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THE KIDNEY IS THE MAJOR SITE FOR THE REGULATION OF SOLUBLE KLOTHO IN HUMANS Free

INTRODUCTION AND AIMS: αKlotho, a transmembrane protein which serves as the co-factor for Fibroblast Growth Factor 23, is a pleiotropic endocrine/paracrine factor that contributes to lifespan prolongation, cardioprotection and tumor inhibition. The kidney is thought to be the major site for the removal and production of soluble αKlotho, which could be released through proteolytic cleavage of its transmembrane form. However our knowledge of the sites and mechanisms which regulate plasma αKlotho in humans is still incomplete. In this study, we measured plasma soluble αKlotho across the kidney and other major organ systems.

METHODS: We measured plasma αKlotho across the kidney, splanchnic organs and lung in 22 patients undergoing elective diagnostic cardiac catheterizations (11M/11F, age 56-82 yr, BMI 25±1 Kg/m²,eGFR 62±5 ml/min-range 23-98 ml/min, Phosphate 3.3±0.1 mg/dL, Calcium 9±0.2 mg/dL, Albumin 3.9±0.05 g/dL).

RESULTS: Mean arterial αKlotho was 202 ± 26 pg/ml. Renal vein αKlotho concentrations were remarkably higher (by ~9 %, p < 0.05) than the corresponding arterial values, indicating that plasma αKlotho increases substantially after a single pass across the kidney. Surprisingly, the fractional enrichment (FE) of αKlotho across the kidney was similar (8±6 vs. 10±9%, respectively) in patients with normal renal function (n=13) and in patients with GFR< 60 ml/min (n=9 eGFR 39±3 ml/min). αKlotho level in the liver vein was lower (by 23±6 %, p<0.05) than the arterial αKlotho level in patients with GFR< 60 ml/min, but not in subjects with normal renal function. Arterial αKlotho levels were almost identical to systemic venous (pulmonary artery) whole body levels, documenting maintained zero balance of αKlotho across the cardiopulmonary circulation. In all subjects, the αKlotho enrichment in the renal vein decreased progressively with the increase in arterial levels, suggesting that Klotho renal production is sensitive to αKlotho levels (r=-0.548; p=0.007).

CONCLUSIONS: Our data show that the human kidney is the only site for αKlotho production in the body, while splanchnic organs (liver/intestine) may participate to αKlotho removal. Besides providing a better understanding of physiology of αKlotho metabolism, the data reported in this study could be useful to understand the alterations in αKlotho that are observed in CKD and many systemic and organ diseases.