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Experimental induction of calcium oxalate nephrolithiasis in mice
Saeed R Khan1, Patricia A Glenton
1Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Purpose:
The availability of various transgenic and knockout mice provides an excellent opportunity to better understand the pathophysiology of calcium oxalate stone disease. However, attempts to produce calcium oxalate nephrolithiasis in mice have not been successful. We hypothesized that calcium oxalate nephrolithiasis in mice requires increasing urine calcium and oxalate excretion, and experimentally induced hyperoxaluria alone is not sufficient. To provide evidence we induced hyperoxaluria by administering hyperoxaluria inducing agents in normocalciuric and hypercalciuric mice, and investigating various aspects of nephrolithiasis.
Materials And Methods:
We administered ethylene glycol, glyoxylate or hydroxyl proline via diet in male and female normocalciuric B6 mice, and in hypercalciuric sodium phosphate co-transporter type 2 a -/- mice for 4 weeks. We collected 24-hour urine samples on days 0, 3, 7, 14, 21 and 28, and analyzed them for pH, creatinine, lactate dehydrogenase calcium and oxalate. Kidneys were examined using light microscopy. Urine was examined for crystals using light and scanning electron microscopy.
Results:
Hypercalciuric mice on hydroxyl proline did not tolerate treatment and were sacrificed before 28 days. All mice on ethylene glycol, glyoxylate or hydroxyl proline became hyperoxaluric and showed calcium oxalate crystalluria. No female, normocalciuric or hypercalciuric mice showed renal calcium oxalate crystal deposits. Calcium oxalate nephrolithiasis developed in all mice on glyoxylate and in some on ethylene glycol. In all mice the kidneys showed epithelial injury. Male mice particularly on glyoxylate had more renal injury and inflammatory cell migration into the interstitium around the crystal deposits.
Conclusions:
Results confirm that hyperoxaluria induction alone is not sufficient to create calcium oxalate nephrolithiasis in mice. Hypercalciuria is also required. Kidneys in male mice are more prone to injury than those in female mice and are susceptible to calcium oxalate crystal deposition. Perhaps epithelial injury promotes crystal retention. Thus, calcium oxalate nephrolithiasis in mice is gender dependent, and requires hypercalciuria and hyperoxaluria.
Insights
Calcium oxalate nephrolithiasis in mice requires both hypercalciuria and hyperoxaluria. Male mice showed increased susceptibility to kidney injury and crystal deposition compared to females.
Area of Science:
- Nephrology
- Urology
- Biochemistry
Background:
- Transgenic and knockout mice offer models for studying kidney stone disease pathophysiology.
- Previous attempts to induce calcium oxalate nephrolithiasis in mice have been unsuccessful.
Purpose of the Study:
- To investigate the hypothesis that calcium oxalate nephrolithiasis in mice requires increased urine calcium and oxalate excretion.
- To determine if experimentally induced hyperoxaluria alone is sufficient to cause kidney stones in mice.
Main Methods:
- Administered ethylene glycol, glyoxylate, or hydroxyl proline to normocalciuric and hypercalciuric mice for 4 weeks.
- Collected and analyzed 24-hour urine samples for calcium, oxalate, and other markers.
- Examined kidneys via light microscopy and urine for crystals using light and scanning electron microscopy.
Main Results:
- All treated mice became hyperoxaluric with calcium oxalate crystalluria.
- No female mice developed renal calcium oxalate crystal deposits.
- Calcium oxalate nephrolithiasis developed in mice on glyoxylate and some on ethylene glycol, with male mice exhibiting more renal injury.
Conclusions:
- Hyperoxaluria induction alone is insufficient for calcium oxalate nephrolithiasis in mice; hypercalciuria is also necessary.
- Male mice are more susceptible to kidney injury and calcium oxalate crystal deposition than female mice.
- Gender-dependent susceptibility and the requirement for both hypercalciuria and hyperoxaluria are crucial for mouse models of calcium oxalate nephrolithiasis.
