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.     

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.     

Hyperuricemia after liver transplantation in children

Uric acid may be involved in the development and progression of kidney diseases. Hyperuricemia is a common feature in adult liver transplant recipients but there is limited information in children. In order to estimate the incidence, predictors of hyperuricemia in pediatric liver transplant recipients, and to assess whether hyperuricemia may impact long-term renal function determined by measured GFR, we reviewed data of 70 children who received a first liver transplant between 1991 and 2005 (median follow-up 7.1 yr). Renal function tests performed annually included uric acid concentration, inulin and uric acid clearances. The cumulative incidence of hyperuricemia was 32% at 10-yr post-transplantation, mainly because of decreased urate excretion. The only factor significantly associated with an increased risk of hyperuricemia was older age. After adjustment for donor and recipient age, gender, primary liver disease, immunosuppression, and post-operative acute renal failure, hyperuricemia as time dependent variable tended to predict (p = 0.05) subsequent CRI. The control of serum urate concentration in eight of the 21 hyperuricemic patients either by nutritional management or by allopurinol was not followed by a significant GFR improvement. Hyperuricemia after liver transplantation in children is a frequent problem which needs further investigation.     

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.     

Glomerular filtration rate in liver transplant for unresectable hepatoblastoma

Most children with hepatoblastoma manifest, at the time of LT, a decrease in renal function due to chemotherapy that could be further deteriorated by the use of calcineurin inhibitors. The purpose of this work was to examine the long‐term follow‐up of renal function in a cohort of children transplanted for unresectable hepatoblastoma. We present a retrospective observational study of 10 pediatric patients who received a LT for unresectable hepatoblastoma between 1996 and 2016. All patients included in this study were followed up on a regular basis and were assessed for GFR before transplantation and at least once a year during follow‐up. All patients received standardized chemotherapy treatment for hepatoblastoma and immunosuppression according to hospital protocols. There was a marked decrease in GFR at the time of the LT in five patients presenting renal complications during the pretransplant cycles of chemotherapy. Three patients, one of them with prior kidney involvement, presented complications after LT, namely acute kidney failure and decrease in GFR. Those patients who presented with the lowest GFR at the time of LT eventually recovered renal function at levels similar to the rest of the group on follow‐up. Chemotherapy‐induced nephrotoxicity is a concern in patients treated for hepatoblastoma. Some individuals will develop low GFR after chemotherapy; therefore, strict follow‐up is recommended, as low GFR may affect the doses of subsequent chemotherapy and immunosuppression. Stabilization of GFR levels and occasional improvement can be observed in the post‐transplant period.     

Evaluation of renal functions in pediatric liver transplantation

AKI is an important complication after LT. As our LT series contains a quite high number of children with ALF unlike published studies, we aimed to determine pre‐LT and long‐term renal functions in children both with ALF and with CLD. Demographic and disease‐related data of 134 transplanted children were evaluated retrospectively. Pre‐LT and follow‐up GFR and pediatric RIFLE scores were determined. Mean pre‐LT GFR was not dependent on the disease presentation or severity of chronic disease. While there was an initial decline until first week of post‐LT in CLD children, an increase was observed in ALF. Neither mean GFR nor the pRIFLE on follow‐up was different with respect to the type of LT or disease presentation. Mean GFR at first and sixth months were lower in children on cyclosporine compared to tacrolimus (p = 0.001 and p = 0.002, respectively). In conclusion, GFR–time curve was different in children with or without ALF. Type of LT, and severity of the CLD were not risk factors for CKD in any time, but younger age at LT, CLD, and cyclosporine usage were at sixth months of follow‐up.     

Comparison between effects of cyclosporine and tacrolimus on glomerular filtration rate in pediatric post-orthotopic liver transplant patients

Tacrolimus (FK506) and cyclosporine, synonymous with immunosuppressive therapy in organ transplantation, are not spared of potential adverse effects such as nephrotoxicity. We retrospectively compared their effects on cGFR in a post-OLT pediatric population. cGFRs of 32 patients from the LTUNUHS either on tacrolimus (group 1) or cyclosporine (group 2) from pretransplantation, transplantation and 3, 6, 9, 12, 18, 24, 30 and 36 months post-transplantation were compared. 95% CI and p-values were calculated for comparison with p < 0.05 considered significant. Longitudinal data analysis revealed no significant cGFR difference between groups 1 and 2 (p = 0.154). However, there was a significant difference in cGFR with time after transplantation (p < 0.0001). The mean difference score between both treatment groups was 277.92 (95% CI = 88.13-643.97). The survival rate post-OLT was 84.4%. In this retrospective sex-matched case controlled study of LTUNUHS patients, there was no difference between tacrolimus and cyclosporine on renal function. However, there was significant difference in cGFR with time post-OLT (p < 0.0001). The reason for this observation could be multifactorial.     

Renal function following liver transplantation for unresectable hepatoblastoma

Combination of cyclosporine (CsA) and tacrolimus immunosuppression post-liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty-six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre- and post-LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2, respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT.     

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.     

Renal tubular dysfunction following treatment with anti-epileptic drugs

To evaluate renal side-effects of anti-epileptic medication in children, we performed a cross-sectional study of various aspects of renal function. We studied 59 patients from our outpatient clinic. They had been on anti-epileptic monotherapy for at least 3 months. None had a history of renal disease. Twenty-three healthy children of the same age group served as controls. After collecting 24-h urine samples, glomerular function was derived from creatinine clearance and from the excretion of albumin. Proximal tubular function was investigated by the urinary excretion of 1-microglobulin and of the tubular enzymes N-acetyl-ß-D-glucosaminidase, alamine-amino-peptidase and fructose-1,6-di-phosphatase. Distal tubular function was examined by the 24-h excretion of Tamm-Horsfall protein. On treatment with carbamazepine (n=27) and phenytoin (n=8), the excretion of 1-microglobulin was significantly increased, as compared with the healthy controls. On valproate (n=20), ethosuximide (n=9) and phenytoin (n=8), therapies significantly increased excretion of N-acetyl-ß-D-glucosaminidase. This must be interpreted as an indication of a functional disturbance of the proximal tubulus. The other parameters, indicating function of the glomerulus, loop of Henle and distal tubules did not differ from normal.Patients on anti-epileptic treatment with therapeutic drug levels may demonstrate minor signs of tubular dysfunction. These are probably insignificant from a clinical standpoint, but they should be considered in drug overdose.     

Renal function outcome in pediatric liver transplant recipients

The orthotopic liver transplantation (OLT) allows survival of children followed for severe hepatic injury, provided that the immunosuppressive treatment is prolonged. The nephrotoxicity of cyclosporine predicts the long-term outcome of the adult patients receiving a liver transplant. The aim of this study was to determine the long-term outcome of renal function in children receiving OLT. This study included 12 children, with a median for age of 7.1 yr (2-15 yr) at the time of OLT. The duration of follow-up was at least 4 yr, being 7 yr in 10 patients and more than 10 yr in seven. Renal function was evaluated with the serum level of creatinine, calculated glomerular filtration rate (cGFR), and measurement of glomerular filtration rate using chrome 51 ethylenediaminetetraacetate ((51)Cr EDTA) clearance performed at least once during follow-up. The doses and the serum concentrations (C(0)) of cyclosporine were reported at each study time. The cGFR decreased significantly 2 yr after the OLT [median (range): 106 mL/min/1.73 m(2) (71-150) at the time of OLT vs. 85 mL/min/1.73 m(2) (57-128) 2 yr after the OLT, p = 0.03], and decreased again between 7 and 10 yr after OLT [median (range): 99 mL/min/1.73 m(2) (76-125) 7 yr after OLT vs. 81 mL/min/1.73 m(2) (66-140) 10 yr after OLT, p = 0.04]. Six patients developed chronic renal failure (cGFR from 57 to 80 mL/min/1.73 m(2)) 2 yr after OLT associated with high doses of cyclosporine [median (range): 8.8 mg/kg/day (3.5-13)]. The cGFR overestimated renal function by 16% compared with the isotopic measurement of GFR (p = 0.03). Using the (51)Cr EDTA measurement, six of seven patients followed up more than 10 yr after OLT presented mild (n = 3) or moderate (n = 3) chronic renal failure. In our study, the majority of OLT recipients developed a chronic renal failure 10 yr after transplantation. Cyclosporine seems to be the most important factor responsible for the impairment of renal function. The use of the mycophenolate mofetil, a new immunosuppressive agent, allowing a reduction in the dose of cyclosporine, could minimize renal dysfunction. While awaiting the results of a prospective long-term study, close drug monitoring is advised.     

Renal function after combined liver‐kidney transplantation: A longitudinal study of pediatric and adult patients

It has been proposed that the liver protects the kidney in CLKT. However, few studies have examined long‐term renal function after CLKT and contrasted renal function of CLKT patients to KT patients beyond one year after transplantation. We studied long‐term renal function of CLKT patients and compared renal function of CLKT patients to KT patients between one and five years after transplantation. Patients who underwent CLKT between 1993 and 2011 were included (n = 34; 11 children and 23 adults). Ninety‐six (27 children and 69 adults) KT patients were selected as controls. GFR was estimated (eGFR) and measured (mGFR) with ⁵¹Cr‐EDTA clearance. Mean mGFR was 63 at one and 70 at ten years after pediatric CLKT. Mean eGFR was 75 at one and 50 at ten years after adult CLKT. Difference in mean mGFR between pediatric CLKT and KT patients was 8 (95% CI ?7 to 23) and 11 (95% CI ?4 to 26) at one and five years after transplantation, respectively. Difference in mean eGFR between adult CLKT and KT patients was 8 (95% CI ?5 to 20) and 1 (95% CI ?10 to 12) at one and five years after transplantation, respectively. Longitudinal changes in GFRs were somewhat similar in CLKT and KT patients in both age‐groups but pediatric CLKT patients had on average higher GFRs than pediatric KT patients. In long‐term follow‐up, renal function remains stable in pediatric CLKT patients but declines in adult CLKT patients.     

Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection

Several factors may contribute to post-transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus-based immunosuppression following liver transplantation and all of them suffered from previous steroid-resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid-resistant graft rejection, even if given in therapeutic doses.     

不同性别、年龄组儿童肾小球滤过率分布情况

目的了解肾小球滤过率（GFR）在不同性别及年龄组儿童中的分布情况。方法2006年6月随机抽取南宁市健康体检儿童184例。记录其身高、体质量，根据体质量指数（BMI）除外肥胖和营养不良儿童；检测其血浆肌酸酐（Cr），通过询问病史及schwartz公式推算GFR，除外泌尿系统疾病。结果1．GFR在儿童期有明显性别差异，女童GFR显著高于男童（P〈0．05）；2．GFR在儿童期有显著年龄差异，幼儿期、学龄前期及学龄期波动较小，至青春期前达到高峰。结论不同性别、年龄组儿童GFR存在明显差异，建议根据GFR在儿童期的分布特征制订适合于儿科临床使用的正常值范围。     

Glomerular filtration rate as a putative 'surrogate end-point' for renal transplant clinical trials in children

Only with prospective randomized controlled trials is it possible to evaluate the several immunosuppressive regimens available to renal allograft recipients. Commonly used surrogate markers of clinical outcome, such as patient and graft survival, are constantly improving. Current immunosuppressive protocols have improved 1-yr graft survival to over 90%. The small differences in graft survival among the various immunosuppressive regimes require large patient cohorts in order to establish statistical significance. Such studies are often difficult to conduct in a timely manner, particularly in children. This necessitates the search for better surrogate markers sensitive enough to detect differences in smaller cohorts and in a shorter period of time. While the degree of fibrosis in transplant biopsies might well predict long-term graft survival, protocol biopsies are expensive, invasive, and unpopular among clinicians. In native kidneys, glomerular filtration rate (GFR) closely correlates with disease progression and interstitial fibrosis and appears to be well positioned as a less invasive surrogate marker for long-term outcome. Nonetheless, the ideal marker for GFR remains obscure. Serum creatinine has several major drawbacks, making it a poor predictor of GFR. This review discusses the several methods used to estimate or measure GFR with emphasis on 125I-iothalamate clearance and serum cystatin C (cys-C). Of all the serum markers, cys-C is the most reliable and the most promising. However, cys-C and other endogenous markers cannot replace the diagnostic sensitivity and reliability of radiolabeled markers of GFR such as 125I-iothalamate in renal transplant clinical trials. Unfortunately, clearance of most radiolabeled markers of GFR including 125I-iothalamate remain costly and time consuming.     

Risk factors for chronic anemia in pediatric orthotopic liver transplantation: analysis of data from the SPLIT registry

Risk factors for chronic anemia in the post-transplant period have not been clearly delineated in pediatric liver transplant recipients. We analyzed data from children transplanted from 2000 to 2008 with at least two consecutive hemoglobin values from follow-up between six months and five yr post-transplant. A multivariate model was derived to determine independent risk factors associated with chronic anemia. Of 1026 children in this analysis, 242 (23.6%) were found to have chronic anemia. On multivariate analysis, GI bleeding (OR 11.83 [2.08-67.49], p = 0.0054), presence of leukopenia (OR 9.55 [95% CI 3.71-24.62], p < 0.0001), use of cyclosporine (OR 3.69, [95% CI 1.56-8.76], p = 0.0039) and corticosteroids (OR 2.90 [95% CI 1.94-4.33], p < 0.0001), and cGFR <90 mL/min/1.73 m(2) (OR 4.62 [95% CI 2.47-8.67], p < 0.0001) represented the most significant risk factors for chronic anemia. Use of antihypertensive medications (OR 1.89 [95% CI 1.23-2.91], p = 0.0039) was also significantly associated with a higher risk. In summary, chronic anemia is common in children following liver transplant. Our findings underscore the need to define the mechanisms by which these risk factors, some of which are modifiable, result in chronic anemia in pediatric liver transplant recipients.     

Successful recovery of aplastic anemia following orthotopic liver transplantation for non-A-E acute liver failure

This report describes a teenager who developed aplastic anemia (AA) because of non-A-E acute liver failure (ALF) requiring orthotopic liver transplantation (OLT). His AA did not recover spontaneously and he required treatment with ATG 9 months post-OLT. Bone marrow recovery occurred 4 months after immunotherapy and coincided with further intensification of immunusuppression required to treat early chronic rejection of the liver graft. Three years post-OLT he remains well with good bone marrow and liver function. Intensification of immunosuppression can lead to successful resolution of AA associated with non-A-E ALF.     

Orthotopic liver transplantation for children with Alagille syndrome

Arnon R, Annunziato R, Miloh T, Suchy F, Sakworawich A, Hiroshi S, Kishore I, Kerkar N. Orthotopic liver transplantation for children with Alagille syndrome.
Pediatr Transplantation 2010: 14:622–628. © 2010 John Wiley & Sons A/S. Abstract: AGS is an inherited disorder involving the liver, heart, eyes, face, and skeleton. Aim: To determine the outcome of LT in children with AGS compared to those with BA. Methods: Children with AGS and BA who had a LT between 10/1987 and 5/2008 were identified from the UNOS database. Results: Of 11 467 children who received a liver transplant, 461 (4.0%) had AGS and 3056 (26.7%) had BA. One‐ and five‐yr patient survival was significantly lower in patients with AGS in comparison with patients with BA (AGS; 82.9%, 78.4%, BA; 89.9%, 84%, respectively). Early death (<30 days from transplant) was significantly higher in AGS than in BA. One‐ and five‐yr graft survival was significantly lower in AGS than in BA (AGS; 74.7%, 61.5%, BA; 81.6%, 70.0%, respectively). Death from graft failure, neurological, and cardiac complications was significantly higher in patients with AGS than in patients with BA. Serum creatinine at transplant, prior LT, and cold ischemic time >12 h were identified as risk factors for death. Conclusion: Children with AGS were older at the time of LT and their one‐ and five‐yr patient and graft survival were significantly lower compared to BA. Risk factors for poor outcome in AGS after LT were identified.