Study Shows Acidic Blood Not Cause of Rare Disease

Published May 23, 2019

Leading a team of researchers, Mark D. Parker, PhD, has found that most symptoms of proximal renal tubular acidosis (pRTA) — a disease characterized by acidic blood — are caused by something other than low blood pH.

Only Treatment is Alkali Therapy

The disease pRTA is associated with loss of a sodium bicarbonate transporter (NBCe1) and is extremely rare, with only about 15 known cases worldwide. In addition to low blood pH, the disease causes developmental impairments and may lead to tooth loss and vision loss.

“The only treatment is alkali therapy, which literally involves ingesting baking soda tablets to normalize the pH of the blood,” says Parker, assistant professor of physiology and biophysics.

He notes that the treatment can be very effective in conditions where the only symptom is low blood pH.

“However, the alkali therapy has never been applied to pRTA patients at an early enough age to determine whether it could prevent the developmental impairments. Our research suggests that these symptoms persist even when blood pH is normalized from birth,” he says.

Alkali Therapy ‘Not a Panacea for This Disease’

To conduct the experiments, researchers developed an animal model analogous to a patient who has been treated with alkali therapy in utero and beyond. The animal model was generated by the Gene Targeting and Transgenic Shared Resource at the Roswell Park Comprehensive Cancer Center.

The mice have the sodium bicarbonate cotransporter NBCe1 in their kidneys — which is missing from patients with pRTA — so their blood pH is normal. However, in both patients and the mice, it’s missing from all other cells in the body. That means they cannot take bicarbonate up into their cells.

“This mimics the situation where the blood pH has been cured of its defects, but the patient still lacks NBCe1,” Parker says.

“In short, we found in these mice nearly every single sign that individuals with this disease have, except the low blood pH. The mice have corneal edema, weak enamel, are short, are underweight and have increased mortality,” he says.

“So it turns out that few of the signs of this disease are due to acidic blood. Thus, alkali therapy is not a panacea for this disease.”

Parker says potential therapies that might address symptoms would need to involve replacing the pathway that would allow sodium bicarbonate to get into cells, possibly involving gene therapy.

Insights Into Mutation Behind the Condition

The research — which was funded by the National Eye Institute of the National Institutes of Health and the American Society of Nephrology Foundation for Kidney Research — also provides some insights into the genetic mutation that causes the condition.

Parker explains that some of the scientific literature suggests that this gene, SLC4A4, may also be involved in cystic fibrosis and other more common diseases.

For that reason, these results may become relevant to conditions such as kidney failure and osteoporosis that may present with similar symptoms.

Undergraduate is Paper’s First Author

The paper was published in the Journal of the American Society of Nephrology on April 30.

First author is Emily Salerno, a graduating senior at the University of Notre Dame, who spent a summer working in Parker’s lab.

“To be first author as an undergraduate on a publication in a prestigious journal, such as this one, is a noteworthy and unusual achievement,” Parker says.

In addition to having a prestigious publication on her resume, Salerno learned firsthand the value of doing research.

“I think it’s important for every undergraduate to gain some sort of research experience within the topic they’re studying,” she says.

“Not only does it connect you with more senior members of the field, but you’re able to see a whole new side of academia. You’re right on the front lines, helping discover information that no one had before. Research is the very foundation of everything in science. Medicine would become stagnant without it.”

“I liked that even studying just one kind of protein could have a significant impact on disease,” she adds.

Other Co-Authors Include Additional Students

Along with Salerno and Parker, other co-authors on “Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice” are:

  • Sangita P. Patel, MD, PhD, clinical assistant professor of ophthalmology who sees patients through UBMD and also has an appointment with Research and Ophthalmology Services of the VA Western New York Healthcare System
  • Aniko Marshall, research technician in the Department of Physiology and Biophysics
  • Jordan Marshall, a senior from Williamsville East High School
  • Cheikh S. Alassane Mballo, a UB undergraduate student
  • Thamer Abdullah H. Alsufayan, a student in the physiology doctoral program
  • Bianca N. Quade, a student in the physiology doctoral program

“The expertise and equipment in the superb core facilities at UB were critical to the success of this project,” notes Parker, adding that Peter Bush in the South Campus Instrument Center and Wade J. Sigurdson, PhD, in the Confocal Microscope and Flow Cytometry Facility were especially helpful.