Bradley A. Warady

Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study.

An estimated 650,000 Americans will have ESRD by 2010. Young adults with kidney failure often develop progressive chronic kidney disease (CKD) in childhood and adolescence. The Chronic Kidney Disease in Children (CKiD) prospective cohort study of 540 children aged 1 to 16 yr and have estimated GFR between 30 and 75 ml/min per 1.73 m2 was established to identify novel risk factors for CKD progression; the impact of kidney function decline on growth, cognition, and behavior; and the evolution of cardiovascular disease risk factors. Annually, a physical examination documenting height, weight, Tanner stage, and standardized BP is conducted, and cognitive function, quality of life, nutritional, and behavioral questionnaires are completed by the parent or the child. Samples of serum, plasma, urine, hair, and fingernail clippings are stored in biosamples and genetics repositories. GFR is measured annually for 2 yr, then every other year using iohexol, HPLC creatinine, and cystatin C. Using age, gender, and serial measurements of Tanner stage, height, and creatinine, compared with iohexol GFR, a formula to estimate GFR that will improve on traditional pediatric GFR estimating equations when applied longitudinally is expected to be developed. Every other year, echocardiography and ambulatory BP monitoring will assess risk for cardiovascular disease. The primary outcome is the rate of decline of GFR. The CKiD study will be the largest North American multicenter study of pediatric CKD.

Metabolic Abnormalities, Cardiovascular Disease Risk Factors, and GFR Decline in Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVESnMetabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnData were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample.nnnRESULTSnCKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m(2). Compared with those with a GFR ≥ 50 ml/min per 1.73 m(2), having a GFR < 30 ml/min per 1.73 m(2) was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was -4.3 ml/min per 1.73 m(2) and -1.5 ml/min per 1.73 m(2) per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms.nnnCONCLUSIONSnGrowth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m(2) in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR.

Association of Proteinuria with Race, Cause of Chronic Kidney Disease, and Glomerular Filtration Rate in the Chronic Kidney Disease in Children Study

BACKGROUND AND OBJECTIVESnProteinuria is associated with chronic kidney disease (CKD), and heavy proteinuria predicts a rapid decline in kidney function. However, the epidemiologic distribution of this important biomarker study is not well described in the pediatric CKD population.nnnDESIGN, SETTING, PARTICIPANTS & MEASUREMENTSnThis cross-sectional study of North American children with CKD examined the association of proteinuria among the baseline clinical variables in the cohort. Urinary protein-to-creatinine ratios (Up/c) were used to measure level of proteinuria.nnnRESULTSnOf the 419 subjects studied, the median GFR as measured by iohexol disappearance (iGFR) was 42 ml/min per 1.73 m(2), median duration of CKD was six yr, and glomerular diseases accounted for 22% of the CKD diagnoses. Twenty-four percent of children had normal range (Up/c <0.2), 62% had significant, and 14% had nephrotic-range proteinuria (Up/c >2.0). A decrease in iGFR was associated with an increase in Up/c. At any level of GFR, a higher Up/c was associated with a glomerular cause of CKD and non-Caucasian race. Among subjects with a glomerular cause of CKD, Up/c was lower in subjects reporting utilization of renin-angiotensin system (RAS) antagonists (median Up/c = 0.93) compared with those who did not (median Up/c = 3.78).nnnCONCLUSIONSnProteinuria is associated with level of iGFR, cause of CKD, and race. The longitudinal study design of Chronic Kidney Disease in Children (CKiD) cohort study and the large number of subjects being studied has created an opportunity to better define the association between proteinuria and CKD progression.

Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation

The mortality rate in children with ESRD is substantially lower than the rate experienced by adults. However, the risk of death while awaiting kidney transplantation and the impact of transplantation on long‐term survival has not been well characterized in the pediatric population. We performed a longitudinal study of 5961 patients under age 19 who were placed on the kidney transplant waiting list in the United States. Of these, 5270 received their first kidney transplant between 1990 and 2003. Survival was assessed via a time‐varying nonproportional hazards model adjusted for potential confounders. Transplanted children had a lower mortality rate (13.1 deaths/1000 patient‐years) compared to patients on the waiting list (17.6 deaths/1000 patient‐years). Within the first 6 months of transplant, there was no significant excess in mortality compared to patients remaining on the waiting list (adjusted Relative Risk (aRR) = 1.01; p = 0.93). After 6 months, the risk of death was significantly lower: at 6–12 months (aRR = 0.37; p < 0.001) and at 30 months (aRR 0.26; p < 0.001). Compared to children who remain on the kidney transplant waiting list, those who receive a transplant have a long‐term survival advantage. With the potential for unmeasured bias in this observational data, the results of the analysis should be interpreted conservatively.

Predictors of Rapid Progression of Glomerular and Nonglomerular Kidney Disease in Children and Adolescents: The Chronic Kidney Disease in Children (CKiD) Cohort

BACKGROUNDnFew studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression.nnnSTUDY DESIGNnProspective multicenter observational cohort study.nnnSETTING & PARTICIPANTSn496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study.nnnPREDICTORSnProteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia.nnnOUTCOMESnParametric 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).nnnRESULTSn398 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 > 2mg/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 >2mg/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.nnnLIMITATIONSnSmall number of events in glomerular patients and use of internal cross-validation.nnnCONCLUSIONSnCharacterization 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.

Association Between Clinical Risk Factors and Progression of Chronic Kidney Disease in Children

BACKGROUND AND OBJECTIVESnChildren with chronic kidney disease (CKD) have an increased risk of progression to ESRD. There is a need to identify treatments to slow the progression of CKD, yet there are limited data regarding clinical risk factors that may be suitable targets to slow progression.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnWe performed a retrospective cohort study using the North American Pediatric Renal Trials and Cooperative Studies CKD database. There were 4166 pediatric subjects with CKD stages II to IV. Disease progression was defined as a GFR on follow-up of <15 ml/min per 1.73 m(2) or termination in the registry because of dialysis or transplantation. We used Kaplan-Meier and Cox proportional hazards methods to describe progression rates and determine factors associated with CKD progression.nnnRESULTSnIn the univariate analysis, CKD progression was associated with age, gender, race, primary disease, CKD stage, registration year, hematocrit, albumin, corrected calcium, corrected phosphorus, and use of certain medications. Factors that remained significant in the multivariate analysis were age, primary disease, CKD stage, registration year, hypertension, corrected phosphorus, corrected calcium, albumin, hematocrit, and medication proxies for anemia and short stature.nnnCONCLUSIONSnThere are multiple risk factors associated with disease progression in the pediatric CKD population. Factors that may be amenable to intervention include anemia, hypoalbuminemia, hyperphosphatemia, hypocalcemia, hypertension, and short stature. Because of the retrospective nature of our study, confirmation of our results from ongoing prospective studies is warranted before recommending prospective interventional trials.

Anemia and Risk of Hospitalization in Pediatric Chronic Kidney Disease

BACKGROUND AND OBJECTIVESnAnemia is a well known complication of chronic kidney disease (CKD); however, the prevalence of anemia within CKD stages in the pediatric population has not been established. Additionally, the associated morbidity of anemia in the pediatric CKD population has not been elucidated.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSn2,779 patients ages 2 yr and older in the North American Pediatric Renal Trials and Collaborative Studies database with CKD stage II to V (excluding dialysis or previous transplant patients) were identified. Descriptive statistics and multivariate modeling using logistic regression was performed to determine the prevalence of anemia and to evaluate the correlation between baseline anemia and hospitalization.nnnRESULTSnThe prevalence of anemia (hematocrit < 33%) increased from 18.5% in CKD stage II to 68% in CKD stage V (predialysis). Anemic children were 55% more likely to be hospitalized when compared with nonanemic children (odds ratio 1.55; 95% confidence interval 1.23 to 1.94). Similar results were obtained using hematocrit cutoffs of 36 and 39%.nnnCONCLUSIONSnIn this pediatric predialysis CKD population, anemia increases with increasing CKD stage and is significantly associated with hospitalization risk. Hematocrit levels above 36 and 39% were not associated with increased risk of hospitalization. Further examination into the effect of correcting anemia on hospitalization rates may provide additional useful information.

Sleep and Fatigue Symptoms in Children and Adolescents With CKD: A Cross-sectional Analysis From the Chronic Kidney Disease in Children (CKiD) Study

BACKGROUNDnAlthough symptoms of sleepiness and fatigue are common in adults with chronic kidney disease (CKD), little is known about the prevalence of these symptoms in children with CKD.nnnSTUDY DESIGNnCross-sectional analysis within a cohort study.nnnSETTING & PARTICIPANTSnWe describe the frequency and severity of sleep problems and fatigue and assess the extent of their association with measured glomerular filtration rate (mGFR) and health-related quality of life (HRQOL) in 301 participants of the Chronic Kidney Disease in Children cohort.nnnOUTCOMES & MEASUREMENTSnSleep and fatigue-related items from the Pediatric Quality of Life Inventory 4.0 Generic Scales and the CKD-related Symptoms List were used.nnnRESULTSnMedian mGFR was 42.0 mL/min/1.73 m(2) (25th-75th percentiles, 31.2-53.2), and median age was 13.9 years (25th-75th percentiles, 10.8-16.2). Children with mGFR of 40-<50, 30-<40, or <30 mL/min/1.73 m(2) had 2.07 (95% CI, 1.05-4.09), 2.35 (95% CI, 1.17-4.72), and 2.59 (95% CI, 1.15-5.85) higher odds of having more severe parent reports of low energy than children with mGFR > or = 50 mL/min/1.73 m(2). Compared with participants with mGFR > or = 50 mL/min/1.73 m(2), those with mGFR < 30 mL/min/1.73 m(2) had 3.92 (95% CI, 1.37-11.17) higher odds of reporting more severe weakness, and those with mGFR of 40-<50 mL/min/1.73 m(2) had 2.95 (95% CI, 1.26-6.88) higher odds of falling asleep during the day. Low energy, trouble sleeping, and weakness were associated with lower HRQOL scores.nnnLIMITATIONSnSymptoms of sleep and fatigue represent the childs or parents perception of symptom severity, whereas individual items can lead to imprecise measurements of sleep and fatigue.nnnCONCLUSIONSnLower mGFR was associated with increased weakness, low energy, and daytime sleepiness. Furthermore, a strong association between trouble sleeping, low energy, and weakness with decreases in overall HRQOL was observed. Detection and treatment of poor sleep and fatigue may improve the development and HRQOL of children and adolescents with CKD.

Progression of Pediatric CKD of Nonglomerular Origin in the CKiD Cohort

BACKGROUND AND OBJECTIVESnCongenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnUrine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study.nnnRESULTSnA total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m(2) (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m(2) per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m(2) per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m(2) per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria.nnnCONCLUSIONSnBaseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.

Genomic imbalances in pediatric patients with chronic kidney disease

BACKGROUNDnThere is frequent uncertainty in the identification of specific etiologies of chronic kidney disease (CKD) in children. Recent studies indicate that chromosomal microarrays can identify rare genomic imbalances that can clarify the etiology of neurodevelopmental and cardiac disorders in children; however, the contribution of unsuspected genomic imbalance to the incidence of pediatric CKD is unknown.nnnMETHODSnWe performed chromosomal microarrays to detect genomic imbalances in children enrolled in the Chronic Kidney Disease in Children (CKiD) prospective cohort study, a longitudinal prospective multiethnic observational study of North American children with mild to moderate CKD. Patients with clinically detectable syndromic disease were excluded from evaluation. We compared 419 unrelated children enrolled in CKiD to multiethnic cohorts of 21,575 children and adults that had undergone microarray genotyping for studies unrelated to CKD.nnnRESULTSnWe identified diagnostic copy number disorders in 31 children with CKD (7.4% of the cohort). We detected 10 known pathogenic genomic disorders, including the 17q12 deletion HNF1 homeobox B (HNF1B) and triple X syndromes in 19 of 419 unrelated CKiD cases as compared with 98 of 21,575 control individuals (OR 10.8, P = 6.1 × 10⁻²⁰). In an additional 12 CKiD cases, we identified 12 likely pathogenic genomic imbalances that would be considered reportable in a clinical setting. These genomic imbalances were evenly distributed among patients diagnosed with congenital and noncongenital forms of CKD. In the vast majority of these cases, the genomic lesion was unsuspected based on the clinical assessment and either reclassified the disease or provided information that might have triggered additional clinical care, such as evaluation for metabolic or neuropsychiatric disease.nnnCONCLUSIONnA substantial proportion of children with CKD have an unsuspected genomic imbalance, suggesting genomic disorders as a risk factor for common forms of pediatric nephropathy. Detection of pathogenic imbalances has practical implications for personalized diagnosis and health monitoring in this population.nnnTRIAL REGISTRATIONnClinicalTrials.gov NCT00327860.nnnFUNDINGnThis work was supported by the NIH, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute.