Diversity of Pediatric Workforce and Education in 2012 in Europe: A Need for Unifying Concepts or Accepting Enjoyable Differences?

OBJECTIVE: To evaluate differences in child health care service delivery in Europe based on comparisons across health care systems active in European nations. STUDY DESIGN: A survey involved experts in child health care of 40 national pediatric societies belonging both to European Union and non-European Union member countries. The study investigated which type of health care provider cared for children in 3 different age groups and the pediatric training and education of this workforce. RESULTS: In 24 of 36 countries 70%-100% of children (0-5 years) were cared for by primary care pediatricians. In 12 of 36 of countries, general practitioners (GPs) provided health care to more than 60% of young children. The median percentage of children receiving primary health care by pediatricians was 80% in age group 0-5 years, 50% in age group 6-11, and 25% in children >11 years of age. Postgraduate training in pediatrics ranged from 2 to 6 years. A special primary pediatric care track during general training was offered in 52% of the countries. One-quarter (9/40) of the countries reported a steady state of the numbers of pediatricians, and in one-quarter (11/40) the number of pediatricians was increasing; one-half (20/40) of the countries reported a decreasing number of pediatricians, mostly in those where public health was changing from pediatric to GP systems for primary care. CONCLUSIONS: An assessment on the variations in workforce and pediatric training systems is needed in all European nations, using the best possible evidence to determine the ideal skill mix between pediatricians and GPs.

Early kidney transplantation improves neurocognitive outcome in patients with severe congenital chronic kidney disease.

Renal replacement therapy has become available for the majority of patients suffering from severe congenital chronic kidney disease (CKD). Data on the long-term neurocognitive outcome and the impact of early kidney transplantation (KTx) in this setting is unclear. Neurocognitive outcomes in 15 patients (11 male) with isolated congenital CKD (stage 3-5) requiring KTx at a mean age of 2.8 ± 1.3 were assessed at a mean age of 8.3 ± 1.4 years. Patients underwent neurological examination and testing for neuromotor and neurocognitive function using three independent tests. Pre-emptive KTx was performed in six patients, and nine patients were dialyzed prior to KTx for a mean period of 11.1 ± 8.6 months. Neuromotor function was abnormal in 8/15 patients. HAWIK-III showed a global intelligence quotient (IQ) of 93.5 ± 11.4 (P = 0.05) due to a significantly reduced performance IQ of 89.1 ± 11.3 (P < 0.01). In three patients, the global IQ was clinically significantly reduced by >1 SD to <85. In patients with neuromotor dysfunction, performance IQ was lower than in patients with normal neuromotor function (83.8 ± 10.2 vs. 96.2 ± 9.0, P = 0.04). Time on dialysis was inversely correlated to verbal IQ (r = 0.78, P = 0.02). Pre-emptive KTx and duration of dialysis treatment <3 months was associated with superior neurocognitive outcome. Early (pre-emptive) KTx results in superior long-term neurocognitive outcome in children with severe congenital CKD.

Growth and maturation improvement in children on renal replacement therapy over the past 20 years.

BACKGROUND: The attainment of normal growth and maturation remains a major challenge in the management of children and adolescents requiring renal replacement therapy (RRT). METHODS: We compared growth and maturation in 384 German children with RRT who were followed between 1998 and 2009 with 732 children who were enrolled in the European Dialysis and Transplant Association (EDTA) Registry from 1985 to 1988; of these children, 78 and 88 %, respectively, were transplanted. RESULTS: The data on the German patients included in the EDTA registry did not differ significantly from those of the patients from other European countries. Overall, the mean height standard deviation score (SDS) has improved over the past 20 years from -3.03 to -1.80 (p < 0.001). Until the age of 6 years, the difference in height SDS was not significant, whereas it improved significantly in adolescence (-3.40 vs. -1.52; p < 0.001). Significant improvements in the delay of the pubertal growth spurt, age at menarche, bone maturation and body mass index (BMI) were noted in the recent German group compared to the EDTA group (each p < 0.001). CONCLUSIONS: Our findings demonstrate a marked improvement of growth and maturation in paediatric patients on RRT during the past 20 years.

Diagnostic pathways for exclusion and diagnosis of kidney diseases.

In 2006, the German Society for Clinical Chemistry and Laboratory Medicine together with the Society of Nephrology founded a working group with the aim to develop diagnostic pathways for the detection and differentiation of renal diseases. Based on existing recommendations, these pathways may be structured to be a basis for implementation into hospital and laboratory information systems. The present paper describes the contents of these pathways regarding glomerular filtration rate, hematuria, leukocyturia and proteinuria.

Urinary proteome analysis to exclude severe vesicoureteral reflux.

OBJECTIVES: High-grade vesicoureteral reflux (VUR, grade IV or V) is a risk factor for renal scarring, impaired renal function, and arterial hypertension. Voiding cystourethrography is the gold standard for detecting the severity of VUR. High-grade VUR is present in the minority of children with urinary tract infection (UTI), thus exposing the majority to invasive diagnostics that have no surgical consequence. We therefore aimed at establishing a noninvasive test to identify children with high-grade VUR. METHODS: In a case-control study, a specific urinary proteome pattern was established by capillary electrophoresis coupled to mass spectrometry in 18 patients with primary VUR grade IV or V, distinguishing these from 19 patients without VUR after UTI. This proteome pattern was independently validated in a blinded cohort of 17 patients with VUR grade IV or V and 19 patients without VUR. RESULTS: Sensitivity in detecting VUR grade IV or V in the blinded study was 88%, specificity was 79%. The test's accuracy was independent of age, gender, and grade of VUR in the contralateral kidney. The odds ratio of suffering from VUR grade IV or V when tested positive was 28 (95% confidence interval: 4.5 to 176.0). CONCLUSIONS: This noninvasive test is ready for prospective validation in large cohorts with the aim of identifying those children with UTI and hydronephrosis in need of further invasive diagnostics, such as voiding cystourethrography, thus sparing most children without pathologic urinary proteome patterns from additional diagnostics.

Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome.

BACKGROUND: There is currently no established standard for maintenance therapy of steroid-resistant nephrotic syndrome (SRNS). We report the long-term clinical course, medication, pharmacokinetic data, and renal function of 23 children with primary, non-familial SRNS with focal segmental glomerulosclerosis (FSGS). METHODS: To achieve initial remission, patients were treated with high-dose intravenous (i. v.) methylprednisolone and oral cyclosporin A (CsA). Maintenance therapy included transient alternate day oral prednisolone, CsA and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers. In 18 patients, mycophenolate mofetil (MMF) (adjusted to achieve blood mycophenolic acid trough concentrations > 2 µg/mL) was sequentially added, and 16 patients were converted to MMF monotherapy. RESULTS: During a mean follow-up time of 7.0 years (1.7-16.5 years; cumulative observation time 161 patient-years), sustained remission could be achieved in all patients. Five of 23 patients (21%) experienced 10 relapses; all responded to relapse therapy. Maintenance therapy could be permanently discontinued in seven patients (30%). After conversion from CsA to MMF, renal function improved significantly; the eGFR at last follow-up was 137 (range 106-198) mL/min × 1.73 m(2). The mean number of anti-hypertensive drugs decreased from 1.86 per patient after initial remission to 0.57 on MMF monotherapy (P < 0.002). CONCLUSIONS: The data of this uncontrolled retrospective study indicate that in children with SRNS/FSGS achieving initial remission, a sequential steroid-free therapy consisting of a combination of CsA and MMF followed by MMF alone (with the addition of ACE inhibitors and angiotensin receptor blockers), can provide sustained long-term remission, preservation of renal function and better control of blood pressure.

Prevention of chronic kidney disease in spina bifida.

OBJECTIVE: The prevalence of progressive chronic kidney disease (CKD) in children and adults with spina bifida is considerable, rising, and entirely preventable. REMOVING THE CAUSE: PREVENTION OF SPINA BIFIDA: The best prevention of CKD in spina bifida is prevention of spina bifida itself through strategies that include folate supplementation, ideally before pregnancy. THE CAUSE OF CKD: Dysfunctional bladder outlet causes febrile Urinary Tract Infections (UTI), even with clean intermittent catheterization (CIC), and subsequent renal scarring. The development of secondary vesicoureteric reflux (VUR) increases the risk of renal scarring and CKD. FINDING THE IDEAL MARKER FOR MEASUREMENT OF RENAL FUNCTION IN SPINA BIFIDA: Creatinine-based methods are insensitive because of low muscle mass and underdeveloped musculature in the legs. Only Cystatin C-based eGFR can reliably assess global renal function in these patients. However, unilateral renal damage requires nuclear medicine scans, such as (99m)Tc DMSA. (VIDEO)URODYNAMICS STUDIES (UDS): Early treatment is recommended based on UDS with anticholinergics, CIC, and antibiotic prophylaxis when indicated. Overnight catheter drainage, Botox, and eventually augmentation cystoplasty are required for poorly compliant bladders. A continent child or one rendered continent following surgery is at a higher risk of renal damage. CONCLUSION: A multidisciplinary approach is required to reduce the burden of CKD in patients with spina bifida. The right tools have to be utilized to monitor these patients, particularly if recurrent UTIs occur. Cystatin C eGFR is preferred for monitoring renal damage in these patients, and (99m)Tc DMSA scans have to be used to detect unilateral renal scarring.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Effective treatment of anemia in pediatric kidney transplant recipients with methoxy polyethylene glycol-epoetin beta.

MPG-EPO is a continuous erythropoietin receptor activator with a longer half-life than darbepoetin, hence requires less frequent injections. It has been successfully used in adults, but currently, there are no published data available for its use in children. This pilot study was performed to verify the effect of MPG-EPO on Hb levels in children. Twelve patients (age 6.4-17.2 yr) were treated with MPG-EPO as an individual "Heilversuch" according to German law after RTx. Five patients were switched from DA, and seven were naïve to erythropoietin. Over a period of six months, Hb levels were measured monthly. A median MPG-EPO dose of 2.5 µg/kg was administered intravenously in a single dose every four wk. The median Hb value increased in naïve patients from 9.9 to 11.2 g/dL (median, p = 0.004) and from 10.3 to 11.6 g/dL (median, p = 0.39) in patients switched from DA to MPG-EPO. No adverse events secondary to MPG-EPO therapy were detected. Our results indicate that a once-monthly injection of MPG-EPO is an effective treatment of anemia in children after renal transplantation. Larger randomized trials will have to confirm our findings.

The podocyte as a direct target of immunosuppressive agents.

Podocytes play a key role in maintaining the blood-urine barrier for high-molecular-weight proteins. They are considered to be terminally differentiated, and podocyte loss cannot be compensated by regenerative proliferation. Various diseases leading to podocyte damage and loss result in proteinuria and cause nephrotic syndrome. Therefore, direct therapeutical strategies to protect podocytes in disease situations are a logical concept to prevent disease or to delay disease progression. Acquired podocytopathies like idiopathic focal segmental glomerulosclerosis and minimal change disease are historically considered as immunological diseases. Therefore, immunosuppressive agents such as steroids and calcineurin inhibitors are the commonly used treatment strategies. However, the causative disease mechanisms behind these treatment strategies remain elusive. Recent evidence shows that immunosuppressive agents, in addition to the effect on the immune system, directly influence the unique structure and function of podocytes. In this context, the actin cytoskeleton of the podocyte and cytokines such as vascular endothelial growth factor play a pivotal role. In this review, we summarize the direct effects on podocytes obtained in vivo and in vitro after treatment with calcineurin inhibitors, mTOR inhibitors and glucocorticoids. These direct effects could play a key role in the treatment concepts of podocytopathies with an important impact on the long-term renal function in patients with pharmacological immunosuppression.

Regional citrate anticoagulation--a safe and effective procedure in pediatric apheresis therapy.

Regional citrate anticoagulation (RCA) has been considered to be a standard component of pediatric apheresis therapy for more than a decade. However, data on dosing recommendations and evaluations of the effectiveness and safety of anticoagulation are rarely found in published reports. The aim of this retrospective analysis was to present our single-center experience with RCA in pediatric apheresis therapy with the aim of developing an operating procedure. Five children aged 7-14 years underwent a total of 72 (range 3-44) therapeutic apheresis sessions with RCA in the form of immunoadsorption therapy (2 patients), low-density lipoprotein (LDL)-apheresis (1 patient), and plasmapheresis (two patients). A 3% citrate solution was used. Citrate flow was started at 4.0% of the blood flow velocity and was adapted to match post-filter ionized calcium levels ≤ 0.30 mmol/l. Once the patient's ionized calcium fell to <1.05 mmol/l, an intravenous 10% calcium gluconate solution was administered. Twenty pediatric apheresis patients who received standard heparinization, matched for age, body surface area, processed plasma volume, and blood flow velocity, were enrolled in the study as a comparison group. No side effects were experienced in 72 apheresis session. The 3% citrate solution had to be reduced gradually during the apheresis session and was infused at a mean of 2.8-3.8% of the blood flow rate. Serum bicarbonate levels before and after the apheresis session with RCA [23.9 (range 18.9-30.1) vs. 26.3 (20.2-33.0) mmol/l, respectively] were significantly different (p=0.013). All patients required intravenous calcium substitution to maintain serum calcium levels within the physiological range. Due to the administration of the 3% citrate solution and calcium, all patients significantly gained weight during the procedure, with a median weight gain of 2.5% (p<0.001). The extra fluid load caused problems in patients with kidney failure. Our regimen with RCA is safe, feasible, and effective in pediatric therapeutic apheresis therapy. For RCA in apheresis, we recommend (1) a citrate (3%) flow of 3.3% of the blood flow, (2) prophylactic intravenous calcium substitution from the beginning, and (3) a more highly concentrated citrate solution in the case of oliguric patients.

Recommendations for biomarker identification and qualification in clinical proteomics.

Clinical proteomics has yielded some early positive results-the identification of potential disease biomarkers-indicating the promise for this analytical approach to improve the current state of the art in clinical practice. However, the inability to verify some candidate molecules in subsequent studies has led to skepticism among many clinicians and regulatory bodies, and it has become evident that commonly encountered shortcomings in fundamental aspects of experimental design mainly during biomarker discovery must be addressed in order to provide robust data. In this Perspective, we assert that successful studies generally use suitable statistical approaches for biomarker definition and confirm results in independent test sets; in addition, we describe a brief set of practical and feasible recommendations that we have developed for investigators to properly identify and qualify proteomic biomarkers, which could also be used as reporting requirements. Such recommendations should help put proteomic biomarker discovery on the solid ground needed for turning the old promise into a new reality.

Estimation of glomerular filtration rate in liver-transplanted children: comparison of simplified procedures using 51Cr-EDTA and endogenous markers with Sapirstein's method as a reference standard.

This study evaluated simple procedures for GFR determination in 48 liver-transplanted children. After injection of (51)Cr-EDTA, blood samples were obtained up to four h, and activity retention in the body was measured for 60 min with scintillation probes. As a reference, GFR was calculated according to Sapirstein. Simplified calculations were performed according to Brochner-Mortensen, Russel, Devaux and Oberhausen. Additionally, GFR was determined using plasma creatinine and cystatin C according to Schwartz and Filler, respectively. The reference revealed mildly reduced GFR (62 +/- 20 mL/min/1.73 m(2)). Russel's method provided the highest degree of correlation (r(2) = 0.95), the smallest bias in GFR determination (-2%), and only one false exclusion plus one false diagnosis of chronic kidney disease. Oberhausen's method with blood sampling at one h post-injection performed slightly worse (r(2) = 0.67, bias: 3%). All other methods resulted in significantly different GFR estimates compared to the reference. Nevertheless, notably, the second narrowest 95% limits of agreement (-31% to 45%) was observed using cystatin C. In conclusion, this data implies to prefer Russel's method as a simplified procedure, and if patients cannot be available long enough (four h) for measurements, Oberhausen's method instead. If radiotracer methods are not available at all or for screening GFR, cystatin C appears to be the procedure of choice.

Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease.

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.

Prematurity, small for gestational age and perinatal parameters in children with congenital, hereditary and acquired chronic kidney disease.

BACKGROUND: Low birth weight has been identified as a risk factor for chronic kidney disease (CKD). METHODS: We analysed perinatal parameters taken from the National Birth Certificates of 435 children with CKD stages 3-5 of different aetiology and time of onset of CKD. Diseases were classified as congenital with onset of renal disease during fetal life (n = 260; 60%), hereditary as genetically determined with onset after 3 months of life (n = 93; 21%) and acquired CKD (n = 82; 19%). RESULTS: The rates of prematurity and small for gestational age (SGA) were elevated in children with congenital (39.3% and 29.2%), hereditary (24.7% and 22.6%) and acquired CKD (15.5% and 29.3%); these compared to 8% (for both) in the normal population. Newborns with congenital CKD had a significantly lower gestational age [median 38 weeks, interquartile range (IQR) 36-40 weeks] than those with hereditary (39.9 weeks, IQR 37.5-40 weeks) or acquired CKD (40 weeks, IQR 38-40 weeks; P < 0.001). Median birth weight and length were lower in newborns with congenital than in hereditary and acquired diseases [2975 g (IQR 2460-3420 g) versus 3250 g (IQR 2740-3580 g) and 3260 g (IQR 2858-3685 g) (P < 0.01); 49 cm (IQR 47-52) versus 50 cm (IQR 48-52.8) and 51 cm (IQR 49-53) (P < 0.01)]. Head circumference was smaller (P < 0.05), and Apgar scores were lower (P < 0.005) in newborns with congenital diseases than in hereditary and acquired diseases. CONCLUSIONS: Children with congenital CKD had the highest rate of prematurity, a significantly lower birth weight, length, head circumference and Apgar score than newborns with hereditary or acquired CKD. Irrespective of the aetiology of CKD, all of the children had a significantly higher rate of SGA and prematurity than the reference population. We conclude that both SGA and prematurity predispose for advanced renal disease in childhood and that fetal kidney disease impairs fetal growth.

Regional citrate anticoagulation is safe in intermittent high-flux haemodialysis treatment of children and adolescents with an increased risk of bleeding.

BACKGROUND: Regional citrate anticoagulation (RCA) is strongly recommended for adults with an increased risk of bleeding complications. The objective of this retrospective analysis was to evaluate an RCA protocol concerning feasibility and safety in intermittent high-flux haemodialysis (iHD) treatment in children and adolescents. METHODS: Eighteen children and adolescents aged 5-17 years (median 15 years) underwent 74 iHD treatment sessions with RCA. Twelve of 18 patients presented with overt local or diffuse haemorrhage before beginning the HD sessions, and six had an increased risk of haemorrhagic complications. Forty children on acute haemodialysis with general heparin anticoagulation, matched for bleeding risk, age and body surface area, served as a control group. Citrate 3% solution was begun with 3.3% blood flow rate, and calcium gluconate 10% substitution was started with 0.4% of blood flow rate. Citrate flow was adapted to achieve a post-filter ionized calcium of ≤0.30 mmol/L; calcium substitution was adapted to maintain the patients' serum calcium levels within the physiological range. Calcium-free dialysis fluid was used. The blood flow rate ranged from 3 to 5 mL per minute and kilogram body weight. RESULTS: Regional anticoagulation was successfully achieved within the extracorporeal blood circuit, while the coagulation of all 18 patients remained within physiological parameters. No adverse effects of RCA were observed. In all 18 children, neither new haemorrhage nor worsening of the bleeding situation occurred, and in 10/12 patients, bleeding stopped during dialysis with RCA. In contrast, one-third of the control group developed new haemorrhagic complications or presented with worsening of pre-existing bleeding during haemodialysis (P = 0.006). CONCLUSION: RCA is feasible, safe and effective in paediatric intermittent haemodialysis treatment.