Childhood-onset Chronic Kidney Disease Research Articles

Trends and socioeconomic inequality of the burden of congenital abnormalities of the kidney and urinary tract among children and adolescents.

Although congenital abnormalities of the kidney and urinary tract (CAKUT) is the leading cause of childhood onset chronic kidney disease (CKD) and kidney failure, comprehensive information on the disease burden among children and adolescents globally is lacking. We aim to report the trends and socioeconomic inequality of CAKUT burden for people aged 0-24 years from 1990 to 2019·. We reported the prevalence, mortality and disability-adjusted life-years (DALYs) for CAKUT based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, quantified the association of disease burden and socio-demographic index (SDI), calculated the slope index of inequality (SII) the relative index of inequality (RII) and concentration index. In 2019, the global prevalence, mortality, and DALYs of CAKUT among individuals aged 0-24 years were 167.11 (95%Confident Interval 166.97, 167.25), 0.30 (0.29, 0.30), and 32.22 (32.16, 32.29) per 100 000 population. The greatest prevalence, mortality and DALYs were recorded in the 0-4 year age group. The greatest mortality and DALYs were recorded in low SDI countries and territories. During 1990 to 2019, the prevalence, mortality and DALYs decreased globally, while in low and low-middle countries and territories the reduction was much less slower. India, Nigeria and Pakistan had the highest DALYs. Saudi Arabia and China exhibited a markedly decrease of CAKUT burden. Globally for every 0.1 increase in SDI, there was a 20.53% reduction in mortality, a 16.31% decrease in DALYs, but a 0.38% rise in prevalence. Inequality for disease burden of varying SDI was increasing globally. Thus, specific preventive and health service measures are needed to reduce the global burden from CAKUT.

Decline in Left Ventricular Early Systolic Function with Worsening Kidney Function in Children with Chronic Kidney Disease: Insights from the 4C and HOT-KID Studies

Adults with childhood-onset chronic kidney disease (CKD) have an increased risk of cardiovascular disease. First-phase ejection fraction (EF1), a novel measure of early systolic function, may be a more sensitive marker of left ventricular dysfunction than other markers in children with CKD. To examine whether EF1 is reduced in children with CKD. Children from the 4C and HOT-KID studies were stratified according to estimated glomerular filtration rate (eGFR). The EF1 was calculated from the fraction of left ventricular (LV) volume ejected up to the time of peak aortic flow velocity. The EF1 was measured in children ages 10.9±3.7 (mean±SD) years, 312 with CKD and 63 healthy controls. The EF1 was lower, while overall ejection fraction was similar, in those with CKD compared with controls and decreased across stages of CKD (29.3%±3.7%, 23.5%±4.5%, 19.8%±4.0%, 18.5%±5.1%, and 16.7%±6.6% in controls, CKD 1, 2, 3, and≥4, respectively, P<.001). The relationship of EF1 to eGFR persisted after adjustment for relevant confounders (P<.001). The effect size for association of measures of LV structure or function with eGFR (SD change per unit change in eGFR) was greater for EF1 (β=0.365, P<.001) than for other measures: LV mass index (β=-0.311), relative wall thickness (β=-0.223), E/e' (β=-0.147), and e' (β=0.141) after adjustment for confounders in children with CKD. Children with CKD exhibit a marked and progressive decline in EF1 with falling eGFR. This suggests that EF1 is a more sensitive marker of LV dysfunction when compared to other structural or functional measures and that early LV systolic function is a key feature in the pathophysiology of cardiac dysfunction in CKD.

Transition of Care in Children with Chronic Kidney Disease, Dialysis, and Transplantation.

Improvement in management of pediatric renal disorders has led to patient survival rates of 85-90%, increasing the number of adolescent and young adult (AYA) patients with childhood onset chronic kidney disease (CKD) transitioning to adult care settings. Pediatric CKD patients differ from adults with CKD in view of early onset of disease (sometimes with fetal onset), different disease spectrum, the potential effect of CKD on neurodevelopment, and substantial involvement of parents in medical decision making. In addition to the usual challenges of emerging adulthood (graduation from school to work, independent living, peak in impulsivity and risk-taking behaviors), young adults with pediatric CKD need to learn to manage a serious medical condition independently. In kidney transplant patients, regardless of the age at transplantation, graft failure rates are higher during adolescence and young adulthood than at any other age. All pediatric CKD patients must move from a pediatric to adult-focused settings and this transition is a longitudinal process requiring collaboration and interactions of AYA patients, their families, providers, health care environment and agencies. Consensus guidelines have provided recommendations to pediatric and adult renal teams to enable successful transition. Suboptimal transition is a risk factor for poor adherence to treatment and unfavorable health outcomes. The authors discuss the process of transition as it applies to pediatric CKD patients and review challenges faced by patients/families, pediatric and adult nephrology teams. They provide some suggestions and available tools to optimize the transition of pediatric CKD patients to adult-oriented care.

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

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

Health and Dental Insurance and Health Care Utilization Among Children, Adolescents, and Young Adults With CKD: Findings From the CKiD Cohort Study

Rationale & ObjectiveTo understand the association between health and dental insurance status and health and dental care utilization, and their relationship with disease severity in a population with childhood-onset chronic kidney disease (CKD).Study DesignObservational cohort study.Settings & ParticipantsNine hundred fifty-three participants contributing 4,369 person-visits (unit of analysis) in the United States enrolled in the Chronic Kidney Disease in Children (CKiD) Study from 2005 to 2019.ExposuresHealth insurance (private vs public vs none) and dental insurance (presence vs absence) self-reported at annual visits.OutcomesSelf-reported suboptimal health care utilization in the past year, defined separately as not visiting a private physician, visiting the emergency room, visiting the emergency room at least twice, being hospitalized, and self-reported suboptimal dental care utilization over the past year, defined as not receiving dental care.Analytical ApproachRepeated measures Poisson regression models were fit to estimate and compare utilization by insurance type and disease severity at the prior visit. Additional unadjusted and adjusted models were fit, as well as models including interactions between insurance and Black race, maternal education, and income.ResultsThose with public health insurance were more likely to report suboptimal health care utilization across the CKD severity spectrum, and lack of dental insurance was strongly associated with lack of dental care. These relationships varied depending on strata of socioeconomic status and race but the effect measure modification was not significant.LimitationsDetails of insurance coverage were unavailable; reasons for emergency care or type of private physician visited were unknown.ConclusionsPediatric nephrology programs may consider interventions to help direct supportive resources to families with public insurance who are at higher risk for suboptimal utilization of care. Insurance providers should identify areas to expand access for families of children with CKD.

Perspectives on life participation by young adults with chronic kidney disease: an interview study

ObjectiveTo describe the perspectives on life participation by young adults with childhood-onset chronic kidney disease (CKD).DesignSemi-structured interviews; thematic analysis.SettingMultiple centres across six countries (Australia, Canada, India, UK, USA and New...

Renal Syndromic Hearing Loss Is Common in Childhood-onset Chronic Kidney Disease.

BackgroundHearing loss (HL) in children may adversely affect their development. HL is more prevalent in patients with chronic kidney disease (CKD) than in the general population. This study evaluated the prevalence of HL and its underlying diseases in patients with childhood-onset in CKD.MethodsIn this retrospective study of a tertiary referral center, childhood-onset CKD patients (stage 2–5, age at onset of renal symptom < 18 years) were recruited. We referred to the “renal” syndromic HL as cases with genetic or syndromic diseases, or extra-renal anomalies in addition to HL and CKD.ResultsA total of 421 patients (male:female = 279:142) were reviewed according to the causes of CKD: congenital anomalies of the kidney and urinary tract (CAKUT; n = 184, 43.7%), glomerulopathies (GP; n = 105, 24.9%), cystic kidney diseases (CYST; n = 39, 9.3%), perinatal problems (PP; n = 29, 6.9%), and others (n = 64, 15.2%). HL was detected in 82 (19.5%) patients, including 51 (12.1%) patients with sensorineural hearing loss (SNHL), 30 (7.1%) with conductive hearing loss (CHL), and 1 patient with mixed HL. The prevalence of HL in each group was as follows: 16.8% in the CAKUT group, 28.6% in the GP group, 12.8% in the CYST group, 24.1% in the PP group, and 14.1% in the others group. HL was more common in higher CKD stages, especially CHL in end-stage renal disease. SNHL was more prevalent in CKD from GP. Of the 82 patients with HL, 50% had renal syndromic HL: 58.8% of SNHL and one-third of CHL were renal syndromic HL.ConclusionOne-fifth of the childhood-onset CKD had HL. Collectively, renal syndromic HL comprised half of the HL in this study. To improve the quality of life in patients with childhood-onset CKD, we suggest that HL should be considered, requiring surveillance, and if necessary, early intervention.

Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children.

Alport syndrome (AS) and atypical hemolytic-uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.

Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases.

Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with end-stage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations. Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease. Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure.

PUK1 - Burden of Childhood Onset Chronic Kidney Disease

PUK1 - Burden of Childhood Onset Chronic Kidney Disease

Transition of adolescent and young adult patients with childhood-onset chronic kidney disease from pediatric to adult renal services: a nationwide survey in Japan.

Transition of adolescent and young adult (AYA) patients with childhood-onset chronic kidney diseases (C-CKD) from pediatric to adult renal services has received increasing attention. However, information on transition of Japanese patients with C-CKD is limited. The Transition Medicine Working Group, in collaboration with the Japanese Society for Nephrology, the Japanese Society for Pediatric Nephrology and the Japanese Society of Pediatric Urology, conducted a retrospective cross-sectional study in 2014 on issues concerning the transition of Japanese patients with C-CKD. Few institutions in Japan had transition programs and/or transition coordinators for patients with C-CKD. Refusal to transfer by patients or their families, lack of concern about transition and inability to decide on transfer were common reasons for non-transfer of patients still followed by pediatric renal services. Around 25% of patients who had ended or interrupted follow-up by pediatric renal services presented to adult renal services because of symptoms associated with C-CKD. Patients with various types of childhood-onset nephrourological diseases were transferred from pediatric to adult renal services. IgA nephropathy, minimal change nephrotic syndrome and congenital anomalies of the kidney and urinary tract were the most frequent primary kidney diseases in adult patients with C-CKD. These survey results indicate the need for introduction of transitional care for Japanese AYA patients with C-CKD. Consensus guidelines for the optimal clinical management of AYA patients with C-CKD are required to ensure the continuity of care from child to adult renal services.

Association between low birth weight and childhood-onset chronic kidney disease in Japan: a combined analysis of a nationwide survey for paediatric chronic kidney disease and the National Vital Statistics Report.

Although numerous epidemiological surveys performed across several continents and ethnic groups have linked low birth weight (LBW) to increased risk of chronic kidney disease (CKD) in adulthood, the effects of birth weight and prematurity on development of CKD in childhood have not been clearly established. Data on sex, LBW incidence and gestational age were compared between paediatric CKD cases and a control group. Paediatric CKD cases were obtained from a nationwide survey conducted by the Pediatric CKD Study Group in Japan. The population attributable fraction was calculated to evaluate the effects of reducing the prevalence of LBW infants (LBWI). Of 447 individuals born between 1993 and 2010 that fulfilled the eligibility criteria, birth weight data were obtained for 381 (85.2%) (231 boys and 150 girls), 106 (27.8%) of whom were LBWI. The proportion of LBWI in the general population during the same period was much lower (8.6%). Therefore, the risk ratio (RR) for paediatric CKD was significantly higher in the LBW group [crude RR: 4.10; 95% confidence interval (CI) 3.62-5.01], and the overall impact on paediatric CKD for removal of LBW amounted to 21.1% (95% CI 16.0-26.1%). In addition, 82 patients (21.9%) with paediatric CKD were born prematurely (before 37 weeks of gestation), and as with LBW, a strong correlation was observed between prematurity and CKD (RR: 4.73; 95% CI 3.91-5.73). Both birth weight and gestational age were strongly associated with childhood-onset CKD in this study.

Chronic kidney disease: Prenatal risk factors for kidney and urinary tract anomalies.

Childhood-onset chronic kidney disease is the result of congenital anomalies of the kidneys and urinary tract in approximately two-thirds of all patients. An area of intense research in recent years, however, is the potential impact of maternal obesity on renal ontogenesis or postnatal renal function in the offspring.

Height in chronic kidney disease

— Thomas R. Welch, MD Short stature is a common accompaniment of childhood-onset chronic kidney disease (CKD). When recombinant human growth hormone (rhGH) became available, children with CKD were among the first and largest groups of children in whom this agent was used. It clearly works, and the new generation of pediatric nephrologists rarely sees the severe renal dwarfism that once was commonplace in pediatric nephrology practice. Of course, short stature is not necessarily bad for overall health per se. The argument for treating it in CKD always has been one of improved quality of life for affected children. Although a reasonable suggestion, it never has been tested carefully. In the current issue of The Journal, the Chronic Kidney Disease in Children Study Group report careful assessment of quality of life, by both patients and their families, in a large group of children with CKD followed for several years. This allowed for longitudinal assessment of quality of life during therapy with rhGH. The parents’ assessments of quality of life in the social and physical domains were significantly improved in children receiving rhGH; interestingly, the assessments of adolescents themselves were not so positive. These data are complicated and deserve very careful reading. Indeed, one may come to more than one conclusion from them. In any case, this report represents the best available data set addressing this problem. Article page 736<

Changes in bone structure and the muscle–bone unit in children with chronic kidney disease

The impact of pediatric chronic kidney disease (CKD) on acquisition of volumetric bone mineral density (BMD) and cortical dimensions is lacking. To address this issue we obtained tibia quantitative computed tomography scans from 103 patients age 5-21 years with CKD (26 on dialysis) at baseline and 12 months later. Gender, ethnicity, tibia length and/or age-specific Z-scores were generated for trabecular and cortical BMD, cortical area, periosteal and endosteal circumference, and muscle area based on over 700 reference subjects. Muscle area, cortical area, and periosteal and endosteal Z-scores were significantly lower at baseline compared to the reference cohort. Cortical BMD, cortical area and periosteal Z-scores all exhibited a significant further decrease over 12 months. Higher parathyroid hormone levels were associated with significantly greater increases in trabecular BMD and decreases in cortical BMD in younger patients (significant interaction terms for trabecular BMD and cortical BMD). The estimated GFR was not associated with changes in BMD Z-scores independent of parathyroid hormone. Changes in muscle and cortical area were significantly and positively associated in control subjects but not in CKD patients. Thus, children and adolescents with CKD have progressive cortical bone deficits related to secondary hyperparathyroidism and potential impairment of the functional muscle-bone unit. Interventions are needed to enhance bone accrual in childhood-onset CKD.

Hypertension in pediatric patients with childhood-onset chronic kidney disease: much to be learned, more to be done

Pediatric patients with chronic kidney disease are increasingly recognized as being at increased risk of developing cardiovascular disease as adults. Numerous risk factors contribute, hypertension being one of the most identifiable and potentially modifiable. Despite this, numerous studies have demonstrated that hypertension is common and is frequently underrecognized and/or undertreated in this population. Greater efforts are needed to identify and effectively treat hypertension in these vulnerable patients to reduce the future burden of adult cardiovascular disease.

Myocardial Infarction in Chronic Kidney Disease

To the Editor .— Lane and Ben-Shachar1 recently reported myocardial infarction (MI) in adolescents with normal cardiac anatomy. Here we describe a patient with childhood-onset chronic kidney disease (CKD) who suffered MI at 22 years of age. The patient's CKD resulted from meningococcemia at 6 years of age. Renal transplantation at the age of 9 years resulted in primary nonfunction, the kidney was removed, and peritoneal dialysis was continued. At 17 years, a computed tomography scan incidentally revealed aortic calcification, indicating vascular disease (Fig 1). At 19 years, he received a deceased-donor renal transplant and was immunosuppressed with …

The central nervous system in childhood chronic kidney disease

Neurodevelopmental deficits in pediatric and adult survivors of childhood onset chronic kidney disease (CKD) have been documented for many years. This paper reviews the available literature on central nervous system involvement incurred in childhood CKD. The studies reviewed include recent work in neuroimaging, electrophysiology, and neuropsychology, along with commentary on school functioning and long-term outcomes. The paper concludes with suggestions for monitoring the neurodevelopmental status and pursuing appropriate early interventions for children with CKD.

Cardiovascular Disease in Children with Chronic Kidney Disease

In children with end-stage renal disease (ESRD), cardiovascular disease (CVD) mortality has not changed for the past 3 decades. Cardiac disease remains the second most common cause of death. Recent data demonstrate a high incidence and prevalence of traditional and chronic kidney disease (CKD)-related CVD risk factors in children. Early markers of cardiomyopathy, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction (LV dysfunction), and early markers of atherosclerosis, such as increased carotid artery intima-media thickness (IMT) and carotid arterial wall stiffness, are frequently found in this patient population. Early identification of modifiable risk factors and treatment of asymptomatic CVD might lead to decrease of cardiovascular morbidity and mortality in young adults who developed CKD during childhood.

Altered Morphologic Properties of Large Arteries in Children with Chronic Renal Failure and after Renal Transplantation

Increased intima-media thickness of the carotid arteries (cIMT) has been found in young adults with childhood-onset chronic kidney disease (CKD). The disease stage at which these patients first develop abnormalities of arterial texture is unknown. The objective of this study was to determine the onset and character of arterial changes in children aged 10 to 20 yr with different stages of CKD and to identify risk factors for early arteriopathy. High-resolution ultrasonography was conducted of common cIMT and femoral superficial artery IMT. Fifty-five children with stages 2 to 4 CKD (GFR 51 +/- 31 ml/min per 1.73 m2), 37 on dialysis, and 34 after renal transplantation (Rtx; GFR 73 +/- 31 ml/min per 1.73 m2) were studied. Control subjects were 270 healthy children, matched for age and gender. Compared with control subjects, cIMT, femoral superficial artery IMT (both as absolute values and as SD score of median of normal value), wall cross-sectional area, and lumen cross-sectional area of carotid artery were significantly increased in all patient groups and most markedly abnormal in dialysis patients. cIMT in CKD and Rtx patients was significantly lower in comparison with dialysis patients. cIMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged mean calcitriol dose. The cumulative phosphate binder intake, time-averaged Ca x P product, and young age were independent predictors of an increased cIMT. In children with CKD, thickening of IMT occurs early in the course of disease and is most marked in dialyzed patients. The changes may be partly reversible after Rtx.