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Engineers Study Drug Dosage Protocol for Dialysis Patients

Anyone on dialysis knows the ravages of uncontrolled anemia: severe fatigue, hospitalization, and, in extreme cases, death. Now a team from the University of Massachusetts Amherst is collaborating with a leading kidney specialist at Baystate Medical Center in Springfield, Mass., to design more effective protocols for dosing a key drug used for controlling anemia in dialysis patients. In dialysis patients the amount of the hormone erythropoietin, or EPO, produced by kidneys to manage the production of red blood cells and control anemia is significantly lower than in healthy persons, resulting in the diminished red blood cell production that characterizes anemia.

These patients are treated with recombinant human EPO, a synthetic form of the hormone. That’s where Professor Yossi Chait of the UMass Amherst Mechanical and Industrial Engineering Department and his research team come in: “By applying engineering principles of feedback control systems, we are developing EPO protocols for patients who have kidney disease and are undergoing dialysis to effectively regulate red blood cell production.”

The UMass research team, made up of experts in mathematics, statistics, system dynamics, and robust feedback control design, is working with Dr. Michael J. Germain, a nephrologist at Baystate Medical Center, to create the new EPO protocols.

“The current management of anemia is unsatisfactory because we can only keep about 40 percent of our dialysis patients in the target range of hemoglobin [the oxygen-transporting protein in red blood cells],” explains Dr. Germain. “Individuals have a good deal of fluctuation of their hemoglobin in and out of the target range, both too high and too low. This variability is associated with increased costs of medication, hospitalization, and death.”

Healthy kidneys normally control the complex process of erythropoiesis, or red blood cell production, but medical science has not yet learned how to duplicate this process.

Engineers view the regulation of hemoglobin as a feedback system, similar to, though more complex than, an engineered system such as a home heating system involving a thermostat. When the first electric thermostat was designed in 1883 by Warren S. Johnson, it was intended to maintain a desired fixed temperature despite variations in conditions such as the outside temperature, the size of the house or unit, or the local climate. From an engineering perspective, the desired red blood cell count produced by erythropoiesis is equivalent to the desired temperature measured by a thermostat. Any closed loop system such as these, whether mechanical, electrical, or biological, is designed to achieve certain engineering goals in accordance with formal control principles.  

“If you don’t approach erythropoiesis as a closed-loop system, I really don’t think you can properly design EPO protocols,” explains Professor Chait. “We use state-of-the-art pharmacokinetic and pharmacodynamic modeling, along with an invaluable set of data that Dr. Germain has provided – probably the best in the world – to try and identify the biological process as much as possible.”

Once the team has a model that describes erythropoiesis of a particular patient sufficiently accurately, the system can be looked at from the viewpoint of control engineering.

“Here is a system, and we would like to control it,” says Chait. “And a controller, in our language, is what doctors call a protocol.”

The end result of a better EPO protocol would be a greatly improved quality of life 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.”

The new protocols are extremely simple to use for either doctors or nurses. In the current pilot study, the patient’s red blood cell markers are measured by the dialysis machine and sent wirelessly into a laptop program that can implement the protocol using an algorithm to prescribe the precise dosage of EPO required by that patient at any particular time.

Dr. Germain and Prof. Chait presented results from this ongoing research at the American Society of Nephrology annual meeting.

Three members of the research team come from the Mechanical and Industrial Engineering Department: Commonwealth Honors College undergraduate students Bill Vogt (presently a grad student at Virginia Polytechnic Institute & State University) and Brendan Nichols, and graduate student Rajiv P. Shreshta. The other members are Professor Christopher Hollot, Electrical and Computer Engineering Department, and Professor Joseph Horowitz, Mathematics and Statistics Department. (December 2010)