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.

Objectives The purpose of this study was to assess whether (1) very small increases in troponin T, measured by a new highly sensitive assay for cardiac troponin T (hs-cTnT), may reflect ischemia without necrosis and (2) serial changes can discriminate ischemia from other causes of cTnT release. Background A new hs-cTnT assay offers greater sensitivity than current assays. Methods Nineteen patients referred for diagnostic catheterization underwent cannulation of the coronary sinus (CS). Serial CS and peripheral plasma samples were obtained at multiple timepoints during and after incremental rapid atrial pacing. cTnT was quantified using a standard and pre-commercial highly sensitive assay. Ischemia was determined by the presence of significant coronary atherosclerosis and myocardial lactate release with pacing. Results cTnT concentrations in CS blood increased from a median of 6.8 to 15.6pg/mL 60-minutes after termination of rapid atrial pacing (p<0.0001), changes that were mirrored at 180-minutes in peripheral blood (5.1 to 11.8pg/mL p<0.0001)]. Although peripheral cTnT concentrations tended to be higher at 180-minutes following pacing for patients with atherosclerosis and lactate elution (n=7) when compared to those without either marker (n=5) (25.0 vs. 10.2pg/mL, p=0.10), relative (1.7- vs 5.2-fold) and absolute (6.8 vs 8.8pg/mL, p=0.50) changes were similar between groups. Conclusions Brief periods of ischemia, without frank infarction, cause low-level cTnT release, and small increases are common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive atherosclerosis. Additional research is needed before hs-cTnT assays are widely adopted in the management of subjects with chest pain syndromes.

During long-term follow-up, use of PES was associated with significantly better clinical outcomes than BMS in SVG lesions. (Stenting of Saphenous Vein Grafts Trial [SOS]; NCT00247208).

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