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The trigger-maintenance model of persistent mild to moderate hyperoxaluria induces oxalate accumulation in non-renal tissues

Abstract

Persistent mild to moderate hyperoxaluria (PMMH) is a common side effect of bariatric surgery. However, PMMH's role in the progression to calcium oxalate (CaOx) urolithiasis and its potential effects on non-renal tissues are unknown. To address these points, a trigger + maintenance (T + Mt) model of PMMH was developed in rats (Experiment 1). The trigger was an i.p. injection of PBS (TPBS) or 288 μmol sodium oxalate (T288). Maintenance (Mt) was given via minipumps dispensing PBS or 7.5–30 μmol potassium oxalate/day for 28 days. Urinary oxalate ranged from 7.7 ± 0.8 μmol/day for TPBS + MtPBS to 18.2 ± 1.5 μmol/day for T288 + Mt30 (p ≤ 0.0005). All rats receiving T288 developed CaOx nephrocalcinosis, and many developed ‘stones’. This was also true for Mt doses that did not elevate urinary oxalate above that of TPBS + MtPBS (p > 0.1) and for rats that did not have a detectable surge in urinary oxalate post T288. When TPBS was administered, CaOx nephrocalcinosis did not develop regardless of the Mt dose even if urinary oxalate was elevated compared to TPBS + MtPBS (p ≤ 0.0005). One of the risks associated with PMMH is oxalate accumulation within tissues. Hence, in a second set of experiments (Experiment 2) different doses of oxalate (Mt0.05, Mt15, Mt30) labeled with 14C-oxalate (14C-Ox) were administered by minipump for 13 days. Tissues were harvested and 14C-Ox accumulation assessed by scintillation counting. 14C-Ox accumulated in a dose dependent manner (p ≤ 0.004) in bone, kidney, muscle, liver, heart, kidney, lungs, spleen, and testis. All these tissues exhibited 14C-Ox concentrations higher (p ≤ 0.05) than the plasma. Extrapolation of our results to patients suggests that PMMH patients should take extra care to avoid dietary-induced spikes in oxalate excretion to help prevent CaOx nephrocalcinosis or stone development. Monitoring for oxalate accumulation within tissues susceptible to damage by oxalate or CaOx crystals may also be required.

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Acknowledgments

This work was supported by the American Urological Foundation and the National Institutes of Health (DK62073, DK073730). Appreciation is expressed to C. A. Mayer and N. Courtney for expert technical assistance and to the Ion Analysis and Hyperoxaluria Laboratory of Wake Forest School of Medicine (Winston-Salem, NC). Appreciation is also expressed to J. W. Jacobberger for the generous access to his laboratory’s resources. This work is dedicated to my editor, the late Steven E. Brown, and my first mentor R. J. Wall.

Conflict of interest

None of the authors have any form of financial or personal conflict of interest with this investigation or manuscript.

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Correspondence to Susan Ruth Marengo.

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Marengo, S.R., Zeise, B.S., Wilson, C.G. et al. The trigger-maintenance model of persistent mild to moderate hyperoxaluria induces oxalate accumulation in non-renal tissues. Urolithiasis 41, 455–466 (2013). https://doi.org/10.1007/s00240-013-0584-5

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Keywords

  • Oxalosis
  • Hyperoxaluria
  • Stone
  • Kidney
  • Rat
  • Calcium oxalate