# Systems Biology Approach to the Management of Chronic Kidney Disease-Mineral Bone Disorder

> **NIH VA I01** · VA NORTH TEXAS HEALTH CARE SYSTEM · 2024 · —

## Abstract

The derangements of mineral metabolism that accompany chronic kidney disease (CKD) greatly
increase the risk of cardiovascular mortality. Veterans suffer from CKD and the cardiovascular
consequences disproportionately compared to the general population. Amelioration of the
biochemical abnormalities, specifically phosphate (Pi), calcium (Ca), and parathyroid hormone (PTH)
is associated with superior survival in dialysis patients; however, only a minority of patients can
achieve and sustain the levels proposed by Kidney Disease: Improving Global Outcomes (KDIGO)
guidelines. The major barriers are the complexity and individual diversity of CKD-MBD and the
heterogeneity in individual response to therapy. We have developed and validated a systems biology
model encompassing both measurable (serum Ca, Pi, and PTH) as well as non-measurable, clinically
relevant parameters of mineral metabolism such as loss of bone mineral and vascular calcification.
Applying artificial intelligence techniques of reinforcement learning in combination with our model,
we have determined that standard therapeutic approaches targeting Pi, Ca, and PTH may not result in
optimal control of the pathophysiologic processes that result in morbidity and mortality.
These results suggested two hypotheses to be tested in this proposal. Hypothesis 1: Based on
individual biochemical and mineral flux responses to therapy, we can identify phenotypic subsets of
CKD-MBD whose courses of disease are distinct, and which mandate different therapeutic
approaches. Hypothesis 2: Targeting the abnormal fluxes of mineral, out of bone and into the
vascular smooth muscle, will lead to significant refinements in the therapy of CKD-MBD for the
individual by incorporating the degree of bone turnover into the recommendations for achieving
KDIGO guidelines for biochemical parameters.
We will address these hypotheses through the following aims:
Aim 1. Obtain human data on non-routinely measured markers of mineral metabolism and
cardiovascular health within CKD-MBD.
Aim 2. Enhance the Systems Biology Model of CKD-MBD with additional markers of mineral
metabolism.
Aim 3. Develop Systems Biology guided treatment regimen to CKD-MBD based on clinical end points.
Aim 4. Validate treatment regimen for physician’s acceptance using Physician-in-the-Loop approach.
This innovative and highly translational approach will advance the over-arching goal of this project to
improve clinical outcomes for Veterans with CKD-MBD through the application of personalized
therapeutics. The use of large Veteran databases to develop personalized medical therapy for complex
disease, exemplified in this application, is a priority for the Department of Veterans Affairs.

## Key facts

- **NIH application ID:** 10700258
- **Project number:** 2I01CX001614-05A2
- **Recipient organization:** VA NORTH TEXAS HEALTH CARE SYSTEM
- **Principal Investigator:** ELEANOR D LEDERER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700258

## Citation

> US National Institutes of Health, RePORTER application 10700258, Systems Biology Approach to the Management of Chronic Kidney Disease-Mineral Bone Disorder (2I01CX001614-05A2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10700258. Licensed CC0.

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