Perspectives in primary hyperoxaluria — historical, current and future clinical interventions

Shee, Kevin; Stoller, Marshall L.

doi:10.1038/s41585-021-00543-4

Cited by 41 publications

(46 citation statements)

References 138 publications

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“…Other LDHA-targeted small molecules are currently in the pipeline, such as CHK-336 from Chinook Therapeutics [ 105 ]. Silencing the LDHA gene using Crispr-Cas9 technology delivered in adeno-associated viral vectors has been recently proven to be safe and efficient in PH1 and PH3 mouse models, thus supporting that LDHA inhibition potentially treats all types of PH [ 106 ].…”

Section: Current Treatment Optionsmentioning

confidence: 99%

Improving Treatment Options for Primary Hyperoxaluria

Höppe¹,

Martín-Higueras

2022

Drugs

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The primary hyperoxalurias are three rare inborn errors of the glyoxylate metabolism in the liver, which lead to massively increased endogenous oxalate production, thus elevating urinary oxalate excretion and, based on that, recurrent urolithiasis and/or progressive nephrocalcinosis. Frequently, especially in type 1 primary hyperoxaluria, early end-stage renal failure occurs. Treatment possibilities are scare, namely, hyperhydration and alkaline citrate medication. In type 1 primary hyperoxaluria, vitamin B 6 , though, is helpful in patients with specific missense or mistargeting mutations. In those vitamin B 6 responsive, urinary oxalate excretion and concomitantly urinary glycolate is significantly decreased, or even normalized. In patients non-responsive to vitamin B 6 , RNA interference medication is now available. Lumasiran ® is already available on prescription and targets the messenger RNA of glycolate oxidase, thus blocking the conversion of glycolate into glyoxylate, hence decreasing oxalate, but increasing glycolate production. Nedosiran blocks liver-specific lactate dehydrogenase A and thus the final step of oxalate production. Similar to vitamin B 6 treatment, where both RNA interference urinary oxalate excretion can be (near) normalized and plasma oxalate decreases, however, urinary and plasma glycolate increases with lumasiran treatment. Future treatment possibilities are on the horizon, for example, substrate reduction therapy with small molecules or gene editing, induced pluripotent stem cell-derived autologous hepatocyte-like cell transplantation, or gene therapy with newly developed vector technologies. This review provides an overview of current and especially new and future treatment options. Key PointsPrimary hyperoxaluria is a rare metabolic disorder, with often a fatal outcome if not treated.New medications based on RNA interference are available but need adequate adjustment into the current therapeutic approaches.Future treatment options are on the horizon.

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Section: Current Treatment Optionsmentioning

confidence: 99%

Improving Treatment Options for Primary Hyperoxaluria

Höppe¹,

Martín-Higueras

2022

Drugs

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“…There are several bacteria inhabiting human gut that can degrade significant amounts of oxalate daily [ 1 ]. Use of oxalate-degrading bacteria to reduce urinary oxalate has been the focus of numerous studies, with limited success [ 2 , 3 ]. In the human gastrointestinal tract (GIT), there are approximately four hundred different bacterial species with the composition of the gut microbiome exhibiting large, inter-individual variability [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Oxalosis can leads to kidneys fail. Extra oxalate which cannot be removed from human body will accumulate in blood and different organs [ 3 ]. Prolonged exposure of breast epithelial cells to oxalate may cause tumor due to expression of proto-oncogene and increase in the proliferation rate of breast cancer cells [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Probiotic Oxalate-Degrading Bacteria: New Insight of Environmental Variables and Expression of the oxc and frc Genes on Oxalate Degradation Activity

Karamad

Khaneghah

Miller

2022

Foods

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Oxalate, a compound produced by many edible plants and as a terminal metabolite in the liver of mammals, is a toxin that has a detrimental role to human health. Humans and other mammals do possess enzymatic systems to degrade oxalate. Moreover, numerous oxalate-degrading bacteria reside in the mammalian gut and, thus, provide an important function for hosts. The current review focuses on the environmental factors that influence the efficacy of probiotic oxalate-degrading bacteria, relative to oxalate metabolism. We describe the mechanism of oxalate catabolism and its consumption by obligate and facultative anaerobic oxalate-degrading bacteria, in both in vitro and in vivo environments. We also explore the environmental variables that impact oxalate degradation. Studies on single species degrade oxalate have not shown a strong impact on oxalate metabolism, especially in high oxalate conditions such as consumption of foods high in oxalate (such as coffee and chocolate for humans or halogeton in animal feed). Considering effective variables which enhance oxalate degradation could be used in application of effective probiotic as a therapeutic tool in individuals with hyperoxaluria. This study indicates probiotics can be considered a good source of naturally occurring oxalate degrading agent in human colon.

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“…Various diseases with excessive oxalate excretion (primary hyperoxaluria, acquired gastrointestinal-related hyperoxaluria, consumption of oxalate-rich foods, excessive intake of vitamin C and ethylene glycol, etc) can cause the precipitation of CaOx crystals in renal tubules lumen, which trigger excessive cell death and inflammation resulting in injury to the tubular epithelial cell (TEC) and then in turn promote crystal adhesion to the injured TECs and aggravate crystal deposition in the kidney to form nephrocalcinosis, which also contributes to acute and chronic kidney diseases and kidney stones ( Liu et al, 2019 ; Khan et al, 2021 ; Demoulin et al, 2022 ). Oxalate-associated kidney diseases are more likely to occur in patients with pre-existing chronic kidney diseases ( Shee and Stoller, 2022 ). Moreover, kidney injury induced by CaOx crystals is often irreversible and can even progress to end-stage renal disease ( Ix, 2019 ; Waikar et al, 2019 ; Shee and Stoller, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Cpd-42 protects against calcium oxalate nephrocalcinosis-induced renal injury and inflammation by targeting RIPK3-mediated necroptosis

Hou

Liu²,

Chen³

et al. 2022

Front. Pharmacol.

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Calcium oxalate (CaOx) crystals, as the predominant component of human kidney stones, can trigger excessive cell death and inflammation of renal tubular epithelial cells, involved in the pathogenesis of nephrocalcinosis. Necroptosis mediated by receptor-interacting protein kinase 3 (RIPK3) serves a critical role in the cytotoxicity of CaOx crystals. Here, we assessed the therapeutic potential of a novel RIPK3 inhibitor, compound 42 (Cpd-42), for CaOx nephrocalcinosis by comparison with dabrafenib, a classic RIPK3 inhibitor. Our results demonstrated that Cpd-42 pretreatment attenuated CaOx crystals-induced renal tubular epithelial cell (TEC) injury by inhibiting necroptosis and inflammation in vitro and in vivo. Furthermore, in an established mouse model of CaOx nephrocalcinosis, Cpd-42 also reduced renal injury while improving the impaired kidney function and intrarenal crystal deposition. Consistent with this finding, Cpd-42 was confirmed to exhibit superior inhibition of necroptosis and protection against renal TEC injury compared to the classic RIPK3 inhibitor dabrafenib in vitro and in vivo. Mechanistically, RIPK3 knockout (KO) tubular epithelial cells pretreated with Cpd-42 did not show further enhancement of the protective effect on crystals-induced cell injury and inflammation. We confirmed that Cpd-42 exerted protective effects by specifically targeting and inhibiting RIPK3-mediated necroptosis to block the formation of the RIPK1-RIPK3 necrosome. Taken together, targeted inhibition of RIPK3-mediated necroptosis with Cpd-42 may provide a potential therapeutic approach for CaOx nephrocalcinosis.

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Perspectives in primary hyperoxaluria — historical, current and future clinical interventions

Cited by 41 publications

References 138 publications

Improving Treatment Options for Primary Hyperoxaluria

Improving Treatment Options for Primary Hyperoxaluria

Probiotic Oxalate-Degrading Bacteria: New Insight of Environmental Variables and Expression of the oxc and frc Genes on Oxalate Degradation Activity

Cpd-42 protects against calcium oxalate nephrocalcinosis-induced renal injury and inflammation by targeting RIPK3-mediated necroptosis

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