Renal function following liver transplantation in children

The literature regarding the etiology and incidence of short and long-term renal functional impairment in pediatric liver allograft recipients was reviewed. Most of the reports include recipients receiving cyclosporine as the primary immunosuppressant. Using calculated glomerular filtration rate (cGFR), creatinine clearance or the serum creatinine level will lead to an overestimation of GFR. In contrast to data in adults, there are a limited number of pediatric recipients whose renal dysfunction has progressed to chronic kidney disease or end-state renal disease. Calcineurin inhibitors minimization has proven effective in reversing or preventing progressive deterioration of GFR; however, rejection episodes and complications have limited efficacy of this approach. Future multicenter studies using optimal GFR measurements are required to delineate the magnitude of renal dysfunction in pediatric recipients.     

Fading renal hyperfiltration in children following liver transplantation

In a prospective longitudinal study, we investigated the renal function (RF) of 23 children before and after orthotopic liver transplantation (OLT). The aim was to assess both the outcome of pretransplant hyperfiltration and the clinical nephrotoxic effects of cyclosporin A (CsA); children with decreased RF prior to OLT were therefore excluded. The RF study of the 13 remaining patients included glomerular filtration rate (GFR) and effective renal plasma flow (RPF) measured by inulin (Cin: mL/min/1.73 m2) and para-amino hippurate (Cpah: mL/min/1.73 m2) clearances, respectively. Hyperfiltration prior to OLT was observed in six children, i.e. Cin>170 [range 172-230] and Cpah>800 [808-1,133]. A significant decrease in RF was noted as soon as 6 months after OLT: Cin (mean+/-SD)=107+/-23 vs. 158+/-46 (p<0.003); Cpah=583+/-119 vs. 791+/-243 (p<0.004). This was due to loss of hyperfiltration in the six children, as there was no significant difference in RF before and 6 months after OLT in the other seven children. With a 36-month follow-up, there was no correlation between CsA trough blood level and RF. In conclusion, following OLT, RF underwent early changes owing to loss of prior hyperfiltration in children without impaired RF before OLT. In addition, no evidence of CsA nephrotoxicity was found and RF remained stable during follow-up.     

Growth in children following irradiation for bone marrow transplantation

Longitudinal height data from 46 pediatric bone marrow transplant (BMT) patients, including 18 with aplastic anemia (AA), 19 with acute nonlymphoblastic leukemia (ANLL), and 9 with acute lymphoblastic leukemia (ALL), were analyzed to assess growth posttransplantation. Patients were prepared for BMT with high-dose cyclophosphamide followed by 7.5 Gy single-dose irradiation; AA patients received total lymphoid irradiation (TLI), and leukemia patients received total body irradiation (TBI). AA patients demonstrated reduced height posttransplant as reflected in a negative mean standard deviation score. The observed reduction was statistically significant only at 3 years following transplant. In contrast, leukemia patients showed a significant loss in relative height that was first visible at 1 year post-BMT and continued until at least 4 years post-BMT. Mean growth velocities in the leukemia patients were significantly below median for the 3 years following transplant. With a median follow-up of 4 years, antithymocyte globulin plus steroids in combination with methotrexate as graft vs. host prophylaxis was associated with less severe growth suppression than methotrexate alone, while there were no significant associations between growth during the first 2 years following transplant and prepubertal status at transplant (as defined by age), graft vs. host disease, thyroid or gonadal function, or previous therapies received by the leukemia patients. Children undergoing marrow transplantation, particularly those receiving TBI, are at significant risk of subsequent growth suppression.     

Post-traumatic stress responses following liver transplantation in older children

Eighteen children aged between 7 and 16 years who had undergone a liver transplantation were interviewed using the Child Post-Traumatic Stress Reaction Index (CPTS-RI) to discover if they had post-traumatic stress symptoms. A case control design was used to define which factors were important for the development of post-traumatic stress. Results of a one-way analysis of variance (ANOVA), with post-traumatic stress symptom intensity as measured on the CPTS-RI as the dependent variable, revealed a significant difference between the liver transplantation group compared with children who had a chronic life-threatening illness or had undergone a routine surgical operation. A post hoc (Tukey's HSD test) statistical analysis was performed and significance at the .05 level was found between the liver transplantation group and both the chronic illness group and the routine surgical operation group. Our results indicate that the acute life-threat involved in the liver transplantation contributed to the development of post-traumatic stress. It was thought that dissociation may be important in preventing the resolution of the trauma. Additional investigations are needed with larger numbers in a longitudinal study beginning before the transplant to determine the course of the PTSD symptoms and the appropriate timing of interventions to reduce the harmful effects of these symptoms.     

Glomerular and tubular function following orthotopic liver transplantation in children

Since its advent, cyclosporine nephrotoxicity has been a major concern to pediatricians attending to liver transplant recipients. The aims of this study were to examine glomerular and tubular function after orthotopic liver transplantation (OLT) in children, their correlation to CsA, and how they differed according to the underlying disease. Patients and methods: Glomerular and tubular function was examined in 28 patients aged 7 months to 14 yr at the time of transplantation (mean 4.0 +/- 3.6), retrospectively examining creatinine clearance, tubular phosphate reabsorption (TRP), calcium/creatinine ratio, sodium excretion fraction, and protein/creatinine ratio. The group with metabolic disease and an underlying tubulopathy was compared with the group with liver disease only. The effect of CsA trough levels and cumulated dose on these indices was examined, as was the effect of antihypertensives on creatinine clearance. Both glomerular and tubular functions improved significantly following liver transplantation. In patients on CsA (n = 21), CrCl decreased significantly at 1 month post-OLT (42.6 +/- 26.6 mL/min/1.73 m(2)) when compared with pretransplantation, and 3, 12 and 60 months post-OLT (p < 0.05). It improved between 12 and 60 months post-OLT (p < 0.05). It was correlated with cyclosporine trough levels (p < 0.03), and with total dose of CsA at 12 months. This was not true for patients on tacrolimus (n = 7). Overall pretransplant TRP was below normal (73.7% +/- 19.6), which was significantly lower than the values at years 2, 3, and 5 post-OLT (p < 0.05), owing mainly to the metabolic group which recovered normal proximal tubular function by the end of the second week post-OLT. Calcium/creatinine ratio was significantly worse in the group with liver disease only (p < 0.01). Protein/creatinine ratio normalized rapidly in both groups. Urinary sodium excretion fraction (FENa) was very abnormal in the early postoperative phase, normalizing thereafter in both groups. Kidney function improved after liver transplantation in patients with and without pre-existing kidney dysfunction. Overall, creatinine clearance was correlated to CsA trough levels suggesting CsA did not have an irreversible 'sclerosing' effect in the medium term. Combined antihypertensive therapy using nifedipine and enalapril may be the optimal choice for patients requiring medical management of their hypertension, although the observed effect on creatinine clearance did not reach statistical significance in this study. Tubular dysfunction is frequent in both groups of patients, pre- and post-transplant, and may contribute to bone mineral density as well as to metabolic disturbances in this population.     

Immunotherapy for severe aplastic anemia following orthotopic liver transplantation in children

Severe aplastic anemia is a well-recognized complication of fulminant non-A, non-B, and non-C hepatitis requiring orthotopic liver transplantation. The first line of therapy for cure in the treatment of aplastic anemia is a histocompatible bone marrow transplant. Immunosuppressive therapy is also effective if a histocompatible donor is not available. We describe two children who developed severe aplastic anemia following orthotopic liver transplant who achieved bone marrow recovery with a single course of anti-thymocyte globulin, solumedrol, and adjustments to their immunosuppressive therapy for prevention of liver allograft rejection.     

Growth and quality of life after living-related liver transplantation in children

Fifty-six consecutive pediatric recipients surviving more than 3 yr after living-related liver transplantation (LRLT) were evaluated in terms of growth, quality of life (QOL) and need for maintenance immunosuppression. Significant improvement in Z-score for height and weight were observed at last follow-up, ranging from 3 to 6 yr after transplantation, although catchup height gain lagged behind recovery in weight (height: -1.77 pre-transplant to -0.77 post-transplant, p<0.001; weight: -1.12 pre-transplant to -0.18 post-transplant, p<0.0001). 82% (46) recipients have remained in good health and have an excellent QOL as assessed in the most recent 6 months; these children lead similar daily lives to normal healthy children, with daily school attendance and full participation in activities including gymnastics and hiking. 3.6% (2) recipients attended school regularly but were unable to participate in sporting activities. 14% (8) recipients remain home or hospital-bound due to persistent complications in the past 6 months, with only minimal school attendance. Less than 10% of recipients were taking steroids by 2 yr post-transplantation, although approximately half of the children were receiving low-dose maintenance steroids at 1 yr. The mainstay immunosuppressant was tacrolimus, with 68% (38) recipients receiving daily therapy, 8.9% (5) alternate-day, 8.9% (5) twice a week, and 5.4% (3) a single dose weekly or alternate weeks. 7.1% (4) recipients were withdrawn completely from all immunosuppressants, including tacrolimus, for various reasons. 8.9% (5) patients have needed multiple immunosuppressive agents over the last 6 months. In conclusion, LRLT restores growth and offers excellent quality of life in pediatric recipients. The majority of recipients require minimal, steroid-free, immunosuppression by 2 yr post-transplant, but the occasional recipient still needs intensive longterm immunosuppression.     

Growth following solid-organ transplantation

One of the ultimate goals of successful transplantation (Tx) in pediatric solid-organ transplant recipients is the attainment of optimal final adult height. Except for kidney Tx there are limited data to address this issue. Remarkably similar factors impact on growth in pediatric kidney, liver, and heart recipients. Age is a primary factor, with younger recipients exhibiting the greatest immediate catch-up growth. Graft function is a significant contributory factor: a reduction in glomerular filtration rate (GFR) correlates with poor growth in kidney recipients, and the need for re-Tx is associated with impaired growth in liver recipients. The known adverse impact of corticosteroids on growth has led transplant physicians/surgeons to either modify the dose or attempt steroid withdrawal. In kidney and liver recipients this is associated with the development of acute rejection episodes. In infant heart transplant recipients the avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of recipients. With the marked improvement in patient and graft survival rates in pediatric solid-organ graft recipients, it is timely that the quality-of-life issues receive paramount attention. In children, normal growth following solid-organ Tx should be an achievable goal that results in normal final adult height.     

Outcomes following liver transplantation

As the field of Liver Transplantation has matured, survival alone is no longer an acceptable single metric of success. This chapter explores the impact of the PELD system for donor organ allocation, surgical modification of donor organs, living donation, and long-term transplant-related complications on overall quality of life and outcome. Strategies to improve survival, overall outcome, and health-related quality of life in long-term recipients are outlined.     

儿童多米诺肝移植初步报告

目的探讨儿童多米诺肝移植的可行性和安全性。方法将一成人左外叶移植给家族性高胆固醇血症3岁男性患儿，同时采用多米诺肝移植技术将该患儿的肝脏移植给先天性胆道闭锁4个月女性患儿。结果家族性高胆固醇血症患儿的血清总胆固醇及低密度脂蛋白于术后第三天降至正常范围，手术后第8天死于心力衰竭。先天性胆道闭锁患儿随访16个月，肝肾功能化验正常，血清总胆固醇及低密度脂蛋白分别为8．87mmol／L和6．21mmol／L，明显低于多米诺供体患儿的术前水平。结论尽管术后多米诺受者出现获得性高胆固醇血症，但FHC可以作为多米诺供肝，近期效果满意，远期效果需进一步观察。     

Living-donor liver transplantation in children

With evolution of surgical technique, advances in immunosuppression, and better understanding of pre- and post-operative care, the 1-yr survival rate after liver transplantation in children has reached 85-90%. As a result, a greater number of patients have been listed for transplantation and waiting times have lengthened. Innovative techniques such as reduced-size, split, and living-donor liver transplantation are being applied more often to decrease long waiting times and reduce associated morbidity and mortality. In this review, living donor liver transplantation in pediatrics is described. Special issues, such as donor and recipient selection, surgical procedures in donors and recipients, and ethical issues, are discussed.     

Growth,body composition,and bone density following pediatric liver transplantation

Patients transplanted for cholestatic liver disease are often significantly fat‐soluble vitamin deficient and malnourished pretransplant, with significant corticosteroid exposure post‐transplant, with increasing evidence of obesity and metabolic syndrome post‐LT. Our study aimed to assess growth, body composition, and BMD in patients post‐pediatric LT. Body composition and bone densitometry scans were performed on 21 patients. Pre‐ and post‐transplant anthropometric data were analyzed. Bone health was assessed using serum ALP, calcium, phosphate, and procollagen‐1‐N‐peptide levels. Median ages at transplant and at this assessment were 2.7 and 10.6 years, respectively. Physiological markers of bone health, median z ‐scores for total body, and lumbar spine aBMD were normal. Bone area was normal for height and BMAD at L3 was normal for age, indicating, respectively, normal cortical and trabecular bone accrual. Median z ‐scores for weight, height, and BMI were 0.6, ?0.9, 1.8 and 0.6, 0.1, 0.8 pre‐ and post‐transplant, respectively. Total body fat percentages measured on 21 body composition scans revealed 2 underweight, 7 normal, 6 overweight, and 6 obese. Bone mass is preserved following pediatric LT with good catch‐up height. About 52% of patients were either overweight/obese post‐transplant, potentially placing them at an increased risk of metabolic syndrome and its sequelae in later life. BMI alone is a poor indicator of nutritional status post‐transplant.     

Glomerular and tubular function following orthotopic liver transplantation in children treated with tacrolimus

The aim of this study was to analyze the impact of TAC on medium term (three-yr follow-up) renal function in pediatric liver transplant (OLT) recipients. Glomerular and tubular indices were retrospectively analyzed in 24 consecutive OLT pediatric recipients on TAC. CrCl increased significantly each month post-OLT (p = 0.003), with a trend toward significance between pre-OLT and 36 months (p = 0.17). There was no correlation between CrCl and TAC troughs (p = 0.783). Sixteen percent of patients had CrCl <60 mL/min/1.73 m(2) pre-OLT vs. none at 36 months post-OLT. TRP values were normal throughout the study. UPr/Cr decreased insignificantly over time and correlated significantly with TAC trough levels (p = 0.031). UCa/Cr values normalized by the third-month post-OLT, decreasing significantly over the time (p = 0.000) but did not correlate with TAC troughs. At three months post-OLT, 65.2% of patients needed antihypertensive therapy, and no patients needed more than one antihypertensive treatment after one yr. Despite nephrotoxic side effects in the early postoperative phase, this study shows that 65.5% patients had a normal renal function by three yr post-OLT. Tubular indices correlated with TAC trough levels.     

Growth factors in children with end-stage liver disease before and after liver transplantation: a review

Growth failure is a common observation in children with end-stage liver disease (ESLD). The liver is an important endocrine organ producing potent anabolic growth factors such as IGF-I (insulin-like growth factor-I) and its major binding-proteins, called IGFBP-1, -2 and -3. Circulating IGF-I and IGFBP-3 levels are low in children with chronic liver failure despite increased GH secretion. This discrepancy suggests that GH resistance is present in chronic liver failure and is mainly due to the associated malnutrition. The advent of orthotopic liver transplantation (OLT) has dramatically improved the life expectancy of children with ESLD. Nevertheless, the growth of 15-20% of the children in recent studies remains poor after successful transplantation. Several factors such as age and height deficit at the time of OLT, etiology of the liver disease and graft function as well as the dose and mode of administration of glucocorticoids have been implicated in the lack of complete catch-up growth following surgery. Few studies have explored the possibility that anomalies in the GH-IGF-I cascade could explain growth retardation. However, it is unlikely that major anomalies of the GH-IGF-I axis contribute to impaired growth. Treatment with GH alone or in combination with IGF-I before or after OLT may improve the growth of children. Randomized multi-center studies are needed to address this issue.