# Developing MRI contrast agents to detect progression in renal disease as a consequence of acidema

> **NIH NIH R01** · HUGO W. MOSER RES INST KENNEDY KRIEGER · 2022 · $395,652

## Abstract

Organic acidemias are a class of inborn metabolic disorders which disrupt amino acid metabolism and
lead to abnormal accumulation of organic acids detectable in blood, urine and other biomaterials. While
individually rare, collectively these disorders have a significant impact on children’s health. Chronic Kidney
Disease (CKD) is a cardinal feature of several organic acidemias, and patients require routine monitoring of
kidney function to manage their treatment. Methylmalonic Acidemia (MMA) is an organic acidemia with a
frequency of 1/50,000 to 1/100,000 caused by mutations in methylmalonyl-CoA mutase (Mut) with a
predictable evolution to CKD. In fact, CKD is developed at a median onset age of 6.5 y in MMA patients who
are at high risk of developing renal insufficiency. Unfortunately, current methods for monitoring renal health
which include measuring blood creatinine and blood nitrogen urea are not reliable for MMA patients. An
alternative strategy is to administer MRI contrast agents to acquire functional information on the kidneys. This
proposal involves administering well tolerated, organic compounds which create MRI contrast through
Chemical Exchange Saturation Transfer (CEST). An attractive feature of this mechanism is that it enables
production of pH maps which reflect the environment surrounding the agents and might be particularly useful
for the kidneys, organs which control the acid-base balance of the body. We will design CEST pH sensors
which can monitor progression towards CKD through changes in pH and perfusion, and will provide a reliable
indicator of the overall health of the kidneys. In Aim 1, we will synthesize a set of imidazole-4,5-dicarboxyamide
probes to provide pH sensitive MRI contrast. The proton exchange rates and resulting CEST contrast will be
quantified as a function of pH in buffered solutions to determine the performance of these in vitro. We will also
optimize our pH and perfusion imaging protocol and characterize the pharmacokinetics using C57BL/6 control
mice. In Aim 2, we will evaluate the sensitivity of our best agents from Aim 1 for detecting the extent of renal
disease in the C57BL/6 Mut-/-;TgINS-Alb-Mut mouse model of MMA and validate the pH measurements using
ISUCA. C57BL/6 Mut-/-;TgINS-Alb-Mut mice manifest chronic tubulointerstitial nephritis and a decreased
glomerular filtration rate (GFR) which is initiated by placing the mice on a high protein (HP) diet for 2 months.
In Aim 3, we will test our best sensor on six groups of mice with three groups treated with sodium citrate
through diet supplementation and three more with CoQ10 + Vitamin E supplemented into their diets. The
groups will also include three different timings for the high protein challenge which induces kidney injury. We
expect our new agents and imaging protocols could provide an earlier detection of CKD without need of
invasive kidney biopsy. This is particularly critical in conditions where standard monitoring methods are not
feasible, su...

## Key facts

- **NIH application ID:** 10337274
- **Project number:** 5R01DK121847-03
- **Recipient organization:** HUGO W. MOSER RES INST KENNEDY KRIEGER
- **Principal Investigator:** MICHAEL T MCMAHON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $395,652
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337274

## Citation

> US National Institutes of Health, RePORTER application 10337274, Developing MRI contrast agents to detect progression in renal disease as a consequence of acidema (5R01DK121847-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10337274. Licensed CC0.

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