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Background There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite–mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < −0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite–mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < −0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions The majority of metabolite–mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR. [ABSTRACT FROM AUTHOR]

Background: Nonadherence is common in children with chronic kidney disease (CKD). This may contribute to inadequate blood pressure control and adverse outcomes. This study examined associations between antihypertensive medication nonadherence, ambulatory blood pressure monitoring (ABPM) parameters, kidney function, and cardiac structure among children with CKD. Methods: We performed secondary analyses of data from the CKD in Children (CKiD) study, including participants with treated hypertension who underwent ABPM, laboratory testing, and echocardiography biannually. Nonadherence was defined by self-report of any missed antihypertensive medication 7 days prior to the study visit. Linear regression and mixed-effects models were used to assess the association of nonadherence with baseline and time-updated ABPM profiles, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and left ventricular mass index (LVMI). Results: Five-hundred and eight participants met inclusion criteria, followed for a median of 2.9 years; 212 (42%) were female, with median age 13 years (IQR 10–16), median baseline eGFR 49 (33–64) ml/min/1.73 m2 and median UPCR 0.4 (0.1–1.0) g/g. Nonadherence occurred in 71 (14%) participants. Baseline nonadherence was not significantly associated with baseline 24-h ABPM parameters (for example, mean 24-h SBP [β − 0.1, 95% CI − 2.7, 2.5]), eGFR (β 1.0, 95% CI − 0.9, 1.2), UCPR (β 1.1, 95% CI − 0.8, 1.5), or LVMI (β 0.6, 95% CI − 1.6, 2.9). Similarly, there were no associations between baseline nonadherence and time-updated outcome measures. Conclusions: Self-reported antihypertensive medication nonadherence occurred in 1 in 7 children with CKD. We found no associations between nonadherence and kidney function or cardiac structure over time. [ABSTRACT FROM AUTHOR]

Background: In children with chronic kidney disease (CKD), certain risk factors are associated with faster eGFR decline and earlier kidney failure. Whether these factors have lingering effects on post-transplant eGFR trajectory remains unclear. We characterized pre- and post-transplant eGFR trajectories in pediatric kidney transplant recipients by their pre-kidney replacement therapy (KRT) risk factors. Methods: We studied eGFR trajectories before KRT initiation and after transplantation among Chronic Kidney Disease in Children (CKiD) Study participants. We used mixed-effects models to compare pre-KRT versus post-transplant eGFR trajectories within individual participants by 7 pre-KRT risk factors: glomerular/non-glomerular etiology, race, preemptive transplant, proteinuria, albuminuria, and systolic/diastolic blood pressure (SBP/DBP). Results: We analyzed 1602 pre-KRT and 592 post-transplant eGFR measurements from 246 transplant recipients. Mean annual eGFR decline was decreased from 18.0% pre-KRT (95%CI, 16.1–19.8) to 5.0% post-transplant (95%CI, 3.3–6.7). All 7 pre-KRT risk factors showed strong associations with faster pre-KRT eGFR decline, but not with post-transplant eGFR decline; only albuminuria, high SBP, and high DBP reached statistical significance with notably attenuated associations. In our multivariable model of the pre-KRT risk factors, post-transplant eGFR decline was more rapid only when albuminuria and high SBP were both present. Conclusions: eGFR decline substantially slows down after transplant even among children with rapidly progressing forms of CKD. Nonetheless, those who had albuminuria and high SBP before KRT might continue to show faster eGFR decline after transplant, specifically when both risk factors were present. This subgroup might benefit from intensive pre-transplant management for at least one of the two risk factors. [ABSTRACT FROM AUTHOR]

Background: The objective was to determine the extent that eGFR formulas correspond to measured plasma iohexol clearance (iGFR) in children with normal or near normal kidney function, particularly how different eGFR formulas yield discordant results. Methods: iGFR from 2 (iGFR-2pt) and 4 (iGFR-4pt) time points along with creatinine and/or cystatin C-based eGFR were measured in children with mild CKD, stages 1–2. eGFR was calculated using 6 equations: 3 under 25 (U25) formulas from the Chronic Kidney Disease in Children (CKiD) study, the full age-combined cystatin C (cysC) and creatinine spectrum (FAS-combined), the European Kidney Function Consortium (EKFC-creatinine) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) cysC-based equation. Results: Twenty-nine children were included, of which 22 had discordant creatinine vs. cystatin C-based eGFR by ≥ 15mL/min/1.73 m2. Overall, the FAS-combined had the least bias, while the U25 most accurately identified children with an eGFR < 90 mL/min/1.73 m2. When Cr-eGFR was ≥ 15 mL/min higher than CysC-eGFR, the U25 creatinine eGFR was closest to iGFR-4pt. When CysC eGFR was higher, the U25-combined was closest to iGFR-4pt. Conclusion: The formulas that most closely approximated the measured GFR varied depending on the pattern of discordant eGFR results. Based on the results, we recommend using the CKiD U25-combined formula to screen for children with a low GFR. Either the CKiD U25-combined or FAS-combined would be recommended for changes in eGFR longitudinally. However, because all formulas were discordant from the iGFR-4pt in over a third of participants, further refinement of pediatric eGFR formulas is needed at the normal/near-normal range. [ABSTRACT FROM AUTHOR]

Background: Uromodulin is the most abundant protein in the urine of healthy adults, and higher urine concentrations mark better tubular health. Greater kidney size and function are predictors of higher uromodulin levels in adults. Urine uromodulin has not yet been studied in children with chronic kidney disease (CKD). Thus, we sought to determine the relationship between age and kidney function with urine uromodulin levels in children with CKD. Methods: In the CKD in Children (CKiD) cohort, we utilized multivariable linear regression to evaluate the relationship of age and eGFR with urine uromodulin levels. The primary outcome was uromodulin indexed to urine creatinine (Umod/Cr, mg/g), which was log2-transformed given its skewed distribution. Results: Among 677 CKiD participants, the median age was 11.8 years (8.2–15.3), the median eGFR was 49 ml/min/1.73 m2 (37–63), the etiology of CKD was glomerular disease in 31%, and the median Umod/Cr level was 0.114 mg/g (0.045–0.226). In the multivariable models, each one-year older age was associated with 0.18 (12%) lower log2(Umod/Cr) and 0.20 (13%) lower log2(Umod/Cr) among those with non-glomerular and glomerular disease, respectively (p < 0.001). However, we did not find a statistically significant association between eGFR and Umod/Cr in either participants with non-glomerular or glomerular disease (p = 0.13 and p = 0.58, respectively). Conclusions: Among children with CKD, older age is significantly associated with lower Umod/Cr, independent of eGFR. Further studies are needed to comprehensively evaluate age-specific reference ranges for urine uromodulin and to evaluate the longitudinal relationship of uromodulin with both age and eGFR in children with CKD. [ABSTRACT FROM AUTHOR]

Background: While hyperkalemia is well described in adult chronic kidney disease (CKD), large studies evaluating potassium trends and risk factors for hyperkalemia in pediatric CKD are lacking. This study aimed to characterize hyperkalemia prevalence and risk factors in pediatric CKD. Methods: Cross-sectional analysis of Chronic Kidney Disease in Children (CKiD) study data evaluated median potassium levels and percentage of visits with hyperkalemia (K ≥5.5 mmoL/L) in relation to demographics, CKD stage, etiology, proteinuria, and acid–base status. Multiple logistic regression was used to identify risk factors for hyperkalemia. Results: One thousand and fifty CKiD participants with 5183 visits were included (mean age 13.1 years, 62.7% male, 32.9% self-identifying as African American or Hispanic). A percentage of 76.6% had non-glomerular disease, 18.7% had CKD stage 4/5, 25.8% had low CO2, and 54.2% were receiving ACEi/ARB therapy. Unadjusted analysis identified a median serum potassium level of 4.5 mmol/L (IQR 4.1–5.0, p <0.001) and hyperkalemia in 6.6% of participants with CKD stage 4/5. Hyperkalemia was present in 14.3% of visits with CKD stage 4/5 and glomerular disease. Hyperkalemia was associated with low CO2 (OR 7.72, 95%CI 3.05–19.54), CKD stage 4/5 (OR 9.17, 95%CI 4.02–20.89), and use of ACEi/ARB therapy (OR 2.14, 95%CI 1.36–3.37). Those with non-glomerular disease were less frequently hyperkalemic (OR 0.52, 95%CI 0.34–0.80). Age, sex, and race/ethnicity were not associated with hyperkalemia. Conclusions: Hyperkalemia was observed more frequently in children with advanced stage CKD, glomerular disease, low CO2, and ACEi/ARB use. These data can help clinicians identify high-risk patients who may benefit from earlier initiation of potassium-lowering therapies. [ABSTRACT FROM AUTHOR]

Background: Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD progression has not been described. Methods: We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan–Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change. Results: Participants had median age of 10.9 years [IQR: 6.5, 14.6], median eGFR of 50 ml/1.73 m2 [IQR: 37, 64] and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years [IQR: 2, 8]. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change. Conclusion: Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Background: Elevated serum uric acid concentration is a risk factor for CKD progression. Its change over time and association with CKD etiology and concomitant changes in estimated glomerular filtration rate (eGFR) in children and adolescents are unknown. Methods: Longitudinal study of 153 children/adolescents with glomerular (G) and 540 with non-glomerular (NG) etiology from the CKD in Children (CKiD) study. Baseline serum uric acid, change in uric acid and eGFR over time, CKD etiology, and comorbidities were monitored. Adjusted linear mixed-effects regression models quantified the relationship between within-person changes in uric acid and concurrent within-person changes in eGFR. Results: Participants with stable uric acid over follow-up had CKD progression which became worse for increased baseline uric acid (average annual percentage changes in eGFR were − 1.4%, − 7.7%, and − 14.7% in those with G CKD with baseline uric acid < 5.5 mg/dL, 5.5 − 7.5 mg/dL, and > 7.5 mg/dL, respectively; these changes were − 1.4%, − 4.1%, and − 8.6% in NG CKD). Each 1 mg/dL increase in uric acid over follow-up was independently associated with significant concomitant eGFR decreases of − 5.7% (95%CI − 8.4 to − 3.0%) (G) and − 5.1% (95%CI − 6.3 to − 4.0%) (NG) for those with baseline uric acid < 5.5 mg/dL and − 4.3% (95%CI − 6.8 to − 1.6%) (G) and − 3.3% (95%CI − 4.1 to − 2.6%) (NG) with baseline uric acid between 5.5 and 7.5 mg/dL. Conclusions: Higher uric acid levels and increases in uric acid over time are risk factors for more severe progression of CKD in children and adolescents. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Background More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care. Methods Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology—Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8–21 years) and caregivers (of children ages 0–21 years) pertaining to blood pressure. Results Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects). Conclusions For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD. [ABSTRACT FROM AUTHOR]

Background: Vegetable or plant-based sources of protein may confer health benefits in children with progressive kidney disease. Our aims were to understand the effect of the proportion of vegetable protein intake on changes in estimated GFR and to understand the effect of the proportion of vegetable protein intake on serum levels of bicarbonate, phosphorus, and potassium. Methods: Children with baseline eGFR between 30 and 90 mL/min/1.73 m2 were recruited from 59 centers across North America as part of the chronic kidney disease in children (CKiD) study. The percentage of dietary vegetable protein (VP%) was gathered from annual Food Frequency Questionnaires. We performed longitudinal linear mixed models to determine the effect of VP% on eGFR and longitudinal logistic mixed models to determine the effect of VP% on electrolyte balance (potassium, phosphorus, bicarbonate). Results: Two thousand visits from 631 subjects. Across all dichotomized groups of children (sex, African American race, Hispanic ethnicity, glomerular etiology of CKD, hypertension, anemia, hyperkalemia, hyperphosphatemia, acidosis, BMI < 95th percentile), the median VP% was 32–35%. The longitudinal mixed model analysis did not show any effect of VP% on eGFR electrolyte (bicarbonate, phosphorus, and potassium) abnormalities (p > 0.1). Conclusions: A diverse cohort of children with CKD has a narrow and homogeneous intake of vegetable protein. Due to the low variability of plant-based protein in the cohort, there were no associations between the percentage of plant protein intake and changes in eGFR nor electrolyte balance. [ABSTRACT FROM AUTHOR]

The Chronic Kidney Disease in Children (CKiD) prospective cohort study was designed to address the neurocognitive, growth, cardiovascular, and disease progression of children and adolescents with mild to moderate CKD. The study has had continuous funding from NIDDK for 17 years and has contributed significant advances in pediatric CKD. The goals of this educational review are threefold: (1) to provide an overview of the neurocognitive and psychosocial studies from CKiD to date; (2) to provide best practice recommendations for those working with the neurocognitive and psychosocial aspects of pediatric CKD based on CKiD findings; and (3) to help chart future goals and directives for both research and clinical practice. This collection of 22 empirical studies has produced a number of key findings for children and adolescents with mild to moderate CKD. While various studies suggest a relatively positive presentation for this population as a whole, without evidence of significant impairment or deterioration, findings do indicate the presence of neurocognitive dysfunction, emotional-behavioral difficulties, and lower quality of life for many children with CKD. These findings support the promotion of best practices that are accompanied by additional future clinical and research initiatives with this patient population. [ABSTRACT FROM AUTHOR]

Pediatric chronic kidney disease (CKD) appears to be a heterogeneous group of conditions, but this heterogeneity has not been explored with respect to its impact on neurocognitive functioning. This study investigated the neurocognitive functioning of those with glomerular (G) vs. non-glomerular (NG) diagnoses. Data from the North American CKiD Study were employed and the current study included 1,003 children and adolescents with mild to moderate CKD. The G Group included 260 participants (median age = 14.7 years) and the NG Group included 743 individuals (median age = 9.0 years). Neurocognitive measures assessed IQ, inhibitory control, attention regulation, problem solving, working memory, and overall executive functioning. Data from all visits were included in the linear mixed model analyses. After adjusting for sociodemographic and CKD-related covariates, results indicated no differences between the diagnostic groups on measures of IQ, problem solving, working memory, and attention regulation. There was a trend for the G group to receive better parent ratings on their overall executive functions (p < 0.07), with a small effect size being present. Additionally, there was a significant G group X hypertension interaction (p < 0.003) for inhibitory control, indicating that those with both a G diagnosis and hypertension performed more poorly than the NG group with hypertension. These findings suggest that the separation of G vs. NG CKD produced minimal, but specific group differences were observed. Ongoing examination of the heterogeneity of pediatric CKD on neurocognition, perhaps at a different time point in disease progression or using a different model, appears warranted. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is associated with many comorbidities requiring complex management. We described treatment patterns for common modifiable CKD complications (high blood pressure, anemia, hyperphosphatemia, and acidosis) according to severity of CKD and examined factors associated with the absence of drug therapy, among participants with a persistent comorbidity, for 1 year in children enrolled in the CKiD study. Methods: A total of 703 CKiD participants contributed 2849 person-visits over a median 3.5 years of follow-up. Using pairs of annual visits, we examined whether participants with abnormal biomarker levels at the first (index) visit persisted in the abnormal levels 1 year later according to CKD risk stage. Multivariate analyses identified demographic and clinical factors associated with the absence of drug therapy among those with persistent comorbid conditions for 1 year. Results: The overall proportions of person-visits prescribing therapy at 1-year follow-up for treating anemia, acidosis, hyperphosphatemia, and high blood pressure were 54%, 45%, 29%, and 81%, respectively. The frequency of therapy increased with advanced CKD risk stage for all comorbidities; however, 19–23% of participants with acidosis, 24–27% with anemia, and 30–39% with hyperphosphatemia at high-risk stages (E and F) were not prescribed appropriate therapy despite the persistence of abnormal levels of these biomarkers for at least 1 year. The resolution of comorbidities at advanced CKD stages without treatment was unlikely. Conclusions: Many children with CKD in the CKiD cohort did not receive pharmacological treatment for common and persistent modifiable comorbidities, even in severe CKD risk stages. [ABSTRACT FROM AUTHOR]

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline.Methods: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020.Recommendations: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines. [ABSTRACT FROM AUTHOR]

An increasing amount of literature has indicated that chronic kidney disease (CKD) is associated with cognitive deficits that increase with worsening disease severity. Although abnormalities in brain structure have been widely documented, few studies to date have examined the functioning of brain areas associated with the specific cognitive domains affected by CKD (namely, attention and executive functions). Furthermore, few studies have examined functional connectivity among CKD youth who are relatively early in the course of the disease. The present study used functional magnetic resonance imaging to examine the resting state connectivity in 67 youth with CKD (mean age, 17 y) and 58 age-matched healthy controls. Using seed-based multiple regression, decreased connectivity was observed within the anterior cingulate portion of the default mode network. In addition, decreased connectivity within the dorsolateral prefrontal cortex, paracingulate gyrus, and frontal pole were correlated significantly with disease severity. These data indicate that connectivity deficits in circuits implementing attentional processes may represent an early marker for cognitive decline in CKD. [ABSTRACT FROM AUTHOR]

Background: We investigated the putative associations of alcohol, cigarette, e-cigarette, and marijuana use with kidney function and proteinuria among adolescents and young adults (AYA) with pediatric-onset chronic kidney disease (CKD) enrolled in the Chronic Kidney Disease in Children (CKiD) study. Methods: Participants responded to questions about past year and 30-day substance use. Associations between each substance and kidney function, proteinuria, nephrotic range proteinuria, and high blood pressure were separately estimated using repeated measures regression models, adjusting for sociodemographic characteristics. Models controlled for covariates at the present visit (contemporaneous) and additionally controlled for disease severity at the year prior to reporting substance use (lagged). Results: A total of 441 participants ≥16 years contributed 1,245 person-visits with 39% reporting alcohol and 16%, 17%, and 15% reporting cigarette, e-cigarette, and marijuana use, respectively, over the previous year. In adjusted lagged models, past year and 30-day cigarette use were significantly associated with higher levels of proteinuria (+18.6%, 95%CI: +2.8%, +36.9%; and +20.0%, 95%CI: +0.7%, +43.1%, respectively). Inferences were similar when controlling for secondhand smoke exposure. Conclusions: In a cohort of AYA with pediatric kidney diseases, substance use was non-trivial, and cigarette use was associated with higher proteinuria, although the prevalence of use was low. Occasional alcohol, e-cigarette, and marijuana use were not associated with proteinuria, disease progression, or elevated blood pressure. Pediatric nephrologists as specialty care providers are well-positioned to discuss substance use and should encourage tobacco prevention/treatment efforts among AYA at high risk for use in order to preserve kidney function and promote well-being. [ABSTRACT FROM AUTHOR]

Background: Hypertension is common among children with chronic kidney disease (CKD), and dihydropyridine calcium channel blockers (dhCCBs) are frequently used as treatment. The impact of dhCCBs on proteinuria in children with CKD is unclear. Methods: Data from 722 participants in the Chronic Kidney Disease in Children (CKiD) longitudinal cohort with a median age of 12 years were used to assess the association between dhCCBs and log transformed urine protein/creatinine levels as well as blood pressure control measured at annual visits. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use was evaluated as an effect measure modifier. Results: Individuals using dhCCBs had 18.8% higher urine protein/creatinine levels compared to those with no history of dhCCB or ACEi and ARB use. Among individuals using ACEi and ARB therapy concomitantly, dhCCB use was not associated with an increase in proteinuria. Those using dhCCBs had higher systolic and diastolic blood pressures. Conclusions: Use of dhCCBs in children with CKD and hypertension is associated with higher levels of proteinuria and was not found to be associated with improved blood pressure control. [ABSTRACT FROM AUTHOR]

Background: Longitudinal changes in body mass index (BMI) among overweight and obese children with chronic kidney disease (CKD) are not well characterized. We studied longitudinal trajectories and correlates of these trajectories, as results may identify opportunities to optimize health outcomes. Methods: Longitudinal changes in age-sex-specific BMI z-scores over 1851 person-years of follow-up were assessed in 524 participants of the Chronic Kidney Disease in Children Study. A total of 353 participants were categorized as normal (BMI > 5th to < 85th percentile), 56 overweight (BMI ≥ 85th to 95th percentile) and 115 obese (BMI ≥ 95th percentile) based on the average of three BMI measurements during the first year of follow-up. Studied covariates included age, sex, race, CKD etiology, corticosteroid usage, household income, and maternal education. Results: In unadjusted analysis, BMI z-scores decreased over time in elevated BMI groups (overweight: mean = − 0.06 standard deviations (SD) per year, 95% CI: − 0.11, − 0.01; obese: mean = − 0.04 SD per year, 95% CI: − 0.07, − 0.01). Among obese children, only age was associated with change in BMI z-score; children < 6 years had a mean decrease of 0.19 SD during follow-up (95% CI: − 0.30, − 0.09). Socioeconomic factors were not associated with change in BMI. Conclusion: Overweight and obese children with CKD demonstrated a significant annual decline in BMI, though the absolute change was modest. Among obese children, only age < 6 years was associated with significant decline in BMI. Persistence of elevated BMI in older children and adolescents with CKD underscores the need for early prevention and effective intervention. [ABSTRACT FROM AUTHOR]

Introduction: The number of medications could serve as a surrogate for burden of care at home and may affect health-related quality of life (HRQoL) in children with chronic kidney disease (CKD). Methods: Using baseline data from the Chronic Kidney Disease in Children (CKiD) Study, we modeled HRQoL scores, self-reported by the child (if ≥ 8 years old) and/or caregiver (all children) on unique counts and administrations of CKD- and non-CKD-related medications, using multivariate linear regression. Heterogeneity of associations between HRQoL and medication burden by age group (≥ 8 vs. < 8 years old) were explored. Results: 734 participants median age 11 years, disease duration 8 years, median eGFR 53 mL/min/1.73 m2, 61% male, 22% African-American, 31% glomerular disease were prescribed median 3 unique CKD-related medications. Regarding HRQoL assessment, 201 children were < 8 years old and had only parent-proxy HRQoL score; 533 children ≥ 8 years of age had both child and parent-proxy scores. Overall, parents of children < 8 years old reported higher HRQoL scores than parents of older children: 84 vs. 76. However, in a unified multivariate regression model, HRQoL scores of children < 8 years showed greater decreases as the number of CKD-related medications increased compared to scores for children ≥ 8 years old. Conclusion: Average HRQoL scores reported by parents of younger CKD children were higher than those of older CKD children but decreased more with increased CKD medication counts than scores of older children. Considerations of HRQoL may be of particular importance for clinicians and caregivers when managing chronic disease comorbidities in younger children. [ABSTRACT FROM AUTHOR]

The Chronic Kidney Disease in Children (CKiD) cohort study is a North American (USA and Canada) multicenter, prospective study of children with chronic kidney disease (CKD). The original aims of the study were (1) to identify novel risk factors for CKD progression; (2) to measure the impact of kidney function decline on growth, cognition, and behavior; and (3) to characterize the evolution of cardiovascular disease risk factors. CKiD has developed into a national and international resource for the investigation of a variety of factors related to CKD in children. This review highlights notable findings in the area of CKD progression and outlines ongoing opportunities to enhance understanding of CKD progression in children. CKiD's contributions to the clinical care of children with CKD include updated and more accurate glomerular filtration rate estimating equations for children and young adults, and resources designed to help estimate the CKD progression timeline. In addition, results from CKiD have strengthened the evidence that treatment of hypertension and proteinuria should continue as a primary strategy for slowing the rate of disease progression in children. [ABSTRACT FROM AUTHOR]

Background: Children with chronic kidney disease (CKD) have delays in normal growth and pubertal development. We describe factors associated with delayed menarche and the association of delayed menarche with short stature in girls with CKD. Methods: Two hundred eighty-seven girls with CKD onset prior to menarche within the Chronic Kidney Disease in Children (CKiD) cohort were studied. Delayed menarche was defined as menarche at age 15 years or older; short stature was defined as last available height 2 standard deviations below projected adult height. Kaplan-Meier cumulative incidence function was used to estimate median age at menarche. Chi-squared and Wilcoxon rank-sum tests were used to assess factors associated with delayed menarche. Chi-squared test was used to evaluate the association between delayed menarche and short stature. Results: Among 287 girls, 68 enrolled with prevalent menarche, 131 were observed to have incident menarche, and 88 were pre-menarchal at their last study visit. Median age at menarche was 12 years. Ten percent had delayed menarche. African American race, lower estimated glomerular filtration rate, ever corticosteroid use, and longer CKD duration were associated with delayed menarche (p < 0.05). Girls with delayed menarche had lower height and weight percentiles at the time of menarche (p < 0.05). Sixty-one percent of girls with delayed menarche had short stature compared with only 35% of girls without delayed menarche (p = 0.03). Conclusion: Median age at menarche is similar among girls with CKD and healthy girls. Ten percent of girls with CKD had delayed menarche and may be at risk for short stature. [ABSTRACT FROM AUTHOR]

Background: Children with mild to moderate chronic kidney disease (CKD) are at increased risk for deficits in neurocognition. Less is known about how CKD affects emotional-behavioral functioning in this population. Methods: Parent ratings of emotional-behavioral functioning at baseline and over time were examined for 845 children with mild to moderate CKD using the Behavior Assessment System for Children, Second Edition Parent Rating Scales (BASC-2 PRS). Associations with demographic and disease-related predictors were also examined. Results: Children with mild to moderate CKD had parent-reported emotional-behavioral functioning largely within normal limits, at baseline and over time. The proportion with T-scores at least 1 SD above the mean was 24% for Internalizing Problems and 28% for Attention Problems. A greater proportion of participants scored lower than expected (worse) on scales measuring adaptive skills (25%). Persistent hypertension predicted attention problems (β = 1.59, 95% CI = 0.24 to 2.94, p < 0.02) and suggested worse behavioral symptoms (β = 1.36, 95% CI = − 0.01 to 2.73, p = 0.05). Participants with proteinuria at baseline, but not at follow-up, had fewer attention problems than participants whose proteinuria had not resolved (β = − 3.48, CI = − 6.79 to − 0.17, p < 0.04). Glomerular diagnosis was related to fewer (β = − 2.68, 95% CI = − 4.93 to − 0.42, p < 0.02) internalizing problems. Conclusions: Although children with CKD generally have average emotional-behavioral parent ratings, a notable percentage of the population may be at risk for problems with attention and adaptive behavior. Providers working with this population should facilitate psychosocial referrals when indicated. [ABSTRACT FROM AUTHOR]

Background: Kidney transplant is the renal replacement therapy (RRT) of choice for children with end stage kidney disease (ESKD). Only 21.3% of children who initiate RRT receive a preemptive kidney transplant (PKT). We characterized the transition to RRT in children in the CKiD cohort including the prevalence of dialysis as first RRT vs. PKT and graft survival. Methods: 258 children enrolled in CKiD have initiated RRT, and 202 had post-RRT initiation data collected through phone or in-person follow-up. Characteristics by first RRT modality were compared using Chi-square and Kruskal-Wallis tests. Parametric-accelerated failure time models were fit for transplantation. Graft failure was characterized using Kaplan-Meier methods and log rank tests. Results: Sixty-one percent received dialysis as first RRT modality and 39% PKT. Those with PKT were less likely to have glomerular disease and to be African-American, and had higher household-income. African-American subjects were nearly twice as likely to undergo dialysis prior to transplant. Those with a living donor and a college-educated mother had 40%-decreased odds of being dialysis experienced. Children with PKT were more likely to receive a living donor transplant. Only 5% of PKT subjects had graft failure by 4 years compared to 16% of those initially treated with dialysis (p = 0.092); however, after adjustment the effect of dialysis exposure was attenuated (p = 0.206). Conclusion: CKiD subjects undergo PKT more often compared to nationally-reported rates, and are more likely to receive a kidney transplant within 1 year of starting dialysis. African-American race and lower household-income are associated with decreased access to PKT. [ABSTRACT FROM AUTHOR]

Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α1-microglobulin (α1M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α1M/Cr, α1M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α1M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α1M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α1M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations. [ABSTRACT FROM AUTHOR]

To examine if parent illness uncertainty is indirectly associated with child depression, anxiety, and HRQOL in the CKD/SLE population. Parent–child dyads (N = 31) from outpatient rheumatology and nephrology clinics included children (ages 9–18) diagnosed with CKD (Stage 1, 2, or nephrotic syndrome) or SLE. Parents completed demographic and uncertainty measures and children completed uncertainty, depression, anxiety, and HRQOL measures. This cross-sectional study examined mediational models using the percentile bootstrapping method. Parent uncertainty had an indirect effect on child depression, anxiety, and HRQOL through the mediator, child uncertainty. In other words, parents' illness uncertainty regarding their child's condition correlates to the child's illness uncertainty, which then is associated with the child's mental health and wellbeing. Reverse mediations illustrated that parent uncertainty did not mediate child uncertainty and outcome variables. Results extend previous research by examining parent and child illness uncertainty in understudied conditions (CKD/SLE) and the relationship to outcome variables commonly related to depression (e.g., anxiety and HRQOL). Findings allow health psychologists and medical personnel to understand the impact of uncertainty on the child's wellbeing and HRQOL. Clinical implications, including using specialized interventions to address illness uncertainty, are discussed. [ABSTRACT FROM AUTHOR]

The Chronic Kidney Disease in Children Study, a prospective cohort study with data collected from 2003 to 2018, provided the first opportunity to characterize the incidence of renal replacement therapy (RRT) initiation over the life course of pediatric kidney diseases. In the current analysis, parametric generalized gamma models were fitted and extrapolated for RRT overall and by specific treatment modality (dialysis or preemptive kidney transplant). Children were stratified by type of diagnosis: nonglomerular (mostly congenital; n  = 650), glomerular–hemolytic uremic syndrome (HUS; n  = 49), or glomerular–non-HUS (heterogeneous childhood onset; n  = 216). Estimated durations of time to RRT after disease onset for 99% of the nonglomerular and glomerular–non-HUS groups were 42.5 years (95% confidence interval (CI): 31.0, 54.1) and 25.4 years (95% CI: 14.9, 36.0), respectively. Since onset for the great majority of children in the nonglomerular group was congenital, disease duration equated with age. A simulation-based estimate of age at RRT for 99% of the glomerular population was 37.9 years (95% CI: 33.6, 63.2). These models performed well in cross-validation. Children with glomerular disease received dialysis earlier and were less likely to have a preemptive kidney transplant, while the timing and proportions of dialysis and transplantation were similar for the nonglomerular group. These diagnosis-specific estimates provide insight into patient-centered prognostic information and can assist in RRT planning efforts for children with moderate-to-severe kidney disease who are receiving regular specialty care. [ABSTRACT FROM AUTHOR]

Background: Depression affects 7–35% of children with chronic kidney disease (CKD), and in adults with CKD, the presence of depression links to poorer medical outcomes, social functioning difficulties, and neurocognitive impairments. The relationship between depression and neurocognitive function in youth with CKD is unclear. We sought to identify factors associated with depression in youth with CKD and to determine whether depression affects neurocognitive performance. Methods: We conducted cross-sectional analyses in 71 CKD and 64 control participants aged 8 to 25 years who completed depression inventories and neurocognitive assessments as part of the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with CKD Study. In the CKD group, multivariable logistic regression analysis determined associations between clinical and demographic factors and depression. In the full study cohort, multivariable linear regression analyses, including an interaction term between CKD status and depression evaluated the effect of depression on 11 neurocognitive outcome domains. Results: Obesity significantly associated with depression in the CKD group (OR 10.25, P = 0.01). In adjusted analyses, depressed youth with CKD scored worse than non-depressed CKD participants by 0.6–1.0 standard deviations in 5 neurocognitive domains: attention, visual memory, visual-spatial, visual working memory, and problem solving. Conclusions: CKD youth with obesity are more likely to be depressed, and those who are depressed exhibit worse neurocognitive performance. Depression may represent a therapeutic target to improve neurocognitive performance in youth with CKD. [ABSTRACT FROM AUTHOR]

Background: Among children who receive a kidney transplant, short stature is associated with a more complicated post-transplant course and increased mortality. Short stature prior to transplant may reflect the accumulated risk of multiple factors during chronic kidney disease (CKD); however, its relationship with post-transplant kidney function has not been well characterized.Methods: In the Chronic Kidney Disease in Children (CKiD) cohort restricted to children who received a kidney transplant, short stature (i.e., growth failure) was defined as age-sex-specific height < 3rd percentile. The outcome was time to estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2 after transplant. Parametric survival models, including adjustment for disease severity, socioeconomic status (SES), and parental height by inverse probability weighting, described the relative times to eGFR< 45 ml/min/1.73 m2.Results: Of 138 children (median CKD duration at transplant: 13 years), 20% (28) had short stature before the transplant. The median time to eGFR < 45 ml/min/1.73 m2 after kidney transplantation was 6.6 years and those with short stature had a significantly faster time to the poor outcome (log-rank p value 0.004). Children with short stature tended to have lower SES, nephrotic proteinuria, higher blood pressure, and lower mid-parental height before transplant. After adjusting for these variables, children with growth failure had 40% shorter time to eGFR < 45 ml/min/1.73 m2 than those with normal stature (relative time 0.60, 95%CI 0.32, 1.03).Conclusions: Short stature was associated with a faster time to low kidney function after transplant. SES, disease severity, and parental height partially explained the association. Clinicians should be aware of the implications of growth failure on the outcome of this unique population, while continued attempts are made to define modifiable factors that contribute to this association. [ABSTRACT FROM AUTHOR]

Background: There are limited data to describe academic achievement outcomes for children with mild to moderate pediatric chronic kidney disease (CKD). The objective of this study was to describe the prevalence of low academic achievement in patients with mild to moderate CKD.Methods: Wechsler Individual Achievement Test, Second Edition, Abbreviated (WIAT-II-A) data were collected at entry into the Chronic Kidney Disease in Children (CKiD) study. Achievement in basic reading, spelling, mathematics, and total achievement was evaluated with a focus on the effects of comorbid CKD-related variables, neurocognitive, and school-based characteristics on academic achievement.Results: WIAT-II-A data were available for 319 children in the CKiD cohort. Low total academic achievement was present in 34% percent of the sample. There was no significant effect of CKD-related medical variables on academic achievement. Mathematics had the lowest distribution of achievement scores. In univariate models, low achievement was significantly related to days of missed school (p = 0.006) and presence of individualized education plan (p < 0.0001).Conclusions: Low academic achievement was seen in over one-third of children with CKD, with the most difficulty observed in the domain of mathematics. Providers and educators should monitor for academic difficulties in this population in order to facilitate early educational assistance and promote positive educational outcomes. [ABSTRACT FROM AUTHOR]

Background: Obstructive uropathy (OU) is a common cause of end-stage renal disease (ESRD) in children. Children who escape the newborn period with mild-to-moderate chronic kidney disease (CKD) continue to be at increased risk. The predictive ability of clinically available markers throughout childhood is poorly defined.Methods: Patients with OU were identified in the Chronic Kidney Disease in Children Study. The primary outcome of interest was renal replacement therapy (RRT) (cases). Controls were age matched and defined as patients within the OU cohort who did not require RRT during study follow-up.Results: In total, 27 cases and 41 age-matched controls were identified. Median age at baseline and age at outcome measurement were 10 vs. 16 years, respectively. First available glomerular filtration rate (GFR) (36.9 vs. 53.5 mL/min per 1.73 m2), urine protein/creatinine (Cr) (0.40 vs. 0.22 mg/mg) and microalbumin/Cr (0.58 vs. 0.03 mg/mg), and serum CO2 (20 vs. 22 mmol/L) and hemoglobin (12.4 vs. 13.2 g/dL) differed significantly between cases and controls, respectively. GFR declined 3.07 mL/min per 1.73 m2/year faster in cases compared to that in controls (p < 0.0001). Urine protein/Cr and microalbumin/Cr increased by 0.16 and 0.11 per year more in cases compared to those in controls, respectively (p ≤ 0.001 for both). Serum phosphate increased by 0.11 mg/dL and serum albumin and hemoglobin decreased by 0.04 (g/dL) and 0.14 (g/dL) per year more for cases compared to those for controls, respectively (p < 0.05 for all).Conclusions: Age-specific baseline and longitudinal measures of readily available clinical measures predict progression to ESRD in children with mild-to-moderate CKD from OU. [ABSTRACT FROM AUTHOR]

Background: 25-Hydroxyvitamin D (25OHD) deficiency is common in children with chronic kidney disease (CKD). It has been associated with an increased risk for anemia in both healthy US children and in adults with CKD. This association has not been explored in children with CKD.Methods: Children aged 1-16 enrolled in the Chronic Kidney Disease in Children (CKiD) study with mild to moderate kidney dysfunction, and with 25OHD measured at baseline (n = 580), were included in the analysis. The cross-sectional associations between 25OHD and hemoglobin (g/dL) and anemia were assessed. Anemia was defined as hemoglobin < 5th percentile for age and sex.Results: Overall 334 (57.59%) children were vitamin D insufficient/deficient and 137 (23.62%) were anemic. Of those who were vitamin D insufficient/deficient, 95 (28.44%) were anemic. In the overall cohort, the odds of being anemic was 1.9 times higher (95% CI, 1.22-3.04, p < 0.01) in vitamin D insufficient/deficient vs sufficient children, when adjusting for covariates (age, sex, race [black, white, or other], body mass index (BMI), iohexol GFR (iGFR), erythropoietin stimulation agent (ESA) use, iron supplementation use, and underlying cause of CKD). Stratified by race, the odds of being anemic was 2.39 times higher (95% CI, 1.41-4.05, p = 0.001) in vitamin D insufficient/deficient vs vitamin D sufficient white children. The association between vitamin D status and anemia was not significant in black children.Conclusions: The data support our hypothesis that vitamin D insufficiency/deficiency increases the odds of anemia in children with CKD. The effect was strong and significant among white, but not black, children. [ABSTRACT FROM AUTHOR]

Background: In pediatric chronic kidney disease (pCKD), traditional factors (proteinuria, etiology, and race) do not fully explain disease progression. The levels of methylated arginine derivatives (MADs: asymmetric and symmetric dimethylarginine, respectively) rise in CKD and increase with CKD progression. The impact of MADs on glomerular filtration rate (GFR) decline has not been examined in pCKD. The aim of this study was to examine the additive impact of baseline (BL) levels of MADs on directly measured GFR (mGFR) decline per year (ml/min/1.73 m2/year) for a period of up to 4 years.Methods: Plasma and data, including mGFR by plasma iohexol clearance, were provided by the prospective, observational Chronic Kidney Disease in Children study. BL MADs were analyzed by high-performance liquid chromatography-tandem mass spectrometry.Results: For 352 pCKD subjects, the median [interquartile range] BL mGFR was 45 [35, 57] ml/min/1.73 m2. The levels of BL MADs were inversely related to the initial mGFR and its decline over time (p < 0.0005) but not to the rate of decline. Covariates, non-glomerulopathy and Tanner stage of ≥ 3 demonstrated weaker relationships between BL levels and beginning mGFR (p = 0.004 and p = 0.002, respectively).Conclusions: In pCKD, higher concentrations of BL MADs were inversely related to BL mGFR. MADs did not affect the CKD progression rate. Quantification of this relationship is novel to the pCKD literature. [ABSTRACT FROM AUTHOR]

The article discusses the link between the epidemics of obesity and kidney disease on the occasion of the 2017 World Kidney Day. Topics addressed include the epidemiology of obesity in adults and children, association between obesity with chronic kidney disease (CKD) and the role of obesity in nephrolithiasis, kidney malignancies and other renal complications. The mechanisms of action for obesity-induced renal diseases are described.

Background: Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study.Methods: Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources.Results: Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies' areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death.Conclusions: iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across studies within this network will be able to be leveraged to identify genetic, behavioral, and health services factors associated with the course of CKD. With an emerging infrastructure to facilitate interactions among the investigators of iNET-CKD and a broadly defined research agenda, we are confident that there will be great opportunity for productive collaborative investigations involving cohorts of individuals with CKD. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1007/s00467-021-05131-7 [ABSTRACT FROM AUTHOR]

Background: The role of environmental exposure to lead as a risk factor for chronic kidney disease (CKD) and its progression remains controversial, and most studies have been limited by a lack of direct glomerular filtration rate (GFR) measurement. Objective: We evaluated the association between lead exposure and GFR in children with CKD. Methods: In this cross-sectional study, we examined the association between blood lead levels (BLLs) and GFR measured by the plasma disappearance of iohexol among 391 participants in the Chronic Kidney Disease in Children (CKiD) prospective cohort study. Results: Median BLL and GFR were 1.2 µg/dL and 44.4 mL/min per 1.73 m2, respectively. The average percent change in GFR for each 1-µg/dL increase in BLL was −2.1 (95% CI: −6.0, 1.8). In analyses stratified by CKD diagnosis, the association between BLL and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1-µg/dL increase in BLL was associated with a −12.1 (95% CI: −22.2, −1.9) percent change in GFR. In analyses stratified by anemia status, each 1-µg/dL increase in BLL among those with and without anemia was associated with a −0.3 (95% CI: −7.2, 6.6) and −4.6 (95% CI: −8.9, −0.3) percent change in GFR, respectively. Conclusions: There was no significant association between BLL and directly measured GFR in this relatively large cohort of children with CKD, although associations were observed in some subgroups. Longitudinal analyses are needed to examine the temporal relationship between lead and GFR decline, and to further examine the impact of underlying cause of CKD and anemia/hemoglobin status among patients with CKD. [ABSTRACT FROM AUTHOR]

Study Objective To evaluate the accuracy of four equations based on serum creatinine concentration-the original Schwartz equation and the Leger, Bedside Chronic Kidney Disease in Children ( CKiD), and Counahan-Barratt equations-for determining glomerular filtration rate ( GFR) in pediatric patients with chronic kidney disease. Design Retrospective, observational, cross-sectional study. Setting Single-center, academic, outpatient pediatric nephrology clinic. Patients Fifty-three pediatric patients with stages 2-5 chronic kidney disease who completed GFR assessment with 125I-iothalamate between January 2002 and January 2005. Measurement and Main Results Data were collected from each patient's medical record. Glomerular filtration rate data were analyzed using 59 evaluations from the 53 pediatric patients. 125I-iothalamate clearance was used as the index GFR. The Bedside CKiD and Counahan-Barratt equations outperformed the Schwartz and Leger equations when the index GFR was less than 60 ml/minute/1.73 m2; the Schwartz and Counahan-Barratt equations performed best for index GFRs of 60 ml/minute/1.73 m2 or greater. Overestimation was highest with the Schwartz and Leger equations (> 20% index GFR in 57.6% and 62.7% of patients, respectively). Underestimation was highest with the Bedside CKiD and Counahan-Barratt equations (> 20% index GFR in 30.5% and 28.8%, respectively). Conclusion The new Bedside CKiD equation performed well for pediatric patients with moderate-to-severe chronic kidney disease, but less well for pediatric patients with mild disease. Additional studies are needed to develop more precise GFR equations using serum creatinine concentration. [ABSTRACT FROM AUTHOR]

Anemia is a common comorbidity in children with chronic kidney disease (CKD). This condition is associated with multiple adverse clinical consequences and its management is a core component of nephrology care. Increased morbidity and mortality, increased risk of cardiovascular disease and decreased quality of life have been associated with anemia of CKD in children. Although numerous complex factors interact in the development of this anemia, erythropoietin deficiency and iron dysregulation (including iron deficiency and iron-restricted erythropoiesis) are the primary causes. In addition to iron supplementation, erythropoietin-stimulating agents (ESAs) can effectively treat this anemia, but there are important differences in ESA dose requirements between children and adults. Also, hyporesponsiveness to ESA therapy is a common problem in children with CKD. Although escalating ESA doses to target increased hemoglobin values in adults has been associated with adverse outcomes, no studies have demonstrated this association in children. The question of appropriate target hemoglobin levels in children, and the approach by which to achieve these levels, remains under debate. Randomized, controlled studies are needed to evaluate whether normalization of hemoglobin concentrations is beneficial to children, and whether this practice is associated with increased risks. [ABSTRACT FROM AUTHOR]

Summary: Linear growth and neurocognitive development are two of the most important differences between adults and children, in terms of clinical issues that must be addressed in patients with chronic kidney disease (CKD). Correction of metabolic acidosis, nutritional deficiency, and renal osteodystrophy improve linear growth, but many children require administration of growth hormone to achieve normal growth. A variety of neurocognitive deficits occur in children with CKD, although there has been an improvement in outcome via improved dialysis, correction of malnutrition, and decreased aluminum exposure. Although growth and neurocognitive development are delayed, cardiovascular complications are accelerated in children with CKD, and are reflected in a dramatic increase in cardiovascular mortality compared with healthy children. Other early cardiovascular complications in children with CKD include left ventricular hypertrophy, cardiac dysfunction, and vascular calcifications. [ABSTRACT FROM AUTHOR]

Glomerular filtration rate (GFR) assesses kidney function. GFR is measured by renal clearance techniques; inulin clearance is the gold standard but is not easily measured. Thus, other methods to determine GFR have been utilized. Endogenous creatinine clearance (CrCl) is the most widely used, but creatinine secretion falsely elevates GFR. Cimetidine inhibits creatinine secretion, such that CrCl equals GFR, provided there are no difficulties with bladder emptying. Estimation of GFR from serum creatinine (e.g. Schwartz formula) is useful clinically; however, such formulae have not been updated for enzymatic creatinine autoanalyzers. Cystatin C, a small protein, is produced at a relatively constant rate and is reabsorbed in the proximal tubule. Cystatin C may be more sensitive than creatinine in detecting a reduction in GFR, but further studies are needed to prove this. Single injection (plasma) clearance techniques are the most precise measures of GFR. Iohexol is an exogenous marker that is comparable to inulin and 51Cr-EDTA and can be measured by high-performance liquid chromatography (HPLC). Our pilot and the Chronic Kidney Disease in Children (CKiD) North American studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve national studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve (10, 30, 120, and 300 min) or, in most cases, a two-point disappearance time (120 and 300 min). [ABSTRACT FROM AUTHOR]

We sought to describe rates of kidney function decline and to identify modifiable risk factors for CKD progression in a multicenter prospective cohort study of adolescents with CKD aged 11 to 18 years seen semiannually for up to three years. Of the 23 subjects meeting inclusion criteria, the average estimated GFR was 51 ± 27 ml/min/1.73 m2 (0.85 ± 0.45 ml/s/1.73 m2) at entry. The overall annualized decline in GFR was 5.6 ml/min/1.73 m2 (0.093 ml/s/1.73 m2) per year (95% confidence interval [95% CI]: 1.9 to 9.3 [0.032 to 0.16]). The adjusted annualized decline in GFR was found to be accelerated in males, as well as among those over 15 years of age. The adjusted annualized decline in GFR was greater among those with either anemia (hematocrit below 36%), or hypoalbuminemia (albumin below 4 g/dl [40 g/L]). After adjustment, anemia was associated with an accelerated decline of 7.8 ml/min/1.73 m2 (0.13 ml/s/1.73 m2) (95% CI: 3.3 to 12 [0.055 to 0.20]) and hypoalbuminemia was associated with an accelerated decline of 17 ml/min/1.73 m2 (0.28 ml/s/1.73 m2) (95% CI: 11 to 22 [0.18 to 0.37]). Further study is needed to evaluate whether treatment of anemia or hypoalbuminemia, as outlined in current clinical care guidelines for CKD, may slow the progression of CKD in adolescents. [ABSTRACT FROM AUTHOR]

Little research has been published assessing changes in the functional health status of children and adolescents with chronic kidney disease (CKD). We know little about which clinical parameters influence functional status or health-related quality of life in these young people. In a prospective study using data from semi-annual visits over a 4-year period from 78 adolescents with CKD aged 11 years to 18 years, we detail the impact of several clinical measures (i.e., kidney function, albumin, hematocrit, height) on short-term changes in health-related quality of life. The 50-item Child Health Questionnaire Parent Form, a validated health-related quality of life measure in children, was used to obtain physical and psychosocial functioning summary scores at each visit. After adjustment for the variables mentioned above, the physical summary score on the Child Health Questionnaire (CHQ) declined as glomerular filtration rate declined. Increasing height was associated with a positive change in physical and psychosocial summary scores. We conclude that decline in kidney function is associated with a subsequent decline in health-related quality of life, particularly in terms of physical activity. [ABSTRACT FROM AUTHOR]

The article presents several research on chronic kidney disease in children including "Overview of Pediatric Chronic Kidney Disease and End-Stage Renal Disease," by Sandra Watkins, "Epidemiological Approaches to the Study of Chronic Kidney Disease in Children," by Susan Furth, "North American Pediatric Renal Transplant Coordinating System and its Registry for Chronic Renal Insufficiency in Children," by William Harmon, "Growth," by Richard Fine, and "Neurodevelopment," by Debbie Gipson.

To identify demographic and clinical characteristics associated with failure to achieve hemoglobin levels ≥11 g/dl in prevalent pediatric end-stage renal disease (ESRD) patients, a cross-sectional analysis of patient clinical data collected by the Mid-Atlantic Renal Coalition in conjunction with the 2000 and 2001 ESRD Clinical Performance Measures Projects was performed. Ninety-nine patients (mean age 12.6 years, SD 5.4) contributed 119 observations to this analysis. Of patients on hemodialysis, 36.6% were anemic, and 39.5% of patients on peritoneal dialysis (PD) were anemic. Associations between age, race, gender, assigned cause of ESRD, Kt/V, transferrin saturation, time on dialysis, serum albumin, dialysis modality, and the achievement of target hemoglobin were examined. In multivariate logistic regression analyses examining age, dialysis modality, time on dialysis, and serum albumin, each 1-year increase in age was significantly associated with hemoglobin levels <11 g/dl [adjusted odds ratio (OR) 1.18, 95% confidence interval (CI) 1.06–1.32] and PD patients were more than twice as likely to have hemoglobin levels <11 g/dl (adjusted OR 2.62, 95% CI 0.98–7.04). Patients on dialysis for 6 months or more were less likely to be anemic than those on dialysis for less than 6 months (adjusted OR 0.39, 95% CI 0.16–0.99). In conclusion, increasing age, dialysis for less than 6 months, and treatment with PD were predictive of anemia in this population. [ABSTRACT FROM AUTHOR]

ABSTRACT. Context. Renal transplantation is the treatment of choice for pediatric patients with end-stage renal disease (ESRD). Black patients wait longer for kidney transplants than do white patients. Objective. To determine whether the increased time to transplantation for black pediatric patients is attributable not only to a shortage of suitable donor organs, but also to racial differences in the time from a child's first treatment for ESRD until activation on the cadaveric kidney transplant waitlist. Design. National longitudinal cohort study. Setting. US Medicare-eligible, pediatric ESRD population. Patients. Children and adolescents is less than or equal to 19 years old at the time of their first dialysis for ESRD between 1988 and 1993, followed through 1996. Patients who received living donor renal transplants were excluded from study. Main Outcome Measures. Time from first dialysis for ESRD until activation on the kidney transplant waiting list, relative hazard of activation on the waiting list for black compared with white pediatric patients. Results. Comparisons of the time from first dialysis for ESRD to waitlisting among the 2162 white (60.7%) and 1122 black (31.5%) patients studied using survival analysis revealed that blacks were less likely to be waitlisted at any given time in follow-up. In multivariate analysis, even after controlling for patient age, gender, socioeconomic status, geographic region, incident year of renal failure, and cause of ESRD, blacks were 12% less likely to be waitlisted than were whites at any point in time (relative hazard: .88: 95% confidence interval: .79-.97). Conclusions. Racial disparities in access to the renal transplant waiting list exist in pediatrics. Whether these disparities are attributable to differences in time of presentation to a nephrologist, physician bias in identification of transplant candidates, or patient preferences warrants further study. Pediatrics 2000;106:756-761; children, race, renal ... [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to describe substance use (SU) among adolescents and young adults (AYA) with chronic kidney disease, compare these findings with the general population, and identify associated risk factors.Methods: 708 AYA participants contributing 2475 person-visits from the Chronic Kidney Disease in Children Study were used to estimate prevalence rates of past year and 30-day alcohol, cigarette, e-cigarette and marijuana use, and were compared with national surveys. Repeated measures logistic regression estimated the association between SU and participant characteristics.Results: There was nearly no SU among those 12 to 14 years, but use increased with age, and past year alcohol use was about 80% for those greater than or equal to 22 years. Rates of use among males were constant or increased with age, while rates of use among females were lower after age 22 compared to ages 18 to 22. Associated risk factors included non-Black and non-Hispanic identity, older age, and worse disease severity. Participants were less likely to use substances compared to the general population, especially those 14-18 years.Conclusions: SU was less common in AYA with chronic kidney disease than the general population, but differences were attenuated among those greater than or equal to 18 years. Ages 12-14 appear to be the ideal time for prevention efforts. As the landscape of e-cigarette and marijuana policies change, these results underscore the need to understand how similar high-risk populations engage in SU. [ABSTRACT FROM AUTHOR]

The Chronic Kidney Disease in Children study is a cohort of about 600 children with chronic kidney disease (CKD) in the United States and Canada. The independent variable for our observations was a measurement of glomerular filtration rate (GFR) by iohexol disappearance (iGFR) at the first two visits 1 year apart and during alternate years thereafter. In a previous report, we had developed GFR estimating equations utilizing serum creatinine, blood urea nitrogen, height, gender, and cystatin C measured by an immunoturbidimetric method; however, the correlation coefficient of cystatin C and GFR (−0.69) was less robust than expected. Therefore, 495 samples were re-assayed using immunonephelometry. The reciprocal of immunonephelometric cystatin C was as well correlated with iGFR as was height/serum creatinine (both 0.88). We developed a new GFR estimating equation using a random 2/3 of 965 person-visits and applied it to the remaining 1/3 as a validation data set. In the validation data set, the correlation of the estimated GFR with iGFR was 0.92 with high precision and no bias; 91 and 45% of eGFR values were within 30 and 10% of iGFR, respectively. This equation works well in children with CKD in a range of GFR from 15 to 75 ml/min per 1.73 m2. Further studies are needed to establish the applicability to children of normal stature and muscle mass, and higher GFR. [ABSTRACT FROM AUTHOR]

An optimal measurement of glomerular filtration rate (GFR) should minimize the number of blood draws, and reduce procedural invasiveness and the burden to study personnel and cost, without sacrificing accuracy. Equations have been proposed to calculate GFR from the slow compartment separately for adults and children. To develop a universal equation, we used 1347 GFR measurements from two diverse groups consisting of 527 men in the Multicenter AIDS Cohort Study and 514 children in the Chronic Kidney Disease in Children cohort. Both studies used nearly identical two-compartment (fast and slow) protocols to measure GFR. To estimate the fast component from markers of body size and of the slow component, we used standard linear regression methods with the log-transformed fast area as the dependent variable. The fast area could be accurately estimated from body surface area by a simple parameter (6.4/body surface area) with no residual dependence on the slow area or other markers of body size. Our equation measures only the slow iohexol plasma disappearance curve with as few as two time points and was normalized to 1.73 m2 body surface area. It is of the form: GFR=slowGFR/[1+0.12(slowGFR/100)]. In a random sample utilizing a third of the patients for validation, there was excellent agreement between the calculated and measured GFR with low root mean square errors being 4.6 and 1.5 ml/min per 1.73 m2 for adults and children, respectively. Thus, our proposed simple equation, developed in a combined patient group with a broad range of GFRs, may be applied universally and is independent of the injected amount of iohexol. [ABSTRACT FROM AUTHOR]

Purpose: African American (AA) adults with chronic kidney disease (CKD) have a faster progression to end-stage renal disease and are less likely to receive a kidney transplant. It is unclear whether AA children experience renal replacement therapy (RRT) for end-stage renal disease sooner than non-AA children after accounting for socioeconomic status (SES).Methods: Among children with nonglomerular CKD in the Chronic Kidney Disease in Children study, we investigated time to RRT (i.e., first dialysis or transplant) after CKD onset using parametric survival models and accounted for SES differences by inverse probability weights.Results: Of 110 AA and 493 non-AA children (median age = 10 years), AA children had shorter time to first RRT: median time was 3.2 years earlier than non-AA children (95% CI: -6.1, -0.3). When accounting for SES, this difference was diminished and nonsignificant (-1.6 years; 95% CI: -4.6, +1.5), and its directionality was consistent with faster glomerular filtration rate decline among AA children (-6.2% vs. -4.4% per year, P = .098). When RRT was deconstructed into dialysis or transplant, the time to dialysis was 37.5% shorter for AA children and 53.7% longer for transplant. These inferences were confirmed by the frequency and timing of transplant after initiating dialysis.Conclusions: Racial differences in time to RRT were almost fully accounted for by SES, and the remaining difference was congruent with a faster glomerular filtration rate decline among AA children. Access to transplant occurred later, yet times to dialysis were shorter among AA children even when accounting for SES which may be due to a lack of organ availability. [ABSTRACT FROM AUTHOR]