University of Massachusetts Amherst

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Interdisciplinary Team Starts Clinical Testing of Drug Protocol for Dialysis Patients

Professor Yossi Chait of the Mechanical and Industrial Engineering Department at the University of Massachusetts Amherst is part of a multidisciplinary team that has been approved by an institutional review board to begin clinical testing of a groundbreaking new protocol for administering a key drug for managing patients in the final stage of kidney disease. “We are developing protocols for patients who have kidney disease and are undergoing dialysis and need precise, effective doses of recombinant human erythropoietin hormone,” says Chait. That hormone, also known as EPO, manages the production of red blood cells, which, among other things, controls anemia.  

Other members of the team include Dr. Michael J. Germain, a nephrologist and the medical director of Renal Transplantation at the Baystate Medical Center, and UMass Professors Joseph Horowitz (Mathematics and Statistics) and Christopher V. Hollot (Electrical and Computer Engineering).

The new medical protocol, based on the principles of engineering feedback control systems, promises to individualize the EPO dosage for every patient and improve his or her treatment outcomes.

“We’ve demonstrated the effectiveness of our protocol in a pilot study, and now we’re moving on to the next stage comprising a crossover clinical study with about 50 dialysis patients,” says Chait, an expert on robust feedback control design. “What we hope to show is that the demonstrated success with the pilot project translates to similar success with the larger study. This study is a much stronger test of the efficacy and safety of our protocol.”

In dialysis patients the amount of EPO produced by the kidneys is inappropriately low for the level of anemia, and so they are treated with recombinant human EPO hormone in order to minimize the need for blood transfusions. Chait notes that current anemia management protocols for administering EPO are more or less “one size fits all” and fail to achieve the desired outcomes for many patients. That’s where Chait’s expertise comes in. By utilizing the principles of feedback control systems, his protocols enable medical personnel to personalize the EPO dosage for each patient.

The current management of anemia is unsatisfactory, which prompted the FDA to issue a 2011 warning for chronic kidney disease patients on dialysis stating that "...No clinical trial to date has identified a hemoglobin target level, ESA dose [Erythropoiesis Stimulating Agent], or dosing strategy that does not increase these risks...The lowest ESA dose sufficient to reduce the need for red blood cell transfusions should be used..."

Healthy kidneys normally control the whole complex process of erythropoiesis, which produces red blood cells, but medical science has not yet learned how to duplicate this process.

However, engineers look at erythropoiesis as a closed-loop system, similar to that of a thermostat. When the first electric thermostat was designed 1883 by Warren S. Johnson, it was designed to maintain a desired set-point temperature, despite such variables as the outside temperature, the size of the house or unit, or the climate of the location. In that sense, a closed-loop system can maintain certain engineered goals by using formal feedback control principles to design the controller, which in the case of EPO dosing is called a protocol. 

“If you don’t approach erythropoiesis as a closed-loop system, I really don’t think you can expect to achieve desired response,” explains Chait. “Now, erythropoiesis is much more complicated than a thermostat, but the same principles of feedback control apply. The protocol for erythropoiesis has to take into account all the variables and adjust to them.”

Chait adds that “Based on the pilot study, we have seen that we can achieve desired hemoglobin levels with smaller amounts of the drugs. That is believed to be medically beneficial for the patient, and it’s also economically beneficial.”

The end result of a better EPO protocol is improved outcomes for dialysis patients. “One of the main complaints of dialysis patients is fatigue and decreased exercise, even walking, tolerance, which is due in part to their anemia,” says Dr. Germain. “If we could keep their hemoglobin stable, their quality of life would improve.”

Related to his research on EPO protocols, Chait is the principal investigator for a four-year National Institutes of Health grant for the purpose of establishing an independent research career at the interface of engineering and medicine. He will be working with Dr. Germain and Dr. Ravi Thadhani, the director of Clinical Research in Nephrology at Massachusetts General Hospital and a professor of Medicine at Harvard Medical School. (October 2013)