Discontinuation of RAAS Inhibition in Children with Advanced CKD.

BACKGROUND AND OBJECTIVES: Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this study, 69 children with CKD (67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73 m2) who discontinued RAASi during prospective follow-up were included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during a median of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling. RESULTS: Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declined more rapidly after discontinuation of RAASi (-3.9 ml/min per 1.73 m2 per year; 95% confidence interval, -5.1 to -2.6) compared with the slope during RAASi treatment (-1.5 ml/min per 1.73 m2 per year; 95% confidence interval, -2.4 to -0.6; P=0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued. CONCLUSIONS: Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD.

Leukocyte matrix metalloproteinase and tissue inhibitor gene expression patterns in children with primary hypertension.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in cardiovascular remodeling. The aim of the study was to analyze MMP/TIMP genes expression in peripheral blood leukocytes of 80 hypertensive children (15.1 ± 2.0 years) in comparison with age-matched 78 normotensive children (14.6 ± 2.0 years; n.s.). TIMP and MMP expression in peripheral blood leukocytes was assessed by quantitative real-time PCR. Hypertensive children independently of age, sex, and body mass index had greater expression of MMP-2 than normotensive controls (p = 0.0001). Patients with left ventricular hypertrophy had greater expression of MMP-14 than patients with normal left ventricular mass (p = 0.006) and TIMP-2 expression correlated with carotid wall cross-sectional area (p = 0.03; r = 0.238). MMP-14 expression correlated with BMI-SDS (p = 0.001; r = 0.371), waist circumference-SDS (p = 0.016; r = 0.290), hsCRP (p = 0.003; r = 0.350), serum HDL-cholesterol (p = 0.008; r = -0.304), and serum uric acid (p = 0.0001; r = 0.394). In conclusion, hypertensive adolescents presented significant alterations of MMP/TIMP expression pattern in comparison with normotensive peers. Moreover, altered MMP/TIMP expression was associated with hypertensive target organ damage and metabolic abnormalities.

Regulatory T-cell subset distribution in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage.

BACKGROUND: The relationship between circulating regulatory T-cell (Tregs) subset distribution and hypertension severity in children with primary hypertension is not known. We aimed to find out if target organ damage (TOD) in children with primary hypertension is related to defects in Tregs distribution reflected by their phenotype characteristics. METHODS: The study constituted 33 nontreated hypertensive children and 35 sex-matched and age-matched controls. Using multicolor flow cytometry technique, we assessed a distribution of the total Tregs (CD4CD25CD127) and their subsets (CD45RA-naive Tregs, CD45RA memory/activated Tregs, CD45RACD31 recent thymic emigrants Tregs and mature naive CD45RACD31 Tregs) in the whole blood. RESULTS: Hypertensive children showed decreased percentage of the total Tregs, the CD45RA-naive Tregs, the total CD31 Tregs and the recent thymic emigrants Tregs but elevation of the CD45RA memory/activated Treg and mature naive CD45RACD31 Tregs. Decreased frequency of the total Tregs, naive Tregs and CD31-bearing Treg cell subsets (CD31 total Tregs, CD45RACD31 recent thymic emigrants Tregs) negatively correlated to TOD markers, arterial stiffness and blood pressure elevation. In contrast, increased percentage of memory Tregs and CD31 Tregs subsets positively correlated to organ damage markers, arterial stiffness and blood pressure values. These changes were independent of BMI, age, sex and hsCRP. CONCLUSION: Both diagnosis of hypertension, TOD and arterial stiffness in hypertensive children were associated with decreased population of total CD4 Tregs, limited output of recent thymic emigrants Tregs, and increased pool of activated/memory Tregs. Hypertension was an independent predictor of the circulating Treg subsets distribution irrespective of hsCRP.

Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study.

INTRODUCTION: Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD. METHODS: Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ±â€Š3.2 years, estimated glomerular filtration rate 29 ±â€Š12 ml/min per 1.73 m). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension. RESULTS: Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT. CONCLUSION: INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function.

Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children.

Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m2. uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m2, and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m2, or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.

Central systolic blood pressure and central pulse pressure predict left ventricular hypertrophy in hypertensive children.

BACKGROUND: Central systolic and pulse pressures are stronger predictors of cardiovascular risk and hypertensive organ damage than brachial blood pressure. It is suggested that isolated systolic hypertension typically seen in adolescents is associated with normal central blood pressure and does not lead to organ damage and this phenomenon is called spurious hypertension. METHODS: We assessed the prevalence of spurious hypertension and analyzed utility of pulse wave analysis as determinant of hypertensive organ damage in 294 children (62 girls; 15.0 ± 2.4 years) diagnosed as primary hypertension. White coat hypertension, ambulatory prehypertension, ambulatory hypertension, and severe ambulatory hypertension were diagnosed in 127, 29, 41, and 97 patients, respectively. RESULTS: Normal central blood pressure was found in 100% in patients with white coat hypertension, 93% in pre-hypertensives, 51.2% in those with ambulatory hypertension, and 27.8% with severe ambulatory hypertension (p = 0.0001). Children with severe ambulatory hypertension had higher central systolic and pulse pressure, pulse wave velocity, and greater prevalence of left ventricular hypertrophy than white coat and prehypertensive children (p < 0.05). Left ventricular mass index and carotid intima-media thickness correlated with central systolic and pulse pressure (p < 0.05 for all). Receiver operating curve area was similar for augmentation pressure (0.5836), 24-h ambulatory systolic blood pressure (0.5841), central systolic blood pressure (0.6090), and central pulse pressure (0.5611) as predictors of left ventricular hypertrophy. CONCLUSIONS: These findings suggest that pulse wave analysis is complementary to ambulatory blood pressure monitoring in assessment of risk of organ damage in hypertensive adolescents.

Loss of CD31 receptor in CD4+ and CD8+ T-cell subsets in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage.

BACKGROUND: Primary hypertension is associated with still poorly known T-cell dependent immunity defects that participate in the disease development. However, the relationship between peripheral T-cell subset distribution and disease severity in humans is not known. The aim of the study was to find out if target organ damage in adolescents with primary hypertension is associated with thymus-dependent lymphocytes renewal reflected by changes in the T-cell subset phenotype characteristics. METHODS: Using seven-color flow cytometry technique, we assessed CD31, CCR7 and CD28 receptors expression in CD45RA and CD45RO bearing peripheral CD4 and CD8 T-cell subsets. The study included 32 hypertensive children/adolescents and 35 sex-matched and age-matched controls. RESULTS: Children with primary hypertension had slightly increased CD4 T-cell pool but decreased population of CD31 expressing CD4 T-cell subsets (recent thymic emigrants). Frequency of the CD4 and CD4/CD45RA+ T cells lacking CD31 correlated positively with the hypertensive organ damage markers (pulse wave velocity, central blood pressure, left ventricular mass index). Left ventricular hypertrophy was associated with decreased CD4/CD45RA:CD4/CD45RO ratio, loss of the CD31 receptor in the CD4 and CD8 T-cell subsets and increased population of effector/memory T cells bearing CD8/CD28 and CD8/CD45RA+/CCR7 phenotype. Regression analysis revealed that these associations were independent of age, sex, and BMI. CONCLUSION: The results suggest that subclinical arterial injury and left ventricular hypertrophy in adolescents with primary hypertension is associated with declined thymic function and increased pool of T cells bearing effector/memory phenotype.

Prevalence of Hypertension in Children with Early-Stage ADPKD.

BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected. RESULTS: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; P=0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; P=0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; P=0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; P=0.10). CONCLUSIONS: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.

Background: Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods: Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results: Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions: CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Metabolic acidosis is common and associates with disease progression in children with chronic kidney disease.

Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. The eGFR and serum bicarbonate were measured every six months. At baseline, the median eGFR was 27 ml/min/1.73m2 and median serum bicarbonate level 21 mmol/l. During a median follow-up of 3.3 years, the prevalence of metabolic acidosis (serum bicarbonate under 22 mmol/l) was 43%, 60%, and 45% in CKD stages 3, 4, and 5, respectively. In multivariable analysis, the presence of metabolic acidosis as a time-varying covariate was significantly associated with log serum parathyroid hormone through the entire follow-up, but no association with longitudinal growth was found. A total of 211 patients reached the composite endpoint (ESRD or 50% decline in eGFR). In a multivariable Cox model, children with time-varying serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15). Thus, metabolic acidosis is a common complication in pediatric patients with CKD and may be a risk factor for secondary hyperparathyroidism and kidney disease progression.

Altered matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 levels in children with primary hypertension.

BACKGROUND: Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are involved in cardiovascular remodeling in hypertension. Because metabolic abnormalities typical of metabolic syndrome is the dominant phenotype of primary hypertension in children, we hypothesized that MMP-9 and TIMP-1 plasma concentrations are altered in hypertensive children and correlate with metabolic abnormalities and target organ damage. METHOD: A total of 109 children (15.6, 10-17 years) with untreated primary hypertension were included to the study. The control group consisted of 74 healthy, normotensive children. RESULTS: Plasma MMP-9, TIMP-1 concentrations, and MMP-9/TIMP-1 ratio were significantly elevated in hypertensive boys in comparison with normotensive boys (P = 0.0001, P = 0.04, and P = 0.001, respectively), whereas there were no differences between hypertensive and normotensive girls. The levels of MMP-9 and TIMP-1 as well as MMP-9/TIMP-1 ratio were not associated either with hypertension stage, left ventricular hypertrophy, or carotid intima-media thickness. However, in a subgroup of 30 hypertensive patients in whom arterial stiffness was measured, TIMP-1 concentrations correlated with aortic pulse pressure (P < 0.05; r = 0.367), augmentation pressure (P < 0.05; r = 0.428), and augmentation index (P < 0.05; r = 0.404).Only hypertensive boys presented negative correlations of both MMP-9 and TIMP-1 levels with high-density lipoprotein cholesterol (r = -0.254, P = 0.01 and r = -0.241, P = 0.02, respectively). CONCLUSION: Hypertensive boys but not girls had elevated MMP-9 and TIMP-1 plasma concentrations, which indicates sex-related role of MMP/TIMP system in pediatric hypertension. The correlation between serum TIMP-1 and markers of arterial stiffness indicates on the involvement of TIMPs in arterial remodeling.

Primary hypertension is a disease of premature vascular aging associated with neuro-immuno-metabolic abnormalities.

There is an increasing amount of data indicating that primary hypertension (PH) is not only a hemodynamic phenomenon but also a complex syndrome involving abnormal fat tissue distribution, over-activity of the sympathetic nervous system (SNS), metabolic abnormalities, and activation of the immune system. In children, PH usually presents with a typical phenotype of disturbed body composition, accelerated biological maturity, and subtle immunological and metabolic abnormalities. This stage of the disease is potentially reversible. However, long-lasting over-activity of the SNS and immuno-metabolic alterations usually lead to an irreversible stage of cardiovascular disease. We describe an intermediate phenotype of children with PH, showing that PH is associated with accelerated development, i.e., early premature aging of the immune, metabolic, and vascular systems. The associations and determinants of hypertensive organ damage, the principles of treatment, and the possibility of rejuvenation of the cardiovascular system are discussed.

Associations of the eNOS G894T gene polymorphism with target organ damage in children with newly diagnosed primary hypertension.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) G894T gene polymorphism is associated with the risk of primary hypertension (PH) and vascular complications in adults with PH. METHODS: We explored the associations of the G894T polymorphism with 24-h ambulatory blood pressure, left ventricular mass (LVM), carotid intima media thickness (cIMT), urinary albumin excretion, oxidative stress and inflammatory parameters in 126 children with newly diagnosed PH and in 83 healthy children. RESULTS: Among the 126 children with PH 92 (73%) had ambulatory hypertension and 34 (27%) had severe ambulatory hypertension. Left ventricular hypertrophy (LVH) was detected in 39 (31%) patients, cIMT of >2 standard deviation scores in 21 (16.6%) patients, albuminuria of >30 mg/24 h in 18 (14.3%) patients and metabolic syndrome (MS) in 22 (17.5%) patients. The frequency of the T allele was 52.4% in the PH group and 54.2% in the control group (not significant), and in both groups the frequency of the T allele was consistent with the Hardy-Weinberg equilibrium. Compared with G allele carriers, hypertensive T allele carriers had increased cIMT (p < 0.05) and more severe albuminuria (not significant, p = 0.1); there was no difference between the groups in hypertension severity and LVM. T and G allele distribution did not differ between patients with and without metabolic syndrome. No significant correlations between the assessed parameters and the eNOS G894T gene polymorphism were found in the controls, although T allele carriers tended to have an increased cIMT (p = 0.09). CONCLUSION: The eNOS T allele is not more prevalent among hypertensive children than among healthy ones, but it is associated with early vascular damage in children with PH, independent of metabolic abnormalities. No associations between the eNOS G894T polymorphism and metabolic abnormalities were found.

Expression of Adiponectin Receptors on Peripheral Blood Leukocytes of Hypertensive Children Is Associated with the Severity of Hypertension.

The aim of the study was to find out whether peripheral blood leukocyte adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) protein expression patterns (flow cytometry) differ between the primary hypertension children (n = 57) and healthy controls (n = 19) and if their expression levels are related to selected clinical parameters. The group of 26 patients [AdipoR(-)] showed lower and the group of 31 patients [AdipoR(+)] showed higher AdipoRs protein expression than the control and each other (P < 0.01 for neutrophils, P < 0.05 for monocytes). The AdipoR(+) leukocytes expressed higher AdipoR1 mRNA levels (RT-PCR) than AdipoR(-) ones and controls (P = 0.022 and P = 0.007, resp.). Despite greater BMI, the AdipoR(-) patients had unchanged serum adiponectin levels. In contrast, AdipoR(+) patients had lower serum adiponectin concentrations than the AdipoR(-) ones and controls (P < 0.001). The AdipoR(+) patients had higher blood pressure (P = 0.042) and greater carotid intima-media thickness (P = 0.017) than the AdipoR(-) ones. The stage of hypertension was associated with increased neutrophil but not monocyte AdipoR1 density (AdipoR1 MFI) (P < 0.05). Severe ambulatory hypertension was presented more often in AdipoR(+) patients than in AdipoR(-) ones (51.6% versus 26.9%, resp.; P < 0.01). In conclusion, neutrophil AdipoRs upregulation was associated with early stages of vascular injury, hypertension severity, and low serum levels of adiponectin.

Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome.

BACKGROUND: The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multi-systemic disorder, almost always characterized by the triad of congenital cataract, cognitive and behavioral impairment and a proximal tubulopathy. METHODS: Twenty-eight novel patients with suspected Lowe syndrome were studied. RESULTS: All patients carried OCRL gene defects with mutational hot spots at CpG dinucleotides. Mutations previously unknown in Lowe syndrome were observed in ten of the 28 patients, and carriership was identified in 30.4 % of the mothers investigated. Mapping the exact breakpoints of a complete OCRL gene deletion revealed involvement of several flanking repeat elements. We noted a similar pattern of documented clinically relevant symptoms, and even though the patient cohort comprised relatively young patients, 32 % of these patients already showed advanced chronic kidney disease. Thrombocytopenia was seen in several patients, and hyperosmia and/or hyperacusis were reported recurrently. A p.Asp523Asn mutation in a Polish patient, associated with the typical cerebrorenal spectrum but with late cataract (10 year), was also evident in two milder affected Italian brothers with ocular involvement of similar progression. CONCLUSIONS: We have identified clinical features in 28 patients with suspected Lowe syndrome that had not been recognized in Lowe syndrome prior to our study. We also provide further evidence that OCRL mutations cause a phenotypic continuum with selective and/or time-dependent organ involvement. At least some of these mutants might exhibit a genotype-phenotype correlation.

Metabolic syndrome in children with chronic kidney disease and after renal transplantation.

Visceral obesity and metabolic abnormalities typical for metabolic syndrome (MS) are the new epidemic in adolescence. MS is not only the risk factor for cardiovascular disease but also for chronic kidney disease (CKD). Thus, there are some reasons to recognize MS as a new challenge for pediatric nephrologists. First, hypertensive and diabetic nephropathy, the main causes of CKD in adults, both share the same pathophysiological abnormalities associated with visceral obesity and insulin resistance and have their origins in childhood. Secondly, as the obesity epidemic also affects children with CKD, MS emerges as the risk factor for progression of CKD. Thirdly, metabolic abnormalities typical for MS may pose additional risk for cardiovascular morbidity and mortality in children with CKD. Finally, although the renal transplantation reverses uremic abnormalities it is associated with an exposure to new metabolic risk factors typical for MS and MS has been found to be the risk factor for graft loss and cardiovascular morbidity after renal transplantation. MS is the result of imbalance between dietary energy intake and expenditure inducing disproportionate fat accumulation. Thus, the best prevention and treatment of MS is physical activity and maintenance of proper relationship between lean and fat mass.

Vitamin D status, body composition and hypertensive target organ damage in primary hypertension.

Overweight/obesity and high blood pressure during growth period are important risk factors of cardiovascular disease later in life. Cardiovascular system, fat and muscles are among target tissues for vitamin D and low 25(OH)D levels are likely to attenuate potential benefits of its action. The study was aimed to evaluate vitamin D status and body composition in children and adolescents with primary hypertension (PH). The study population comprised 78 patients aged 15.4±2.3yrs (9-18yrs; 15 girls) with diagnosed PH. Total 25(OH)D and parathyroid hormone (PTH) were assayed by Cobas e411 machine (Roche Diagnostics). DXA (Prodigy, GE Lunar) was used to assess total body bone mineral content (TBBMC; g), total body bone mineral density (TBBMD; g/cm(2)), lean body mass (LBM; g), % lean body mass (%LBM), fat mass (FM; g), % fat mass (% FM), Android %Fat, Gynoid %Fat and Trunk fat mass (Trunk FM; g). Hypertensive cases (BMI=25.6±4.2kg/m(2)), compared to reference, had slightly increased TBBMD and TBBMC Z-scores (+0.40±0.91 and +0.59±0.96; both p<0.001), and had markedly increased FM and FM/body weight ratio Z-scores of ±1.83±1.63 (p<0.0001) and +1.43±1.05 (p<0.0001). LBM Z-scores were slightly increased as well (+0.34±1.08, p<0.001). In contrast, markedly reduced LBM/body weight ratio Z-scores of -1.47±0.90 (p<0.0001) and disturbed relationship between FM and LBM as assessed by FM/LBM ratio Z-score of +1.53±1.29 (p<0.0001) were noted. The average serum levels of 25(OH)D of 17.8±6.9ng/mL and PTH of 34.8±16.8pg/mL were noted in PH group. 91% PH cases showed 25(OH)D levels lower than 30ng/mL. 71% of PH subjects revealed vitamin D deficiency (25(OH)D<20ng/ml). 10% of PH cases showed 25(OH)D levels lower than 10ng/mL. 25(OH)D levels negatively correlated with PTH showing r=-0.24 (p=0.03). Absolute LBM/body weight ratio values positively correlated with 25(OH)D levels (r=0.31; p=0.01). In contrast, absolute FM/body weight ratio values correlated negatively with 25(OH)D levels (r=-0.32; p<0.01). Moreover, 25(OH)D levels negatively correlated with absolute Trunk FM (r=-0.29; p<0.05), Android %Fat (r=-0.32; p<0.01) and with Gynoid %Fat (r=-0.28; p<0.05). PTH and 25(OH)D concentrations did not differ when severity of hypertension, left ventricular mass and carotid intima-media thickness were controlled for. Concluding, higher muscle mass stores in body weight coincided with higher 25(OH)D levels. Higher fat mass stores coincided with lower 25(OH)D levels in PH group. Whether vitamin D insufficiency/deficiency in PH group should be considered as a cause of disease or epiphenomenon remains unknown. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.