Kidney Stone Formation Research Articles

The Cause of Kidney Stone Formation and Treatment from the Perspective of Conventional and Traditional Persian Medicine

Urinary stone disease is the most common urinary tract disease that has caused human suffering since ancient times. The observation of a 7000-year-old bladder stone in an Egyptian skeleton proves this claim. This disease causes many complications for patients, but its pathogenesis is unclear. The knowledge about the cause of urinary stones formation and treatment recommendations from ancient physicians' perspectives is probably helpful in preventing and treating kidney stones. Data for this review were provided by search in five Traditional Persian sources available, including Canon of Medicine (Avicenna, 980-1037 AD), Kamil al–Sana al-Tibbiya (Majusi Ahwazi (Haly Abbas), died 982-994), Zakhire Kharazmshahi (Jorjani, 1042-1137 AD), Makhzan al Adviyeh (Mohammad Hossein Aghili Khorasani Shirazi in 18th AD), and Tib-e-Akbari (Mohammad Akbar Arzani-11th and 12th centuries AD) and Until January of 2023, all English publications in Science Direct, PubMed, Google Scholar and Scopus, using various search terms such as urolithiasis, lithiasis, and kidney stone. Some dietary recommendations in Traditional Persian Medicine (TPM) for treatment of urinary tract stones and 134 recommended plant species, in addition to studies of in vivo effects of some of them in conventional medicine have been described in this article. The TPM with long experience and special principles has good potential in the field of diagnosis and treatment in its own way and can act as a strong complementary treatment system for diseases that have challenging treatment. It seems using the experiences in the TPM sources and relying on today's knowledge can create a way to prevent the formation and recurrence of urinary tract stones.

Sex-specific Stone-forming Phenotype in Mice During Hypercalciuria/Urine Alkalinization

Sex differences in kidney stone formation are well known. Females generally have slightly acidic blood and higher urine pH when compared with males, which makes them more vulnerable to calcium stone formation, yet the mechanism is still unclear. We aimed to examine the role of sex in stone formation during hypercalciuria and urine alkalinization through acetazolamide and calcium gluconate supplementation, respectively, for 4 weeks in wild-type (WT) and moderately hypercalciuric [TRPC3 knockout [KO](−/−)] male and female mice. Our goal was to develop calcium phosphate (CaP) and CaP+ calcium oxalate mixed stones in our animal model to understand the underlying sex-based mechanism of calcium nephrolithiasis. Our results from the analyses of mice urine, serum, and kidney tissues show that female mice (WT and KO) produce more urinary CaP crystals, higher [Ca2+], and pH in urine compared to their male counterparts. We identified a sex-based relationship of stone-forming phenotypes (types of stones) in our mice model following urine alkalization/calcium supplementation, and our findings suggest that female mice are more susceptible to CaP stones under those conditions. Calcification and fibrotic and inflammatory markers were elevated in treated female mice compared with their male counterparts, and more so in TRPC3 KO mice compared with their WT counterparts. Together these findings contribute to a mechanistic understanding of sex-influenced CaP and mixed stone formation that can be used as a basis for determining the factors in sex-related clinical studies.

Inhibitory Potential of Tribulus terrestris on Calcium Oxalate Crystals, Struvite Crystals and Bacterial Pathogens: A Preliminary Investigation

Kidney stone formation and recurring urinary tract infection (UTIs) are common among the general population. An alternative herbal treatment potential was investigated in this study. This study aims to investigate anti-urolithiasis efficacy of herbal Tribulus terrestris (TT) plant leaf extract in reducing the growth of calcium oxalate and struvite crystal using in vitro methods. In vitro antiurolithiatic potential of TT leaf extract was studied using nucleation, aggregation, and crystal formation assays in synthetic media and in synthetic urine samples. In vitro antiurolithiasis potential of Tribulus terrestris (TT) plant leaf extract was investigated at concentrations ranging from 100 to 1000 μg/ml. Initially, the principal phytochemical constituents of TT methanolic leaf extract was examined. Then antibacterial properties of TT plant leaf extract were tested against common urinary tract pathogens such as Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The results of the nucleation assay revealed that TT leaf extract reduced up to 55% of calcium oxalate (CaOx) crystallization and inhibits struvite crystal formation up to 85% with 5% (0.43 g) of TT extract. This study revealed a dose-dependent suppression of crystal formation by increased TT plant leaf extract dosage. The antibacterial activity of TT plant leaf extract is greater against E. coli than S. aureus. This anti-urolithiasis potential of TT plant extract can be used as an antidote for individuals who are prone to urinary crystal formation as well as to control urinary tract infections.

Could Microbiota Edit Oxalate Nephrolithiasis’ Story?

Abstract: Nephrolithiasis is a complex multifactorial pathology which contributes to the onset of genetics factors, environmental factors, diet and lifestyle, in addition this pathology has recently been associated with an increased risk of developing cardiovascular diseases increasing the burden of health care costs1. Nephrolithiasis is characterized by a complex of manifestations resulting from the formation and transit along the urinary tract of crystalline agglomerates stones, composed of poorly soluble substances. Kidney stones are elements of hard consistency, consisting of a solid component mixed with an organic matrix, i.e. proteins normally present in the urine. Most stones are calcium based, it is estimated that those of calcium oxalate (CaOx) and calcium phosphate (CaP) correspond to 80% of all calculations. In 9% of cases they are of uric acid, in 10% struvite (magnesium ammonium phosphate hexahydrate) and in 1% are other type (cystine, ammonium urate acid)2. Nephrolithiasis is a common cause of morbidity in the United States, responsible for hospitalization in 1 per 1000 of the population every year3-4, while in Asia the probability of forming kidney stones is very low (1-5%). The peak incidence was observed in subjects between 18 and 45 years, with a prevalence greater than 5-10 times in males. Was estimated that 5% of American women and 12% of men will develop an episode of calculating at some point in life5. 40% of patients with a first episode of nephrolithiasis have a second episode within 2-3 years and 75% relapse within 7-10 years. After 20 years, it is estimated that in less than 10% of patients do not develop stones again6

INCIDENCE OF KIDNEY STONES IN KIDNEY TRANSPLANT RECIPIENTS

The incidence of kidney stones in kidney transplant recipients is a significant concern within the realm of post-transplant complications. The study's main objective is to find the incidence of kidney stones in kidney transplant recipients. This retrospective study was conducted at the Institute of Kidney Diseases Peshawar from 2017 to 2023. Data was collected from 420 kidney transplant patients. All patients above 18 years with available medical records who underwent renal transplants in IKD and outside IKD and who presented to IKD for follow-up were included in the study—patients with a history of kidney stones before the transplant process were excluded. Demographic information, including age, gender, and pre-transplant comorbidities, was recorded for each patient. Data were collected from 420 patients with kidney transplants. Out of 420 patients, 35 patients developed kidney stones after transplantation. The mean age of the patients who developed stones was 48.7 ± 10.2 years. There were 45.7% male and 54.3% female patients in the kidney stone group. 25.7% of patients had pre-transplant DM. Most kidney stones analyzed in the study comprised calcium oxalate, representing 18 cases, followed by calcium phosphate with eight instances. The correlation analysis revealed that age and gender did not significantly correlate with kidney stone formation in transplant patients, with p-values of 0.32 and 0.17, respectively. It is concluded that kidney transplant recipients exhibit a notable incidence of kidney stone formation, with tacrolimus-based immunosuppressive regimens potentially contributing to this risk. While age and pre-transplant diabetes show trends toward association with kidney stone development.

Preliminary study of the role of nanobacteria in the formation of renal stones in experimental rats and its mechanism.

The aim of the study was to study the role of nanobacteria in the formation of renal calculi and the underlying mechanism. A total of 90 clean Wistar male rats were randomly divided into a negative control group, an experimental group, and an interference group. From the end of the first week of modelling, 10 consecutive times once a week, 3 rats in each group were randomly selected to measure the biochemical blood markers and urine metabolism. After sacrifice, the formation of kidney stones was assessed by observing the ultrastructure of the kidney by electron microscopy and pathohistology. Finally, the expression of calcium-sensitive receptor (CaSR) and claudin-14 protein in the kidney tissue was examined by western blotting. Compared with the control group, the gross structure of the kidney was changed in the model group. At the fourth week of modelling, the rats in the nanobacteria group had significantly enlarged kidneys and increased kidney-to-body ratio, and the difference had statistical significance (p < 0.05). The colour of the kidney profile was dark, the structure of the skin pulp was less clear, and the accumulation of yellowish particles was observed at the junction of the cortical pulp. The creatinine, uric acid, urea nitrogen, and urinary calcium of the rats in the nanobacteria group began to increase at the third week, and the difference between the third and eighth week had statistical significance (p < 0.05). However, the difference between the 3 groups had no statistical significance after the eighth week. At the fourth week, we observed the formation of calculi, which were mainly distributed in the renal tubules and surrounding tissues. The kidney stone formation rate was 52.4% in the nanobacteria group and 27.8% in the interference group, and the difference had statistical significance (p < 0.05). Ultrastructure observations revealed that from the fourth week, the renal tissues in the nanobacteria group showed expanded renal tubules, swollen renal tubular epithelium, granular degeneration, shedding and lymphocyte infiltration of renal tubular epithelial cells, and a small amount of calcium salt crystals in renal tubules. At the third week, the expression of CaSR and Claudin-14 protein in the nanobacteria group increased, and the difference had statistical significance (p < 0.05). The expression of CaSR and Claudin-14 was positively correlated with urinary calcium (p < 0.05). The formation of renal calculi began in the fourth week after the model was established, and the crystals were mostly located in the renal tubules. During the formation of renal calculi, the renal tubular epithelial cells were damaged, showing granular degeneration and small amounts of calcium salt crystals, accompanied by a few renal tubules beginning to expand and epithelial swelling, granular degeneration, necrosis and shedding of renal tubular epithelial cells, lymphocyte infiltration in the renal interstitium, and small amounts of calcium salt crystals in the renal tubules, which aggravated with time. The serum creatinine, serum uric acid, urea nitrogen, and urinary calcium levels increased with time from the third week and returned to normal after the eighth week. The expression of CaSR and Claudin-14 protein was upregulated and positively correlated with the 24-h urinary calcium excretion value.

Calcium supplementation for the prevention of hypertension: a synthesis of existing evidence and implications for practise.

Hypertension (also known as high blood pressure), is a medical condition characterized as a persistently raised blood pressure of the pulmonary artery. Effective interventions to treat hypertension typically involve two approaches: lifestyle modifications and pharmacotherapy. One specific lifestyle intervention which aims to increase calcium uptake through dietary supplementation, has recently gained popularity because of its potential to be low-cost and population based. Research suggests that this intervention may be effective given that calcium has been found to have an inverse relationship with blood pressure and hypertension. That said, studies have shown that there may be potential risks to patient health through adverse events such as kidney stone formation and increased cardiovascular events. Association between calcium supplementation and adverse events could have an impact on population health and prevent widespread adoption of the intervention. Because of the need to establish the effectiveness of this intervention assessed against any possible harms, it is now necessary to review the current evidence and evaluate its implications for clinical practise.

StoneMod 2.0: Database and prediction of kidney stone modulatory proteins

Stone modulators are various kinds of molecules that play crucial roles in promoting/inhibiting kidney stone formation. Several recent studies have extensively characterized the stone modulatory proteins with the ultimate goal of preventing kidney stone formation. Herein, we introduce the StoneMod 2.0 database (https://www.stonemod.org), which has been dramatically improved from the previous version by expanding the number of the modulatory proteins in the list (from 32 in the initial version to 17,130 in this updated version). The stone modulatory proteins were recruited from solid experimental evidence (via PubMed) and/or predicted evidence (via UniProtKB, QuickGO, ProRule, STITCH and OxaBIND to retrieve calcium-binding and oxalate-binding proteins). Additionally, StoneMod 2.0 has implemented a scoring system that can be used to determine the likelihood and to classify the potential stone modulatory proteins as either “solid” (modulator score ≥ 50) or “weak” (modulator score < 50) modulators. Furthermore, the updated version has been designed with more user-friendly interfaces and advanced visualization tools. In addition to the monthly scheduled update, the users can directly submit their experimental evidence online anytime. Therefore, StoneMod 2.0 is a powerful database with prediction scores that will be very useful for many future studies on the stone modulatory proteins.

Detection of oxalyl-CoA decarboxylase (oxc) and formyl-CoA transferase (frc) genes in novel probiotic isolates capable of oxalate degradation in vitro

Oxalate degradation is one of lactic acid bacteria’s desirable activities. It is achieved by two enzymes, formyl coenzyme A transferase (frc) and oxalyl coenzyme A decarboxylase (oxc). The current study aimed to screen 15 locally isolated lactic acid bacteria to select those with the highest oxalate degradation ability. It also aimed to amplify the genes involved in degradation. MRS broth supplemented with 20 mM sodium oxalate was used to culture the tested isolates for 72 h. This was followed by an enzymatic assay to detect remaining oxalate. All isolates showed oxalate degradation activity to variable degrees. Five isolates demonstrated high oxalate degradation, 78 to 88%. To investigate the oxalate-degradation potential of the selected isolates, they have been further tested for the presence of genes that encode for enzymes involved in oxalate catabolism, formyl coenzyme A transferase (frc) and oxalyl coenzyme A decarboxylase (oxc). Three strains showed bands with the specific OXC and FRC forward and reverse primers designated as (SA-5, 9 and 37). Species-level identification revealed Loigolactobacillus bifermentans, Lacticaseibacillus paracasei, and Lactiplantibacillus plantarum. Preliminary results revealed that the tested probiotic strains harbored both oxc and frc whose products are putatively involved in oxalate catabolism. The probiotic potential of the selected strains was evaluated, and they showed high survival rates to both simulated gastric and intestinal fluids and variable degrees of antagonism against the tested Gram-positive and negative pathogens and were sensitive to clarithromycin but resistant to both metronidazole and ceftazidime. Finally, these strains could be exploited as an innovative approach to establish oxalate homeostasis in humans and prevent kidney stone formation.

Accelerated Molecular Dynamics and AlphaFold Uncover a Missing Conformational State of Transporter Protein OxlT.

Transporter proteins change their conformations to carry their substrate across the cell membrane. The conformational dynamics is vital to understanding the transport function. We have studied the oxalate transporter (OxlT), an oxalate:formate antiporter from Oxalobacter formigenes, significant in avoiding kidney stone formation. The atomic structure of OxlT has been recently solved in the outward-open and occluded states. However, the inward-open conformation is still missing, hindering a complete understanding of the transporter. Here, we performed a Gaussian accelerated molecular dynamics simulation to sample the extensive conformational space of OxlT and successfully predicted the inward-open conformation where cytoplasmic substrate formate binding was preferred over oxalate binding. We also identified critical interactions for the inward-open conformation. The results were complemented by an AlphaFold2 structure prediction. Although AlphaFold2 solely predicted OxlT in the outward-open conformation, mutation of the identified critical residues made it partly predict the inward-open conformation, identifying possible state-shifting mutations.

The Vitamin D Metabolite Diagnostic Ratio Associates With Phenotypic Traits of Idiopathic Hypercalciuria

IntroductionUnderlying mechanisms for hypercalciuria remain unknown in most cases, hence the designation “idiopathic”. We hypothesized that the Vitamin D-inactivating enzyme CYP24A1 contributes to the pathogenesis of hypercalciuria in kidney stone formers. MethodsWe conducted association analyses between CYP24A1 activity, estimated by the Vitamin D metabolite diagnostic ratio (25(OH) Vitamin D3/total 24,25 (OH)2 Vitamin D ratio; VMDR), and the phenotype of participants in two observational cohorts of kidney stone formers, the Swiss Kidney Stone Cohort and the Bern Kidney Stone Registry. Circulating 25(OH)- and 24,25 (OH)2 Vitamin D were quantified using a validated LC-MS/MS assay. Results974 participants were included in the analysis. We found a positive association of VMDR (and hence negative association of CYP24A1 activity) with total (β 0.009 mmol/L; 95% CI 0.002, 0.016; p = 0.02) and ionized plasma calcium (β 0.005 mmol/L; 95% CI 0.002, 0.008; p < 0.01), absolute and fractional excretion of urinary calcium (β 0.054 mmol/24h; 95% CI 0.010, 0.097; p = 0.02 and β 0.046 %; 95% CI 0.018, 0.074; p < 0.01, respectively). Further, VMDR was associated with an increased likelihood of forming calcium oxalate dihydrate stones (Odds ratio 1.64; 95% CI 1.22, 2.35; p < 0.01) and reduced bone mineral density at the femoral neck (β -0.005 g/cm2; 95% CI -0.010, -0.001; p = 0.04). The described associations became stronger when the analysis was confined to idiopathic calcium stone formers. ConclusionOur study reveals that CYP24A1 activity, estimated by VMDR, is associated with clinical traits previously linked to idiopathic hypercalciuria.

Renal stones: An updated review about natural remedies

Background: Urolithiasis is a prevalent global health issue characterized by the formation of kidney stones, significantly impacting patient quality of life and healthcare costs. The increasing incidence of kidney stones, particularly among individuals over 30, places a considerable financial burden on healthcare systems, with estimates reaching USD 5.3 billion in 2014. Aim: This review aims to provide a comprehensive overview of the latest natural remedies for managing renal stones, discussing their efficacy and integration into existing treatment paradigms. Methods: A thorough literature review was conducted, focusing on recent studies and clinical guidelines from organizations like the American Urology Association (AUA) and the European Association of Urology (EAU). The effectiveness of various natural remedies was analyzed alongside conventional treatment options. Results: The review identifies several natural remedies that may complement traditional therapies for renal stones. These include dietary modifications, hydration strategies, and herbal supplements that demonstrate potential benefits in stone prevention and management. Conclusion: While conventional medical treatments remain the cornerstone of urolithiasis management, natural remedies may offer valuable adjunctive options. Further research is warranted to establish standardized protocols for integrating these remedies into clinical practice.

CCL7 and olfactory transduction pathway activation play an important role in the formation of CaOx and CaP kidney stones.

Background: The deposition of calcium oxalate (CaOx) and calcium phosphate (CaP) is the most common cause of kidney stone disease (KSD). Whether KSDs caused by CaOx and CaP have common genetic targets or signaling pathways remained unclear. Methods: The present study utilized public data GSE73680 to analyze differentially expressed genes between CaOx or CaP tissues and normal tissues, respectively. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of co-DEGs were performed. The protein-protein interaction (PPI) network was constructed to identify hub genes, and the top hub gene was selected for gene set enrichment analysis (GSEA). Finally, real-time PCR of patients' urine was performed to validate the bioinformatic results. Results: In total, 155 significantly co-upregulated DEGs and 64 co-downregulated DEGs were obtained from the datasets. The Gene Ontology analysis showed that DEGs were significantly enriched in chemical stimulus in sensory perception, detection of chemical stimulus in sensory perception of smell, and olfactory receptor activity. The KEGG analysis showed that the olfactory transduction pathway was significantly enriched. According to protein-protein interaction, 10 genes were identified as the hub genes, and CCL7 was the top hub gene. The olfactory transduction, maturity-onset diabetes of the young, linoleic acid metabolism, and fat digestion and absorption were significantly enriched in the high-CCL7 subgroup by GSEA. In total, 9 patients who had primarily CaOx mixed with some CaP stones and 9 healthy subjects were enrolled. The RT-PCR results showed that CCL7 level in the stone group was significantly higher than that in the control group (p < 0.05). For the olfactory transduction pathway, the expression of OR10A5, OR9A2, and OR1L3 was significantly upregulated in the stone group compared with the control group (p < 0.05). Conclusion: CCL7 may play a key role in the development of both CaOx and CaP, and this process may depend on olfactory transduction pathway activation.

Different Degrees of Sulfated Laminaria Polysaccharides Recovered Damaged HK-2 Cells and Inhibited Adhesion of Nano-COM and Nano-COD Crystals.

The crystal adhesion caused by the damage of renal tubular epithelial cells (HK-2) is the key to the formation of kidney stones. However, no effective preventive drug has been found. This study aims to explore the recovery effects of four Laminaria polysaccharides (SLPs) with different sulfate (-OSO3-) contents on damaged HK-2 cells and the difference in the adhesion of damaged cells to nanometer calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) before and after recovery. Sodium oxalate (2.6 mmol/L) was used to damage HK-2 cells to establish a damaged model. SLPs (LP0, SLP1, SLP2, and SLP3) with -OSO3- contents of 0.73%, 15.1%, 22.8%, and 31.3%, respectively, were used to restore the damaged cells, and the effects of SLPs on the adhesion of COM and COD, with a size of about 100 nm before and after recovery, were measured. The following results were observed after SLPs recovered the damaged HK-2 cells: increased cell viability, restored cell morphology, decreased reactive oxygen levels, increased mitochondrial membrane potential, decreased phosphatidylserine eversion ratio, increased cell migration ability, reduced expression of annexin A1, transmembrane protein, and heat shock protein 90 on the cell surface, and reduced adhesion amount of cells to COM and COD. Under the same conditions, the adhesion ability of cells to COD crystals was weaker than that to COM crystals. As the sulfate content in SLPs increases, the ability of SLPs to recover damaged HK-2 cells and inhibit crystal adhesion increases. SLP3 with high -OSO3- content may be a potential drug to prevent kidney stones.

Insights from a Brief Study of Renal Calculi: Recent Diagnostic and Treatment Approaches

Background: Renal calculi, commonly known as kidney stones, is a prevalent urological condition that affects a substantial portion of the population worldwide. The formation of kidney stones is a complex process influenced by various factors, including diet, fluid intake, genetics, and metabolic abnormalities. The pathogenesis of renal calculi involves a complex interplay of multiple factors, including supersaturation of urine with stone-forming constituents, urinary supersaturation, crystallization, and aggregation. Objective: This review aims to provide an overview of the present understanding of renal calculi, their pathophysiology, diagnostic approaches, and available treatment modalities. Methods: This review discusses the different types of kidney stones, such as calcium oxalate, calcium phosphate, uric acid, and struvite stones, and explores their formation mechanisms and associated risk factors. The management of renal calculi relies on stone characteristics, patient symptoms, stone size, and location. Furthermore, counseling and education regarding lifestyle modifications and risk factor management are essential for long-term management. Conclusion: Accurate diagnosis and appropriate management based on stone characteristics and patient symptoms are essential for successful outcomes. Preventive strategies to reduce stone recurrence are vital for long-term management and patient well-being. However, further research is needed to refine diagnostic techniques, improve treatment options, and enhance the understanding of the underlying pathophysiology of renal calculi.

Resveratrol inhibits calcium oxalate crystal growth, reduces adhesion to renal cells and induces crystal internalization into the cells, but promotes crystal aggregation

Resveratrol is a natural phenolic compound that belongs to stilbenoid group found in diverse plants. Health benefits and therapeutic potentials of resveratrol have been widely recognized in various diseases. In kidney stone disease, it can alleviate oxalate-induced hyperproduction of free radicals in renal epithelial cells. Nevertheless, its direct effects on calcium oxalate (CaOx) crystal, which is the major stone component, remained unclear. This study therefore addressed the direct effects of resveratrol (at 1, 10 or 100 μM) on each step of CaOx kidney stone formation. The results revealed that resveratrol had no significant effects on CaOx crystallization. However, resveratrol significantly decreased CaOx crystal growth and adhesion to renal epithelial cells at all concentrations, and induced crystal internalization into the cells (a process related to crystal degradation by endolysosomes) in a concentration-dependent manner. On the other hand, resveratrol promoted crystal aggregation. These data indicate that resveratrol serves as a dual modulator on CaOx stone formation. While it inhibits CaOx stone development by reducing crystal growth and adhesion to renal cells and by inducing crystal internalization into the cells, resveratrol promotes crystal aggregation, which is one of the mechanisms leading to kidney stone formation.

Confining calcium oxalate crystal growth in a carbonated apatite-coated microfluidic channel to better understand the role of Randall's plaque in kidney stone formation.

Effective prevention of recurrent kidney stone disease requires the understanding of the mechanisms of its formation. Numerous in vivo observations have demonstrated that a large number of pathological calcium oxalate kidney stones develop on an apatitic calcium phosphate deposit, known as Randall's plaque. In an attempt to understand the role of the inorganic hydroxyapatite phase in the formation and habits of calcium oxalates, we confined their growth under dynamic physicochemical and flow conditions in a reversible microfluidic channel coated with hydroxyapatite. Using multi-scale characterization techniques including scanning electron and Raman microscopy, we showed the successful formation of carbonated hydroxyapatite as found in Randall's plaque. This was possible due to a new two-step flow seed-mediated growth strategy which allowed us to coat the channel with carbonated hydroxyapatite. Precipitation of calcium oxalates under laminar flow from supersaturated solutions of oxalate and calcium ions showed that the formation of crystals is a substrate and time dependent complex process where diffusion of oxalate ions to the surface of carbonated hydroxyapatite and the solubility of the latter are among the most important steps for the formation of calcium oxalate crystals. Indeed when an oxalate solution was flushed for 24 h, dissolution of the apatite layer and formation of calcium carbonate calcite crystals occurred which seems to promote calcium oxalate crystal formation. Such a growth route has never been observed in vivo in the context of kidney stones. Under our experimental conditions, our results do not show any direct promoting role of carbonated hydroxyapatite in the formation of calcium oxalate crystals, consolidating therefore the important role that macromolecules can play in the process of nucleation and growth of calcium oxalate crystals on Randall's plaque.

PPARγ agonist alleviates calcium oxalate nephrolithiasis by regulating mitochondrial dynamics in renal tubular epithelial cell.

Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood. An animal model of calcium oxalate-related nephrolithiasis was established in adult male Sprague‒Dawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis. Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo. Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis.

The complex relationship between vitamin D and kidney stones: balance, risks, and prevention strategies.

The association between vitamin D and kidney stones is characterized by a remarkable multi-dimensional complexity involving numerous physiological and metabolic pathways. Vitamin D is pivotal in maintaining calcium-phosphorus metabolic homeostasis and bone health. However, fluctuations in its intake, whether excessive or insufficient, May potentially increase the risk of kidney stones. Vitamin D exerts its influence on kidney stone formation indirectly by increasing the efficiency of intestinal calcium absorption and regulating renal calcium excretion. Moreover, there is a robust correlation between various states of vitamin D, particularly its active form, 1,25-dihydroxyvitamin D, and the development of numerous kidney stones. This finding underscores the necessity of individualized medical treatment in vitamin D supplementation and kidney stone prevention. When developing treatment strategies, it is essential to consider the patient's genetic background, lifestyle, environmental factors, and overall health. To prevent the formation of kidney stones, it is recommended that patients adopt a comprehensive approach, which May include measures such as moderate sun exposure, dietary modification, moderate exercise, and weight management. These preventive measures are designed to maintain healthy calcium and phosphorus metabolism and reduce kidney stone formation risk. Future studies should aim to elucidate the detailed mechanisms of vitamin D metabolism, individual differences, and the role of genes in this process. Furthermore, the role of lifestyle interventions in preventing kidney stones requires greater attention. Moreover, the implementation of large-scale, long-term prospective studies and randomized controlled trials will facilitate the assessment of the actual effects of diverse vitamin D supplementation strategies, thereby providing a robust scientific foundation for advancing more precise prevention strategies and clinical guidelines.

Iron oxide nanozymes enhanced by ascorbic acid for macrophage-based cancer therapy.

In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O2) production in solid tumors. The H2O2 is then converted into cytotoxic hydroxyl free radicals (HO˙) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H2O2 to HO˙ by wüstite (Fe1-xO) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H2O2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.