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 Bank. 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.
An 8 year-old child with hemolytic uremic syndrome is referred for a living related donor. HUS onset was associated to diarrhea and E coli verotoxin was detected.
Do you think that a pre-transplant genetic screening is needed?
A: Yes, it is appropriate to guide the post-transplant management and to exclude the disease in the donor.
B: No, as this is clearly a typical HUS.
C: It is an expensive evaluation. It should be performed in case of evidence of relapse.
D: It should be performed if the diagnosis is uncertain.
E: Genetic diagnosis is unnecessary due to eculizumab availability.
A: Yes, it is appropriate to guide the post-transplant management and to exclude the disease in the donor.
Rationale
Thrombotic microangiopathy (TMA) defines a histopathological lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis and obstruction of the vessel lumen. Consumption of platelets and erythrocytes occurs in the microvasculature of kidney, brain and other organs, which causes laboratory features of thrombocytopenia and microangiopathic hemolytic anemia. Depending on whether brain or renal lesions prevail, two clinical entities have been described: the thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (HUS) (Noris American Journal of Transplantation 2010; 10: 1517–1523)
Typical HUS is caused by strains of E. coli (STEC) that produce Shiga-like toxins (Stx) and cause a hemorrhagic colitis. There are atypical forms, which are unrelated to STEC and account for less than 10% of cases (aHUS). These forms can occur sporadically or within families. The clinical outcome of aHUS is unfavorable (Noris American Journal of Transplantation 2010; 10: 1517–1523)
However, diarrhea may be an initial trigger of the disease in 39% of children (Clin J Am Soc Nephrol 8: 554–562, 2013). Thus, diarrhea at onset does not exclude an atypical HUS.
Various hereditary or acquired deficiencies in the complement alternative pathway proteins have been identified, including inactivating mutations in the genes coding for regulatory proteins of the alternative pathway C3 convertase (C3bBb), factor H (CFH), factor I (CFI), membrane cofactor protein (MCP), or thrombomodulin (THBD), anti-CFH antibodies associated with homozygous CFHR1-CFHR3 deletion and gain-of-function mutations in the genes coding for two components of the C3bBb convertase, factor B (CFB) and C3 (Clin J Am Soc Nephrol 8: 554–562, 2013.)
Risk of recurrence is significantly correlated with the type of mutation. The risk is highest (approximately 80 %) in patients with CFH, C3 or CFB mutations, and approximately 50% in patients with CFI mutation, compared to approximately 20% in patients with no identified complement mutation. The risk of post-transplant recurrence in patients with MCP mutation has been shown to be low. No post-transplant recurrence has been observed to date in patients with DGKE mutation. The recurrence risk is low in anti-CFH antibody-associated HUS if the antibody titer is low (< 500–1,000 AU/ml) at the time of transplantation, while substantial if elevated. THBD mutation may be followed by post-transplant recurrence (Pediatr Nephrol (2016) 31:15–39)
In aHUS patients with high risk of recurrence, treatment with anti-C5 therapy proved to be highly effective for preventing and treating posttransplant aHUS recurrence (American Journal of Transplantation 2012; 12: 3337–3354) and Eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function American Journal of Transplantation 2012; 12: 1938–1944 American Journal of Transplantation 2012; 12: 3337–3354
Live-related donation in patient with aHUS and identified mutation is a possible option, provided that complete genotyping of the donor is performed excluding the mutation identified in the patient or other possibly predisposing mutation American Journal of Transplantation 2010; 10: 1517–15238
It is therefore evident that genetic mutations should be identified prior transplantation in order to stratify the risk of recurrence and guide the best treatment.
Which imaging modality is used for children who have vascular imaging before renal transplantation?
A: Doppler ultrasound of aorta and IVC
B: Doppler ultrasound of aorta, IVC and iliac vessels
C: MRA/MRV (or CTA or formal angiography)
D: Angiography only if abnormal or inadequate ultrasound
E: 3D printing
B: Doppler ultrasound of aorta, IVC and iliac vessels.
You are the transplant physician evaluating an 8 year old child with renal hypoplasia and chronic kidney disease (CKD) stage 5, who is currently treated with continuous cycling peritoneal dialysis (CCPD). As a secondary complication of CKD, he suffers from growth failure with a longitudinal height below the 3rd percentile for age and sex and a height velocity below the 25th percentile despite adequate nutritional intake. According to the pre-transplant immunology work-up, the patient has a low immunological risk profile. You are counseling the parents regarding listing of the child for renal transplantation and find out that no living donor is available. You are also counseling the parents on the options for the post-transplant immunosuppressive therapy.
Which of the following options would be an appropriate recommendation for the family at this time?
A: You recommend an immunosuppressive regimen, which is the current standard of care in adult renal transplant recipients (standard-dose tacrolimus with mycophenolate mofetil and glucocorticoids), because differences in the side effect profiles of immunosuppressive drugs between a pediatric and adult patient are minor and can be neglected.
B: You recommend an immunosuppressive regimen consisting of low-dose tacrolimus in conjunction with everolimus and steroid elimination at month 5, because there is recent scientific evidence that this regimen has the best long-term efficacy-safety profile in this patient population.
C: You recommend an immunosuppressive regimen consisting of standard-dose tacrolimus in conjunction with mycophenolate mofetil and steroid elimination either at an early point in time post-transplant (requiring induction therapy with an interleukin 2 receptor antagonist or anti-thymocyte globulin) or late, because this regimen has a good immunosuppressive efficacy regarding the prevention of acute rejection with an acceptable side effect profile, and steroid elimination allows post-transplant catch-up growth in the majority of prepubertal children with CKD-associated growth failure.
D: Defer listing and continue aggressive nutritional management and treatment with recombinant human growth hormone while the child grows to at least 40 kg prior to transplantation as the outcomes are much better in larger children.
E: List for deceased donor transplantation only from a pediatric donor, as this is the best way to achieve normal growth rates post-transplant irrespective of the immunosuppressive regimen.
C: You recommend an immunosuppressive regimen consisting of standard-dose tacrolimus in conjunction with mycophenolate mofetil and steroid elimination either at an early point in time post-transplant (requiring induction therapy with an interleukin 2 receptor antagonist or anti-thymocyte globulin) or late, because this regimen has a good immunosuppressive efficacy regarding the prevention of acute rejection with an acceptable side effect profile, and steroid elimination allows post-transplant catch-up growth in the majority of prepubertal children with CKD-associated growth failure.
In children, an immunosuppressive regimen allowing steroid elimination at some point in time post-transplant has the important advantage to allow normal longitudinal growth and avoid other steroid-associated side effects. Glucocorticoids (steroids) in pharmacological doses interfere with normal longitudinal growth by suppressing the secretion of endogenous growth hormone from the pituitary gland and induce resistance to the action of growth hormone in the growth plate; hence, steroid-free immunosuppressive regimens are important for pediatric patients after renal transplantation. While the 1 year data of the CRADLE study on a reduced dose tacrolimus regimen in conjunction with everolimus and steroid elimination at month 5 are promising (1), they do not provide currently sufficient scientific evidence that this regimen allows better longitudinal growth, while other previous randomized studies both from North America and Europe have documented improved growth rates with either steroid avoidance (2) or early (3, 4) or late (5) steroid elimination. There is no rationale to defer listing for renal transplantation in a 7 year old boy because renal transplantation at this age is standard of care and long-term dialysis in children is associated with multiple medical complications and psychosocial drawbacks. A renal allograft from a pediatric donor is not associated with better longitudinal body growth compared to an allograft from an adult donor.
Tönshoff B, Ettenger R, Dello Strologo L, et al. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial. Am J Transplant. 2018 Aug 20. doi: 10.1111/ajt.15081.
Sarwal MM, Ettenger RB, Dharnidharka V, et al. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant. 2012 12:2719-29.
Grenda R, Watson A, Trompeter R, et al. A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST study. Am J Transplant. 2010 10:828-36.
Webb NJ, Douglas SE, Rajai A, et al. Corticosteroid-free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial. Transplantation. 2015 99:1178-85.
Höcker B, Weber LT, Feneberg R, et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant. 2010 25:617-24.
You are taking care of a 13 year old girl with a well-functioning renal allograft on a standard-dose tacrolimus regimen in conjunction with mycophenolate mofetil (MMF), who suffers from tremor since the time of renal transplantation. The patient is seronegative for the Epstein Barr virus (EBV). The tacrolimus whole blood trough levels were between 6 to 8 µg/L. The tremor interferes with school and sports activity. A neurological work-up did not reveal any specific cause for this tremor other than tacrolimus-associated neurotoxicity.
Which are the therapeutic options in this situation, which you can offer to your patient and his parents?
A: Tremor is a well-known neurological side effect of standard-dose tacrolimus, and there is nothing that can be done against it
B: Treatment with a beta-blocker, for example metoprolol, is an established pharmacological therapy for tacrolimus-associated tremor
C: Because the tremor is likely to be tacrolimus-associated, stopping tacrolimus therapy and giving dual immunosuppressive therapy with mycophenolate mofetil and glucocorticoids is an appropriate solution
D: Because the tremor is likely to be tacrolimus-associated, reducing the tacrolimus exposure aiming at a trough level between 2 to 4 µg/L in conjunction with everolimus could be a therapeutic option. There is recent evidence from the pediatric CRADLE study and the adult TRANSFORM study that reduced-dose tacrolimus in conjunction with everolimus is non-inferior to standard-dose tacrolimus and MPA regarding immunosuppressive efficacy and preservation of renal graft function in the first year post-transplant.
E: A tacrolimus-free, belatacept-based immunosuppressive therapy in conjunction with MMF and steroids is the treatment of choice in this situation.
D: Because the tremor is likely to be tacrolimus-associated, reducing the tacrolimus exposure aiming at a trough level between 2 to 4 µg/L in conjunction with everolimus could be a therapeutic option. There is recent evidence from the pediatric CRADLE study and the adult TRANSFORM study that reduced-dose tacrolimus in conjunction with everolimus is non-inferior to standard-dose tacrolimus and MPA regarding immunosuppressive efficacy and preservation of renal graft function in the first year post-transplant.
Tremor that interferes with school and sports activity has significance for the patient and should not be neglected. Since the tremor is likely to be tacrolimus-associated, stopping this drug would be straight-forward, but dual therapy with mycophenolate mofetil and glucocorticoids has too little immunosuppressive activity for the majority of patients (1, 2). Belatacept-based immunosuppressive therapy could be an option, but belatacept is not yet licensed for pediatric patients and is contraindicated in EBV-seronegative patients. Reduced-dose tacrolimus in conjunction with everolimus is a therapeutic option, because this regimen is non-inferior to standard-dose tacrolimus and MPA regarding immunosuppressive efficacy and preservation of renal graft function. Another option would be to switch the patient from tacrolimus to the other calcineurin inhibitor cyclosporine, which is associated with less neurotoxicity.
Harmon W, Meyers K, Ingelfinger J, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol. 2006 17:1735-45.
Cransberg K, Cornelissen M, Lilien M, Van Hoeck K, Davin JC, Nauta J. Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk. Transplantation. 2007 83:1041-7.
A 4 year old boy who underwent living donor renal transplantation (CMV donor+/recipient-, D+/R-) for renal hypo/dysplasia received 90 days of valganciclovir for CMV prophylaxis. Approximately one month after discontinuation of prophylaxis, he is found to have CMV replication on routine surveillance screening, with a plasma quantitative CMV DNA PCR result of 900 IU/ml. He is asymptomatic, with no laboratory abnormalities on complete blood count (CBC) and no elevation of transaminases.
Which of the following statements is correct?
A: This patient’s CMV D+/R- serostatus places him at no increased risk for symptomatic CMV disease following transplantation.
B: The patient is at high risk for progression from asymptomatic CMV DNAemia to CMV disease, because even though his CMV viral load is relatively low, he will likely lack an effective CMV-specific cytotoxic T cell response. Oral valganciclovir for treatment of asymptomatic CMV DNAemia should therefore be initiated.
C: The updated edition of the “International Consensus Guidelines” recommends frequent monitoring for the presence of CMV DNAemia for at least the one year following discontinuation of prophylaxis, when the risk of CMV DNAemia is known to be increased.
D: Everolimus is contra-indicated in patients at high-risk for CMV, because it favors CMV replication.
E: Because the patient is asymptomatic (no fever, malaise, diarrhea and/or respiratory symptoms), no further action is required.
B: The patient is at high risk for progression from asymptomatic CMV DNAemia to CMV disease, because even though his CMV viral load is relatively low, he will likely lack an effective CMV-specific cytotoxic T cell response. Oral valganciclovir for treatment of asymptomatic CMV DNAemia should therefore be initiated
The recommendation by the updated CMV guideline (1) is to initiate antiviral therapy with any primary CMV infection, independent of organ type or viral load. Although prior versions recommended the use of IV ganciclovir in this setting, the updated guidelines now firmly support the use of oral valganciclovir for treatment of asymptomatic CMV DNAemia. The updated edition of the “International Consensus Guidelines” recommends frequent monitoring for the presence of CMV DNAemia for at least the 2-3 months following discontinuation of prophylaxis, when the risk of CMV DNAemia is known to be increased (2). The CMV-protective effect of the mTOR inhibitors has a well-defined mechanism of action and has been described in numerous studies (3,4). The BK-protective effect is not a consistent finding.
Tönshoff B, Ettenger R, Dello Strologo L, et al. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial. Am J Transplant. 2018 Aug 20. doi: 10.1111/ajt.15081.
Kotton CN, Kumar D, Caliendo AM, et al.; The Transplantation Society International CMV Consensus Group The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931.
Brennan DC, Legendre C, Patel D, et al. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: Pooled analysis of three clinical trials. Am J Transplant 11: 2453–2462, 2011
Höcker B, Zencke S, 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.
You are counseling a 15 year old female adolescent (CMV D+/R- serostatus) with recurrent CMV DNAemia and explain to her the option of switching the immunosuppressive therapy from MMF with standard-dose tacrolimus to everolimus in conjunction with low-dose tacrolimus because of the CMV-protective effects of mTOR inhibitors.
Which information about the mTOR inhibitor everolimus do you give the patient beforehand?
A: Side effects of immunosuppressive drugs are not relevant, because they do not determine major outcome variables such as patient and transplant survival.
B: Overall, only 5% of patients treated with everolimus discontinue the study drug because of adverse events.
C: Diarrhea, nausea, vomiting, tremor, leukopenia, and insomnia is more frequent in everolimus-treated than in MMF-treated patients.
D: Everolimus can be associated with hyperlipidemia, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications.
E: The use of mTOR inhibitors does not require therapeutic drug monitoring.
D: Everolimus can be associated with hyperlipidemia, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications
Side effects of immunosuppressive drugs are a major determinant of outcome. In the recent large TRANSFORM trial, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events (1). Gastrointestinal side effects are more common with MMF than with everolimus. The use of mTOR inhibitors also requires therapeutic drug monitoring, which when used in combination with a CNI, doubles the cost of immunosuppressive monitoring.
Pascual J, Berger SP, Witzke O, et al. Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation. J Am Soc Nephrol. 2018 29:1979-1991.
PREVIOUS QUESTIONS
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?
A: Donor and recipient are highly likely to benefit
B: Surgical risk for donor is extremely low
C: Emotional and psychological risks to donor are minimized
D: All other deceased and living donor options have been exhausted (no adult donor, deceased donor unlikely)
E: The minor freely assents to donate without coercion
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.
Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000; 284(22): 2919-2926.
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?
A: Petechiae on his right foot
B: Splitting of the first heart sound
C: Dry mucous membranes
D: Gallop rhythm
E: Soft 1/6 systolic murmur at the left upper sternal border
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).
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?
A: Trimethoprim/sulfamethoxazole
B: Phenytoin
C: Loratadine
D: Fluconazole
E: Metoprolol
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.
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?
A: Post-transplant lymphoproliferative disorder
B: Cytomegalovirus viremia
C: Bronchiolitis obliterans
D: Congestive heart failure
E: Tuberculosis
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?
A: Prednisone
B: Mycophenolate mofetil
C: Amlodipine
D: Tacrolimus
E: Sirolimus
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.
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?
A: Prednisone
B: Mycophenolate mofetil
C: Amlodipine
D: Tacrolimus
E: Aspirin
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.
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)?
A: Minimize immunosuppression therapy due to EBV mismatch
B: Start antiviral therapy directed at CMV immediately post-transplant
C: Identify and treat early rejection
D: Close monitoring of CMV titers in the first year following transplant
E: Early transition of the primary immunosuppressant medication from a calcineurin inhibitor to mTOR inhibitor
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.
Dixon T and Twombley KE, Infections in Pediatrics Kidney Transplant Recipients. J Pediatr Infect Disease 2016;11:106-112.
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:
A: Administration of antiobiotics
B: Administration of pulsed steroids
C: Conversion of tacrolimus to cyclosporine
D: Plasmapheresis
E: Evaluate the patient for cardiac re-transplantation
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.
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:
A: More CMV and BKPyV infections
B: A higher number of acute rejections
C: More Proteinuria
D: A higher rate of de novo Donor specific antibodies
E: None of the above
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.
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
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
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?
A: Patient with undetectable soluble urokinase receptor (suPAR) serum level
B: Identified podocin mutation
C: Patient receiving peri- transplant plasmapheresis to prevent recurrence
D: Patient receiving living donor kidney
E: Patient who had showed an initial steroid response
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.
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.
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.
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?
A: Malnutrition
B: HIV
C: Active Infection
D: Oxalosis
E: All of the above
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.
McKay DB, Milford EL, Sayegh MH. Clinical aspects of renal transplantation. In: The Kidney, 5th ed, Brenner BM, Rector FC (Eds), Saunders, Philadelphia 1995.
Evaluation of potential renal transplantation. In: Handbook of Kidney Transplantation, 4th ed., Danovitch GM (Ed), Lippincott, Williams & Wilkins, Philadelphia 2005.
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?
A: Tacrolimus is more potent than cyclosporine on a molecular weight basis
B: Cyclosporine is a macrolide antibiotic
C: Tacrolimus increases expression of TGF-beta
D: Both have better absorption if taken with a fatty meal.
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.
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.
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.
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.
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.
