Acidic polyanion poly(acrylic acid) prevents calcium oxalate crystal deposition

Kleinman, Joel C.; Alatalo, Laura J.; Beshensky, Ann M.; Wesson, Jeffrey A.

doi:10.1038/ki.2008.253

Cited by 16 publications

(18 citation statements)

References 30 publications

(35 reference statements)

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“…Second, except for poly(acrylic acid), [ 42 ] no data on in vivo efficacy of tested CaOx inhibitors is available, despite great efforts to optimize the structure of, for example, peptidic inhibitors or citrate derivatives. [ 21,22 ] Herein, we show reduced renal deposition of CaOx by subcutaneous administration of OEG 4 ‐(IP5) 2 in an acute model of nephrocalcinosis.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

et al. 2020

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“…To date, to the best of our knowledge, only two molecules showed evidence of inhibition of CaOx crystallization in vitro , as well as in vivo activity in reducing renal CaOx deposition, namely, poly(acrylic acid) and a divalent inositol phosphate molecule , (Figure ). In 2004, Jung and co-workers demonstrated superior in vitro efficacy of poly(acrylic acid) (5.1 kDa molecular weight), a negatively charged non-biodegradable polymer, compared to poly(aspartic acid) (8.3 kDa) and poly(glutamic acid) (6.63 kDa), in inhibiting CaOx crystal growth step velocity in specific directions .…”

Section: Targeting the Underlying Molecular Defect In The Livermentioning

confidence: 99%

Investigational Therapies for Primary Hyperoxaluria

Kletzmayr

Ivarsson²,

Leroux

2020

Bioconjugate Chem.

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Recent years have brought exciting new insights in the field of primary hyperoxaluria (PH), both on a basic research level as well as through the progress of novel therapeutics in clinical development. To date, very few supportive measures are available for patients suffering from PH, which, together with the severity of the disorder, make disease management challenging. Basic and clinical research and development efforts range from correcting the underlying gene mutations, preventing calcium oxalate crystal-induced kidney damage, to the administration of probiotics favoring the intestinal secretion of excess oxalate. In this review, current advances in the development of those strategies are presented and discussed.

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“…Normal urine contains macromolecules that inhibit crystal adherence to the renal epithelial cells in culture [70,71]. Increased expression of OPN on renal epithelial surfaces promote crystal adherence [56,72] while free OPN suppresses it [73,74]. Surface bound NRP similarly mediates crystal attachment to the inner medullary collecting duct cells of the renal tubular epithelium [75] through highly acidic region.…”

Section: Animal Modelsmentioning

confidence: 99%

Histological aspects of the “fixed-particle” model of stone formation: animal studies

Khan

2016

Urolithiasis

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Crystallization by itself is not harmful as long as the crystals are not retained in the kidneys and are allowed to pass freely down the renal tubules to be excreted in the urine. A number of theories have been proposed, and studies performed, to determine the mechanisms involved in crystal retention within the kidneys. It has been suggested that urinary transit through the nephron is too fast for crystals to grow large enough to be retained. Thus free particle mechanism alone cannot lead to stone formation, there must be a mechanism for crystal fixation within the kidneys. Animal model studies suggest that crystal retention is possible through both the free and fixed particle mechanisms. Crystal cell interaction leads to pathological changes which promote crystal attachment to either epithelial cells or their basement membrane. Alternatively, crystals aggregate and produce large enough particles to block the tubules particularly at sites where urinary flow is affected because of changes in the luminal diameter of the tubule. Crystal deposits plugging the openings of the ducts of Bellini may be the result of such a phenomenon. Intra-tubular crystals translocating to renal interstitium may produce osteogenic changes in the epithelial or endothelial cells resulting in the formation of the Randall’s plaques. Thus, fixation appears to be either through the formation of Randall’s plugs, crystal plugs clogging the openings of the ducts of Bellini or sub-epithelial crystal deposits, the Randall’s plaques.

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Acidic polyanion poly(acrylic acid) prevents calcium oxalate crystal deposition

Cited by 16 publications

References 30 publications

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

Investigational Therapies for Primary Hyperoxaluria

Histological aspects of the “fixed-particle” model of stone formation: animal studies

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