Background: Paediatric reference values for novel markers of phosphate homeostasis, bone formation and resorption and their putative relationship to growth are lacking. Methods: A total of 424 healthy children, adolescents and young adults (221 males) aged 0.1–21 y, were enrolled in this cross-sectional study. Height, weight and height velocity were assessed. Plasma/serum samples for determination of C-terminal fragment of fibroblast growth factor-23 (cFGF-23), sclerostin, bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRAP5b) were available from 222, 264, 352 and 338 individuals, respectively. Calculation of cross-sectional centiles and z-scores was based on median (M), standard coefficient of variation (S) and the Box-Cox power (L) of transformation (LMS method) per age cohort. Correlations between variables as well as with growth were assessed. Results: cFGF-23, BAP and TRAP5b were significantly correlated with age (each P < 0.01), with highest values during infancy and adolescence. Serum levels of BAP and TRAP5b were significantly higher in adolescent boys compared with girls (each P < 0.01). In contrast, sclerostin levels were independent of age and gender. BAP and TRAP5b were strongly correlated and both were significantly associated with cFGF-23 and sclerostin as well (each P < 0.01). cFGF-23 was positively correlated with serum phosphate and renal phosphate threshold concentration (each P < 0.01). Height, weight, body mass index and height velocity were weakly correlated with BAP and TRAP5b (each P < 0.05). Conclusions: This study provides age- and gender-related centile charts and z-scores for cFGF-23, BAP, TRAP5b and sclerostin and highlights the link between phosphate homeostasis and markers of bone metabolism during growth.

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin–angiotensin–aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.

Background. Autosomal recessive polycystic kidney disease (ARPKD) [MIM 263200] belongs to a group of congenital hepatorenal fibrocystic syndromes and is caused by mutations in the PKHD1 gene encoding the multidomain protein fibrocystin/polyductin (FPC). The serine-threonine kinase mammalian target of rapamycin (mTOR) is one of the most important gate-keepers integrating numerous signals related to cell proliferation and growth. Whereas the direct activation of mTOR has been shown recently in autosomal-dominant PKD, no data are available on the role of mTOR signalling in proliferation and progression of ARPKD. Methods. Formalin-fixed and paraffin-embedded kidney specimens obtained during nephrectomy from children with ARPKD ( n = 12) were used for immunohistochemical investigation of FPC expression (monoclonal antibody (mAb) 18, mAb 5a), proliferative activity (Ki-67) and activation of the mTOR pathway. Kidney specimens from children ( n = 4) who died from causes not associated with kidney disease served as controls. For the detection of AKT, mTOR and S6K antibodies specifically recognizing the activated (phosphorylated) isoforms of these proteins were used. In all patients mutation analysis of the PKHD1 gene was performed. Results. In 10 out of 12 patients, we could confirm the diagnosis by the identification of PKHD1 mutations. The tubular cyst epithelium of all kidney specimens stained strongly positive with the FPC-specific monoclonal antibody (mAb) 18 but only very faint signals were obtained with mAb 5a. In contrast, healthy kidneys showed rather weak signals with both FPC-specific mAbs, indicating dysregulated expression of FPC in our patients. Phosphorylated AKT as well as activated mTOR and its down-stream effector S6K were strongly expressed in cystic epithelia of all kidney specimens but not in control tissues. No association between the activation of this pathway and the proliferative activity (Ki-67 expression) was observed. Conclusions. Our results point to a central role of AKT/mTOR signalling in ARPKD and justify further investigations to evaluate the therapeutic potential of mTOR inhibitors in ARPKD patients.

Optical coherence tomography (OCT) of the retina and corneal confocal laser scanning microscopy (CLSM) of the subbasal nerve plexus (SBP) are noninvasive techniques for quantification of the ocular neurodegenerative changes in individuals with type 1 diabetes mellitus (T1DM). In adult T1DM patients these changes are hardly related to T1DM only. Instead, ageing and/or lifestyle associated comorbidities have to be considered as putative confounding variables. Therefore, we investigated pediatric T1DM patients (n = 28; 14.2 ± 2.51 y; duration of disease: 5.39 ± 4.16 y) without clinical signs of diabetic retina disease, neuropathy, vasculopathy or nephropathy and compared our findings with those obtained in healthy controls (n = 46; 14.8 ± 1.89 y). The SBP was characterized by the averaged length, thickness, and tortuosity of nerve fibers as well as the number of branching and connecting points. OCT was used to determine the total thickness of the retina (ALL) and the thickness of each retinal layer. Both methods revealed signs of early neurodegenerative changes, e.g. thinning of distinct retinal layers at the pericentral ring and shortening of corneal nerve fibers that are already present in pediatric T1DM patients. Standardization of instruments and algorithms are urgently required to enable uniform comparison between different groups and define normative values to introduce in the clinical setting.

A semi-automated devise for oscillometric measurement (Vicorder) of carotid-femoral pulse wave velocity (cfPWV) has been considered to be especially suited for multicenter studies in children and adolescents. Within a healthy pediatric population (156 boys/158 girls; mean age 10.8 years, range 5.0-19.6 years), the transit time of the pulse wave was measured oscillometrically (Vicorder) between a carotid and femoral cuff. For calculation of cfPWV, the traveled path length was set to 80% of the direct distance between both sites of measurement. Reference tables were generated using the maximum-likelihood curve-fitting technique and SD scores were calculated. Normalizing the same set of data with reference values specific for applanation tonometry yielded Z(at)values. Effects of sex, age, height, weight, BMI, blood pressure (BP), and heart rate on cfPWV as well as the correlation between sex-specific age-related and height-related Z(osci) and Z(at)were investigated. Sex-specific reference values and curves for cfPWV as a function of age and height are presented. cfPWV correlated positively with age, height, weight, SBP, mean arterial BP, and sex (each P < 0.005). Multiple regression analysis identified age, sex, and mean arterial pressure as significant independent predictors of cfPWV explaining 42% of the overall variability. Strong linear relationships between Z(osci) and Z(at) were noted and per sex a set of age and height-related equation for conversion was derived: Z(at),age = -0.22 + 0.68 × Z(osci),age; r = 0.98 and Z(at),height = -0.33 + 0.66 × Z(osci),height; r = 0.99 in boys and Z(at),age = -0.61 + 0.81 × Z(osci),age; r = 0.98 and Z(at),height = -0.73 + 0.72 × Z(osci),height; r = 0.97 in girls (each P < 0.001). A strong linear association between height-related oscillometric and tonometric Z-scores was observed. Age-related Z-scores are of limited value when comparing results across different populations and methods.

The term chronic kidney disease-mineral bone disorder has been coined recently to highlight that the disturbed mineral and bone metabolism is a major contributor to vascular calcification and finally cardiovascular disease. This syndrome is characterized by clinical, biochemical and/or histological findings, i.e. i) biochemical alterations in the homeostasis of calcium, phosphate and their key player parathyroid hormone (PTH), Fibroblast growth factor-23 (FGF-23), klotho and vitamin-D, ii) the occurrence of vascular and/or soft tissue calcification, and iii) an abnormal bone structure and/or turnover. Apart from the combined and synergistic action of "traditional" and uremia-related risk factors, promoters and inhibitors of calcification have to be considered as well. This review will focus on the disturbed mineral metabolism as the triggering force behind distortion of vascular integrity and cardiovascular malfunction in CKD patients.