Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation.

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val-)ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen.

Ambulatory blood pressure monitoring in children and adolescents. Current insights into a new technique.

Ambulatory blood pressure monitoring (ABPM) is a new technique recently introduced into paediatrics. Devices with auscultatory blood pressure measurement may be more precise but give more erroneous readings than those with oscillometric measurement. For the interpretation of the results, mean day- and night-time values should be calculated according to patients' diaries and gender- and height-specific percentiles for ABPM measurements should be used to define hypertension. The use of "blood pressure load" as the percentage of single readings above a given upper level is not standardised in children and adolescents. A nocturnal blood pressure decline of less than 10% is defined as "non-dipping", although this is an arbitrary definition whose prognostic value is not evaluated in paediatric patients. Several studies showed that ABPM in children is superior in detecting "white-coat''-hypertension, shows a better reproducibility and is a better prognostic factor for left ventricular mass compared to casual blood pressure measurements. Clinical studies show the value of ABPM in obese children, in children with renal diseases, on dialysis therapy and after renal transplantation as well as in diabetic children or in children after surgical repair of aortic coarctation. Ambulatory blood pressure monitoring in children and adolescents has grown to a valuable method for the daily management of patients with suspected or established hypertension. However, there is still a lot of work before all technical problems are solved and international guidelines can be published which are based on evidence from follow-up studies.

Spontaneous baroreflex sensitivity in children and young adults calculated in the time and frequency domain.

Spontaneous baroreflex receptor sensitivity (BRS) was calculated in 22 healthy normotensive children and young adults (age 14 +/- 5 years) using the sequence technique (time domain) and the alpha-coefficient or the gain of the transfer function between coherent oscillations (frequency domain). BRS estimated by the sequence technique (median: 16.7 ms/mm Hg) was significantly higher than BRS calculated from the gain of the transfer function using all frequencies (median: 13.0 ms/mm Hg; p = 0.009). However, there was a high correlation between these methods (r = 0.92). The reproducibility coefficient (RC) was high for all methods, but the coefficient of variability (VC) was best for the sequence technique and the gain of the transfer function, but significantly worse for the estimates of the alpha-coefficient in the low or high frequency band. The differentiation between increasing or decreasing blood pressure (BP) ramps did not give further information showing the same BRS values. The best BRS estimates will be achieved by using three consecutive beats without lag by the sequence technique and by using only frequencies with a proven correlation of BP and pulse interval (PI) and then calculating the gain of the transfer function using coherent oscillations.

Ciprofloxacin-induced acute renal failure in a patient with cystic fibrosis.

Acute renal failure is a rare adverse reaction of antibiotic therapy with quinolones seldom seen in young patients. We report an 18-year-old young woman with cystic fibrosis who experienced a pronounced decline in renal function after oral treatment with ciprofloxacin for 3 weeks. Withdrawal of the drug led to normalization of renal function after 10 days.

[Home blood pressure self-measurement in children and adolescents with renal replacement therapy]. / Häusliche Blutdruck-Selbstmessung bei Kindern und Jugendlichen mit Nierenersatztherapie.

BACKGROUND: Most patients with terminal renal failure show arterial hypertension. In addition to casual blood pressure measurements in the clinic, home blood pressure measurement is recommended for these patients to control arterial blood pressure. PATIENTS: The study was performed in children with hemodialysis (HD; n = 11), peritoneal dialysis (PD; n = 14) or after renal transplantation (NTX; n = 21) from one department of Pediatric Nephrology. We performed a retrospective analysis of home blood pressure values from patients' diaries. METHODS: The average number of blood pressure measurements per day and the mean blood pressure values were calculated from the blood pressure data documented during one month at home. Single measurements above the 95th percentile for height and gender were defined to be hypertensive and the frequency as percentage of all documented values was calculated. RESULTS: Four patients did not document any blood pressure values at home. The other patients documented an average of 2.3 measurements per day. Systolic hypertension was found in 7% of patients defined by home BP measurements compared to 30% defined by casual BP measurements. Prevalence of diastolic hypertension did not differ between both methods (35% vs. 46%). Mean home BP was significantly higher than values after HD and lower than values before HD. Mean clinic BP was significantly higher in PD-patients compared to home BP. Home and clinic blood pressure values did not differ in patients after renal transplantation. The mean percentage of hypertensive readings for systolic BP was 5 and for diastolic BP 39%. CONCLUSIONS: Blood pressure measurement at home is performed reliably by most children and adolescents with chronic renal failure and shows lower values than clinic BP in many patients. It is an important method for control of blood pressure and a valuable supplement to 24 h blood pressure monitoring.

Measurement of blood pressure at home: survey among pediatric nephrologists.

Recently, an international consensus paper was published for standardization of home self-blood pressure (BP) measurement in adults. However, few data exist regarding home BP measurement in children, although it is recommended for all pediatric patients on renal replacement therapy in Germany. Therefore, a survey was performed among German-speaking pediatric nephrologists (members of the Arbeitsgemeinschaft Pädiatrische Nephrologie) in order to study their opinions about home blood pressure measurements. Approximately 75% of German pediatric nephrology centers responded to the survey. More than 70% of the interviewees prescribed a blood pressure device for all children with renal diseases and hypertension or on renal replacement therapy. For children with antihypertensive medication, 2.8 daily measurements were recommended at mean and 2.2 measurements for children without therapy. Auscultation of Korotkoff sounds and oscillometric BP measurements were used in the same percentage for home BP recordings. The upper cut of level for home blood pressure values was rated by the pediatric nephrologists and compared to reference values of casual blood pressure. There was good agreement for upper systolic BP, but as many as 40 to 50% of the interviewees accepted upper diastolic BP values higher than the 97th percentile for casual BP. Home BP measurement was judged to be more important than office BP measurement by 64% of the nephrologists and less important than 24 h ambulatory blood pressure monitoring by 67%. The results of the survey showed wide discrepancies for standards of home BP measurement in children and adolescents, especially for the recommendations for upper diastolic BP. Before home blood pressure measurements can be recommended unrestrictedly in children and adolescents, we stress the need for standardization of blood pressure devices and measurement. Prospective studies in children are needed to demonstrate that these standards facilitate better prediction of cardiovascular outcome using home BP measurements compared to office BP recordings in children.

Hypothyroidism mimicking chronic renal failure in reflux nephropathy.

An adolescent with a history of pyelonephritis and renal scarring had antireflux surgery at the age of 2.5 years. His serum creatinine was high at the age of 14 years (133 micromol/l; glomerular filtration rate (GFR) 56 ml/min x 1.73 m(2)), and reflux nephropathy with chronic renal failure was diagnosed. Because of a fall in height velocity, endocrinological investigations were performed six months later which showed hypothyroidism caused by autoimmune thyroiditis. Substitution with thyroxine was started; renal function improved to normal six months later (GFR 108 ml/min x 1.73 m(2)). Metabolic changes of hypothyroidism led to a reduction of GFR in this patient and mimicked chronic renal failure.

Arterial hypertension in children and adolescents after surgical repair of aortic coarctation defined by ambulatory blood pressure monitoring.

BACKGROUND: Despite early operation, persistent and late systolic hypertension are common among children and adolescents after surgical repair of aortic coarctation and can contribute to early cardiovascular morbidity. METHODS: Ambulatory blood pressure monitoring was performed for 78 patients (aged 3.6-22.8 years, 41 male) after successful surgical repair of aortic coarctation (median duration of follow-up 6.5 years, range 0.7-20.1 years). Hypertension was defined as mean systolic blood pressure exceeding the 95th percentile for sex and height. RESULTS: Twenty-three patients (29%) exhibited systolic hypertension during daytime. Hypertensive patients had been older at the time of operation than had normotensive patients (5.4+/-5.0 versus 2.4+/-3.1 years, P<0.01). Prevalence of hypertension was 21% among patients who had undergone surgery during the first year of life and 38% among patients who had been operated upon later. Decline in blood pressure during night was similar for all patients (systolic 11+/-5% and diastolic 19+/-8%). Systolic hypertension during night-time was found in 24% of patients who were normotensive during day. Diastolic hypertension was rare. Follow-up measurements were performed for 41 patients after 2.3+/-1. 3 years, and most normotensive patients remained normotensive during this time. CONCLUSIONS: Ambulatory blood pressure monitoring allows one to estimate nocturnal hypertension in children and adolescents after surgical repair of aortic coarctation which is common also among normotensive patients during daytime.

Production of chromatid breaks by single dsb: evidence supporting the signal model.

PURPOSE: The signal model proposes that all chromatid breaks arise from a single DNA double strand break (dsb) via a recombinational exchange mechanism. Here the prediction that chromatid breaks arise from a single dsb is tested. METHOD: The genetically engineered Chinese hamster cell line GS19-43 containing a unique yeast I-SceI recognition site was treated with I-SceI endonuclease (Meganuclease) in the presence of the porating agent streptolysin O. Chromatid breaks were scored at 4h, chromosome breaks at 18 and 22h following treatment (cells used for a 4h fixation were prelabelled with BrdU over two cell-cycles). Positive controls were treated with the restriction endonuclease Pst 1. RESULTS: I-SceI endonuclease produced chromatid breaks and at higher enzyme concentrations isochromatid breaks but no chromatid interchanges. About 16% of the chromatid breaks had a 'colour-switch' between the sister-chromatids at the site of breakage, as revealed by FPG staining. At the longer fixation times (18 and 22 h) chromosome breaks were observed, but again no interchanges were seen. Chromatid and chromosome breaks always appeared on the same chromosome. CONCLUSIONS: The production of chromatid breaks from a single dsb fulfils the prediction of the signal model. Moreover, the production of colour-switch breaks at a similar frequency to that for ionizing radiation indicates that chromatid breaks are produced via recombinational exchanges, a significant proportion of which occurs between sister chromatids. The majority is intrachromatid, not involving strand-switches. The absence of interchromosomal exchanges at all fixation times indicates a requirement of two dsb in two different chromosomes for their formation.

Elevated plasma concentrations of neuropeptide Y in children and adults with chronic and terminal renal failure.

Neuropeptide Y (NPY) is a peptide hormone that is expressed, stored, and released in sympathetic neurones together with noradrenaline. Elevated plasma concentrations of NPY have been reported in patients with neural crest tumors (neuroblastoma, pheochromocytoma) and following exercise. We studied plasma concentrations of NPY in children and adults with chronic and terminal renal failure and compared them with those in healthy controls. Neuropeptide Y was significantly higher in children and adolescents receiving peritoneal dialysis (5.3 +/- 2.8 pmol/L; n = 11 [mean +/- SD]) or hemodialysis (5.4 +/- 2.1 pmol/L; n = 14) than in healthy children (2.3 +/- 0.9 pmol/L; n = 19) or pediatric patients with impaired renal function who are not receiving dialysis (2.7 +/- 0.6 pmol/L; n = 8; mean glomerular filtration rate, 41 mL/min x 1.73 m2). There was a small but insignificant negative correlation between glomerular filtration rate and NPY concentrations in children with impaired renal function (r = 0.49; P = 0.25). In healthy adults, NPY concentration was similar to that in healthy children (1.8 +/- 1.0 pmol/L; n = 13), and it was significantly elevated in adults receiving hemodialysis (5.9 +/- 1.7 pmol/L; n = 16). No significant changes in NPY concentrations were found before and after hemodialysis in pediatric or adult patients. We conclude that plasma concentrations of NPY are elevated in patients with chronic renal failure who are receiving either peritoneal or hemodialysis, but not in patients with moderately impaired renal function. Whether elevated NPY concentration indicates increased sympathetic activity or is caused by reduced NPY clearance remains to be shown.

Calcium acetate versus calcium carbonate as oral phosphate binder in pediatric and adolescent hemodialysis patients.

Calcium carbonate is widely used as an oral phosphorus binder to control hyperphosphatemia in children on maintenance hemodialysis. Intestinal calcium absorption may induce hypercalcemia, particularly if calcitriol is given simultaneously. In adults, calcium acetate binds phosphorus more effectively than calcium carbonate, while reducing the frequency of hypercalcemic events. We therefore compared calcium acetate with calcium carbonate in nine pediatric patients on long-term maintenance hemodialysis. Following a 1-week withdrawal of phosphorus binders, calcium carbonate was administered for 7 weeks; after a second withdrawal, calcium acetate was given for another 7 weeks. All patients received calcitriol regularly. Both agents lowered the serum phosphorus concentration significantly (calcium carbonate 5.7 +/- 1.4 vs. 7.7 +/- 2.1 mg/ dl, P < 0.005; calcium acetate 5.8 +/- 1.4 vs. 7.8 +/- 2.0 mg/dl, P < 0.005). Significantly less elementary calcium was ingested with calcium acetate than with calcium carbonate: 750 (375-1,500) vs. 1,200 (0-3,000) mg calcium/day, P < 0.0001. Wit calcium carbonate serum calcium increased significantly. The number of episodes of hyperphosphatemia or hypercalcemia did not differ between treatments. Intact plasma parathyroid hormone (PTH) decreased significantly with both phosphate binders, and serum 25-hydroxyvitamin D3 increased. There was a close relationship between serum phosphorus and PTH in prepubertal but not in pubertal patients. We conclude that hyperphosphatemia can be controlled effectively by both calcium acetate and calcium carbonate in pediatric hemodialysis patients. The oral load of elementary calcium is reduced significantly by binding phosphorus with calcium acetate instead of calcium carbonate; nevertheless, hypercalcemic episodes remain equally frequent with both phosphate binders.

24-hour blood pressure monitoring in children and adolescents after recovery from hemolytic uremic syndrome.

24-hour blood pressure monitoring is a valuable method for the diagnosis of arterial hypertension as well as for assessment of the diurnal rhythm of the arterial blood pressure (BP). The nocturnal decrease of blood pressure ("dipping") may be attenuated or abolished in children with advanced renal failure and glomerular diseases. Arterial hypertension is a longlasting problem in children who had recovered from hemolytic uremic syndrome (HUS). We therefore performed BP monitoring in 11 children and adolescents (age 1.3 to 18.8 years, 6 males, 5 females) after HUS using a portable oscillometric device (SpaceLabs 90207). Six of the subjects had a normal renal function (group A). The other 5 patients had impaired renal function with a glomerular filtration rate <60 ml/min/1.73 m2 (group B). Nocturnal dipping was calculated as nocturnal mean blood pressure minus diurnal mean blood pressure given in per cent of diurnal mean blood pressure. Two of the patients in group A had diurnal mean BP above the 95th percentile of the German collaboration study, but none of the group was hypertensive during the night, and nocturnal dipping was 13.6% (9.7-15.5%, median and range) for systolic BP and 23.7% (15.5-29.9%) for diastolic BP which is very similar to healthy children. All of the patients had a normal diurnal BP rhythm. From patients of group B, 4 had elevated diurnal mean BP and also 4 were hypertensive during the night. Nocturnal dipping was 1.4% (0.7-4.1%) for systolic and 6.8% (0-10.7%) for diastolic BP which is clearly attenuated compared to group A. We therefore conclude that arterial hypertension is more common in patients after HUS if they have impaired renal function, and diurnal rhythm of arterial blood pressure is attenuated in these patients. However, nocturnal dipping of blood pressure is not disturbed in children after HUS without renal insufficiency, even if they were hypertensive.

Blood pressure monitoring at the wrist: is it reliable in children and adolescents?

We studied in children and adolescents the performance of two devices for blood pressure measurements at the wrist: "Blood pressure watch" (BPW) and Omron R1 (OR1). They were tested against auscultatory blood pressure readings at the upper arm. Wrist circumference correlated to the aged was greater than 13.5 cm in nearby all subjects older than 12 years. BPW overestimated systolic blood pressure for more than 10 mm Hg and diastolic blood pressure for 4 to 7 mm Hg in all subjects. OR1 underestimated both systolic and diastolic blood pressure by 5 to 6 mm Hg in the group with a wrist greater than 13.5 cm and by 8 to 9 mm Hg in the group with a smaller wrist. No difference was found between left and right wrists by OR1.

Atrial natriuretic peptide and cyclic guanosine-monophosphate in children and adolescents on peritoneal dialysis.

Plasma concentrations of atrial natriuretic peptide (ANP) and its second messenger cyclic guanosine-monophosphate (cGMP) were studied in 28 children and adolescents (1 to 19 years) on peritoneal dialysis and compared to 55 healthy children (1 to 20 years). Dialysate concentrations of the hormones were measured also in the patients. Plasma ANP was not significantly different in patients and controls (28.8 pmol/l [15.5-53.6 pmol/l] [median, lower and upper quartile] versus 26.3 pmol/l [19.9-31.8 pmol/l]). In seven children on peritoneal dialysis it exceeded an upper normal limit of 50 pmol/l, but it fell to normal values in four of them after forced fluid withdrawal. Plasma cGMP was elevated in the patients compared to the control children (1.6 nmol/l [1.1-1.7 nmol/l] versus 1.0 nmol/l [0.8-1.2 nmol/l]; p < 0.05). There were only weak correlations between plasma and dialysate concentrations of ANP and cGMP. Plasma concentrations of ANP seem to be elevated in children on peritoneal dialysis in case of fluid overload.

Validity and reliability of 24h blood pressure monitoring in children and adolescents using a portable, oscillometric device.

Noninvasive 24h BP monitoring using portable devices is a new method for the diagnosis of arterial hypertension and for the control of antihypertensive therapy in adults. Recently, it is also used in juvenile hypertension. We now report on the validity and reliability of an oscillometric BP recorder (SpaceLabs 90207) widely used in children and adolescents. Single BP recordings with this monitor were compared with manual auscultation of Korotkoff sounds and with measurements by an other oscillometric device (Dinamap). SBP measured by the SpaceLabs monitor was 5 mmHg (2-10 mmHg, median and quartiles) higher than manual readings whereas there was no difference in DBP between these methods. With the Dinamap monitor, SBP was identical to manual readings but DBP was underestimated by 8.5 mmHg (1-13 mmHg). The 24h BP monitoring was performed in 101 children < 13 years of age and in 58 adolescents > 12 years of age. Seventy-eight per cent (64-89%) of all readings were complete in the younger probands and 91% (84-95%) in the older ones (P < 0.01). Measurements failed more often during daytime compared with nighttime in both groups. In conclusion, long-term BP monitoring using an oscillometric device is useful and reliable in adolescents and even in smaller children.

Clinical settings and vasopressin function in hyponatraemic children.

Hyponatraemia is one of the most common electrolyte abnormalities in hospitalised children. In a prospective study we tested whether hyponatraemia is associated with sustained release of the antidiuretic hormone arginine vasopressin (AVP). Out of 27 children with persistent hyponatremia (serum sodium < 130 mmol/l), 25 had measurable plasma concentrations of AVP [median and quartiles 5.0 pg/ml (1.5-8.3)]. Volume contraction as consequence of sodium loss caused hyponatraemia in 16 patients. Hyponatraemia in the presence of extracellular volume expansion and reduced effective arterial blood volume occurred in 5 patients. Only 3 patients had normovolaemic hyponatraemia (so-called syndrome of inappropriate antidiuretic hormone secretion) and 3 suffered from chronic renal failure. It is concluded that plasma AVP concentration is measurable in most children with hyponatraemia. Non-osmotic stimulation of AVP release and lack of suppression of this hormone is an important pathogenetic mechanism of hyponatraemia in children.