Food allergies developing after solid organ transplant

The development of food allergy is an increasingly recognized form of morbidity after solid organ transplant. It occurs more commonly in liver transplant recipients, although it has also been reported in heart, lung, kidney, and intestinal transplants. Pediatric transplant recipients are more likely to develop symptoms compared to adults, and reports of frequency vary widely from 5% to 38% in pediatric liver transplant recipients. Multiple mechanisms have been proposed in the literature, although no single mechanism can yet account for all reported observations. As food allergy can have at worst potentially fatal consequences, and at best require lifestyle adjustment through food avoidance, it is important for recipients to be aware of the donor's food allergies and particularly in pediatrics, the possibility of completely de novo allergies. This review explores the recent reports surrounding food allergy after solid organ transplant, including epidemiology, proposed mechanisms, and implications for practice.     

Kidney and liver transplantation in children with fibrocystic liver–kidney disease: Data from the US Scientific Registry of Transplant Recipients: 1990–2010

The natural history and survival of children with fibrocystic liver–kidney disease undergoing solid organ transplantation have infrequently been described. We report outcomes in a cohort of US children with fibrocystic liver–kidney disease receiving solid organ transplants over 20 yr. Retrospective cohort study of pediatric transplant recipients with diagnoses of fibrocystic liver–kidney disease from 1/1990 to 3/2010, using data from the SRTR. Subjects were categorized by the first transplanted organ: LT, KT, or SLK. Primary outcomes were death, re‐transplant, transplant of the alternate organ, or initiation of dialysis. Seven hundred and sixteen subjects were transplanted in this period. Median age at first transplant was 9.7 yr. Of the LT, 14 (19%) required a second liver transplant at median of 0.2 yr, and five (7%) required kidney transplant or dialysis at a median of 9.0 yr. Of the KT, 188 (31%) required a second kidney transplant or dialysis at a median of 5.9 yr. Twenty‐nine (5%) subsequently received liver transplant at a median of 6.0 yr. Among patients in this registry, far more children underwent kidney than liver transplants. The risk of subsequently needing transplantation of an alternate organ was low.     

Long-term mortality in pediatric solid organ recipients—A nationwide study

Background

The present study aimed at investigating long-term mortality of patients who underwent solid organ transplantation during childhood and at identifying their causes of death.

Methods

A cohort of 233 pediatric solid organ transplant recipients who had a kidney, liver, or heart transplantation between 1982 and 2015 in Finland were studied. Year of birth-, sex-, and hometown-matched controls (n = 1157) were identified using the Population Register Center registry. The Causes of Death Registry was utilized to identify the causes of death.

Results

Among the transplant recipients, there were 60 (25.8%) deaths (median follow-up 18.0 years, interquartile range of 11.0–23.0 years). Transplant recipients' risk of death was nearly 130-fold higher than that of the controls (95% CI 51.9–1784.6). The 20-year survival rates for kidney, liver, and heart recipients were 86.1% (95% CI 79.9%–92.3%), 58.5% (95% CI 46.2%–74.1%), and 61.4% (95% CI 48.1%–78.4%), respectively. The most common causes of death were cardiovascular diseases (23%), infections (22%), and malignancies (17%). There were no significant differences in survival based on sex or transplantation era.

Conclusion

The late mortality is still significantly higher among pediatric solid organ recipients in comparison with controls. Cardiovascular complications, infections, and cancers are the main causes of late mortality for all studied transplant groups. These findings emphasize the cruciality of careful monitoring of pediatric transplant recipients in order to reduce long-term mortality.     

Varicella vaccination in pediatric kidney and liver transplantation

Prelog M, Zimmerhackl LB. Varicella vaccination in pediatric kidney and liver transplantation.
Pediatr Transplantation 2010: 14: 41–47. © 2009 John Wiley & Sons A/S.
Abstract:  Reports about efficacy and safety of live-virus attenuated vaccines in patients before and after transplantation are mainly based on small patient numbers, making general recommendations for this patient population difficult. Children and adults as well as their close relatives and contact persons should be preferably immune to VZV before solid organ transplantation to avoid VZV-associated complications, thus making VZV vaccination necessary in susceptible individuals. The following literature review focused on efficacy and safety of VZV vaccination in pediatric kidney and liver transplant recipients. Review of literature also revealed that in all pediatric transplant candidates, humoral and cellular immunity against VZV should be consistently monitored to assess waning immunity under immunosuppressive treatment. This approach is desirable to estimate the risk of severe varicella disease after exposure in these patients.     

Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients - A single-center experience

Hoerning A, Hegen B, Wingen A‐M, Cetiner M, Lainka E, Kathemann S, Fiedler M, Timm J, Wenzel JJ, Hoyer PF, Gerner P. Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients – A single‐center experience. Abstract: HEV infection appears to be an emerging disease in industrialized countries. The aim of this study was to evaluate the prevalence of HEV infection in pediatric solid organ transplant recipients. One hundred and twenty‐four pediatric recipients of liver (n = 41) or kidney (n = 83) transplants aged between one and 18 yr were screened for anti‐HEV IgG antibodies. Patients were tested for fecal HEV RNA excretion if they showed anti‐HEV seropositivity. As a control group, 108 immunocompetent pediatric patients without liver disease aged between three and 18 yr were screened for anti‐HEV IgG. HEV seroprevalence was 2.4% in renal Tx (2/83), 4.9% in liver Tx patients (2/41), and 3.2% overall (4/124). Three of these four patients were HEV RNA‐negative. In one renal transplant patient, HEV genotype 3 RNA excretion persisted and liver enzymes were elevated, indicating chronic hepatitis. In the control group, eight patients (7.4%) were HEV IgG‐positive without biochemical evidence of hepatitis. The prevalence of HEV infection in pediatric renal or liver transplant recipients is not higher compared with immunocompetent children. Chronic HEV infection with long‐term carriage of the virus may develop in pediatric transplant recipients. Autochthonous HEV infection needs to be considered in uncertain cases of hepatitis in immunosuppressed as well as immunocompetent children.     

Prevalence of polyomavirus viruria (JC virus/BK virus) in children following liver transplantation

Brinkert F, Briem-Richter A, Ilchmann C, Kemper MJ, Ganschow R. Prevalence of polyomavirus viruria (JC virus/BK virus) in children following liver transplantation.
Pediatr Transplantation 2010: 14: 105–108. © 2009 John Wiley & Sons A/S.
Abstract:  BKV infection is a potential cause of renal dysfunction in non-renal organ transplant recipients. JCV is the causative agent of PML. Furthermore, polyomaviruses are tumor inducing viruses and molecular data suggest an association with malignancies among solid organ transplant patients. So far, there are no studies analyzing polyomavirus viruria following Ltx in children. We performed a prospective prevalence study at a mean of 2187 (range 20–5671) days after transplantation in 100 consecutive children admitted for the routine follow-up examination post-Ltx. The urine was screened for BKV and JCV DNA by using PCR in each case. A plasma analysis by PCR was also done if more than 100 000 DNA copies/mL urine were detected. BKV or JCV viruria was found in 19% (n = 19) of our patients. All patients were free of clinical signs of viral infection, PML, or nephropathy. GFR was normal in 97% of patients and we found no statistical difference of kidney function between patients with and without BKV/JCV viruria. The extent of immunosuppressive therapy had no influence on the polyomavirus viruria. Overall, we found a higher prevalence of polyomavirus viruria in our pediatric liver transplant recipients than reported in adult patients.     

A longitudinal retrospective analysis of left ventricular mass in a cohort of pediatric kidney transplant recipients

Childhood end‐stage kidney disease is associated with increased risk for early adulthood cardiovascular (CV) morbidity and mortality. Increased LVM is an early indicator of CV disease. Previous studies have suggested that LVM decreases after kidney transplantation; however, trends have been inconsistent. A single center retrospective longitudinal cohort analysis of LVM, documented annually, starting before kidney transplantation for up to 10 yr after transplantation was performed. BP documented by annual 24‐h ambulatory monitoring studies, and BMI values were also reviewed. Twenty‐seven children followed for a mean period of 5.3 yr were included. Depending on definition of LVH, its prevalence pretransplant and in the first years post‐transplant was up to 33% dropping to 0–25% thereafter. Individual longitudinal LVM z‐score trends were highly variable but generally trended toward the mean immediately after transplant and toward negative values in the following years. BP was stable during the follow‐up period while mean annual BMI increased in the first‐year post‐transplant but declined thereafter. In a cohort of pediatric renal transplant recipients, prevalence of LVH decreased after transplant; however, individual longitudinal LVM trends were highly variable among patients. Prospective studies are needed to correlate individual LVM trends with outcomes.     

Cardiovascular risk assessment in children following kidney transplantation

Dégi A, Kerti A, Kis é, Cseprekál O, Tory K, Szabó AJ, Reusz GS. Cardiovascular risk assessment in children following kidney transplantation. Abstract: CV diseases are the leading cause of death among patients with ESRD. RTX decreases the CV risk; however, it still remains definitely higher than that of the general population. Large multicenter and longitudinal studies are difficult to perform and hard end-points of CV events are usually missing among pediatric population. Thus, appropriate estimation of CV risk is of crucial importance to define the potential hazards and to evaluate the effect of treatments aimed to reduce the risk. A number of validated non-invasive methods are available to assess the extent of CV damage in adults, such as calcification scores, cIMT, aPWV, 24-h ABPM, AASI, and HRV; however, they need adaptation, standardization, and validation in pediatric studies. cIMT and PWV are the most promising methods, as pediatric normative values are already present. The up-to-date treatment of ESRD aims not only to save life, but to offer the patient a life expectancy approaching that of the healthy population and to ensure a reasonable quality of life.     

Liver allograft pathology in healthy pediatric liver transplant recipients

Liver transplantation offers excellent results for children with end‐stage liver disease, and efforts should be directed toward maintaining long‐term graft health. We evaluate graft pathology in healthy pediatric transplant recipients with low‐maintenance immunosuppressive medications to assess whether protocol biopsies are helpful for adapting immunosuppression and protecting long‐term graft function. Liver biopsies were performed on 60 healthy pediatric liver transplant recipients, and histological findings were correlated with laboratory, serological, and radiological results. Fourteen patients (23%) were diagnosed with acute or early chronic rejection, and immunosuppressive medications were increased in these children. Liver function tests did not correlate with histological findings. The incidence of fibrosis was 36% in transplant recipients five or more years after liver transplantation. We observed an unexpectedly high prevalence of rejection and fibrosis in children with no laboratory abnormalities, which led to changes in their immunosuppressive medications. Scheduled biopsies appear to be useful in pediatric transplant recipients with low immunosuppressive medications for early detection of morphological changes in liver transplants. Further studies are needed to evaluate whether adaption of immunosuppression helps to reduce tissue damage and the incidence of allograft dysfunction in the long term.     

Cardiometabolic risks vary by weight status in pediatric kidney and liver transplant recipients: A cross‐sectional,single‐center study in the USA

There is an increasing need to understand long‐term metabolic changes and resultant comorbidities because life expectancy is increasing after pediatric kidney and liver transplants. We evaluated differences in classic and novel cardiometabolic biomarkers among obese and normal weight adolescent transplant recipients. We enrolled a total of 80 adolescent (mean±SD, 14.8 years ±3.0) transplant recipients (63 kidney, 17 liver) with mean duration from transplantation of 6.0 (±4.1) years. Among kidney transplant recipients, overweight and obese individuals had higher leptin (16.7 vs 7.5 μg/mL, P<.001), lower HDL (1.1 vs 1.3 mmol/L, P=.02), higher free fatty acid (0.6 vs 0.5 mmol/L, P=.03), higher apoB‐to‐apoA1 ratio (0.8 vs 0.6, P=.03), and higher glucose (5.8 vs 4.3 mmol/L, P=.03) concentrations compared to normal weight individuals. Regardless of obesity status, over half of all participants (57.5%) were considered at high cardiometabolic risk using consensus guidelines, and this was more pronounced for kidney transplant recipients (61.9%). Post‐transplantation adolescents have increased cardiometabolic risk characterized by traditional risk factors of obesity and diabetes. The presence of obesity significantly worsens biomarkers of cardiometabolic risk. Future studies should explore whether treatment of obesity can improve the health and long‐term outcomes for children undergoing solid organ transplant.     

Quantitation of peripheral blood cytomegalovirus DNA for monitoring recurrent cytomegalovirus retinitis in pediatric solid organ transplant recipients

Cytomegalovirus (CMV) infection is a major concern following solid organ transplantation, especially in the pediatric population who remain at high risk of primary infection. CMV disease leads not only to increased patient and graft morbidity, but also to increased health care costs. This study describes the usefulness of a quantitative CMV polymerase chain reaction (PCR) technique for monitoring peripheral blood CMV DNA in pediatric recipients of kidney and liver allografts who had recurrent CMV retinitis. The incidence of CMV disease in 28 pediatric transplant recipients was 28.6%, one-half of whom developed retinitis. Two of these patients had recurrent retinitis on cessation of anti-viral treatment. A peripheral blood CMV DNA copy number of > or =500/microg of DNA was associated with recrudescence of the retinitis in these patients. We conclude that the measurement of peripheral blood CMV DNA by PCR is a useful tool for the surveillance of disease resolution and recurrence. This is particularly important in patients with CMV retinitis, who may remain asymptomatic for a period of time, despite recurrences.     

Challenges in pediatric transplantation: the impact of chronic kidney disease and cardiovascular risk factors on long-term outcomes and recommended management strategies

Barriers to successful outcomes following pediatric transplantation have shifted from ischemic reperfusion injury and rejection to more long-term complications. Of particular concern is the high prevalence of CKD owing to preexisting damage and nephrotoxicity, as well as other CV complications such as hypertension and cardiomyopathy. All of these contribute to graft loss and shortened life expectancy, thereby limiting the success story of solid-organ transplantation. Managing CKD and related CV morbidity should be integral to the care of pediatric transplant patients, and timely detection of any irregularities would increase the chances of restoring lost kidney function. GFR is still the widely accepted indicator of renal function, and nuclear medicine techniques are the gold standard measurement methods. These methods are limited by costs, radiation exposure and substrate injection, and current practice still uses the Schwartz estimate, despite its well-documented limitations. Newer endogenous markers of GFR, such as cystatin C clearance, give a more accurate measure of true GFR but have not been embraced in the management of pediatric transplant recipients. Furthermore, indirect markers (e.g., microalbuminuria and hypertension) could also aid early detection of renal damage. The effects of mainstay immunosuppressants on kidney and heart function are varied, with available data indicating favorable outcomes with tacrolimus compared with ciclosporin. There is a need for appropriately designed and powered randomized controlled trials to validate innovative concepts for tailored immunosuppression in the pediatric population. To date, very few studies have generated long-term data in pediatric renal transplant patients - results of 1-4-yr study favored tacrolimus over ciclosporin, but other immunosuppressive agents also need to be evaluated.     

Cytokine concentrations and regulatory T cells in living donor and deceased donor liver transplant recipients

Outcomes of pediatric liver transplantation have constantly improved in the last decade. Living‐related liver transplantation does not seem to improve long‐term outcomes following liver transplantation, but few studies have evaluated immunological parameters of the alloimmune response after living vs. deceased donor organ transplantation. We analyzed numbers of regulatory T cells, lymphocyte subsets, and serum cytokine concentrations in 12 pediatric recipients of living‐related liver transplants and in 28 pediatric recipients of deceased donor organs during their annual follow‐ups. Transplant recipients who underwent living donor organ transplantation had significantly higher numbers of regulatory T cells and IL‐4 serum concentrations than recipients of deceased donor organs; both of these factors are associated with beneficial outcomes and transplantation tolerance. Living‐related liver transplantation may have potentially beneficial immunological aspects, although long‐term outcomes do not seem to be better in recipients of living donor organs than in recipients of deceased donor organs. Further studies are needed to compare immunological aspects of the two transplant procedures.     

Post‐transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection‐prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.     

Presentation of atopic disease in a large cohort of pediatric liver transplant recipients

Atopic disease occurs in solid organ transplant recipients with an increasingly recognized frequency. The time course for the development of these atopic diseases in liver transplantation has not been described. The objective was to characterize the atopic manifestations of children receiving chronic immunosuppression after orthotopic liver transplantation (OLT). Chart review and follow-up questionnaire were utilized for 176 OLT pediatric recipients at a single institution for manifestations of allergic disease. Atopic disease was present in 25 (14.2%) patients. Median age at transplant was 16 months with a median follow-up of 63 months. Food allergy and non-food related atopic symptoms presented at a median of 11.5 (IQR, 6-28) and 19 (IQR, 5-41) months post-transplantation, respectively. The median age at transplant of the non-atopic children was 72 months, higher than patients with atopy (p < 0.001). Food allergy and atopic skin disease symptoms were present in 40% and 56% of cases, respectively. Asthma, allergic rhinitis, or both were found in 66% of cases. The onset of symptoms of food allergy and eczema (median, 12 months post-transplantation) preceded symptoms of allergic rhinitis and asthma. (median of 27 and 30 months post-transplantation, respectively). Atopy occurs in ～14% of pediatric liver transplant recipients, with manifestations including food allergy, eczema, allergic rhinitis, and asthma.     

Increased carotid intima‐media thickness in African American pediatric kidney transplant recipients

Early signs of subclinical CV dysfunction can be detected by ultrasound for CIMT. Although A‐A are at high risk for CV disease, CIMT of A‐A kidney transplant recipients has not been previously investigated. The aim of this prospective, controlled, longitudinal study was to investigate determinants of CIMT in a multiracial pediatric kidney transplant population, with a focus on A‐A. Transplant recipients (n = 42) had BMI, waist‐to‐height ratio, fasting glucose, lipid panel, HbA1c%, and CIMT measured at 1, 18, and 30 months post‐transplant. Twenty‐four healthy children (14 A‐A) served as controls. CIMT of A‐A transplant (0.49, 0.49, and 0.48 mm) was higher than non‐AA transplant (0.43, 0.44, and 0.44 mm) at 1, 18, and 30 months and higher than A‐A controls (0.47 mm). Hyperparathyroidism prior to transplant predicted high CIMT‐for‐race. A‐A race was associated with 10% higher CIMT vs non‐A‐A transplant. Metabolic syndrome was associated with 0.03 ± 0.01 mm increase in CIMT among A‐A transplant recipients only. In conclusion, A‐A kidney transplant recipients have increased CIMT. Metabolic syndrome disproportionately affects CIMT of A‐A children post‐transplant. Identification of subclinical CV damage, detected by CIMT, may provide an opportunity for early detection of CV risk in this vulnerable population.     

Donor‐to‐recipient weight ratio is a risk factor for hepatic artery thrombosis after whole‐liver transplantation in children under 25 kg

Hepatic artery thrombosis (HAT) following pediatric liver transplantation increases morbidity and risk of graft failure. We performed a retrospective chart review of all patients who underwent deceased‐donor liver transplantation from August 2002 to July 2016. Multi‐organ transplant recipients were excluded. We examined the incidence of HAT at our institution and sought to identify associated donor or recipient risk factors. A total of 127 deceased‐donor liver transplant patients with a median age of 1.7 years (IQR 0.67‐6.7) were identified. Of those, 14 developed HAT, all weighing under 25 kg. Among 100 patients under 25 kg, whole‐liver graft recipients had an odds ratio of 3.98 (95% confidence interval [CI]: 1.03, 15.34; P = .045) for developing HAT compared with split‐liver graft recipients. Within the whole‐liver recipient group under 25 kg, 11 patients developed HAT with a median donor‐to‐recipient ratio (DRWR) of 0.9 (IQR: 0.7‐1.2) compared with a median DRWR of 1.4 (IQR: 1.1‐1.9) for those who did not develop HAT. Multivariate analysis showed DRWR to be an independent risk factor for HAT in patients weighing under 25 kg who received whole organ grafts, with an odds ratio of 3.89 (95% CI: 1.43, 10.54; P = .008) for each 0.5 unit decrease in DRWR. Our results suggest that in recipients under 25 kg 1) split‐liver grafts may have a lower rate of HAT and 2) selecting whole organ donors with a higher DRWR may decrease the incidence of HAT.     

The importance of cardiovascular disease in pediatric transplantation and its link to the kidneys

Cardiovascular disease is a frequent cause of morbidity and mortality in pediatric patients following solid organ transplant. CKD is also common in pediatric patients after a solid organ transplant, and the link between CKD and cardiovascular morbidity is strong. In this review, we examine potential etiologies to explain the risk of cardiovascular morbidity and mortality in pediatric solid organ recipients and identify targets for improving outcomes.     

Cardiovascular risk factors and cardiac disorders in long‐term survivors of pediatric liver transplantation

The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single‐center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post‐transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty‐eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow‐up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow‐up being significant risk factors. Fifty‐three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.     

The use of everolimus in pediatric liver transplant recipients: first experience in a single center

The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.