What is the calcineurin inhibitor of choice for pediatric renal transplantation?

Cyclosporine microemulsion (CyA) and tacrolimus (Tac) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. In the majority of patients, these calcineurin inhibitors have been used in combination with other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil (MMF). In this review we will address the question of what calcineurin inhibitor we should use in an individual pediatric renal transplant patient. Well-designed randomized studies in children showed no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However Tac is significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population when used in conjunction with azathioprine and corticosteroids. This difference disappears when calcineurin inhibitors are used in combination with MMF as both Tac and CyA produce similar rejection rates and graft survival. However, Tac is associated with improved graft function at 1 and 2 yr post-transplant. Adverse events of hypomagnesaemia and diarrhea seem to be higher in Tac group whereas hypertrichosis, flu syndrome and gum hyperplasia occurs more frequently in the CyA group. The incidence of post-transplant diabetes mellitus was almost identical between Tac and CyA treated patients. The recommendation drawn from the available data is that both CyA and Tac can be used safely and effectively in children. However Tac may be preferable to CyA because of steroid sparing effect and less hirsutism. We recommend that cyclosporine should be chosen when patients experience Tac-related adverse events. Nevertheless, the best calcineurin inhibitor should be decided on individual patients according to variable risk factors, such as risk of rejection in sensitized patient or delayed graft function. The possibility of adverse events should also be considered.     

Post-transplant diabetes mellitus in children following renal transplantation

Abstract:  PTDM plays a role in chronic allograft nephropathy and decreases graft and patient survival. Considering the serious outcome of chronic hyperglycemia, the importance of early recognition and the few data in children, in this retrospective analysis we studied the characteristics and risk factors of PTDM in 45 pediatric renal transplant recipients receiving Tac or CyA-based immunosuppression. Fasting blood sampling and OGTT were performed. PTDM has been developed in six patients (13%), while seven children (16%) had IGT, with the overall incidence of a glucose metabolic disorder of 29% in pediatric renal transplants. Patients in the PTDM + IGT group were younger and had higher systolic blood pressure and serum triglyceride level than children with normal glucose tolerance. Multivariate analysis identified Tac treatment, Tac trough level, steroid pulse therapy and family history of diabetes to be associated with the onset of PTDM. In pediatric renal transplants, OGTT and frequent assessment of blood glucose levels might be essential not only in the post-transplant management, but also prior to transplantation, particularly with family history of diabetes. Careful monitoring and modified protocols help to minimize the side effects of Tac and corticosteroids.     

Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.     

Novel Cardiac Magnetic Resonance Feature Tracking (CMR-FT) Analysis for Detection of Myocardial Fibrosis in Pediatric Hypertrophic Cardiomyopathy

Myocardial fibrosis is a risk factor for sudden cardiac death in hypertrophic cardiomyopathy (HCM) and is conventionally identified by cardiac magnetic resonance imaging (CMR) using late gadolinium enhancement (LGE). This study evaluates utility of a novel 16-segment CMR feature tracking (CMR-FT) technique for measuring left ventricular (LV) strain (S) and strain rate (SR) on non-contrast cine images to detect myocardial fibrosis in pediatric HCM. We hypothesized that CMR-FT-derived S and SR will accurately differentiate HCM patients with and without myocardial fibrosis. Consecutive children with HCM who underwent CMR with LGE at our institution from 2006 to 2014 were included. Global and regional longitudinal, radial and circumferential S and SR of the LV in 2D and 3D were obtained using a CMR-FT software. Comparisons were made between HCM patients with (+LGE) and without (?LGE) delayed enhancement. Of the 29 HCM patients (mean age 13.5 ± 6.1 years; 52 % males), 11 (40 %) patients (mean age 17.5 ± 8.4 years) had +LGE. Global longitudinal, circumferential and radial S and SR were lower in +LGE compared to ?LGE patients, in both 2D and 3D. Regional analysis revealed lower segmental S and SR in the septum with fibrosis compared to free wall without fibrosis. A global longitudinal S of ≤ ?12.8 had 91 % sensitivity and 89 % specificity for detection of LGE. In pediatric HCM patients with myocardial fibrosis, global LV longitudinal, circumferential and radial S and SR were reduced, specifically in areas of fibrosis. A global longitudinal S of ≤ ?12.8 detected patients with fibrosis with high degree of accuracy. This novel CMR-FT technique may be useful to identify myocardial fibrosis and risk-stratify pediatric HCM without use of contrast agents.     

Clinical Spectrum in a Family with Tropomyosin-Mediated Hypertrophic Cardiomyopathy and Sudden Death in Childhood

This report demonstrates variable clinical courses in several members of a family with tropomyosin-mediated hypertrophic cardiomyopathy (HCM) (L185R mutation). The index case was an 8-year-old girl who died from sudden cardiac death and was diagnosed with HCM on autopsy. Her father had minimal hypertrophy but had an implantable cardioverter defibrillator placed prophylactically with no appropriate shocks. Two brothers progressed from normal phenotype to HCM on follow-up, the younger with significant hypertrophy and the older with mild hypertrophy. They both had malignant arrhythmia courses with VF, which was terminated by ICD shock. In conclusion, family members with same genotype can have significantly variable phenotypes.     

Right diaphragmatic hernia after liver transplant in pediatrics: A case report and review of the literature

Diaphragmatic hernias (DH) are an unusual complication after pediatric liver transplantation; however, they have been reported with increased frequency in the past few years. DHs are responsible for nearly half of the small bowel obstructions requiring surgical intervention in this patient population. It has been suggested that the use of a left lobe liver graft, surgical trauma, malnourishment, elevated intra‐abdominal pressures, and mTor inhibitors may predispose to development of DH. The use of a segmental graft may increase the recognition of diaphragmatic hernia because the surgically damaged right hemi‐diaphragm often remains exposed to underlying viscera, instead of being covered by the right hepatic lobe. Treatment is surgical reduction, with up to 20% of the patients requiring resection of the herniated intestine. Herein we describe a case of DH after left segmental liver transplant in a two‐ yr‐old boy that presented one month post left lobe split liver transplant with abdominal pain, anorexia, and respiratory distress. Just like in the majority of the reported cases, an urgent laparotomy with primary repair was performed. No resection of the herniated segment of intestine was required. For pediatric patients with otherwise unexplained respiratory or gastrointestinal symptoms after a left lateral segment liver transplant, right‐sided diaphragmatic hernias should always be high in the differential diagnosis.     

Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.     

Hypertrophic cardiomyopathy in children

Hypertrophic cardiomyopathy (HCM) is a genetic condition causing unexplained left ventricular hypertrophy. The diagnosis management and risk stratification in the pediatric ages is often a challenge. At present the pillars of the diagnosis are echocardiography, electrocardiography and comprehensive family screening. The genetic diagnosis still only available in research units allows the diagnosis of those carrying a mutation. HCM is however characterized by broad heterogeneity as well a variable penetrance. It is important to stress the importance diagnosis of HCM within the spectrum of other conditions different than the typical HCM originated in mutation in the genes encoding the sarcomeric proteins. Other causes of unexplained left ventricular hypertrophy like mitochondrial diseases, Noonan syndrome, Danon's disease, Anderson-Fabry disease, metabolic syndrome and storage disease need to be excluded in order to improve the management and genetic counseling advice. HCM is a recognized cause of sudden cardiac death, therefore routine follow up need to ensure the identification of the subjects at high risk of sudden cardiac death. Severe left ventricular hypertrophy and non sustained ventricular tachycardia are amongst the risk markers for sudden cardiac death the ones with stronger predicted value in childhood. ICD implantation is effective in preventing sudden cardiac death in children with HCM. There is increasing evidence and experience to support the decision process leading to safe implantation of an ICD. Management of symptomatic patients with HCM requires identification of those with left ventricular outflow tract gradient.     

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??Hypertrophic cardiomyopathy??HCM?? is the second commonest cardiac muscle disease affecting children and adolescents and is a leading cause of sudden death in young athletes. HCM is highly heterogeneous in pediatric population??and currently the precision diagnosis of the etiology of the disease faces enormous challenges. In addition??prospective and randomized controlled clinical studies in the diagnosis??treatment and prognosis of pediatric HCM are extremely rare. Evidence-based consensus or guidelines needs to be developed urgently for personalized risk assessment and treatment??as well as standardized family management and genetic counseling.     

Tacrolimus without or with the addition of conventional immunosuppressive treatment in juvenile autoimmune hepatitis

Aim: To investigate tacrolimus (Tac)‐based treatment in juvenile autoimmune hepatitis (AIH). Twenty patients (13 girls; age, 8–17 years; median, 13.25 years) with AIH were treated with two daily oral doses of Tac. Six of them had advanced liver disease and/or cirrhosis. Methods: Drug concentrations in blood were measured regularly, and the target trough levels were 2.5–5 ng/mL. The patients were followed up for 1 year. Their clinical, biochemical, immunological and histological status was obtained at baseline and after 1 year. Results: In three cases, Tac alone led to complete remission. In 14 cases, additional low doses of prednisolone or azathioprine were used for a short time to achieve remission. In two cases, the treatment was discontinued: in one because of therapeutic failure, in another because of a suspected but unverified adverse event. Ten patients reported headache and/or recurrent abdominal pain. Two patients developed inflammatory bowel disease. Renal function remained intact. Conclusion: Tac is a promising alternative first line of treatment for AIH. Although monotherapy with Tac is usually not sufficient to achieve complete remission, the prednisolone and azathioprine doses can be drastically reduced, and most of their side effects avoided.     

Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children

Current data indicate that pharmacokinetic (PK) monitoring of cyclosporin microemulsion (CsA) should be performed using the 2-h concentration (C2), that tacrolimus (Tac) is commonly monitored using the trough level, and mycophenolate mofetil (MMF) should be monitored using the 1-h (C1), 2-h (C2) and 6-h (C6) concentrations. The three differing time-point requirements are cumbersome, and we aimed to develop universal guidelines for all three drugs using a large number of full PK profiles in children. One-hundred and twenty two stable pediatric patients, receiving either CsA (165 PK profiles, 69 patients, 24 with concomitant MMF) or Tac (122 PK profiles, 53 patients, 18 with MMF) were analyzed retrospectively. Pearson r for the CsA C2 was 0.90 [95% confidence interval(CI): 0.86-0.92], for Tac C2 r was 0.86 (95% CI: 0.80-0.90), and for MPA C2 r was 0.77 (95% CI: 0.68-0.83), respectively. For MPA, at least three time-points are required to accurately estimate the area under the concentration-time curve (AUC), and C1, C2 and C6 serve as best markers. Excellent AUC estimations could be obtained from a limited sampling strategy from C1, C2 and C6 or C0, C1, C2 and C4 with clinically acceptable errors for all three drugs. The AUC can be estimated with great precision by using an identical approach for all three drugs. Target AUCs for a given time-point after transplantation remain to be established.     

Growing experience with mTOR inhibitors in pediatric solid organ transplantation

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single‐arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low‐dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.     

Mycophenolate mofetil promotes prolonged improvement of renal dysfunction after pediatric liver transplantation: experience of a single center

Few studies have evaluated the long-term use of MMF in liver transplanted children with renal dysfunction. The aim of this study is to report the experience of a pediatric transplantation center on the efficacy and security of long-term use of a MMF immunosuppressant protocol with reduced doses of CNIs in stable liver transplanted children with renal dysfunction secondary to prolonged use of CsA or Tac. Between 1988 and 2003, 191 children underwent OLT and 11 patients developed renal dysfunction secondary to CNIs toxicity as evaluated by biochemical renal function parameters. The interval between liver transplantation and the introduction of the protocol varied from one to 12 yr. Renal function was evaluated by biochemical parameters in five phases: immediately prior to MMF administration; 3, 6, 12 and 24 months after the introduction of MMF. Among the patients, nine of them (82%) showed improvement of renal function parameters in comparison with the pretreatment values. The two patients that did not show any improvement were patients in whom the interval of time between OLT and the introduction of MMF was longer. All parameters of liver function remained unchanged. No episodes of acute or chronic rejection or increases in infection rates during the period were detected. Two patients developed transitory diarrhea and leukopenia that were reverted with reduction of MMF dosage. In conclusion, in liver transplanted pediatric patients with CNI-induced chronic renal dysfunction, the administration of MMF in addition to reduced doses of CNIs promotes long-term improvement in renal function parameters with no additional risks.     

Parental Knowledge and Attitudes Toward Hypertrophic Cardiomyopathy Genetic Testing

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant condition with an increased risk of sudden cardiac death. Although clinical genetic testing can be used for confirmation of a clinical diagnosis as well as a predictive test, based on our clinical experience it is underutilized. Therefore, we developed and administered a questionnaire to assess potential determinants of parental interest in this testing. Of the 30 adult caregivers who participated, 80% had heard of genetic testing, whereas only 30% knew about genetic testing specifically for HCM. Once informed of the availability, 62% said they would consider testing in the future and 28% would consider it in the next year. Participants’ younger age, higher education level, knowledge of carrier testing, and positive view of genetic testing were significantly associated with the participant considering HCM genetic testing for their child (p ≤ 0.05). Based on a logistic regression model, age, education level, and knowing that HCM is an inherited disease were the best predictors of who would consider genetic testing. This study provides healthcare providers with a framework to understand caregivers’ knowledge and views of genetic testing, which can be used to improve clinical care for pediatric HCM patients.     

Comprehensive Versus Targeted Genetic Testing in Children with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the sarcomere that can be found in both children and adults and is associated with many causative mutations. In children who are not the index case of HCM in their families, current recommendations call only for targeted genetic testing for familial mutations. However, clinical experience suggests that de novo mutations are possible, as are mutations inherited from apparently an unaffected parent. A chart review was conducted of all patients who received HCM genetic testing at Johns Hopkins from 2004 to 2013. In total, 239 patient charts were analyzed for personal and familial genetic findings. Eighty-one patients with sarcomere gene mutations were identified, of which 66 had a clinical diagnosis of HCM. Importantly, eight patients had >1 pathogenic or likely pathogenic mutation, including six patients who were diagnosed with HCM as children (18 or younger). In this analysis, when a sarcomere mutation is identified in a family, the likelihood of a child with HCM having >1 mutation is 25 % (6/24), compared to 4.8 % (2/42) for adults. The large number of children with multiple mutations suggests that broad panel rather than targeted genetic testing should be considered in HCM presenting during childhood even if the child is not the index case.     

Hypertrophic cardiomyopathy in childhood

Hypertrophic cardiomyopathy (HCM) is a heterogeneous and relatively common genetic cardiac disease that has been the subject of intense scrutiny and investigation for over 40 years. HCM is an important cause of disability and death in patients of all ages, although unexpected sudden death in the young is perhaps the most devastating component of the natural history. Therefore, while HCM is uncommon in pediatric cardiology practice, it is nevertheless a disease of great importance to young people and those clinicians charged with their care. Due to marked heterogeneity in clinical expression, natural history and prognosis, diagnostic and management strategies often represent a dilemma (and even the source of controversy) to both primary care clinicians and cardiovascular specialists. Consequently, it is timely to place perspective and clarify many of these relevant clinical issues, and profile the rapidly evolving concepts regarding HCM, especially as they may impact on this disease in childhood.     

Can an athlete have too much ticker? Hypertrophic cardiomyopathy in young athletes

Sudden cardiac death (SCD) is an uncommon but devastating potential consequence of participation in competitive sport. It is seen in adolescent and young adult athletes. The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable. Screening is undertaken for HCM, using differing strategies in Europe and North America. Screening and early diagnosis have reduced the mortality rate but has come at a significant economic cost. The evidence and relevant arguments for and against screening are presented together with management strategies as reflected by an illustrative case.     

Transient right sided hypertrophic cardiomyopathy in an infant born to a diabetic mother

Hypertrophie cardiomyopathy (HCM) is a rare primary myocardial disease, characterized by hypertrophy of the left and/or right ventricle. Infants of diabetic mothers (IDM) are at risk for development of HCM, respiratory distress and persistent pulmonary hypertension. A case of severe right sided HCM in an infant born to a diabetic mother is presented. The patient’s findings were complementary to the previous observations reporting HCM in IDM. The presence of disproportionate septal hypertrophy in the echocardiography of an infant born to a diabetic mother is highly suggestive of HCM in IDM. In our opinion, further cardiac evaluation is not indicated unless other cardiac abnormalities are suspected.     

Hypertrophic cardiomyopathy in Noonan syndrome

Noonan syndrome, a well-known multiple congenital anomalies syndrome, is frequently accompanied by cardiovascular diseases including hypertrophic cardiomyopathy (HCM). The incidence of HCM in Noonan syndrome is approximately 20–30% and one-third of cases reveal ventricular outflow obstruction. HCM in Noonan syndrome is occasionally associated with a congenital heart defect, whereas classic HCM seldom accompanies cardiac malformations. Asymmetric septal hypertrophy and symmetric septal hypertrophy (concentric hypertrophy) can be observed both in HCM with Noonan syndrome and in classic HCM. but apical hypertrophy has not been reported in Noonan syndrome yet, although it appears in classic HCM. Congestive heart failure is the major cause of death in patients with HCM in Noonan syndrome, but cases of sudden death have also been reported. The histopathologic findings of ventricular myocardial tissue in HCM with Noonan syndrome are similar to those in classic HCM.     

The role of liver transplantation for hepatic adenomatosis in the pediatric population: Case report and review of the literature

Wellen JR, Anderson CD, Doyle M, Shenoy S, Nadler M, Turmelle Y, Shepherd R, Chapman WC, Lowell JA. The role of liver transplantation for hepatic adenomatosis in the pediatric population: Case report and review of the literature.
Pediatr Transplantation 2010: 14: E16–E19. © 2009 John Wiley & Sons A/S. Abstract: Hepatic adenomas are benign lesions often found in young women during childbearing age. These tumors are often solitary but can also be multiple in which case this is referred to as hepatic adenomatosis (HA). HA is defined as having greater than or equal to ten adenomas within an otherwise normal liver. We present a case of a teenager with HA who underwent an orthotopic liver transplant for complications of her HA. To date there are only four reports of teenagers, without an underlying glycogen storage disease, who have undergone a liver transplant for HA. Liver transplantation within the pediatric population is an acceptable treatment for HA that are deemed unresectable.