Identification of Resolvin D1 and Protectin D1 as Potential Therapeutic Agents for Treating Kidney Stones.

Intrarenal calcium oxalate (CaOx) crystals induce renal tubular epithelial cell (TEC) inflammatory and oxidative injury. This study is aimed at exploring potential therapeutic lipid components in kidney stones because lipids are involved in the development of several diseases and indicate the risk of kidney stones. Serum specimens were collected from 35 kidney stone patients and 35 normal controls. The lipid components in serum were measured, and differences were analyzed. The documented biological importance was comprehensively reviewed to identify lipids that differed significantly between the two groups to find potential agents associated with kidney stones. CaOx nephrocalcinosis mouse model was established to examine the therapeutic effects of specific lipids on CaOx deposition and CaOx-induced oxidative renal injury. Several lipids with significantly different levels were present in the serum of patients with stones and normal controls. Resolvin D1 (RvD1) (4.93-fold change, P < 0.001) and protectin D1 (PD1) (5.06-fold change, P < 0.001) were significantly decreased in the serum of patients with kidney stones, and an integrative review suggested that these factors might be associated with inflammatory responses, which is a crucial mechanism associated with stone damage. The administration of RvD1 and PD1 significantly inhibited kidney CaOx deposition and suppressed CaOx-induced renal tubular cell inflammatory injury and necrosis in a CaOx nephrocalcinosis mouse model. Furthermore, RvD1 and PD1 facilitated the expression of the oxidative indicator superoxide dismutase 2 (SOD2), inhibited NADPH oxidase 2 (NOX2) expression, and diminished intracellular reactive oxygen species (ROS) levels. This study preliminarily elucidated the role of lipids in kidney stones. The inhibitory effects of RvD1 and PD1 on oxidative damage induced by CaOx deposition provide a promising perspective for kidney stone treatment strategies.

Untargeted lipidomics based on UPLC-QTOF-MS/MS and structural characterization reveals dramatic compositional changes in serum and renal lipids in mice with glyoxylate-induced nephrolithiasis.

Nephrolithiasis is a systemic metabolic disease with a worldwide incidence that is increasing yearly, as well as a high recurrence rate; however, this disease's pathogenesis has not been thoroughly elucidated to date. Several epidemiological studies have shown that the risk for developing kidney stones increases in people with dyslipidemia. To explore the mechanism of lipid-induced kidney stones, we established a mouse model for renal urolithiasis based on intraperitoneal injections of glyoxylate (120 mg/kg/d). Lipidomics based on ultra high performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-QTOF-MS/MS) was performed to determine the changes in lipid metabolism in serum and kidneys. We screened 179 and 196 different lipid metabolites in the kidneys and serum, respectively, including fatty acyls, glycerophospholipids, sphingolipids, glycerolipids and prenol lipids. We found that polyunsaturated fatty acids, such as arachidonic acid, eicosapentaenoic acid, and docosahexoenoic acid, and ceramides and lysophosphocholines mediated inflammatory responses and that the oxidative stress induced by oleylethanolamine and glycerophosphoethanolamine plasmalogens is closely related to the development of kidney stones. These results provide strong evidence for the relationship between lipid metabolism and the development of kidney stones and suggest a clear direction for future research.

Role of osteopontin in early phase of renal crystal formation: immunohistochemical and microstructural comparisons with osteopontin knock-out mice.

Osteopontin (OPN) is an important matrix protein of renal calcium stone. However, the function of OPN in the early phase of renal crystal formation is not well defined. In this study, we examined OPN expression in the early phase of renal crystal formation with ultra-microstructural observations and immuno-TEM (transmission electron microscopy) in control and OPN knock-out (OPN-KO) mice. Glyoxylate (100 mg/kg) was intra-abdominally administered to male wild-type mice (C57BL/6, 8 weeks of age) and OPN-KO mice (C57BL/6, 8 weeks of age). Kidney was collected before and 6, 12, and 24 h after administration. We examined the relation between renal crystal formation and microstructural OPN location using TEM and immunohistochemical staining of OPN as well as western blotting and quantitative RT-PCR for OPN. OPN protein expression gradually increased in the renal cortex-medulla junction after glyoxylate administration, and OPN mRNA was increased until 12 h, but decreased at 24 h. In ultra-microstructural observation, OPN began to appear on the luminal side of renal distal tubular cells at 6 h and was gradually detected in the tubular lumen at 12 h. OPN was present in the crystal nuclei and collapsed mitochondria in the tubular lumen. In the OPN-KO mice, collapsed mitochondria were present, but no crystal nuclei formation were detected at 24 h. Based on the results this study proposed that the appearance of organelles, such as mitochondria and microvilli, in the tubular lumen after cell injury may be the starting point of crystal nucleus formation due to the aggregation ability of OPN.

[13 cases of drug-induced calculi]. / A propos de treize cas de calculs médicamenteux.

All urinary stones should undergo detailed studies to identify those related to drug therapy. Among 520 stones analyzed by infrared spectrophotometry, we found 13 drug-induced stones (13/520: 2.5%). Drug-induced stones were caused by glafenine in 7 cases, piridoxylate in 4 cases, triamterene in one case and an unknown organic compound in one case. Glafenine stones appear to develop more readily in infected urine. Triamterene stones are often associated with uric acid disorders. Piridoxylate induces the formation of glyoxylate which is responsible for hyperoxaluria and formation of oxalocalcium stones.

Piridoxilate-associated nephrocalcinosis: a new form of chronic oxalate nephropathy.

Piridoxilate is an association of glyoxylic acid and pyridoxine in which pyridoxine is supposed to facilitate in vivo transformation of glyoxylic acid to glycine rather than to oxalic acid. However, it has recently been shown that long-term treatment with piridoxilate may result in overproduction of oxalic acid and in calcium oxalate nephrolithiasis. We report a patient in whom piridoxilate induced both oxalate nephrolithiasis and chronic oxalate nephropathy with renal insufficiency, an association that has not been previously described. Therefore, piridoxilate should be added to the list of chemicals responsible for chronic oxalate nephropathy.

[Drug-induced crystalluria: myths and realities]. / Cristalluries médicamenteuses: mythes et réalités.

Medicinal crystalluria is often difficult to recognize and identify. Whether due to therapeutic overdoses or individual susceptibility, the diagnosis is always important. 70% of the drugs involved in crystalluria can induce kidney stones or promote their growth. In addition, approximately one medicinal crystalluria out of ten is clinically or biologically accompanied by kidney failure. On the basis of 59 cases of medicinal crystalluria, the means of identification, the molecules involved and the frequency of these iatrogenic crystalluria is discusses.