By Jillian Rose Lim
Our kidneys work hard to keep us healthy, from regulating fluids, to flushing out waste, to supporting strong, supple bones. Protecting these key functions is especially critical for children, who rely on the all-important organ to keep their bodies growing and nutrients flowing. Thankfully, chronic kidney disease (CKD), in which kidneys sustain progressive and permanent damage over time, is rare in children. But this rarity also means researchers and clinicians need to work harder to gather enough patients and data to mount effective clinical trials and improve outcomes.
And though pediatric CKD is uncommon, the condition can be devastating, leaving a long-term impact on a child’s adult life. The overall life expectancy of children with kidney disease is approximately 40 years less than the average population.
At Children’s Hospital of Philadelphia, researchers across multiple disciplines and departments are approaching the barriers to childhood kidney disease research with a new collaborative effort, the Pediatric Center of Excellence in Nephrology (PCEN). In 2018, the National Institute of Diabetes and Digestive and Kidney Diseases tapped CHOP to lead the development of the Center, which is the first of its kind to focus on translational research and pediatric clinical trials. To truly harness the power of teamwork, the PCEN works in partnership with a network of other regional and national children’s hospitals that have established kidney research bases.
“Despite CKD and end-stage renal disease causing reduced quality of life, increased mortality, and significant economic strain, the number of randomized clinical trials in Nephrology remains fewer than all other medicine specialties,” said Susan Furth, MD, PhD, chief of the Division of Nephrology at CHOP and principal investigator of the PCEN. “The focus of the Pediatric Center of Excellence in Nephrology — to decrease barriers to implementing trials of new therapies — is to change that metric and yield new options for treatment for this vulnerable patient population.”
Breaking Down the Barriers to Breakthroughs
When it comes to clinical research, identifying an adequate number of children with specific kidney disorders for trials isn’t the only barrier to success. Because kidney diseases are uncommon, many pediatric nephrologists don’t have the resources or expertise to design or carry out clinical studies well or conduct the necessary analyses.
Furthermore, methods to clinically phenotype children with kidney disease, including a patient’s growth, development, nutritional issues, cardiovascular risk factors, and bone and mineral health, are variable between studies and between institutions — making quality control variable and standardized measures difficult.
How can researchers across separate institutions connect the dots when it comes to kidney disease research? For the PCEN, the answer lies in the implementation of two key cores to address these barriers: a learning health system core and a clinical phenotyping core.
Enlisting the EHR: Sharing Information to Improve Outcomes
The PCEN’s learning health system core leverages the electronic health record (EHR) across eight collaborating children’s hospitals through PEDSnet to provide resources for nephrologists and researchers at multiple centers. With information about patients who have particular kidney disorders handy, these researchers can study patient outcomes, identify treatments that appear to be effective, and investigate specific laboratory markers that might predict patients’ response to a certain intervention. Ultimately, they can recruit more patients into clinical trials.
“PEDSnet links these eight children’s hospitals, and over the last several years, it has made all the electronic health records of those hospitals talk to each other,” Dr. Furth said. “If I am a nephrologist who wants to study a rare disease in children, like focal segmental glumerulosclerosis that can lead to kidney failure, I will be able to use the information synthesized from electronic health records across these eight hospitals to identify children who have that diagnosis. And then for observational studies, I potentially could look at how they were treated at these eight hospitals and how those treatments affected outcomes. It effectively breaks down a lot of barriers to research.”
Additionally, the learning health systems core could be used for quality improvement.
One PCEN project already making progress is led by Michelle Denburg, MD, MSCE, an attending physician in Nephrology at CHOP. Dr. Denburg has worked with investigators at collaborating PEDSnet hospitals to develop a glomerular disease learning network (GLEAN), essentially a group of investigators particularly interested in studying glomerular diseases in children, which can be extremely aggressive in terms of progressive kidney damage. GLEAN researchers have already come together for a number of quality improvement initiatives to make sure they are standardizing the data collected on pediatric patients, which lays the groundwork for clinical trials.
“Currently, if I had a child with a particular kidney disorder, and I took them to three different nephrologists, we’d have the same general approach but vary in different things,” Dr. Furth said. “With this approach, we can assess the outcomes of care with these variations in practice and then get people to adopt the best practice patterns.”
Speaking the Same Language: Clinical Phenotyping Core
From a child’s growth to their cardiovascular health, measuring different factors in kidney disease through a standardized method is important when it comes to understanding a patient’s particular phenotype. Within the PCEN, a clinical phenotyping core provides researchers at participating sites with a resource to assess these many areas and to streamline measurements. The core will focus on specific measurements of bone health, kidney function, cardiovascular risk factors, and growth and development.
“All of these things are very important in outcomes for children with kidney disease because those are the things that they are affected by,” Dr. Furth said. “This core will have the expertise to help everybody conduct their work the same way so we are all measuring the same thing. This is important if you’re planning a clinical trial, let’s say, to decrease some cardiovascular disease risk profile: Everyone at the sites is measuring these risk factors in the same way before you start the trial and after the trial. We’d be much more certain if our treatment is effective or not because we’d all be measuring and finding things the same way. We’d all be speaking the same language.”
The core will help reduce variability in studies that Dr. Furth has observed in the past. For example, in a CKD research study led by Dr. Furth, 900 children were enrolled across 45 sites, with each institution enrolling about five to 10 patients. Researchers at partnering sites reported the cause of a child’s kidney disease by ticking off a box — but Dr. Furth noted such a report could be incomplete, as researchers don’t know the original test that was used to make that diagnosis, and the same measures may not have been used at all the sites. Thus, it can’t completely describe the kidney anatomy of a patient.
Sites may not have all assessed children equally for the presence of cardiovascular disease risk factors, a major factor that leads to adverse outcomes when children with kidney disease become adults. Through the clinical phenotyping core, Dr. Furth and her team will develop and disseminate standardized assessments that can be used across centers in clinical research studies to more precisely and consistently evaluate the effects of new treatments.
“I've been a nephrologist for a long time now, and there are very few adequately designed and powered trials — meaning having enough patients enrolled — to really improve therapies for these children,” Dr. Furth said. “And we have a lot of terrific doctors who are all each trying to do what they think is best, but the evidence based on clinical trials is very thin. So, I’m really, really excited to be able to use this network to improve our evidence for what works and what doesn’t work for kids with kidney disease and really improve their outcomes, from their kidney health to their cardiovascular health to their bone health.”