Credit: Original article published here.
The incidence of pediatric chronic kidney disease (CKD) is low, and there are gaps in the quantity and quality of evidence informing clinical decision-making in pediatric CKD. Causes of CKD in children include congenital anomalies of the kidney and urinary tract (CAKUT) and acquired disease. Glomerular disease is the most common form of acquired pediatric CKD leading to kidney failure. Repeated episodes of acute kidney injury are also associated with increased risk for the development and progression of CKD in children.
The most comprehensive data on the progression of CKD in children are from the Chronic Kidney Disease in Children (CKiD) study, an ongoing prospective cohort study that has enrolled more than 1000 children over three recruitment waves. According to Caroline A. Gluck, MD, and colleagues, CKiD data are limited by the relatively small sample size. The researchers conducted a study utilizing electronic heath record (EHR) data from a national multicenter pediatric network in the United States to identify a large cohort of children with CKD.
The retrospective cohort study was designed to evaluate progression of CKD in the pediatric population and examine clinical risk factors for decline in kidney function. Results of the study were reported online in the Clinical Journal of the American Society of Nephrology [2023;18(2):173-182].
The cohort included children seen in six pediatric health systems in PEDSnet between January 1, 2009, and February 28, 2022. PEDSnet is a clinical research network that has aggregated EHR data from inpatient and outpatient settings in the United States for more than 7 million patients. Criteria used to identify children with CKD were two estimated glomerular filtration rate (eGFR) values <90 mL/min/1.73 m2 and ≥15 mL/min/1.73 m2 separated by at least 90 days, without an intervening value >90 mL/min/1.73 m2.
CKD progression was defined as a composite outcome of eGFR <15 mL/min/1.73 m2, ≥50% decline in eGFR, long-term dialysis, or kidney transplant. Subcohorts were identified based on CKD etiology (glomerular, nonglomerular, or malignancy). The association of hypertension (two or more visits with hypertension diagnosis code) and proteinuria (one or more urinalysis with one or more + protein) within 2 years of cohort entrance on the composite outcome was examined.
The study sample derivation yielded a cohort of 11,240 children. Overall, median age at entrance to the cohort was 11 years, and median follow-up time was 5.1 years. Children in the nonglomerular cohort included those with CAKUT, such as hydronephrosis renal dysplasia, renal agenesis, and obstructive and reflux nephropathy. Those with a history of malignancy were younger at cohort entrance and had longer follow-up time than those in the other subcohorts. There were no significant differences in sex across cohorts.
At cohort entrance, most children had eGFR 60 to 89 mL/min/1.73 m2. Median eGFR was 75.3 mL/min/1.73 m2. In the glomerular CKD subcohort, median eGFR was lower and a greater proportion had eGFR 15 to 59 mL/min/1.73 m2 compared with the other subcohorts.
Within 2 years of cohort entrance, overall and across subcohorts, at least 31% had proteinuria and at least 32% had hypertension. The burden of proteinuria and hypertension was highest among those with glomerular CKD. Sixty-one percent of those with hypertension were treated with any antihypertensive within the first 2 years, and 59% of those with both hypertension and proteinuria were treated with renin-angiotensin-aldosterone system blockade. Across the subcohorts, the proportion of children with a cardiac diagnosis at cohort entrance was 16% to 26%.
Overall, 1874 children progressed to the composite kidney failure outcome. A ≥50% decline in eGFR occurred in 15% of the overall cohort (n=1633), and 10% of the cohort (n=1135) reached eGFR <15 mL/min/1.73 m2. Long-term dialysis occurred in 4% of the cohort (n=448) and 4% (n=465) underwent kidney transplant. Those in the glomerular CKD subcohort were more likely to reach the composite outcome compared with those with nonglomerular CKD and those with a history of malignancy (40%, 13% and 23%, respectively).
The most rapid progression to kidney failure was seen in children in the glomerular CKD subcohort; children in the history of malignancy subcohort progressed to kidney failure more rapidly than children in the nonglomerular CKD subcohort. The effect of disease etiology was mitigated by worse eGFR category on cohort entrance.
There were associations between hypertension and proteinuria and more rapid decline in kidney function. Those with CKD and both hypertension and proteinuria had the fastest progression to kidney failure.
In the sensitivity analysis for the cohort with eGFR <60 mL/min/1.73 m2, CKD associated with glomerular disease and CKD associated with malignancy were associated with higher risk for progression of kidney disease. When death was analyzed as a competing risk, there was no significant effect on cumulative incidence of the composite kidney failure outcomes in both the main analysis and the sensitivity analysis requiring eGFR <60 mL/mnin/1.73 m2 for cohort entry.
Results of multivariable Cox analyses demonstrated the significant and independent effects of hypertension and proteinuria on CKD progression: adjusted hazard ratio (aHR) associated with hypertension, 1.49 (95% CI, 1.22-1.82) and proteinuria, 2.23 (95% CI, 1.89-2.62). Those with glomerular disease and a history of malignancy compared with those with nonglomerular CKD had higher risks of CKD progression (aHR, 2.01 [95% CI, 1.78-2.28] and aHR, 1.79 [95% CI, 1.52-2.11], respectively).
Children with both proteinuria and hypertension had higher risk of CKD progression compared with those without proteinuria or hypertension (aHR, 3.98; 95% CI, 3.40-4.68). The highest risk of reaching the composite outcome was among children with greater CKD severity (lower eGFR category) at cohort entrance; the highest risk was among children with eGFR 15 to 29 mL/min/1.73 m2 (aHR, 5.75; 95% CI, 5.05-6.55).
Study limitations cited by the authors included basing determinations of CKD etiology and comorbid conditions on diagnosis codes only, the inability to determine whether hypertension was controlled, and lack of information on the method of creatinine measurement in the study cohort.
In conclusion, the researchers said, “Overall, this study leveraged large-scale multi-institutional EHR data collected in real-world settings to study a rare disease, pediatric CKD, over an extended time period and includes a previously underrepresented population, children with a history of cancer. Our findings confirm several previously established risk factors for CKD progression from prior observational studies (glomerular disease, proteinuria, and hypertension) and provide face validity to our novel approach for studying pediatric CKD. This study may serve as the foundation for future pragmatic clinical trials in children with CKD and as a roadmap for use of EHR data networks to adequately power the study of rare disease.”
Takeaway Points
- Researchers reported results of a retrospective cohort study using electronic health record data to identify a large cohort of children with chronic kidney disease (CKD), examine progression of CKD, and identify clinical risk factors for decline in kidney function.
- Seventeen percent of the overall cohort progressed to the composite kidney failure outcome.
- Lower estimated glomerular filtration rate category, hypertension, and proteinuria were associated with increased risk for progression to kidney failure among children with CKD.
