Genetic Variant at the GLUL Locus Predicts All-Cause Mortality in Patients With Type 2 Diabetes

Single nucleotide polymorphism (SNP) rs10911021 at the glutamate-ammonia ligase (GLUL) locus has been associated with an increased risk of coronary heart disease in individuals with type 2 diabetes. The effect of this SNP on mortality was investigated among 1,242 white subjects with type 2 diabetes from the Joslin Kidney Study (JKS) (n = 416) and the Gargano Mortality Study (GMS) (n = 826). During a mean follow-up of 12.8 ± 5.8 and 7.5 ± 2.2 years, respectively, a total of 215 and 164 deaths were observed in the two studies. In both cohorts, the all-cause mortality rate significantly increased with the number of rs10911021 risk alleles, with allelic hazard ratios (HRs) of 1.32 (95% CI 1.07–1.64, P = 0.01), 1.30 (1.10–1.69, P = 0.04), and 1.32 (1.12–1.55, P = 0.0011), respectively, in the JKS, the GMS, and the two studies combined. These associations were not affected by adjustment for possible confounders. In the JKS, for which data on causes of death were available, the HR for cardiovascular mortality was 1.51 (1.12–2.04, P = 0.0077) as opposed to 1.15 (0.84–1.55, P = 0.39) for mortality from noncardiovascular causes. These findings point to SNP rs10911021 as an independent modulator of mortality in patients with type 2 diabetes and, together with the previous observation, suggest that this results from an effect of this variant on cardiovascular risk.     

CAGS and ACS Evidence Based Reviews in Surgery. 34: Effects of β-blockers in patients undergoing noncardiac surgery

Question: Do β-blockers have an effect on the 30-day risk of major cardiovascular events in patients with or at risk of atherosclerotic disease undergoing noncardiac surgery? Design: Randomized controlled trial. Setting: Multicentre trial in 190 hospitals in 23 countries. Patients: In total, 8351 patients with or at risk of atherosclerotic disease undergoing noncardiac surgery. Intervention: Patients were randomly assigned by a computerized 24-hour phone service to receive extended-release metoprolol succinate 200 mg (n = 4174) or placebo (n = 4177). Treatment was started 2–4 hours before surgery and continued for 30 days. Main outcome: Cardiovascular death, nonfatal myocardial infarction (MI) and nonfatal cardiac arrest. Results: Of those randomized, 8331 (99.8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group had an MI (176 [4.2%] v. 239 [5.7%] patients; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.60–0.089, p = 0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] v. 97 [2.3%] patients; HR 1.33, 95% CI 1.03–1.74, p = 0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] v. 19 [0.5%] patients; HR 2.17, 95% CI 1.26–3.74, p = 0.0053). Conclusion: A perioperative β-blocker regimen results in fewer MIs but is associated with an increased risk of stroke and perioperative death in patients with or at risk for atherosclerotic disease undergoing noncardiac surgery. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol use.     

Genetic polymorphisms in HIF1A are associated with prostate cancer risk in a Chinese population

The hypoxia-inducible factor-1α (HIF-1α) plays an important role in regulating angiogenesis, which is essential for tumor growth and metastasis. Genetic variations of HIF1A (coding HIF-1α) have been shown to influence an individual''s susceptibility to many human tumors; however, evidence on associations between HIF1A single-nucleotide polymorphisms (SNPs) and prostate cancer (PCa) risk is conflicting. We genotyped three potentially functional polymorphisms in HIF1A (rs11549465, rs11549467 and rs2057482) using the TaqMan method and assessed their associations with PCa risk in a case–control study of 662 PCa patients and 716 controls in a Chinese Han population. Compared with rs11549467 GG genotype, the variant genotypes GA+AA had a significantly increased PCa risk (adjusted odds ratio (OR)=1.70; 95% confidence interval (CI)=1.06–2.72), particularly among older patients (OR=2.01; 95%CI=1.05–3.86), smokers (OR=2.06; 95%CI=1.07–3.99), never drinkers (OR=2.16; 95%CI=1.20–3.86) and patients without a family history of cancer (OR=1.71; 95%CI=1.02–2.89). Furthermore, patients with rs11549467 variant genotypes were associated with a higher Gleason score (OR=2.14; 95%CI=1.22–3.75). No altered PCa risk was associated with the rs11549465 and rs2057482 polymorphism. However, the combined variant genotypes of rs2057482 and rs11549467 were associated with increased PCa risk (OR=2.10; 95%CI=1.23–3.57 among subjects carrying three or more risk alleles). These results suggest that HIF1A polymorphisms may impact PCa susceptibility and progression in the Chinese Han population.     

Risk of cardiovascular thrombotic events after surgical castration versus gonadotropin-releasing hormone agonists in Chinese men with prostate cancer

We investigated the cardiovascular thrombotic risk after surgical castration (SC) versus gonadotropin-releasing hormone agonists (GnRHa) in Chinese men with prostate cancer. All Chinese prostate cancer patients who were treated with SC or GnRHa from year 2000 to 2009 were reviewed and compared. The primary outcome was any new-onset of cardiovascular thrombotic events after SC or GnRHa, which was defined as any event of acute myocardial infarction or ischemic stroke. The risk of new-onset cardiovascular thrombotic event was compared between the SC group and the GnRHa group using Kaplan–Meier method. Multivariate Cox regression analysis was performed to adjust for other potential confounding factors. A total of 684 Chinese patients was included in our study, including 387 patients in the SC group and 297 patients in the GnRHa group. The mean age in the SC group (75.3 ± 7.5 years) was significantly higher than the GnRHa group (71.8 ± 8.3 years) (P < 0.001). There was increased risk of new cardiovascular thrombotic events in the SC group when compared to the GnRHa group upon Kaplan–Meier analysis (P = 0.014). Upon multivariate Cox regression analysis, age (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.04–1.11, P< 0.001), hyperlipidemia (HR 2.455, 95% CI 1.53–3.93, P< 0.001), and SC (HR 1.648, 95% CI 1.05–2.59, P = 0.031) were significant risk factors of cardiovascular thrombotic events. In conclusion, SC was associated with increased risk of cardiovascular thrombotic events when compared to GnRHa. This is an important aspect to consider while deciding on the method of androgen deprivation therapy, especially in elderly men with known history of hyperlipidemia.     

Subclinical Atherosclerosis Measures for Cardiovascular Prediction in CKD

Whether inclusion of the coronary artery calcium score improves cardiovascular risk prediction in individuals with CKD, a population with unique calcium-phosphate homeostasis, is unknown. Among 6553 participants ages 45–84 years without prior cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, coronary artery calcium score was assessed for cardiovascular risk prediction beyond the Framingham predictors in those with (n=1284) and without CKD and contrasted with carotid intima-media thickness and ankle-brachial index (two other measures of subclinical atherosclerosis). During a median follow-up of 8.4 years, 650 cardiovascular events (coronary heart disease, stroke, heart failure, and peripheral artery disease) occurred (236 events in subjects with CKD). In Cox proportional hazards models adjusted for Framingham predictors, each subclinical measure was independently associated with cardiovascular outcomes, with larger adjusted hazard ratios (HRs; per 1 SD) for coronary artery calcium score than carotid intima-media thickness or ankle-brachial index in subjects without and with CKD (HR, 1.69; 95% confidence interval [95% CI], 1.45 to 1.97 versus HR, 1.12; 95% CI, 1.00 to 1.25 and HR, 1.20; 95% CI, 1.08 to 1.32, respectively). Compared with inclusion of carotid intima-media thickness or ankle-brachial index, inclusion of the coronary artery calcium score led to greater increases in C statistic for predicting cardiovascular disease and net reclassification improvement. Coronary artery calcium score performed best for the prediction of coronary heart disease and heart failure, regardless of CKD status. In conclusion, each measure improved cardiovascular risk prediction in subjects with CKD, with the greatest improvement observed with coronary artery calcium score.     

Urine Collagen Fragments and CKD Progression—The Cardiovascular Health Study

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m², and median urine PIIINP was 2.6 (interquartile range, 1.4–4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.     

Mineral and bone disorder and longterm survival in a chronic kidney disease grade 3b-4cohort

Mineral and bone disorder biomarkers ‘normal ranges’ are controversial. The aim of the study was to evaluate the association between serum calcium (Ca), phosphate (P), intact parathyroid hormone (iPTH), and 25(OH) vitamin D levels and mortality risk, in a chronic kidney disease (CKD) grade (G) 3b-4 cohort. The Uruguayan National Renal Healthcare Program (NRHP-UY) CKD patients’ cohort, included between 1 October 2004 and 1 March 2020 and followed-up until 1 March 2021, was analyzed with the Ethics Committee approval. A total of 6473 patients were analyzed: 56% men, median age 73 (65–79) years, 55% on CKD G3b. At the end of the follow-up, 2459 (37.7%) patients had died (6.4/100 patient–year). There were iPTH data on 2013 patients (younger, with lower estimated glomerular filtration rate (eGFR) and lesser comorbidities). By bivariate Cox analysis the lowest death risk was observed with mean Ca between 9.01 and 10.25 mg/dl, P between 2.76 and 4.0 mg/dl, iPTH ≤ 105 pg/ml, and 25(OH) vitamin D >10 ng/ml. The multivariate Cox regression mortality risk adjusted to age, sex, CKD etiology, diabetes, smoking, cardiovascular comorbidity, blood pressure, proteinuria, eGFR, renin-angiotensin system blockers and vitamin D treatments, serum Ca, P, iPTH, and 25(OH) vitamin D (n = 964) showed that a higher mortality risk was associated with p > 4.00 mg/dl (HR 1.668, CI 95%: 1.201–2.317), iPTH >105 pg/ml (HR 1.386, CI 95%: 1.012–1.989), and 25(OH) vitamin D ≤ 10 ng/ml (HR 1.958, CI 95%: 1.238–3.098) and a lower mortality risk with 1,25(OH)₂ vitamin D treatment (HR 0.639, CI 95%: 0.451–0.906). These data may contribute to the precise G3b-4 CKD-MBD biomarkers levels definition.     

Prostate cancer risk and aggressiveness associated with the CYP1B1 4326C/G (Leu432Val) polymorphism: a meta-analysis of 2788 cases and 2968 controls

To derive a precise estimation of the associations between the cytochrome P450 1B1 (CYP1B1) 4326C/G variants and prostate cancer (PCa) risk or aggressiveness, a meta-analysis was performed using all eligible published studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association in seven literature studies with 2788 cases and 2968 controls. In the overall analysis, no significant association was found between the CYP1B1 4326C/G polymorphism and PCa risk, but ethnicity subgroup analyses and a case-source analysis revealed significant associations. The 4326G allele showed a significant association with increased PCa risk in Asians (OR=1.52, 95% CI: 1.20–1.92), and significant associations were also observed in a heterozygote comparison (OR=1.40, 95% CI: 1.03–1.89), a homozygote comparison (OR=2.38, 95% CI: 1.31–4.33) and in a dominant genetic model (OR=1.52, 95% CI: 1.14–2.01). Moreover, the 4326G allele was also significantly correlated with an increased risk of sporadic PCa (OR=1.13, 95% CI: 1.04–1.24), and significant associations were observed in a heterozygote comparison (OR=1.16, 95% CI: 1.02–1.33), a homozygote comparison (OR=1.24, 95% CI: 1.03–1.49) and a dominant genetic model (OR=1.19, 95% CI: 1.05–1.34). The overall analyses and all subgroup analyses showed no significant association between the 4326C/G polymorphism and PCa aggressiveness. Our meta-analysis showed that CYP1B1 4326G allele is significantly associated with an increased PCa risk in Asians and in sporadic PCa cases.     

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r²=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8–133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1–6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min–max] 71.2 μM [29.2–189.7 μM] pretransplant versus 11.4 μM [8.9–20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.     

Low Vitamin D and High Fibroblast Growth Factor 23 Serum Levels Associate with Infectious and Cardiac Deaths in the HEMO Study

Longitudinal studies testing the relationship between repeated measures of vitamin D or fibroblast growth factor 23 (FGF23) and infectious and cardiac hospitalizations and death in hemodialysis patients have not been reported. We examined the association between yearly 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)₂D), and FGF23 serum levels and various clinical outcomes using time-dependent Cox regression models with repeated yearly measures and fixed-covariate Cox models with only baseline values after controlling for important clinical covariates in the HEMO study. During a median follow-up of 3 years, 582 of the 1340 participants died, and 499 and 514 participants had a hospitalization or death attributed to infectious and cardiac causes, respectively. Patients in the highest 25(OH)D quartile had the lowest risk of infectious events (hazard ratio [HR] 0.66 versus the lowest quartile; 95% confidence interval [95% CI], 0.49–0.89), cardiac events (HR, 0.71; 95% CI, 0.53–0.96), and all-cause mortality (HR, 0.46; 95% CI, 0.34–0.62) in time-dependent analyses. No significant associations of 1,25(OH)₂D with clinical outcomes were observed in time-dependent or fixed-covariate Cox models. In contrast, the highest FGF23 quartile was associated with a higher risk of infectious events (HR, 1.57 versus the lowest quartile; 95% CI, 1.13–2.18), cardiac events (HR, 1.49; 95% CI, 1.06–2.08), and all-cause mortality (HR, 1.50; 95% CI, 1.07–2.12) in fixed-covariate Cox models. The addition of inflammation markers into the statistical models did not attenuate these associations. Thus, disordered mineral metabolism may affect outcomes in chronic hemodialysis patients.     

Influencing factors for mortality in prostate cancer patients with T1 and T2 stage: a retrospective cohort study

BackgroundFew reports have focused on the influencing factors of localized prostate cancer (PCa)-specific mortality so far. This study aimed to develop a competitive risk model for identifying the factors influencing the localized PCa mortality rate based on 135,310 subjects in the Surveillance, Epidemiology, and End Results (SEER) database.MethodsWe included 135,310 localized PCa male patients from SEER database 2004–2016 in this cohort study, and collected the baseline information of all patients, including age of diagnosis, race, marital status, socioeconomic status (SES), American Joint Committee on Cancer (AJCC) stage, prostate-specific antigen (PSA) Gleason score, and so on. The outcome was considered as PCa-specific mortality in this study. The end time of follow-up was November 2018. Independent risk factors were examined by multivariate Fine-Gray analysis. The results are shown by hazard ratio (HR) and 95% confidence interval (CI).ResultsAll patients were divided into three groups: died from localized PCa (n=1,400), died from other causes (n=16,996), and survived (n=116,914). The diagnostic age of 119,899 patients was ≥55 years. The multivariate Fine-Gray analysis indicated that age of diagnosis (55–70 years: HR =1.473, 95% CI: 1.124–1.930; >70 years: HR =2.528, 95% CI: 1.901–3.362), race (American India/Alaska Native, Asian/Pacific Islander: HR =0.653, 95% CI: 0.490–0.870), marital status (divorced: HR =1.433, 95% CI: 1.197–1.717; single: HR =1.463, 95% CI: 1.244–1.719; widowed: HR =1.485, 95% CI: 1.222–1.804), therapeutic method (radiotherapy: HR =1.500; 95% CI: 1.119–2.011), SES (4–10: HR =0.799, 95% CI: 0.664–0.961; ≥11: HR =0.670; 95% CI: 0.534–0.839), AJCC stage (HR =0.820, 95% CI: 0.715–0.940), level of PSA (HR: 1.002, 95% CI: 1.002–1.002) and Gleason score (HR: 2.226, 95% CI: 2.108–2.350) were associated with the risk of localized PCa mortality.ConclusionsThe study determined the influencing factors for mortality in patients with localized PCa through a competitive risk model. This finding may provide a reference for localized PCa patients: localized PCa patients who are older, divorced, widowed, single, have a radiotherapy, have a high PSA level, and Gleason score may be at high risk.     

Mid-term outcomes of coronary artery bypass grafting in patients with mild left ventricular systolic dysfunction: a multicentre retrospective cohort study

 Open in a separate windowOBJECTIVESLeft ventricular systolic dysfunction (LVSD) is common and associated with adverse events in patients receiving coronary artery bypass grafting (CABG). However, the prognosis of mild LVSD has not been clearly described. We aimed to evaluate the mid-term outcomes of patients with mild LVSD following CABG.METHODSThis multicentre cohort study using propensity score matching took place from December 2012 to October 2019 in Jiangsu Province, China, with a mean and maximum follow-up of 3.2 and 7.2 years, respectively. Patients were classified to normal left ventricular systolic function (left ventricular ejection fraction ≥53%) and mild LVSD (left ventricular ejection fraction >40%/<53%). The primary outcomes were death from all causes and death from cardiovascular causes. The secondary outcomes were heart failure, myocardial infarction, repeat revascularization and a composite of all mentioned outcomes, including death from all causes (major adverse events).RESULTSA total of 581 pairs were formed after matching. In-hospital death (1.5% vs 2.1%, P = 0.51) did not differ between 2 cohorts. Throughout 7 years, mild LVSD was associated with higher rates of death from all causes [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.39–0.89; P = 0.012], death from cardiovascular causes (HR 0.55, 95% CI 0.36–0.90; P = 0.017), heart failure (HR 0.60, 95% CI 0.37–0.93; P = 0.023) and major adverse events (HR 0.66, 95% CI 0.49–0.91; P = 0.009). There was no difference in the rates of myocardial infarction and repeat revascularization.CONCLUSIONSMild LVSD was associated with a worse mid-term prognosis in patients following CABG.     

Delayed-type hypersensitivity (DTH) test anergy does not impact CD4 reconstitution or normalization of DTH responses during antiretroviral therapy

Introduction

Delayed-type hypersensitivity (DTH) testing is an in vivo assessment of cell-mediated immunity. Although highly active antiretroviral therapy (HAART) improves immunologic parameters, the relationship between DTH responsiveness and CD4 gains on HAART is not completely understood. We investigated CD4 reconstitution and the change in DTH responses from treatment baseline through 24 months of viral load (VL)-suppressive HAART in the U.S. Military HIV Natural History Study.

Methods

Treatment-naïve subjects with VL <400 copies/mL after ≥24 months on HAART were included (n=302). DTH testing consisted of ≥3 recall antigens, and responses were classified by the number of positive skin tests: anergic (0–1) or non-anergic (≥2). Pre-HAART DTH results were compared for the outcome of CD4 reconstitution at 24 months of HAART. Improvement in DTH responses was also analyzed for those anergic before HAART initiation.

Results

Non-anergic responses were observed in 216 (72%) participants, while 86 (28%) individuals were anergic prior to HAART initiation. Demographically there were similar distributions of age at HIV diagnosis and HAART initiation, as well as gender and race or ethnicity. There were no significant differences between non-anergic and anergic participants in pre-HAART CD4 count (409 cells/μL, interquartile range (IQR) 315–517 vs. 373 cells/μL, IQR 228–487; p=0.104) and VL (4.3 log₁₀ copies/mL, IQR 3.4–4.9 vs. 4.4 log₁₀ copies/mL, IQR 3.6–5.0; p=0.292). Median CD4 gains 24 months after HAART initiation were similar between the non-anergic (220 cells/μL, IQR 115–358) and anergic groups (246 cells/μL, IQR 136–358; p=0.498). For individuals anergic before HAART initiation, DTH normalization occurred at 24 months post-HAART in the majority of participants (51 of 86, 59%). Normalization of DTH responses was not associated with CD4 count at HAART initiation (OR 0.73, 95% CI 0.47, 1.09 per 100 cells; p=0.129) nor with AIDS diagnoses prior to HAART (OR 0.34, 95% CI 0.04, 2.51; p=0.283).

Conclusions

DTH responsiveness has been shown to predict HIV disease progression independent of CD4 count in untreated individuals. In the setting of HAART, pre-HAART anergy does not appear to impact CD4 gains or the ability to normalize DTH responses after 24 months of VL-suppressive HAART.     

Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease: The PREDIAN Trial

Diabetic kidney disease (DKD) is the leading cause of ESRD. We conducted an open-label, prospective, randomized trial to determine whether pentoxifylline (PTF), which reduces albuminuria, in addition to renin-angiotensin system (RAS) blockade, can slow progression of renal disease in patients with type 2 diabetes and stages 3–4 CKD. Participants were assigned to receive PTF (1200 mg/d) (n=82) or to a control group (n=87) for 2 years. All patients received similar doses of RAS inhibitors. At study end, eGFR had decreased by a mean±SEM of 2.1±0.4 ml/min per 1.73 m² in the PTF group compared with 6.5±0.4 ml/min per 1.73 m² in the control group, with a between-group difference of 4.3 ml/min per 1.73 m² (95% confidence interval [95% CI], 3.1 to 5.5 ml/min per 1.73 m²; P<0.001) in favor of PTF. The proportion of patients with a rate of eGFR decline greater than the median rate of decline (0.16 ml/min per 1.73 m² per month) was lower in the PTF group than in the control group (33.3% versus 68.2%; P<0.001). Percentage change in urinary albumin excretion was 5.7% (95% CI, −0.3% to 11.1%) in the control group and −14.9% (95% CI, −20.4% to −9.4%) in the PTF group (P=0.001). Urine TNF-α decreased from a median 16 ng/g (interquartile range, 11–20.1 ng/g) to 14.3 ng/g (interquartile range, 9.2–18.4 ng/g) in the PTF group (P<0.01), with no changes in the control group. In this population, addition of PTF to RAS inhibitors resulted in a smaller decrease in eGFR and a greater reduction of residual albuminuria.     

HDL Cholesterol Efflux Predicts Graft Failure in Renal Transplant Recipients

High-density lipoprotein (HDL) particles are involved in the protection against cardiovascular disease by promoting cholesterol efflux, in which accumulated cholesterol is removed from macrophage foam cells. We investigated whether HDL cholesterol efflux capacity is associated with cardiovascular mortality, all-cause mortality, and graft failure in a cohort of renal transplant recipients (n=495, median follow-up 7.0 years). Cholesterol efflux capacity at baseline was quantified using incubation of human macrophage foam cells with apolipoprotein B–depleted plasma. Baseline efflux capacity was not different in deceased patients and survivors (P=0.60 or P=0.50 for cardiovascular or all-cause mortality, respectively), whereas recipients developing graft failure had lower efflux capacity than those with functioning grafts (P<0.001). Kaplan–Meier analysis demonstrated a lower risk for graft failure (P=0.004) but not cardiovascular (P=0.30) or all-cause mortality (P=0.31) with increasing gender-stratified tertiles of efflux capacity. Cox regression analyses adjusted for age and gender showed that efflux capacity was not associated with cardiovascular mortality (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.67 to 1.19; P=0.43). Furthermore, the association between efflux capacity and all-cause mortality (HR, .79; 95% CI, 0.63 to 0.98; P=0.031) disappeared after further adjustment for potential confounders. However, efflux capacity at baseline significantly predicted graft failure (HR, 0.43; 95% CI, 0.29 to 0.64; P<0.001) independent of apolipoprotein A-I, HDL cholesterol, or creatinine clearance. In conclusion, this prospective study shows that cholesterol efflux capacity from macrophage foam cells is not associated with cardiovascular or all-cause mortality but is a strong predictor of graft failure independent of plasma HDL cholesterol levels in renal transplant recipients.     

CAGS AND ACS EVIDENCE BASED REVIEWS IN SURGERY. 47: Does the long-term use of aspirin decrease the risk of death due to cancer?

Question: Does the long-term use of acetylsalicylic acid (ASA) decrease the risk of death due to cancer? Design: Pooled analysis. Data source: Cochrane Collaboration, Database of Systematic reviews, PubMed and Embase. Study selection: Individual patient data from all randomized trials of daily ASA versus no ASA with a mean duration of scheduled trial treatment of 4 years or longer were used to determine the effect of allocation to ASA on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal (GI) and non-GI cancers. Results: In 8 eligible trials (25 570 patients, 674 cancer-related deaths), allocation to ASA reduced the risk of death due to cancer (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68–0.92, p = 0.003). On analysis of individual patient data, which were available from 7 trials (23 535 patients, 657 cancer-related deaths), the benefit was apparent only after 5 years’ follow-up (all cancers, hazard ratio [HR] 0.66, 95% CI 0.50–0.87; GI cancers, 0.46, 95% CI 0.27–0.77; both p = 0.003). The 20-year risk of cancer death (deaths in 12 659 patients in 3 trials) remained lower in the ASA groups than in the control groups (all solid organ cancers, HR 0.80, 95% CI 0.72–0.88, p < 0.001; GI cancers, HR 0.65, 95% CI 0.54–0.78, p < 0.001), and benefit increased (interaction p = 0.01) with scheduled duration of trial treatment (≥ 7.5 years: all solid cancers, HR 0.69, 95% CI 0.54–0.88, p = 0.003; GI cancers, HR 0.41, 95% CI 0.26–0.66, p < 0.001). The latent period before an effect on deaths could be observed was about 5 years for esophageal, pancreatic, brain and lung cancer, but was longer for stomach, colorectal and prostate cancer. For lung or esophageal cancer, the benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer-related death was greatest for adneocarcinomas (HR 0.66, 95% CI 0.56–0.77, p < 0.001). The benefit was unrelated to ASA dose (75 mg or higher), sex or smoking, but was increased with age; the absolute reduction in 20-year risk of cancer-related death reached 7.08% at age 65 years and older. Conclusion: Daily ASA reduced deaths due to several common cancers during and after the trials. The benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of ASA and for understanding carcinogenesis and its susceptibility to drug intervention.     

In-hospital acute kidney injury and atrial fibrillation: incidence,risk factors,and outcome

BackgroundThe incidence and the risk factors of in-hospitalized acute kidney injury (AKI) in patients hospitalized for atrial fibrillation (AF) were unclear.MethodsThe Improving Care for Cardiovascular Disease in China-AF (CCC-AF) project is an ongoing registry and quality improvement project, with 240 hospitals recruited across China. We selected 4527 patients hospitalized for AF registered in the CCC-AF from January 2015 to January 2019. Patients were divided into the AKI and non-AKI groups according to the changes in serum creatinine levels during hospitalization.ResultsAmong the 4527 patients, the incidence of AKI was 8.0% (361/4527). Multivariate logistic analysis results indicated that the incidence of in-hospital AKI in patients with AF on admission was 2.6 times higher than that in patients with sinus rhythm (OR 2.60, 95% CI 1.77–3.81). Age (per 10-year increase, OR 1.22, 95% CI 1.07–1.38), atrial flutter/atrial tachycardia on admission (OR 2.16, 95% CI 1.12–4.15), diuretics therapy before admission (OR 1.48, 95% CI 1.07–2.04) and baseline hemoglobin (per 20 g/L decrease, OR 1.21, 95% CI 1.10–1.32) were independent risk factors for in-hospital AKI. β blockers therapy given before admission (OR 0.67, 95% CI 0.51–0.87) and non-warfarin therapy during hospitalization (OR 0.71, 95% CI 0.53–0.96) were associated with a decreased risk of in-hospital AKI. After adjustment for confounders, in-hospital AKI was associated with a 34% increase in risk of major adverse cardiovascular (OR 1.34, 95% CI 1.02–1.90, p = 0.023).ConclusionsClinicians should pay attention to the monitoring and prevention of in-hospital AKI to improve the prognosis of patients with AF.     

BP,Cardiovascular Disease,and Death in the Folic Acid for Vascular Outcome Reduction in Transplantation Trial

The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52±9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7–7.4); mean systolic BP was 136±20 mmHg and mean diastolic BP was 79±12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial.     

Urine N-terminal pro-B-type natriuretic peptide and plasma proenkephalin are promising biomarkers for early diagnosis of cardiorenal syndrome type 1 in acute decompensated heart failure: a prospective,double-center,observational study in real-world

BackgroundPatients with acute decompensated heart failure (ADHF) show cardiorenal syndrome type 1 (CRS-1) are more likely to have a poor outcome. However, the current criteria often lead to delayed CRS-1 diagnosis. Therefore, we evaluated the predictive value of plasma proenkephalin (pPENK) and urine NT-proBNP (uNT-proBNP) for early diagnosis of CRS-1 and vulnerable-phase prognosis in ADHF patients.MethodsThe plasma NT-proBNP (pNT-proBNP), pPENK, and uNT-proBNP were measured in 121 ADHF patients on admission. The plasma neutrophil gelatinase-associated lipocalin (pNGAL) was chosen as the reference. Logistic regression was used to determine the predictors of CRS-1. The area under the receiver operating curves (ROCs) was calculated to assess the early diagnostic value of pNGAL, pPENK, and uNT-proBNP/uCr for CRS-1. To evaluate the prognostic risk of factors for the 90-d outcomes of all ADHF patients, the Cox regression was performed and the cumulative risk curve was plotted.ResultsWe found that pPENK [OR 1.093 (95% CI 1.022–1.169), p = 0.010; AUROC = 0.899 (95% CI 0.831–0.946)] and uNT-proBNP/uCr ratio [OR 1.015 (95% CI 1.003–1.028), p = 0.012; AUROC = 0.934 (95% CI 0.874–0.971)] could independently predict the occurrence of CRS-1 in hospitalized patients with ADHF. The pPENK [HR 1.014 (95% CI 1.000–1.042), p = 0.044] and uNT-proBNP/uCr ration [HR 0.998 (95% CI 0.997–1.000), p = 0.045] were also independent predictors of the risk of HF readmission or all-cause death 90 d after discharge in ADHF patients.ConclusionsThe newly found pPENK and noninvasive test of uNT-proBNP/uCr ratio (pg/nmol) on admission may be two promising novel predictive biomarkers for early diagnosis of CRS-1 occurrence and vulnerable-phase outcomes in ADHF patients.     

Partial vs. radical nephrectomy and the risk of all-cause mortality,cardiovascular, and nephrological outcomes

IntroductionThe study’s objective was to examine the effects of renal-preservation surgery on long-term mortality, cardiovascular outcomes, and renal-related outcomes.MethodsWe performed a retrospective cohort study of all partial (n=575) and radical nephrectomies (n=882) for tumors ≤7 cm in diameter between 2002 and 2010 across three academic centers in Ontario, Canada. We linked records from provincial databases to assess patient characteristics and outcomes (median seven years’ followup using retrospective data). A weighted propensity score was used to reduce confounding. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization with major cardiovascular events, non-cancer related mortality, kidney cancer-related mortality, and dialysis.ResultsMean one-year postoperative estimated glomerular filtration rate (eGFR) was 71 mL/min/1.73 m² in the partial group and 52 mL/min/1.73 m² in the radical group. Partial nephrectomy was associated with a lower risk of all-cause mortality in the first five years after surgery (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.27–0.66), which did not extend beyond five years (HR 1.01, 95% CI 0.68–1.49). Kidney cancer-related mortality was lower in the partial compared to the radical group for the first four years after surgery (HR 0.16, 95% CI 0.04–0.72). There were no significant differences between the groups for cardiovascular outcomes or non-cancer related deaths.ConclusionsOverall survival and cancer-specific survival was reduced in radical nephrectomy patients. However, despite reduced renal function in the radical nephrectomy group, non-cancer-related death, cardiovascular events, and dialysis were not significantly different between groups. Long-term benefits of partial nephrectomy may be less than previously believed.