Association of post‐transplant donor‐specific HLA antibody with liver graft fibrosis during long‐term follow‐up after pediatric liver transplantation

The aim of this study was to evaluate the significance of post‐transplant DSA as a predictor of liver fibrosis during long‐term follow‐up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between‐group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non‐adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti‐DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti‐DQ DSA was higher in the fibrosis group, but non‐significantly (2052 vs 384; P = .46). Post‐transplant anti‐DR DSA is associated with graft fibrosis during long‐term follow‐up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti‐DR DSA, after pediatric LT.     

Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow‐up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non‐invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non‐invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100‐fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval ‐0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non‐invasive, reliable tool for the assessment of graft fibrosis in the follow‐up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.     

Structural lung changes,lung function,and non‐invasive inflammatory markers in cystic fibrosis

Robroeks CMHHT, Roozeboom MH, de Jong PA, Tiddens HAWM, Jöbsis Q, Hendriks HJ, Yntema J‐BL, Brackel HL, van Gent R, Robben S, Dompeling E. Structural lung changes, lung function, and non‐invasive inflammatory markers in cystic fibrosis.
Pediatr Allergy Immunol 2010: 21: 493–500.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non‐invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non‐invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8‐isoprostane, hydrogen peroxide, interferon‐gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non‐invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas‐negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8‐isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non‐invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non‐invasive monitoring of airway inflammation in CF adds to better follow‐up of patients.     

The histological quantification of alpha‐smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients

Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, “baseline” and “follow‐up” biopsies taken at 1‐ to 2‐year intervals from 18 stable pediatric LT recipients, transplanted between 2006 and 2012 were selected. Morphometric quantification of “ASMA‐positive area percentage” was performed on the baseline biopsy. Histological and fibrosis assessment using Metavir and LAFSc was performed on all biopsies. The difference of fibrosis severity between the “baseline” and “follow‐up” was termed “prospective change in fibrosis.” Significant association was seen between extent of ASMA positivity on baseline biopsy and “prospective change in fibrosis” using Metavir (P=.02), cumulative LAFSc (P=.02), and portal LAFSc (P=.01) values. ASMA‐positive area percentage >1.05 predicted increased fibrosis on next biopsy with 90.0% specificity. Additionally, an association was observed between extent of ASMA positivity and concomitant ductular reaction (P=.06), but not with histological inflammation in the portal tract or lobular area. Hence, ASMA quantification can predict the future course of fibrosis.     

The use of transient elastography and non‐invasive serum markers of fibrosis in pediatric liver transplant recipients

The use of non‐invasive markers to diagnose liver allograft fibrosis is not well established in children after LTx. TE, FT, and ELF score were performed in 117 liver‐transplanted children (60M, 8.9 [0.5–18.5] yr) and 336 healthy controls. Liver biopsy was available in 36 children. Results of histology and non‐invasive markers were compared using correlation coefficient or Mann–Whitney U‐test as appropriate. TE correlated best with histological degree of fibrosis (r = 0.85 vs. r = 0.04 [FT] or r = ?0.38 [ELF]). Liver stiffness values for transplanted children without fibrosis were significantly higher than those of healthy controls (7.55 [5.4–20.4] kPa vs. 4.5 [2.5–8.9] kPa). Presence of rejection was a potent confounder for the performance of TE. Both TE and FT reflected clinical changes (acute rejection, cholestasis, increasing fibrosis) in a total of 16 patients who underwent serial measurements. TE correlates better with histological degree of fibrosis in liver‐transplanted children than FT or ELF, but an individual baseline value needs to be determined for each patient. Normal or cutoff values for pathological degrees of fibrosis cannot be transferred from non‐transplanted children. Follow‐up studies, preferably with protocol biopsies, might help to improve the diagnostic quality of TE.     

Unique clinical conditions associated with different acinar regions of fibrosis in long‐term surviving pediatric liver grafts

In the majority of long‐term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation‐related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus‐based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1‐year and 5‐year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.     

Short‐term and long‐term effects of slow graft function on graft survival in pediatric live donor renal transplantation

Otukesh H, Hosein R, Fereshtehnejad S‐M, Riahifard A, Basiri A, Simforoosh N, Chalian M, Jazayeri S, Chalian H, Safarzadeh AE, Sharifian M, Hoseini S. Short‐term and long‐term effects of slow graft function on graft survival in pediatric live donor renal transplantation. Pediatr Transplantation 2010:14:196–202. © 2009 John Wiley & Sons A/S. Abstract: SGF generally has early and long‐term consequences for allograft survival. Limited studies have been performed on SGF and its complications in pediatric renal transplantation. Therefore, 230 children who received transplants between 1985 and 2005 in Labafi Nejad hospital were included in this study. SGF was defined if the serum creatinine level increased, remained unchanged, or decreased by <10% per day immediately after surgery during three consecutive days in the first week after transplantation. The children were divided into two groups: 183 children in group A (non‐SGF) and 47 patients in group B (SGF). The impact of SGF on renal function within the first year, long‐term graft survival and post‐transplantation complications were analyzed and compared using logistic regression model and Kaplan–Meier survival analysis. The incidence of graft failure at the end of follow‐up period was significantly more common in SGF group (53.2% vs. 22.4%, p < 0.001). The median survival time was 140.25 (s.e.m. = 19.35) months in group A (non‐SGF) and 60 (s.e.m. = 17.90) months in group B (SGF) (p < 0.001). The graft survival rate was 94.9%, 91.9%, 83.9%, 79.2%, and 72% at one, three, five, seven, and twelve yr after transplantation in children without SGF vs. 75.6%, 53.2%, 47.2%, 40% at one, three, five, and seven yr after transplantation in patients with SGF. The results of our study showed that slow graft function could remarkably affect graft survival and worsen both short‐term and long‐term transplantation outcomes. Thus, the prevention of SGF is one of the most important issues in graft survival improvement.     

Non‐invasive assessment of liver fibrosis in patients after the Fontan operation

Background: This study analyzed the change in liver fibrosis markers after the Fontan operation and investigated their clinical usefulness as an index of congestive liver fibrosis. Methods: The study enrolled 24 patients who underwent the Fontan operation between January 1994 and December 2008. We subdivided the postoperative period into four intervals and then compared the hepatological markers during each. Eighteen patients underwent postoperative cardiac catheterization and the correlation between hepatological markers and the inferior vena cava (IVC) pressure was analyzed. Results: The mean age of the patients was 138.6 months and the mean interval between the Fontan operation and the examination was 97.8 months. Type IV collagen was extremely high in every interval (I, 286 ± 93; II, 265 ± 93; III, 305 ± 143; IV, 206 ± 70), while none of the laboratory variables changed significantly in each interval. A significant positive correlation was observed between type IV collagen and the IVC pressure, but no significant correlation with any other hepatological marker was detected. Conclusions: No specific parameter that reflects the progress in liver fibrosis was identified in this study. The possibility exists that type IV collagen reflects the degree of hepatic congestion.     

Agreement of invasive versus non‐invasive blood pressure in preterm neonates is not dependent on birth weight or gestational age

Purpose: Blood pressure constitutes an important parameter in the assessment of the cardiovascular status in preterm infants. Invasive arterial blood pressure (IBP) is considered the ‘gold‐standard’, but non‐invasive blood pressure (NIBP) is used frequently in preterm infants. The aim of this prospective study was to compare mean IBP and mean NIBP arterial blood pressure measurements in three subsets of preterm infants (>1500 g; 1000–1500 g, and <1000 g, and >31 weeks, 28–31 weeks, and <28 weeks of gestation). Methods: Prospective, simultaneous assessment of both IBP and NIBP measurements in 50 preterm neonates at 6, 12, 18, 24 h after birth in a tertiary University centre. Results: Mean gestational age was 26.7 ± 2.2 (24–32) in group I (n= 18), 29.6 ± 2.0 (27–34) in group II (n= 19) and 32.2 ± 1.9(30–36) weeks in group III (n= 13), respectively; mean birth weight was 777 ± 161 (495–995), 1251 ± 154 (1010–1490) and 2010 ± 332 (1590–2550) g. Mean IBP and mean NIBP increased significantly during the first 24 h of life in all three sub‐groups (P < 0.01); IBP and NIBP measurements were significantly correlated, and showed good agreement, irrespective of birth weight and gestational age. Conclusions: Although IBP monitoring is considered the ‘gold standard’, NIBP values showed good agreement with those obtained invasively irrespective of gestational age and birth weight. We conclude that NIBP monitoring constitutes an important parameter in the assessment of the cardiovascular status even in extremely low birth weight infants.     

Long‐term experience of steroid‐free pediatric renal transplantation: Effects on graft function,body mass index,and longitudinal growth

Increased focus on the potential negative side effects of steroid usage in pediatric transplantation has led to steroid minimization or steroid‐free transplantation. In this study, we report results after complete steroid avoidance in renal transplantation in the period 1994–2009. We evaluate the effects of complete steroid avoidance on allograft function, BMI, and linear growth. The majority of transplanted children were induced with antithymocyte globulin and immunosuppressed with a calcineurin inhibitor and mycophenolate mofetil. Steroids were given only when rejection occurred or due to comorbidities. Anthropometric data were collected from 65 transplantations in 60 children. Patient survival was 93%; graft survival was 81% after five yr (N = 42) and 63% after 10 yr (N = 16). Acute rejection within the first year of transplantation was 9%. The distribution of the children's BMI before transplantation was normal; the mean BMI‐SDS was 0.21 before transplantation, and this value remained stable during the next five yr. Post‐transplantation the children demonstrated significant improved growth as the mean height‐SDS increased significantly from ?1.7 to ?1.1. Catch‐up growth was most pronounced in the youngest (< six yr). Steroid‐free immunosuppression in pediatric renal transplantation is safe and protects against steroid‐induced obesity and short stature.     

Practical matters,rather than lack of trust,motivate non‐participation in a long‐term cohort trial

Objective: The objective of this study was to investigate the importance of trust in researchers and other reasons that participating parents, former participants, and non‐participants had for participating, or not participating, in a longitudinal cohort study on prediction and development of diabetes in children. Study design: A questionnaire addressing each of these groups, where respondents graded the importance of a set of listed reasons for participating/not participating, was randomly distributed to 2500 families in the All Babies in Southeast Sweden (ABIS) study region with children born between 1997 and 1999. Results: Lack of trust was not a central factor to a great majority of respondents who decided not to participate in the ABIS study or who later decided to opt out. Practical matters, like blood sampling and lack of time, were important factors to many more. Yet, four fifths of those who still participate in the ABIS study stated trust in the researchers to be an important factor to their initial decision to participate. Conclusions: Trust in researchers may be a necessary prerequisite in order for people to be willing to participate in research, but practical matters such as time that has to be spent or pain involved in collecting blood were more important factors than lack of trust in explaining opt out in relation to the ABIS study.     

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.     

Detection of graft fibrosis by vibration‐controlled transient elastography in pediatric liver transplant recipients

Pediatric liver transplant recipients are at risk of developing graft fibrosis which can affect patient survival. VCTE is a non‐invasive tool that measures LSM and has been shown to correlate with hepatic fibrosis. The aim of this study was to therefore evaluate the ability of LSM to predict fibrosis in pediatric liver transplant recipients with different graft types. We performed a cross‐sectional study evaluating LSM of 28 pediatric liver transplant recipients who underwent a total of 20 liver biopsies within 1 month of LSM. LSM was compared to liver histology as well as graft type: WL or PL. The median LSM of all post‐transplant patients was 5.6 kPa (range = 2.7‐18.3). There was a statistically significant correlation between LSM and METAVIR fibrosis score (P = .001) and LAF score (P < .001). There was no difference in LSM between graft type (P = .088). The AUROC curve for LSM predicting any significant fibrosis (F ≥ 2) was 0.863. A cutoff value of 7.25 had a sensitivity of 71%, specificity of 100%, NPV of 87%, and PPV of 100% for significant fibrosis. LSM by VCTE is feasible in pediatric liver transplant recipients regardless of graft type. We found a significant correlation between LSM and hepatic fibrosis and established a cutoff value that may help determine which patients warrant further evaluation for graft fibrosis.     

Incidence of bacteremias and invasive mycoses in children with acute non‐lymphoblastic leukemia: Results from a multi‐center Italian study

Background

Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce.

Design and Methods

In a multi‐center, retrospective study, we analyzed proportion, rate per 1,000 person‐days at risk, and cumulative risk of bacteremias and IFD in children with AML.

Results

Between January 1998 and December 2005, 240 children were treated for AML at 8 Italian Centers, for a total of 521 treatment courses and 63,232 person‐days at risk. Bacteremia was observed in 32% of treatment courses and IFD was seen in 10% (P < 0.0001), with rates of 2.62 and 0.84, respectively (P < 0.001). There was a significantly higher frequency of IFD during relapse treatment: proportion 15% versus 9% (P = 0.05), rate 2.10 versus 0.64 (P = 0.008) and cumulative risk 32% versus 12% (P = 0.007), while there were no differences in the proportion, rate and cumulative risk of bacteremia during front‐line or relapse treatment. The epidemiology of bacteremias and IFD was different during front‐line therapy for M3 as compared to other types of AML, but the differences were not statistically significant.

Conclusions

Severe infectious complications are frequent during the treatment of pediatric AML, especially during relapse treatment, and bacteremias are more frequent than IFD. Pediatr Blood Cancer. 2010;55:1103–1107. © 2010 Wiley‐Liss, Inc.

     

Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation

Liu H, Wang X, Geng L, Tang B, Tong J, Yao W, Wang Z, Sun Z. Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation.
Pediatr Transplantation 2010: 14:465–470. © 2009 John Wiley & Sons A/S. Abstract: GF is a common and life‐threatening complication of UCBT. Here, we report that successful second transplantation of five patients using G‐CSF‐mobilized maternal stem cells with non‐myeloablative conditioning after GF following double UCBT. The median interval between the two transplants were 38 days. The first transplantation was administered after myeloablative conditioning for hematologic malignancies (n = 3), and rabbit ATG in combination with cyclophosphamide for SAA (n = 2). The second conditioning consisted of Flu and ATG‐based non‐myeloablative regimen. All five patients acquired quick and sustained engraftment after the second transplant. Treatment‐related toxicity was minimal. Three patients developed acute GVHD (>grade II = 1). Three patients developed chronic GVHD (limited = 1, extensive = 2). Severe infectious episodes were significant but manageable. With a median follow‐up of 713 days (592–1127), all patients have currently had an event‐free survival. These results indicate that a second transplant with non‐myeloablative conditioning using mother as the donor for young patient after GF is feasible.     

APRI评价胆道闭锁和胆汁淤积综合征肝脏纤维化程度的临床意义

目的 探讨肝功能检查和门冬氨酸氨基转移酶/血小板指数(aspartate aminotransferase-to-platelet ratio index,APRI)与肝脏纤维化程度的关系,阐述其在BA肝纤维化评估中的临床价值.方法 收集2006年2月至2011年8月间在我院治疗的胆道闭锁患儿38例和胆汁淤积综合征患儿25例为研究对象.临床观察指标包括肝功能检查,肝脏活检切片,血小板指数;肝硬化程度采用Metavir分类,APRI的诊断性评估采用ROC曲线,应用SPSS 16.0统计学软件进行统计分析.并对本组患儿进行随访,随访时间是3～69个月(平均随访时间:20.7个月).结果 胆道闭锁组患儿ALP、γ-GT、DBIL(564.14±257.75、153.36±97.47、7.55±2.57)较胆汁淤积综合征组患儿存在明显升高(P＜0.05);胆道闭锁肝硬化组患儿Age、ALT、AST、γ-GT(84.50±24.72、225.07±109.68、331.64±130.93、951.07±667.24)较非肝硬化组明显升高,两组差异具有统计学意义(P＜0.05);胆汁淤积综合征肝纤维化组患儿Age、ALT、AST(84.76±14.28、159.92±61.76、238.15±62.60)较非肝纤维化组(54.17±11.17、98.92±58.08、151.17±41.44)明显升高,两组差异具有统计学意义(P＜0.05).患儿绘制APRI的ROC曲线,用于判定肝硬化程度,胆道闭锁组敏感性为79％,特异性为88％;胆汁淤积综合征组敏感性为91％,特异性为79％.胆道闭锁中肝硬化组病死率显著高于非肝硬化组,且自体肝生存情况低于非肝硬化组.结论 肝功能检查可以作为胆道闭锁的初步判断指标,绘制APRI的ROC曲线对于评价胆道闭锁及胆汁淤积综合征患儿的肝脏纤维化情况均有较高准确性和可靠性,可用于预测预后和提早做好肝移植准备,因其简单、无创性可以在临床上广泛应用.