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Kidney stone disease is increasing in prevalence, and the most common stone composition is calcium oxalate. Dietary oxalate intake and endogenous production of oxalate are important in the pathophysiology of calcium oxalate stone disease. The impact of dietary oxalate intake on urinary oxalate excretion and kidney stone disease risk has been assessed through large cohort studies as well as smaller studies with dietary control. Net gastrointestinal oxalate absorption influences urinary oxalate excretion. Oxalate-degrading bacteria in the gut microbiome, especially Oxalobacter formigenes, may mitigate stone risk through reducing net oxalate absorption. Ascorbic acid (vitamin C) is the main dietary precursor for endogenous production of oxalate with several other compounds playing a lesser role. Renal handling of oxalate and, potentially, renal synthesis of oxalate may contribute to stone formation. In this review, we discuss dietary oxalate and precursors of oxalate, their pertinent physiology in humans, and what is known about their role in kidney stone disease.

Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure. Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al . show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.

The prevalence of kidney stone disease is increasing worldwide. The recurrence rate of urinary stones is estimated to be up to 50%. Nephrolithiasis is associated with increased risk of chronic and end stage kidney disease. Diet composition is considered to play a crucial role in urinary stone formation. There is strong evidence that an inadequate fluid intake is the major dietary risk factor for urolithiasis. While the benefit of high fluid intake has been confirmed, the effect of different beverages, such as tap water, mineral water, fruit juices, soft drinks, tea and coffee, are debated. Other nutritional factors, including dietary protein, carbohydrates, oxalate, calcium and sodium chloride can also modulate the urinary risk profile and contribute to the risk of kidney stone formation. The assessment of nutritional risk factors is an essential component in the specific dietary therapy of kidney stone patients. An appropriate dietary intervention can contribute to the effective prevention of recurrent stones and reduce the burden of invasive surgical procedures for the treatment of urinary stone disease. This narrative review has intended to provide a comprehensive and updated overview on the role of nutrition and diet in kidney stone disease.

Calcium oxalate (CaOx) crystals occur as intravacuolar deposits in most angiosperm species. Different functions have been attributed to these crystals, some of which are very speculative, until now. Calcium regulation and homeostasis seem to be the most widespread function of CaOx crystals. Being rich in calcium, these crystals constitute a reserve of calcium for plants. However, despite being bioavailable, this reserve is functional in just a few situations due to the low mobility of calcium for phloem translocation. Therefore, CaOx crystals as a calcium reserve is a paradox because in most cases the reserve cannot be used. However, in most plants, these crystals occur in organs or tissues that will be discarded, which allows the elimination of excess calcium. This suggests that CaOx crystals have a functional role in excess calcium excretion. There is some evidence that, for calcium, this excretory function is relevant for plants since they lack an excretory system dedicated to discarding solid wastes, such as calcium salts.

High intake of dietary linoleic acid may increase the incidence of many diseases. The aim of this research is to examine the impact of linoleic acid on the damage caused by calcium oxalate kidney stones on renal tubular epithelial cells. Calcium oxalate monohydrate (COM) crystals were prepared and used to treat HK‐2 cells, which were further treated with different concentrations of linoleic acid in vitro. Also, a small‐interfering RNA lentiviral vector of milk fat globule epidermal growth factor 8 (MFGE8) was constructed and transfected into HK‐2 cells. The cell viability, level of intracellular ROS and autophagy were tested. In vivo experiments were also carried out with a rat model for renal urolithiasis treated with linoleic acid. The results indicated that COM crystals promoted crystal deposition and apoptosis, increased levels of intracellular Ca2+ and ROS levels and inhibited the proliferation of HK‐2 cells. Linoleic acid exacerbated the damage of COM crystal‐treated HK‐2 cells and renal tubular epithelial cells of the rat model for renal urolithiasis, which can be partially reversed by downregulation of MFGE8. These results collectively suggest that linoleic acid might enhance the damage of renal tubular epithelial cells caused by COM crystals.

Oxalate-induced crystalline kidney injury is one of the most common types of crystalline nephropathy. Unfortunately, there is no effective treatment to reduce the deposition of calcium oxalate crystals and alleviate kidney damage. Thus, proactive therapeutic is urgently needed to alleviate the suffering it causes to patient. Here, we investigated whether IL-22 exerted nephroprotective effects to sodium oxalate-mediated kidney damage and its potential mechanism. Crystalline kidney injury models were developed in vitro and in vivo that was often observed in clinic. We provided evidence that IL-22 could effectively decrease the accumulation of ROS and mitochondrial damage in cell and animal models and reduce the death of TECs. Moreover, IL-22 decreased the expression of the NLRP3 inflammasome and mature IL-1β in renal tissue induced by sodium oxalate. Further studies confirmed that IL-22 could play an anti-inflammatory role by reducing the levels of cytokines such as IL-1β, IL-18, and TNF-α in serum. In conclusion, our study confirmed that IL-22 has protective effects on sodium oxalate-induced crystalline kidney injury by reducing the production of ROS, protecting mitochondrial membrane potential, and inhibiting the inflammatory response. Therefore, IL-22 may play a potential preventive role in sodium oxalate-induced acute renal injury. Key points • IL-22 could reduce sodium oxalate-mediated cytotoxicity and ameliorate renal injury. • IL-22 could alleviate oxidative stress and mitochondrial dysfunction induced by sodium oxalate. • IL-22 could inhibit inflammatory response of renal injury caused by sodium oxalate.

Chitosan is widely used in the biomedical field due its chemical and pharmacological properties. However, intake of chitosan results in renal tissue accumulation of chitosan and promotes an increase in calcium excretion. On the other hand, the effect of chitosan on the formation of calcium oxalate crystals (CaOx) has not been described. In this work, we evaluated the antioxidant capacity of chitosan and its interference in the formation of CaOx crystals in vitro. Here, the chitosan obtained commercially had its identity confirmed by nuclear magnetic resonance and infrared spectroscopy. In several tests, this chitosan showed low or no antioxidant activity. However, it also showed excellent copper-chelating activity. In vitro, chitosan acted as an inducer mainly of monohydrate CaOx crystal formation, which is more prevalent in patients with urolithiasis. We also observed that chitosan modifies the morphology and size of these crystals, as well as changes the surface charge of the crystals, making them even more positive, which can facilitate the interaction of these crystals with renal cells. Chitosan greatly influences the formation of crystals in vitro, and in vivo analyses should be conducted to assess the risk of using chitosan.

Calcium mineralization in biological and geological systems is often regulated by (macro)molecules enriched with anionic functional moieties. Relatively few studies have examined the effects of phosphate-based modifiers that are integral in calcification underlying human bone formation and pathological diseases. Here we mimic posttranslational phosphorylated moieties of a biologically-active inhibitor protein and demonstrate that polyphosphates and phosphonates suppress calcium oxalate nucleation, tailor solvate crystal structure, and irreversibly inhibit crystal growth in ways that significantly deviate from commonly investigated carboxylate-rich modulators of biomineralization. The most potent modifiers exhibit an uncommon dual mode of action, wherein nucleation is suppressed by altering prenucleation clusters and crystal surface growth is impeded irreversibly by inducing lattice strain. Once crystal surfaces are exposed to modifiers, recrystallization is severely restricted. This exemplifies the uniqueness and efficiency of phosphates wherein their multiple modes of action are promising characteristics for designing de novo biologically-inspired molecules as mineralization regulators. Control of crystallisation is important in biogenic and pathological biomineralisation. Here, the authors report on phosphorylated molecules that mimic proteins which can suppress calcium oxalate nucleation and irreversibly inhibit crystal growth in ways that significantly deviate from commonly investigated carboxylate-rich modulators of biomineralization.

Carbon–calcium inclusions (CCaI) either as calcium oxalate crystals (CaOx) or amorphous calcium carbonate cystoliths are spread among most photosynthetic organisms. They represent dynamic structures with a significant construction cost and their appearance during evolution indicates an ancient origin. Both types of inclusions share some similar functional characteristics providing adaptive advantages such as the regulation of Ca levels, and the release of CO₂ and water molecules upon decomposition. The latter seems to be essential under drought conditions and explains the intense occurrence of these structures in plants thriving in dry climates. It seems, however, that for plants CaOx may represent a more prevalent storage system compared with CaCO₃ due to the multifunctionality of oxalate. This compound participates in a number of important soil biogeochemical processes, creates endosymbiosis with beneficial bacteria and provides tolerance against a combination of abiotic (nutrient deprivation, metal toxicity) and biotic (pathogens, herbivores) stress factors. We suggest a re-evaluation of the roles of these fascinating plant structures under a new and holistic approach that could enhance our understanding of carbon sequestration at the whole plant level and provide future perspectives.

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.