Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall's plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular calcification, Randall's plaques consist of calcium phosphate crystals mixed with an organic matrix that is rich in proteins, such as inter-α-trypsin inhibitor, as well as lipids, and includes membrane-bound vesicles or exosomes, collagen fibres and other components of the extracellular matrix. Kidney tissue surrounding Randall's plaques is associated with the presence of classically activated, pro-inflammatory macrophages (also termed M1) and downregulation of alternatively activated, anti-inflammatory macrophages (also termed M2). In animal models, crystal deposition in the kidneys has been associated with the production of reactive oxygen species, inflammasome activation and increased expression of molecules implicated in the inflammatory cascade, including osteopontin, matrix Gla protein and fetuin A (also known as α2-HS-glycoprotein). Many of these molecules, including osteopontin and matrix Gla protein, are well known inhibitors of vascular calcification. We propose that conditions of urine supersaturation promote kidney damage by inducing the production of reactive oxygen species and oxidative stress, and that the ensuing inflammatory immune response promotes Randall's plaque initiation and calcium stone formation.

Randall's plaque and calcium oxalate stone formation: role for immunity and inflammation.

Bladder calculi account for 5% of urinary calculi and usually occur because of bladder outlet obstruction, neurogenic voiding dysfunction, infection, or foreign bodies. Children remain at high risk for developing bladder lithiasis in endemic areas. Males with prostate disease or relevant surgery and women who undergo anti-incontinence surgery are at a higher risk for developing vesical lithiasis. Open surgery remains the main treatment of bladder calculus in children. In adults, the classical treatment for bladder calculi is endoscopic transurethral disintegration with mechanical cystolithotripsy, ultrasound, electrohydraulic lithotripsy, Swiss Lithoclast, and holmium:YAG laser. Novel modifications of these treatment modalities have been used for large calculi. Open and endoscopic surgery requires anesthesia and hospitalization. Alternatively, extracorporeal shock wave lithotripsy has been demonstrated to be simple, effective, and well tolerated in high-risk patients. Recently, simultaneous percutaeous suprapubic and transurethral cystolithotripsy has been tested as well as percutaneous cystolithotomy by using a laparoscopic entrapment sac.

Bladder lithiasis: from open surgery to lithotripsy.

Background
The role of calcium oxalate crystals and deposits in UTI pathogenesis has not been established. The objectives of this study were to identify bacteria present in pediatric urolithiasis and, using in vitro and in vivo models, to determine the relevance of calcium oxalate deposits during experimental pyelonephritis.

/pdf/the-interaction-between-enterobacteriaceae-and-calcium-221byb0jdc.pdf

The Interaction between Enterobacteriaceae and Calcium Oxalate Deposits

Urolithiasis, a complex multifactorial disease, results from interactions between environmental and genetic factors. Epidemiological studies have shown the association of urolithiasis with a number of lifestyle-related diseases, including cardiovascular diseases, hypertension, chronic kidney disease, diabetes and metabolic syndrome. Elucidation of the mechanisms underlying urinary stone formation will enable development of new preventive treatments. The present article reviews the epidemiology, pathophysiology and potential treatment of urolithiasis. Recent literature has shown that oxidative stress and reactive oxygen species could be one such mechanistic pathway. Calcium oxalate crystals adhering to renal tubular cells are incorporated into the cells through the involvement of osteopontin. Stimulation of crystal-cell adhesion impairs acceleration of the mitochondrial permeability transition pore in tubular cells, resulting in mitochondrial collapse, oxidative stress and activation of the apoptotic pathway in the initial steps of renal calcium crystallization. With regard to genetic factors, studies show that single nucleotide polymorphisms in genes encoding calcium-sensing receptor, vitamin D receptor and osteopontin are correlated with urolithiasis. Genome-wide association studies have shown that CLDN14 and NPT2 are associated with urolithiasis in Caucasian and Japanese populations, respectively. Thus, single nucleotide polymorphism analysis would aid in the prediction of urolithiasis risk and recurrence. New diagnostic methods and preventive approaches, along with complete removal of stones, will improve the management of urolithiasis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/iju.13187

Pathophysiology-based treatment of urolithiasis.

We previously established a mouse kidney stone formation model and showed that mice have a higher tolerance to stone formation than rats Furthermore, we showed that the generated calcium oxalate crystal deposits could be eliminated after several days This study investigated the transcriptome of stone formation and elimination in the mouse kidney based on gene selection using a microarray technique Eight-week-old male C57BL/6N mice were administered 80 mg/kg glyoxylate for 15 days, and kidney calcium oxalate crystal depositions had increased by day 6; thereafter, depositions decreased gradually and had almost disappeared by day 15 On microarray analysis, mRNA expression in the crystal-formed kidneys showed the significant expression of 18,064 genes Thirty-one, 21, and 25 genes showed at least a 2-fold increased expression during the experimental course (days 3-15), stone formation phase-specific (days 3-6), and stone elimination phase-specific (days 9-15) stages, respectively Among these genes, those related to chemotaxis and monocyte/macrophage activation were identified Gene ontology analysis to identify overexpressed genes highlighted categories related to inflammation, immune reactions and the complement activation pathway Quantitative PCR of 17 previously reported stone-related genes with a significant expression on microarray analysis showed significantly increased chemokines, stone matrix proteins, and their receptors; the significant decrease of several types of transporters and superoxide dismutase; and the persistently high expression of Tamm-Horsfall protein throughout the experiment In conclusion, inflammation and immune reactivity through macrophage migration are involved in stone formation and elimination in mouse kidneys

Genome‐Wide Analysis of Genes Related to Kidney Stone Formation and Elimination in the Calcium Oxalate Nephrolithiasis Model Mouse: Detection of Stone‐Preventive Factors and Involvement of Macrophage Activity

The establishment of an experimental animal model would be useful to study the mechanism of kidney stone formation. A calcium kidney stone model in rats induced by ethylene glycol has been used for research; however, to investigate the genetic basis affecting kidney stone formation, which will contribute to preventive medicine, the establishment of a kidney stone model in mice is essential. This study indicates the optimum conditions for inducing calcium oxalate stones in normal mouse kidney. Various doses of oxalate precursors, ethylene glycol, glycolate and glyoxylate, were administered either by free drinking or intraabdominal injection for 2 months as a preliminary study. Stone formation was detected with light microscopy, polarized light optical microscopy and electron microscopy. Stone components were detected with X-ray diffraction analysis. The expression of osteopontin (OPN), a major stone-related protein, was detected with immunohistochemical staining, in situ hybridization and quantitative reverse transcriptase polymerase chain reaction. Kidney stones were not detected in ethylene glycol- or glycolate-treated groups even at the highest dose of LD50. Whereas, numerous kidney stones were detected in glyoxylate-treated mice (more than 60 mg/kg) at 3, 6 and 9 days after glyoxylate were administered intraabdominally. However, the number of kidney stones decreased gradually at day 12, and was hardly detected at day 15. The stone component was further analyzed as calcium oxalate monohydrate. A dramatic increase in the expression of OPN was observed by the administration of glyoxylate. We established a mouse kidney stone experimental system in this study. The difficulty of inducing kidney stones suggested that mice have greater intrinsic ability to prevent stone formation with hyperoxaluric stress than rats. The differing response to hyperoxaluric stress between mice and rats possibly contributes to the molecular mechanism of kidney stone formation and will aid preventive medicine in the future.

Successful formation of calcium oxalate crystal deposition in mouse kidney by intraabdominal glyoxylate injection

Between 1991 and 1997, 17 male patients with bladder stones underwent extracorporeal shock-wave lithotripsy (ESWL) therapy in our department. One patient required epidural anesthesia and 5 patients were treated under intravenous sedation. Complete fragmentation was achieved after a single session in 9 patients and 4 required 2 sessions. Four patients underwent initial ESWL followed by mechanical cystolithotripsy. No major complications were noted. Fourteen patients were stone-free within 1 week after the procedure. Four patients were treated by transurethral resection of the prostate (TUR-P) on the day after completion ESWL. In conclusion, ESWL therapy is a simple, effective and safe modality for the management of vesical lithiasis.

Extracorporeal Shock Wave Lithotripsy for Vesical Lithiasis

We studied the effects of cholesterol load on urinary stone in rats receiving a standard diet or a high fat diet Sixty male rats were randomized to two groups and were fed either a standard diet (SD group) or a high fat diet (HFD group) for 8 weeks Then the two groups were further divided into four groups SD group, HFD group, SD + EG group (with standard diet + ethylene glycol administration for two weeks), and HFD + EG group (with high fat diet + ethylene glycol administration) The starting date of EG administration was considered to be week 0 Twenty-four-hour urine samples were collected in week 0, week 1, and week 2, and oxalate excretion and citrate excretion were measured by capillary electrophoresis analyzer The excretion of phosphorus, magnesium, and creatinine for 24 hours was measured using an automated analyzer Serum sodium, potassium, chloride, calcium, phosphate, magnesium, creatinine, total cholesterol, triglyceride, HDL-cholesterol and glucose were determined using an automated analyzer The kidney tissues were obtained to perform hematoxyline-eosine staining and Pizzolato's staining to detect oxalate-containing crystals The average body weight in HFD groups and HFD + EG group in week 0 was significantly higher than that of SD group and SD + EG group The calcium oxalate crystal deposition was not observed in all groups in week 0 HFD + EG group in week 1 had sporadically calcium oxalate crystal deposition in renal distal tubular cells and tubular lumens In week 2, the number of crystal deposition in HFD + EG group was increased remarkably The crystals were slightly observed in SD + EG group in week 2 The excretion of urinary calcium and phosphate in HFD group and HFD + EG group was significantly higher than that of the SD group and SD + EG group in week 0 The amount of urinary citrate excretion in the SD group and SD + EG group showed a significantly higher value compared with that of the HFD group and HFD + EG group in week 0 The level of serum total cholesterol in the HFD group and HFD + EG group was higher compared to that in the SD group and SD + EG group The serum triglyceride level was not significantly different in the four groups in week 0 Interestingly, the level of triglyceride of EG administration groups (SD + EG and HFD + EG group) was significantly higher than that in EG no-administration groups (SD group and HFD group) in week 1 and week 2 The serum glucose level in the HFD group and HFD + EG group was significantly higher than that in the SD group and SD + EG group in week 0 In week 2, the glucose level of EG administration groups (HDF + EG group and SD + EG group) was significantly lower than that of EG no-administration groups (HFD group and SD group) In conclusion, this result suggested that long-term loading of cholesterol could increase renal calcium stone formation

The role of long-term loading of cholesterol in renal crystal formation.

Many drugs have been used in the treatment of renal colic, but the safest and most effective drug has not yet been clearly defined. A questionnaire was used to collate the types of treatment for renal colic used by Japanese urologists. The main treatments were nonsteroidal analgesic (suppository) and anticholinergic agent. A new protocol was developed on the basis of this result, and its effect on renal colic was verified. The combination of an injection of a local anesthetic and pointillage was found to be superior to non-steroidal analgesic anti-inflammatory drugs and anticholinergic agent in terms of both duration of action and effectiveness.

Optimal treatment of urolithiasis pain

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Successful formation of calcium oxalate crystal deposition in mouse kidney by intraabdominal glyoxylate injection

Extracorporeal Shock Wave Lithotripsy for Vesical Lithiasis

The role of long-term loading of cholesterol in renal crystal formation.

Optimal treatment of urolithiasis pain