Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance.

BACKGROUND: The proximal tubules eliminate protein-bound toxins and drugs through secretion. Measurements or estimates of GFR do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. METHODS: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography/high-resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. RESULTS: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found seven highly (>50%) protein-bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile compared with GFR. We also found four highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. CONCLUSIONS: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.

Left Ventricular Volume-Time Relation in Patients With Heart Failure With Preserved Ejection Fraction.

Elevated left ventricular (LV) filling pressures are commonly reported in patients with heart failure with preserved ejection fraction (HFpEF) and are associated with impaired relaxation in diastole. Relaxation has been assessed by Doppler, but the methods for doing so are indirect and heavily influenced by loading conditions. The aim of this study is to assess LV volume-time relation in patients with HFpEF, when correcting for left atrial driving pressure and chamber size, using cardiac magnetic resonance imaging (cMRI). Cine short-axis views by cMRI (1.5T-magnet) at 26 Hz were used for measurement of LV volume. We compared the following diastolic parameters: peak filling rate/end-diastolic volume (PFR/EDV); PFR/EDV/pulmonary capillary wedge pressure (PFR/EDV/PCWP); time to PFR (TPFR); and %TPFR for cardiac cycle calculated by cMRI between patients with HFpEF (n = 10, 73 ± 7 years) and age-matched controls (n = 12, 70 ± 3 years). PCWP was significantly greater in the HFpEF group than in controls (HFpEF vs controls: 15.6 ± 5.2 vs 11.2 ± 1.3 mmHg, p = 0.0092). PFR/EDV was significantly slower in the HFpEF group than in controls (2.68 ± 0.85 vs 3.59 ± 0.87/s, p = 0.03), and was nearly 50% slower when corrected for left atrial driving pressure: PFR/EDV/PCWP (0.18 ± 0.07 vs 0.33 ± 0.10/s/mmHg, p = 0.002). In addition, TPFR (246 ± 17.2 vs 188 ± 15.7 ms, p = 0.04) and %TPFR of cardiac cycle (36.4 ± 10.4 vs 25.6 ± 5.9%, p = 0.012) were significantly longer in the HFpEF group than in controls. Patients with HFpEF have an abnormal volume-time relation, including lower PFR/EDV (PFR/EDV/PCWP) and prolonged TPFR, due to the impairment of active relaxation during early diastole.