Dataset Information

ABCC6 Deficiency Promotes Development of Randall Plaque.

ABSTRACT: BACKGROUND:Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the ABCC6 gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models. METHODS:We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from Abcc6-/- mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications. RESULTS:Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). Abcc6-/- mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, Abcc6-/- mice had low urinary excretion of pyrophosphate. CONCLUSIONS:The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and Abcc6-/- mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.

SUBMITTER: Letavernier E

PROVIDER: S-EPMC6115671 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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ABCC6 Deficiency Promotes Development of Randall Plaque.

Letavernier Emmanuel E Kauffenstein Gilles G Huguet Léa L Navasiolava Nastassia N Bouderlique Elise E Tang Ellie E Delaitre Léa L Bazin Dominique D de Frutos Marta M Gay Clément C Perez Joëlle J Verpont Marie-Christine MC Haymann Jean-Philippe JP Pomozi Viola V Zoll Janna J Le Saux Olivier O Daudon Michel M Leftheriotis Georges G Martin Ludovic L

Journal of the American Society of Nephrology : JASN 20180710 9

<h4>Background</h4>Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the <i>ABCC6</i> gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models.<h4>Methods</h4>We conducted a retrospective st ...[more]

PMID: 29991491

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Project description:The ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) and ATP-binding cassette subfamily C member 6 (ABCC6) proteins play a prominent role in inhibiting ectopic calcification and arterial stenosis. Patients with ENPP1 Deficiency or infant onset ABCC6 Deficiency often present with pathological calcification, narrowed blood vessels, multiorgan dysfunction and high infant mortality. The heterogenous presentation and progression is well documented. Our objective was to characterize how these morbidities lead to burden of illness and poor quality of life across ages from the patient/caregiver perspective. Patients/caregivers were interviewed via phone using Institutional Review Board–approved questionnaires. Patient-reported outcomes were collected via validated instruments. Thirty-one caregivers and 7 patients participated: infant onset ABCC6 Deficiency, n = 6 (infants/children); ENPP1 Deficiency, n = 32 (13 infants, 12 children, 7 adults). ENPP1 and ABCC6-deficient children aged <8 years and aged 8–18 years reported poor school functioning (0.69 vs 0.72 effect size, respectively) and poor physical health (0.88 vs 1, respectively). In the total ENPP1 cohort, 72% (23/32) reported bone/joint pain and/or mobility/fatigue issues. Three of seven ENPP1-deficient adults reported moderate to severe pain (>4), as measured by the Brief Pain Inventory (BPI), that interfered with daily activities despite pain medication. Top reported burdens for caregivers of infants with ABCC6/ENPP1 Deficiencies included heart-related issues and hospitalizations. Treatment/medications, and hearing loss were the highest burdens reported by caregivers/families of the pediatric ENPP1 Deficiency cohort, whereas adults reported bone/joint pain and mobility impairment as the greatest burdens. Individuals with ENPP1 Deficiency or infant onset ABCC6 Deficiency experience lifelong morbidity causing substantial physical and emotional burden to patients/caregivers.

Project description:AimsAtherosclerotic plaque development has been associated with wall shear stress (WSS). However, the multidirectionality of blood flow, and thus of WSS, is rarely taken into account. The purpose of this study was to comprehensively compare five metrics that describe (multidirectional) WSS behaviour and assess how WSS multidirectionality affects coronary plaque initiation and progression.Methods and resultsAdult familial hypercholesterolaemic pigs (n = 10) that were fed a high-fat diet, underwent imaging of the three main coronary arteries at three-time points [3 (T1), 9 (T2), and 10-12 (T3) months]. Three-dimensional geometry of the arterial lumen, in combination with local flow velocity measurements, was used to calculate WSS at T1 and T2. For analysis, arteries were divided into 3 mm/45° sectors (n = 3648). Changes in wall thickness and final plaque composition were assessed with near-infrared spectroscopy-intravascular ultrasound, optical coherence tomography imaging, and histology. Both in pigs with advanced and mild disease, the highest plaque progression rate was exclusively found at low time-averaged WSS (TAWSS) or high multidirectional WSS regions at both T1 and T2. However, the eventually largest plaque growth was located in regions with initial low TAWSS or high multidirectional WSS that, over time, became exposed to high TAWSS or low multidirectional WSS at T2. Besides plaque size, also the presence of vulnerable plaque components at the last time point was related to low and multidirectional WSS. Almost all WSS metrics had good predictive values for the development of plaque (47-50%) and advanced fibrous cap atheroma (FCA) development (59-61%).ConclusionThis study demonstrates that low and multidirectional WSS promote both initiation and progression of coronary atherosclerotic plaques. The high-predictive values of the multidirectional WSS metrics for FCA development indicate their potential as an additional clinical marker for the vulnerable disease.

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ABCC6 Deficiency Promotes Development of Randall Plaque.

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ABCC6 Deficiency Promotes Development of Randall Plaque.

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