Oxalate is toxic to renal tubular cells only at supraphysiologic concentrations

Schepers, Marieke S.J.; Ballegooijen, Eddy S. Van; Bangma, Chris H.; Verkoelen, Carl F.

doi:10.1111/j.1523-1755.2005.00576.x

Cited by 61 publications

(51 citation statements)

References 25 publications

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“…It is well known that the high rate of oxalate excretion among patients with PH results in supersaturation of CaOx in the urine, favoring CaOx crystal formation (16). CaOx crystals not only aggregate in the urinary space, producing stones (urolithiasis), but they also interact with the renal tubule epithelium and deposit in the renal interstitium (nephrocalcinosis), where they can induce an inflammatory response and progressive interstitial fibrosis that can compromise kidney function (17)(18)(19)(20). In this cohort, higher urinary oxalate excretion at both diagnosis and follow-up were associated with poorer renal outcome.…”

Section: Discussionmentioning

confidence: 90%

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

Zhao

Bergstralh

Mehta

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry.Design, setting, participants, & measurements We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models.Results Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m 2 and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/ 1.73 m 2 per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8).Conclusions Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.

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Section: Discussionmentioning

confidence: 90%

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

Zhao

Bergstralh

Mehta

et al. 2016

Clinical Journal of the American Society of Nephrology

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“…8 COM crystals could modify the membrane structure and function, activate ROS, cause oxidant/antioxidant imbalance, lead to mitochondrial dysfunction, and increase lipid peroxidation, 19 which induces apoptotic or necrotic cell death in renal epithelial cells. 9,[47][48][49] COD is the second most common component of CaOx renal stones, although existing studies on the toxic effect of COD crystals on renal epithelial cells are inadequate. Our previous study reported that nano-COD induced higher toxicity on Vero cells compared with the micro-sized crystals.…”

Section: Discussionmentioning

confidence: 99%

Reinjury risk of nano-calcium oxalate monohydrate and calcium oxalate dihydrate crystals on injured renal epithelial cells: aggravation of crystal adhesion and aggregation

Gan¹,

Sun²,

Bhadja³

et al. 2016

IJN

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Background Renal epithelial cell injury facilitates crystal adhesion to cell surface and serves as a key step in renal stone formation. However, the effects of cell injury on the adhesion of nano-calcium oxalate crystals and the nano-crystal-induced reinjury risk of injured cells remain unclear. Methods African green monkey renal epithelial (Vero) cells were injured with H 2 O 2 to establish a cell injury model. Cell viability, superoxide dismutase (SOD) activity, malonaldehyde (MDA) content, propidium iodide staining, hematoxylin–eosin staining, reactive oxygen species production, and mitochondrial membrane potential (Δψm) were determined to examine cell injury during adhesion. Changes in the surface structure of H 2 O 2 -injured cells were assessed through atomic force microscopy. The altered expression of hyaluronan during adhesion was examined through laser scanning confocal microscopy. The adhesion of nano-calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) crystals to Vero cells was observed through scanning electron microscopy. Nano-COM and COD binding was quantitatively determined through inductively coupled plasma emission spectrometry. Results The expression of hyaluronan on the cell surface was increased during wound healing because of Vero cell injury. The structure and function of the cell membrane were also altered by cell injury; thus, nano-crystal adhesion occurred. The ability of nano-COM to adhere to the injured Vero cells was higher than that of nano-COD crystals. The cell viability, SOD activity, and Δψm decreased when nano-crystals attached to the cell surface. By contrast, the MDA content, reactive oxygen species production, and cell death rate increased. Conclusion Cell injury contributes to crystal adhesion to Vero cell surface. The attached nano-COM and COD crystals can aggravate Vero cell injury. As a consequence, crystal adhesion and aggregation are enhanced. These findings provide further insights into kidney stone formation.

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“…Uric acid crystal binding did not depend on anionic cell surface binding molecules (79). CaOx dihydrate (COD) nucleated directly on the cell surface via their [101] face (80), to become associated with the membrane through their [100] face (81,82). Crystal binding stimulated additional crystal attachment and was inhibited by arachidonic acid or other compounds that raise intracellular cAMP (83).…”

Section: Crystal-cell Interactionsmentioning

confidence: 93%

“…A recent animal study demonstrated that the production of free radicals probably is the consequence of oxalate-mediated renal tubular injury rather than the initiating cause (99). In cell culture studies, it was found that oxalate cannot become very high in the presence of physiologic amounts of calcium (100,101) and that oxalate seemed to be relatively harmless in the absence of calcium (101). Accumulating evidence suggests that the assumed oxalate-induced cell injury in fact often is caused by crystals (75,102,103).…”

Section: Crystal-cell Interactionsmentioning

confidence: 99%

Crystal Retention in Renal Stone Disease

Verkoelen¹

2006

Journal of the American Society of Nephrology

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The mechanisms that are involved in renal stone disease are not entirely clear. In this article, the various concepts that have been proposed during the past century are reviewed briefly and integrated into current insights. Much attention is dedicated to hyaluronan (HA), an extremely large glycosaminoglycan that may play a central role in renal stone disease. The precipitation of poorly soluble calcium salts (crystal formation) in the kidney is the inevitable consequence of producing concentrated urine. HA is a major constituent of the extracellular matrix in the renal medullary interstitium and the pericellular matrix of mitogen/stress-activated renal tubular cells. HA is an excellent crystal-binding molecule because of its size, negative ionic charge, and ability to form hydrated gel-like matrices. Crystal binding to HA leads to crystal retention in the renal tubules (nephrocalcinosis) and to the formation of calcified plaques in the renal interstitium (Randall's plaques). It remains to be determined whether one or both forms of renal crystal retention are involved in the development of kidney stones (nephrolithiasis).

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Oxalate is toxic to renal tubular cells only at supraphysiologic concentrations

Abstract: This study shows that oxalate is toxic to renal tubular cells, but only at supraphysiologic concentrations.

Cited by 61 publications

References 25 publications

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

Reinjury risk of nano-calcium oxalate monohydrate and calcium oxalate dihydrate crystals on injured renal epithelial cells: aggravation of crystal adhesion and aggregation

Crystal Retention in Renal Stone Disease

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