Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional ...diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations.
Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated.
Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (
<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%;
=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%;
=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL interquartile range, -536 to 153 mL versus -14 mL interquartile range, -282 to 335 mL;
=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL;
=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (
=0.02) and all other neurohormones were similar (
<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (
=0.20) or renal dysfunction (
>0.11 for all biomarkers), whereas both serum magnesium (
<0.001) and uric acid levels (
=0.008) improved.
Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.
Electromagnetic interference (EMI) shields in the form of coatings and films are useful for blocking radiations in various household and industrial settings. Being transparent and flexible would ...enhance their utility domain. In this study, we have fabricated transparent and flexible EMI shields made of metal meshes produced using the crack templating method pioneered in the laboratory. A Cu metal mesh with polyethylene terephthalate (PET) sheet as its substrate exhibited a visible transmittance of ∼85% and a sheet resistance of ~0.83 Ω per square. The shielding efficiency was tested over a wide spectral range of the K
u
band (12–18 GHz), relevant to communication electronics. The Cu mesh/PET film showed a remarkably high value for total EMI shielding (SE
T
) with the average value being ~41 dB. The film could be laminated using a commonly available method, thus protecting exposure of the mesh to the environment. The laminated film is multifunctional, and this aspect was demonstrated by fabricating a large area (3.5 × 2.2 cm
2
) Joule heater for defrosting and defogging applications.
Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such ...biomarkers, we performed a nested case-control study (
=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (
=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.
Oxalate, a uremic toxin that accumulates in dialysis patients, is associated with cardiovascular disease. As oxalate crystals can activate immune cells, we tested the hypothesis that plasma oxalate ...would be associated with cytokine concentrations and cardiovascular outcomes in dialysis patients. In a cohort of 104 US patients with kidney failure requiring dialysis (cohort 1), we measured 21 inflammatory markers. As IL-16 was the only cytokine to correlate with oxalate, we focused further investigations on IL-16. We searched for associations between concentrations of IL-16 and mortality and cardiovascular events in the 4D cohort (1255 patients, cohort 2) and assessed further associations of IL-16 with other uremic toxins in this cohort. IL-16 levels were positively correlated with pOx concentrations (ρ = 0.39 in cohort 1, r = 0.35 in cohort 2) and were elevated in dialysis patients when compared to healthy individuals. No significant association could be found between IL-16 levels and cardiovascular events or mortality in the 4D cohort. We conclude that the cytokine IL-16 correlates with plasma oxalate concentrations and is substantially increased in patients with kidney failure on dialysis. However, no association could be detected between IL-16 concentrations and cardiovascular disease in the 4D cohort.
The present study describes the uptake and distribution of fungicides, fluopyram, and tebuconazole in tomato and bell pepper plant tissues from the soil drench application of their combination ...product fluopyram17.7% + tebuconazole 17.7%. For extraction and cleanup of fluopyram, its metabolite fluopyram benzamide, and tebuconazole samples, the QuEChERS method was used in conjunction with LC-MS/MS. The limit of detection (LOD) and limit of quantification (LOQ) of the method determined were 1.5 μg kg
−1
and 0.005 mg kg
−1
, respectively, and recoveries of all analytes from sample matrices remained within the acceptable range of 70–120%. Rapid uptake of the fungicides by tomato and bell pepper plants was observed from the first day onwards. In the tomato plant, the major part of the fungicides accumulated in the roots, whereas in bell pepper plant, it accumulated both in the roots and in the leaves. Accumulation of fluopyram and tebuconazole residues was lowest in tomato and bell pepper fruits which were much below their respective maximum residue limits (MRLs). The highest residue concentration of fluopyram and tebuconazole in tomato fruits was 0.060 and 0.009 mg kg
−1
; the corresponding values in bell pepper fruits were 0.080 and 0.013 mg kg
−1
. In field soil, fluopyram residues were 3.18–3.570 mg kg
−1
initially which dissipated at the half-life of 36 days. Tebuconazole concentration was 1.57–1.892 mg kg
−1
initially, and it dissipated at the half-life of 44.5–49.5 days. The major metabolite of fluopyram, fluopyram benzamide, was detected in plant tissues as well as in soil, and remained within 12% of the parent compound. The results of the study indicated that fluopyram and tebuconazole are less likely of entry into food chain through intake of tomato and bell pepper fruits if these crops are grown on soil contaminated with these fungicides.
Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop ...DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (
=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for
assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (
=52; 16.6%±9.2%;
=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (
<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (
=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.
Neonicotinoid insecticides such as imidacloprid, indoxacarb and thiamethoxam are widely used for control of a large number of insect pests of pomegranate crop. Their residue levels were evaluated on ...pomegranate fruits over 2 years during the same cropping season. The QuEChERS analytical method in conjunction with LC-MS/MS was validated to analyse the insecticides on pomegranate fruits with peel (whole fruit), without peel (aril) and in the field soil. The method performance was satisfactory with the limit of quantification (LOQ) of 0.005 mg/kg which was below the maximum residue limits (MRLs) in pomegranate for the 3 compounds. A first order reaction kinetics was observed for the three insecticides with the half -life of degradation of 8–11.1 days for imidacloprid; 7.4–8.4 days for indoxacarb and 9.8–14.2 days for thiamethoxam. Though the insecticides are systemic in nature, the residues in the edible pomegranate aril were always < LOQ. The maximum residue levels of imidacloprid on pomegranate was less than its MRL of 1 mg/kg, so the pre-harvest interval (PHI) required was 1 day only. For indoxacarb, 31–42 days PHI was needed for the residues to reduce to its MRL of 0.02 mg/kg. The PHI of thiamethoxam was 46–77 days, the time required for its residues to reduce to its MRL of 0.01 mg/kg. Higher rainfall possibly facilitated faster dissipation of imidacloprid residues from pomegranate whereas indoxacarb and thiamethoxam remained unaffected. The results of the study can be utilized to incorporate these three chemicals in the plant protection program of pomegranate and fixation of MRL in India.
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•Imidacloprid, indoxacarb and thiamethoxam residues remained on pomegranate fruit surface.•In the edible aril (pomegranate fruit without peel) residues were < 0.005 mg/kg.•Dissipation of the neonicotinoids on pomegranate followed first order rate kinetics.•Residue dissipation data can be used for notification of MRL.
Random assignment to intensive blood pressure (BP) lowering (systolic BP<120mmHg) compared to a less intensive BP target (systolic BP<140mmHg) in the Action to Control Cardiovascular Risk in Diabetes ...BP (ACCORD-BP) trial resulted in a more rapid decline in estimated glomerular filtration rate (eGFR). Whether this reflects hemodynamic effects or intrinsic kidney damage is unknown.
Longitudinal analysis of a subgroup of clinical trial participants.
A subgroup of 529 participants in ACCORD-BP.
Urine biomarkers of tubular injury (kidney injury molecule 1, interleukin 18 IL-18), repair (human cartilage glycoprotein 39 YKL-40), and inflammation (monocyte chemoattractant protein 1) at baseline and year 2.
Changes in eGFR from baseline to 2 years.
We compared changes in biomarker levels and eGFRs across participants treated to an intensive versus less intensive BP goal using analysis of covariance.
Of 529 participants, 260 had been randomly assigned to the intensive and 269 to the standard BP arm. Mean age was 62±6.5 years and eGFR was 90mL/min/1.73m2. Baseline clinical characteristics, eGFRs, urinary albumin-creatinine ratios (ACRs), and urinary biomarker levels were similar across BP treatment groups. Compared to less intensive BP treatment, eGFR was 9.2mL/min/1.73m2 lower in the intensive BP treatment group at year 2. Despite the eGFR reduction, within this treatment group, ACR was 30% lower and 4 urinary biomarker levels were unchanged or lower at year 2. Also within this group, participants with the largest declines in eGFRs had greater reductions in urinary IL-18 and YKL-40 levels. In a subgroup analysis of participants developing incident chronic kidney disease (sustained 30% decline and eGFR<60mL/min/1.73m2; n=77), neither ACR nor 4 biomarker levels increased in the intensive treatment group, whereas the level of 1 biomarker, IL-18, increased in the less intensive treatment group.
Few participants with advanced baseline chronic kidney disease. Comparisons across treatment groups do not represent comparisons of treatment arms created solely through randomization.
Among a subset of ACCORD-BP trial participants, intensive BP control was associated with reductions in eGFRs, but not with an increase in injury marker levels. These findings support that eGFR decline observed with intensive BP goals in ACCORD participants may predominantly reflect hemodynamic alterations.
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Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The ...authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration.
The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy.
Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor (<50 mmol), suboptimal (<100 mmol), or excellent (>150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol.
Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p < 0.05 for all cutpoints). In the YDP cohort (n = 161) using the NRPE to direct therapy mean daily urine output (1.8 ± 0.9 l vs. 3.0 ± 0.8 l), net fluid output (-1.1 ± 0.9 l vs. -2.1 ± 0.9 l), and weight loss (-0.3 ± 0.3 kg vs. -2.5 ± 0.3 kg) improved substantially following initiation of the YDP (p < 0.001 for all pre-post comparisons).
Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.
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