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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 Cr-51-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.

Few studies compare HRQOL and PSA in children who have undergone different types of solid organ Tx. In this cross-sectional study, HRQOL and PSA were assessed in 74 Tx patients (16 heart, 44 kidney, 14 liver) at a mean age of 11.5 (range 6.3-16.7), 7.2 yr post-Tx (range 1.0-15.0). HRQOL was self-assessed using standardized health utility questionnaires (15D-17D). The patients' PSA was evaluated using the Child Behavior Checklist for parents, Youth Self-Report for patients aged 11-16 yr, and Teacher Report Form. Outcomes did not differ significantly between Tx groups. Preadolescents (8-11 yr) reported poorer HRQOL compared with same-age peers (p = 0.020). In contrast, adolescents reported similar HRQOL and PSA compared to the general population. Proxy-reports revealed more PSA problems compared with age expectations (p < 0.01), mainly in internalizing behavior (p < 0.01). Lower HRQOL was associated with shorter follow-up time since Tx, congenital disease, and a psychiatric or neurological diagnosis. PSA problems were associated with family- related variables, neurological diagnosis, shorter follow-up time, and in teacher-reports longer disease duration before Tx. Different pediatric Tx groups have similar outcome. Neurological comorbidity and shorter follow-up time are important risk factors, but the impact of family- related variables on PSA indicate the need of family interventions.

Subclinical rejection may be associated with decreased graft function after renal transplantation (Tx). Detection by protocol biopsies and treatment could thus be important for the long-term prognosis. We have earlier discovered that glomerular filtration rate (GFR) declined in young children during the first 18 months. Consequently, we slightly enhanced and individualized each patient's immunosuppression. This was a retrospective study of 59 pediatric renal Tx patients between 1995 and 2001. The 35 historical controls received triple-therapy of azathioprine, methylprednisolone and cyclosporine. GFR was measured by protocol at discharge, 6 and 18 months, and a core biopsy was obtained at 18 months. The 24 study patients in addition received basiliximab, had GFR measured at 3 and 12 months, and a biopsy taken at 3 months. Based on histology and function, immunosuppression was individually adjusted. The groups were compared for GFR and histology at 18 months after Tx. There were less acute rejection episodes in the study group (0.38 vs. 1.23 per patient) and serum creatinine concentrations were lower. Subclinical rejection was detected and treated in 39% at 3 months. There were more chronic changes in the control (47%) than in the study group (29%) at 18 months. GFR was significantly higher in the study group at 18 months (87 vs. 68 mL/min/1.73 m(2)), most remarkably in patients < or =2 yr of age (99 vs. 68 mL/min/1.73 m(2)). Detection of subclinical rejection and slightly enhanced and individualized immunosuppression improved GFR 18 months after renal Tx, especially in the youngest patients.

Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age ( 8 yr), according to the predicted dose (within or outside ±25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m 2 /d) for patients 8 yr old] but the average B-CsA remained in the target range of 250-450 μg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R 2 = 0.70) and adjustments to dosing were made during the next weeks (R 2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R 2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients < 2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.

The clinical manifestations of different complications after organ transplantation (Tx) are often vague, and simple laboratory tests for early diagnosis would be valuable. In this work we retrospectively analyzed our data on the daily measurements of serum C-reactive protein (CRP) in 132 children after 63 liver and 83 kidney Txs. A total of 3,886 CRP measurements were performed and 353 episodes of elevated CRP were recorded. One-third of these were regarded as a response to surgery. The CRP level normalized within 5-10 days post-operatively in patients who had a favorable outcome, but in patients with a poor outcome CRP tended to remain elevated. Half of the CRP elevations were associated with complications such as acute rejection, infection or thrombotic events. An elevated serum CRP level was found in 68% of the rejection episodes, in 88% of the bacterial infections, and in 73% of the viral infections. The most significant elevations were associated with bacterial infection. In nine of 11 vascular complications, an elevation of CRP was also recorded. Serum CRP responded to rejection therapy in 86% of the episodes. The initial CRP level did not predict steroid-resistant rejection. CRP seemed to be a more sensitive marker than fever or white blood cell (WBC) count in all complications. We conclude that the daily measurement of serum CRP is a simple and fairly sensitive, but non-specific, method for detecting rejection and infectious complications after pediatric liver and kidney Tx.

Patient and graft survival rates of pediatric renal transplant recipients are currently excellent, but there are few reports regarding the long-term neurodevelopmental outcome after renal transplantation (Tx) in early childhood. Children with renal failure from infancy would be expected to have a less favorable developmental prognosis. We report the neurodevelopmental outcome in 33 school-age children transplanted between 1987 and 1995 when < 5 yr of age. We prospectively performed a neurological examination, magnetic resonance imaging (MRI) of the brain, electroencephalograms (EEGs), audiometry, and neuropsychological tests (NEPSY), and measured cognitive performance (WISC-R); we related these results to school performance and to retrospective risk factors prior to Tx. Twenty-six (79%) children attended normal school and 76% had normal motor performance. Six of the seven children attending a special school had brain infarcts on MRI. The EEG was abnormal in 11 (35%), and five (15%) received anti-convulsive treatment after Tx. Sensorineural hearing loss was documented in six patients. The mean intelligence quotient (IQ) was 87, and 6-24% showed impairment in neuropsychological tests. The children attending a special school had been more premature, but had not had a greater number of pre- or neonatal complications. They had experienced a greater number of hypertensive crises (p = 0.002) and seizures (p = 0.03), mainly during dialysis, but the number of septic infections and the mean serum aluminum levels were not significantly greater than in the children with normal school performance. In these previously lethal diseases, the overall neurodevelopmental outcome is reassuring. However, it is of crucial importance to further minimize the risk factors prior to Tx.

A minority of children with liver transplants exhibit significant delay in global intelligence; others have specific learning disabilities. More specific data on neurocognitive strengths and weaknesses are lacking. Eighteen children aged 7-16 yr, who had undergone LTx in Finland participated in the study. They were assessed on an average 7.6 (s.d. 4.5, range 1.0-15.0) years post-operatively at a mean age of 11.8 (s.d. 3.1, range 7.2-16.1). A standardized test of intelligence (WISC-III), a neuropsychological test battery (NEPSY-II), and a parental questionnaire on the child's development (FTF) were administered. The neuropsychological test profile of the LTx group was compared with that of a matched control group of healthy children. The LTx children achieved on an average normal FSIQ 94.0 and VIQ 99.6. Their Performance Intelligence Quotient (PIQ 88.9, p=0.043) was, however, significantly lower than the population mean. On neuropsychological assessment, the LTx children scored generally lower than the control group (p=0.004), a difference significant in sub-tests assessing visuospatial and visuoconstructive functions and social perception. No differences emerged in sub-tests of attention and executive functions, memory and learning, or language functions. LTx children are at increased risk for impairment in the visuospatial domain.

A minority of children with liver transplants exhibit significant delay in global intelligence; others have specific learning disabilities. More specific data on neurocognitive strengths and weaknesses are lacking. Eighteen children aged 7-16 yr, who had undergone LTx in Finland participated in the study. They were assessed on an average 7.6 (s.d. 4.5, range 1.0-15.0) years post-operatively at a mean age of 11.8 (s.d. 3.1, range 7.2-16.1). A standardized test of intelligence (WISC-III), a neuropsychological test battery (NEPSY-II), and a parental questionnaire on the child's development (FTF) were administered. The neuropsychological test profile of the LTx group was compared with that of a matched control group of healthy children. The LTx children achieved on an average normal FSIQ 94.0 and VIQ 99.6. Their Performance Intelligence Quotient (PIQ 88.9, p=0.043) was, however, significantly lower than the population mean. On neuropsychological assessment, the LTx children scored generally lower than the control group (p=0.004), a difference significant in sub-tests assessing visuospatial and visuoconstructive functions and social perception. No differences emerged in sub-tests of attention and executive functions, memory and learning, or language functions. LTx children are at increased risk for impairment in the visuospatial domain.

The prevalence and characteristics of headache were studied in a national cohort of 177 pediatric patients with kidney, liver, and heart transplants. All patients received triple drug immunosuppression with CsA, Aza, and MP. Data on headaches were collected by sending two questionnaires and reviewing the medical records. Statements on headache were found in the medical records of 46% of the patients. According to a questionnaire, two thirds had experienced headaches sometime after transplantation, and 40% had present headaches. The episodes had significantly affected the quality of life in a third of the patients, and resulted in neurological examination in 15%. Most of the subjects (61%) described typical episode as mild or moderate, and 39% as severe or very severe. The usual episodes lasted4 h in 73% of the patients and4 h in 27%. The headache could be classified as migraine, probable migraine or headache without specific features in 33%, 31%, and 36%, respectively. Most patients (82%) had used pain-killers, mainly acetaminophen and ibuprofen. Headache episodes may significantly impair the quality of life in children and adolescents after organ transplantation.

The levels and protein/lipid compositions of major lipoprotein particles of 19 pediatric cardiac transplant recipients (4–18 yr of age) were studied in this prospective, open clinical follow-up study before and at one yr of pravastatin therapy (10 mg/day). The recipients were grouped into those with (n = 6; group A) and those without (n = 13; group B) angiographically detectable vasculopathy. Twenty-one pediatric non-transplant controls were studied at baseline. At baseline, the group A recipients had 29% lower HDL-C concentrations (p = 0.031) and 29% higher apoB-100/apoA-I ratios (p = 0.034) than the group B recipients. At one yr of pravastatin, the respective figures were 29% (p = 0.013) and 33% (p = 0.005). Compared with the healthy pediatric controls, the transplant recipients had significantly higher serum TG before pravastatin [median (range): 1.3 mmol/L (0.6–3.2) vs. 0.7 mmol/L (0.3–2.4), p = 0.0002] and at one yr [1.3 mmol/L (0.5–3.5) vs. 0.7 mmol/L (0.3–2.4), p = 0.0004]. The baseline apoB-100/apoA1 ratios of the recipients were 33% higher (p = 0.005). In conclusion, low HDL-C and high apoB-100/apoA-I ratio were associated with angiographically detectable vasculopathy. Even though pravastatin effectively lowered the TC and LDL-C and improved compositional properties of LDL and HDL2 particles, it failed to normalize the elevated TG and, in some patients, to prevent the progression of transplant vasculopathy.

Psychosocial adjustment and quality of life has been reported good in children after a successful renal transplantation (Tx). There are, however, few reports of using standardized methods in evaluating these issues, particularly in small children. We investigated the psychosocial adjustment in 32 children at school age (mean 9.6 +/- 1.6), who had received a renal Tx under the age of 5 yr, using the Achenbach Child Behavior Checklist with data collected from both parents (CBCL) and teachers (CBCL-TRF). Health-related quality of life (HRQOL) was assessed by interviewing the children using a 17-dimensional (17D) health-related measure and compared to HRQOL of 244 normal school children. The effect of additional diseases and comorbidity on psychosocial adjustment and HRQOL was assessed. The total scores on the CBCL did not differ from normative samples of healthy children. However, somatic complaints and social problems were reported more frequently in boys, and attention problems in both boys and girls. Patients with pathological scores had significantly more comorbidity (p = 0.03) and were more often attending a special school (p = 0.007) than patients with normal scores. The global 17D HRQOL index was significantly lower than measured in healthy controls (94 +/- 5 for controls and 85 +/- 7 for patients, p < 0.0001). It is of crucial importance to further minimize the risk factors leading to comorbidity in children after Tx. HRQOL assessment by the children themselves can be used to direct interventions and support the children's psychosocial adjustment.

Chronic renal failure (CRF) is known to have adverse effects on the neurodevelopmental outcome of affected children. Some of these effects can be ameliorated by transplantation (TX). The cause and nature of the underlying brain injury is not known. We performed a brain magnetic resonance imaging (MRI) study on a group of children after TX to look for brain abnormalities and, if possible, to draw conclusions about their origin. Thirty-three children who received a renal allograft before 5 yr of age were studied. The most common diagnosis was the congenital nephrotic syndrome of Finnish type (29 patients). The male/female ratio was 22/11, the age range 6–11 yr. Pre-TX CT studies of 26 patients were available for comparison. The patient files were studied for relevant clinical history, including pre- and perinatal events, infections, hypertension, hypertensive crises, hypovolemic states and medical emergencies. These risk factors were correlated with the MRI findings. Eighteen patients (54%) had ischemic lesions in the vascular border zones. Mild lesions were seen in 10 patients, moderate in six and severe in two patients. Other findings were rare, including infarcts in the main vascular territories and basal ganglia, and central and cortical atrophy. The pre-TX CT's revealed border zone infarcts in six patients. Hemodynamic crises were reported in 14 patients and correlated well with border zone infarcts. The age at TX was greater and the duration of dialysis longer in those with border zone infarcts than in those without. Low gestational age, perinatal complications, and septic infections were not statistically significant risk factors. Because of the lack on serial imaging studies we do not know the exact timing of these brain infarcts. The good correlation to pre-TX hemodynamic crises seems, however, to indicate that most of these lesions could be prevented by careful clinical monitoring and early TX.

Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age (2, 2-8 and8 yr), according to the predicted dose (within or outside +/-25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m2/d) for patients2, 2-8, and8 yr old] but the average B-CsA remained in the target range of 250-450 microg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R2 = 0.70) and adjustments to dosing were made during the next weeks (R2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.