Molecular modifiers of kidney stones

Alamani, Bryan G.; Rimer, Jeffrey D.

doi:10.1097/mnh.0000000000000330

Cited by 24 publications

(26 citation statements)

References 63 publications

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“…On the other hand, numerous organic additives with different ionic entities, including natural macromolecules, synthetic polymers and proteins have been studied from a CC point of view [16][17][18][19]. The main focus of these studies has been the characterization of the role played by urinary macromolecules, because these are the main organic component of the kidney stone matrix [20].…”

Section: Introductionmentioning

confidence: 99%

Stabilization of Calcium Oxalate Precursors during the Pre- and Post-Nucleation Stages with Poly(acrylic acid)

et al. 2021

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In this work, calcium oxalate (CaOx) precursors were stabilized by poly(acrylic acid) (PAA) as an additive under in vitro crystallization assays involving the formation of pre-nucleation clusters of CaOx via a non-classical crystallization (NCC) pathway. The in vitro crystallization of CaOx was carried out in the presence of 10, 50 and 100 mg/L PAA by using automatic calcium potentiometric titration experiments at a constant pH of 6.7 at 20 °C. The results confirmed the successful stabilization of amorphous calcium oxalate II and III (ACOII and ACO III) nanoparticles formed after PNC in the presence of PAA and suggest the participation and stabilization of polymer-induced liquid-precursor (PILP) in the presence of PAA. We demonstrated that PAA stabilizes CaOx precursors with size in the range of 20–400 nm. PAA additive plays a key role in the in vitro crystallization of CaOx stabilizing multi-ion complexes in the pre-nucleation stage, thereby delaying the nucleation of ACO nanoparticles. Indeed, PAA additive favors the formation of more hydrated and soluble phase of ACO nanoparticles that are bound by electrostatic interactions to carboxylic acid groups of PAA during the post-nucleation stage. These findings may help to a better understanding of the pathological mineralization resulting in urolithiasis in mammals.

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Section: Introductionmentioning

confidence: 99%

Stabilization of Calcium Oxalate Precursors during the Pre- and Post-Nucleation Stages with Poly(acrylic acid)

et al. 2021

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“…CaOx crystallization inhibitors have already been proposed as a general therapeutic modality in the 1960s, but bridging in vitro to in vivo efficacy has proven to be very challenging. [ 17,18 ] A broad array of candidate molecules has been explored ranging from various small molecules, such as citrate derivatives or polyphosphates, to macromolecules, including peptides and synthetic polymers with carboxylic acid, sulfate, hydroxyl, and/or phosphate groups. [ 17–25 ] In recent years, the majority of studies focused on the effects of endogenous urinary CaOx inhibitors, such as osteopontin, and synthetic peptide mimetics rich in aspartic and glutamic acid residues.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

et al. 2020

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Calcium oxalate (CaOx) crystal‐induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Although CaOx crystallization inhibitors have been suggested as a therapeutic modality already decades ago, limited progress has been made in the discovery of potent molecules with efficacy in animal disease models. Herein, an image‐based machine learning approach to systematically screen chemically modified myo‐inositol hexakisphosphate (IP6) analogues is utilized, which enables the identification of a highly active divalent inositol phosphate molecule. To date, this is the first molecule shown to completely inhibit the crystallization process in the nanomolar range, reduce crystal–cell interactions, thereby preventing CaOx‐induced transcriptomic changes, and decrease renal CaOx deposition and kidney injury in a mouse model of hyperoxaluria. In conclusion, IP6 analogues based on such a scaffold may represent a new treatment option for CaOx nephropathies.

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“…Subsequent research supported the notion that protein-beared oligosaccharides could be involved in the overall inhibitory effect of glycoproteins on crystal growth, e.g., sialic acid side chains on Tamm-Horsfall protein ( 47 , 48 ). The most efficient modifiers of calcium stones have a large number of carboxylic, hydroxyl, sulfate or phosphate functions on their structure ( 49 ). The PTX3 protein has a single N-glycosylation site in the C-terminal domain that is occupied by fucosylated and sialylated complex type sugars ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, we identified PTX3 as a previously unknown endogenous protein inhibitor of intrarenal CaOx crystal growth and adhesion ( 49 ). The field agrees that nephrocalcinosis, kidney stone disease and urolithiasis do not have a monogenic cause ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

The Long Pentraxin PTX3 Is an Endogenous Inhibitor of Hyperoxaluria-Related Nephrocalcinosis and Chronic Kidney Disease

et al. 2018

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The long pentraxin 3 (PTX3) exerts a variety of regulatory functions in acute and chronic tissue inflammation. In particular, PTX3 acts as an opsonin for a variety of pathogens and endogenous particles. We hypothesized that PTX3 would exhibit opsonin-like functions toward calcium oxalate crystals, too, and inhibit crystal growth. This process is fundamental in kidney stone disease as well as in hyperoxaluria-related nephrocalcinosis, the paradigmatic cause of chronic kidney disease (CKD) in children with primary hyperoxaluria type I due to genetic defects in oxalate metabolism. Direct effects of PTX3 on calcium oxalate crystals were investigated in chemico by adding recombinant PTX3 to supersaturated calcium and oxalate solutions. PTX3, but not isomolar concentrations of albumin, dose-dependently inhibited crystal growth. In vivo, the PTX3 protein was undetectable in tubular epithelial cells and urine of wild-type mice under physiological conditions. However, its levels increased within 3 weeks of feeding an oxalate-rich diet, an exposure inducing hyperoxaluria-related nephrocalcinosis and CKD in selected mouse strains (male and female C57BL/6N and male Balb/c mice) but not in others (male and female 129SV and CD-1, male and female Balb/c mice). Genetic ablation of ptx3 in nephrocalcinosis un-susceptible B6;129 mice was sufficient to raise the oxalate nephropathy phenotype observed in susceptible strains. We conclude that PTX3 is an endogenous inhibitor of calcium oxalate crystal growth. This mechanism limits hyperoxaluria-related nephrocalcinosis, e.g., in primary or secondary hyperoxaluria, and potentially also in the more prevalent kidney stone disease.

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Molecular modifiers of kidney stones

Cited by 24 publications

References 63 publications

Stabilization of Calcium Oxalate Precursors during the Pre- and Post-Nucleation Stages with Poly(acrylic acid)

Stabilization of Calcium Oxalate Precursors during the Pre- and Post-Nucleation Stages with Poly(acrylic acid)

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

The Long Pentraxin PTX3 Is an Endogenous Inhibitor of Hyperoxaluria-Related Nephrocalcinosis and Chronic Kidney Disease

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