The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody

Barker, Sarah L.; Pastor, Johanne; Carranza, Danielle; Quiñones, Henry; Griffith, Carolyn; Goetz, Regina; Mohammadi, Moosa; Ye, Jianfeng; Zhang, Jianning; Hu, Ming; Kuro‐o, Makoto; Moe, Orson W.; Sidhu, Sachdev S.

doi:10.1093/ndt/gfu291

Cited by 135 publications

(137 citation statements)

References 68 publications

(69 reference statements)

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“…Clinical and experimental animal studies showed low renal tubular aKlotho expression in both acute kidney injury and CKD 10,40,42,43,[56][57][58][59][60][61][62] and low circulating aKlotho levels in kidney diseases of a variety of etiologies in animals 42,43,56,62 and humans. 32,44,61,63 These data suggest that the kidney contributes to circulating aKlotho. Now we provide direct experimental evidence that the kidney is the source of circulating aKlotho by demonstrating step-up of aKlotho concentration from infrarenal to suprarenal vena cava in both mice and humans.…”

Section: Discussionmentioning

confidence: 79%

“…37,40 Animal studies provide more consistent data supporting CKD as a state of global aKlotho deficiency, 10,41-43 which was recently confirmed in humans. 44 This finding supports but does not prove the model that the kidney is the source of endocrine aKlotho. The strongest evidence to date comes from renal tubule-specific partial deletion of aKlotho, which caused reduced serum aKlotho levels and systemic features closely resembling the phenotype in global aKlotho deletion mice; indicating that the kidney may be the principal source of endocrine aKlotho.…”

mentioning

confidence: 81%

“…Signal was visualized by enhanced chemiluminescence (GE Healthcare), and quantified densitometrically by the Scion/NIH ImageJ software (Scion, Frederick, MD). For assay of serum aKlotho, 100 ml of serum from rodents was subjected to immunoprecipitated enrichment by sb106 aKlotho 44 and was immunoblotted by rat anti-human aKlotho (KM2076).…”

Section: Immunoblotmentioning

confidence: 99%

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Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

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ABSTRACTaKlotho is a multifunctional protein highly expressed in the kidney. Soluble aKlotho is released through cleavage of the extracellular domain from membrane aKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating aKlotho production and handling is incompletely understood, however. Here, we found higher aKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum aKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of aKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous aKlotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant aKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that aKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in aKlotho homeostasis, producing and releasing aKlotho into the circulation and clearing aKlotho from the blood into the urinary lumen.

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Section: Discussionmentioning

confidence: 79%

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confidence: 81%

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Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

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“…Currently, CKD is considered as a pan state of Klotho deficiency and premature aging disease [14,27,49] . Low Klotho mRNA expression in the kidney was found in CKD patients and positively correlated with their estimated glomerular filtration rate (eGFR) [50][51][52] .…”

Section: Klotho Deficiency In Ckdmentioning

confidence: 99%

Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

2016

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FGF23 may also contribute to CVD. Prevention of Klotho decline, reactivation of endogenous Klotho production, or supplementation of exogenous Klotho attenuate renal fibrosis, retard CKD progression, improve mineral metabolism, ameliorate cardiomyopathy, and alleviate vascular calcification in CKD. However, the poor CVD outcome after depletion of FGF23 with FGF23 antibody stimulates the generation of a more specific inhibitor of FGF23 for CKD treatment. Key Message: Klotho/FGF23 may not only be diagnostic and/or prognostic biomarkers for CKD and CVD, but are also pathogenic contributors to CKD progression and CVD development. The Klotho/FGF23 axis should be a novel target for renal clinics.

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“…Importantly, Kim et al (76) found that low levels of serum Klotho are linked to the progression of CKD independently of FGF23, proteinuria, or PTH, suggesting that a-Klotho may serve as a useful clinical biomarker for progression of CKD. In addition, Barker et al (77), using a novel synthetic antibody, recently found that soluble Klotho was decreased early in CKD, preceding hyperphosphatemia and increases in FGF23 and PTH. This further emphasizes the role of Klotho as a biomarker of kidney injury.…”

Section: Phosphate and Ckdmentioning

confidence: 99%

Phosphate Toxicity in CKD: The Killer among Us

Ritter¹,

Slatopolsky²

2016

CJASN

117

113

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Maintenance of a normal serum phosphate level depends on absorption in the gut, reabsorption and excretion by the kidney, and the flux between the extracellular and skeletal pools. Phosphate homeostasis is a coordinated, complex system of crosstalk between the bone, intestine, kidney, and parathyroid gland. Dysfunction of this system has serious clinical consequences in healthy individuals and those with conditions, such as CKD, in which hyperphosphatemia is associated with increased risks of cardiovascular morbidity and mortality. The last halfcentury of renal research has helped define the contribution of the parathyroid hormone, calcitriol, fibroblast growth factor 23, and Klotho in the regulation of phosphate. However, despite new discoveries and insights gained during this time, what remains unchanged is the recognition that phosphate retention is the initiating factor for the development of many of the complications observed in CKD, namely secondary hyperparathyroidism and bone and cardiovascular diseases. Controlling phosphate load remains the primary goal in the treatment of CKD. This review discusses the clinical effects of dysregulated phosphate metabolism, particularly in CKD, and its association with cardiovascular disease. The importance of early control of phosphate load in the treatment of CKD is emphasized, and the latest research in the treatment of phosphate retention is discussed.

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The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody

Cited by 135 publications

References 68 publications

Renal Production, Uptake, and Handling of Circulating αKlotho

Renal Production, Uptake, and Handling of Circulating αKlotho

Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

Phosphate Toxicity in CKD: The Killer among Us

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