Erik Qvist

Neurodevelopmental outcome in high-risk patients after renal transplantation in early childhood

Abstract: 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.

Graft function 5-7 years after renal transplantation in early childhood.

BACKGROUND Low recipient age is still a risk factor for graft failure after kidney transplantation (Tx). Detailed prospective reports on long-term graft function in small children after renal Tx are still lacking. METHODS Forty-nine kidney allograft recipients who received transplants before the age of 5 years were followed prospectively. The most common disease was congenital nephrotic syndrome of the Finnish type. Twenty patients were recipients of living related donors (LRD), and 29 were cadaveric kidney (CAD) recipients. All patients received triple immunosuppression. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), sodium, urate, and potassium handling, and concentrating capacity were studied for up to 7 years after Tx. RESULTS Patient survival 7 years after Tx was 100% for LRD and 96% for CAD recipients. Graft survival was 94% for LRD and 79% for CAD recipients (P=NS) and 89% and 83% for children >2 years and <2 years of age at Tx, respectively (P=NS). Five years after Tx, GFR was 70 vs. 64 and ERPF was 380 vs. 310 ml/min/1.73 m2 for LRD and CAD recipients, respectively (P=NS). Mean absolute GFR remained stable. GFR was lower in children who received transplants at <2 years than in children who received transplants at >2 years of age, 54 vs. 75 ml/min/1.73 m2 (P=0.02). Sodium handling remained intact, but hyperuricemia was seen in 43-67%; 17-33% showed abnormal handling of potassium; and most patients had a subnormal concentrating capacity. CONCLUSIONS Excellent long-term graft survival and good graft function can be achieved with triple immunosuppression, even in young CAD kidney recipients.

Neuroradiologic findings in children with renal transplantation under 5 years of age.

Abstract:  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 CTs 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.

Neuropsychological profile of children with kidney transplants

BACKGROUND Varying results on the cognitive outcome of children who have undergone kidney transplantation (KTx) have raised concern for specific neurocognitive difficulties. METHODS Fifty children with KTx were assessed at a mean age of 11.1 (SD 3.2; range 6.3-16.4), on average 6.9 (SD 3.6; range 1.0-14.1) years post-operatively. A standardized test of intelligence [Wechsler Intelligence Scale for Children (WISC-III)] and neuropsychological tests from NEPSY-II were administered. The neuropsychological profile of KTx children was compared to that of a control group matched for gender, age and maternal education. RESULTS The KTx children had a lower intelligence quotient (83.9) than the test norms (100.0, P < 0.001). On neuropsychological assessment, the KTx group scored generally lower than the control group did (P < 0.001). The difference was evident in both the verbal and visuospatial domains, on a sub-test of complex auditory attention, verbal working memory and facial affect recognition. When children with neurological co-morbidity were excluded, the remaining group still scored lower than the controls did on Comprehension of Instructions (P = 0.06), Design Copying (P = 0.007) and Affect Recognition (P = 0.018). A better cognitive outcome was mainly associated with the absence of neurological co-morbidity, younger age, shorter disease duration and sustained kidney function. Children with congenital nephrosis had a similar outcome to those with other diagnoses. CONCLUSIONS KTx children exhibit a pattern of effects in their cognitive outcome in which both the visuospatial and language domains are affected, but visual memory and simple auditory attention remain intact. Patients without neurological co-morbidity exhibit impairment in receptive language, visuospatial functions and in recognizing emotional states.

Plasma exchange and retransplantation in recurrent nephrosis of patients with congenital nephrotic syndrome of the Finnish type (NPHS1).

Background. Recurrent nephrotic syndrome (NS) is a severe problem after renal transplantation in patients with congenital nephrotic syndrome of the Finnish type (NPHS1). The NPHS1 kidneys do not express nephrin, and antibodies against this major glomerular filter protein have been observed in NPHS1 children with recurrent NS. We evaluated here the use of plasma exchange (PE) therapy and kidney retransplantation in NPHS1 patients with recurrent NS and extended our studies on the pathogenesis of the recurrence. Methods. Clinical data on 65 NPHS1 patients who received 77 kidney transplants between the years 1986 and 2006 was collected. Serum anti-nephrin antibodies were assayed with an enzyme-linked immunosorbent assay method, and the kidney biopsy samples were evaluated by light microscopy and immunohistochemistry. Results. Twenty-three episodes of recurrent NS occurred in 19 grafts of 13 NPSH1 patients homozygous for Fin-major mutation. Six retransplantations were performed to four NPHS1 patients, who lost their graft because of recurrent NS, and heavy proteinuria developed immediately in all cases. Although 73% of the patients had detectable serum anti-nephrin antibodies, the kidney biopsy findings were minimal. Introduction of PE alongside cyclophosphamide proved effective in the treatment of the proteinuric episodes (one graft loss out of nine). If remission was achieved, recurrent NS did not significantly deteriorate the long term graft function. Conclusions. The clinical and pathological data suggest that anti-nephrin antibodies effectively impair the glomerular function in kidney grafts of NPHS1 patients homozygous for Fin-major mutation. Plasma exchange is a useful adjunct to the treatment of the recurrent NS.

Pubertal development is normal in adolescents after renal transplantation in childhood.

Background. This study was conducted to evaluate the pubertal development in adolescents after renal transplantation (RTx) in childhood. Methods. We performed a retrospective review of medical records of 109 RTx recipients (72 males) transplanted at the median age of 4.5 years (range: 0.9–15.8 years). Data on the clinical signs of puberty, growth, bone age, medication, and graft function of 98 patients were analyzed. Furthermore, serum levels of reproductive hormones in 87 patients were assessed to evaluate the progression and outcome of pubertal development. Results. The age at the onset of puberty averaged 12.7 years (range: 9.4–16.2 years) in 55 males and 10.7 years (range: 8.9–12.7 years) in 29 females. The mean age at menarche was 12.5 years (range: 10.5–14.5 years). Twenty-two percent of the boys and none of the girls had a moderately delayed onset of puberty. Children who underwent RTx before the age of 5 years reached puberty earlier than those transplanted at later age (boys 12.3±1.2 vs. 13.4±1.5 years, P<0.01; girls 10.3±0.9 vs. 11.0±1.0 years, P>0.05). The mean length of puberty was 3.9 and 4.7 years for boys and girls, respectively. The bone age was delayed in practically all, and final height was reached at the mean age of 18.1 and 16.0 years in boys and girls, respectively. Pubertal maturation resulted in acceptable final height and reproductive hormone status in great majority of the patients. Conclusion. Pubertal development was normal in all female and most male adolescents after RTx in childhood.

Blood Pressure Profiles 5 to 10 Years After Transplant in Pediatric Solid Organ Recipients

Arterial hypertension is a major risk factor for cardiovascular disease after solid organ transplantation, emphasizing the need for blood pressure (BP) monitoring. The authors studied 24‐hour ambulatory BP monitoring (ABPM) parameters (index, load, dipping) and their predictive value with regard to hypertension as well as correlations with graft function and metabolic parameters such as obesity and dyslipidemias. The ABPM profiles of 111 renal, 29 heart, and 13 liver transplant recipients were retrospectively analyzed 5 to 10 years after transplant (median 5.1 years). The BP profiles among the different transplant groups were similar. The BP index and load were abnormal especially at nighttime and the nocturnal BP dipping was often blunted (in 49% to 83% of the patients). The BP variables were found to be equally valued when assessing hypertension. BP load of 50% instead of 25% seems to be a more adequate cutoff value. The BP variables correlated poorly with the metabolic parameters and kidney function. Antihypertensive medication did not notably change the ABPM profile in renal transplant recipients. Hypertension, including nocturnal hypertension, is present in children receiving solid organ transplant, underlining the importance of use of ABPM in the follow‐up of these patients.

Quality of life in adult survivors of pediatric kidney transplantation.

Background. There are few studies assessing long-term adult outcome and health-related quality of life (HRQOL) in former pediatric high-risk kidney transplant (TX) recipients. Methods. Twenty-one patients were assessed at mean age of 21.1 years. Mean age at first TX was 2.4 years. Brain arterial border zone infarcts had been documented in 54% of the children. HRQOL was assessed with the general 15-dimensional (15D) instrument generating an index on a 0 and 1 scale (1 for best). The results were compared with the corresponding childhood 17-dimensional instrument and an adult control group from the general population. Psychosocial adjustment was assessed with the ASEBA Adult Self Report (ASR) and compared with the childhood Child Behavior Checklist assessments. Results. Half of the patients (52%) had a secondary level general or vocational education. The educational outcome was evenly distributed (compulsory vs. secondary) regardless of previous childhood brain ischemia. The ASR Total Problems score was in the normal range for all patients. Four patients had scores in the pathological range for Externalizing or Internalizing Problems. There was a correlation between the childhood Child Behavior Checklist problem scores and the adult ASR scores for Internalizing and Total Problems but not for Externalizing Problems. Their mean 15D HRQOL index was 0.94 and lower than for the control group (0.97, P=0.04). There was a strong correlation between the childhood 17-dimensional and the adult 15D HRQOL index (r=0.63, P=0.003). Conclusion. The long-term outcome is fair in former high-risk pediatric TX patients with neurological comorbidity. Childhood psychosocial adjustment and HRQOL may predict the outcome in adults.

Metabolic risk factors and long-term graft function after paediatric renal transplantation.

The aim of this study was to evaluate metabolic risk factors and their impact on long‐term allograft function in paediatric renal transplant (RTx) patients. We reviewed the medical records of 210 RTx patients who underwent transplantation at a median age of 4.5 years (range 0.7–18.2) and a median follow‐up of 7.0 years (range 1.5–18.0). Data on lipid and glucose metabolism, uric acid levels, weight and blood pressure were collected up to 13 years post‐RTx, and the findings were correlated with the measured glomerular filtration rate (GFR). Beyond the first year, GFR showed gradual deterioration with a mean decline of 2.4 ml/min/1.73 m2/year. Metabolic syndrome, overweight, hypertension and type 2 diabetes were diagnosed in 14–19%, 20–23%, 62–87% and 3–5% of the patients, respectively. These entities showed only mild association with the concomitant or long‐term GFR values. Dyslipidaemia was common and hypertriglyceridaemia associated with a lower GFR at 1.5 and 5 years post‐RTx (P = 0.008 and P = 0.017, respectively). Similarly, hyperuricaemia was frequent and associated significantly with GFR (P < 0.001). Except for hyperuricaemia and hypertriglyceridaemia, metabolic risk factors beyond the first postoperative year associated modestly with the long‐term kidney graft function in paediatric RTx patients.

A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A

AIMS Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. METHODS Patient records at the Childrens Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t90). RESULTS Data from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40 h mg l⁻¹), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t90 was 5.8 days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4 days (6.4-11.7) for short dialysis times (10th percentile). CONCLUSIONS A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.