Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

Letavernier, Emmanuel; Bouderlique, Elise; Martin, Ludovic; Daudon, Michel

doi:10.3390/ijms20246353

Cited by 23 publications

(20 citation statements)

References 74 publications

(102 reference statements)

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“…The influence of the diet on plasma PPi levels is very limited (Dedinszki et al, 2017;Pomozi et al, 2017). Finally, circulating PP i is hydrolyzed by ALP and eliminated in urine (Letavernier et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease

Laurain

Rubera

Duranton

et al. 2020

Front. Cell Dev. Biol.

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IntroductionPatients on dialysis and kidney transplant recipients (KTR) present the syndrome of mineral and bone disorders (MBD), which share common traits with monogenic calcifying diseases related to disturbances of the purinergic system. Low plasma levels of inorganic pyrophosphate (PPi) and ectopic vascular calcifications belong to these two conditions. This suggests that the purinergic system may be altered in chronic kidney disease with MBD. Therefore, we perform a transversal pilot study in order to compare the determinants of PPi homeostasis and the plasma levels of PPi in patients on dialysis, in KTR and in healthy people.Patients and MethodsWe included 10 controls, 10 patients on maintenance dialysis, 10 early KTR 3 ± 1 months after transplantation and nine late KTR 24 ± 3 months after transplantation. We measured aortic calcifications, plasma and urine levels of PPi, the renal fractional excretion of PPi (FePPi), nucleoside triphosphate hydrolase (NPP) and ALP activities in plasma. Correlations and comparisons were assessed with non-parametric tests.ResultsLow PPi was found in patients on dialysis [1.11 (0.88–1.35), p = 0.004], in early KTR [0.91 (0.66–0.98), p = 0.0003] and in late KTR [1.16 (1.07–1.45), p = 0.02] compared to controls [1.66 (1.31–1.72) μmol/L]. Arterial calcifications were higher in patients on dialysis than in controls [9 (1–75) vs. 399 (25–526) calcium score/cm2, p < 0.05]. ALP activity was augmented in patients on dialysis [113 (74–160), p = 0.01] and in early KTR [120 (84–142), p = 0.002] compared to controls [64 (56–70) UI/L]. The activity of NPP and FePPi were not different between groups. ALP activity was negatively correlated with PPi (r = −0.49, p = 0.001).DiscussionPatients on dialysis and KTR have low plasma levels of PPi, which are partly related to high ALP activity, but neither to low NPP activity, nor to increased renal excretion of PPi. Further work is necessary to explore comprehensively the purinergic system in chronic kidney disease.

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Section: Introductionmentioning

confidence: 99%

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease

Laurain

Rubera

Duranton

et al. 2020

Front. Cell Dev. Biol.

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“…To date, there are no mouse models for Randall's plaque, except for a mutant mouse lacking ABCC6 (ATP-binding cassette sub-family C member 6) 42 . However, mutations in ABCC6 are rarely responsible for kidney stone disease in humans 43 . Generally, single-gene mutations only account for 10-20% of kidney stone disease 44,45 , and the common pathogenesis of kidney stone disease is believed to involve the environmental and lifestyle factors.…”

Section: Discussionmentioning

confidence: 99%

Essential roles of oncostatin M receptor β signaling in renal crystal formation in mice

Yamashita

Komori

Kohjimoto

et al. 2020

Sci Rep

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Oncostatin M (OSM), a member of the IL-6 family of cytokines, has important roles in renal diseases. The relationship between OSM and kidney stone disease, however, remains unclear. To investigate the roles of OSM in the development of kidney stone disease, we generated a mouse model of renal crystal formation using OSM receptor β (OSMRβ)-deficient mice (OSMRβ−/− mice). There were fewer renal crystal deposits in OSMRβ−/− mice than in wild-type (WT) mice. Crystal-binding molecules (osteopontin, annexin A1, and annexin A2), inflammatory cytokines (TNF-α and IL-1β), and fibrosis markers (TGF-β, collagen 1a2, and α-smooth muscle actin) were also decreased in the kidneys of OSMRβ−/− mice compared with those in WT mice. Immunofluorescence staining showed that OSMRβ was expressed in renal tubular epithelial cells (RTECs) and renal fibroblasts in the model of renal crystal formation. In the cultured RTECs and renal fibroblasts, OSM directly induced the expression of crystal-binding molecules and fibrosis markers. Expressions of inflammatory cytokines were increased by stimulation with OSM in cultured renal fibroblasts. OSM may promote the formation of renal crystal deposits by directly acting on RTECs and renal fibroblasts to produce crystal-binding molecules and inflammatory cytokines.

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“…The first in depth analysis of renal manifestations in a cohort of 113 French PXE patients showed a history of kidney stones in 40% of patients, which is much higher than the general population. Computed tomography scans revealed evidence of significant papillary calcifications (Randall’s plaques) [ 45 , 46 ].…”

Section: The Pathologies Associated With Abcc6 and Enpp1 Deficienciesmentioning

confidence: 99%

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Shimada

Pomozi

Zoll

et al. 2021

IJMS

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Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

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Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

Cited by 23 publications

References 74 publications

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease

Essential roles of oncostatin M receptor β signaling in renal crystal formation in mice

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

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