Chronic kidney disease (CKD) is a life-long condition associated with substantial morbidity and premature death due to complications from a progressive decrease in kidney function. The incidence and ...prevalence of all stages of CKD in children continues to increase worldwide. Between 2000 and 2008, the kidney replacement therapy incidence rate in those aged 0-19 years increased 5.9% to 15 per million population, highlighting the importance of CKD research in children. Many comorbid conditions seen in adults with CKD, including cardiovascular disease and cognitive impairment, also are highly prevalent in children, implicitly demonstrating the crucial need for initiating therapy early to improve health outcomes in children with CKD. The CKiD (Chronic Kidney Disease in Children) Study is a prospective cohort study of 586 children aged 1-16 years with an estimated glomerular filtration rate of 30-90 mL/min/1.73 m2 . Since its inception, CKiD has identified risk factors for CKD progression and cardiovascular disease in children with CKD and highlighted the effects of CKD on outcomes unique to children, including neurocognitive development and growth. This review summarizes the findings to date, illustrating the spectrum of CKD-associated complications in children and emphasizing areas requiring further investigation. Taken in sum, these elements stress that initiating treatment at an early age is essential for reducing long-term morbidity and mortality in children with CKD.
Using data (2655 observations from 928 participants) from the Chronic Kidney Disease in Children Study, we developed and internally validated new glomerular filtration rate estimating equations for ...clinical use in children and young adults: two forms of K × heigh(ht) / serum creatinine(sCr) and two forms of K × 1 / cystatin C(cysC). For each marker, one equation used a sex-dependent K; in the other, K is sex-and age-dependent. Glomerular filtration rate (GFR) was measured directly by plasma iohexol disappearance. The equations using ht⁄sCr had sex-specific constants of 41.8 for males and 37.6 for females. In the age- dependent models, K increased monotonically for children 1-18 years old and was constant for young adults 18-25 years. For males, K ranged from 35.7 for one-year-olds to 50.8 for those 18 and older. For females, the values of K ranged from 33.1 to 41.4. Constant K values for cystatin-C equations were 81.9 for males and 74.9 for females. With age-dependency, K varied non-monotonically with the highest values at age 15 for males (K of 87.2) and 12 years for females (K of 79.9). Use of an age-dependent K with ht/sCr models reduced average bias, notably in young children and young adults; age-dependent cystatin-C models produced similar agreement to using a constant K in children under 18 years, but reduced bias in young adults. These age-dependent proposed equations were evaluated alongside estimated GFRs from 11 other published equations for pediatrics and young adults. Only our proposed equations yielded non- significant bias and within 30% accuracy values greater than 85% in both the pediatric and young adult subpopulations.
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Purpose Kidney stone disease has become increasingly common during childhood and adolescence. However, the rate of symptomatic kidney stone recurrence for pediatric patients is uncertain. We sought ...to determine the recurrence rate of symptomatic kidney stones in a cohort of children with incident symptomatic nephrolithiasis. Materials and Methods We performed a retrospective cohort study of patients 3 to 18 years old without anatomical abnormalities or genetic causes of nephrolithiasis who presented with a first symptomatic kidney stone between 2008 and 2014. We determined recurrence rates of symptomatic nephrolithiasis, defined as a new kidney stone on ultrasound and/or computerized tomogram associated with pain and/or vomiting. We also estimated associations between completing 24-hour urinalysis and symptomatic kidney stone recurrence using Kaplan-Meier curves and multivariable Cox regression models. Results A total of 285 children with a median age of 14.8 years (IQR 11.3–16.6) at nephrolithiasis diagnosis were followed for 492 person-years. A total of 86 symptomatic recurrent stones developed in 68 patients (24%) during the followup period. The probability of symptomatic stone recurrence was 50% at 3 years after the index kidney stone. Median time to stone recurrence was 3 years at the first recurrence and 5 years at the second. Adjusting for confounders including adherence to followup, completing a 24-hour urinalysis after a kidney stone episode was associated with a 60% decreased risk of recurrence (hazard ratio 0.40, 95% CI 0.18–0.91). Conclusions The risk of kidney stone recurrence is high during childhood, with approximately 50% of children presenting with symptomatic recurrence within 3 years of the first stone. The role and usefulness of analyzing 24-hour urine chemistries in decreasing kidney stone recurrence should be explored in future prospective studies.
The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an ...update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.
To evaluate the diagnostic accuracy of ultrasound elastography with acoustic radiation force impulse (ARFI) to detect congenital hepatic fibrosis and portal hypertension in children with autosomal ...recessive polycystic kidney disease (ARPKD).
Cross-sectional study of 25 children with ARPKD and 24 healthy controls. Ultrasound ARFI elastography (Acuson S3000, Siemens Medical Solutions USA, Inc, Malvern, Pennsylvania) was performed to measure shear wave speed (SWS) in the right and left liver lobes and the spleen. Liver and spleen SWS were compared in controls vs ARPKD, and ARPKD without vs with portal hypertension. Linear correlations between liver and spleen SWS, spleen length, and platelet counts were analyzed. Receiver operating characteristic analysis was used to evaluate diagnostic accuracy of ultrasound ARFI elastography.
Participants with ARPKD had significantly higher median liver and spleen SWS than controls. At a proposed SWS cut-off value of 1.56 m/s, the left liver lobe had the highest sensitivity (92%) and specificity (96%) for distinguishing participants with ARPKD from controls (receiver operating characteristic area 0.92; 95% CI 0.82-1.00). Participants with ARPKD with portal hypertension (splenomegaly and low platelet counts) had significantly higher median liver and spleen stiffness than those without portal hypertension. The left liver lobe also had the highest sensitivity and specificity for distinguishing subjects with ARPKD with portal hypertension.
Ultrasound ARFI elastography of the liver and spleen, particularly of the left liver lobe, is a useful noninvasive biomarker to detect and quantify liver fibrosis and portal hypertension in children with ARPKD.
•A fully automatic segment method for clinical ultrasound kidney images.•End-to-end learning of boundary detection and pixelwise classification networks.•Achieved significantly better performance ...than pixelwise classification networks.•Data-augment improved the segmentation performance.
It remains challenging to automatically segment kidneys in clinical ultrasound (US) images due to the kidneys’ varied shapes and image intensity distributions, although semi-automatic methods have achieved promising performance. In this study, we propose subsequent boundary distance regression and pixel classification networks to segment the kidneys automatically. Particularly, we first use deep neural networks pre-trained for classification of natural images to extract high-level image features from US images. These features are used as input to learn kidney boundary distance maps using a boundary distance regression network and the predicted boundary distance maps are classified as kidney pixels or non-kidney pixels using a pixelwise classification network in an end-to-end learning fashion. We also adopted a data-augmentation method based on kidney shape registration to generate enriched training data from a small number of US images with manually segmented kidney labels. Experimental results have demonstrated that our method could automatically segment the kidney with promising performance, significantly better than deep learning-based pixel classification networks.
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Background Hyperuricemia is associated with essential hypertension in children. No previous studies have evaluated the effect of hyperuricemia on progression of chronic kidney disease (CKD) in ...children. Study Design Prospective observational cohort study. Setting & Participants Children and adolescents (n = 678 cross-sectional; n = 627 longitudinal) with a median age of 12.3 (IQR, 8.6-15.6) years enrolled at 52 North American sites of the CKiD (CKD in Children) Study. Predictor Serum uric acid level (<5.5, 5.5-7.5, and >7.5 mg/dL). Outcomes Composite end point of either >30% decline in glomerular filtration rate (GFR) or initiation of renal replacement therapy. Measurements Age, sex, race, blood pressure status, GFR, CKD cause, urine protein-creatinine ratio (<0.5, 0.5-<2.0, and ≥2.0 mg/mg), age- and sex-specific body mass index > 95th percentile, use of diuretics, and serum uric acid level. Results Older age, male sex, lower GFR, and body mass index > 95th percentile were associated with higher uric acid levels. 162, 294, and 171 participants had initial uric acid levels < 5.5, 5.5 to 7.5, or >7.5 mg/dL, respectively. We observed 225 instances of the composite end point over 5 years. In a multivariable parametric time-to-event analysis, compared with participants with initial uric acid levels < 5.5 mg/dL, those with uric acid levels of 5.5 to 7.5 or >7.5 mg/dL had 17% shorter (relative time, 0.83; 95% CI, 0.62-1.11) or 38% shorter (relative time, 0.62; 95% CI, 0.45-0.85) times to event, respectively. Hypertension, lower GFR, glomerular CKD cause, and elevated urine protein-creatinine ratio were also associated with faster times to the composite end point. Limitations The study lacked sufficient data to examine how use of specific medications might influence serum uric acid levels and CKD progression. Conclusions Hyperuricemia is a previously undescribed independent risk factor for faster progression of CKD in children and adolescents. It is possible that treatment of children and adolescents with CKD with urate-lowering therapy could slow disease progression.
In this issue of
we see the results of a randomized clinical trial of dapagliflozin or saxagliptin in pediatric type 2 diabetes (T2D). In children and adolescents with T2D, dapagliflozin achieved ...significant improvements in glycemia in the trial.
In June 2023, following another pivotal trial, the U.S. Food and Drug Administration (FDA) approved empagliflozin and the combination of empagliflozin and metformin as additions to diet and exercise to improve blood sugar control in children 10 years and older with T2D. Metformin, the only other oral therapy available for the treatment of children with T2D, was first approved for pediatric use in 2000.
Background
Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function.
...Methods
We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up.
Results
A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth.
Conclusions
CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Background Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression. Study Design ...Prospective multicenter observational cohort study. Setting & Participants 496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study. Predictors Proteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia. Outcomes Parametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR). Results 398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow-ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2 mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2 mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally. Limitations Small number of events in glomerular patients and use of internal cross-validation. Conclusions Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD.
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