Stricter Blood Pressure Control Is Associated With Lower Left Ventricular Mass in Children After Kidney Transplantation: A Longitudinal Analysis of the 4C-T Study.

BACKGROUND: We assessed the effect of blood pressure (BP) control on left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH). METHODS: Ninety-six patients (64 males) ≥9 months post-kidney transplantation from the 4C-T (Cardiovascular Comorbidity in Children with Chronic Kidney Disease and Transplantation) study were analyzed longitudinally (mean follow-up, 2.6±1.3 years). Cumulative systolic blood pressure (SBP)/diastolic BP exposure was calculated as a time-averaged area under the curve and categorized: ≤50th, 50th to ≤75th, 75th to ≤90th, and >90th percentile (pct). We performed adjusted linear and logistic mixed models for LVMI and LVH, respectively. RESULTS: At baseline, LVMI was 49.7±12.7g/m2.16 with 64% (n=61) kidney transplantation recipients displaying LVH. Compared with patients with cumulative SBP exposure >90th pct, patients with cumulative SBP of 50th to ≤75th showed a significant LVMI reduction of -5.24g/m2.16 (P=0.007). A similar tendency was seen for cumulative SBP≤50th (ß=-3.70 g/m2.16; P=0.067), but patients with cumulative SBP of 75th to ≤90th pct showed no reduction. A post hoc analysis in patients with cumulative SBP≤75th revealed that median SBP exposure was at 57.5th pct. For cumulative diastolic BP, a significant LVMI reduction was seen in all 3 categories ≤90th pct compared with patients >90th pct. Patients with cumulative SBP of ≤50th or 50th to ≤75th pct showed 79% or 83% lower odds of developing LVH, respectively. Patients with cumulative diastolic BP ≤50th showed a tendency of 82% lower odds for LVH (95% CI, 0.03-1.07). CONCLUSIONS: Stricter BP control led to regression of LVMI and LVH. Our data suggest a BP target below the 60th pct, which needs to be substantiated in a randomized controlled trial.

Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study.

BACKGROUND: Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions. METHODS: In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. FINDINGS: 659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5·6% [95% CI -8·6 to -2·7] vs 1·0% [-1·9 to 3·9], p<0·0001, in ESCAPE; -6·2% [-7·3 to -5·0] vs -1·5% [-2·9 to -0·1], p<0·0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0·27 [95% CI 0·14 to 0·55], p=0·0003, number needed to treat 4·0 [95% CI 3·7 to 4·4] vs 250·0 [66·9 to ∞]) and the need for kidney replacement therapy (HR 0·33 [0·13 to 0·85], p=0·021, number needed to treat 6·7 [6·1 to 7·2] vs 31·0 [27·4 to 35·9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0·0001). INTERPRETATION: Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering. FUNDING: None.

Sepsis associated acute kidney injury in pediatric intensive care unit.

BACKGROUND: We aimed to compare the acute kidney injury (AKI) incidence in pediatric septic shock patients according to the three different classifications. METHODS: We analyzed retrospectively 52 patients with severe sepsis between January 2019 and December 2019. RESULTS: While 21 patients have been diagnosed with SA-AKI according to the pRIFLE criteria, 20 children have been diagnosed according to the AKIN criteria, and 21 children have been diagnosed according to the KDIGO criteria. Older age, lower platelet count were determined as independently risk factor for SA-AKI. Older age and higher PRISM score were associated with mortality. According to Canonical correlation coefficients, pRIFLE is the most successful classification to distinguish AKI state. The canonical correlation coefficients for pRIFLE, KDIGO, and AKIN were 0.817, 0.648, and 0.615, respectively. CONCLUSION: Although AKI incidence was similar between the three classifications, pRIFLE was the most successful classification to distinguish AKI state.

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.

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.

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.

Cardiovascular functional and structural changes in children with primary hypertension.

BACKGROUND: Primary hypertension in children is not a benign condition because of end-organ damage. Early investigations of cardiovascular effects rely on vascular structural and functional changes. We aimed to determine presence of early cardiovascular involvement in children with primary hypertension. For this purposes, we investigated functional and morphological changes in vascular system. METHODS: Seventy-five consecutive patients with primary hypertension and 35 healthy children comparable for age and gender were studied. Patients were classified according to the stages of blood pressure. Intima-media thickness of the carotid arteries (cIMT), carotid-femoral pulse wave velocity (PWVcf) and Pulse Wave Augmentation Index (AIx) and Left Ventricular Mass Index (LVMi) were investigated. RESULTS: PWVcf and AIx were higher in patients (5.87±0.87 m/s vs. 5.29±0.67 m/s, P=0.02; 9.41±8.54% vs. 8.36±3.59%, P=0.04, respectively) than in controls. cIMT was evaluated significantly higher in study group than controls (0.46±0.06 mm vs. 0.35±0.12 mm, respectively, P=0.01). The mean LVMi was higher in patients (32.9±11.5 vs. 28.8±1.55, P=0.01). CONCLUSION: Our results demonstrated that vascular findings were more sensitive for target organ changes than the more frequently utilized LVMi in patients with pre-hypertension.

Are we late for the diagnosis of acute kidney injury in the intensive care units in pediatric patients? A preliminary, retrospective observational study among 66 patients.

BACKGROUND: The purposes of this study were to emphasize the importance of Risk, Injury, Failure, Loss, and End-Stage (RIFLE) classification in early diagnose and prognosis of acute kidney injury (AKI), and to evaluate the practicability of the RIFLE criteria in intensive care units. METHODS: Sixty-six patients applied acute peritoneal dialysis were included into the study. Patients having acute peritoneal dialysis within the first 24 hours of intensive care unit admission were named group 1, between 24-48 hours group 2, and those who had acute peritoneal dialysis 48 hours or more after admission to the intensive care unit were named group 3. Retrospectively, we evaluated patients by RIFLE criteria at the consultation time, and patients who had been just in AKI were called late referral patients. The mean interval time between the onset of AKI and the consultation time was defined as delay time in late referral patients. RESULTS: There were 20 patients in group 1, 15 were in group 2 and 31 in group 3. In total there were 18/66 patients in risk, 13/66 in injury while 35/66 in failure. There was statistically difference between delay times of in risk and failure class in group 3 (P<0.05). Also delayed patient numbers of both risk and failure class were found statistically highly significant (P<0.001). CONCLUSIONS: Most of the patients were in failure class at the time of consultation. We guess that if they would have been diagnosed earlier, prognosis might have been better. Therefore early diagnosis of AKI with RIFLE criteria and early initiation of acute peritoneal dialysis would probably improve prognosis.

The long-term outlook to final outcome and steroid treatment results in children with idiopathic nephrotic syndrome.

Idiopathic Nephrotic Syndrome (INS) was defined as combination of a nephrotic syndrome and non-specific histological abnormalities of the kidney. Among these abnormalities, minimal change nephrotic syndrome (MCNS) is the most common. We report our experience with MCNS; its clinical course, treatments and outcomes. One-hundred twenty children (66 male, 54 female) with MCNS, admitted to Nephrology Department between 1987-2009 was assessed. Their clinical presentations, treatment and disease courses were reviewed. The mean duration of follow-up was 11.5 ± 1.9 years. Initially, all patients given prednisone 2 mg/kg/ day single dose per four weeks a followed by eight weeks of the same daily dose given every other day. After week 12, prednisone was progressively tapered off at the rate of 0.5 mg/kg per 15 daily intervals until complete discontinuation had been achieved by week 16. Steroid resistance was accepted as no achievement of remission following four weeks of prednisone 2 mg/kg/day followed by three intravenous pulses of corticosteroids. At the end of the initial steroid treatment, 106 (88.3%) patients were determinate steroid responsive while 14 (11.7%) patients were steroid resistance. Thirty-eight patients underwent biopsy. At the end of study recovery rate was increased from 88.3% to 94.1%. In conclusion, most of patients entered remission by our therapy end of follow up time. With the support of our satisfactory results among the whole study group, long-term prednisolone treatment still remains valid.

The long-term outlook to final outcome and steroid treatment results in children with idiopathic nephrotic syndrome.

Idiopathic Nephrotic Syndrome (INS) was defined as combination of a nephrotic syndrome and non-specific histological abnormalities of the kidney. Among these abnormalities, minimal change nephrotic syndrome (MCNS) is the most common. We report our experience with MCNS; its clinical course, treatments and outcomes. One-hundred twenty children (66 male, 54 female) with MCNS, admitted to Nephrology Department between 1987-2009 was assessed. Their clinical presentations, treatment and disease courses were reviewed. The mean duration of follow-up was 11.5 ± 1.9 years. Initially, all patients given prednisone 2 mg/kg/ day single dose per four weeks a followed by eight weeks of the same daily dose given every other day. After week 12, prednisone was progressively tapered off at the rate of 0.5 mg/kg per 15 daily intervals until complete discontinuation had been achieved by week 16. Steroid resistance was accepted as no achievement of remission following four weeks of prednisone 2 mg/kg/day followed by three intravenous pulses of corticosteroids. At the end of the initial steroid treatment, 106 (88.3%) patients were determinate steroid responsive while 14 (11.7%) patients were steroid resistance. Thirty-eight patients underwent biopsy. At the end of study recovery rate was increased from 88.3% to 94.1%. In conclusion, most of patients entered remission by our therapy end of follow up time. With the support of our satisfactory results among the whole study group, long-term prednisolone treatment still remains valid.

Bioimpedance for assessing volume status in children with nephrotic syndrome.

BACKGROUND/AIM: The effectiveness of assessing volume load via bioimpedance in pediatric patients with nephrotic syndrome (NS) was investigated. MATERIALS AND METHODS: Patients with NS (n = 34) were compared with healthy controls (n = 20). The inferior vena cava index and inferior vena cava collapsibility index (IVCCI) scores were determined for all subjects. Bioimpedance measurements were used to directly determine volume load. Clinical findings, relative fluid load, and echocardiographic measurements were determined and compared with bioimpedance in calculating volume load. RESULTS: The sensitivity and specificity of bioimpedance in determining volume load were found to be 65% and 90%, respectively. IVCCI was lower in NS patients than in controls. There were also significant differences in IVCCI values between patients with localized and generalized edema. Relative fluid load was higher in NS patients with generalized edema as opposed to patients with localized edema. For calculating volume load, the sensitivity of bioimpedance, clinical findings, and echocardiographic measurements was 87%, 95%, and 83%, respectively, whereas the specificity of determining volume load by bioimpedance, clinical findings, and echocardiographic measurements was 50%, 10%, and 80%, respectively. CONCLUSION: Our data suggest that bioimpedance may be superior to echocardiography in determining volume load in children with NS, because it is cost-effective, reliable, and relatively simple to perform.

Reference values for serum dehydroepiandrosterone-sulphate in healthy children and adolescents with emphasis on the age of adrenarche and pubarche.

OBJECTIVE: Adrenarche is a component of normal pubertal development. Recent decades have witnessed changes in the timing and tempo of puberty in different populations. We aimed to obtain normative data on dehydroepiandrosterone-sulphate (DHEA-S) secretion in healthy children and to evaluate the age of adrenarche, pubarche and the DHEA-S levels at which pubarche starts in both sexes. METHODS: Serum DHEA-S concentrations were measured in 531 healthy (291 female) Turkish children aged 1 month-18 years by an automated chemiluminescence method. Pubic hair development was evaluated. DHEA-S concentrations >108·4 nmol/l (40 µg/dl) were regarded as adrenarche. Age-related normative data were constructed. Age at adrenarche and pubarche and the DHEA-S levels at pubarche were estimated using ROC analyses. RESULTS: Serum DHEA-S levels were high in the first 6 months of life then declined below 108·4 nmol/l (40 µg/dl) with a cut-off age of 0·46 years for girls and 0·61 years for boys with 98% and 96% statistical sensitivity. Stable minimum levels were observed for the following 5 years. The cut-off age for DHEA-S levels rising above 108·4 nmol/l (40 µg/dl) was 8·0 and 7·0 years for girls for boys, respectively. DHEA-S levels at transition from Tanner stage P1 to P2 was 90·5 nmol/l (33·4 µg/dl) in girls and 118 nmol/l (43·6 µg/dl) in boys. Median (CI) DHEA-S levels were 170·7(94·8-336) and 244(119·2-357·7) nmo/l [63(35-124) and 90(44-132) µg/dl] in girls and boys, respectively, with Tanner stage P2 pubic hair. CONCLUSIONS: We established reference data of serum DHEA-S levels in a large group of children. Currently, adrenarche (DHEA-S>108·4 nmol/l) starts 1 year earlier in boys but higher DHEA-S levels are needed for transition from P1 to P2 in boys.

Success of continuous veno-venous hemodiafiltration treatment in children monitored in the intensive care units.

INTRODUCTION: As intensive care units (ICU) have improved, presence of multiple-organ dysfunctions in majority of patients with acute renal failure (ARF) has become clearer. To facilitate multi-organ support, continuous renal replacement therapy (CRRT) techniques have been developed. This study is the one that reports the experience on children including newborns receiving CRRT monitored in ICU. MATERIALS AND METHODS: The study was performed retrospectively in children who had Continuous Veno- Venous Hemodiafiltration (CVVHDF) as a CRRT modality in ICU. Clinical data, primary cause, consultation time, duration and initiation time of CVVHDF were recorded. Patients were classified as cardiac and non-cardiac in respect to primary dysfunction. Stage of renal failure was evaluated according to pRIFLE criteria. Outcome was identified as primary and secondary. Primary outcome was accepted as the composite correction of uremia and metabolic parameters, and regression of fluid overload, while secondary outcomes were assessed as improvement of hemodynamic instability and survival. RESULTS: A total of 36 patients' files were scanned. There were 10 cases in cardiac group and 26 cases in non-cardiac group. There were statistically better differences between primary and secondary outcome rates of cardiac cases. Although there was no difference between cardiac and non-cardiac cases in terms of primary outcome, secondary outcome was statistically significant. Timing of consultation and CVVHDF was not found to have an effect on the outcome. CONCLUSION: Our results indicated that CVVHDF treatment was successful even in cardiac patients with high mortality and in patients at their later stage of ARF.