermis and none of the dermis.
B. Split-thickness grafts offer better pigment matching.
C. Split-thickness grafts offer better resistance to contraction.
D. Split-thickness grafts offer better resistance to infection.
E. Split-thickness grafts survive better on surfaces with compromised blood supply.
Answer: DE
DISCUSSION: Split-thickness grafts include all of the epidermis but only a part of the dermis. Full-thickness skin grafts include all of both layers, so surgical closure of the donor wound is necessary whereas the portion of dermis left at the split-thickness skin donor site regenerates a skin covering. Because all layers of the skin are included in a full-thickness skin graft, pigment matching is better and less contraction occurs than with split-thickness grafts. Full-thickness grafts require a better blood supply for survival than the split-thickness grafts because the graft vessels are cut below the level of the dermal branching. Relatively fewer cut vessels are available to absorb nutrients from the wound bed to meet the relatively greater nutritional needs of the thicker graft. The poor resistance of full-thickness grafts to infection precludes their use on contaminated wounds, whereas split-thickness skin, which is more richly supplied with open blood vessels on its underside, is able to survive on compromised surfaces, including granulating wounds contaminated with bacteria.
48. The most commonly used substitutes for peripheral arteries are:
A. Dacron grafts.
B. Expanded polytetrafluoroethylene (Gore-Tex) grafts.
C. Internal, external, and/or common iliac artery autografts.
D. Bovine carotid artery xenografts.
E. Saphenous vein autografts.
Answer: E
DISCUSSION: The greater saphenous vein has proved to be the most satisfactory and most commonly used arterial substitute. The wall is sufficiently strong to withstand arterial pressures without becoming dilated or aneurysmal, yet is flexible and easily sutured. The diameter is sufficiently great to avoid thrombosis and nourishment is provided by the intraluminal blood flow. The smooth, natural endothelial lining is less thrombogenic than any known synthetic surface. The lining surface heals itself and may sequester white cells to fight infection, unlike Dacron grafts, which provide a haven for infecting organisms in the interstices of their synthetic fibers. Saphenous vein autografts heal even when placed into the infected bed of a previous synthetic graft.
49. Endocrine autografts were among the first successful transplantation procedures. The demonstration by Berkhold in 1849 that autotransplanted testes led to the acquisition of secondary sexual characteristics in castrated cocks marked the beginning of experimental endocrinology. Endocrine autografts used successfully in modern surgical practice include:
A. Adrenal medulla to the brain.
B. Thyroid to the forearm.
C. Parathyroid to the forearm.
D. Testicle to the scrotum.
E. Pancreatic islets to the liver.
Answer: CDE
DISCUSSION: The report in 1987 of open microsurgical autotransplantation of the adrenal medulla to the caudate nucleus of the brain for treatment of intractable Parkinson's disease aroused great interest in the topic. Subsequent multicenter trials showed improvement but not cure of the disease and substantial post-operative morbidity, so the technique was not recommended for widespread use. Excellent synthetic hormone replacement is available for thyroid insufficiency, so implantation of the thyroid gland in the forearm is not necessary. However, parathyroid hormone replacement is not available, and medical therapy for hypoparathyroidism is complicated. When parathyroid tissue is removed it should be autografted to prevent the deficiency symptoms of tetany, psychological disturbances, convulsions, coma and death. One-millimeter pieces may be implanted into pockets in the sternocleidomastoid muscle. When all glands are removed for diffuse parathyroid hyperplasia, implantation of fragments into the forearm muscles facilitates subsequent removal of more tissue under local anesthesia if hyperparathyroidism persists. Autotransplantation is the treatment of choice for undescended testes. The cryptorchid or ectopic testicle must be taken out of the abdomen and placed into a cooler location prior to age 6 (preferably at 1 year) for normal spermatogenesis to occur. Approximately half of the pancreatic islet transplants performed after pancreatectomy for relief of chronic pancreatitis pain have produced patients who are insulin independent. Islets for autotransplantation are difficult to isolate in sufficient quantities from the fibrotic adult pancreas. Dispersed islets injected directly into the human portal vein have occasionally produced untoward effects such as disseminated intravascular coagulation, portal hypertension, and even hepatic necrosis.
50. Several types of gastrointestinal autografts have been used to replace the esophagus after extirpation of carcinomas. Successful reconstructions have been achieved most frequently with:
A. Stomach.
B. Jejunum.
C. Ileum.
D. Ascending colon.
E. Descending colon.
Answer: A
DISCUSSION: Although all of the listed bowel segments have been used successfully for reconstruction of the esophagus following removal of carcinomas, the stomach remains the most frequently used autograft for esophageal reconstruction. Because of its excellent blood supply the procedure can be performed at little risk as a single operation and achieve satisfactory long-term relief of dysphasia in at least 90% of patients. Either the entire stomach can be drawn into the chest or a gastric tube created in an isoperistaltic or antiperistaltic manner of sufficient length to reconstruct the entire esophagus. The advantages of a mucosal lining, serosal covering, natural opening into the stomach, and excellent blood supply based on the gastroepiploic vessels make the stomach the autograft of choice in most situations.
51. Which of the following statement(s) is/are true concerning the options for managing the exocrine secretions following pancreatic transplantation?
a. Ductal ligation is associated with no adverse effects to pancreatic parenchyma
b. Drainage of the pancreatic ductal system into the bladder is useful in the early diagnosis of rejection
c. All pancreatic grafts should be placed in a retroperitoneal position
d. Complications following enteric drainage of the pancreas (without the duodenum) are primarily associated with anastomatic leakage
Answer: b, d
There are, in principal, three options in managing the exocrine secretions following pancreatic transplant. In the first option, maintenance of exocrine secretions by internal drainage of the exocrine pancreas can be achieved by anastomosing the ductal system to either the intestinal tract (stomach, small intestine) or the urinary tract (ureter, bladder). These techniques are the most common in use today and provide the best overall results. The second technique, free drainage of the pancreatic juice into the peritoneal cavity, is certainly the least technically demanding method of transplantation. It is, however, associated with many other complications. Ablation of the exocrine secretion, the third option, can be accomplished by two techniques. The first, duct ligation, has been associated with exocrine atrophy and extensive fibrosis, usually resulting eventually in endocrine insufficiency. Ductal ligation has also had unpredictable effects on the exocrine tissue, associated with a high risk of acute pancreatitis and peripancreatic sepsis. The other method of ductal ligation involves injecting the pancreatic system with a synthetic polymer that solidifies within several minutes, with a result that exocrine secretion is completely blocked. The enterically drained pancreas (without duodenum) has in the past been associated with a significant incidence of anastomatic leakage, leading to pancreatic fistula, perigraft abscess, and systemic sepsis. Many of these allografts had to be removed. These problems can be oveated to a large extent if the donor duodenum (removed in block with the pancreas) is used to establish anastomosis. The bladder drainage technique greatly facilitates early diagnosis of rejection by providing a means to measure the output of amylase from the graft, as determined by the urinary amylase activity.
Regardless of the type of graft transplanted (either whole organ or segmental), most transplant surgeons agree that graft should be placed intraperitoneally. The extensive surface of the peritoneum is probably of considerable help in absorbing the exudate that escapes from the surface of the pancreas. The incidence of anastomatic leaks and wound complications has been greatly reduced with the intraperitoneal placement of grafts.
52. The term “tolerance” refers to responses observed which include long-term graft acceptance without the need for chronic immunosuppression. There are a variety of specific ways in which T and B lymphocytes can be tolerant or nonresponsive to antigen. Which of the following is/are mechanisms of tolerance?
a. Clonal abortion
b. Clonal deletion
c. Clonal anergy
d. Suppression
Answer: a, b, c, d
Clonal abortion refers to the developmental process whereby nascent T and B cell clones, which recognize autoantigen with high affinity, are eliminated. Clonal deletion may encompass the processes of clonal abortion but it also refers to the elimination of mature T and B cell clones. Clonal anergy is a state in which the potential relative reactive clones and their receptors are physically present but fail to respond to antigen. Suppression generally refers to an active process in which a leukocyte and/or its soluble products inhibit the development or effector function of immune lymphocytes.
53. Which of the following statement (s) is/are true concerning currently approved immunosuppressant agents?
a. Azathioprine (Imuran) is useful in the treatment of acute ongoing rejection
b. Methylprednisolone is particularly useful in immunosuppression as it has lesser toxicity than Prednisone
c. Cyclosporine blocks transcription of several early T-cell activation genes
d. FK-506 is both more potent and less toxic than cyclosporine
e. The monoclonal antibody OKT3 interferes with T-cell antigen recognition function
Answer: c, e
The major principle of immunosuppression is to induce the patient with high doses of drugs at the time of allografting in order to prophylax rejection. The drugs are then reduced rapidly within a period of days to weeks to less toxic maintenance levels. The anti-metabolite azathioprine (Imuran) interferes with nucleic acid metabolism inhibiting proliferation and clonal expansion of activated lymphocytes, eliminating alloantigen specific immune responses. This agent is used during induction immunosuppression and for maintenance immunosuppression but has little role for treating an acute, ongoing rejection. Glucocorticoids are the mainstays of virtually all immunosuppressive regimens. All glucocorticoids have similar immunosuppressive actions and none is more effective than any other at equipotent doses. Complications and side effects are equivalent at all equipotent doses. Cyclosporine inhibits the rotamase activity of cyclophilin. Therefore the major immunosuppressive activity of cyclosporine is to block transcription of several early T-cell activation genes. The macrolide antibiotic, FK-506 is 10-100 times more potent than cyclosporine on a molar basis but it too is associated with a number of significant and similar toxicities. Antibodies are given for only short periods of time to prophylax rejection and to treat acute ongoing rejection. There are two major types of antibody preparations—polyclonal antibodies such as antilymphocyte (ALG) or antithymocyte globulin (ATG) or monoclonal antibodies. The only monoclonal antibody currently available is OKT3 which is the used for both induction and treatment of rejection and is the most efficacious agent currently available for the treatment of rejection.
54. Which of the following patients would be a candidate for a liver transplant?
a. A 48-year-old man with end-stage liver disease secondary to non-A, non-B hepatitis
b. A 35-year-old man with both primary sclerosing cholangitis and ulcerative colitis and end-stage liver disease
c. A 22-year-old woman with fulminant hepatic failure secondary to acetaminophen overdose
d. A 4-year-old child with congenital biliary atresia having failed a previous Kasai procedure
e. A 48-year-old patient with alcoholic cirrhosis and a 2.5 cm central unresectable hepatoma
Answer: a, b, c, d, e
In the absence of contraindications, virtually any disease resulting in liver failure is amenable to liver transplantation. Primary sclerosing cholangitis is a common indication for transplantation since there is no other effective treatment. The common association with inflammatory bowel disease can somewhat complicate the timing of the procedure, however, in general hepatic transplantation does not affect the outcome of the ulcerative colitis. Non-A, non-B hepatitis is the most common form of hepatitis leading to liver transplantation. Recurrence of viral hepatitis in the transplanted liver occurs, but usually follows an indolent course. Biliary atresia is by far the most common indication for hepatic transplantation in pediatric patients. Recommended treatment includes creation of a portoenterostomy (Kasai procedure), if this can be done before three months of age. After this point, success rates diminish markedly. Patients without a satisfactory course, multiple revisions of the portoenterostomy should be avoided to facilitate subsequent transplantation. The most common cause of fulminant hepatic failure are non-A, non-B hepatitis, hepatitis B, and various drug toxicities. In the latter group, acetaminophen toxicity is particularly prominent. Primary hepatic malignancy, most often hepatoma, is sometimes an indication for transplantation but the results are usually worse than in other disease states because of recurrent disease. Transplantation is justified in the occasional case in which the tumor is central but relatively small, if the patient is otherwise healthy, and there is no evidence of extrahepatic disease after exhaustive evaluation.
55. Which of the following statement(s) is/are true concerning changes in physiology following lung transplant?
a. In patients with pulmonary hypertension, changes in right ventricular function and pulmonary artery pressure takes weeks to months to resolve
b. In single lung transplantation, changes in pulmonary function are seen almost immediately following transplantation
c. Patients with double lung transplants have both better pulmonary function studies as well as better exercise capabilities
d. After single-lung transplant, ventilation perfusion mismatch persists and carbon dioxide retention is seen
Answer: b
Performing single-lung transplantation in a patient with pulmonary hypertension has been particularly illustrative in demonstrating the potential for reversal of right ventricular dysfunction. As soon as the lung is implanted, the morphology of the right ventricular changes significantly as assessed by transesophageal echocardiography. The intraventricular septum, previously bulging into the left ventricle, immediately assumes the normal position. An increase in contractility of the right ventricle occurs with significant decrease in dilatation. The pulmonary artery pressure immediately decreases and is essentially normal by the time the patient leaves the operating room.
One would also expect significant ventilation perfusion mismatch to occur with ventilation to the native lung occurring preferentially because the native lung is significantly more compliant. Conversely, perfusion should preferentially go to the newly transplanted lung because of lower pulmonary vascular resistance. Despite this occurrence, patients with this operation do well from a functional standpoint. By three months after transplantation, the ventilation/perfusion mismatch narrows. Despite this mismatch, patients do not demonstrate carbon dioxide retention. From a clinical standpoint, improvement in pulmonary function is seen almost immediately after transplantation. The measurement most often used is FEV1 and marked improvement is seen within two weeks. The FEV1 essentially triples and then remains fairly stable. Improvement after bilateral lung transplant is slightly better. Although patients who receive two lungs may do better on pulmonary function tests, this benefit is not translated to significantly better exercise capability.
56. Current clinical protocols determine a limited number of variables and parameters for matching and allocation of donor organs to potential recipients. Which of the following statement(s) is/are true concerning aspects of immunity important for clinical transplantation?
a. HLA matching is important for kidney, pancreas, and liver transplantation
b. A cross match assay determines if there are preformed antibodies in the recipient’s serum which will react with antigens on the cell surface of the potential donor’s lymphocytes
c. A patient with a history of multiple transfusions or previous transplant will have a high panel reactive antibody (PRA)
d. A normal heterozygous individual with a complete donor-recipient match will have a four-antigen match
Answer: b, c
ABO compatibility is obviously required for successful transplantation. The central position of the MHC in immune regulation suggests that HLA matching is also very important for allografting. There is significant data to prove that HLA matching is important for kidney and pancreas transplantation. There is good data also to show that HLA matching is not important for liver transplantation and does not affect graft survival. The main loci typed are HLA-A, HLA-B, and HLA-DR. Thus, for a normal completely heterozygous individual this results in six antigens typed and a complete donor-recipient match is referred to as a six-antigen match. An important test for graft compatibility is the cross match. This assay determines if there are preformed antibodies in the potential recipient’s serum which will react with antigens on the cell surface of the potential donor’s lymphocytes. A positive cross-match means that such antibodies are present and that hyperacute rejection will ensue if the transplant were to be performed. Another important test which is also a reflection of the presence of host anti-donor antibodies is the panel reactive antibody (PRA). Most recipients on transplant lists send serum samples to the transplant center on a regular basis which are tested against a panel of typing cells of known HLA specificities. Most individuals should have no anti-HLA antibodies and have a low PRA (0–5%). Patients who have been transfused, pregnant, previously transplanted, or have an autoimmune disorder which induces a lot of antibodies might have a high PRA (50–99%). The presence of a very high PRA suggests that a patient is likely to have a positive cross-match.
57. T-lymphocytes are divided into two main sub-classes: CD4+ and CD8+. Which of the following statement(s) is/are true concerning these classes of T-cells?
a. CD4+ T-cells are restricted to recognizing antigens of the class II major histocompatibility complex (MHC)
b. CD8+ T-cells perform primarily cytotoxic functions
c. CD4+ 8+ double positive cells are well-differentiated mature cells
d. CD4+ T-cells also perform suppressor functions
Answer: a, b, d
T-cells are divided into two main sub-classes: CD4+ and CD8+. CD4+ 8+ double positive cells are usually immature T-cells or thymocytes while the fully differentiated T-cell is usually single positive. Because of molecular interactions, CD4+ T-cells are restricted to recognizing antigens in the context of class II major histocompatibility complex (MHC) and usually perform roles related to B-cell help, T-cell help, and inflammatory responses such as delayed and contact hypersensitivity. CD8+ T-cells are restricted to class I MHC and perform cytotoxic functions. In addition, experimental studies have demonstrated that both CD4+ and CD8+ T-cells can act as T suppressor cells.
58. Correct statement(s) concerning postoperative complications after hepatic transplantation include:
a. Primary nonfunction occurs in 5 to 10% of transplanted livers in the immediate postoperative period
b. A biliary leak, although a common complication, is usually of minimal clinical importance
c. Portal vein thrombosis occurs much more commonly than hepatic artery thrombosis
d. If postoperative bleeding is encountered, immediate return to the operating room is indicated
Answer: a
Primary nonfunction of the allograft occurs in about 5% to 10% of transplanted livers. Most cases of nonfunction are related to inadequate tissue preservation or occult organ dysfunction in the donor but a sizeable percentage may arise from immunologic mechanisms. In the worst case scenario, the patient does not regain consciousness, a coagulopathy ensues, and multiple organ failure develops. Liver enzymes show hepatocellular injury with SGOT and SGPT values in the range of 5000 to 10,000 and little bile production. Hepatic artery thrombosis occurs in 5% of adult hepatic transplantation cases and up to 25% of pediatric cases. Postoperative vein thrombosis is much less common than hepatic artery thrombosis, occurring in 2% to 3% of cases. Laparotomy to control postoperative bleeding is required in 15% of cases. In about half of the reoperations, a specific bleeding point is identified. Survival is higher in these cases in contrast to those in which diffuse bleeding is encountered, presumably since the latter circumstance is usually associated with poor allograft function and resultant coagulopathy. If significant bleeding occurs after hepatic transplantation, a common and sensible policy is to transfuse the patient until hypothermia and coagulopathy are corrected with subsequent (one to three days) evacuation of blood from the peritoneal cavity. Biliary leakage is a feared complication, with a high (50%) mortality. The high mortality may be the result of a concomitant hepatic arterial thrombosis and infection of the leaked bile, or difficulty of bile duct repair in the area of inflamed tissue.
59. Which of the following statement(s) is/are true concerning renal transplantation?
a. Living-related donor transplants typically can be expected to have one-year graft survival rates of over 90%
b. Preconditioning of the recipient with the use of donor-specific blood transfusions from their living donor improves graft survival and therefore should be used routinely
c. Pre-transplant blood transfusions result in improved graft survival following cadaveric renal transplant in the cyclosporine era
d. Age of the recipient over 50 years is generally associated with a poorer outcome due to graft rejection
Answer: a
The use of living-related donor renal transplant has multiple advantages including improved short-and long-term graft survival, routine immediate allograft function, and fewer rejection and infectious episodes. Nearly all transplantation centers that perform living-related donor transplantations report one-year graft survival rates of over 90%. The use of preconditioning of the recipient with donor-specific blood transfusions from their living donor can improve graft survival. The major drawback to this maneuver is the development of recipient anti-donor antibodies (sensitization) which occurs in nearly one-third of recipients. The development of sensitizing antibodies eliminates the use of that donor. With the introduction of cyclosporine, the use of donor-specific transfusions with subsequent immunosuppression, was compared to nontransfused recipients treated with cyclosporine and prednisone. These investigations have demonstrated excellent graft survival rates over long-term follow-up and therefore routine donor-specific transfusions are seldom performed in adults. In the azathioprine and prednisone immunosuppression era, several immunologic and nonimmunologic risk factors were identified as having an adverse effect on graft outcome. Historically, older renal allograft recipients (older than 50 years) did poorly compared with younger counterparts. Much of the graft loss was found to be associated with patient deaths, and usually was the result of overwhelming infection. With the cautious use of cyclosporine and prednisone, however, excellent patient and graft survival rates are now reported. Data from the azathioprine and prednisone era show a clear-cut benefit from improved graft survival after multiple random blood transfusions. More recent studies again showed no advantage to blood transfusion when cyclosporine is used. Since transfused patients have a risk of developing anti-HLA antibodies, these patients may become more difficult to undergo organ transplantation in a timely fashion.
60. Which of the following statement(s) is/are true concerning clinical syndromes of rejection?
a. Hyperacute rejection occurs with kidney, heart, liver and lung transplants
b. The histologic characteristics of acute rejection include lymphocyte infiltration accompanied by plasma cells, eosinophils, or neutrophils
c. Vascular atherosclerosis and obliteration are characteristic of chronic rejection
d. Transplantation across major ABO incompatibility will result in hyperacute rejection of a renal or cardiac transplant
Answer: b, d
Hyperacute rejection is the result of pre-formed antibody binding to the allograft at the time of revascularization in the operating room. Complement is activated resulting in endothelial cell destruction, vascular leak, recruitment of platelets and neutrophils, thrombosis of vessels, and destruction of the graft in a period of minutes to hours. Kidney, heart, pancreas, and lung allografts are all susceptible to hyperacute rejection; however, liver grafts are relatively resistant to this process and are often transplanted across antibody differences and even across an ABO difference. Acute rejection usually occurs days to weeks after transplantation and is initiated by T-cell dependent immunity characterized microscopically by lymphocytic infiltration accompanied by plasma cells, eosinophils, and a few Mast cells or neutrophils. Chronic rejection usually occurs months to years after transplant. It is characterized by loss of normal histologic structure, fibrosis and atherosclerosis. Chronic rejection is the major cause of graft failure and patient loss with all organs.
61. Which of the following statement(s) is/are true concerning techniques for multiple organ procurement and preservation?
a. The liver and pancreas are generally removed en bloc and separated as a bench procedure
b. Renal allograft function is improved by the use of machine perfusion
c. UW (University of Wisconsin) cold storage solution is the method of choice of most programs for hepatic and pancreatic transplantation
d. Cardiac allografts have the shortest limit of cold ischemia
Answer: a, c, d
The complexity of multiple organ procurement involves the coordination of at least two teams (thoracic and abdominal). The liver and pancreas are generally removed en bloc with the organs separated as a bench procedure, retaining the celiac axis for the liver. The kidneys are also removed en bloc. Studies indicate that post-transplantation renal allograft function is similar regardless of whether simple hypothermia or the more cumbersome technique of machine perfusion are used. For decades, the primary solution used for cold storage preservation of kidneys was Euro-Collins solution. Recently, a new solution, UW solution, has been developed with ingredients designed to provide high-energy phosphate precursors, hydrogen ion buffering capacity, and anti-oxidant properties. Although the advantage of this solution over Euro-Collins solution for kidneys is unclear, UW solution is used as the preservation method of choice by nearly all programs performing hepatic and pancreatic transplantations. Both organs can reliably be stored for 24 hours. Kidneys can generally be safely stored for 36 to 48 hours before transplantation. Cardiac preservation has changed relatively little in recent years. Hyperkalemic crystalloid cardioplegia solution is used at 4°C and four hours is generally the accepted limit of cold ischemia. The current limit of cold ischemia for small bowel is approximately 12 hours.
62. Which of the following statement(s) is/are true concerning the outcome of renal transplantation?
a. Two-thirds of all graft losses alone (without death) occur from one to six months after transplantation
b. The most common cause for graft loss after one year following transplantation is patient death
c. Most patient deaths following transplantation are related to immunosuppression
d. An acute rejection episode in a renal allograft recipient is the most important clinical event, determining both short-term and long-term graft survival
e. The period between the six months and one year following transplantation is the most critical time period following renal transplant
Answer: a, b, d
There are two ways to lose a renal allograft—graft loss alone and death of the patient regardless of the degree of graft function at the time of death. Two-thirds of all graft losses alone (without death) occur from one to six months after transplantation. Only 14% of all graft losses occur after one year. In contrast, half of the patient losses (most dying with functioning grafts) occur more than one year after transplantation. More than half the deaths are due to cardiovascular complications not related to immunosuppression but closely related to comorbid cardiovascular variables present at the time of transplantation. Less than 25% of deaths are related to immunosuppression. The period between one and six months after transplantation is the most active and crucial time in the clinical course of a patient with a renal transplant. During this time 63% of all graft losses, 22% of deaths, and 74% of all acute rejection episodes occur. An acute rejection episode in a renal allograft recipient is the single most important clinical event determining both short and long-term graft survival. The post-transplant period that begins at six months and continues to the one year mark is the quiescent time with very few influential clinical events. Only 9% of all graft losses and 9% of all acute rejection episodes occur during this time period.
63. Which of the following characteristics or conditions will exclude a patient as a suitable cadaveric organ donor?
a. Active systemic bacterial infection
b. Primary CNS malignancy
c. Age over 65
d. History of prior cholecystectomy for a possible hepatic donor
Answer: a
The characteristics of a suitable cadaveric organ donor can be divided into those that are general in nature and those that are organ-specific. Broadly stated, the general attributes of an acceptable organ donor include the establishment of a diagnosis of brain death, previously good general health, and relative hemodynamic stability from the time of the advanced precipitating brain death until organ procurement is complete. As experience has been gained with donors considerably less than ideal, it has become apparent that arbitrarily defined chronological age limits for organ donors are unnecessary.
Active systemic infection is an absolute contraindication to organ donation. Documented positive blood cultures for known systemic infection that has not been completely eradicated rule out the potential organ donor because of risk of transmission of infection to an immunosuppressed recipient. Furthermore, all potential organ donors, regardless of whether they are considered high risk, should be tested for infection with human immunodeficiency virus as well as hepatitis B and C. Cancer, whether treated or not, has long been considered to contravene organ donation. The only exception to this rule has been the donor with a primary malignancy of the central nervous system.
The condition of particular organs in great measure dictate their individual suitability for transplantation. Preexisting hepatic disease can usually be identified before organ procurement. A history of hepatitis or cirrhosis of any kind preclude donation. Although calculous biliary tract disease would appear at first blush to be a contraindication of hepatic procurement, prior cholecystectomy for uncomplicated cholelithiasis is not an absolute contraindication to liver donation.
64. Which of the following statement(s) is/are true concerning associated renal and pancreatic transplantation?
a. The most important advantage is the use of renal function as an early indicator of pancreatic graft rejection
b. After renal transplant, there is no additional risk associated with immunosuppression
c. A major disadvantage of simultaneous renal/pancreatic transplant is the potential adverse effect on renal allograft as the result of a pancreatic complication
d. A diabetic with a renal transplant continues to be at risk for diabetic nephropathy
Answer: a, b, c, d
In the patient with a functional renal transplant, because of the need for long-term immunosuppression, the demonstration of a prior allograft acceptance and a continued risk for recurrent diabetic nephropathy are compelling reasons to offer pancreatic transplantation. The advantages to simultaneous renal-pancreatic transplantation compared to a sequential procedure (renal followed by pancreatic) include 1) the recipient’s need to accept only one set of donor antigens; 2) the ability to monitor rejection of the pancreas by identifying the well-recognized signs of renal allograft rejection; 3) the immunosuppressive effect of uremia; 4) transportation in patients who have not been maintained on chronic immunosuppression; and 5) a single albeit longer anesthetic exposure. Of these advantages, the most important is the use of renal function as an early indicator of pancreatic graft rejection. The disadvantages of simultaneous renal-pancreatic transplantation include extensive surgery in a uremic diabetic patient and the potential adverse effect on renal allograft function as the result of a pancreatic complication. Ideally, pancreatic transplantation should be performed in patients who do not yet have, but are designed to develop, secondary complications to diabetes that are more serious than the potential side-effects of immunosuppression. In recipients of a pancreas after a kidney, the only risks of pancreatic transplant are related to the surgery since immunosuppression is already obligatory.
65. There are numerous toxicities and adverse effects associated with immunosuppression. Which of the following statement(s) is/are true concerning complications of immunosuppression?
a. Transplant recipients are susceptible primarily to infections with unusual organisms (fungus, virus, atypical bacteria)
b. Immunosuppressive agents may blunt the inflammatory response to infection leading to a late presentation of an infectious process
c. The development of malignancy appears primarily due to direct mitogenic effects of the agent
d. Lymphomas are the most common malignant tumors developing in the transplant patient
e. Graft-vs-host disease is a progressive condition and extremely difficult to treat
Answer: b
The most obvious complication of immunosuppression is infection. As immunosuppression becomes stronger and more effective, the recipient’s ability to resist infection diminishes. Transplant recipients are susceptible both to typical bacterial infections (UTI, pneumonia, wound infections) and to infections with unusual organisms (fungus, virus, atypical bacteria). Immunosuppressives also block the inflammatory response to infection so that patients present with very subtle signs and symptoms or they present late in the infectious process.
Another complication in allograft recipients is malignancy. The immunosuppressive drugs do not appear to be directly mitogenic or transforming, but rather probably suppress immune mechanisms which keep transformed cells in check. Squamous cell carcinomas of the exposed area of the skin are by far the most common malignancy. Lymphomas are the next most common tumor and are 10–100 times more common in transplant recipients than in the general population. These are usually non-Hodgkins B cell lymphomas and are often related to malignant transformation by Epstein-Barr virus (EBV).
Another complication of organ allografting is graft-vs-host disease (GVHD). GVHD is usually self-limited as donor cells, stimulated by the host alloantigen, are eliminated either by immunosuppression or by host anti-donor responses.
66. Which of the following statement(s) is/are true concerning the results of lung transplantation?
a. One year survival following single lung transplant is significantly better than following bilateral transplant
b. The worst survival is seen in patients with pulmonary hypertension
c. Patients with cystic fibrosis have a markedly poorer result than do patients with emphysema
d. Infection is a common cause of mortality in both the early and late post-transplant period
Answer: b, d
In just over ten years since the first successful lung transplant, approximately 3000 transplants have been performed. Overall, one-year actuarial survival following lung transplant is approximately 70% (single lung = 70%; bilateral lung = 74%). At two years, survival drops to 63%. Patients with emphysema have the best survival at one and two years while those with pulmonary hypertension had the worse (77% vs 61%). Patients with cystic fibrosis do almost as well as the group with emphysema (72%). Overall there is some continuing to fall off in survival at three years with an overall survival of 57% which drops to 51% at four years and 46% at five years. Causes of recipient death can be categorized according to the time frame in which they occur. Early (less than 90 days following transplant) death most commonly results from bacterial infection. Infection also accounts for approximately one-third of late deaths (greater than 90 days) following transplantation. A similar percentage results from manifestations of chronic rejection and obliterative bronchiolitis.
67. Categories of patients in which pancreatic transplantation is applicable includes:
a. Diabetics with a functioning renal transplant
b. Diabetic patients with end-stage renal disease requiring renal transplantation
c. Nonuremic diabetics with other complications of their disease
d. Well-controlled adult onset diabetics
Answer: a, b, c
Pancreatic transplantation can be applied to three categories of patients. In the first category are diabetic patients who already have undergone successful renal transplantations. In the patient with a functioning renal transplant, because of the need for long-term immunosuppression, the demonstration of prior allograft acceptance, and the continued risk of recurrent diabetic nephropathy, are compelling reasons to offer pancreatic transplantation. The second group of patients are those with end-stage renal disease requiring renal transplantation. These people may benefit either from simultaneous or sequential renal-pancreatic transplantation. The final and largest potential group of patients are nonuremic diabetics with other complications of their disease.
68. Which of the following statement(s) is/are true concerning the results of cardiac transplantation?
a. Overall one-year survival is approximately 80%
b. Survival following transplant in the pediatric age group is significantly worse than in adults
c. There is no difference in survival when cardiac transplantation is performed in a heterotopic position versus an orthotopic position
d. The survival rate for retransplantation is approximately 50%
Answer: a, d
Collected data from a multi-center registry has shown that the overall one-year survival following cardiac transplantation is 80%. Overall five-year survival is approximately 65%. Survival in patients receiving heterotopic cardiac transplants is significantly lower than in patients receiving hearts in the orthotopic position. The overall one-year survival rate for retransplantation as reported from the same registry is only 54%. In the pediatric age group, actuarial survival at two years is 80% and 76% at five years.
A. Homer, the Greek who described the Chimaera in his Iliad.
B. Gasparo Tagliacozzi, the Italian who described a method of reconstructing the nose.
C. John Hunter, the Scot who performed autografts and xenografts.
D. Emrick Ullmann, the Austrian who performed the first successful renal allograft.
E. Alexis Carrel, the Franco-American who described a successful technique for vascular anastomosis.
Answer: C
DISCUSSION: All of the descriptions are correct and represent important contributions to the history of transplantation. However, the Scottish surgeon John Hunter (1728–1793), is rightfully known as the father of experimental surgery because of his pioneering research. Several of his experimental procedures involved
transplantation, including autografting of a cock's spur to its comb and xenografting of a human tooth to the comb of a cock.
2. Transplantation terminology contains terms to describe the relationship of the graft donor to the graft recipient. Historical terms such as “homograft” and “heterograft” have been replaced by less ambiguous terms. The correct modern terminology for a graft between genetically nonidentical members of the same species is:
A. Allogeneic graft.
B. Autogeneic graft.
C. Isogeneic graft.
D. Syngeneic graft.
E. Xenogeneic graft.
Answer: A
3. The modern era of clinical organ transplantation began with the advent of chemical immunosuppression. The important drug discovery that produced the initial success of cadaveric transplantation was:
A. Cyclophosphamide.
B. Azathioprine.
C. Cyclosporine.
D. Antilymphocyte serum.
E. Monoclonal antibody OKT3.
Answer: B
DISCUSSION: All of the listed drugs have immunosuppressive activity that has proved useful in transplant recipients. However, the discovery in 1959 by Schwartz and Dameshek that 6-mercaptopurine blocked antibody production and the subsequent creation by Hitchings in 1961 of its safe, convenient imidazole derivative named azathioprine produced the first consistently effective immunosuppression for successful cadaveric renal transplantation.
4. Which of the following statements correctly characterize the genetic basis of histocompatibility?
A. Histocompatibility is determined by a series of genes inherited as a complex and subject to the mendelian rules that characterize recessive traits.
B. Histocompatibility depends in part on the inheritance of histocompatibility genes and in part on the inheritance of T-cell receptor genes.
C. Major histocompatibility genes are polymorphic.
D. Histocompatibility genes are independently segregating and co-dominant.
E. Histocompatibility is learned.
Answer: CDE
DISCUSSION: Histocompatibility refers to the genetic determinants of graft rejection. The determinants of overwhelming importance consist of a series of histocompatibility genes that segregate independently during meiosis. Each gene has multiple, dominant alleles. Histocompatibility genes and the proteins they encode are highly polymorphic (i.e., they exist in multiple forms).
5. The major histocompatibility complex (MHC) includes genes that encode which of the following proteins?
A. HLA-A.
B. HLA-DR.
C. TAP-1.
D. 21-Hydroxylase.
E. HLA-L.
Answer: ABCD
DISCUSSION: The major histocompatibility complex (MHC) includes genes encoding histocompatibility antigens, some other proteins, and a number of pseudogenes that do not encode proteins. The class I region encodes more than 15 genes, including the classical transplant genes A, B, and C as well as HLA-E, F, and G and four pseudogenes, H, J, K, and L. The class II region contains more than 25 genes, including those for the transplantation antigens HLA-DR, DQ, and DP. The region also includes two alpha genes, DMA and DNA, and two beta genes, DMB and DOB, genes for the low-molecular-weight proteins (LMPs) LMP2 and LMP3 and for the transporter molecules TAP1 and TAP2. The class III region, lying between class II and class I, contains more than 30 genes, among which are the genes encoding the complement components factor B, C2, and both C4 molecules, both tumor necrosis factor genes alpha and beta, and the heat shock proteins Hsp 1H and Hsp 70 2, and 21-hydroxylase.
6. Which of the following distinguish MHC class I from MHC class II antigens?
A. MHC class I and class II antigens are encoded in different regions of the MHC complex.
B. MHC class I antigens are expressed on specialized antigen-presenting cells, whereas MHC class II antigens are expressed on all cells.
C. MHC class I and class II are members of different supergene families.
D. MHC class I are considered to be the major histocompatibility antigens and MHC class II the minor histocompatibility antigens.
E. MHC class I is recognized by the CD8 glycoprotein, whereas MHC class II is recognized by the CD4 glycoprotein.
Answer: AE
DISCUSSION: MHC class I and class II antigens are encoded by genes in different regions of the MHC. The genes and the proteins they encode are homologous to immunoglobulins and thus are members of the immunoglobulin supergene family. MHC class I antigens are expressed on the surface of all cells, whereas MHC class II antigens are largely restricted in expression to antigen-presenting cells and endothelial cells. Both MHC class I and class II antigens are major histocompatibility antigens because their incompatibility in the donor and recipient can lead to very rapid and vigorous rejection of an allograft. The T cells that have antigen receptors specific for MHC class I plus peptide express CD8, a co-receptor that binds to the MHC class I molecules. The T cells that have antigen preceptors specific for MHC class II plus peptide express CD4, a co-receptor that binds to MHC class II molecules.
7. Which of the following characterize the role of the major histocompatibility antigens in immune responses?
A. The major histocompatibility antigens are critical in antigen processing and presentation.
B. Major histocompatibility antigens contribute to the maturation of T cells in the thymus.
C. T cells recognize only foreign antigens that are complexed with major histocompatibility antigens.
D. Expression of major histocompatibility antigens is increased in inflammation.
E. Recognition of major histocompatibility antigens is critical to the development of tolerance.
Answer: ABCDE
DISCUSSION: Once thought to be solely markers of individuality, MHC antigens are crucial to cell-mediated immune responses. Foreign antigens taken up by antigen-presenting cells are degraded and then become complexed with MHC molecules and expressed on the cell surface, and these events are enhanced in inflammation. Since T cells recognize only foreign antigens expressed as peptides in association with MHC antigens, the possibility for recognition is increased as a consequence of inflammation. Since T cells recognize only antigens expressed in association with MHC antigens, recognition of these antigens is critical to the development of tolerance to “self.”
8. The unusual intensity of alloimmune responses reflects which of the following characteristics?
A. The presence of a peptide-binding groove in the MHC molecule.
B. Recognition of the native structure of allogeneic MHC molecules.
C. The high frequency of T cells able to recognize directly allogeneic MHC antigens.
D. Stimulation of many T-cell receptors during the interaction of a T cell with an antigen-presenting cell.
E. The high frequency of antigen-presenting cells able to be recognized by T cells.
Answer: BCDE
DISCUSSION: Allotransplantation evokes an unusually intense and rapid cellular immune response. In contrast to conventional cellular immune responses, in which foreign antigens are recognized only as peptides in the groove of self MHC antigens, allogeneic MHC antigens are recognized directly as native proteins on the surface of allogeneic antigen-presenting cells. Thus, a large fraction of antigen-presenting cells is able to present alloantigen in this fashion, and a large fraction (up to 10%) of T cells is able to respond.
9. Which of the following statements correctly characterize the role of histocompatibility typing in transplantation?
A. Histocompatibility typing must be carried out before transplantation can safely be undertaken.
B. The “rules” of histocompatibility were established shortly after the advent of immunosuppressive therapy made transplantation feasible.
C. Histocompatibility typing may involve serologic, cellular, and molecular procedures for typing.
D. The role of histocompatibility matching in transplantation is controversial.
E. The cross-match test is carried out to determine whether a potential graft recipient has antibodies against the donor.
Answer: CDE
DISCUSSION: The concept of histocompatibility and the rules governing the susceptibility to rejection were deduced early in this century by such investigators as Jensen, Little, and Tyzzer, who were interested in the inherited resistance or susceptibility to transplanted tumors. The application of histocompatibility to clinical transplantation, however, had to await the advent of immunosuppressive therapy. Despite the practice of organ transplantation for more than 30 years, the role of histocompatibility typing in transplantation is controversial. Although grafts between HLA-matched donors and recipients exhibit better survival than HLA-mismatched grafts, matching is not routinely performed before transplantation of the heart or liver, and the outcome of these grafts may be very good. Histocompatibility typing involves the use of a variety of techniques—serologic, cellular, and molecular—to identify the antigens carried by the donor and the recipient. In addition to formal typing, the recipient is tested via cross-match for antibodies against the donor.
10. Activation of T cells requires:
A. Stimulation of the antigen receptor.
B. Stimulation of the MHC antigen.
C. Co-stimulation.
D. Anergy.
E. CD3.
Answer: ACE
DISCUSSION: The activation of T cells generally involves the delivery of two types of signals. One signal is initiated when the T-cell antigen receptor binds in a cognate manner to an MHC antigen bearing an antigenic peptide expressed on the surface of an antigen-presenting cell. This interaction is enhanced by the co-ordinate binding of CD4 or CD8 to the MHC antigen complex. This interaction initiates signaling through CD3, as well as through CD4 or CD8, both of which are associated with tyrosine kinases. Full activation of the T cell also requires the delivery of “co-stimulatory” signals. These signals may arise through the interaction of CD28 expressed by the T cell with B7-1 or B7-2 expressed on antigen-presenting cells. If only the T-cell antigen receptor is stimulated (and co-stimulation is not provided) the T-cell becomes anergic, that is, resistant to further stimulation. Anergy may be an important mechanism contributing to tolerance.
11. Which of the following statements characterize the biology of allotransplantation?
A. The rejection response is systemic.
B. The rejection response is learned.
C. The rejection response involves a constellation of immunologic and environmental factors.
D. Allotransplantation evokes a cellular immune response.
E. Allotransplantation evokes a humoral immune response.
Answer: ABDE
DISCUSSION: Medawar and Gibson elucidated some of the basic principles of transplantation biology. Rejection of a second skin graft from the donor of a first graft is very much hastened, indicating that the response is learned and that the second response evokes “memory.” The second graft is rejected rapidly, regardless of its location, indicating that the response is systemic. The major immune reaction causing rejection of a first graft is a cellular immune response; however, the recipient exposed to allogeneic cells develops antibodies against alloantigens, indicating that a humoral response has also occurred.
12. Allograft rejection may involve which of the following?
A. Helper T cells.
B. Veto cells.
C. Cytotoxicity.
D. Cytokines.
E. The Arthus reaction.
Answer: ACD
DISCUSSION: The effector mechanisms that underlie the pathogenesis of allograft rejection remain the subject of controversy. Rejection, like delayed-type hypersensitivity, may be mediated by helper T cells, which release cytokines that activate other cells such as macrophages and directly alter endothelial cell functions. On the other hand, rejection may be mediated by cytotoxic T cells, which kill or injure target cells through direct interactions. Both types of cells can be found in grafts undergoing rejection, and there is experimental evidence suggesting that both may be involved. Veto cells kill T cells, which recognize MHC antigens on the veto cell surface; this action is thought to contribute to tolerance and not to rejection. The Arthus reaction is an immune response that, in contrast to allograft rejection, is mediated primarily by antibodies and not by cells.
13. Which of the following statements about allograft rejection are true?
A. In the absence of immunosuppression, the time and intensity of rejection of transplants between unrelated donors and recipients is highly variable.
B. Allograft rejection may be mediated by antibodies or by cells.
C. Allograft rejection is thought to be caused by Th2 cells.
D. Acute cellular rejection is the major cause for loss of clinical organ transplants.
E. An individual with “tolerance” is unable to reject an allograft.
Answer: B
DISCUSSION: In the absence of immunosuppression, allografts from randomly selected donors are always rejected, and the rate of rejection is rapid as compared with the rate of development of most immune responses. Although allograft rejection in naive recipients is mediated predominantly by cells, antidonor antibodies can cause very severe types of rejection, including hyperacute and acute vascular rejection. Antidonor antibodies or cellular responses may contribute to the development of chronic rejection, which is now the most common cause of graft loss. Recent studies demonstrate that helper T cells may differentiate along one of two pathways. The Th1 pathway leads to secretion of interferon-gamma and other cytokines and is associated with delayed-type hypersensitivity and allograft rejection. The Th2 pathway is associated with secretion of interleukin-10 (IL-10) and IL-4 and may actually inhibit alloimmune responses. The development of Th2 responses may thus contribute to tolerance. Like allograft rejection, tolerance is highly specific. Thus, a person who is tolerant to one antigen or one individual is still able to mount an immune response against other antigens and other individuals.
14. The presence of donor-reactive lymphocytotoxic antibodies in the serum of a potential kidney transplant recipient:
A. Can be detected by in vitro testing with recipient leukocytes and donor serum.
B. Is a contraindication to kidney transplantation.
C. Can be found in all male patients older than 20 years.
Answer: B
DISCUSSION: The presence of donor-reactive antibodies, detected by incubation of the recipient's serum with donor lymphocytes in the presence of complement, results in a “positive crossmatch,” and is a contraindication to renal transplantation. They occur as a result of pregnancy, blood transfusions, or previous organ transplants.
15. Utilization of a living related donor instead of a cadaver donor is no longer an advantage in renal transplantation because:
A. Public recognition of transplantation as a successful therapy has facilitated obtaining family permission for recovery of transplantable organs. Thus, because sufficient kidneys are available from “brain-dead” accident victims, there is no need to use related donors.
B. Cyclosporine therapy after cadaveric renal transplants has improved their outcome, which is now comparable to related-donor transplants.
C. Modern preservation techniques can maintain viability of kidneys from cadaver donors for many hours, consistently allowing their early function to be as good as that of kidneys from living donors.
D. None of the above.
Answer: D
DISCUSSION: It is generally accepted that transplantation is a useful therapy; however, the number of recipients continues to greatly exceed the number of suitable cadaver donors whose families grant permission for organ recovery. Thus, availability of a living donor may shorten the waiting period for a transplant by several years. Cyclosporine has improved the short-term results of cadaveric transplantation, but the attrition of these grafts is greater than that for living-donor transplants, especially those with close histocompatibility. The predicted 10-year survival of grafts from HLA-identical siblings is 80%, whereas for cadaver grafts it is only 40%. Although preservation techniques can maintain viability of kidneys for 36 to 48 hours, cadaver kidneys suffer a much higher rate of posttransplant acute tubular necrosis than those from related donors. Acute tubular necrosis has been shown to have a definite detrimental effect on long-term graft survival.
16. Large volumes of urine in the early postoperative course of renal transplant patients:
A. Result from osmotic stimuli to diuresis.
B. May signify reversible polyuric acute tubular necrosis.
C. Should be replaced by administration of equal volumes of crystalloid.
D. Facilitate the diagnosis of rejection and obstruction of the renal artery and/or collecting system.
Answer: ABCD
DISCUSSION: Factors responsible for the brisk diuresis following renal transplantation include osmotic stimuli secondary to high urea and/or glucose concentrations in the serum, and mild proximal tubular damage resulting from allograft ischemia. To avoid severe dehydration in the early postoperative period, an attempt should be made to replace urine losses with equal volumes of 0.45% NaCl solution to which 20 to 30 mEq. NaHCO 3 per liter may be added. The diagnosis of rejection and/or obstruction to urine flow is made easier when a transplanted kidney is undergoing voluminous diuresis rather than demonstrating oliguria or anuria secondary to severe acute tubular necrosis.
17. As compared with the early immunosuppressive drugs (azathioprine, steroids, antilymphocyte serum) some newer agents have the following specific advantages:
A. Cyclosporine, which interferes with lymphokine production, exhibits neither bone marrow nor renal toxicity.
B. Monoclonal antibody (OKT3) is more available and has greater specificity and fewer side effects than antilymphocyte serum.
C. Tacrolimus (FK506) has properties similar to those of cyclosporine but is especially valuable for rescue of grafts that are failing on cyclosporine therapy.
D. None of the above.
Answer: C
DISCUSSION: Cyclosporine interferes with production of cytokines and lacks the bone marrow toxicity of azathioprine. Unfortunately its chief toxicity is renal. Although OKT3 is more available, more uniform, and more specific than antilymphocyte serum, some of its side effects are even greater, such as fever, chills, nausea, vomiting, diarrhea, and pulmonary edema. Tacrolimus has been used most extensively for liver grafts. It has been found especially valuable in reversing rejection of failing grafts.
18. Survival rates for patients on dialysis are better than those for patients receiving renal allografts in the following circumstances:
A. A living related donor is available.
B. A cadaver donor must be used.
C. The recipient's renal failure is secondary to diabetes.
D. None of the above.
Answer: D
DISCUSSION: Patients receiving chronic dialysis have a mortality rate of 6% to 20% per year, every year. The mortality rate is as high as 11% to 25% per year in diabetic dialysis patients. Patients undergoing renal transplantation have an operative mortality rate of less than 2%, and the 1-year survival for recipients of living related kidneys is better than 95%. Survival is greater than 90% for recipients of cadaver kidneys. The 5-year patient survivals are approximately 80% for nondiabetic recipients of living related and cadaver kidneys, and 60% to 70% for diabetic recipients. Thus, a well-functioning renal allograft provides a greater chance for a longer life than does chronic dialysis.
19. Posttransplantation hypertension can be caused by:
A. Rejection.
B. Cyclosporine nephrotoxicity.
C. Renal transplant artery stenosis (RTAS).
D. Recurrent disease in the allograft.
Answer: ABCD
DISCUSSION: Both acute and chronic rejection may result in hypertension. The former causes acute fluid retention and plugging of peritubular capillaries with inflammatory cells. This may progress to intimal swelling and medial necrosis and eventuate in ischemia secondary to endothelial proliferation and obliteration of small vessels. Chronic rejection, thought to be related to protracted humoral injury, results in obliteration of capillaries via the development of intimal hyperplasia. Cyclosporine has a vasoconstrictive effect which, through activation of the renin-angiotensin system, may lead to hypertension. RTAS is responsible for hypertension in 4% to 12% of renal allograft recipients. It responds well to percutaneous angioplasty. A careful trial of angiotensin-converting enzyme inhibitors may be diagnostic of RTAS. Recurrent disease such as membranoproliferative glomerulonephritis and focal glomerular sclerosis may result in significant hypertension in renal allograft recipients.
20. Which of the following statements about posttransplantation malignancy is correct?
A. Certain immunosuppressive agents increase the incidence of malignancy in transplant recipients, whereas others do not.
B. Those malignancies most commonly seen in the general population (breast, colon) are substantially more common in transplant recipients.
C. Lymphoproliferative states and B-cell lymphomas are associated with Epstein-Barr virus.
D. None of the above.
Answer: C
DISCUSSION: Both naturally occurring and iatrogenic states of immune deficiency are associated with an increased rate of de novo malignancy. Transplant recipients have a rate of malignancy approximately 100 times that of the normal population. The degree of immunosuppression, rather than a specific immunosuppressive agent, appears to be responsible. Squamous and basal cell carcinomas of the skin are most common; however other tumors that are common in the general population, such as breast and colon cancers, do not appear to be increased in incidence. Lymphomas, which occur at a rate that is 350 times normal, and the lymphoproliferative states that often precede them appear to be associated with Epstein-Barr virus. Possible explanations for these high malignancy rates include defective immunosurveillance, chronic stimulation of the reticuloendothelial system by the allograft, the carcinogenic effect of immunosuppressive drugs, and viral oncogenesis.
21. One week after receiving a cadaver renal allograft, the recipient remains oliguric and dialysis dependent. Ultrasonography reveals a larger perigraft fluid collection. Your next step in management includes:
A. No further investigations (since perigraft collections are fairly common after renal transplantation).
B. Aspiration of the perigraft fluid collection and instillation of a fibrosis-inducing agent to obliterate the dead space.
C. Angiography for localization of a bleeding site in the renal allograft.
D. Aspiration of the perigraft fluid collection for chemical analysis.
Answer: D
DISCUSSION: Urine leaks usually occur early after transplantation, and the most frequent site of leakage is from the ureteroneocystostomy or ischemic ureter. The clinical signs are pain, swelling, and deterioration of renal function before leakage from the wound is observed. Aspiration of the perigraft fluid collection for chemical analysis of blood urea nitrogen (BUN) and creatinine would aid the differentiating urinoma from lymphocele. The composition of urinoma reveals BUN and creatinine concentrations several orders of magnitude higher than those of a lymphocele, which are comparable to the values in blood.
22. Regarding access for hemodialysis, which of the following statements is/are incorrect?
A. Some patients are not candidates for hemodialysis.
B. Some complications can lead to exsanguination.
C. The best access to place for a patient beginning dialysis is a leg polytetrafluoroethylene (PTFE) graft from the femoral artery to the saphenous vein.
D. First of all one should attempt to create a Brescia-Cimino fistula.
E. The leading complication of PTFE grafts is infection.
Answer: CE
DISCUSSION: Some patients do not tolerate hemodialysis because of cardiac difficulties or because they cannot be heparinized for hemodialysis. If a peripheral shunt becomes disconnected, the patient can exsanguinate. This can occur if a cap or clamp is inadvertently removed from a central dialysis catheter. The ideal location for a dialysis fistula or graft is in the upper extremity as far distal as possible, such as with a Brescia-Cimino fistula or a forearm loop graft. The leading complication of PTFE grafts is thrombosis caused by intimal hyperplasia in the venous limb. Infection is the second leading complication with these grafts.
23. Access to the peritoneal cavity for peritoneal dialysis can be gained:
A. Percutaneously.
B. Surgically.
C. Using laparoscopy.
D. Only using general anesthesia.
Answer: ABC
DISCUSSION: Chronic ambulatory peritoneal dialysis (CAPD) catheters may be placed at the bedside with a straight Tenckhoff catheter under local anesthesia. They can be placed laparoscopically or by making a small perimedian incision and placing the catheter through the rectus muscle. All of the techniques can be performed using local anesthesia; however, use of the laparoscopy commonly calls for general anesthesia.
24. Which of the following are true concerning immunosuppression?
A. Current immunosuppressive agents function in a nonspecific manner to suppress rejection.
B. The use of immunosuppressive agents is associated with an increased rate of opportunistic infections.
C. An increased rate of malignancy is not associated with the use of immunosuppressive agents.
D. In almost all cases, the graft is rejected if immunosuppression is discontinued.
Answer: ABD
DISCUSSION: At the present time, clinical immunosuppression involves the use of agents that function in a nonspecific manner to prevent rejection. These agents suppress almost all aspects of the immune response. Because of their mechanism of action, they have associated toxicities and side effects, such as an increased rate of opportunistic infections. An increase in certain malignancies is also associated with use of these agents. In almost all cases, the graft is rejected if the immunosuppression is discontinued. Therefore, immunosuppression must be continued for the life of the graft.
25. Which of the following is true for hyperacute rejection?
A. It is mediated by preformed cytotoxic antibody.
B. It occurs late in the life of the graft.
C. It is usually reversible with a bolus of steroids.
D. None of the above.
Answer: A
DISCUSSION: Hyperacute rejection is mediated by preformed cytotoxic antibody. It can be screened for by cross-matching procedures. It usually occurs immediately after graft placement or within the first 24 to 48 hours after graft placement. It is almost never reversible.
26. The major components of the immune system include which of the following?
A. T lymphocytes.
B. B lymphocytes.
C. Cytokines.
D. Macrophages.
Answer: ABCD
DISCUSSION: The development of the lymphoid system begins with a pluripotent stem cell in the liver and bone marrow of the fetus. With maturation of the fetus toward term, the bone marrow becomes the primary site for lymphopoiesis. It produces the T lymphocytes, B lymphocytes, and macrophages that are critical to the immune response. These cells then produce cytokines or soluble growth factors, which amplify the immune response.
27. The most common types of immunosuppressive agents used clinically include which of the following?
A. Antimetabolites.
B. Alkylating agents.
C. Inhibitors of helper T-cell activation.
D. Irradiation.
E. Lymphocyte depletion compounds.
Answer: ABCDE
DISCUSSION: Much of the susceptibility of lymphocytes to immunosuppression is due to the vast cellular changes that follow immune stimulation. The biosynthetic events that take place make the lymphocytes vulnerable to inhibition at various stages of the cell cycle. Cyclosporine inhibits cytokine gene expression, whereas alkylating agents and radiation produce cross-linkages and breaks in DNA strands that interfere with cell differentiation and division. Agents that produce depletion of lymphocytes include antilymphocyte globulin (ALG) and monoclonal antibodies (OKT3).
28. Which of the following is/are true of the antiproliferative agents?
A. They act by preventing the differentiation and division of the immunocompetent lymphocyte after it encounters antigen.
B. The antimetabolites in this group have a structural similarity to cell metabolites and either inhibit enzymes of a metabolic pathway or are incorporated during synthesis to produce faulty molecules.
C. The most frequently used antiproliferative agent is azathioprine.
Answer: ABC
DISCUSSION: Antiproliferative agents inhibit the full expression of the immune response by preventing the differentiation of the immunocompetent lymphocyte after it encounters antigen. They act in one of two ways: they either structurally resemble necessary metabolites, or they combine with certain cellular components, such as DNA, and thereby interfere with function. Until recently, azathioprine was the most widely used immunosuppressive drug in transplantation, and it still has a major clinical role in preventing rejection.
29. Which of the following is the one true statement about acute rejection.
A. Acute rejection is mediated by T lymphocytes.
B. Acute rejection is mediated by preformed cytotoxic antibody.
C. Acute rejection most frequently occurs over months.
Answer: A
DISCUSSION: Acute rejection is mediated primarily by T lymphocytes. It occurs over 1 to 3 weeks after placement of an allograft. Hyperacute rejection is mediated by preformed cytotoxic antibody. It occurs within 48 hours of placement of a graft. Chronic rejection is mediated by both T cells and B cells and occurs over months.
30. Which of the following are true of cyclosporine?
A. It was the first immunosuppressive agent to be used clinically.
B. It acts selectively on T cells to suppress rejection.
C. Toxic effects include hirsutism, hypertension, nephrotoxicity, and increased risk of opportunistic infections.
Answer: BC
DISCUSSION: Cyclosporine is a product of a fungus and was discovered in 1972. It has contributed very significantly to the development of the field of transplantation. The mechanism of action is relatively specific for T lymphocytes. Other inflammatory cells are much less sensitive to its immunosuppressive effects. It inhibits activated T lymphocytes and prevents the cells from manufacturing and releasing interleukin 2 (IL-2). Toxicities include hirsutism, hypertension, nephrotoxicity, and increased risk of opportunistic infections (because it still functions as a nonspecific immunosuppressive agent).
31. Which of the following are true of OKT3?
A. It is not a monoclonal antibody.
B. It binds to the T-cell receptor and inactivates T-cell function.
C. It is the monoclonal antibody most frequently used in clinical transplantation.
Answer: BC
DISCUSSION: OKT3 is a monoclonal antibody produced in limitless supply by a hybridoma. It binds to a site associated with the T-cell receptor complex to inactivate the T cell. It is the most widely used monoclonal antibody in clinical transplantation.
32. Hypothermia (0؛ to 4؛ C) is a critical component of successful organ cold storage because:
A. Oxygen is more soluble in cold solutions and provides a continual supply for energy metabolism.
B. There is no way to suppress microbial growth except by cooling and slowing the growth rate.
C. Hypothermia diminishes energy requirements and allows the limited energy reserve to keep the organ alive.
D. It slows metabolism and the enzymic processes that would destroy the cell.
Answer: D
DISCUSSION: Hypothermia in simple organ cold storage serves one primary function but secondary ones as well. The primary function is to slow metabolism. Metabolic rates decrease about twofold for every 10؛ C drop in temperature. Cooling an organ from 37؛ to 0؛ to 4؛ C drops metabolism about 12- to 13-fold. This is related to the activation energy of enzymatic processes as expressed by Arrhenius and van't Hoff. Thus, catabolism of structural and functional cellular element is retarded for a long period—up to 3 days for some organs. The cold also suppresses microbial growth, but this can be accomplished by other means as well. The cold also allows time for the transplantation operation, and during this time it is important to be quick or to keep cooling the organ.
33. Is the following statement true or false? Organs should be preserved only for short periods of time (4 to 8 hours) because longer periods lead to too many complications, and even loss of the organ.
Answer: FALSE
DISCUSSION: The logistics of organ transplantation make it very difficult to use all available cadaver organs within 4 to 8 hours. To use all the organs requires the capability to preserve them for at least 24 hours. It has been shown that most organs can be matched to a recipient within about 17 to 24 hours. For all but the heart and lung, most intra-abdominal organs tolerate preservation for 20 to 30 hours and perform as well as those preserved for 4 to 8 hours. Although undue delay should not be purposefully used, certainly, most organ transplants do not need to be done on an emergency basis. However, this is not true for hearts and lungs, which should be transplanted as quickly as possible.
34. Which of the following statements about hepatic artery thrombosis following liver transplantation is/are correct?
A. Thrombosis of the hepatic artery following liver transplantation is more common in children than in adult patients.
B. Thrombosis of the hepatic artery usually occurs several weeks after transplant as a result of arteriosclerosis.
C. Thrombosis of the hepatic artery in the early days following transplantation is a serious complication leading to death unless retransplantation can be performed within 36 to 72 hours.
D. Late thrombosis of the hepatic artery may present as biliary complication or intrahepatic abscesses.
E. Thrombosis of the portal vein is more frequent than hepatic artery thrombosis following liver transplantation.
Answer: ACE
DISCUSSION: Thrombosis of the hepatic artery remains one of the most serious early complications of liver transplantation. This complication is three to five times more common in children than in adults. The major cause of this complication is related to technical error, although the hypercoagulable state may play a significant role in some situations. Early thrombosis of the hepatic artery leads to rapid liver failure with a fatal outcome unless a transplant can be performed within 36 to 72 hours. Although thrombolytic therapy through percutaneous or surgical access can be successful, most of these patients require retransplantation. Stenosis of the hepatic artery or late thrombosis of the hepatic artery can lead to multiple intrahepatic strictures of the bile duct and/or hepatic abscesses. This complication also often requires retransplantation. Portal vein thrombosis is a rarer complication. It is a devastating condition when it occurs early, but can be tolerated well if it develops after several months. Portal hypertension due to late portal vein thrombosis can often be treated successfully by a shunt procedure.
35. Which of the following statements about fulminant hepatic failure (FHF) is/are correct?
A. Fulminant hepatic failure can occur in the setting of pre-existing chronic liver disease.
B. Coagulopathy and coma are important findings in patients with FHF.
C. Liver transplant should not be attempted in patients with FHF because of the high mortality rate, regardless of the treatment used.
D. The main cause of death in these patients is cerebral edema.
E. One of the most important factors in prognosis of FHF is the cause of liver disease.
Answer: BDE
DISCUSSION: FHF corresponds to the rapid loss of hepatic function in the absence of pre-existing liver disease, causing jaundice, coagulopathy, and coma. One of the major prognostic factors is the cause of the liver disease. Early admission to an intensive care unit and management by physicians experienced in liver transplantation are mandatory. The major cause of death in these patients is cerebral edema. In patients who rapidly develop coma, subdural intracerebral pressure monitoring is mandatory for optimal management as well as for identification of patients who can benefit from liver transplantation. The survival rate for patients with FHF who underwent liver transplantation is currently above 65%. This is the only cure in most patients with FHF.
36. Which of the following statements about immunology in liver transplantation is/are correct?
A. Good human leukocyte antigen (HLA) matching between recipient and donor is mandatory for a good outcome for liver transplantation.
B. Hyperacute rejection is almost nonexistent following liver transplantation.
C. Acute rejection occurs in more than 50% of patients and is reversible in most patients with large doses of steroids.
D. Acute rejection is very rare later than 2 months after liver transplantation unless the patient is inadequately immunosuppressed.
E. Chronic rejection is different from acute rejection, is usually irreversible, and often requires retransplantation.
Answer: BCDE
DISCUSSION: Immune-mediated reactions following liver transplantation are clearly different from those that follow other solid organ transplants. The liver is tolerated quite well, and currently donors and recipients are matched only for their ABO group. Even when the ABO barrier is not respected, survival is still over 60%. T cell–mediated acute rejection occurs in about half of the patients within 6 weeks after liver transplantation, and acute rejection is reversed by large doses of steroids in most cases. Chronic rejection, on the other hand, is a different entity that is ill-understood and corresponds to destruction of small arteries and bile ducts. Change in the immunosuppression regimen sometimes may hinder the progression of this disease, but often retransplantation is required.
37. An elevated serum amylase level following pancreas-kidney transplantation may be due to:
A. Preservation/procurement injury.
B. Rejection.
C. Reflux pancreatitis.
D. Duodenal segment leak or bladder leak.
E. Native pancreatitis.
F. Constipation.
Answer: ABDEF
DISCUSSION: During the immediate postoperative period, an elevated serum amylase is usually due to preservation or procurement injury to the transplanted pancreas. If UW (University of Wisconsin) solution and a good flushout technique is used in an acceptable donor, amylase is usually elevated only several hundred points and will decline in a day or two. Rejection of the pancreas can also cause elevated serum amylase and is usually accompanied by a rise in the creatinine value due to concomitant renal transplant rejection. Reflux pancreatitis is generally caused by bladder dysfunction: increased pressure transmitted back through the pancreatic ducts causes pancreatitis. It is generally relieved by bladder decompression with a Foley catheter. Naturally, leakage from the anastomosis of the pancreas transplant to the bladder causes absorption of amylase from the peritoneal cavity and an elevated serum amylase value. Constipation causes a rise in the amylase level of pancreas-kidney transplant recipients, for reasons that remain unclear. Native pancreatitis has to be borne in mind in the differential diagnosis of hyperamylasemia in transplant patients. Contributing factors may include underlying gallbladder disease, as well as side effects of steroids and Imuran.
38. Complications of a pancreas transplant drained into the bladder include:
A. Duodenal segment leak.
B. Recurrent urinary tract infections.
C. Recurrent hematuria.
D. Urethritis.
E. Refractory loss of bicarbonate.
Answer: ABCDE
DISCUSSION: All of the listed problems are potential complications of bladder drainage. The most useful diagnostic tests for a duodenal segment leak include CT cystogram and technetium-based nuclear cystogram. Cystoscopy should be performed in patients with recurrent urinary tract infections to evaluate the presence of sutures or foreign bodies acting as a nidus for infection. Severe recurrent hematuria, as well as urethritis (most commonly affecting males), may occur with bladder drainage. Finally, severe bicarbonate loss may be associated with bladder drainage, and some patients may have difficulty keeping up with the loss by oral bicarbonate replacement. All of the above situations can be effectively treated with enteric conversion
39. Patient selection criteria for simultaneous pancreas-kidney transplantation should include:
A. Type I diabetes mellitus.
B. Type II diabetes mellitus.
C. Dialysis dependence.
D. Renal dysfunction with a creatinine value greater than 3.0.
E. Minimal extrarenal morbidity related to diabetes.
Answer: ADE
DISCUSSION: Simultaneous pancreas-kidney transplantation should be reserved for patients with Type I, juvenile, insulin-dependent diabetes mellitus. Although patients with Type II diabetes could potentially be helped, these older patients generally are not in good condition for simultaneous pancreas-kidney transplantation, nor are they reliably cured. In order to reliably monitor renal transplant function, the pretransplant creatinine value should be above 3, but the patient must not necessarily be on dialysis. To achieve good long-term results with pancreas-kidney transplantation it is appropriate to select patients with minimal extrarenal morbidity related to their diabetes.
40. Criteria for a pancreas donor include:
A. No history of diabetes.
B. No liver donation.
C. No replaced hepatic artery vessels arising from the superior mesenteric artery (SMA).
D. No previous splenectomy.
E. No pancreatitis.
Answer: AE
DISCUSSION: Combined liver-pancreas procurement should be routine, even if the right hepatic artery arises from the superior mesenteric artery. In this situation, since the transplanted liver is the life-saving organ, the proximal superior mesenteric artery should remain with the liver and the distal superior mesenteric artery supplying the head of the pancreas can be reconstructed on a Y-graft of iliac artery with the splenic artery. Successful pancreas transplantation can be performed using donors who have previously undergone splenectomy; however, there should be no significant pancreatitis and no history of diabetes in the donor.
41. For which of the following clinical scenarios would cardiac transplantation be an appropriate therapeutic modality?
A. A 50-year-old man with angina pectoris, three-vessel coronary artery disease, and a left ventricular ejection fraction of 25%.
B. A 75-year-old woman with irremediable heart failure secondary to critical aortic stenosis.
C. A 25-year-old male athlete with insidious onset of heart failure secondary to idiopathic dilated cardiomyopathy.
D. A 55-year-old woman who is status post two previous surgeries for coronary artery revascularization, now presenting with heart failure in the absence of angina, left ventricular ejection fraction of 15%, and insufficient target coronary arteries for a third bypass procedure.
E. A newborn infant with hypoplastic left heart syndrome and no other congenital anomalies.
F. A 30-year-old woman who develops irremediable heart failure due to postpartum cardiomyopathy after giving birth.
Answer: CDEF
DISCUSSION: Scenarios A and B are not appropriate for cardiac transplantation. The patient in example A would be far better served by a conventional revascularization procedure such as coronary artery bypass grafting. The risk might be somewhat greater than normal because of his depressed left ventricular ejection fraction; however, cardiac transplantation is a therapy that is necessarily reserved for persons for whom no other procedure is available. That clearly is not the case in this example. In example B, despite the fact that this patient's disease might be benefited by cardiac transplantation, she is too old to withstand the rigors of this procedure and its attendant therapies. Examples, C, D, E, and F, all represent situations in which cardiac transplantation would be appropriate. In all these cases there is end-stage heart disease, and no other therapies are available that are likely to have any substantial benefit. Therefore, it is appropriate to consider cardiac transplantation for these patients, as a last resort.
42. Suitable donors for heart transplantation have which of the following characteristics?
A. Normal electrocardiogram (ECG).
B. Normal echocardiogram.
C. Positive serology for HIV or hepatitis B or C.
D. Patient requiring high-dose epinephrine to maintain a systolic blood pressure of 90 mm. Hg.
E. Age over 70 years.
Answer: AB
DISCUSSION: To be suitable for cardiac donation, individuals must have a normal ECG and a normal echocardiogram. Clearly, positive serologic tests for HIV or hepatitis B or C would render donors unsuitable for solid organ transplantation. Similarly, high-dose pressor support and age greater than 60 years, in most programs, contraindicate cardiac donation.
43. Heart-lung transplant is currently the therapy of choice for which of the following conditions?
A. Primary pulmonary hypertension with reasonably well-preserved right ventricular function.
B. Eisenmenger's syndrome due to single ventricle and truncus arteriosus.
C. Validated cardiomyopathy in a patient with cystic fibrosis and end-stage lung disease.
D. Cystic fibrosis and end-stage lung failure with normal heart function.
E. Eisenmenger's syndrome due to an atrial septal defect.
F. End-stage lung disease secondary to emphysema.
Answer: BC
DISCUSSION: Heart-lung transplantation is now properly used only for persons with end-stage disease of the heart and lungs. Therefore, a patient with primary pulmonary hypertension and reasonably wellpreserved right ventricular function is best treated with a single or bilateral lung transplant. A person with complex congenital heart disease and Eisenmenger's syndrome or one who has end-stage disease of the heart and lungs would be better treated with combined heart-lung transplantation. Patients with Eisenmenger's syndrome secondary to relatively straightforward defects (e.g., atrial septal defect, ventricular septal defect) are best treated with concomitant correction of the congenital defect and single or bilateral lung transplantation. Similarly, the patient with end-stage emphysema with normal heart function can be treated very well with single or bilateral lung transplantation, preserving the donor heart for someone who truly has heart failure.
44. Both single and bilateral lung transplantation are suitable technical alternatives for which of the following conditions?
A. Obstructive lung disease (chronic obstructive pulmonary disease, emphysema).
B. Restrictive lung disease (pulmonary fibrosis).
C. Primary pulmonary hypertension.
D. Cystic fibrosis.
Answer: ABC
DISCUSSION: Single-lung transplantation is inappropriate for cystic fibrosis or for any patient with chronic bilateral pulmonary sepsis. Leaving a septic native lung in situ in an immunocompromised patient would leave the patient at risk for local and systemic septic complications. Single-lung transplantation with contralateral pneumonectomy would be associated with a high risk of empyema in the pneumonectomy space and also disruption of the bronchial stump. Both single- and bilateral lung transplantation have been applied successfully in all of the other disease categories listed here.
45. Which of the following are contraindications to lung transplantation?
A. Age 65 years or older.
B. Current corticosteroid therapy.
C. History of thoracotomy.
D. Ventilator-dependent respiratory failure.
Answer: D
DISCUSSION: Single-lung transplantation is still offered up to age 65 years. Current low-dose corticosteroid therapy has not been demonstrated to lead to a higher risk of airway complications after lung transplantation. Advancements in operative technique have lessened the risk of surgery, so prior thoracotomy is no longer a contraindication to lung transplantation. However, patients with chronic ventilator-dependent respiratory failure who have no potential for cardiopulmonary rehabilitation currently are not accepted for evaluation for potential lung transplantation.
46. Which of the following is the single most useful approach for diagnosing acute lung allograft rejection?
A. Clinical diagnosis.
B. Decline in spirometry and oxygenation.
C. Chest radiographic abnormalities.
D. Fiberoptic bronchoscopy with transbronchial lung biopsy.
Answer: D
DISCUSSION: Virtually all lung transplant patients experience at least one episode of acute rejection during their postoperative recovery in hospital. All of the approaches mentioned above are useful in leading to the diagnosis. Clinically, the patient experiences malaise and fever. There is also typically a slight decline in spirometry and arterial oxygenation. The chest radiograph typically shows a hilar or basal shadow; however, although these findings all suggest acute rejection, they are not specific. The one test with high specificity for detection of acute rejection is bronchoscopy with transbronchial lung biopsy.
47. Advantages of split-thickness skin grafts over full-thickness skin grafts include:
A. Split-thickness grafts include only part of the epidermis and none of the dermis.
B. Split-thickness grafts offer better pigment matching.
C. Split-thickness grafts offer better resistance to contraction.
D. Split-thickness grafts offer better resistance to infection.
E. Split-thickness grafts survive better on surfaces with compromised blood supply.
Answer: DE
DISCUSSION: Split-thickness grafts include all of the epidermis but only a part of the dermis. Full-thickness skin grafts include all of both layers, so surgical closure of the donor wound is necessary whereas the portion of dermis left at the split-thickness skin donor site regenerates a skin covering. Because all layers of the skin are included in a full-thickness skin graft, pigment matching is better and less contraction occurs than with split-thickness grafts. Full-thickness grafts require a better blood supply for survival than the split-thickness grafts because the graft vessels are cut below the level of the dermal branching. Relatively fewer cut vessels are available to absorb nutrients from the wound bed to meet the relatively greater nutritional needs of the thicker graft. The poor resistance of full-thickness grafts to infection precludes their use on contaminated wounds, whereas split-thickness skin, which is more richly supplied with open blood vessels on its underside, is able to survive on compromised surfaces, including granulating wounds contaminated with bacteria.
48. The most commonly used substitutes for peripheral arteries are:
A. Dacron grafts.
B. Expanded polytetrafluoroethylene (Gore-Tex) grafts.
C. Internal, external, and/or common iliac artery autografts.
D. Bovine carotid artery xenografts.
E. Saphenous vein autografts.
Answer: E
DISCUSSION: The greater saphenous vein has proved to be the most satisfactory and most commonly used arterial substitute. The wall is sufficiently strong to withstand arterial pressures without becoming dilated or aneurysmal, yet is flexible and easily sutured. The diameter is sufficiently great to avoid thrombosis and nourishment is provided by the intraluminal blood flow. The smooth, natural endothelial lining is less thrombogenic than any known synthetic surface. The lining surface heals itself and may sequester white cells to fight infection, unlike Dacron grafts, which provide a haven for infecting organisms in the interstices of their synthetic fibers. Saphenous vein autografts heal even when placed into the infected bed of a previous synthetic graft.
49. Endocrine autografts were among the first successful transplantation procedures. The demonstration by Berkhold in 1849 that autotransplanted testes led to the acquisition of secondary sexual characteristics in castrated cocks marked the beginning of experimental endocrinology. Endocrine autografts used successfully in modern surgical practice include:
A. Adrenal medulla to the brain.
B. Thyroid to the forearm.
C. Parathyroid to the forearm.
D. Testicle to the scrotum.
E. Pancreatic islets to the liver.
Answer: CDE
DISCUSSION: The report in 1987 of open microsurgical autotransplantation of the adrenal medulla to the caudate nucleus of the brain for treatment of intractable Parkinson's disease aroused great interest in the topic. Subsequent multicenter trials showed improvement but not cure of the disease and substantial post-operative morbidity, so the technique was not recommended for widespread use. Excellent synthetic hormone replacement is available for thyroid insufficiency, so implantation of the thyroid gland in the forearm is not necessary. However, parathyroid hormone replacement is not available, and medical therapy for hypoparathyroidism is complicated. When parathyroid tissue is removed it should be autografted to prevent the deficiency symptoms of tetany, psychological disturbances, convulsions, coma and death. One-millimeter pieces may be implanted into pockets in the sternocleidomastoid muscle. When all glands are removed for diffuse parathyroid hyperplasia, implantation of fragments into the forearm muscles facilitates subsequent removal of more tissue under local anesthesia if hyperparathyroidism persists. Autotransplantation is the treatment of choice for undescended testes. The cryptorchid or ectopic testicle must be taken out of the abdomen and placed into a cooler location prior to age 6 (preferably at 1 year) for normal spermatogenesis to occur. Approximately half of the pancreatic islet transplants performed after pancreatectomy for relief of chronic pancreatitis pain have produced patients who are insulin independent. Islets for autotransplantation are difficult to isolate in sufficient quantities from the fibrotic adult pancreas. Dispersed islets injected directly into the human portal vein have occasionally produced untoward effects such as disseminated intravascular coagulation, portal hypertension, and even hepatic necrosis.
50. Several types of gastrointestinal autografts have been used to replace the esophagus after extirpation of carcinomas. Successful reconstructions have been achieved most frequently with:
A. Stomach.
B. Jejunum.
C. Ileum.
D. Ascending colon.
E. Descending colon.
Answer: A
DISCUSSION: Although all of the listed bowel segments have been used successfully for reconstruction of the esophagus following removal of carcinomas, the stomach remains the most frequently used autograft for esophageal reconstruction. Because of its excellent blood supply the procedure can be performed at little risk as a single operation and achieve satisfactory long-term relief of dysphasia in at least 90% of patients. Either the entire stomach can be drawn into the chest or a gastric tube created in an isoperistaltic or antiperistaltic manner of sufficient length to reconstruct the entire esophagus. The advantages of a mucosal lining, serosal covering, natural opening into the stomach, and excellent blood supply based on the gastroepiploic vessels make the stomach the autograft of choice in most situations.
51. Which of the following statement(s) is/are true concerning the options for managing the exocrine secretions following pancreatic transplantation?
a. Ductal ligation is associated with no adverse effects to pancreatic parenchyma
b. Drainage of the pancreatic ductal system into the bladder is useful in the early diagnosis of rejection
c. All pancreatic grafts should be placed in a retroperitoneal position
d. Complications following enteric drainage of the pancreas (without the duodenum) are primarily associated with anastomatic leakage
Answer: b, d
There are, in principal, three options in managing the exocrine secretions following pancreatic transplant. In the first option, maintenance of exocrine secretions by internal drainage of the exocrine pancreas can be achieved by anastomosing the ductal system to either the intestinal tract (stomach, small intestine) or the urinary tract (ureter, bladder). These techniques are the most common in use today and provide the best overall results. The second technique, free drainage of the pancreatic juice into the peritoneal cavity, is certainly the least technically demanding method of transplantation. It is, however, associated with many other complications. Ablation of the exocrine secretion, the third option, can be accomplished by two techniques. The first, duct ligation, has been associated with exocrine atrophy and extensive fibrosis, usually resulting eventually in endocrine insufficiency. Ductal ligation has also had unpredictable effects on the exocrine tissue, associated with a high risk of acute pancreatitis and peripancreatic sepsis. The other method of ductal ligation involves injecting the pancreatic system with a synthetic polymer that solidifies within several minutes, with a result that exocrine secretion is completely blocked. The enterically drained pancreas (without duodenum) has in the past been associated with a significant incidence of anastomatic leakage, leading to pancreatic fistula, perigraft abscess, and systemic sepsis. Many of these allografts had to be removed. These problems can be oveated to a large extent if the donor duodenum (removed in block with the pancreas) is used to establish anastomosis. The bladder drainage technique greatly facilitates early diagnosis of rejection by providing a means to measure the output of amylase from the graft, as determined by the urinary amylase activity.
Regardless of the type of graft transplanted (either whole organ or segmental), most transplant surgeons agree that graft should be placed intraperitoneally. The extensive surface of the peritoneum is probably of considerable help in absorbing the exudate that escapes from the surface of the pancreas. The incidence of anastomatic leaks and wound complications has been greatly reduced with the intraperitoneal placement of grafts.
52. The term “tolerance” refers to responses observed which include long-term graft acceptance without the need for chronic immunosuppression. There are a variety of specific ways in which T and B lymphocytes can be tolerant or nonresponsive to antigen. Which of the following is/are mechanisms of tolerance?
a. Clonal abortion
b. Clonal deletion
c. Clonal anergy
d. Suppression
Answer: a, b, c, d
Clonal abortion refers to the developmental process whereby nascent T and B cell clones, which recognize autoantigen with high affinity, are eliminated. Clonal deletion may encompass the processes of clonal abortion but it also refers to the elimination of mature T and B cell clones. Clonal anergy is a state in which the potential relative reactive clones and their receptors are physically present but fail to respond to antigen. Suppression generally refers to an active process in which a leukocyte and/or its soluble products inhibit the development or effector function of immune lymphocytes.
53. Which of the following statement (s) is/are true concerning currently approved immunosuppressant agents?
a. Azathioprine (Imuran) is useful in the treatment of acute ongoing rejection
b. Methylprednisolone is particularly useful in immunosuppression as it has lesser toxicity than Prednisone
c. Cyclosporine blocks transcription of several early T-cell activation genes
d. FK-506 is both more potent and less toxic than cyclosporine
e. The monoclonal antibody OKT3 interferes with T-cell antigen recognition function
Answer: c, e
The major principle of immunosuppression is to induce the patient with high doses of drugs at the time of allografting in order to prophylax rejection. The drugs are then reduced rapidly within a period of days to weeks to less toxic maintenance levels. The anti-metabolite azathioprine (Imuran) interferes with nucleic acid metabolism inhibiting proliferation and clonal expansion of activated lymphocytes, eliminating alloantigen specific immune responses. This agent is used during induction immunosuppression and for maintenance immunosuppression but has little role for treating an acute, ongoing rejection. Glucocorticoids are the mainstays of virtually all immunosuppressive regimens. All glucocorticoids have similar immunosuppressive actions and none is more effective than any other at equipotent doses. Complications and side effects are equivalent at all equipotent doses. Cyclosporine inhibits the rotamase activity of cyclophilin. Therefore the major immunosuppressive activity of cyclosporine is to block transcription of several early T-cell activation genes. The macrolide antibiotic, FK-506 is 10-100 times more potent than cyclosporine on a molar basis but it too is associated with a number of significant and similar toxicities. Antibodies are given for only short periods of time to prophylax rejection and to treat acute ongoing rejection. There are two major types of antibody preparations—polyclonal antibodies such as antilymphocyte (ALG) or antithymocyte globulin (ATG) or monoclonal antibodies. The only monoclonal antibody currently available is OKT3 which is the used for both induction and treatment of rejection and is the most efficacious agent currently available for the treatment of rejection.
54. Which of the following patients would be a candidate for a liver transplant?
a. A 48-year-old man with end-stage liver disease secondary to non-A, non-B hepatitis
b. A 35-year-old man with both primary sclerosing cholangitis and ulcerative colitis and end-stage liver disease
c. A 22-year-old woman with fulminant hepatic failure secondary to acetaminophen overdose
d. A 4-year-old child with congenital biliary atresia having failed a previous Kasai procedure
e. A 48-year-old patient with alcoholic cirrhosis and a 2.5 cm central unresectable hepatoma
Answer: a, b, c, d, e
In the absence of contraindications, virtually any disease resulting in liver failure is amenable to liver transplantation. Primary sclerosing cholangitis is a common indication for transplantation since there is no other effective treatment. The common association with inflammatory bowel disease can somewhat complicate the timing of the procedure, however, in general hepatic transplantation does not affect the outcome of the ulcerative colitis. Non-A, non-B hepatitis is the most common form of hepatitis leading to liver transplantation. Recurrence of viral hepatitis in the transplanted liver occurs, but usually follows an indolent course. Biliary atresia is by far the most common indication for hepatic transplantation in pediatric patients. Recommended treatment includes creation of a portoenterostomy (Kasai procedure), if this can be done before three months of age. After this point, success rates diminish markedly. Patients without a satisfactory course, multiple revisions of the portoenterostomy should be avoided to facilitate subsequent transplantation. The most common cause of fulminant hepatic failure are non-A, non-B hepatitis, hepatitis B, and various drug toxicities. In the latter group, acetaminophen toxicity is particularly prominent. Primary hepatic malignancy, most often hepatoma, is sometimes an indication for transplantation but the results are usually worse than in other disease states because of recurrent disease. Transplantation is justified in the occasional case in which the tumor is central but relatively small, if the patient is otherwise healthy, and there is no evidence of extrahepatic disease after exhaustive evaluation.
55. Which of the following statement(s) is/are true concerning changes in physiology following lung transplant?
a. In patients with pulmonary hypertension, changes in right ventricular function and pulmonary artery pressure takes weeks to months to resolve
b. In single lung transplantation, changes in pulmonary function are seen almost immediately following transplantation
c. Patients with double lung transplants have both better pulmonary function studies as well as better exercise capabilities
d. After single-lung transplant, ventilation perfusion mismatch persists and carbon dioxide retention is seen
Answer: b
Performing single-lung transplantation in a patient with pulmonary hypertension has been particularly illustrative in demonstrating the potential for reversal of right ventricular dysfunction. As soon as the lung is implanted, the morphology of the right ventricular changes significantly as assessed by transesophageal echocardiography. The intraventricular septum, previously bulging into the left ventricle, immediately assumes the normal position. An increase in contractility of the right ventricle occurs with significant decrease in dilatation. The pulmonary artery pressure immediately decreases and is essentially normal by the time the patient leaves the operating room.
One would also expect significant ventilation perfusion mismatch to occur with ventilation to the native lung occurring preferentially because the native lung is significantly more compliant. Conversely, perfusion should preferentially go to the newly transplanted lung because of lower pulmonary vascular resistance. Despite this occurrence, patients with this operation do well from a functional standpoint. By three months after transplantation, the ventilation/perfusion mismatch narrows. Despite this mismatch, patients do not demonstrate carbon dioxide retention. From a clinical standpoint, improvement in pulmonary function is seen almost immediately after transplantation. The measurement most often used is FEV1 and marked improvement is seen within two weeks. The FEV1 essentially triples and then remains fairly stable. Improvement after bilateral lung transplant is slightly better. Although patients who receive two lungs may do better on pulmonary function tests, this benefit is not translated to significantly better exercise capability.
56. Current clinical protocols determine a limited number of variables and parameters for matching and allocation of donor organs to potential recipients. Which of the following statement(s) is/are true concerning aspects of immunity important for clinical transplantation?
a. HLA matching is important for kidney, pancreas, and liver transplantation
b. A cross match assay determines if there are preformed antibodies in the recipient’s serum which will react with antigens on the cell surface of the potential donor’s lymphocytes
c. A patient with a history of multiple transfusions or previous transplant will have a high panel reactive antibody (PRA)
d. A normal heterozygous individual with a complete donor-recipient match will have a four-antigen match
Answer: b, c
ABO compatibility is obviously required for successful transplantation. The central position of the MHC in immune regulation suggests that HLA matching is also very important for allografting. There is significant data to prove that HLA matching is important for kidney and pancreas transplantation. There is good data also to show that HLA matching is not important for liver transplantation and does not affect graft survival. The main loci typed are HLA-A, HLA-B, and HLA-DR. Thus, for a normal completely heterozygous individual this results in six antigens typed and a complete donor-recipient match is referred to as a six-antigen match. An important test for graft compatibility is the cross match. This assay determines if there are preformed antibodies in the potential recipient’s serum which will react with antigens on the cell surface of the potential donor’s lymphocytes. A positive cross-match means that such antibodies are present and that hyperacute rejection will ensue if the transplant were to be performed. Another important test which is also a reflection of the presence of host anti-donor antibodies is the panel reactive antibody (PRA). Most recipients on transplant lists send serum samples to the transplant center on a regular basis which are tested against a panel of typing cells of known HLA specificities. Most individuals should have no anti-HLA antibodies and have a low PRA (0–5%). Patients who have been transfused, pregnant, previously transplanted, or have an autoimmune disorder which induces a lot of antibodies might have a high PRA (50–99%). The presence of a very high PRA suggests that a patient is likely to have a positive cross-match.
57. T-lymphocytes are divided into two main sub-classes: CD4+ and CD8+. Which of the following statement(s) is/are true concerning these classes of T-cells?
a. CD4+ T-cells are restricted to recognizing antigens of the class II major histocompatibility complex (MHC)
b. CD8+ T-cells perform primarily cytotoxic functions
c. CD4+ 8+ double positive cells are well-differentiated mature cells
d. CD4+ T-cells also perform suppressor functions
Answer: a, b, d
T-cells are divided into two main sub-classes: CD4+ and CD8+. CD4+ 8+ double positive cells are usually immature T-cells or thymocytes while the fully differentiated T-cell is usually single positive. Because of molecular interactions, CD4+ T-cells are restricted to recognizing antigens in the context of class II major histocompatibility complex (MHC) and usually perform roles related to B-cell help, T-cell help, and inflammatory responses such as delayed and contact hypersensitivity. CD8+ T-cells are restricted to class I MHC and perform cytotoxic functions. In addition, experimental studies have demonstrated that both CD4+ and CD8+ T-cells can act as T suppressor cells.
58. Correct statement(s) concerning postoperative complications after hepatic transplantation include:
a. Primary nonfunction occurs in 5 to 10% of transplanted livers in the immediate postoperative period
b. A biliary leak, although a common complication, is usually of minimal clinical importance
c. Portal vein thrombosis occurs much more commonly than hepatic artery thrombosis
d. If postoperative bleeding is encountered, immediate return to the operating room is indicated
Answer: a
Primary nonfunction of the allograft occurs in about 5% to 10% of transplanted livers. Most cases of nonfunction are related to inadequate tissue preservation or occult organ dysfunction in the donor but a sizeable percentage may arise from immunologic mechanisms. In the worst case scenario, the patient does not regain consciousness, a coagulopathy ensues, and multiple organ failure develops. Liver enzymes show hepatocellular injury with SGOT and SGPT values in the range of 5000 to 10,000 and little bile production. Hepatic artery thrombosis occurs in 5% of adult hepatic transplantation cases and up to 25% of pediatric cases. Postoperative vein thrombosis is much less common than hepatic artery thrombosis, occurring in 2% to 3% of cases. Laparotomy to control postoperative bleeding is required in 15% of cases. In about half of the reoperations, a specific bleeding point is identified. Survival is higher in these cases in contrast to those in which diffuse bleeding is encountered, presumably since the latter circumstance is usually associated with poor allograft function and resultant coagulopathy. If significant bleeding occurs after hepatic transplantation, a common and sensible policy is to transfuse the patient until hypothermia and coagulopathy are corrected with subsequent (one to three days) evacuation of blood from the peritoneal cavity. Biliary leakage is a feared complication, with a high (50%) mortality. The high mortality may be the result of a concomitant hepatic arterial thrombosis and infection of the leaked bile, or difficulty of bile duct repair in the area of inflamed tissue.
59. Which of the following statement(s) is/are true concerning renal transplantation?
a. Living-related donor transplants typically can be expected to have one-year graft survival rates of over 90%
b. Preconditioning of the recipient with the use of donor-specific blood transfusions from their living donor improves graft survival and therefore should be used routinely
c. Pre-transplant blood transfusions result in improved graft survival following cadaveric renal transplant in the cyclosporine era
d. Age of the recipient over 50 years is generally associated with a poorer outcome due to graft rejection
Answer: a
The use of living-related donor renal transplant has multiple advantages including improved short-and long-term graft survival, routine immediate allograft function, and fewer rejection and infectious episodes. Nearly all transplantation centers that perform living-related donor transplantations report one-year graft survival rates of over 90%. The use of preconditioning of the recipient with donor-specific blood transfusions from their living donor can improve graft survival. The major drawback to this maneuver is the development of recipient anti-donor antibodies (sensitization) which occurs in nearly one-third of recipients. The development of sensitizing antibodies eliminates the use of that donor. With the introduction of cyclosporine, the use of donor-specific transfusions with subsequent immunosuppression, was compared to nontransfused recipients treated with cyclosporine and prednisone. These investigations have demonstrated excellent graft survival rates over long-term follow-up and therefore routine donor-specific transfusions are seldom performed in adults. In the azathioprine and prednisone immunosuppression era, several immunologic and nonimmunologic risk factors were identified as having an adverse effect on graft outcome. Historically, older renal allograft recipients (older than 50 years) did poorly compared with younger counterparts. Much of the graft loss was found to be associated with patient deaths, and usually was the result of overwhelming infection. With the cautious use of cyclosporine and prednisone, however, excellent patient and graft survival rates are now reported. Data from the azathioprine and prednisone era show a clear-cut benefit from improved graft survival after multiple random blood transfusions. More recent studies again showed no advantage to blood transfusion when cyclosporine is used. Since transfused patients have a risk of developing anti-HLA antibodies, these patients may become more difficult to undergo organ transplantation in a timely fashion.
60. Which of the following statement(s) is/are true concerning clinical syndromes of rejection?
a. Hyperacute rejection occurs with kidney, heart, liver and lung transplants
b. The histologic characteristics of acute rejection include lymphocyte infiltration accompanied by plasma cells, eosinophils, or neutrophils
c. Vascular atherosclerosis and obliteration are characteristic of chronic rejection
d. Transplantation across major ABO incompatibility will result in hyperacute rejection of a renal or cardiac transplant
Answer: b, d
Hyperacute rejection is the result of pre-formed antibody binding to the allograft at the time of revascularization in the operating room. Complement is activated resulting in endothelial cell destruction, vascular leak, recruitment of platelets and neutrophils, thrombosis of vessels, and destruction of the graft in a period of minutes to hours. Kidney, heart, pancreas, and lung allografts are all susceptible to hyperacute rejection; however, liver grafts are relatively resistant to this process and are often transplanted across antibody differences and even across an ABO difference. Acute rejection usually occurs days to weeks after transplantation and is initiated by T-cell dependent immunity characterized microscopically by lymphocytic infiltration accompanied by plasma cells, eosinophils, and a few Mast cells or neutrophils. Chronic rejection usually occurs months to years after transplant. It is characterized by loss of normal histologic structure, fibrosis and atherosclerosis. Chronic rejection is the major cause of graft failure and patient loss with all organs.
61. Which of the following statement(s) is/are true concerning techniques for multiple organ procurement and preservation?
a. The liver and pancreas are generally removed en bloc and separated as a bench procedure
b. Renal allograft function is improved by the use of machine perfusion
c. UW (University of Wisconsin) cold storage solution is the method of choice of most programs for hepatic and pancreatic transplantation
d. Cardiac allografts have the shortest limit of cold ischemia
Answer: a, c, d
The complexity of multiple organ procurement involves the coordination of at least two teams (thoracic and abdominal). The liver and pancreas are generally removed en bloc with the organs separated as a bench procedure, retaining the celiac axis for the liver. The kidneys are also removed en bloc. Studies indicate that post-transplantation renal allograft function is similar regardless of whether simple hypothermia or the more cumbersome technique of machine perfusion are used. For decades, the primary solution used for cold storage preservation of kidneys was Euro-Collins solution. Recently, a new solution, UW solution, has been developed with ingredients designed to provide high-energy phosphate precursors, hydrogen ion buffering capacity, and anti-oxidant properties. Although the advantage of this solution over Euro-Collins solution for kidneys is unclear, UW solution is used as the preservation method of choice by nearly all programs performing hepatic and pancreatic transplantations. Both organs can reliably be stored for 24 hours. Kidneys can generally be safely stored for 36 to 48 hours before transplantation. Cardiac preservation has changed relatively little in recent years. Hyperkalemic crystalloid cardioplegia solution is used at 4°C and four hours is generally the accepted limit of cold ischemia. The current limit of cold ischemia for small bowel is approximately 12 hours.
62. Which of the following statement(s) is/are true concerning the outcome of renal transplantation?
a. Two-thirds of all graft losses alone (without death) occur from one to six months after transplantation
b. The most common cause for graft loss after one year following transplantation is patient death
c. Most patient deaths following transplantation are related to immunosuppression
d. An acute rejection episode in a renal allograft recipient is the most important clinical event, determining both short-term and long-term graft survival
e. The period between the six months and one year following transplantation is the most critical time period following renal transplant
Answer: a, b, d
There are two ways to lose a renal allograft—graft loss alone and death of the patient regardless of the degree of graft function at the time of death. Two-thirds of all graft losses alone (without death) occur from one to six months after transplantation. Only 14% of all graft losses occur after one year. In contrast, half of the patient losses (most dying with functioning grafts) occur more than one year after transplantation. More than half the deaths are due to cardiovascular complications not related to immunosuppression but closely related to comorbid cardiovascular variables present at the time of transplantation. Less than 25% of deaths are related to immunosuppression. The period between one and six months after transplantation is the most active and crucial time in the clinical course of a patient with a renal transplant. During this time 63% of all graft losses, 22% of deaths, and 74% of all acute rejection episodes occur. An acute rejection episode in a renal allograft recipient is the single most important clinical event determining both short and long-term graft survival. The post-transplant period that begins at six months and continues to the one year mark is the quiescent time with very few influential clinical events. Only 9% of all graft losses and 9% of all acute rejection episodes occur during this time period.
63. Which of the following characteristics or conditions will exclude a patient as a suitable cadaveric organ donor?
a. Active systemic bacterial infection
b. Primary CNS malignancy
c. Age over 65
d. History of prior cholecystectomy for a possible hepatic donor
Answer: a
The characteristics of a suitable cadaveric organ donor can be divided into those that are general in nature and those that are organ-specific. Broadly stated, the general attributes of an acceptable organ donor include the establishment of a diagnosis of brain death, previously good general health, and relative hemodynamic stability from the time of the advanced precipitating brain death until organ procurement is complete. As experience has been gained with donors considerably less than ideal, it has become apparent that arbitrarily defined chronological age limits for organ donors are unnecessary.
Active systemic infection is an absolute contraindication to organ donation. Documented positive blood cultures for known systemic infection that has not been completely eradicated rule out the potential organ donor because of risk of transmission of infection to an immunosuppressed recipient. Furthermore, all potential organ donors, regardless of whether they are considered high risk, should be tested for infection with human immunodeficiency virus as well as hepatitis B and C. Cancer, whether treated or not, has long been considered to contravene organ donation. The only exception to this rule has been the donor with a primary malignancy of the central nervous system.
The condition of particular organs in great measure dictate their individual suitability for transplantation. Preexisting hepatic disease can usually be identified before organ procurement. A history of hepatitis or cirrhosis of any kind preclude donation. Although calculous biliary tract disease would appear at first blush to be a contraindication of hepatic procurement, prior cholecystectomy for uncomplicated cholelithiasis is not an absolute contraindication to liver donation.
64. Which of the following statement(s) is/are true concerning associated renal and pancreatic transplantation?
a. The most important advantage is the use of renal function as an early indicator of pancreatic graft rejection
b. After renal transplant, there is no additional risk associated with immunosuppression
c. A major disadvantage of simultaneous renal/pancreatic transplant is the potential adverse effect on renal allograft as the result of a pancreatic complication
d. A diabetic with a renal transplant continues to be at risk for diabetic nephropathy
Answer: a, b, c, d
In the patient with a functional renal transplant, because of the need for long-term immunosuppression, the demonstration of a prior allograft acceptance and a continued risk for recurrent diabetic nephropathy are compelling reasons to offer pancreatic transplantation. The advantages to simultaneous renal-pancreatic transplantation compared to a sequential procedure (renal followed by pancreatic) include 1) the recipient’s need to accept only one set of donor antigens; 2) the ability to monitor rejection of the pancreas by identifying the well-recognized signs of renal allograft rejection; 3) the immunosuppressive effect of uremia; 4) transportation in patients who have not been maintained on chronic immunosuppression; and 5) a single albeit longer anesthetic exposure. Of these advantages, the most important is the use of renal function as an early indicator of pancreatic graft rejection. The disadvantages of simultaneous renal-pancreatic transplantation include extensive surgery in a uremic diabetic patient and the potential adverse effect on renal allograft function as the result of a pancreatic complication. Ideally, pancreatic transplantation should be performed in patients who do not yet have, but are designed to develop, secondary complications to diabetes that are more serious than the potential side-effects of immunosuppression. In recipients of a pancreas after a kidney, the only risks of pancreatic transplant are related to the surgery since immunosuppression is already obligatory.
65. There are numerous toxicities and adverse effects associated with immunosuppression. Which of the following statement(s) is/are true concerning complications of immunosuppression?
a. Transplant recipients are susceptible primarily to infections with unusual organisms (fungus, virus, atypical bacteria)
b. Immunosuppressive agents may blunt the inflammatory response to infection leading to a late presentation of an infectious process
c. The development of malignancy appears primarily due to direct mitogenic effects of the agent
d. Lymphomas are the most common malignant tumors developing in the transplant patient
e. Graft-vs-host disease is a progressive condition and extremely difficult to treat
Answer: b
The most obvious complication of immunosuppression is infection. As immunosuppression becomes stronger and more effective, the recipient’s ability to resist infection diminishes. Transplant recipients are susceptible both to typical bacterial infections (UTI, pneumonia, wound infections) and to infections with unusual organisms (fungus, virus, atypical bacteria). Immunosuppressives also block the inflammatory response to infection so that patients present with very subtle signs and symptoms or they present late in the infectious process.
Another complication in allograft recipients is malignancy. The immunosuppressive drugs do not appear to be directly mitogenic or transforming, but rather probably suppress immune mechanisms which keep transformed cells in check. Squamous cell carcinomas of the exposed area of the skin are by far the most common malignancy. Lymphomas are the next most common tumor and are 10–100 times more common in transplant recipients than in the general population. These are usually non-Hodgkins B cell lymphomas and are often related to malignant transformation by Epstein-Barr virus (EBV).
Another complication of organ allografting is graft-vs-host disease (GVHD). GVHD is usually self-limited as donor cells, stimulated by the host alloantigen, are eliminated either by immunosuppression or by host anti-donor responses.
66. Which of the following statement(s) is/are true concerning the results of lung transplantation?
a. One year survival following single lung transplant is significantly better than following bilateral transplant
b. The worst survival is seen in patients with pulmonary hypertension
c. Patients with cystic fibrosis have a markedly poorer result than do patients with emphysema
d. Infection is a common cause of mortality in both the early and late post-transplant period
Answer: b, d
In just over ten years since the first successful lung transplant, approximately 3000 transplants have been performed. Overall, one-year actuarial survival following lung transplant is approximately 70% (single lung = 70%; bilateral lung = 74%). At two years, survival drops to 63%. Patients with emphysema have the best survival at one and two years while those with pulmonary hypertension had the worse (77% vs 61%). Patients with cystic fibrosis do almost as well as the group with emphysema (72%). Overall there is some continuing to fall off in survival at three years with an overall survival of 57% which drops to 51% at four years and 46% at five years. Causes of recipient death can be categorized according to the time frame in which they occur. Early (less than 90 days following transplant) death most commonly results from bacterial infection. Infection also accounts for approximately one-third of late deaths (greater than 90 days) following transplantation. A similar percentage results from manifestations of chronic rejection and obliterative bronchiolitis.
67. Categories of patients in which pancreatic transplantation is applicable includes:
a. Diabetics with a functioning renal transplant
b. Diabetic patients with end-stage renal disease requiring renal transplantation
c. Nonuremic diabetics with other complications of their disease
d. Well-controlled adult onset diabetics
Answer: a, b, c
Pancreatic transplantation can be applied to three categories of patients. In the first category are diabetic patients who already have undergone successful renal transplantations. In the patient with a functioning renal transplant, because of the need for long-term immunosuppression, the demonstration of prior allograft acceptance, and the continued risk of recurrent diabetic nephropathy, are compelling reasons to offer pancreatic transplantation. The second group of patients are those with end-stage renal disease requiring renal transplantation. These people may benefit either from simultaneous or sequential renal-pancreatic transplantation. The final and largest potential group of patients are nonuremic diabetics with other complications of their disease.
68. Which of the following statement(s) is/are true concerning the results of cardiac transplantation?
a. Overall one-year survival is approximately 80%
b. Survival following transplant in the pediatric age group is significantly worse than in adults
c. There is no difference in survival when cardiac transplantation is performed in a heterotopic position versus an orthotopic position
d. The survival rate for retransplantation is approximately 50%
Answer: a, d
Collected data from a multi-center registry has shown that the overall one-year survival following cardiac transplantation is 80%. Overall five-year survival is approximately 65%. Survival in patients receiving heterotopic cardiac transplants is significantly lower than in patients receiving hearts in the orthotopic position. The overall one-year survival rate for retransplantation as reported from the same registry is only 54%. In the pediatric age group, actuarial survival at two years is 80% and 76% at five years.
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