A randomized prospective crossover trial of amlodipine in pediatric hypertension.

Amlodipine has potential advantages in children since it can be dissolved into a liquid preparation and has a long elimination half-life, allowing for once-daily administration. The objective of this study was to compare the efficacy and compliance of amlodipine with that of standard long-acting calcium channel blockers (felodipine or nifedipine) in hypertensive children. A randomized, prospective, crossover study of 11 hypertensive children (9-17 years of age, 10 renal transplant patients) was performed with electronic monitoring of compliance. Each treatment arm was 30 days. No significant differences were observed in mean systolic (SBP) and diastolic blood pressures (DBP) between amlodipine and the other calcium channel blockers. Using 24-h blood pressure monitoring there were no significant differences over each drug treatment period in both mean day-time and night-time SBP and DBP. Patient compliance was similar in both the amlodipine and the nifedipine/felodipine treatment periods. These data suggest that amlodipine is as effective in pediatric nephrology patients as nifedipine and felodipine. Amlodipine may be optimally suited for treatment of young children because at present it is the only calcium channel blocker which can be administered once daily as a liquid preparation.

Verotoxin targets lymphoma infiltrates of patients with post-transplant lymphoproliferative disease.

Post-transplant lymphoproliferative disease (PTLD) is an invasive, EBV expressing B lymphoma and a major cause of morbidity and mortality following organ transplantation. Presently there is limited therapy available; rather the patient often loses the allograft or succumbs to the malignancy. CD77 (or globotriaosyl ceramide -Gb(3)) is a germinal center B cell marker [Gregory et al. Int J Cancer 1998;42:213-20; Gregory et al., J Immunol 1987;139:313-8; Mangeney et al. Eur J Immunol 1991;21:1131-40], expressed on most EBV infected B cells and is the receptor for the E. coli derived verotoxin (VT) [Lingwood CA. Advances in Lipid Research 1993;25:189-212]. We present the basis of a possible novel approach to PTLD therapy utilizing the specific targeting of VT to the infiltrating lymphoma cells. Biopsies of adenoid, kidney or liver tissue of four PTLD patients were stained with verotoxin to determine expression of CD77. VT is a potent inducer of necrosis/apoptosis of receptor positive cells. In each PTLD case, the infiltrating EBV positive B lymphoma cells were strongly and selectively stained with VT, identifying CD77 as a new marker for these cells. For such individuals, VT might provide the basis of an approach to control their malignancy.

Acute plasmacytic interstitial nephritis in a child with Down syndrome.

A 7.5-year-old boy with Down syndrome presented in acute renal failure (ARF) needing dialysis. When 1.5 years old he had a neuroblastoma, was treated for 1 year with chemotherapy and radiotherapy, and off chemotherapy had since been in remission. Renal biopsy revealed an interstitial inflammation, principally of plasma cells with some lymphocytes and eosinophils. Immunofluorescence showed no deposition of immunoglobulins or complement (C3). The plasma cells were a mixture of kappa and lambda light chain-producing cells. The patient spontaneously improved a week after admission. Initial ultrasonography showed enlarged kidneys with loss of corticomedullary differentiation. We are unaware of a report of ARF in a child, resulting primarily from a polyclonal plasmacytic interstitial nephritis. The etiology remains unclear.

Efficacy of amlodipine in pediatric bone marrow transplant patients.

The calcium antagonist amlodipine may have the potential for expanded use in children owing to its physiochemistry and pharmacokinetic profile that facilitates once-daily dosing in a liquid formulation. Its safety and efficacy have not been previously evaluated in children. A retrospective analysis of 15 pediatric bone marrow transplant patients who had amlodipine incorporated into their antihypertensive drug regimen reveals significantly lower blood pressure as compared with baseline therapy (123.5+/-2.1 mmHg and 117.2+/-2.2 mmHg, systolic blood pressure before and during amlodipine, P<0.05; 81.5+/-1.8 mmHg and 75.5+/-2.6 mmHg, diastolic blood pressure before and during amlodipine, P<0.05). Amlodipine provided improved blood pressure control in this cohort and may provide a valuable pharmacologic alternative for treatment of pediatric hypertension.

Non-steroidal anti-inflammatory drug-associated nephrotoxicity in Bartter syndrome.

We have followed four patients with Bartter syndrome for a mean of 25.4 years (range 21.5-28.8 years) after diagnosis. All patients received non-steroidal anti-inflammatory drugs (NSAID). In all patients, various degrees of renal dysfunction were noted to be temporally associated with NSAID therapy. In two patients, renal dysfunction resolved after discontinuing NSAID therapy, while maintaining other chronic medications such as potassium-sparing diuretics. Renal dysfunction persisted after NSAID withdrawal in two patients. We report these cases as a warning that NSAID should be considered an important cause of either reversible or irreversible renal dysfunction in Bartter syndrome.

Compliance with cyclosporine in adolescent renal transplant recipients.

Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving > or = consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliance patients demonstrated low cyclosporine trough levels (< 50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance.

Cardiomyopathy: a late complication of hemolytic uremic syndrome.

This report describes a child who presented with classic hemolytic uremic syndrome (HUS) and 4 months later developed a life-threatening but reversible cardiomyopathy with global cardiac dysfunction and a left ventricular ejection fraction of 14%. There was no evidence of electrolyte abnormalities, anemia, hypertension, severe fluid overload, or viral infection. Endomyocardial biopsies were consistent with a dilated cardiomyopathy. This paper highlights the importance of considering the diagnosis of associated cardiomyopathy when presenting with late-onset edema following HUS.

Association of verotoxin-producing E. coli and verotoxin with hemolytic uremic syndrome.

It has been over 10 years since we first showed an association [1] between classical hemolytic uremic syndrome (hemolytic anemia, thrombocytopenia, and uremia, following a diarrheal prodome) and certain E. coli [1] capable of producing a toxin, initially called verotoxin (VT) because of its cytopathic effect on Vero cells [2] and later Shiga-like toxin (SLT) because of the toxin's close biological and structural similarity to Shiga toxin. Although we initially reported that 75% of children with idiopathic hemolytic uremic syndrome (HUS) [1] had evidence of a verotoxin-producing E. coli (VTEC) [1], a later study showed that over a seven year period (1980-86), of 86 children seen with HUS, 91% had a classical presentation and 88% of these had evidence of a VTEC infection [3]. This paper traces the path of the incriminating organisms (VTEC) from the time of ingestion, up to and including internalization of the toxin into a target cell; in vitro experiments demonstrating the effect of toxin on endothelial cells are included. It is hoped that we might gain a clearer insight into factors that might predispose an individual to contracting HUS. Once a better understanding of the pathogenesis of VTEC associated HUS is known, areas for therapeutic intervention might be realized.

Long-term neurological sequelae of hemolytic-uremic syndrome: a preliminary report.

Seven patients with hemolytic-uremic syndrome who had major neurological symptoms during the acute illness were neurologically and cognitively evaluated prospectively several years after recovery from the illness. Four patients showed evidence of subtle neurological sequelae, including posturing, clumsiness, poor fine-motor coordination, hyperactivity, and distractibility. Psychoeducational evaluation of all seven subjects revealed mean scores within the average range in cognitive abilities, academic achievement, single word receptive vocabulary, visual/motor planning, overall adaptive functioning, and hyperactivity. The lapse of time (minimum of 7 years) between the acute illness and the psychometric evaluation could have been responsible for our normal results.

A crossover comparison of extended release felodipine with prolonged action nifedipine in hypertension.

In a crossover design, control of blood pressure by extended release felodipine was compared with control by prolonged action nifedipine in 21 children with renal hypertension. Compliance with once daily felodipine was higher than with nifedipine, at 95.6 (SEM 2.7)% v 78.9 (6.0)% (p = 0.02). Mean diastolic blood pressure was lower during the day with felodipine than with nifedipine, at 77.6 (2.4) v 84.4 (2.8) mm Hg (p = 0.05). Similarly, blood pressure load (the percentage of the day during which the child had blood pressure exceeding the upper limits of normal for age) was lower for felodipine than for nifedipine: 43.5 (5.5)% v 61.3 (6.3)%. There was an opposite trend during the night, though this did not reach statistical significance. These data suggest that once a day felodipine is effective in children with hypertension. This may be because of improved compliance.

Enzyme-linked immunosorbent assay for detection of immunoglobulin G antibodies to Escherichia coli Vero cytotoxin 1.

The frequency of Vero cytotoxin 1 (VT1)-neutralizing antibody (NAb) in serum specimens from 790 age-stratified (0 to 70 years) control individuals from Toronto was 61 of 790 (7.7%), with a peak of 19% in the 20- to 30-year-old age group and a second peak of 16.7% in the 60- to 70-year-old age group. A total of 568 serum specimens, including 538 from the 790 Toronto control subjects, 21 from patients from three outbreaks of VT-producing Escherichia coli (VTEC) infection, and 9 known VT1-NAb-positive serum specimens from patients with hemolytic-uremic syndrome (HUS), were then tested for the presence of anti-VT1 immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay (ELISA). The mean ELISA values of 522 VT1-NAb-negative serum specimens and 46 VT1-NAb-positive serum specimens were 0.09 +/- 0.06 (range, 0 to 0.56) and 0.78 +/- 0.66 (range, 0.16 to 2.91), respectively (P < 0.001; Student's t test). With a breakpoint of 0.21 (mean ELISA value of the VT1-NAb-negative sera + 2 standard deviations), the sensitivity, specificity, positive predictive value, and negative predictive value of the VT1 IgG ELISA compared with those of the VT1-NAb assay were, respectively, 95.7, 98.7, 86.3, and 99.6%. There were nine discrepant serum specimens, of which seven were anti-VT1 IgG positive and VT1-NAb negative and two were anti-VT1 IgG negative and VT1-NAb positive. The ELISA was also used for testing 238 control serum specimens from The Netherlands, Japan, and India and acute- and convalescent-phase serum specimens from 42 Toronto patients with HUS. The frequencies of anti-VT1 IgG (with VT1-NAb frequencies in parantheses) in control sera from the Netherlands, Japan, and India were 6% (3%), 1.1% (0%), and 12% (10%), respectively, with no age clustering. The frequencies of anti-VT1 IgG seropositivity in HUS patients were 5 of 14 (35.7%) in patients with unknown toxin exposure, 2 of 22 (9.1%) in individuals with known exposure to VT1 plus VT2 or VT1 alone, and 0 of 6 (0%) in patients exposed to only VT2. Development of serum anti-VT1 IgG response appears to be the exception rather than the rule in sporadic HUS patients infected with VTEC expressing VT1. However, in two family outbreaks associated with VTEC strains expressing VT1 alone and VT1 plus VT2, respectively, the presence of anti-VT1 IgG in virtually all exposed individuals who remained symptom free suggests that the presence of antibody was associated with protection.

Epidermal growth factor and phorbol myristate acetate increase expression of the mRNA for cytosolic phospholipase A2 in glomerular mesangial cells.

We have previously shown that phospholipase A2 (PLA2) activity is rapidly activated by epidermal growth factor (EGF) and phorbol 12-myristate 13-acetate (PMA) in renal mesangial cells and other cell systems in a manner that suggests a covalent modification of the PLA2 enzyme(s). This PLA2 activity is cytosolic (cPLA2) and is distinct from secretory forms of PLA2, which are also stimulated in mesangial cells in response to cytokines and other agonists. However, longer-term regulation of cPLA2 in renal cells may also occur at the level of gene expression. Cultured rat mesangial cells were used as a model system to test the effects of EGF and PMA on the regulation of cPLA2 gene expression. EGF and PMA both produced sustained increases in cPLA2 mRNA levels, with a parallel increase in enzyme activity over time. Inhibition of protein synthesis by cycloheximide increased basal cPLA2 mRNA accumulation in serum-starved mesangial cells, and the combination of EGF and cycloheximide resulted in super-induction of cPLA2 gene expression compared with EGF alone. Actinomycin D treatment entirely abrogated the effect of EGF on cPLA2 mRNA accumulation. These findings suggest that regulation of cPLA2 is achieved by factors controlling gene transcription and possibly mRNA stability, in addition to previously characterized posttranslational modifications.

Hospitalization in children during the first year after kidney transplantation.

Length of hospital stay post-renal transplant was investigated in 2171 North American pediatric patients. Hospitalization for those surviving one year with a functioning graft was 28.8 versus 36.0 days (P < 0.05) for living donor (LD) compared with cadaveric donor (CAD) recipients during the first year post-transplant. Significantly prolonged hospital stays were recorded for LD recipients who (a) were less than one-year-old, (b) were receiving prophylactic ALG/OKT3, and (c) had a history of prior dialysis, and for CAD recipients who (a) were non-White and (b) received kidneys with cold ischemic times over 24 hours. In period II (2 to 6 months post-transplant), 51% and 68% of LD and CAD recipients, respectively were hospitalized while the corresponding values were 27% or 31% in period III (7 to 12 months post-transplant). Hospitalization was due mainly to graft loss or rejection episodes. Prolonged hospital stay coupled with poor graft survival might help to determine which aspects of the clinical practice of transplanting children warrant changes.

Evaluation of factors contributing to mortality in pediatric renal transplant recipients.

From 1969 to 1985, 303 renal allografts (290 cadaveric) were placed in 215 pediatric recipients. A review of actuarial recipient and allograft survival 2 years posttransplant showed good results in patients over 6 years of age (greater than 90% for patients, about 70% for allografts) but less satisfactory results in younger patients (75% for patients, about 45% for allografts). Thirty-nine patients died. Loss of allograft function preceded death in 67% of cases and was due to rejection (61%), renal vascular thrombosis (35%), and recurrence of original disease (4%). On retrospective analysis, 13 deaths might have been preventable with current diagnostic and therapeutic modalities. Allograft dysfunction from thrombosis occurs at a higher frequency in the young child and may be confused with rejection. Treatment of rejection without biopsy, overagressive treatment of a chronically failing graft, and failure to withdraw immunosuppressive therapy in face of infection are poorly tolerated in the very young recipient and are prominent causes of preventable mortality. Transplant nephrectomy and repeated attempts at transplantation are poorly tolerated in very young patients. Patient survival is very dependent on the success of the initial allograft in children.

Medical and social outcome in adolescents with end-stage renal failure.

Clinical information was collected on 118 adolescents who developed ESRF at age 143 months or older and were treated between 1966 and 1986 at the Toronto Hospital for Sick Children. The cumulative survival rate in transplanted patients (N = 109) was 80.1% after 15 years. Survival rates after four years were 93.9% in transplanted and 46.9% in nontransplanted patients (P less than 0.001). No patient receiving dialysis alone (N = 9) was followed longer than four years. Nine patients received three transplants and had an 89% survival rate. Six of these had a functioning graft at end of the follow-up. The cumulative survival of the entire group was 76.4% at eighteen years. Forty-two (35.6%) patients had a height below the third percentile. Functional status obtained by a structure telephone interview with a member of the present treating nephrology service was good (G) or excellent (E) for 66.7% of all patients (73.5% of transplant patients (N = 68) and 45% of dialysis patients (N = 20). Hemodialysis patients functioned less well [25% G/E (N = 12)] than peritoneal dialysis patients [75% G/E (N = 8)]. Most patients achieved an appropriate level of formal education although more slowly than normal adolescents. Only 11 patients were neither enrolled in an educational institution nor employed. We conclude that aggressive treatment for adolescents with ESRF is an appropriate application of health care resources.

Amantadine neurotoxicity in a pediatric patient with renal insufficiency.

Amantadine hydrochloride, a dopamine agonist with antiviral and antiparkinsonism properties, is used for the prevention and treatment of influenza A respiratory infections in high-risk populations. The occurrence of amantadine-induced hallucinations and tremors is described in a young, renal transplant patient with declining renal function. Following discontinuation of amantadine, plasma amantadine concentrations were correlated with central nervous system toxicity. In view of the usage of amantadine in renal transplant recipients and the elderly, clinicians must be alert to the possibility of amantadine-induced neurotoxicity in patients with changing renal function.

Aminoaciduria as a marker of acute renal transplant rejection--a patient study.

Over 12 months, urine samples were systematically collected from 40 children who underwent renal transplantation for the treatment of end-stage renal disease. Sequential determinations of the excretion of individual amino acids relative to that of creatinine were carried out on 15 subjects. Nine of these (including three who sustained episodes of acute rejection) retained a native kidney in-situ, while in six patients (including three who underwent an episode of acute rejection) both native kidneys had been removed. In both subgroups, the amino acid/creatinine ratios of early morning urine samples were higher shortly before clinical manifestations of acute rejection became evident than in patients who, following renal transplantation, had stable kidney function, chronic graft rejection, or acute tubular necrosis, with one exception: a patient with one native kidney in-situ in whom acute tubular necrosis developed immediately after transplantation. The amino acids showing the greatest increase included Thr, Ser, Gly, and Ala. These values fell dramatically immediately prior to the clinical episode of acute rejection, with Thr, Ala, and Phe showing the most consistent changes. These alterations in urinary amino acid excretion occurred several days before changes in urinary protein excretion or the serum concentrations of urea and creatinine, and may have a role to play in the monitoring of renal transplant recipients.

Survival of cadaveric renal transplant grafts from young donors and in young recipients.

Evidence from multicenter registries has suggested that cadaveric renal graft survival is poorer when either the recipient or the donor is very young. We therefore analyzed our results from a single pediatric center. There was a significant correlation between greater recipient age and improved cadaveric graft (P = 0.002) and patient (P = 0.0009) survival. The age of the donor also appeared important, particularly in very young children, but became less so as donor age rose. Forty-four percent of recipients under 3 years old who received cadaveric kidneys from donors less than 4 years old lost their grafts as a result of renal thrombosis, ischemia, or technical problems, compared with only 3% of recipients over 9 years of age, whose grafts came from donors who were also over 9 years. The 1-year first cadaveric graft survival rates for these two age groups were 33% and 82% respectively. Our experience confirms the poor findings reported in very young recipients and with very young donors.