# Metabolomics of Uremic Symptoms in Dialysis Patients

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $537,959

## Abstract

ABSTRACT
 End stage renal disease (ESRD) requiring hemodialysis (HD) affects >400,000 patients in the US, and over
one million people will start dialysis in the next decade. While HD prevents immediate death due to uremia,
patients continue to experience debilitating uremic symptoms including fatigue, pruritus, and anorexia among
others. These symptoms are common—the prevalence of each is >30%, and >90% of patients have two or
more—and are a major contributor to poor health-related quality of life (HRQOL). Thus, managing uremic
symptoms is considered a top research priority by patients and physicians. However, the underlying cause of
uremic symptoms is unknown.
 Our central hypothesis is that retained uremic metabolites, substances cleared by the kidney that
accumulate in kidney failure, are the cause of uremic symptoms. Emerging metabolomics technologies provide
an unprecedented opportunity to simultaneously assess thousands of blood metabolites in an efficient and
unbiased fashion. Here, we seek to use a leading untargeted metabolomics platform to discover and validate
the uremic toxins associated with uremic symptoms across two large hemodialysis cohorts that utilized a
common, validated tool for symptom assessment. Our co-primary outcomes will be symptom scores for the
three most common and debilitating uremic symptoms—fatigue, pruritus, and anorexia—each considered
separately as their mechanisms may differ. Secondary outcomes will be: a) symptom scores for other uremic
symptoms (nausea, difficulty concentrating, excessive daytime sleepiness, and pain) and b) HRQOL. For the
discovery phase (Aim 1), we will identify novel metabolites associated with symptoms and HRQOL at study
entry in the Longitudinal US/Canada Incident Dialysis Study (LUCID), an ongoing multicenter prospective
cohort study of HD patients (N=700). We will consider metabolites individually, adjusting for multiple
comparisons, as well as use systems-based approaches to account for metabolite inter-correlations and to
assess results in the context of established biochemical pathways. Next, we will conduct internal validation
(Aim 2) of metabolite associations with symptoms and HRQOL in a random sub-cohort (N=300) of LUCID at 1-
year follow-up. For external validation (Aim 3), we will confirm these associations in a random sub-cohort
(N=300) of the Hemodialysis (HEMO) Study, an NIH-funded multicenter randomized controlled trial of HD dose
(Kt/Vurea) and dialysis membranes.
 This proposal brings together leading expertise in ESRD epidemiology, metabolomics, computational
biology, uremic toxicity, and symptom science. If successful, our collective effort will provide valuable insight
into the metabolic derangements responsible for uremic symptoms and poor HRQOL. Our findings will also
spur mechanistic studies of uremic toxicity, advance the development of new treatments, and inform the design
of patient-centered clinical trials, with downstream implications for patient management a...

## Key facts

- **NIH application ID:** 9940780
- **Project number:** 5R01NR017399-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** EUGENE P. RHEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,959
- **Award type:** 5
- **Project period:** 2018-08-22 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940780

## Citation

> US National Institutes of Health, RePORTER application 9940780, Metabolomics of Uremic Symptoms in Dialysis Patients (5R01NR017399-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9940780. Licensed CC0.

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