September 10, 2020
6 min read
The value of precision medicine has been shown with the identification of the genetic causes of tumors that differ among patients. Applied to nephrology, precision medicine can offer an earlier look at the potential risk for kidney disease.
“Precision medicine is a personalized approach to disease management of the patient … The goal is to have the right dose, delivered at the right time, for the right patient,” according to Shweta Bansal, MD, an associate professor of nephrology at the University of Texas-San Antonio School of Medicine. “It is not about one approach that fits all patients. It must be tailored.”
The treatment regimen is the last step in precision medicine, Bansal said. The work begins with the detection of the origins of disease through genomics.
“[NIH director] Francis Collins said it most straightforward. Precision medicine is the application of prevention and treatment strategies that take individual variability into account,” Michael Eadon, MD, assistant professor of medicine in the divisions of nephrology and clinical pharmacology at Indiana University School of Medicine, told Nephrology News & Issues. “There has always been an overarching connotation that genomic information, either from your genome or downstream applications like gene expression, would be integrated into evidence-based medicine.”
Two examples of the application of genomics to detect the risk of end-stage kidney disease is research on the efficacy of the drug tolvaptan for patients with autosomal-dominant polycystic kidney disease (ADPKD) and the identification of risk variants in the apolipoprotein L1 (APOL1) gene that can lead to kidney disease.
In a study in Clinical Journal of the American Society of Nephrology, David J. Friedman, MD, and colleagues wrote that many types of severe kidney disease are higher in Black patients than in other patient groups. That disparity is attributed to genetic variants in the apoL1 (APOL1) gene found only in individuals with recent African ancestry, the authors wrote. “These variants greatly increase rates of hypertension-associated ESKD, [focal segmental glomerulosclerosis] FSGS, HIV-associated nephropathy, and other forms of nondiabetic kidney disease.”
Friedman and colleagues said the discovery of the APOL1 risk variants has led to discussions about incorporating genetic testing in the screening process for living kidney donors. Those with the APOL1 genomic makeup could pass on the gene.
“[T]he large benet of better outcomes for recipients of a living donor kidney vs. continuing dialysis (or even vs. receiving a deceased donor kidney) may outweigh some level of risk to the donor in some cases,” they wrote.
In the area of treatment for ADPKD, the FDA approved the use of tolvaptan in April 2018 as the first disease-modifying drug for the disease. Bansal said the drug was developed using genomic information from patients with ADPKD.
“It is not approved for everyone; you give it only to the patients who have progressive kidney disease defined by their GFR or their cyst growth,” Bansal said. “It is a good example of precision medicine – providing a medication that will benefit certain patients the most and given at the right time.”
At this year’s Kidney Week, the American Society of Nephrology will hold a session on the future of genomics in kidney disease. The program will cover topics that include single-cell genomics and operationalizing genomic testing in the nephrology clinic.
To reach the result of precision medicine – either a treatment or establishing risk factors of disease – researchers must take a number of steps to gather genomic information and map out variants, Eadon said.
“In Indiana, our emphasis is on common variants that are disease predictors and on pharmacogenomic predictors. Pharmacogenomics is using predictors to determine how someone will respond to a known therapy or drug,” he said.
At New York Presbyterian Hospital Columbia University Medical Center in New York, Krzysztof Kiryluk, MD, is researching genetics of various forms of kidney diseases using whole genome sequencing and transcriptomics. His lab is focused on detecting new ways to diagnose and treat immune-mediated glomerular diseases, such membranous nephropathy (MN) and IgA nephropathy (IgAN).
“IgAN leads to progressive kidney failure in up to 50% of affected individuals,” Kiryluk told Nephrology News & Issues. “The prognosis, however, is variable and the outcome is difficult to predict in individual patients.
“Our aim is to validate new genetic and molecular markers to enable precise diagnosis, improve prognostication, predict relapse and recurrence, and ultimately lead to improved personalized treatment strategies,” he said.
The Kidney Precision Medicine Project, funded by the National Institutes of Diabetes and Digestive and Kidney Diseases, focuses exclusively on evaluating human kidney biopsies from patients with AKI or chronic kidney disease. The multi-year project will also include the creation of a kidney tissue atlas, define disease subgroups and identify critical cells, pathways, and targets for novel therapies.
“Acute kidney injury (AKI) and chronic kidney disease (CKD) impose a significant global health burden,” the Kidney Precision Medicine Project website notes. “ … Access to human kidney biopsy tissue is a critical first step to define disease heterogeneity and determine the precise molecular pathways that will facilitate identification of specific drug targets and ultimately enable individualized care for people with AKI and CKD.”
Multiomics and detection
What makes genomic research applicable to nephrology is the multiple disease states it can address.
“There are applications of precision medicine across the spectrum of kidney diseases,” Eadon said. “Sequencing and genotyping can be useful to diagnose causes of kidney stones, cystic kidney disease, glomerulonephritis and incident CKD. There are also pharmacogenomics predictors which are relevant across the spectrum of disease even in an end-stage renal disease patient. For example, when that ESRD patient receives a transplant, your genome will predict what dose immunosuppression to use. Before that, should the ESRD patient have high blood pressure, your genome can predict your response.”
However, there are challenges in developing a case for genomic review of patients with kidney disease, Eadon said.
“There is considerably heterogeneity of cell types within the kidney, and our clinical trial outcomes of mortality, dialysis initiation or loss of renal function take years to occur,” he told Nephrology News & Issues. “This reduces the pace at which we can acquire evidence to support the clinical utility of precision medicine.”
At the University of Texas-San Antonio, Bansal works with UT’s Center for Renal Precision Medicine, led by Kumar Sharma, MD, to measure metabolomics in urine and blood to help identify which patients will respond to certain pharmaceuticals. Sharma’s research has focused primarily on the pathogenesis of chronic kidney disease, including diabetic kidney disease (DKD), and hypertensive kidney disease.
Recent studies at the Center for Renal Precision Medicine with metabolomics have established a key role for mitochondrial dysfunction in DKD and hypertensive kidney disease by identifying key metabolites whose levels are altered in DKD and hypertensive kidney disease.
These metabolites indicate the individual patient’s response to their environment and may serve as biomarkers for individuals at risk for the development of CKD. Current clinical studies are validating this hypothesis, Sharma said.
Sharma said nephrology is right at the door for witnessing the benefits of precision medicine.
“The idea is starting to catch on in nephrology, and we are in the beginning stages of implementing it,” he said.
The team at the Center for Precision Medicine has discovered that DKD has a different response to the selective sodium glucose cotransporter2 inhibitors and can change the metabolic signature.
“That seems to correlate well with GFR changes … we now have long-term studies for the prognostic implications of the metabolic data,” Sharma said. Certain metabolites have also been identified that lead to long-term progression in patients with type 2 diabetic kidney disease.
“Precision medicine is a multipronged-type approach. We think this is applicable for patients with diabetic kidney disease, hypertension kidney disease” and other comorbid conditions, he said.
Texas Kidney Foundation CEO Tiffany Jones-Smith, who has lost nine family members due to complications from CKD, said the center’s focus on biomarkers that can lead to early detection would be helpful for the state’s Hispanic and Black population who are at high risk for kidney failure.
“Ten percent of end-stage kidney disease patients in the United States are here in Texas,” Jones-Smith told Nephrology News & Issues. “We support the center’s efforts to help us identify patients before CKD begins.”
For precision medicine to move forward, Eadon said patient education is important.
“Patients need to be fully informed of what genomics can and can’t do,” he said, “especially on disease and prognosis predictors. Most kidney diseases have multiple factors including diet, exercise, medications [and] environment. Genomics is only one piece.”
- For more information:
- Shweta Bansal, MD, is an associate professor of nephrology at the University of Texas-San Antonio School of Medicine. She can be reached at [email protected]
- Michael Eadon, MD, is an assistant professor of medicine in the divisions of nephrology and clinical pharmacology at Indiana University School of Medicine. He can be reached at [email protected]
- Tiffany Jones-Smith is CEO of the Texas Kidney Foundation, based in San Antonio, and can be reached at [email protected]
- Krzysztof Kiryluk, MD, is a physician-scientist in the division of nephrology in the department of Medicine at Columbia University. He can be reached at [email protected]
- Kumar Sharma, MD, is the Hillis-endowed Distinguished Chair in medicine and director of the Center for Renal Precision medicine. He is also chief of the division of nephrology and vice chair of research in the department of medicine at the University of Texas Health San Antonio. He can be reached at [email protected]