Charting a Course for Children With Kidney Disease

Children are not just little adults”: It’s a phrase heard often in pediatric medicine, whether you’re a parent, doctor, or researcher. With their dynamically developing bodies, unique psychology and biolochronic kidney disease (CKD) is just one example of a condition whose causes, consequences, and outcomes differ distinctly from adults. And at Children’s Hospital of Philadelphia, clinician-researchers in our Division of Nephrology are constantly learning more about the important differences between pediatric and adult CKD.

Earlier this year, Susan Furth, MD, PhD, chief of the Division of Nephrology, and her colleagues developed a new staging system to help doctors better estimate when a particular child with CKD will reach end-stage renal disease (ESRD). When a patient reaches ESRD, they must undergo renal replacement therapy (RRT) through either a kidney transplant or dialysis. Though a classification system for predicting CKD progression has been developed for adults by the Kidney Disease: Improving Global Outcomes (KDIGO) initiative, it’s based primarily on adult data.

The new staging system, in contrast, uses data from children forchildren: By drawing on two large multi-center cohorts of children with CKD — including the Chronic Kidney Disease in Children (CkiD) cohort — it gives pediatricians the opportunity to introduce a more concrete timeline of what their patient might expect.

“There are a number of variables that affect the risk that a particular child will progress to end-stage renal disease,” Dr. Furth said. “And I think as clinicians, we have a good concept of those factors. What we haven’t had the ability to do before this, and what we’re trying to do with this research, is put some estimates of actual time around that.”

Not Just Little Adults

To understand the need for such a tool in children with CKD, it helps to first understand the key differences of the disease in children and adults. In adults, the two most common causes for CKD are diabetes and hypertension. But according to Dr. Furth, neither are really common causes of CKD in children at all: Most children develop CKD due to inherited conditions or structural developmental problems (like when a child’s kidneys or the bladder don’t develop normally in utero) that disrupt kidney function. These congenital anomalies of the kidneys and urinary tract and inherited disorders fall into the broad category of “nonglomerular” kidney disease, and it’s more common in children than in adults.

Children might also develop CKD from acquired causes, such as when inflammatory disorders like lupus affect a child’s kidney function. This broad category of “glomerular” kidney disease occurs when inflammation inside the glomeruli, the kidney’s filtration units, impairs normal filtration.

The etiology of a child’s CKD is one of the factors that Dr. Furth and her team took into account when creating their new classification system. On top of that, Dr. Furth says that the stressors placed on a child’s kidney differ greatly between children and adults.

“A child’s main job is to grow, and during periods of greatest growth, your kidneys actually have to work harder,” Dr. Furth said. “Kids grow a ton in the first couple years of life and then even more so at puberty, and add those factors of growth with poor kidney function, because maybe you’re born with very small kidneys.”

Adults, on the other hand, don’t have the added stressor of growth, except perhaps during pregnancy. Pediatricians must thus take into account the normal developmental processes that go along with a child’s growth over their lifespan when keeping children’s kidneys healthy.

Estimating CKD Progression in Children

In Dr. Furth’s paper, recently published in the American Journal of Kidney Diseases, the team categorized children with CKD into six stages, ranked from best to worst prognosis. Each of the six categories indicate an approximate time estimate of how soon a patient will progress to the need for RRT.

Based on the 891 patients in the CKiD cohort and 378 additional patients in the ESCAPE study, Dr. Furth’s team identified three main risk factors that helped to inform their development of risk stages: whether the CKD is nonglomerular or glomerular, how efficiently the kidney filters waste products from the blood, and the presence of protein in the urine (known as proteinuria). A combination of these risk factors provide the best predictors for estimating disease progression, the team concluded.

Knowledge Through Numbers: The CKiD Cohort

Beyond the new classification system, the CKiD cohort has led to more insights into pediatric CKD — discoveries that would not have been possible without the large amounts of data from children and followed throughout many years.

“We’ve learned about kidney disease in children in a couple of important areas, including the underlying causes of kidney disease in children, and some of the important consequences in kidney disease that affect adult health,” Dr. Furth said.

By partnering with colleagues with expertise in the genetics of kidney development, Dr. Furth and her fellow CHOP researchers have been able to use data from the CKiD cohort to pinpoint a variety of genes that may underlie CKD. By understanding the mechanisms by which those genes contribute to abnormal development, she hopes to someday develop new therapies to target these abnormalities.

“We’re using our data to discover new genes that contribute to kidney development and contribute to some of these abnormalities in development of the kidney and the bladder,” Dr. Furth said.

Data from the CKiD study is also helping to inform some of the long-term consequences of kidney disease. Because children with CKD sometimes don’t do as well in school despite having fairly normal IQ’s, Dr. Furth said researchers are trying to understand the causes of those delays. In collaboration with genetics researchers, they have found that some genes that appear to contribute to kidney development in other populations have also been associated with developmental delay.

“It may be that the things that are causing kidney problems may also be contributing to the developmental issues some of these kids face,” Dr. Furth said.

But she adds that there is an opportunity to prevent some of these delays by identifying issues early enough.

The CKiD cohort also revealed that many of the children — the median age of which was 11 at the beginning of the study — had one, and often even two or three, cardiovascular disease risk factors. These included hypertension, obesity, abnormal lipid metabolism, and evidence of insulin resistance, among others. Dr. Furth said that identifying which children with CKD might be at risk at an early age is important for their long-term health, since many of these things can be acted on and treated by clinicians.

“We have a lot of opportunity when we follow kids with CKD now,” Dr. Furth said. “We’re starting to understand the causes of kidney disease and, with papers like this, we can identify risk factors for progression so we can intervene and modify the course. For example, we can closely monitor and treat the risk for cardiovascular disease, and we can better predict long-term outcomes into adulthood so these kids can live full and healthy lives.”

Learn more about our Division of Nephrology

Take a look back at our story on the CkiD cohort study from 2014