Calcium Oxalate Stone Agglomeration Reflects Stone-Forming Activity: Citrate Inhibition Depends on Macromolecules Larger Than 30 Kilodalton

Erwin, D. T.; Kok, Dirk J.; Alam, Jawed; Vaughn, James L.; Coker, O.; Carriere, B.; Lindberg, Jill S.; Husserl, Fred E.; Fuselier, Harold A.; Cole, Francis E.

doi:10.1016/s0272-6386(12)81057-2

Cited by 30 publications

(13 citation statements)

References 18 publications

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“…18 These citrates retard crystal formation by complexing with calcium in a soluble form, thus decreasing urinary supersaturation 16,30,31 and also by modulating macromolecules associated with crystal formation. 32 Indeed, in the present study, co-treatment with sodium citrate increased the excretion of soluble calcium in EG-treated rats, as would be expected from its ability to complex calcium. In contrast, aluminum citrate has a mechanism of action completely different from that of the currently used citrate salts because it interacts with already formed COM to block its binding, uptake, and toxicity by tubular cells.…”

Section: Discussionsupporting

confidence: 65%

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

Besenhofer

Cain

Dunning

et al. 2012

Journal of the American Society of Nephrology

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Calcium oxalate monohydrate crystals are responsible for the kidney injury associated with exposure to ethylene glycol or severe hyperoxaluria. Current treatment strategies target the formation of calcium oxalate but not its interaction with kidney tissue. Because aluminum citrate blocks calcium oxalate binding and toxicity in human kidney cells, it may provide a different therapeutic approach to calcium oxalateinduced injury. Here, we tested the effects of aluminum citrate and sodium citrate in a Wistar rat model of acute high-dose ethylene glycol exposure. Aluminum citrate, but not sodium citrate, attenuated increases in urea nitrogen, creatinine, and the ratio of kidney to body weight in ethylene glycol-treated rats. Compared with ethylene glycol alone, the addition of aluminum citrate significantly increased the urinary excretion of both crystalline calcium and crystalline oxalate and decreased the deposition of crystals in renal tissue. In vitro, aluminum citrate interacted directly with oxalate crystals to inhibit their uptake by proximal tubule cells. These results suggest that treating with aluminum citrate attenuates renal injury in rats with severe ethylene glycol toxicity, apparently by inhibiting calcium oxalate's interaction with, and retention by, the kidney epithelium. Ethylene glycol (EG) is a common household poison found in antifreeze, automotive engine coolants, and water-based latex paints. Approximately 5000 accidental or intentional EG ingestions occur per year in the United States, resulting in about 20-30 deaths. 1 Acute EG poisoning can result in central nervous system depression, metabolic acidosis, acute renal failure, coma, and death. 2 Ethylene glycol itself is nontoxic. However, the end metabolite, oxalate, is insoluble in the presence of calcium and forms oxalate crystals (primarily calcium oxalate monohydrate [COM]) that are deposited in the kidney tissue. Pathologic studies have shown that COM accumulation in the tubule correlates strongly with the degree of proximal tubule cell necrosis and with renal failure. 3,4 Experiments using kidney cell cultures have convincingly shown that COM, and not the metabolites glycolate, glyoxylate, or ionic oxalate, is the metabolite responsible for the renal toxicity associated with EG poisoning. 5-9 COM crystals can bind to kidney cell membranes and can be internalized by kidney cells, 7,10-12 where they induce mitochondrial dysfunction leading to cell death. [12][13][14] The ability to induce cell death is closely linked with the degree of cellular internalization of COM crystals. 12 EG is metabolized fairly rapidly, so there is little time between ingestion and the formation of the toxic metabolites; thus, quick and aggressive treatment is required. 2,15 With early diagnosis, inhibition of the enzyme alcohol dehydrogenase using fomepizole or ethanol can block the metabolism of EG, effectively preventing the formation of COM. If renal failure has already occurred, longterm hemodialysis (2-6 months) must be used to

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Section: Discussionsupporting

confidence: 65%

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

Besenhofer

Cain

Dunning

et al. 2012

Journal of the American Society of Nephrology

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“…In general, the available studies do not suggest that the urinary THP excretion is different between kidney stone formers and non-stone formers [17][18][19][20] . Nevertheless, in some studies the urinary THP excretion was reduced in stone formers or subgroups [21][22][23][24] .…”

Section: Discussionmentioning

confidence: 89%

Comparison of Urinary Proteins in Calcium Stone Formers and Healthy Individuals: A Case-Control Study

Pourmand

Nasseh²,

Sarrafnejad³

et al. 2006

Urol Int

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Objective: This study aimed at comparing the urinary protein levels in calcium stone formers with those of healthy individuals. Patients and Methods: From January 2002 until June 2004, 100 calcium stone formers (mean age 38.6 ± 10.3 years), who had at least two episodes of calcium stone formation, were compared with 100 healthy individuals (mean age 33.8 ± 9.7 years). Their 24-hour urinary protein levels, using SDS-PAGE, were measured. Results: The mean 24-hour urinary Tamm-Horsfall protein (THP) levels were 3.3 ± 0.8 mg in the case group and 4.6 ± 1.9 mg in the controls, and the difference was not statistically significant (p = 0.53). However, the THP levels in individuals with and without bacteriuria were significantly different (15.8 ± 3.3 mg vs. 2.6 ± 1.0 mg, p = 0.0001). The mean 24-hour urinary albumin concentrations were 163.31 ± 15.1 mg in the case group and 74.26 ± 4.6 mg in the controls. The mean 24-hour urinary transferrin levels were 8.09 ± 2.7 mg in the case group and 0.40 ± 0.3 mg in the controls. The differences were statistically significant for both albumin and transferrin (p < 0.0001 and p = 0.0063, respectively). There were no significant differences in any other mean urinary protein concentrations between cases and controls. Conclusions: The THP level in the urine of stone formers is not quantitatively different from that of healthy individuals, but it increases in association with bacteriuria. Albumin and transferrin may play a presumptive role in stone formation.

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“…In studies using quantitative electroimmunodiVusion, THP excretion rates were 40-50 mg/day, without diVerences between stone formers and healthy subjects [21,22]. More recent studies used radioimmunoassay or ELISA and demonstrated that THP excretion rates varied more widely among subjects, generally ranging between 10 and 70 mg/day [17,[23][24][25][26]. THP excretion rates were either equal to healthy controls [23,24] or reduced in "common" stone formers [17,25,26].…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies used radioimmunoassay or ELISA and demonstrated that THP excretion rates varied more widely among subjects, generally ranging between 10 and 70 mg/day [17,[23][24][25][26]. THP excretion rates were either equal to healthy controls [23,24] or reduced in "common" stone formers [17,25,26]. The latter was at least partly due to the fact that some studies included uric acid stone formers in whom ELISA measurements have indicated lower THP excretions rates [17,27].…”

Section: Discussionmentioning

confidence: 99%

Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function

et al. 2007

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Tamm-Horsfall protein (THP) powerfully inhibits calcium oxalate crystal aggregation, but structurally abnormal THPs from recurrent calcium stone formers may promote crystal aggregation. Therefore, increased urinary excretion of abnormal THP might be of relevance in nephrolithiasis. We studied 44 recurrent idiopathic calcium stone formers with a positive family history of stone disease (RCSF(fam)) and 34 age- and sex-matched healthy controls (C). Twenty-four-hour urinary THP excretion was measured by enzyme linked immunosorbent assay. Structural properties of individually purified THPs were obtained from analysis of elution patterns from a Sepharose 4B column. Sialic acid (SA) contents of native whole 24-h urines, crude salt precipitates of native urines and individually purified THPs were measured. THP function was studied by measuring inhibition of CaOx crystal aggregation in vitro (pH 5.7, 200 mM sodium chloride). Twenty-four-hour urine excretion of THP was higher in RCSF(fam) (44.0 +/- 4.0 mg/day) than in C (30.9 +/- 2.2 mg/day, P = 0.015). Upon salt precipitation and lyophilization, elution from a Sepharose 4B column revealed one major peak (peak A, cross-reacting with polyclonal anti-THP antibody) and a second minor peak (peak B, not cross-reacting). THPs from RCSF(fam) eluted later than those from C (P = 0.021), and maximum width of THP peaks was higher in RCSF(fam )than in C (P = 0.024). SA content was higher in specimens from RCSF(fam) than from C, in native 24-h urines (207.5 +/- 20.4 mg vs. 135.2 +/- 16.1 mg, P = 0.013) as well as in crude salt precipitates of 24-h urines (10.4 +/- 0.5 mg vs. 7.4 +/- 0.9 mg, P = 0.002) and in purified THPs (75.3 +/- 9.3 microg/mg vs. 48.8 +/- 9.8 microg/mg THP, P = 0.043). Finally, inhibition of calcium oxalate monohydrate crystal aggregation by 40 mg/L of THP was lower in RCSF(fam) (6.1 +/- 5.5%, range -62.0 to +84.2%) than in C (24.9 +/- 6.0%, range -39.8 to +82.7%), P = 0.022, and only 25 out of 44 (57%) THPs from RCSF(fam )were inhibitory (positive inhibition value) vs. 25 out of 34 (74%) THPs from C, P < 0.05. In conclusion, severely recurrent calcium stone formers with a positive family history excrete more THP than healthy controls, and their THP molecules elute later from an analytical column and contain more SA. Such increasingly aggregated THP molecules predispose to exaggerated calcium oxalate crystal aggregation, an important prerequisite for urinary stone formation.

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Calcium Oxalate Stone Agglomeration Reflects Stone-Forming Activity: Citrate Inhibition Depends on Macromolecules Larger Than 30 Kilodalton

Cited by 30 publications

References 18 publications

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

Comparison of Urinary Proteins in Calcium Stone Formers and Healthy Individuals: A Case-Control Study

Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function

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