Adjustment For Renal Function Research Articles

Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which-at least in part-could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.

Serum Orotidine: A Novel Biomarker of Increased CVD Risk in Type 2 Diabetes Discovered Through Metabolomics Studies.

To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked in previous metabolomics studies of CVD. We conducted a global serum metabolomics analysis using the Metabolon platform in a discovery set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed up with absolute quantification assays in a validation set from the Joslin Heart Study including 599 individuals with T2D with and without clinical evidence of significant coronary heart disease (CHD). In the discovery set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39-2.72], P = 0.0001, and 1.62 [1.26-2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [1.11-1.75]), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (P < 0.05) C statistics and discrimination indices for CVD risk (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with the clinical predictors alone. Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D.

Vitamin B-12 malabsorption and renal function are critical considerations in studies of folate and vitamin B-12 interactions in cognitive performance: NHANES 2011–2014

Cognitive health is a public health concern among older adults. Dietary supplement (SUP) use is common and concerns have been raised about high folic acid intake among those with vitamin B-12 deficiency and exacerbation of poor cognitive performance (PCP). We evaluated SUP use, usual folic acid intake, and blood folate and vitamin B-12 concentrations in relation to cognitive performance. We used NHANES 2011-2014 data on adults aged ≥60 y (n=2867) and estimated total usual folic acid intake from diet and supplements, vitamin B-12 intake from SUPs, blood folates, vitamin B-12 concentrations, vitamin B-12 insufficiency (≤258pmol/L), high folate (serum folate ≥59nmol/L or RBC folate ≥1609nmol/L), and PCP (<34 on the Digit Symbol Substitution Test). We assessed folate distributions adjusted for multiple variables, including renal function. Compared with persons without PCP, adults with PCP were less likely to use supplements containing folic acid (mean±SEE: 34.4%±2.4%) or vitamin B-12 (mean±SEE: 47.5%±1.6%). Among vitamin B-12-insufficient adults, 18.0%±1.6% (mean±SEE) reported taking a vitamin B-12 supplement. Among participants with high folate and insufficient vitamin B-12 concentrations, 34.3%±11.5% (mean±SEE) reported taking vitamin B-12-containing supplements. Persons with high folate and normal vitamin B-12 concentrations had lower odds of PCP [aOR (adjusted odds ratio): 0.61; 95% CI: 0.45, 0.83] than persons with normal folate and vitamin B-12. Persons with high folate and normal methylmalonic acid (MMA) had lower odds of PCP (OR: 0.56; 95% CI: 0.40, 0.78) than those with normal folate and MMA concentrations. After adjustment for renal function, elevated risk of PCP was attenuated among persons with high folate and MMA. Concurrent high folate and insufficient vitamin B-12 concentrations were not associated with PCP. Differential associations between vitamin B-12 and MMA highlight the need to consider renal function in studies of high folate and low vitamin B-12 status. Consumption of vitamin B-12 supplements concurrent with low vitamin B-12 status may indicate vitamin B-12 malabsorption.

Patterns of objectively measured physical activity differ between men living with and without HIV.

To use accelerometers to quantify differences in physical activity (PA) by HIV serostatus and HIV viral load (VL) in the Multicenter AIDS Cohort Study (MACS). MACS participants living with (PLWH, n = 631) and without (PWOH, n = 578) HIV wore an ambulatory electrocardiogram monitor containing an accelerometer for 1-14 days. PA was summarized as cumulative mean absolute deviation (MAD) during the 10 most active consecutive hours (M10), cumulative MAD during the six least active consecutive hours (L6), and daily time recumbent (DTR). PA summaries were compared by HIV serostatus and by detectability of VL (>20 vs. ≤20 copies/ml) using linear mixed models adjusted for sociodemographics, weight, height, substance use, physical function, and clinical factors. In sociodemographic-adjusted models, PLWH with a detectable VL had higher L6 (β = 0.58 mg, P = 0.027) and spent more time recumbent (β = 53 min/day, P = 0.003) than PWOH. PLWH had lower M10 than PWOH (undetectable VL β = -1.62 mg, P = 0.027; detectable VL β = -1.93 mg, P = 0.12). A joint test indicated differences in average PA measurements by HIV serostatus and VL (P = 0.001). However, differences by HIV serostatus in M10 and DTR were attenuated and no longer significant after adjustment for renal function, serum lipids, and depressive symptoms. Physical activity measures differed significantly by HIV serostatus and VL. Higher L6 among PLWH with detectable VL may indicate reduced amount or quality of sleep compared to PLWH without detectable VL and PWOH. Lower M10 among PLWH indicates lower amounts of physical activity compared to PWOH.

MO216: The Importance of Nephrotic Range Proteinuria in Renal Survival of Patients With IGA Nephropathy

Abstract BACKGROUND AND AIMS Persistent proteinuria (urinary protein level [UPr]&amp;gt;1 g/24 h) and especially nephrotic range proteinuria, is a poor prognostic factor in IgA nephropathy. Patients with proteinuria &amp;gt; 3.5 g/24 h have a 24-fold faster decline of renal function as compared with those with &amp;lt; 1g/24 h. The aim of this study was to explore the relationship between nephrotic range proteinuria and renal survival in patients with IgA nephropathy. METHOD All records from patients who were followed in a renal outpatient clinic and had a biopsy-proven IgA nephropathy were retrospectively screened. Patients with nephrotic range proteinuria (UPr &amp;gt; 3.5 g/24 h) at the time of diagnosis were compared, regarding their clinical and epidemiological characteristics, with patients with lower levels of proteinuria. Renal survival was defined as the absence of end-stage kidney disease [estimated Glomerular Filtration Rate (eGFR)≤15 mL/min/1.73 m2] or/and a ≥ 50% reduction of eGFR from baseline values. RESULTS We included 53 patients with IgA nephropathy. Their mean age was 46.24 (±16.92) and the median follow-up time was 49 (17–111) months. The median UPr value at the time of diagnosis was 1.89 (0.83–3.50) g/24 h and 17 patients had UPr &amp;gt; 3.5 g/24 h. Patients with nephrotic range proteinuria had worse renal function (eGFR 29 versus 73 mL/min/1.73 m2 P &amp;lt; .001), developed more frequently hypertension (82.35% versus 50%, P = .02) and rapidly progressive glomerulonephritis (23.53% versus 5.56%, P = .05) compared with those with lower levels of proteinuria. The episodes of macroscopic hematuria were less frequent in the group of patients with nephrotic range proteinuria (11.76% versus 38.89%, P = .05). Regarding patients treated with prednisone, the mean daily dose of prednisone was 23.42 mg for the nephrotic patients versus 16.61 mg for the patients with UPr &amp;lt; 3.5 g/24 h (P = .03). Proteinuria &amp;gt; 3.5 g/24 h was an independent risk factor for poor renal survival (HR 15.48, P = .01). The 5-year renal survival of patients with nephrotic range proteinuria was reduced compared with those with lower levels of proteinuria (66.64% versus 100%). CONCLUSION This study showed that the presence of nephrotic range proteinuria at the time of diagnosis was an independent risk factor for reduced renal survival. This relationship persisted after sex, age and renal function adjustment at the time of diagnosis.

P–650 Body weight is the main determinant of systemic follicle stimulating hormone (FSH) concentrations during controlled ovarian stimulation with follitropin delta

Abstract Study question Which individual subject characteristics affect systemic FSH concentrations in women undergoing controlled ovarian stimulation with follitropin delta? Summary answer Body weight is the main determinant of systemic FSH concentrations. Renal function, Asian race, country/region, hepatic function and age have at most a small influence. What is known already After administration of FSH, systemic FSH concentrations are inversely related to body weight. It has been observed that the impact of body weight on ovarian response is clinically relevant at low doses but not at high doses. In patients with anti-Müllerian hormone (AMH) ≥15 pmol/L, follitropin delta is dosed according to each patient’s body weight, which influences systemic FSH concentrations, and her AMH level which predicts ovarian response. Study design, size, duration Serum FSH concentrations were assessed in five randomised, controlled, assessor-blinded, multicentre trials of follitropin delta in women undergoing an assisted reproductive technology programme. The trials were conducted in Europe, America and Asia. In all, 1.665 women treated with follitropin delta contributed to the evaluation with 4052 serum FSH concentrations, measured at steady state by an immunoassay. Participants/materials, setting, methods FSH concentrations were described with a pre-specified one-compartment population pharmacokinetic model. The key model parameters were the apparent total clearance (CL/F) of follitropin delta, the interindividual variability herein and the effects of baseline values of body weight, age, race, country/region, renal and hepatic function on CL/F. Renal function was assessed using the estimated glomerular filtration rate (eGFR) and hepatic function by alanine transaminase (ALT) and bilirubin levels. Main results and the role of chance The area under the FSH concentration-time curve during a dosing interval (AUC) was derived from dose and CL/F. Body weight was the covariate with the most pronounced effect on AUC, both in terms of the effect magnitude and statistical significance. AUC was 1.51-fold higher (90% confidence limits: 1.48; 1.54) in women with the lowest observed body weight of 40 kg compared to women with a typical body weight of 58 kg. The effect of renal function on AUC was small and in the same order of magnitude as the bioequivalence limits (0.8; 1.25). AUC was 1.28-fold higher (90% confidence limits: 1.23; 1.33) in women with the lowest observed eGFR value of 44 mL/min/1.73m2, compared to women with a typical eGFR value of 98 mL/min/1.73m2. The effects of Asian race and country/region (Japan, China, Other Asian) were confounded with each other and well within the bioequivalence limits when evaluated independently. The effects of age and the hepatic function markers ALT and bilirubin were well within the bioequivalence limits. Limitations, reasons for caution The women participating in the trials were generally healthy and the results cannot be transferred to women with renal or hepatic disease. A limited number of Black women contributed to the present analysis but the trend was similar. Data is forthcoming from ongoing trials including larger numbers of Black women. Wider implications of the findings: The findings support dosing follitropin delta by body weight and without adjustment for renal function, hepatic function, race, age or country/region. Trial registration number NCT01426386, NCT02309671, NCT01956110, NCT03228680 and NCT03296527

MO209NUOVI PROTOCOLLI TERAPEUTICI NEI PAZIENTI NON IDONEI AL TRAPIANTO CON AMILOIDOSI AL: FOLLOW UP A LUNGO TERMINE

Abstract Background and Aims Immunoglobulin light-chain (AL)amyloidosis is a rare life-threatening disease caused by light chains that are toxic to vital organs such as the kidneys. New therapeutic strategies with bortezomib and lenalidomide have improved the prognosis. The aim of our study was to evaluate the long term efficacy of therapeutic protocol utilizing bortezomib in induction and in conditioning with lenalidomide for PRR (partial renal response) AL renal Amyloidosis transplant-ineligible patients. Method This is a prospective analysis of 16 transplant-ineligible patients with histological diagnosis of renal amyloidosis admitted to our Nephrology Department from 01/2010 to 01/10/2020. All patients have overt nephrotic syndrome at the diagnosis. Two/thirds of them have renal failure. The diagnosis of amyloid is based on the kidney biopsy finding, by light microscopic examination, of amorphous extracellular Congo red positive deposits, which display characteristic dichroism and apple green birefringence under polarised light. Bortezomib-based (BD) regimen is used (Bortezomib 1.3mg/m2 subcutaneously; Cyclophosphamide 200mg/m2 and Dexamethasone 40mg) for 9 cycles. Hematological and organ response were evaluated according to the novel criteria of the International Society of Amyloidosis. The patients with partial renal response (PRR: decreased of 24 hour urine protein and serum creatinine &amp;gt; 50% over baseline) were treated with cycles of Lenalidomide (dose adjustments for renal function, orally on days 1 trough 21 of each 28-days cycle) in combination with dexamethasone and prophylactic anti-thrombotic treatment. Results The mean age was 63±7 years and 7/16 (43.7%) were males. By immunohistochemistry the protein composition of the amyloid deposits was FLC k in 6/16 and FLC lambda in 10/16. Periombelical fat aspirate was positive in 5 patients (31.2%). At onset the mean proteinuria was 13.1 ± 3.6 gr/24h with average MDRD of 37.2 ml/min (III stage CKD), average pro-BNP 420.1 and SIV 12.5 mm. At onset three patients (18.7%) had confirmed multiple myeloma (Clone of plasma cells proliferation &amp;gt; 30% in the bone marrow). 3/16 patients died for cardiac arrhythmia at 3 and 4 months after CyBorD cycles initiation. Therefore CyBorD regimen was completed in 13/16 patients. After 9 CyBorD cycles: 3/13 patients showed a complete renal response (CRR: MDRD &amp;gt; 90 ml/min, proteinuria/24h&amp;lt; 300 mg) and CHR (normal serum FLC ratio); 10/13(76.9%) showed a PRR and PHR (dFLC decrease &amp;gt;50% compared to baseline), one patient died for Sepsis, All patients with CRR or PRR showed a complete cardiological response (normal BNP and SIV). Adverse events during therapy: HZV nevralgy in 3. The 9 patients in PRR were treated with Lenalidomide. After median 6 treatment cycles 7/9 (77.7%) patients showed a CRR and CHR. Haemodialysis was started in 2/9 (22.2%) patients. We decided to discontinue the therapy for adverse events in 3 patients: breast cancer in one, transient troponin I increase and angina in an other patient, pneumonia events in one. The pneumoniae infectious and anginal episodes regressed with drug discontinuation. Median follow-up time from diagnosis of Renal Amyloidosis was 46 months. Median follow-up from the start of Lenalidomide was 36 months. One patients died for breast cancer, but in CRR. All the others patients with CRR (9/13, 69.2%), including the two who suspended Lenalidomide for its toxic effects have been in remission for 30 months on average. Conclusion We conclude the following Lenalidomide therapy is very effective at increasing the number of CRR. In addition, the two treatment regimens (induction therapy with CyBorD and conditioning with Lenalidomide) kept patients in remission for more than 30 months on average. Further studies on larger samples are needed to validate the data.

Abstract 17168: Myocardial Natriuretic Peptide Expression in Heart Failure With Preserved Ejection Fraction

Introduction: Serum natriuretic peptides (NP) are reduced in heart failure with preserved ejection fraction (HFpEF) compared to HFrEF; however, myocardial NP expression in HFpEF is unknown. We analyzed serum NTproBNP and myocardial RNAseq data to test the hypothesis that 1) lower myocardial NP expression in HFpEF drives the difference in serum levels, and 2) HFpEF with higher NP expression have transcriptomic signatures more similar to HFrEF. Methods: HFpEF patients (n=41) with clinical HF, LVEF≥50%, and meeting current consensus criteria for HFpEF underwent right heart catheterization and right ventricular (RV) endomyocardial biopsy. We performed differential gene expression analysis of RV septal tissue from HFpEF and compared to explanted HFrEF (n=30) and unused donor hearts (n=24, Control). Results: Myocardial NPPB expression was 5-fold higher in HFrEF vs Control (p&lt;0.001) and unchanged in HFpEF vs Control, while NPPA expression was 9-fold higher in HFrEF and 5-fold higher in HFpEF vs Control (p&lt;0.0001 for both comparisons). After adjustment for renal function and BMI, myocardial NPPB expression was significantly associated with serum NTproBNP in HFpEF (R 2 0.68; p&lt;0.0001 for renal function, NPPB expression; p=0.03 for BMI). Pulmonary artery (PA) systolic pressure and PA wedge pressure correlated with myocardial NPPB expression (PASP R 2 0.45, p&lt;0.0001; PAWP R 2 0.25, p=0.01), even after adjustment for comorbidities. HFpEF patients with high (≥ median NPPB expression in HFpEF) vs low NPPB expression had transcriptomic signatures more similar to HFrEF using ~13,000 genes in a Principal Component Analysis (Figure), quantified by vector distance from HFrEF (p=0.017). Conclusions: HFpEF patients have reduced serum NTproBNP due to lower myocardial NPPB gene expression. HFpEF patients with higher NPPB expression have transcriptomic signatures more similar to HFrEF, highlighting a HFpEF subgroup that may benefit from targeted therapies.

Feasibility and safety of non-contrast percutaneous coronary intervention in patients with complicated acute coronary syndrome

Abstract Background Contrast-induced acute kidney injury (CI-AKI) occurs in 10% to 20% of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), resulting in a poor short- and long-term prognosis. Reducing the amount of contrast medium can prevent CI-AKI. Objectives This study aimed to examine the feasibility and safety of non-contrast PCI in patients with ACS. Methods The study was a prospective and single-center registry. Successful non-contrast PCI was confirmed when contrast medium was not injected from the guiding catheter engagement to wire removal in ad-hoc PCI. Coronary angiography after the PCI procedure was permitted once. CI-AKI was defined as an increase in the serum creatinine of ≥0.5 mg/dL from or ≥1.25 times the baseline within 72 hours after PCI. Worsening renal function (WRF) was defined as an increase in the serum creatinine of ≥0.3 mg/dL from baseline after the PCI. Results The present study included 106 lesions from 81 patients. Forty-eight lesions were (45%) type C lesions. Successful non-contrast PCI was performed in 95 lesions (90%). CI-AKI was observed in 4 (5%); coronary perforation, 0; no/slow flow, 9 (11%); periprocedural death, 0. The follow-up period was 348 (190–492) days. Successful non-contrast PCI was not associated with the incidence of CI-AKI. However, WRF at 6-month was observed in 18 individuals (22%). Successful non-contrast PCI was inversely associated with WRF (hazard ratio, 0.28; 95% confidence interval, 0.09–0.90) after adjustment for renal function. Conclusions The present study suggests that non-contrast PCI is feasible and safe in ACS patients with complex lesions. Funding Acknowledgement Type of funding source: None

Feasibility and safety of noncontrast percutaneous coronary intervention in patients with complicated acute coronary syndrome.

This study aimed to examine the feasibility and safety of noncontrast percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Contrast-induced acute kidney injury (CI-AKI) occurs in 10-20% of ACS patients undergoing PCI, resulting in poor short- and long-term prognoses. Reducing the amount of contrast medium can prevent CI-AKI. This was a prospective single-center study. In successful noncontrast PCI, contrast medium was not injected from guiding catheter engagement to wire removal in ad-hoc PCI. Coronary angiography after PCI was permitted once. CI-AKI was defined as an increase in the serum creatinine level of ≥0.5 mg/dl or ≥1.25 times the baseline within 72 hr post PCI. Worsening renal function (WRF) was defined as an increase in the serum creatinine level of ≥0.3 mg/dl from baseline after PCI. This study included 106 lesions from 81 patients. Forty-eight (45%) lesions were Type C lesions. Successful noncontrast PCI was performed in 95 (90%) lesions. CI-AKI, coronary perforation, no/slow flow, and periprocedural death were observed in 4 (5%), 0, 9 (11%), and 0 patients, respectively. The follow-up period was 348 (190-492) days. Six-month WRF was observed in 18 individuals (22%). While successful noncontrast PCI was not associated with the incidence of CI-AKI, successful noncontrast PCI was inversely associated with WRF (hazard ratio, 0.28; 95% confidence interval, 0.09-0.90) after adjustment for renal function. The present study suggests that noncontrast PCI is feasible and can be safely performed in ACS patients with complex lesions.

Association between anemia and hyperuricemia: results from the Korean National Health and Nutrition Examination Survey

Hyperuricemia and anemia share several comorbidities, but the association between the two conditions remains unclear. The purpose of this study was to investigate the association between hyperuricemia and anemia. Data of 10794 subjects from the Korean National Health and Nutrition Examination Survey conducted in 2016–2017 were analyzed using multivariate logistic regression analyses. An association between anemia and hyperuricemia was not evident in subjects without chronic kidney disease (CKD). In patients with CKD, anemia increased the risk of hyperuricemia by 2-fold. This association remained significant when adjusting for the glomerular filtration rate. In subgroup analyses, the association of anemia with hyperuricemia was significant in subjects aged ≥65 years, and in those with diabetes or hypertension. Subgroup analyses of CKD patients showed similar results. In the current study using data from Korean representative samples, anemia in subjects with CKD was associated with a 2-fold increase in the risk of hyperuricemia, which remained significant even after adjustment for renal function.

Plasma neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease: Findings from the PREVEND prospective cohort study

BackgroundNeutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker of acute kidney injury, might play a role in the development of atherosclerotic cardiovascular disease (CVD). We aimed to assess the association of circulating NGAL with CVD risk. Materials and methodsPlasma NGAL concentrations were measured at baseline in 5275 participants in the PREVEND prospective study. Hazard ratios (95% confidence intervals [CI]) for CVD were estimated. ResultsAfter a median follow-up of 8.3 years, 338 participants developed first CVD events. Plasma NGAL was weakly to moderately correlated with several CVD risk markers. There was a non-linear relationship between NGAL and CVD risk. In analyses adjusted for established risk factors, the hazard ratio (95% CI) for CVD in a comparison of the top quartile versus bottom quartiles 1–2 of NGAL values was 1.35 (1.05–1.75; P = 0.022), which was abrogated after additional adjustment for other potential confounders (mainly attributed to high sensitivity C-reactive protein) 1.20 (0.92–1.57; P = 0.176). The association was considerably attenuated following further adjustment for renal function 1.05 (0.79–1.40; P = 0.745). The association between NGAL and CVD risk did not vary importantly in relevant clinical subgroups. ConclusionEvidence suggests a non-linear association between NGAL and CVD risk, which is dependent on inflammation and renal function.

Brief Report: Adherence Biomarker Measurements in Older and Younger HIV-Infected Adults Receiving Tenofovir-Based Therapy.

Concentrations of tenofovir (TFV) in hair and tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs) as measures of cumulative exposure have been primarily studied in younger, HIV-uninfected individuals taking preexposure HIV prophylaxis. Data on these measures among older HIV-infected individuals are limited. We evaluated longitudinal TFV and TFV-DP concentrations in hair and DBS, respectively, from HIV-infected adults. Multivariable model variables included age group (18-35 and 60 years and older), creatinine clearance (CrCl), hematocrit (TFV-DP), and gray hair color (TFV). Baseline hair TFV and DBS TFV-DP were moderately correlated [r = 0.5 (0.2 to 0.7); P = 0.001] across both age groups [younger (N = 23) and older (N = 22)]. In adjusted models, CrCl was associated with increases of 15.9% (7.4% to 25.0%); P = 0.0006, and 5.7% (-0.2% to 11.9%); P = 0.057 for TFV in hair and TFV-DP in DBS, respectively, for every 20-mL/min CrCl decrease. Although older age (versus younger age) was univariately associated with increased TFV hair levels, older age was not significantly associated with higher concentrations in hair [-1.4% (-26.7% to 32.7%); P = 0.93] or DBS [4.0% (-14.1% to 25.9%); P = 0.68] after adjustment. Similarly, gray color was not significantly associated with higher TFV levels in hair [27.6% (-11.1% to 83.0%; P = 0.18)] in adjusted models. In both adjusted and unadjusted models of TFV-DP levels in DBS, a 1% hematocrit increase was associated with a 3.3% (0.2% to 6.5%) TFV-DP increase (P = 0.04). Cumulative drug exposure measures (hair and DBS) were comparable in younger and older HIV-infected individuals on TFV-based therapy after adjustment for renal function.

Association of Serum Retinol-Binding Protein 4 Concentration With Risk for and Prognosis of Amyotrophic Lateral Sclerosis

Knowledge about the metabolic states of patients with amyotrophic lateral sclerosis (ALS) may provide a therapeutic approach. To investigate the association between the onset and prognosis of ALS and serum retinol-binding protein 4 (RBP4) concentration as a biomarker for insulin resistance and vitamin A metabolism. Case-control design for risk factors of ALS; cohort design for prognostic factors within ALS cases. Between October 1, 2010, and June 30, 2014, a population-based case-control study with randomly selected controls was established based on the ALS Registry Swabia in southern Germany, with a target population of 8.4 million inhabitants. Response rates were 64.8% among the cases and 18.7% among the controls. The dates of analysis were April 2016 to May 2017. Serum samples were measured for RBP4. Information on covariates was assessed by an interview-based standardized questionnaire. Main outcomes and measures were adjusted odds ratios for risk of ALS associated with serum RBP4 concentration, as well as time to death associated with RBP4 concentration at baseline in ALS cases only. Conditional logistic regression was applied to calculate multivariable odds ratios for risk of ALS. Survival models were used in cases only to appraise their prognostic value. Data from 289 patients with ALS (mean [SD] age, 65.7 [10.5] years; 172 [59.5%] male) and 504 controls (mean [SD] age, 66.3 [9.8] years; 299 [59.3%] male) were included in the case-control study. Compared with controls, ALS cases were characterized by lower body mass index, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes. The median serum RBP4 concentration was lower in ALS cases than in controls (54.0 vs 59.5 mg/L). In the multivariable model, increasing RBP4 concentration was associated with reduced odds for ALS (top vs bottom quartile odds ratio, 0.36; 95% CI, 0.22-0.59; P for trend <.001), which persisted after further adjustment for renal function and for leptin and adiponectin. Among 279 ALS cases during a median follow-up of 14.5 months, 104 died (mean [SD] age, 68.9 [10.3] years; 56 [53.9%] male). In this ALS cohort, an inverse association was found between serum RBP4 concentration as a continuous measure and survival. RBP4 was inversely related to risk for and prognosis of ALS, suggesting that vitamin A metabolism or impaired insulin signaling could be involved. Further research, including a prospective design and other biological markers, is necessary to clarify the role of insulin resistance in the pathogenesis of ALS.

Low serum magnesium levels are associated with increased risk of fractures: a long-term prospective cohort study

Magnesium, which is an essential trace element that plays a key role in several cellular processes, is a major component of bone; however, its relationship with risk of major bone fractures is uncertain. We aimed to investigate the association of baseline serum magnesium concentrations with risk of incident fractures. We analyzed data on 2245 men aged 42–61 years in the Kuopio Ischemic Heart Disease prospective cohort study, with the assessment of serum magnesium measurements and dietary intakes made at baseline. Hazard ratios [95% confidence intervals (CI)] for incident total (femoral, humeral, and forearm) and femoral fractures were assessed. During a median follow-up of 25.6 years, 123 total fractures were recorded. Serum magnesium was non-linearly associated with risk of total fractures. In age-adjusted Cox regression analysis, the hazard ratio (HR) (95% CIs) for total fractures in a comparison of the bottom quartile versus top quartile of magnesium concentrations was 2.10 (1.30–3.41), which persisted on adjustment for several established risk factors 1.99 (1.23–3.24). The association remained consistent on further adjustment for renal function, socioeconomic status, total energy intake, and several trace elements 1.80 (1.10–2.94). The corresponding adjusted HRs for femoral fractures were 2.56 (1.38–4.76), 2.43 (1.30–4.53) and 2.13 (1.13–3.99) respectively. There was no evidence of an association of dietary magnesium intake with risk of any fractures. In middle-aged Caucasian men, low serum magnesium is strongly and independently associated with an increased risk of fractures. Further research is needed to assess the potential relevance of serum magnesium in the prevention of fractures.

P2X7 Receptor and APOE Polymorphisms and Survival from Heart Failure: A Prospective Study in Frail Patients in a Geriatric Unit.

Heart failure (HF) is one of the most frequent cause of hospitalization in elderly and often coexists with concurrent geriatric syndromes, like cognitive disturbances; various pathophysiological mechanisms are shared by HF and cognitive decline, notably a substrate of low-grade inflammation. We investigated whether SNPs in the purinergic receptor (P2X7R) and apolipoprotein (APO) E genes, both involved in a series of inflammatory responses, are associated to HF or cognitive impairment and are able to predict post-discharge mortality in the elderly. We prospectively analyzed 198 patients (age 85 ± 8 years, predominantly females) admitted to a Geriatric unit for acute HF, whose diagnosis was based on clinical signs, brain natriuretic peptide (BNP) values and ecocardiography in uncertain diagnosis (BNP values between 100 and 400 pg/mL); cognitive performance was assesed by Short Portable Mental Status Questionnaire (SPMSQ). In all the participants, SNPs rs208294 and rs3751143 for P2X7R gene and rs429558 and rs7412 for APOE gene were assessed. Information on all-cause mortality was adjudicated by medical records review 36 months after discharge. We found no relationship between P2X7R and APOE polymorphisms and 36-month post-discharge mortality; a better outcome for overall survival was observed in patients with BNP values below the median (281 pg/mL) (p=0.002) persisting after adjustment for renal function and age, and in those with cognitive impairment (p<0.001). Patients harboring APOE-ε4 genotype showed higher BNP concentrations than noncarriers (1289.9 ± 226.9 vs 580.5 ± 90.2 pg/mL respectively,p=0.004), whereas none of the studied SNPs were associated to impairment in cognitive performance. In conclusion, neither P2X7R or APOE genotype seem to predict long-term mortality in elderly patients. Interestingly, APOE-ε4 genotype was associated to higher BNP values, suggesting a putative interaction between genetic and biochemical markers in identifying people at risk for HF.

Abstract 13891: Prognostic Value of Simple Risk Index at Discharge in Patients Admitted for Acute Decompensated Heart Failure With Reduced or Preserved Left Ventricular Ejection Fraction

Backgrounds: Increased heart rate (HR) and low systolic blood pressure (SBP) are associated with adverse clinical outcomes in patients (pts) admitted for acute decompensated heart failure (ADHF). It has been reported that simple risk index (SRI) based on easily assessed clinical characteristics (age, HR, and SBP) is useful for the prediction of short-term mortality in pts with acute myocardial infarction. However, there is no information available on the prognostic significance of pre-discharge SRI in pts admitted for ADHF relating to reduce or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods and Results: We studied 303 consecutive ADHF pts discharged with survival (HFrEF(LVEF&lt;50%);n=163, HFpEF(LVEF≥50%);n=140), and obtained clinical characteristics, conventional hemodynamic parameters and laboratory data. SRI was calculated as (HRх[age/10] 2 )/SBP. During a follow up period of 4.2±3.3 yrs, 96 pts had all-cause death. In HFrEF group, at multivariate Cox analysis, SRI at the discharge (adjusted hazard ratio:1.055[95%CI 1.029 to 1.081], p&lt;0.0001) was significantly associated with total mortality, independently of prior heart failure hospitalization, and serum sodium and albumin levels after adjustment for anemia and renal function. The mortality risk significantly increased by SRI tertiles (lowest tertile [&lt;26.3]: 19%, middle tertile [26.3-36.3]: 38% and highest tertile [&gt;36.3]: 54%, p=0.0001). In HFpEF group, SRI at the discharge (adjusted hazard ratio:1.065[95%CI 1.022 to 1.109], p=0.0026) was also significantly associated with total mortality, independently of anemia and serum sodium level after adjustment for renal function. Pts with highest and middle SRI tertile had a increased risk of total mortality than those with lowest tertile (30% vs 28% vs 13%, p=0.002, respectively). Conclusion: SRI at the discharge would provide the long-term prognostic information in ADHF pts, regardless of HFrEF or HFpEF.

Serum zinc concentrations and incident hypertension: new findings from a population-based cohort study.

Zinc is an essential trace element that plays a key role in several cellular processes and has been suggested to be involved in blood pressure regulation. We aimed to prospectively investigate the association between baseline concentrations of serum zinc and incident hypertension. We analyzed data involving 1652 men aged 42-61 years without a known history of hypertension at baseline in the Kuopio Ischemic Heart Disease population-based cohort study, with the assessment of serum zinc concentrations. Hazard ratios [95% confidence intervals (CIs)] for incident hypertension were assessed. During a median follow-up of 24.7 years, 259 participants developed hypertension. Serum zinc was weakly correlated with several risk markers for hypertension and nonlinearly associated with incident hypertension. In analyses adjusted for age, the hazard ratio (95% CIs) for hypertension in a comparison of the top quartile vs. bottom quartiles 1-3 of zinc concentration was 1.65 (1.27-2.15; P < 0.001), which was minimally attenuated on adjustment for several established risk factors 1.48 (1.13-1.93; P = 0.004). The association remained unchanged on further adjustment for renal function, socioeconomic status, and dietary factors. The findings were generally consistent across several clinical subgroups. There was no evidence of an association of dietary zinc intake with risk of hypertension. This prospective study suggests higher serum zinc concentration is positively and independently associated with incident hypertension in men. Further evidence from large-scale population-based studies is needed to support these findings and assess the mechanisms underlying the association.

GlycA, a Pro-Inflammatory Glycoprotein Biomarker, and Incident Cardiovascular Disease: Relationship with C-Reactive Protein and Renal Function.

ObjectiveGlycA is a novel nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation. We determined whether GlycA is associated with incident cardiovascular disease (CVD) in men and women, examined whether this association with CVD is modified by renal function, and compared this association with high sensitivity C-reactive protein (hsCRP).Research design and methodsA prospective cohort study was performed among 4,759 subjects (PREVEND study) without a history of CVD and cancer. Incident CVD was defined as the combined endpoint of cardiovascular morbidity and mortality. Cox regression analyses were used to examine associations of baseline GlycA and hsCRP with CVD.Results298 first CVD events occurred during a median follow-up of 8.5 years. After adjustment for clinical and lipid measures the hazard ratio (HR) for CVD risk in the highest GlycA quartile was 1.58 (95% CI, 1.05–2.37, P for trend = 0.004). This association was similar after further adjustment for renal function (estimated glomerular filtration rate and urinary albumin excretion). After additional adjustment for hsCRP, GlycA was still associated with incident CVD (HR: 1.16 per SD change (95% CI, 1.01–1.33), P = 0.04). Similar results were obtained for hsCRP (HR per SD change after adjustment for GlycA: 1.17 (95% CI 1.17 (95% CI, 1.01–3.60), P = 0.04). CVD risk was highest in subjects with simultaneously higher GlycA and hsCRP (fully adjusted HR: 1.79 (95% CI, 1.31–2.46), P<0.001).ConclusionGlycA is associated with CVD risk in men and women, independent of renal function. The association of GlycA with incident CVD is as strong as that of hsCRP.

Novel measure of electrical dyssynchrony predicts response in cardiac resynchronization therapy: Results from the SMART-AV Trial

Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in selected heart failure patients. However, not all patients respond to CRT. We hypothesized that a novel measure of electrical dyssynchrony, sum absolute QRST integral (SAI QRST), predicts CRT response independent of QRS duration and morphology. We retrospectively analyzed baseline 12-lead electrocardiograms of SmartDelay Determined AV Optimization: A comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial study participants (N = 234; mean age 67 years; 163 (70%) men; 140 (60%) ischemic cardiomyopathy; mean left ventricular ejection fraction 25%; mean QRS duration 152 ms; 179 (77%) had left bundle branch block). Baseline pre-implant electrocardiograms were digitized, transformed into orthogonal XYZ, and analyzed automatically by customized MATLAB software. SAI QRST was measured as an averaged arithmetic sum of absolute areas under the QRST curve. Patients were followed prospectively 6 months after CRT-defibrillator implantation. Patients with a decrease in left ventricular end-systolic volume ≥15 mL after 6 months of CRT were considered responders. The logistic regression model was adjusted for age, sex, bundle branch block morphology, left ventricular ejection fraction, cardiomyopathy type, and QRS duration. Patients with the high mean SAI QRST (third tertile) had 2.5 times greater odds of response than those with the low mean SAI QRST (first tertile: odds ratio [OR] 2.5; 95% confidence interval [CI] 1.3-5.0; P = .010) and 1.9 times greater than the lower 2 tertiles combined (OR 1.9; 95% CI 1.1-3.5; P = .03). Adjustment for renal function (OR 2.33; 95% CI 1.32-4.11; P = .003) and left ventricular lead position in right anterior oblique and left anterior oblique views (OR 1.7; 95% CI 0.9-3.2; P = .087) did not attenuate association of SAI QRST with outcome. High SAI QRST independently predicts CRT response in the SMART-AV study.