B: Doppler ultrasound of aorta, IVC and iliac vessels.

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.

1. 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.


2. 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.


3. 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.


4. 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.


5. 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.

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.

1. 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.


2. 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.

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.

1. 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.


2. 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.


3. 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


4. 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.

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.

1. 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.

C: Emotional and psychological risks to donor are minimized

Answer C was added as a 5^th 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.

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.

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.

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

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.

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: 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.

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.

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

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. 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.

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.

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.