Long-term follow-up results of patients with ADCK4 mutations who have been diagnosed in the asymptomatic period: effects of early initiation of CoQ10 supplementation.

Atmaca M, Gülhan B, Atayar E, Karabay Bayazit A, Candan C, Arici M, Topaloglu R, Özaltin F. Long-term follow-up results of patients with ADCK4 mutations who have been diagnosed in the asymptomatic period: effects of early initiation of CoQ10 supplementation. Turk J Pediatr 2019; 61: 657-663. ADCK4-related glomerulopathy is a recently recognized clinical entity associated with insidious onset in young children and a high potential to progress to chronic kidney disease in adolescents. Early initiation of exogenous coenzyme Q10 (CoQ10) supplementation in the asymptomatic period could be protective on renal functions. In the present study, we aimed to investigate long-term follow-up of patients that we have diagnosed during the asymptomatic period and in whom we started CoQ10 treatment. We analyzed long-term effects of CoQ10 on proteinuria and estimated glomerular filtration rate (eGFR) in this patient population. A total of 8 patients (4 female, 4 male) from 6 different families were included. The mean age at diagnosis and at last visit were 16.8±11.2 years and 20.7±11.7 years, respectively. None of the patients had extrarenal system involvement. At the time of initiation of treatment; median eGFR was 107.8 ml/min/1.73 m2, median proteinuria was 1008 mg/m2/day. After a median follow-up period of 25.3±5.8 months, median proteinuria decreased to 318.5 mg/m2/day (p=0.03) and median eGFR remained stable at 99.6 ml/min/1.73 m2 (p=0.21). Coenzyme Q10 treatment is effective for reducing proteinuria and seems to be renoprotective.

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.

Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment.

BACKGROUND: ADCK4-related glomerulopathy is an important differential diagnosis in adolescents with steroid-resistant nephrotic syndrome (SRNS) and/or chronic kidney disease (CKD) of unknown origin. We screened adolescent patients to determine the frequency of ADCK4 mutation and the efficacy of early CoQ10 administration. METHODS: A total of 146 index patients aged 10-18 years, with newly diagnosed non-nephrotic proteinuria, nephrotic syndrome, or chronic renal failure and end-stage kidney disease (ESKD) of unknown etiology were screened for ADCK4 mutation. RESULTS: Twenty-eight individuals with bi-allelic mutation from 11 families were identified. Median age at diagnosis was 12.4 (interquartile range [IQR] 8.04-19.7) years. Upon first admission, all patients had albuminuria and 18 had CKD (6 ESKD). Eight were diagnosed either through the screening of family members following index case identification or during genetic investigation of proteinuria in an individual with a history of a transplanted sibling. Median age of these 8 patients was 21.5 (range 4.4-39) years. CoQ10 supplementation was administered following genetic diagnosis. Median estimated glomerular filtration rate (eGFR) just before CoQ10 administration was 140 (IQR 117-155) ml/min/1.73m2, proteinuria was 1,008 (IQR 281-1,567) mg/m2/day. After a median follow-up of 11.5 (range 4-21) months following CoQ10 administration, proteinuria was significantly decreased (median 363 [IQR 175-561] mg/m2/day, P=0.025), whereas eGFR was preserved (median 137 [IQR 113-158] ml/min/1.73m2, P=0.61). CONCLUSIONS: ADCK4 mutations are one of the most common causes of adolescent-onset albuminuria and/or CKD of unknown etiology in Turkey. CoQ10 supplementation appears efficacious at reducing proteinuria, and may thereby be renoprotective.

Cardiovascular Phenotypes in Children with CKD: The 4C Study.

BACKGROUND AND OBJECTIVES: Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m2. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. RESULTS: A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. CONCLUSIONS: The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.

Genetic, Environmental, and Disease-Associated Correlates of Vitamin D Status in Children with CKD.

BACKGROUND AND OBJECTIVES: Vitamin D deficiency is endemic in children with CKD. We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5. All patients were participants of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study, had CKD stage 3-5, and were age 6-18 years old. Patients were genotyped for single-nucleotide polymorphisms in the genes encoding 25-hydroxylase, vitamin D binding protein, 7-dehydrocholesterol reductase, and 24-hydroxylase. Associations of genetic status, season, local solar radiation, oral vitamin D supplementation, and disease-associated factors with vitamin D status were assessed. RESULTS: Two thirds of patients were vitamin D deficient (25-hydroxy-vitamin D <16 ng/ml). 25-Hydroxy-vitamin D concentrations varied with season and were twofold higher in vitamin D-supplemented patients (21.6 [14.1] versus 10.4 [10.1] ng/ml; P<0.001). Glomerulopathy, albuminuria, and girls were associated with lower 25-hydroxy-vitamin D levels. 24,25-dihydroxy-vitamin D levels were closely correlated with 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D (r=0.87 and r=0.55; both P<0.001). 24,25-dihydroxy-vitamin D concentrations were higher with higher c-terminal fibroblast growth factor 23 and inversely correlated with intact parathyroid hormone. Whereas 25-hydroxy-vitamin D levels were independent of renal function, 24,25-dihydroxy-vitamin D levels were lower with lower eGFR. Vitamin D deficiency was more prevalent in Turkey than in other European regions independent of supplementation status and disease-related factors. Single-nucleotide polymorphisms in the vitamin D binding protein gene were independently associated with lower 25-hydroxy-vitamin D and higher 24,25-dihydroxy-vitamin D. CONCLUSIONS: Disease-related factors and vitamin D supplementation are the main correlates of vitamin D status in children with CKD. Variants in the vitamin D binding protein showed weak associations with the vitamin D status.

Traditional and "new" cardiovascular risk markers and factors in pediatric dialysis patients.

Cardiovascular disease (CVD) is the principal cause of mortality in patients with end-stage renal disease (ESRD). The aim of this study was to analyze carotid intima-media thickness (cIMT), endothelium-dependent dilatation (EDD), and left ventricular mass index (LVMI) as the cardiovascular risk markers and to investigate the independent risk factors of these markers in pediatric dialysis patients. This study included 39 children and adolescents undergoing dialysis (15 hemodialysis and 24 peritoneal dialysis) and 15 age- and gender-matched healthy subjects. The cIMT and EDD were assessed by high-resolution ultrasound, and LVMI was calculated from standard echocardiographic measurements. Compared with control subjects, cIMT standard deviation scores (SDS), LVMI, total homocysteine (tHcy), and high-sensitivity C-reactive protein (hs-CRP) values were significantly higher in patients, but EDD values did not differ. The mean hs-CRP level was significantly higher in hemodialysis (HD) patients than in peritoneal dialysis (PD) patients. The cIMT-SDS and LVMI were associated with several variables in univariate analysis. Stepwise linear regression analysis, indexed SBP (p = 0.017), and hemoglobin (p = 0.001) turned out to be independent variables for predicting LVMI, and a significant predictor of cIMT was indexed diastolic blood pressure (DBP) (p = 0.035). The causes of atherosclerosis and left ventricular hypertrophy are multifactorial in children and adolescents with ESRD. Better management of hypertension and anemia may be priorities for preventing or improving CVD in these patients.

Coronary artery calcifications in children with end-stage renal disease.

Coronary artery calcification (CAC) is common in adults with end-stage renal disease (ESRD), but little is known about the prevalence and the extent of it in children. We used multidetector spiral computed tomography (MDCT), echocardiography, and carotid and brachial high-resolution ultrasonography to screen for the presence and predisposing factors of CAC in 53 children with ESRD [15 hemodialysis (HD) patients, 24 peritoneal dialysis (PD) patients, and 14 renal transplant (rTx) recipients]. CAC was present in 15% of patients (three HD patients, three PD patients, and two rTx). The mean age of the patients with CAC was 16.4 years (range: 11.0-21.2 years), and their median CAC score was 101.3, ranging from 8.5 to 4,322 according to the Agatston method. The patients with CAC had longer duration of total dialysis (P=0.005), had higher time-integrated serum phosphorus (P<0.001), calcium-phosphate (CaxP) product (P=0.012), intact parathyroid hormone (P=0.010), vitamin B(12) levels (P=0.010), the amount of cumulative calcium-containing oral phosphate binders (OBPs) (P<0.001), and calcitriol intake (P<0.001), and had lower serum hemoglobin level (P=0.014). Interventricular septum systolic thickness (P=0.033) was significantly higher, relative wall thickness (P=0.062) tended to be higher, and flow-mediated endothelium-dependent dilatations (P=0.071) were lower without reaching statistically significant levels in those with CAC. A stepwise logistic regression analysis revealed that serum phosphorus (P=0.018) and the cumulative exposure to calcium-containing OPBs (P=0.016) were the most significant independent predictors in the development of CAC. These results indicate that even adolescents and children with ESRD may have coronary calcifications. We concluded that impaired divalent ion metabolism is the main factor in the formation of CAC in this age group.