CKiD Study Spurs New Insights Into Chronic Kidney Disease

Identifying the best strategies to slow the progression to kidney failure for children with chronic kidney disease (CKD) is a constant challenge for clinicians. They must finely tune their treatment plans and judiciously anticipate when to begin dialysis or place patients on a kidney transplant waiting list.

The Chronic Kidney Disease in Children Study (CKiD) is a prospective cohort study that was initiated in 2003 to provide evidence to help inform these disease management decisions. A decade later, almost 900 children between the ages of 1 and 16 with decreased kidney function have entered the study. As a one of two clinical coordinating centers for CKiD, The Children’s Hospital of Philadelphia has contributed many research projects under the leadership of principal investigator Susan L. Furth, MD, chief of the division of nephrology.

The data collected from the CKiD has prompted new insights and approaches to improve care for children with CKD. These include a new gold standard in the measurement of kidney function, identification of acidosis and low birth rate as risk factors for poor growth, models to predict overall rates of decline of kidney function over time, and awareness that children with chronic kidney disease have a remarkable constellation of risk factors for heart disease.

“The rationale for CKiD was that chronic kidney disease and end stage renal disease in this country in adults really are a substantial burden,” Dr. Furth said. “The latest estimate is 10 million Americans have chronic kidney disease. It’s very likely that many of the origins of chronic kidney disease in adults start in children. We’ve found ways that we can intervene to extend life and promote the health of these kids.”

The primary goals of CKiD are to determine participants’ risk factors for decline in renal function, track their behavior and abilities to learn and think, monitor their growth, and evaluate possible connections to future cardiovascular disease. Several CHOP investigators recently have published studies related to CKiD and also presented their findings at the Pediatric Academic Societies Annual Meeting (PAS) held in May.

In a study presented at PAS by Michelle Denburg, MD, MSCE, an attending nephrology physician at CHOP, researchers used CKiD data to show for the first time that children with CKD have increased risk of fracture, especially among teenage boys. Children with CKD have problems with absorbing calcium from the foods that they eat, and often as their kidney function worsens, their calcium gets low. In order to compensate, their bodies secrete a hormone that takes calcium out of their bones, which weakens them.

The study results showed that the incidence of fracture in a CKiD cohort of 556 children was two-fold higher than general population rates. Fractures of the arm and elbow were most common. These findings support the need for future CKiD research that will focus on bone frailty as an important therapeutic target in the pediatric CKD population.

Erum A. Hartung, MD, also an attending nephrology physician at CHOP, and colleagues published a study in the May issue of Pediatric Nephrology that concentrated on the neurocognition of a particular group of children with autosomal recessive polycystic kidney disease (ARPKD) who are born with abnormal kidneys. A previous CKiD study demonstrated that children with CKD have normal IQs, but they have challenges in the areas of attention and their ability to make and carry out plans. Parents of children with ARPKD had expressed concerns that their children could face increased risks for behavior and learning difficulties because they have early onset CKD and more severe high blood pressure — both of which are known risk factors for neurocognitive deficits.

The study’s results were reassuring to parents because they showed that the cognitive function of children with ARPKD was comparable to children in the CKiD cohort with mild-to-moderate kidney disease from other causes. The investigators concluded that, “Further studies are needed to determine if these findings are applicable to children with more severe manifestations of ARPKD.” Dr. Hartung also shared this study’s results at the PAS.

Dr. Furth encourages other investigators and collaborators to access the “wealth of data” in the CKiD’s national database to conduct research projects that potentially could lead to better outcomes for children with CKD. In the meantime, the CKiD’s second wave has begun, which involves a cohort of about 280 children.

“We’re looking more at vascular health and added tests of vascular stiffness to this study as we move forward,” Dr. Furth said. “Increased stiffness of the blood vessels, as measured by pulse wave velocity, has been associated with increased risk of adverse cardiovascular events in adults. We’re trying to see if this happens even earlier in children.”

Dr. Furth also is excited about a new partnership called the 4C Study with investigators in Europe. The aim is to gather a total sample size of about 1,500 children, including CKiD study participants and another cohort from a recently concluded interventional study in children with CKD called the ESCAPE trial, in order to conduct a genome-wide search for genetic risk markers of CKD progression.

“We’re finding out if there are new genetic associations with structural abnormalities of the kidney and also if there’s genetic variability that contributes to things like accelerated kidney function decline or anemia,” Dr. Furth said.

The National Institute of Diabetes and Digestive and Kidney Diseases, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute, recently renewed funding for the CKiD. It is a cooperative agreement between the two clinical coordinating centers — CHOP and Children’s Mercy Hospital in Kansas City — a central biochemistry laboratory at the University of Rochester in New York, and a data coordinating center at Johns Hopkins School of Public Health in Baltimore.