Abstract: FR-PO272

Oxygen Consumption Is the Major Determinant of Klotho Release by the Kidney

Session Information

Category: Mineral Disease

  • 1202 Mineral Disease: Vitamin D, PTH, FGF-23

Authors

  • Picciotto, Daniela, Genoa University, Genoa, Italy
  • Garibotto, Giacomo, Genoa University, Genoa, Italy
  • Milanesi, Samantha, University of Genoa, Genoa, Italy
  • Murugavel, Abitha, University of Genoa, Genoa, Italy
  • Viazzi, Francesca, University of Genoa, Genoa, Italy
  • Verzola, Daniela, University of Genoa Di.M.I. Nephrology, Genoa, Italy
Background

Plasma levels of soluble αKlotho (sKlotho), an anti-aging protein which serves as the co-factor for FGF23, progressively decline along with CKD progression. However, our knowledge of the sites and mechanisms which regulate circulating sKlotho is still incomplete.

Methods

To explore the role of the kidney and of the extra-renal sites on the metabolic handling of sKlotho, we measured sKlotho levels in venous effluents from different organs, including the kidney, the splanchnic organs and lung, as well as in arterial blood, in a cohort of patients (n=20,10M/10F, age 56-82 yr, BMI 25±1 Kg/m2,eGFR 63±4 ml/min-range 23-98 ml/min), undergoing a right-sided cardiac catheterization.

Results

Mean arterial sKlotho was 202 ± 26 pg/ml. Renal vein αKlotho concentrations were remarkably higher (by ~8 %, p < 0.05) than the corresponding arterial values, indicating that plasma αKlotho increases substantially after a single pass across the kidney. The fractional enrichment (FE) of sKlotho across the kidney was similar (8±6 vs. 9±4%, respectively) in patients with normal renal function (n=11) and in patients with GFR< 60 ml/min (n=9, eGFR 39±3 ml/min). sKlotho level in the liver vein was lower (by 23±6 %, p<0.05) than the arterial one in patients with GFR< 60 ml/min. Arterial sKlotho levels were almost identical to pulmonary artery levels.

In all subjects, at univariate analysis, fractional enrichment (FE) of sKlotho across the kidney was directly related to the fractional extraction of oxygen (r=0.412, p< 0.05), and inversely, to plasma sodium (r=0.434, p< 0.05) and uric acid (r=0.357, p < 0.06) but not to eGFR, hemoglobin and phosphate levels. At multivariate analysis, the fractional extraction of oxygen across the kidney was the only determinant of sKlotho FE.

Conclusion

Our data show that the human kidney is the only site for sKlotho production in the body, while splanchnic organs may participate to sKlotho removal. Oxygen uptake by the kidney is the major determinant of sKlotho production by the human kidney, suggesting a role for hypoxemia on reducing the availability of sKlotho to the systemic circulation. 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.

Funding

  • Government Support - Non-U.S.