A 26-year-old man with ethylene glycol poisoning develops irreversible brain damage and acute kidney injury. He is on continuous venovenous hemodiafiltration for a week with no improvement in brain function. The family decides to donate his organs, and he is pronounced brain dead. Which one of the following immunologic events is expected to occur within the donor kidney at the time of donor harvest?

One of the ways that resident dendritic cells become activated is through renal ischemia/anoxia caused by low blood flow to the donor kidneys. Brain death causes initially high BP followed by low BP. These swings in BP result finally into ischemia, which starts immunologic events in the donor kidney. Thus, E is correct.

In transplant immunobiology, the human major histocompatibility complex (MHC) plays an important role both in innate (natural) and adaptive immune systems. Regarding MHC and kidney transplantation, which one of the following statements is CORRECT?

All of the statements are correct and also self-explanatory. Successful organ transplantation depends on the donor and recipient HLAs that are encoded by HLA (MHC) genes. These antigens are called alloantigens (a cell or tissue antigens that are present in some members of species but not in others), and are recognized as foreign antigens. The genes for these alloantigens (proteins) are clustered in MHC on the short arm of chromosome 6. Because MHC genes, also called HLA genes, are polymorphic, the products of these genes are also polymorphic. A new World Health Organization classification has been introduced in 2010 to include all HLA genes and their products.

HLA genes are classified into three classes: HLA class I, HLA class II, and HLA class III. HLA class I genes include HLA-A, HLA-B, and HLA-C genes and are present on cell surfaces of all nucleated cells. HLA class II genes include HLA-DP, HLA-DQ, and HLA-DR; the proteins of these genes are present in antigen-presenting cells such as dendritic cells, macrophages, B cells, endothelial cells, and some epithelial cells. Only HLA class I and HLA class II genes and their antigens participate in kidney transplants.

In transplant immunobiology, the effector cells for rejection are T cells, although B cells are also important. The ability of T cells to recognize antigens is dependent on association of these antigens with either class I or class II HLA proteins. For examples, T helper (CD4) cells respond to antigens in association with class II proteins, whereas cytotoxic T (CD8) cells respond to class I proteins. Thus, either the rejection or acceptance of a transplant is dependent on either class I or class II HLA proteins on donor cells. Generally, class II proteins play a major role in these processes. Matching the class I and class II antigens between the donor and recipient is important for successful kidney transplantation. It should, however, be noted that many transplants are done successfully with six antigen mismatch as well.

Which one of the following immunologic barriers should be considered for any successful kidney transplantation?

Prior to kidney transplantation, both donor and recipient undergo certain tests to prevent rejection. These tests include blood type matching, HLA antigen matching, and anti-HLA antibody test. The first barrier to successful transplantation is blood group mismatch (A is correct). There are four types of blood groups: A, B, AB, and O. The most frequently found blood groups in the USA are A and O (42–44 %). The A and B groups are glycosylated, whereas group O lacks glycosylation. Individuals with A or B blood types produce natural antibodies to the opposite type, and individuals with group O produce antibodies to both A and B. Because group O lacks glycosylated moiety, both A and B fail to produce antibodies to group O. Thus, group O grafts can be transplanted into patients with blood types A, B, and AB. However, it is not a common practice for ethical reasons in order to prevent depletion of available transplants for type O recipients, who must receive an O transplant. When ABO incompatible kidney is transplanted, it is immediately rejected because of preformed anti-A and/or anti-B antibodies. The following table (Table 11.1 ) shows the blood compatibility between donor and recipient blood groups.

The second barrier is mismatched HLA antigens. Despite many advances, HLA matching continues to be a major determinant of graft survival. The survival of grafts with no mismatches is much greater than those with one mismatch. However, concerns were raised about the HLA antigen mismatch, as no benefit in survival of grafts was observed with HLA matching in African Americans. A recent review concludes that HLA matching should continue because it allows the use of lower dosages of immunosuppressive agents. This conclusion was based on: (1) HLA matching overrides the impact of cold ischemia time (as longer time has negative impact on graft survival) on graft survival; (2) HLA mismatched patients were frequently hospitalized for malignancies due to high dosages of immunosuppressive agents; and, finally, HLA mismatches at Class II level (HLA-DR) appear to be associated with the development of de no development of donor-specific antibody 4.6 years after transplantation. Thus, HLA matching is important (B is correct).

The rhesus (Rh) factor either negative or positive is not an issue in kidney transplantation, as the kidney does not express this blood group. Thus, D is incorrect

In addition to the above tests, crossmatch testing is necessary prior to surgical transplantation to detect anti-HLA antibodies in the recipient. Which one of the following tests is NOT used to detect anti-HLA antibodies in the recipient?

The following table (Table 11.2 ) gives a list of various assays for detection of alloantibodies in the recipient.

The reader is referred to the following suggested reading for technical aspects of these tests.

Patients awaiting cadaveric kidneys have their serum screened for antibodies. Which one of the following antibody testing is MOST important in screening of these patients?

The most important screening test in the recipient awaiting nationwide deceased donor kidney is the PRA test, which is expressed from 0 to 100 % (D is correct). This test is done by testing the recipient serum with lymphocytes from individuals who are considered representatives of the general population. Most laboratories perform the test by using the lymphocytes from 30 to 50 subjects. A 0 % of PRA indicates no antibodies against the general population. On the other hand, if the recipient has a PRA of 30, it tells that 30 % of the population is not a suitable donor of the kidney. The higher the percentage, the longer is the waiting time and less likely to have a kidney transplant. It is suggested that this test should be discouraged because of falsely elevated percentage points. Also, this screening test should not be confused with crossmatch testing. Tests from A to C are not screening tests

The new deceased donor kidney allocation system has been revised and implemented on December 4, 2014. Which one of the following variables is included in designing Estimated Posttransplant Survival (EPTS) ?

The revised system of kidney allocation has been developed with the participation of transplant professionals and people who have personal experience with donation and transplantation. This system was built on two designs to improve the allocation of the kidney: EPTS and KDPI (Kidney Donor Profile Index ). EPTS is a tool to estimate the anticipated posttransplant survival in the recipient. It is built on four variables: age of the patient, time on dialysis in years, diabetes status, and the number of prior solid organ transplants (E is correct). A score is calculated based on these variables, which is expressed as percentage from 0 to 100 %. The transplanted kidney is expected to last longer in patient with a score <20 % compared to a patient with a score >20 %.

KDPI incorporates ten donor factors which provide the relative risk of posttransplant kidney graft failure. Thus, KDPI measures donor quality. KDPI is applicable to only deceased donors and not living donors. Lower KDPI scores indicate high donor quality, whereas higher KDPI scores are associated with lower donor quality. Table 11.3 shows the ten donor factors (variables).

EPTS scores are used to divide patients on the waiting list into the top 20 % and remaining 80 %. The top 20 % will receive the kidney with the longest estimated posttransplant survival . Based on EPTS and KDPI, the kidneys are allocated in four sequences:

Thus, this new allocation kidney system may fulfil the principles of utility and equity (justice).

Which one of the following statements regarding the presence of antibodies and rejection of transplanted kidney is CORRECT?

All of the above statements except D are correct (E). Lupus or medication-induced antibodies are of IgM isotype, and are not important in kidney transplantation as they do not mediate rejection (D is incorrect). However, IgM antibodies can cause a positive crossmatch.

A 42-year-old Caucasian woman donates her kidney to her son with Alport syndrome. At the time of donation, her eGFR was 96 mL/min, BP 128/74 mmHg, and normal glucose and urinalysis. Currently, she is being followed by a nephrologist for health-related issues. Which one of the following statements regarding posttransplant medical conditions is CORRECT?

Posttransplant development of complications is rather common. The kidney function seems to be preserved, and the expected decline in eGFR is similar to those of controls (A is correct). However, the risk of having a GFR <60 mL/min was associated with older age, females, and higher BMI. Studies have shown that follow-up of live donors for albuminuria/proteinuria showed that approximately 12 % develop albuminuria/proteinuria after 7–12 years (B is correct). Development of hypertension is common, and reported to occur in approximately 30 % of donors (C is correct). The results of progression to ESRD after donation are mixed. Some studies have shown no progression, and some studies reported progression. In the latter studies, the incidence of ESRD after 15 years of donation was found to be 0.3 %, as compared with 0.04 % in controls (a 15-fold increase). Also, another study showed a 7.4-fold increase in the development of ESRD after 7.8 years post-donation, as compared with controls. Thus, the progression to ESRD is controversial (D is correct).

A 40-year-old woman is willing to donate her kidney to her daughter with type 2 diabetes. Her BMI is 38 kg/m², BP 142/92 mmHg, and 24-h proteinuria of 310 mg. She has a history of recurrent calcium oxalate stones. Which one of the following statements regarding her kidney donation is CORRECT?

All of the above statements are correct (E). A BMI >35 kg/m ² is considered a relative contraindication for donation at many transplant centers. The obese individuals are advised to lose weight to <25 kg/m ² before donation, as obesity >25 kg/m ² is associated with ESRD. Uncontrolled hypertension (ambulatory BP >140/90 mmHg) is also a relative contraindication for donation. However, the kidney donation is accepted provided the donors are >50 years of age, eGFR ≥80 mL/min, and normal urinalysis.

Proteinuria of 310 mg/day generally indicates an underlying glomerular disease. Since proteinuria is a risk factor for progression of kidney and cardiovascular disease, donor kidney is not accepted from those with proteinuria >300 mg/d with or without hypertension. Generally, the obese subjects experience more surgical complications during nephrectomy than lean subjects; however, some studies reported no surgical risk at all. Recurrence of kidney stones is a contraindication for kidney donation. Weight loss may improve many of the conditions of metabolic syndrome and make the obese subjects suitable for kidney donation. The donor has many health-related issues that make her unsuitable for kidney donation.

A 50-year-old woman, mother of three children, develops ESRD and on hemodialysis for 2 years. Prior to transplantation, she was found to have higher titers of anti-HLA antibodies on crossmatching. Which one of the following exposures is associated with the development of antibodies is CORRECT?

Unlike anti-ABO antibodies, anti-HLA antibodies do not occur naturally. The exposure of HLA antigens and subsequent development of anti-HLA antibodies are seen in three conditions: pregnancy, blood transfusion, and prior transplantation (E is correct). Autoimmune-induced antibodies (IgM isotype) do not participate in kidney transplantation. Thus, D is incorrect.

Because of the presence of anti-HLA antibodies, the above recipient is highly sensitized. Which one of the following interventions is helpful in desensitizing (removal of antibodies) the patient?

All of the above intervention modalities have been tried alone or in combination to desensitize the patient, and mixed results were obtained (E is correct). However, patients with very high titers still retain some antibodies despite the use of these techniques. Acute and chronic rejections of allografts are expected in patients with elevated titers of antibodies. However, some patients maintain graft survival and renal function for several years after transplantation despite the presence of some anti-HLA antibodies. Splenectomy, eculizumab (inhibitor of C5a and C5b that prevents the formation of the terminal complement complex C5b-9), and proteosome inhibitor (bortezomib) have also been used as desensitization procedures.

Which one of the following effects is expected to occur after desensitization?

Desensitization procedures are expensive, and these procedures have been associated with increased fungal infections, increased rate of AMR, and higher subclinical and chronic antibody-mediated rejection compared to nonsensitized or placebo groups. A study from Johns Hopkins reported increased patient survival following plasmapheresis/IVIG treatment , as compared with those patients on dialysis. Thus, E is correct.

A 72-year-old nonobese woman wants to donate her kidney to her only daughter of 50-years-old with hypertensive nephrosclerosis and eGFR <15 mL/min. She approached several transplant centers, and one center decides to perform preemptive transplantation. Which one of the following statements regarding graft and recipient survival from older donors is CORRECT?

A study by Berger et al. showed that the graft survival from live donors aged 70 years or older was much lower than the graft survival from donors aged 50–59 years after 1, 5, and 10 years of transplantation. Similarly, patient survival was much lower in those who received kidneys from older (>70 years) compared to the recipient survival who received kidneys from younger group (50–59 years). The actual data are shown below (Table 11.4 ):

Thus, graft failure was higher and patient survival was lower in recipients who received kidneys from donors aged >70 years compared to those who received kidneys from younger donors (D is correct). Interestingly, there was no difference in survival between donors compared to the survival of age-matched general population.

A 40-year-old woman is evaluated for kidney donation. All the pertinent tests are negative except for microscopic hematuria. She had menstrual cycle 15 days ago. Urine sediment shows six dysmorphic RBCs on phase contrast microscopy. Which one of the following tests you recommend for this donor?

In general, isolated hematuria with three to five isomorphic RBCs/HPF is not a contraindication for kidney donation. On the other hand, dysmorphic RBCs indicate glomerular origin and disease. In donors with dysmorphic RBCs, a renal biopsy is indicated for evaluation of IgA nephropathy, thin basement membrane, or Alport syndrome (C is correct). If the donor has IgA nephropathy, she is prohibited from donation. Some centers may accept kidney donation from patients with thin basement membrane nephropathy if the donor does not have proteinuria, hypertension, or reduced renal function. If the donor is a carrier for Alport syndrome and the renal function is normal without proteinuria, or hypertension, she may donate the kidney even in the presence of microscopic hematuria. On the other hand, if the biopsy shows pathology of Alport syndrome, the donor should not be accepted because the recipient may develop anti-GBM-antibody disease. All the other tests in this donor may not provide adequate information.

The following diagram shows the activation of the recipient adaptive immune system following transplantation. Immunosuppressive drugs act on several steps of this activated adaptive immune system. Match the letters shown in the figure with the appropriate immunosuppressive agents (Fig. 11.1 ):

Finally, the rejection of donor kidney is prevented by several immunosuppressive agents at several steps of T cell activation. Cyclosporine and tacrolimus inhibit the calcineurin pathway (B), daclizumab and basiliximab inhibit the interaction between IL-2 and its receptor (C), and sirolimus and everolimus inhibit mTOR, whereas mycophenolate mofetil and azathioprine inhibit cell division. More specifically, mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, and this enzyme controls the synthesis of RNA. Azathioprine is a purine synthesis inhibitor, and purines are involved in the synthesis of RNA, DNA, ATP, etc. JAK3 inhibitors (CP-690 550) inhibit JAK/STAT pathway. The following diagram shows T cell activation by the donor dendritic cell and the inhibitory sites by various immunosuppressive agents (Fig. 11.2 ).

Which one of the following drugs does NOT increase blood levels of calcineurin inhibitors (CNIs)?

CNIs include cyclosporine and tacrolimus, and are the most commonly used immunosuppressive agents. Both agents are metabolized by cytochrome P-450 (CYP450) enzyme system, and drugs that either induce or inhibit CYP450 may influence the levels of CNIs. Also, the levels of CNIs are influenced by a protein called P-glycoprotein. Except for caspofungin, all other drugs inhibit CYP450 and increase CNIs levels. Thus, option E is correct. The following table (Table 11.5 ) shows all the drugs that either increase or decrease blood CNIs levels.

Nephrotoxicity is a well-known complication of calcineurin inhibitors (CNIs). Which one of the following renal-related complications due to CNIs is CORRECT?

Both cyclosporine and tacrolimus cause nephrotoxicity. Hypertension is common in posttransplant patients receiving one of these drugs. The mechanism of hypertension includes endothelial dysfunction, decreased production of nitric oxide and other vasodilators with an increase in endothelin levels. These changes lead to renal and systemic vasoconstriction with resultant hypertension. Hyperkalemia is due mainly to inhibition of K ⁺ channel in the distal tubule, and decreased renin-AII-aldosterone activity. Type 4 RTA has also been reported, which is due to a decrease in NH ₄ ⁺ synthesis by hyperkalemia. Hypomagnesemia and hypophosphatemia are due to renal loss of these electrolytes. Interestingly, long-term use of cyclosporine in patients with liver and heart transplantation can lead to CKD and progression to end-stage renal disease. Chronic tubulointerstitial disease, cytokine production (TGF-β1), and renal vasoconstriction seem to be responsible for CKD. Thus, option E is correct.

In addition to above changes, CNIs cause endothelial damage as well as renal vasoconstriction, resulting in thrombotic microangiopathy and renal ischemia.

Many drugs exacerbate calcineurin inhibitor (CNI) nephrotoxicity. Which one of the following agents does NOT potentiate nephrotoxicity of CINs?

It is very important to recognize certain drugs that potentiate CNIs nephrotoxicity. These include amphotericin, NSAIDs, inappropriately high doses of aminoglycosides, and sirolimus. Also, concomitant use of ACE-Is or ARBs with CNIs requires close monitoring for hyperkalemia and acute kidney injury. P _G E is a vasodilator, which has least interaction with CNIs. Thus, option E is correct.

A renal transplant patient is on cyclosporine and mycophenolate mofetil (MMF) for maintenance therapy. Which one of the following statements is FALSE regarding the use of MMF in this patient?

MMF and enteric-coated MMF are potentially useful antiproliferative immunosuppressive drugs with wide popularity. Both drugs are metabolized to mycophenolic acid. MMF requires acid environment for absorption, whereas enteric-coated MMF requires alkaline pH for absorption. Thus, MMF is absorbed in the stomach and enteric-coated MMF in the intestine. Both drugs are potent reversible inhibitors of inosine monophosphate dehydrogenase, which is the rate-limiting enzyme in the synthesis of guanosine monophosphate. Thus, these drugs inhibit the de novo synthesis of purines. Because of few side effects, well tolerability, and documented efficacy, MMF largely replaced azathioprine as the drug of choice in the maintenance phase of immunosuppression. Both animal and human studies have shown teratogenicity with MMF during pregnancy, and azathioprine is usually recommended until pregnancy is completed. Cyclosporine but not tacrolimus lowers serum levels of MMF. Thus, option D is false.

Drug–drug interactions are clinically significant. Which one of the following drugs LOWERS plasma levels of sirolimus?

Sirolimus is an antiproliferative agent, which is an mTOR (mammalian target of rapamycin) inhibitor. Another mTOR inhibitor is everolimus. Both of them are metabolized by P450 enzyme system. Thus, an interaction occurs when 2 P450 metabolizable drugs are used simultaneously. Because of this interaction, the primary drug’s levels may be either low or elevated. Except for rifabutin, all other drugs increase plasma levels of sirolimus by decreasing its metabolism. Rifabutin lowers sirolimus levels by increasing its (sirolimus) metabolism. When cyclosporine and sirolimus are used as immunosuppressive drugs, it is preferable to administer sirolimus 4 h after cyclosporine. Adverse effects of sirolimus include hyperlipidemia, anemia, and neutropenia.

Which one of the following biologic immunosuppressive drugs does NOT deplete lymphocytes?

Basiliximab is a monoclonal CD25 antibody that binds to the α-chain of the IL-2 receptor activated cells. It is an IgG1 antibody and blocks the proliferative signal without depleting lymphocytes. Thus, option D is correct.

Match the following drugs with their mechanism of action in renal transplantation:

Alemtuzumab is a humanized IgG1 monoclonal antibody against CD52, which is present on cell surface of T and B lymphocytes, macrophages, monocytes, and granulocytes. It is approved for the treatment of B cell chronic lymphocytic leukemia. However, alemtuzumib is used in induction therapy of organ transplantation , which depletes peripheral and central lymphoid cells.

Rituximab is a monoclonal antibody that is directed against CD20 and IgG1 constant region. CD20 mediates B cell proliferation and differentiation, and rituximab inhibits these processes. B cells act as antigen presenting cells and activate T cells, and rituximab inhibits this T cell activation.

Bortezomib is a proteosome inhibitor, causing cell cycle arrest and apoptosis. It causes thrombocytopenia and peripheral neuropathy. It is also used in desensitizing patient.

Eculizumab is a humanized monoclonal antibody directed against complement factor C5 and prevents its conversion into C5a and C5b. It is used in paroxysmal nocturnal hemoglobinuria and atypical HUS. Eculizumab is used for prevention of antibody-mediated rejection. Meningococcal infection is a serious complication of eculizumab treatment.

A 33-year-old African American male receives a deceased donor kidney transplant, and had antibody induction therapy. Which one of the following statements regarding induction therapy is CORRECT?

It has become a common practice to use a brief course of immunosuppressive agents to prevent acute rejection in both high and low risk patients at the time of transplant. This strategy is called induction therapy. According to one source, 83 % of kidney transplant recipients received induction therapy in the USA in 2011. There are several risk factors for acute rejection. One of them that is still considered is the African American ethnicity, although a French study found no difference in rejection rates in European Africans and European Caucasians (A is correct).

Among polyclonal antibody preparations, rATG (thymoglobulin) is the most commonly used agent for induction therapy (B is correct). OKT3 is a monoclonal antibody that is directed against CD3 complex. It causes a “cytokine storm” that is potentially dangerous. Because of this profound cytokine release, OKT3 is withdrawn from market in 2009 with remaining stocks to be used up (C is correct).

Induction agents are classified as T cell depleting or nondepleting agents (see question 21). It has been shown that T cell depleting agents may predispose patients to the development of lymphomas compared to either nondepleting agents or no induction therapy (D is correct). The above (Table 11.6 ) summarizes the drugs that are used for induction therapy.

A 52-year-old woman on hemodialysis is called for kidney transplantation from a 60-year-old deceased donor. She was explained the medical history of hypertension, smoking, alcoholism, and prostatism of the donor. She is curious about transmission of infection and malignancy from the donor. Which one of the following statements regarding transmission of malignancy from the donor history of smoking and alcoholism and transmission of infection from prostatism is CORRECT?

Donors are routinely screened for HIV, hepatitis B, and hepatitis C. However, these tests may be negative during the “window period,” a period between infection and detection by routine tests. Thus, transmission of these viruses may be missing at time of donation or removal of the kidney from a deceased donor (D is correct).

Which one of the following statements regarding the epidemiology of malignancy in kidney transplant recipients is CORRECT?

All of the statements are correct (E). In 2004, Kasiske et al. reported the rates of malignancies in a large number of first time recipients of either deceased or living donor kidney transplantations between 1995 and 2001 using Medicare billing claims. A twofold higher rate for cancers such as colon, lung, prostate, stomach, esophagus, pancreas, ovary and breast, cancer rates was reported after kidney transplantation as compared with the general population. A fivefold higher rates for melanoma, leukemia, hepatobiliary tumors, cervical and vulvovaginal tumors, a threefold higher rates for testicular and bladder cancers, a 15-fold higher rates for kidney cancers, and >20-fold for Kaposi’s sarcoma, non-Hodgkin’s lymphomas, and nonmelanoma skin cancers. The authors concluded that the rates for most malignancies are higher after kidney transplantation as compared with the general population.

Among all cancers, skin cancers are the most common de novo posttransplant cancers in adults and their occurrence increases with time. Among nonskin malignant cancers, PTLDs are the most common type of tumors. Cancers such as Kaposi sarcoma, PTLDs, testicular cancer, cancer of the small intestine, and thyroid occur before 800 days after transplantation

In patients with a history of preexisting malignant neoplasms, close monitoring for recurrences after kidney transplantation is highly recommended. Among malignancies, the recurrence rate for multiple myeloma is 67 % followed by 53 % for nonmelanoma skin cancers, 29 % for bladder cancers, 29 % for sarcomas, 27 % for symptomatic renal cell carcinomas, and 23 % for breast carcinomas. The recurrence of prostate cancer is dependent on the stage of the disease, with highest rate for stage III disease. Thus, cancer screening is mandatory for recurrent disease after kidney transplantation.

De novo development of malignancy is common in recipients of solid organ transplantation. Which one of the following choices regarding the mechanisms of malignancy after transplantation is CORRECT?

All of the above choices are correct (E). Immunosuppressive drugs may alter the tumor surveillance by affecting both innate and adaptive immunity. This causes potentially malignant cells to be seeded in the host and escape usual killing by the immune system. Also, the foreign HLA antigens in the allograft may stimulate its own lymphoreticular system in the development of lymphomas. In addition, immunosuppressive drugs themselves may deplete T cells, and promote the development of posttransplant lymphoproliferative disorders (PTLDs) following induction therapy. Both cyclosporine and tacrolimus have been shown to cause higher rates of malignancy by stimulating transforming growth factor-β. Belatacept, an inhibitor of costimulatory signals, is associated with higher incidence of PTLDs, particularly in EBV seronegative recipients who received kidneys from EBV seropositive donors. Similarly, azathioprine, an antimetabolite, may sensitize skin to UV light and promote skin cancer. Finally, immunosuppressive therapy may activate latent oncogenic viruses (EBV, herpes virus, papilloma virus, hepatitis B and C viruses), which promote the development of malignancy. In addition, preexisting cancers that were undetectable at time of transplantation may be activated by any one of the above mechanisms. Thus, E is correct.

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