# Low Molecular Weight Protein Nephrotoxicity

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

Multiple myeloma (MM) is a malignant plasma cell disorder that has an incidence rate of
about 1.1% among all malignancies and constitutes 12-13% of hematologic malignancies in the
US. The epidemiology is similar in our veteran population and includes a 3-fold higher
prevalence of monoclonal gammopathy of undetermined significance, a premalignant lesion, in
African American veterans. Renal dysfunction, determined by serum creatinine elevation ≥ 1.3
mg/dl, is frequently (about 48%) associated with MM, and an increase in the serum creatinine
concentration beyond 2.0 mg/dl portends a poor prognosis. One large study concluded that
reversibility of renal function was a more important prognostic factor than response to
chemotherapy. Recent work has shown that monoclonal immunoglobulin free light chains (FLC)
produced in multiple myeloma are biologically active proteins that generate intracellular
oxidative stress in the proximal tubule and promote significant changes in epithelial cell biology.
The working hypothesis of this application is that the physicochemical structure of the variable
domain of the FLC determines the type and consequences of tubulointerstitial renal disease in
myeloma.
 To address this hypothesis, two aims are proposed:
Aim 1. Determine if susceptibility of the CDR3 domain to proteolysis is a determinant of cast
nephropathy. FLC may serve as substrates for kidney proteases; cleavage of the CDR3
domain opens the loop structure, changing the secondary structure, which affects binding to
THP. Hypothesis: resistance of the CDR3 domain to protease cleavage is a critical
determinant of binding to THP and development of cast nephropathy.
Aim 2. Define the role of redox signaling in the development of progressive kidney disease in
cast nephropathy. Hypothesis: nephrotoxic monoclonal FLCs promote a pro-
inflammatory/fibrotic state that stimulates an AKI to CKD transition.
Aim 2.1 Determine the function of Signal Transducer and Activator of Transcription 1 (STAT1)
 in FLC nephrotoxicity. Hypothesis: STAT1 activation in kidney epithelium produces
 IL-1b and TGF-b and plays a critical role in the development of CKD following AKI
 due to cast nephropathy.
Aim 2.2 Determine if the intrinsic ability of the FLC to generate hydrogen peroxide is involved
 in the development of myeloma kidney. Hypothesis: the production of hydrogen
 peroxide by FLCs is a critical element in the generation of progressive kidney injury.
 The proposal will use in vitro and in vivo models to determine how monoclonal FLCs
generate pro-inflammatory and pro-fibrotic growth factors that induce tubulointerstitial renal
fibrosis. The long-term goal of this proposal is to shift clinical practice paradigms in the
management of progressive renal failure occurring in the setting of MM, by exploring novel
theoretical concepts to devise strategies that limit the development of chronic kidney disease
and thereby improve outcomes in MM.

## Key facts

- **NIH application ID:** 10975906
- **Project number:** 5I01CX001326-09
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** PAUL W. SANDERS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975906

## Citation

> US National Institutes of Health, RePORTER application 10975906, Low Molecular Weight Protein Nephrotoxicity (5I01CX001326-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10975906. Licensed CC0.

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