Question Bank

QB

Want to stay up to date on transplantation? Want to test your knowledge? Here’s your chance! Introducing a new IPTA member benefit, the IPTA question. Members will have access to new questions with each newsletter with additional questions and answers available on the website. Each question will be accompanied by references to explain the correct and incorrect answers. Can be used as a teaching tool for students, residents and fellows as well.

Which criteria was not one of the original 4 criteria from the 2000 Consensus Statement on the Live Organ Donor in regards to when a minor may ethically act as a live organ donor?

  1.   Donor and recipient are highly likely to benefit
  2.   Surgical risk for donor is extremely low
  3.   Emotional and psychological risks to donor are minimized
  4.   All other deceased and living donor options have been exhausted (no adult donor, deceased donor unlikely)
  5.   The minor freely assents to donate without coercion

Correct Answer C: Emotional and psychological risks to donor are minimized

Answer C was added as a 5th condition proposed by the American Academy of Pediatrics in 2008.

Families need to be educated about the psychological risks that the donor may feel, particularly if most of the family’s resources remain focused on the ill recipient. Families must also be educated about the importance of affirming the donor’s role and the discomfort that some of the procedures may cause. Data in the bone marrow transplantation literature suggest that the risks can be minimized by preparing future donors through medical role-playing, allowing them to ask questions, and including them in the decision-making process.

  1. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000; 284(22): 2919-2926.
  2. Ross LF. Thistlewaite JR, et al. Minors as solid-organ donors. Pediatrics 2008; 122(2): 454-461.

A 15 month old male is 4 weeks post orthotopic heart transplantation. His parents bring him in with new-onset fussiness over the past day. He has been refusing to eat or drink for the last 4 hours.

Of the following new physical exam findings, which one is most concerning for allograft rejection?

  1.   Petechiae on his right foot
  2.   Splitting of the first heart sound
  3.   Dry mucous membranes
  4.   Gallop rhythm
  5.   Soft 1/6 systolic murmur at the left upper sternal border

Correct Answer D: Gallop rhythm

Of all exam findings listed above, the presence of a new gallop rhythm is the most sensitive for rejection, though there typically are a constellation of findings. There may also be tachycardia, new murmurs of mitral regurgitation or tricuspid regurgitation, or evidence of congestion (hepatomegaly, jugular venous distension, abnormal chest x-ray, etc). Early after transplant, the patient may be anemic resulting in the soft flow murmur as in answer (E).

  1. Weber SA. Diagnosis, Prevention and Treatment of Acute Rejection. In Tejani AH, Harmon WE, and Fine RN. Pediatric Solid Organ Transplantation. Munksgaard, Copenhagen; 2000, 396-401.

A 7 year old female with a history of heart transplantation 2 years ago presents with new-onset seizures. The seizures are controlled successfully with benzodiazepine administration. Laboratory evaluation reveals that the patient’s tacrolimus level is 31.2 (goal range 6-8). Two weeks ago, the child’s tacrolimus level was 7.9. The family reports that the child was started on a new medication one week ago by their primary care pediatrician.

Which of the following is the most likely medication that was started?

  1.   Trimethoprim/sulfamethoxazole
  2.   Phenytoin
  3.   Loratadine
  4.   Fluconazole
  5.   Metoprolol

Correct Answer D: Fluconazole

The antifungal medications are a consistent cause of increased calcineurin inhibitor levels in transplant patients. As such, any time any of these medications are considered being started, close monitoring of tacrolimus/cyclosporine is required. Other medications that may increase tacrolimus/cyclosporine levels include amiodarone, macrolide antibiotics, calcium channel blockers, and metoclopramide. Medications that may decrease tacrolimus/cyclosporine levels include octreotide, some anti-convulsants (phenytoin, phenobarbital, carbamazepine), and some antibiotics (nafcillin, IV Bactrim). Beta blockers have little effect on tacrolimus/cyclosporine levels. Patients who have tacrolimus toxicity have irritability, tremulousness, and may have seizures if levels are high enough.

  1. Mahnke CB, Sutton RM, Venkataramanan, et al. Tacrolimus dosage requirements after initiation of azole therapy in pediatric thoracic organ transplantation. Pediatr Transplant: 2003, Dec;7(6):474-8.

A 17 year old male, post heart-lung transplantation 7 years ago, presents with exertional dyspnea. He reports that his daily incentive spirometry values have decreased progressively in recent week, though otherwise he has felt well. He is noted to have elevated exhaled nitric oxide levels, and there is a decrease in mid-expiration flow rates (FEF 25-75). Echocardiography reveals normal left and right ventricular systolic function.

Which of the following is the most likely cause of his symptoms?

  1.   Post-transplant lymphoproliferative disorder
  2.   Cytomegalovirus viremia
  3.   Bronchiolitis obliterans
  4.   Congestive heart failure
  5.   Tuberculosis

Correct Answer C: Bronchiolitis obliterans

Bronchiolitis obliterans is chronic inflammation of the bronchioles that results in fibrous deposition, ultimately obstructing airways. It is considered a form of chronic rejection in lung transplant recipients. Clinical presentation can be non-specific and subtle, and may resemble a upper respiratory infection at first. An increase in exertional dyspnea may be common, as well as noted decreases in daily spirometry values. While this may not seem relevant to a pediatric cardiology board review, the ABP lists knowledge of bronchiolitis obliterans as a complication of heart-lung transplant in their content specifications for the cardiology exam.

  1. Rosen JB, Smith EO, Schecter MG, et al. Decline in 25% to 75% forced expiratory flow as an early predictor of chronic airway rejection in pediatric lung transplant recipients. J Heart Lung Transplant. 2012 Dec;31(12):1288-92

A 13 year old male sees you in clinic for routine follow-up.  He is 2 years post orthotopic heart transplantation for dilated cardiomyopathy.  He reports that he has felt “jittery” lately.  When he lifts his hand, he is unable to keep it still. 

Which of the following medications likely is causing this degree of tremulousness in this patient?

  1.   Prednisone
  2.   Mycophenolate mofetil
  3.   Azathioprine
  4.   Tacrolimus
  5.   Sirolimus

Correct Answer D: Tacrolimus

Irritability and tremulousness are common side effects of tacrolimus, that tend to happen when serum levels are high.  At high enough levels, tacrolimus toxicity can cause seizures to occur.  The most common complication of azathioprine and mycophenolate is leukopenia, though many patients may have gastrointestinal side effects as well (constipation, diarrhea, nausea).  The most common side effects of sirolimus are diarrhea and the development of mouth sores.  The side effects of prednisone are well documented, including mood changes, increased appetite, increased blood glucose, weight gain, and a Cushingoid appearance.  Long-term use is associated with the development of osteoporosis.

  1. Tejani AH.Induction and Maintenance Immunosuppression. In Tejani AH, Harmon WE, and Fine RN. Pediatric Solid Organ Transplantation. Munksgaard, Copenhagen; 2000, 91-114.

A 3 year old male sees you in clinic for routine follow-up.  He is 1 year post orthotopic heart transplantation for congenital heart disease.  On laboratory evaluation, he is found to have a white blood cell count of 1.2, with an absolute neutrophil count of 0.4. 

Which of the following medications is likely causing this his leukopenia?

  1.   Prednisone
  2.   Mycophenolate mofetil
  3.   Amlodipine
  4.   Tacrolimus
  5.   Aspirin

Correct Answer B: Mycophenolate mofetil

The most common complication of azathioprine and mycophenolate is leukopenia, though many patients may have gastrointestinal side effects as well (constipation, diarrhea, nausea).  Irritability and tremulousness are common side effects of tacrolimus that tend to happen when serum levels are high.  The side effects of prednisone are well documented, including mood changes, increased appetite, increased blood glucose, weight gain, and a Cushingoid appearance.  Long-term use is associated with the development of osteoporosis.

  1. Tejani AH.Induction and Maintenance Immunosuppression. In Tejani AH, Harmon WE, and Fine RN. Pediatric Solid Organ Transplantation. Munksgaard, Copenhagen; 2000, 91-114.

A 7 year old female undergoes orthotopic heart transplantation for restrictive cardiomyopathy.  Her serologic testing shows:

  • Donor: CMV positive, EBV positive, Toxoplasma positive
  • Recipient: CMV negative, EBV negative, Toxoplasma negative

The patient received induction therapy with anti-thymocyte globulin in the operating room.

Considering the results of the serologic testing, which of the following would most likely be recommended to reduce the likelihood of the patient developing post-transplant lymphoproliferative disorder (PTLD)?

  1.   Minimize immunosuppression therapy due to EBV mismatch
  2.   Start antiviral therapy directed at CMV immediately post-transplant
  3.   Identify and treat early rejection
  4.   Close monitoring of CMV titers in the first year following transplant
  5.   Early transition of the primary immunosuppressant medication from a calcineurin inhibitor to mTOR inhibitor

Correct Answer A: Minimize immunosuppression therapy due to EBV mismatch

Post-transplant lymphoproliferative disorder is a significant cause of graft loss and death after transplant.  Reduction in immunosuppression early after transplant has been recommended and led to improved survival.  While monitoring for CMV is important, the majority of lymphomas after heart transplant have been found to be related to EBV.  Re-transplantation for survivors of PTLD continues to be controversial and institution-dependent.

  1. Dixon T and Twombley KE, Infections in Pediatrics Kidney Transplant Recipients. J Pediatr Infect Disease 2016;11:106-112.
  2. Jordan CL, Taber DJ, Kyle MO, et al. Incidence, risk factors, and outcomes of opportunistic infections in pediatric renal transplant recipients. Pediatric Transplant, 2016 Feb;20(1):44-8.

An 11 year old female undergoes myocardial biopsy and coronary angiography as part of a routine post-heart transplant protocol. She is 10 years post orthotopic heart transplantation for congenital heart disease. The pathologist reports that the biopsy samples showed no evidence of rejection. On coronary angiography, areas of diffuse coronary luminal narrowing are noted in multiple branches. The left ventricular end-diastolic pressure is measured at 25 mmHg. The patient’s current medications include tacrolimus and mycophenolate mofetil.

The most appropriate next step in management for this patient is:

  1.   Administration of antiobiotics
  2.   Administration of pulsed steroids
  3.   Conversion of tacrolimus to cyclosporine
  4.   Plasmapheresis
  5.   Evaluate the patient for cardiac re-transplantation

Correct Answer E: Evaluate the patient for cardiac re-transplantation

The patient is presenting with severe coronary artery vasculopathy.  Options for management of the patient after this diagnosis are limited, but may include using aspirin, a statin drug such as pravastatin, and/or switching the patient from a calcineurin inhibitor (CNI) to an mTOR inhibitor such as sirolimus or everolimus.  Stenting can be considered in certain situations, but typically does not have long-term benefit due to a very high incidence of re-stenosis.  As such, listing the patient for re-transplantation is the best option.  Steroids or plasmapheresis are treatments for rejection, and in absence of pathological findings or other evidence of acute rejection are not indicated.  This being said, many patients will often receive presumptive treatment for rejection in this setting, in the hope of clinical improvement, though it should not be done in lieu of listing for re-transplantation.

  1. Schumacher KR1, Gajarski RJ, Urschel S. Pediatric coronary allograft vasculopathy--a review of pathogenesis and risk factors. Congenit Heart Dis. 2012 Jul-Aug;7(4):312-23.

Immunosuppression consisting of an mTOR inhibitor and a low-dose CNI in solid organ transplantation is associated with:

  1.   More CMV and BKPyV infections
  2.   A higher number of acute rejections
  3.   More Proteinuria
  4.   A higher rate of de novo Donor specific antibodies
  5.   None of the above

Correct Answer E: None of the above

Studies in pediatric transplantation have shown, that mTOR inhibitors are protective for viral diseases. In combination with a low-dose CNI, there are no differences in acute rejections, proteinuria or the development of DSAs.

  1. Hocker B, Zencke B, Pape L et al. Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation. Am J Transplant 2016;16:921-9
  2. Brunkhorst LC, Fichtner A, Höcker B et al. Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients. PLoS One. 2015 Sep 25;10(9):e0135439
  3. Toenshoff B, Ettenger B, Dello Strologo L. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial. Am J Transplant 2018, submitted

A 2 year-old child with end stage renal disease due to focal segmental glomerulosclerosis is presented for transplant.

Which of the following is associated with the lowest risk for relapse?

  1.   Patient with undetectable soluble urokinase receptor (suPAR) serum level
  2.   Identified podocin mutation
  3.   Patient receiving peri- transplant plasmapheresis to prevent recurrence
  4.   Patient receiving living donor kidney
  5.   Patient who had showed an initial steroid response

Correct Answer B: Identified podocin mutation

suPAR was not confirmed as a reliable marker to predict FSGS relapse, the incidence and time to recurrence of FSGS in the kidney allograft are not significantly different between patients who did and did not undergo prophylactic plasmapheresis. Although, living donor kidneys may be used to transplant children with FSGS they are not associated to a reduced risk of relapse and children who had had an initial steroid response are at higher risk for relapse.

  1. Meijers B, Maas RJ, Sprangers B, et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int. 2014 Mar;85(3):636-40. doi: 10.1038/ki.2013.505.
  2. Verghese PS, Rheault MN, Jackson S. The effect of peri-transplant plasmapheresis in the prevention of recurrent FSGS. Pediatr Transplant. 2018 Feb 1. doi: 10.1111/petr.13154.
  3. Francis A., Trnka P. and McTaggart SJ. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 11: 2041–2046, 2016.
  4. Ding WY, Koziell A, McCarthy HJ, et al. Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol 25: 1342–1348, 2014.

A child comes to you for evaluation for kidney transplant.

Which of the following is an absolute contraindication for kidney transplantation?

  1.   Malnutrition
  2.   HIV
  3.   Active Infection
  4.   Oxalosis
  5.   All of the above

Correct Answer C: Active Infection

While we would like all of our patients to be at the optimal nutritional status at the time of transplantation, this is not always the case. It is definitely not a contraindication. HIV was an absolute contraindicated until the recent antivirals were developed. There are centers that will transplant HIV + patients with good outcomes. Oxalosis was an absolute contraindication until recent years because of the risk of reoccurrence. Now it can be treated with combined liver kidney transplantation. Active infections should be treated before transplantation and immunosuppression to prevent increased morbidity and mortality from infection.

  1. McKay DB, Milford EL, Sayegh MH. Clinical aspects of renal transplantation. In: The Kidney, 5th ed, Brenner BM, Rector FC (Eds), Saunders, Philadelphia 1995.
  2. Evaluation of potential renal transplantation. In: Handbook of Kidney Transplantation, 4th ed., Danovitch GM (Ed), Lippincott, Williams & Wilkins, Philadelphia 2005.
  3. Review of transplantation in HIV patients during the HAART era. Pelletier SJ, Norman SP, Christensen LL, Stock PG, Port FK, Merion RM. Clin Transpl. 2004:63-82. Review.

Tacrolimus and Cyclosporine are both calcineurin inhibitors, with some minor differences.

Which of the following is a true statement regarding these two CNIs?

  1.   Tacrolimus is more potent than cyclosporine on a molecular weight basis
  2.   Cyclosporine is a macrolide antibiotic
  3.   Tacrolimus increases expression of TGF-beta
  4.   Both have better absorption if taken with a fatty meal.

Correct Answer A: Tacrolimus is more potent than cyclosporine on a molecular weight basis

Tacrolimus is more potent than cyclosporine on a molecular weight basis hence 1-10mg tables of tacrolimus and 100s for cyclosporine. Tacrolimus is a macrolide antibiotic, not cyclosporine. Cyclosporine increases expression of TGF-beta and not tacrolimus. Both Cyclosporine and tacrolimus have some decreased absorption when ingested with a fatty meal, and it is recommended that they be taken on an empty stomach, if possible

  1. Shin GT, Khanna A, Ding R, et al. In vivo expression of transforming growth factor-beta1 in humans: stimulation by cyclosporine. Transplantation 1998; 65:313.
  2. Slattery C, Campbell E, McMorrow T, Ryan MP. Cyclosporine A-induced renal fibrosis: a role for epithelial-mesenchymal transition. Am J Pathol 2005; 167:395.
  3. Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J Clin Pharmacol 2001; 41:289.