# Research Project

> **NIH NIH P20** · MAYO CLINIC ROCHESTER · 2024 · $389,623

## Abstract

Project Summary/Abstract:
Urinary stone disease (USD) is the 3rd most common urological disease in men and women. Prevention of
USD and its associated costs and morbidity requires an understanding of early and late USD pathogenesis.
Emerging evidence suggests pathophysiological interactions between intrarenal crystal nucleation, growth, and
phagocytic cellular responses may play a key but unrecognized role in USD. Studies in vitro demonstrate that
calcium phosphate (CaP) and calcium oxalate (CaOx) crystals induce renal tubular and phagocytic cellular
secretion of cytokines, chemokines, and extracellular vesicles (EVs; exosomes and microvesicles). These
biomarkers can attract blood or residential monocytes and convert monocytes into pro (M1) or anti (M2)-
inflammatory macrophages (Mφ ’s ). Observations in experimental animal models and human tissues suggest
that renal tissue monocytes and Mφ ’s can phagocytose and metabolize intrarenal crystals, and urinary stone
formers appear to have increased medullary M1 and decreased M2 Mφ populations. In a hyperoxaluric mouse
model, suppression of monocyte to M2 Mφ conversion significantly increased intrarenal CaOx deposition. Our
studies also demonstrated that urinary excretion of EVs bearing inflammatory markers derived from specific
segments of renal tubules were significantly lower in idiopathic calcium stone formers (ICSFs) compared to
controls. Thus, multiple lines of evidence suggest that tubular and monocyte derived Mφ populations can
phagocytose and degrade crystals as a crystal clearance mechanism, and defects in these clearance
mechanisms could promote interstitial Randall’s plaque (RP) and/or collecting duct plug (CDP) formation. The
proposed research project is designed to evaluate the role of Mφ ’s in RP and CDP formation using a novel
hypercalciuric claudin-2 global knockout mouse model (over 3-24 months age) that resembles the phenotype of
patients with idiopathic hypercalciuria and USD (Aim 1), and to define the frequency and spatial distribution of
monocyte/ Mφ populations in carefully phenotyped ICSFs (20-70 years) with hydroxyapatite, brushite, and
calcium oxalate stones plus varying amounts of RP (Aim 2). The proposed innovative study will elucidate the
role of renal medullary pro-and anti-inflammatory phagocytic cells in the development of RP, CDP, and USD
and whether urinary cytokines, chemokines or EVs carrying biomarkers of pro-/anti-inflammatory phagocytic
cells can be used to non-invasively monitor intrarenal crystal deposition. Completion of this study will also
facilitate the formation of a skilled multidisciplinary team including a promising early-stage surgeon-scientist (Dr
Kevin Koo) under the mentorship of an experienced and skilled USD clinical and researcher (Dr. Lieske). The
resulting preliminary data will provide evidence of the effectiveness of our team. This work will also enable
submission of future detailed grant or center proposals that will extend these mechanistic ...

## Key facts

- **NIH application ID:** 10839868
- **Project number:** 5P20DK135097-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** John C Lieske
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,623
- **Award type:** 5
- **Project period:** 2022-09-23 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839868

## Citation

> US National Institutes of Health, RePORTER application 10839868, Research Project (5P20DK135097-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10839868. Licensed CC0.

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