CHICAGO – The Frenova research division of global nephrology care firm Fresenius Medical Care this month began enrolling patients in what the company expects to be the world's largest renal genomic registry.
Fresenius, based in Bad Homburg, Germany, with North American headquarters in Waltham, Massachusetts, hopes that the registry will grow to include biosamples from 100,000 to 200,000 patients over the next five to six years. "We have a goal just in this year of consenting and doing our initial sequencing on up to 20,000 patients," said Fresenius Medical Care global CMO Franklin Maddux.
Fresenius Medical Care focuses mostly but not exclusively on kidney care. The publicly traded firm includes a products division, a services division, and an arm for value-based care risk contracting.
Globally, Fresenius actively manages 350,000 patients with end-stage renal disease and provides nearly 52 million dialysis treatments annually in about 50 different countries. The products division sells medical equipment and supplies in approximately 150 nations, according to Maddux.
"We have this very, very large and rich phenotypic database of people with kidney diseases who have all developed advanced kidney disease, so we understand what their comorbid illnesses are, we understand what their direct consequences are, their kidney failure, what kind of medicines they require and utilize," Maddux said.
But there has been a dearth of genetic data as the company looks to provide more targeted care.
"It was clear to me that one of the things that is different about nephrology than certain other fields is that … precision medicine and more precise prescribing hasn't moved as fast as some of the other fields that we've had, like oncology and skin disease and other such things," said Maddux, a nephrologist by training.
Maddux said that renal diseases are mostly classified today on pathologic or immunopathologic bases. As evidence of genetic variations associated with kidney disease has mounted, it became clear to him that there was not a broad enough repository of molecular data to conduct adequate research going forward.
For example, the APOL1 variant of apolipoprotein has been associated with chronic kidney disease in African Americans in the US. There are other genetic associations with polycystic kidney disease, Maddux noted.
Maddux said that causes of chronic kidney diseases have not been adequately studied. "It's an area of medicine that I think needs more investment, more research, and more specific diagnoses to understand what the mechanisms of injury are," he said.
This kind of knowledge would also help clinicians and pharmaceutical researchers alike develop better treatments and preventive measures, according to Maddux.
"We're trying to catalyze additional research and investment in the field, not do it ourselves," Maddux said. "But we think that it's going to require large numbers of patients to really meaningfully get some answers, and we're quite committed towards making our clinical data and this genotypic data something that will really help advance the field."
He said that the company determined that existing kidney registries are not large enough to support the kind of research that Maddux wants to see.
"Our registry really is being designed to build something that is large enough to try to untangle this Gordian knot of complexity that exists for these diseases that are rarely diseases that sit strictly in isolation of each other," Maddux said. "Our target is to develop a registry that is both phenotypic and genotypic, that is scaled orders of magnitude larger than what's out there today," he said.
The global reach of Fresenius means that the Frenova registry likely will be more diverse than typical Western genomic datasets, according to Maddux.
Fresenius has four operating regions: North America, Latin America, Europe-Middle East-Africa, and Asia-Pacific. Sample collection is beginning in North America, where the company has the most sites and patients. "Ultimately, we will look towards trying to build the registry out in a way that gives insight into many of those different cultural and ethnic bases," Maddux said.
Collection kicked off this month on a pilot basis by surveying patients for whom Fresenius already has biosamples on, chiefly through blood draws. Maddux said more than 75 percent of the small pilot population indicated that they are interested in consenting to and participating in the registry, even though these patients are far enough along in their journeys that they are unlikely to benefit personally from ensuing research.
"It's an incredibly altruistic move for those patients," Maddux said. "They're really doing this to try to help other people, and I think that's an extraordinary gift from these patients."
While patients are being enrolled now, sequencing likely will not start until the registry has at least 5,000 samples, a goal Maddux expects to reach by midyear. He said that the company is in talks with several external sequencing laboratories, and is not ready to disclose any names.
Ali Gharavi, chief of nephrology at Columbia University Irving Medical Center in New York, will serve as principal investigator for the registry project. The registry requires an external PI, as well as approval by an institutional review board, which Frenova has already obtained, according to Maddux.
Gharavi was corresponding author of a 2018 study in the New England Journal of Medicine that looked at exome sequencing for diagnosing certain forms of chronic kidney disease.
In that study, the researchers performed exome sequencing on two groups of chronic kidney disease patients, representing more than 3,300 individuals in all. In combination with their diagnostic analyses, the exomes yielded variants with diagnostic significance in 307 cases, including 39 monogenic conditions found in individual patients.
Through a Fresenius North America spokesperson, Gharavi declined an interview request.
Initially, the registry will include sequences of single-nucleotide polymorphisms and exomes because nephrology researchers already know how to interrogate and analyze those, Maddux said. That may or may not expand to whole-genome sequencing in the future.
"I don't know to what degree whole-genome analysis is going to be necessary or required to untangle the complexity [of genetic associations to kidney disease]," Maddux said. "I have the sense that it's such a complicated computational problem."
Regardless, he is certain now that computational research in this area will require far more genetic data than is currently available. The Frenova research unit already has a rich compendium of phenotypic data pulled from its own clinical care, but still will have to compile genotypic data and then figure out how to make that dataset available to academic and industry investigators so they can conduct their own studies, according to Maddux.
Frenova is looking to build some new bioinformatics tools to support the registry.
"We have the analytical tools to put the phenotypic dataset together because we've got quite a bit of information," Maddux said. What is missing is the technology to process the genomic data.
He would like to be able to segment out subsets of the registry for researchers looking at specific cohorts, such as patients with diabetes or polycystic kidney disease or Fabry's disease. "We [want to] have the ability to pull out subpopulations from that, and therefore create collaborative research relationships," Maddux said.
Investigators wishing to access the registry will have to obtain a license from Frenova for a subset of the anonymized database based on their research needs.
"Our expectation is that we won't be the interrogators of very much of that data from the genetic standpoint. We don't have that capability in house, but we want to catalyze this kind of scientific research that others do and will need to be doing over the next decade or so," Maddux said.
Maddux noted that Fresenius already has research and collaboration relationships with many academic institutions and master service arrangements with pharmaceutical companies. He said that the firm will lean on these relationships as well as look to develop new ones for this genetic registry.
Data will be stored in the cloud, and Frenova will create "safe environments" for research to work with subsets of the anonymized genomic dataset, much like it has for its phenotypic data, according to Maddux. Users will be able to choose from a number of statistical analytics tools, including SAS, R, and others that the company is currently developing with REDCap, he said.
"I could also imagine that there might well be a license in which an extract from the aggregate registry might move into a particular licensee's cloud-based system if they already have an environment they do their research in," Maddux said. This could include larger pharma companies that already have powerful bioinformatics research infrastructure.
"We would be open to either of those scenarios where they come into an environment where we prep the data or they have an environment of their own," Maddux said.