Systems biology approach to the management of chronic kidney disease-mineral bone disorder

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Veterans are at an increased risk of kidney disease compared to the non-Veteran US population. Cardiovascular and bone disease are two major causes of death in Veterans with end stage renal disease (ESRD) resulting from abnormal mineral metabolism. Specifically, Mineral and Bone Disorder (MBD) is a universal complication of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD). The multifactorial nature of MBD in the Veteran ESRD population makes the effective management of this condition complex. Proper management entails the maintenance of serum calcium, phosphorus, and intact PTH levels within guidelines established and refined by international working groups using dietary counseling, phosphate binders, active vitamin D analogues, calcium sensing receptor agonists, and parathyroidectomy. Achievement of the target goals for each parameter in every patient has been elusive, though studies have demonstrated that attainment of the desired guideline goals for all three parameters is associated with lower cardiovascular risk. The hypothesis to be tested is that the success rate in achievement of the guidelines for MBD management can be improved and better informed by systems biology modeling of mineral metabolism and development of a personalized algorithm for prescription of each of the current therapies. The broad-based long term goal of this research endeavor is to address critical technological barriers to the progress of personalized MBD management thus improving cardiovascular and bone outcomes in Veteran patients. Preliminary work in this area has demonstrated the feasibility of the systems biology modeling approach to the achievement of established clinical guidelines. Current care of these Veteran Patients is based in a trial and error approach. Ideally, dosing of multiple agents for MDB should be guided by individual response to each of these agents. To address the challenges outlined above, a systems biology approach to modeling the complex disorder, MBD with be utilized. The hypothesis is that advanced computational techniques can be used to optimally guide dosing of the agents used in MBD. The plan to accomplish this objective are outlined in these five specific aims: 1. Development of a QSP-SB model for metabolic bone disorder. 2. Development of a drug dosing and hemodialysis model 3. Development of a database of clinically derived data obtained from CPRS. 4. Development of a dosing algorithm and a clinical tool used for CKD-MBD management. 5. Testing of the developed MBD-CKD dosing algorithm and tool in in-center hemodialysis patients. A broad, inclusive, population of Veterans will be studied to develop these novel dosing algorithms. Improved individualized control of calcium, phosphorus, and PTH has been shown to improve cardiovascular mortality when recommended concentrations are achieved. These tools will result in an advance in the dosing of drugs for chronic conditions that will be applicable to areas other than bone disease and an improvement in the health of each individual Veteran with kidney disease.