Parathyroid hormone and plasma phosphate are predictors of soluble α-klotho levels in adults of European descent.

CONTEXT α-klotho is an integral membrane protein, that serves as a co-receptor for fibroblast growth factor 23 (FGF23) in conjunction with cognate fibroblast growth factor receptors. Proteolytic cleavage sheds the ectodomain of α-klotho (soluble α-klotho) as an endocrine substance into blood, urine and cerebrospinal fluid. OBJECTIVE To study the relationship of soluble α-klotho to mineral metabolism in the general population with mainly preserved kidney function. DESIGN Cross-sectional analysis of the associations between soluble α-klotho with laboratory markers of markers of mineral metabolism in a population-based cohort. SETTING Three centers in Switzerland including 1128 participants. MEASURES Soluble full-length α-klotho levels by a specific immunoassay and markers of mineral metabolism. RESULTS The median serum level of soluble α-klotho was 15.0 pmol/L. Multivariable analyses using α-klotho as outcome variable revealed a sex-by-parathyroid hormone (PTH) interaction: In men, PTH was positively associated with α-klotho levels whereas this association was negative in women. Plasma phosphate associated with soluble α-klotho levels in an age-dependent manner, changing from a positive association in young adults gradually to a negative association in the elderly. The decline of 1,25 (OH)2 vitamin D3 levels in parallel to the gradual impairment of kidney function was greatly attenuated in the setting of high circulating soluble α-klotho levels. CONCLUSIONS Soluble α-klotho level is associated with plasma phosphate in an age-dependent manner and with PTH in a sex-dependent manner. Furthermore, our data reveal soluble α-klotho as a modulator of 1,25 (OH)2 vitamin D3 levels in individuals with preserved renal function.

[1]  H. Hulter,et al.  A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects. , 2018, Journal of the American Society of Nephrology : JASN.

[2]  E. Brown,et al.  Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia , 2018, Proceedings of the National Academy of Sciences.

[3]  M. Mohammadi,et al.  αKlotho is a Non-Enzymatic Molecular Scaffold for FGF23 Hormone Signaling , 2018, Nature.

[4]  I. Reid,et al.  Serum phosphate is related to adiposity in healthy adults , 2017, European journal of clinical investigation.

[5]  B. Kestenbaum,et al.  Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function , 2017, The Journal of clinical endocrinology and metabolism.

[6]  Jennifer J. Kohler,et al.  Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling , 2017, Proceedings of the National Academy of Sciences.

[7]  F. Paccaud,et al.  Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function. , 2016, Kidney international.

[8]  Tsutomu Inoue,et al.  Xeno‐Klotho Inhibits Parathyroid Hormone Signaling , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[9]  Han Jun Cho,et al.  Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. , 2015, Journal of the American Society of Nephrology : JASN.

[10]  F. Paccaud,et al.  New anthropometry-based age- and sex-specific reference values for urinary 24-hour creatinine excretion based on the adult Swiss population , 2015, BMC Medicine.

[11]  M. Mohammadi,et al.  The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. , 2015, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[12]  T. Yoo,et al.  Decreased Circulating Klotho Levels in Patients Undergoing Dialysis and Relationship to Oxidative Stress and Inflammation , 2015, Peritoneal Dialysis International.

[13]  Shih-Ming Huang,et al.  Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway. , 2014, The Biochemical journal.

[14]  B. Lanske,et al.  The kidney is the principal organ mediating klotho effects. , 2014, Journal of the American Society of Nephrology : JASN.

[15]  D. Fliser,et al.  Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. , 2014, Clinical journal of the American Society of Nephrology : CJASN.

[16]  C. Iselin,et al.  Acute and long term mineral metabolism adaptation in living kidney donors: a prospective study. , 2014, Bone.

[17]  B. Lanske,et al.  Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion , 2013, PLoS genetics.

[18]  T. Yoo,et al.  Circulating α-klotho levels in CKD and relationship to progression. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[19]  H. Sugiyama,et al.  A Decreased Level of Serum Soluble Klotho Is an Independent Biomarker Associated with Arterial Stiffness in Patients with Chronic Kidney Disease , 2013, PloS one.

[20]  R. Wüthrich,et al.  Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[21]  M. Kuro-o,et al.  Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease , 2012, BMC Nephrology.

[22]  S. Devaraj,et al.  Validation of an immunoassay for soluble Klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease. , 2012, American journal of clinical pathology.

[23]  R. Considine,et al.  Serum leptin, parathyroid hormone, 1,25-dihydroxyvitamin D, fibroblast growth factor 23, bone alkaline phosphatase, and sclerostin relationships in obesity. , 2012, The Journal of clinical endocrinology and metabolism.

[24]  Huiliang Xie,et al.  Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. , 2011, Kidney international.

[25]  Jane H. Zhang,et al.  Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. , 2010, The Journal of clinical endocrinology and metabolism.

[26]  K. Rosenblatt,et al.  Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  M. Econs,et al.  Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. , 2010, Biochemical and biophysical research communications.

[28]  P. Saftig,et al.  Klotho is a substrate for α‐, β‐ and γ‐secretase , 2009 .

[29]  Yuhong Wang,et al.  Klotho Gene Delivery Prevents the Progression of Spontaneous Hypertension and Renal Damage , 2009, Hypertension.

[30]  C. Schmid,et al.  A new equation to estimate glomerular filtration rate. , 2009, Annals of internal medicine.

[31]  K. Rosenblatt,et al.  Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1 , 2008, Proceedings of the National Academy of Sciences.

[32]  S. Leeman,et al.  Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17 , 2007, Proceedings of the National Academy of Sciences.

[33]  J. Zerwekh,et al.  Aromatase Deficiency Causes Altered Expression of Molecules Critical for Calcium Reabsorption in the Kidneys of Female Mice , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[34]  K. White,et al.  A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. , 2007, Journal of musculoskeletal & neuronal interactions.

[35]  C. Kuo,et al.  Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging , 2007, Science.

[36]  N. Tomita,et al.  Amelioration of progressive renal injury by genetic manipulation of Klotho gene , 2007, Proceedings of the National Academy of Sciences.

[37]  K. Okawa,et al.  Klotho converts canonical FGF receptor into a specific receptor for FGF23 , 2006, Nature.

[38]  I. Reid,et al.  Fat mass is an important predictor of parathyroid hormone levels in postmenopausal women. , 2006, Bone.

[39]  J. Hoenderop,et al.  The ß-Glucuronidase Klotho Hydrolyzes and Activates the TRPV5 Channel , 2005, Science.

[40]  Animesh Nandi,et al.  Suppression of Aging in Mice by the Hormone Klotho , 2005, Science.

[41]  K. Nozaki,et al.  Secreted Klotho protein in sera and CSF: implication for post‐translational cleavage in release of Klotho protein from cell membrane , 2004, FEBS letters.

[42]  Y. Takeuchi,et al.  Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. , 2004, The Journal of clinical investigation.

[43]  A. Tamori,et al.  Severely reduced production of klotho in human chronic renal failure kidney. , 2001, Biochemical and biophysical research communications.

[44]  Tadashi Kaname,et al.  Mutation of the mouse klotho gene leads to a syndrome resembling ageing , 1997, Nature.

[45]  K. Katsouyanni,et al.  ORAL CONTRACEPTIVES, TOBACCO SMOKING, AND BREAST CANCER RISK , 1989, The Lancet.

[46]  A. Kenny,et al.  Tests of phosphate reabsorption. , 1973, Lancet.

[47]  D. Morgan,et al.  The assessment of phosphate reabsorption. , 1969, Clinica chimica acta; international journal of clinical chemistry.

[48]  Patrick Breheny,et al.  Visualization of Regression Models Using visreg , 2017, R J..

[49]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[50]  S. Muto,et al.  The impact of nephrectomy and renal transplantation on serum levels of soluble Klotho protein. , 2013, Transplantation proceedings.

[51]  D. Fliser,et al.  Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. , 2013, Kidney international.

[52]  M. Kuro-o,et al.  Klotho deficiency causes vascular calcification in chronic kidney disease. , 2011, Journal of the American Society of Nephrology : JASN.