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Oxidative modifications switch modulatory activities of urinary proteins from inhibiting to promoting calcium oxalate crystallization, growth and aggregation.

ABSTRACT: The incidence/prevalence of kidney stone disease has been increasing around the globe but its pathogenic mechanisms remained unclear. We evaluated effects of oxidative modifications of urinary proteins on calcium oxalate (CaOx) stone formation processes. Urinary proteins derived from 20 healthy individuals were modified by performic oxidation and the presence of oxidatively modified urinary proteins was verified, quantified and characterized by Oxyblot assay and tandem mass spectrometry (nanoLC-ESI-LTQ-Orbitrap-MS/MS). Subsequently, activities of oxidatively modified urinary proteins on CaOx stone formation processes were examined. Oxyblot assay confirmed the marked increase in protein oxidation level in the modified urine. NanoLC-ESI-LTQ-Orbitrap-MS/MS identified a total of 193 and 220 urinary proteins in non-modified and modified urine samples, respectively. Among these, there were 1,121 and 5,297 unambiguous oxidatively modified peptides representing 42 and 136 oxidatively modified proteins in the non-modified and modified urine samples, respectively. Crystal assays revealed that oxidatively modified urinary proteins significantly promoted CaOx crystallization, crystal growth and aggregation. By contrast, the non-modified urinary proteins had inhibitory activities. This is the first direct evidence demonstrating that oxidative modifications of urinary proteins increase the risk of kidney stone disease by switching their modulatory activities from inhibiting to promoting CaOx crystallization, crystal growth and aggregation.

SUBMITTER: Chaiyarit S

PROVIDER: S-EPMC8551538 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An indole-reacted calcium oxalate crystallization index (iCOCI) test was developed to quantify the total competence of urine to precipitate calcium oxalate (CaOx) crystals. We conducted the prospective cohort study in accordance with the STARD guideline to evaluate the accuracy of urinary iCOCI test (index test) for diagnosing urolithiasis. A total of 281 participants were recruited for the study. Levels of urinary iCOCI were determined in the pre-diagnostic 24-h urine samples. Positive urinary iCOCI (? 0.6 COM eqv., g/L) was accounted for 51% (144/281), and the rest of 49% (137/281) were negative. Non-contrast CT imaging (reference standard) was subsequently performed for the definite diagnosis of urolithiasis to divide the participants into two groups, non-stone subjects (NSS, n?=?122) and stone-forming subjects (SFS, n?=?159). It should be noted that only subjects who currently had urinary stone at the time of study were classified as SFS. Urinary iCOCI levels in the SFS were significantly higher than the NSS. ROC analysis revealed an area under curve (AUC) of 0.893 (95% CI: 0.855-0.932) in separating NSS from all SFS. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, positive likelihood ratio (LH+) and negative likelihood ratio (LH-) of urinary iCOCI test for diagnosis of all urolithiasis were 87%, 80%, 84%, 84%, 83%, 4.44 and 0.16, respectively. Of 159 SFS, 38 were confirmed to have CaOx stones. Among these 38 CaOx SFS, only 2 had negative urinary iCOCI test. The AUC of urinary iCOCI test for separating CaOx SFS from NSS was markedly high (0.946, 95% CI: 0.914-0.978). Sensitivity, specificity, PPV, NPV, accuracy, LH+ and LH- of urinary iCOCI test for diagnosing CaOx urolithiasis were 95%, 86%, 68%, 98%, 88%, 6.80 and 0.06, respectively. Conclusion, we clinically validated that an innovative non-invasive urinary iCOCI test was highly accurate to diagnose urolithiasis, especially CaOx stone. With its high sensitivity and NPV, urinary iCOCI test is clinically intended to use as a screening test for CaOx urolithiasis. LH- of 0.06 indicates that negative result of urinary iCOCI test is highly accurate to rule out the CaOx stone formation. It is noted that urinary iCOCI level is expressed as arbitrary unit, and it is not directly related to the actual physiological level of urinary oxalate.

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Oxidative modifications switch modulatory activities of urinary proteins from inhibiting to promoting calcium oxalate crystallization, growth and aggregation.

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