# The Alternative Pathway of Complement: A Potential Contributor to Adverse Outcomes in CKD

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $634,659

## Abstract

PROJECT SUMMARY
Chronic kidney disease (CKD) is a powerful mediator of morbidity and an independent predictor of death due to
cardiovascular disease (CVD). Specifically, reduced glomerular filtration rate (GFR) is a powerful predictor of
adverse outcomes. In this application we propose that the accumulation of Factor D (FD), which is filtered by the
kidney and activates the alternative pathway (AP) of complement, represents an acquired dysregulation in the
AP which then contributes to CVD and CKD progression. We compared the proteome of CKD patients to healthy
controls. The strongest signal we observed was for components of the AP pathway. CKD patients had
significantly higher levels of FD in circulating microparticles (sub-micrometer membrane vesicles that are shed
from cells in response to activation or injury) and higher levels of Ba in the plasma (Ba is a biomarker of AP
activation). FD activates the AP resulting in the generation of complement fragments including Ba. Factor H (FH)
is the main inhibitor of the AP, but CKD was not associated with differences in the levels of FH. Our in vivo data
indicate that even small increments in FD, if unopposed by adequate levels of FH, result in systemic AP
activation. Furthermore, we found that plasma Ba levels are elevated in CKD and correlate with brachial artery
flow-mediated dilation and with albuminuria, two indicators of endothelial dysfunction. Thus, increased levels of
FD (as observed with reduced GFR in CKD) links CKD with systemic AP dysregulation, which may be an
important mechanism of CVD and CKD progression in patients with CKD. Genetic variants in complement
regulatory genes may also affect AP activation and may contribute to the risk of CVD and CKD progression in
patients with CKD. Our group has identified several common CFH gene polymorphisms that associate with
functional AP activation. Thus, our overall hypothesis is that CKD patients develop an acquired imbalance
between FD and FH (high FD/FH ratio) leading to AP dysregulation (i.e., activation) such that biomarkers of the
AP are predictive of CVD, CKD progression, and death in CKD. Secondarily, we hypothesize that individuals
with a genetic propensity towards AP dysregulation will be the most susceptible to AP dysregulation in the setting
of CKD. To test our hypothesis, we propose to utilize samples from two clinical trials: Veterans Affairs
Nephropathy in Diabetes (VA NEPHRON-D) and the Systolic Blood Pressure Interventional Trial (SPRINT). In
aim 1, if CKD is independently associated with AP activation and determine if high FD/FH ratio predicts AP
activation in CKD. In aims 2a and 2b we will examine whether plasma Ba independently predicts CVD or CKD
progression in CKD patients, respectively. In aim 3, we will determine if CKD subjects with the highest degree of
AP activation are enriched for genetic variants in CFH and other genes of the AP vs those with the lowest degree
of AP activation. The proposed experiments will help us un...

## Key facts

- **NIH application ID:** 10874758
- **Project number:** 5R01DK133240-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Diana I Jalal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $634,659
- **Award type:** 5
- **Project period:** 2023-06-23 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874758

## Citation

> US National Institutes of Health, RePORTER application 10874758, The Alternative Pathway of Complement: A Potential Contributor to Adverse Outcomes in CKD (5R01DK133240-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10874758. Licensed CC0.

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