Abstract
Background and Aims
Male sex is considered a major risk factor for cardiovascular (CV) disease in the general population, but the role of this factor in the high risk for CV disease in the ...pre-dialysis CKD population is still debated.
Methods
We tested the relationship between sex and fatal and non-fatal major CV events (myocardial infarction, heart failure, arrhythmia, angina, stroke, transient ischemic attack, peripheral vascular disease, major arterial or venous thrombotic episodes and sudden death) in a cohort including 759 stage 2-5 CKD consecutively recruited from 22 Nephrology units in southern Italy between October 2005 and September 2008. After the initial assessment, patients were followed up for a median time of 36 months (range 0.3–48 months).
Results
Four hundred fifty-five patients were males (60%). The proportion of smokers was about 4 times higher in males (71.4%) than in females (17.4%). Males and females differed in the prevalence of diabetes (38.5% versus 29.6%) and the frequency of background CV comorbidities (35.6% versus 19.7%, P<0.001). Waist circumference (100.9±12.4 versus 96±14.1 cm), eGFR (37.5±13.4 versus 33±12.7 ml/min/1.73 m2), 24-hour urinary protein excretion (median: 0.7 g/24h, IQR: 0.2-1.6 g/24h versus 0.5, IQR: 0.2-1.2 g/24 h), and haemoglobin (13.4±1.9 versus 12.0±1.4 g/dL) were higher in males than in females. Serum phosphate (3.6±0.75 versus 3.9±0.75 mg/dL), hs-CRP (median; 2.2 mg/dl, IQR: 1-4.7mg/dl versus 2.8 mg/dl, IQR: 1.2-6.4 mg/dl) and total cholesterol (178.3±42.1 versus 198.8±45.6 mg/dl) were lower in males than in females. During follow-up, 42 patients died, and 118 had fatal and non-fatal CV events. On univariate Cox regression analyses, male gender failed to be associated with all-cause mortality but was strongly related to the incidence rate of fatal and non-fatal major CV events HR 1.75, 95% CI: 1.18-2.60, P=0.006. Data adjustment for a series of major potential confounders did not materially affect the strength of this relationship HR:1.78, 95% CI: 1.03-3.09. Further analysis testing the effect of age on major CV outcomes by gender showed an effect modification by this risk factor on the same outcome (P=0.037) because the hazard ratio of male versus female CV events increased progressively with ageing (Figure 1).
Conclusion
The excess risk for CV mortality by the male gender in the general population holds in stage G2-5 CKD patients. Age is a modifier for the excess risk for CV events in CKD patients because the risk excess of the male gender increases linearly across a wide age spectrum in CKD patients.
Abstract
Background and Aims
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that regulates various physiological processes in both the central and peripheral nervous systems, including ...cardiovascular and metabolic control. We showed that high plasma NPY predicts CKD progression (NDT 2018;33:1805-1812) in a cohort of 735 patients with stage G2-5 CKD. Whether this association is causal in nature is undetermined.
Method
In the same cohort of the previous study, we tested the relationship between NPY gene variability, as assessed by six single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure which explained about 80% of gene variability, and the incidence rate of renal events (dialysis/transplantation/eGFR reduction >30%) over a median follow up of 36 months (inter-quartile range 35-37 months).
Results
Three variants rs16131 (TT, n = 563; CT+CC, n = 172), rs16140 (CG+GG, n = 413; CC, n = 322), rs16148 (CT+CC, n = 456; TT, n = 279) coherently associated to the incidence rate of renal events (HR ranging from 1.36 to 1.57, P≤0.029). A dose response relationship was found between the number of risk variants and renal events, the HR for this outcome being highest in patients with three risk genotypes (HR: 1.66, 95% 1.05-2.61). In a multivariate model adjusting for traditional risk factors (age, gender, smoking, diabetes, cholesterol, systolic BP and background cardiovascular comorbidities) and factors peculiar to CKD (haemoglobin, eGFR, albumin, phosphate, and C-reactive protein), the association remained highly significant (P for trend = 0.001). In a separate analysis including the three variants simultaneously, only the rs16131 variant maintained an independent association with the risk for renal events (HR: 1.58, 95% CI 1.11-2.24, P = 0.01).
Conclusion
This Mendelian randomization study based on three gene variants is fully in line with findings indicating that high plasma NPY predicts a high risk for renal events and lends support to the hypothesis that NPY is causally involved in CKD progression. Establishing the functional significance of the rs16131 variant is a clinical research priority. Drugs antagonizing circulating NPY or its receptors, indeed, might favourably impact on CKD progression.
Behavior of neural networks is irremediably determined by the specific loss and data used during training. However it is often desirable to tune the model at inference time based on external factors ...such as preferences of the user or dynamic characteristics of the data. This is especially important to balance the perception-distortion trade-off of ill-posed image-to-image translation tasks. In this work, we propose to optimize a parametric tunable convolutional layer, which includes a number of different kernels, using a parametric multi-loss, which includes an equal number of objectives. Our key insight is to use a shared set of parameters to dynamically interpolate both the objectives and the kernels. During training, these parameters are sampled at random to explicitly optimize all possible combinations of objectives and consequently disentangle their effect into the corresponding kernels. During inference, these parameters become interactive inputs of the model hence enabling reliable and consistent control over the model behavior. Extensive experimental results demonstrate that our tunable convolutions effectively work as a drop-in replacement for traditional convolutions in existing neural networks at virtually no extra computational cost, outperforming state-of-the-art control strategies in a wide range of applications; including image denoising, deblurring, super-resolution, and style transfer.
The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine ...dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis
. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production
. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRAS
cell lines display decreased glutaminolysis, lower NADPH/NADP
and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRAS
PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRAS
PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRAS
rewired glutamine metabolism
, and thus it should be considered a key metabolic target for the treatment of this refractory tumour.
HDAC6 is a unique histone deacetylase that targets cytoplasmic non-histone proteins and has a specific ubiquitin-binding activity. Both of these activities are required for HDAC6-mediated formation ...of aggresomes, which contain misfolded proteins that will ultimately be degraded via autophagy. HDAC6 deacetylase activity is increased following phosphorylation on serine 22 (phospho-HDAC6). In human, HDAC6 localizes in neuronal Lewy bodies in Parkinson’s disease (PD) and in oligodendrocytic Papp-Lantos bodies in Multiple System Atrophy (MSA). However, the expression of phospho-HDAC6 in post-mortem human brains is currently unexplored. Here, we evaluate and compare the distribution of HDAC6 and its phosphorylated form in human brains obtained from patients affected by three forms of parkinsonism: two synucleinopathies (PD and MSA) and a tauopathy (Progressive Supranuclear Palsy, PSP). We find that both HDAC6 and its phosphorylated form localize with pathological protein aggregates, including -Synuclein-positive Lewy bodies in PD and Papp-Lantos bodies in MSA, and phospho-Tau-positive neurofibrillary tangles in PSP. We further find a direct interaction of HDAC6 with -Synuclein with proximity ligation assay (PLA) in Lewy bodies and in neuropil of PD patients. Taken together, our findings suggest that both HDAC6 and phospho-HDAC6 regulate the homeostasis of intra-neuronal proteins in parkinsonism.
BACKGROUND:Neuropeptide Y (NPY) is a multifaceted sympathetic neurotransmitter regulating reflex cardiovascular control, myocardial cell growth, inflammation and innate immunity. Circulating NPY ...levels predict cardiovascular mortality in patients with end stage kidney disease on dialysis but this relationship has never been tested in predialysis chronic kidney disease (CKD) patients.
METHODS:We investigated the relationship between circulating NPY and the risk for cardiovascular events (Fine & Gray competing risks model) in a cohort of 753 stages 2–5 CKD patients over a median follow-up of 36 months.
RESULTS:Independently of other risk factors, plasma NPY was directly related with the glomerular filtration rate (β = −0.19, P < 0.001) but was independent of systemic inflammation as quantified by serum IL6 and C reactive protein. Over follow-up 112 patients had cardiovascular events and 12 died. In analyses fully adjusted for traditional risk factors and a large series of CKD-specific risk factors and considering death as a competing event (Fine and Gray model) a 0.25 μmol/l increase in NPY robustly predicted the incident risk for cardiovascular events (subdistribution hazard ratio1.25; 95% confidence interval1.09–1.44; P = 0.002). Furthermore, the fully adjusted NPY – cardiovascular outcomes relationship was modified by age (P = 0.012) being quite strong in young patients but weaker in the old ones.
CONCLUSION:NPY is an independent, robust predictor of cardiovascular events in predialysis CKD patients and the risk for such events is age-dependent being maximal in young patients. These findings suggest that NPY may play a role in the high risk of cardiovascular disease in this population.
Hyperkalemia is a potential life-threatening condition among chronic kidney disease (CKD) patients. Available estimates of the burden of this alteration in CKD are mainly derived from large ...administrative databases. Since K measurements in patients in these databases are often dictated by clinical reasons, longitudinal studies including pre-planned measurements of potassium independently of clinical complication/symptoms may produce more reliable estimates of the frequency and the risk factors underlying hyperkalemia in CKD patients. We estimated the prevalence and the incidence of hyperkalemia in a longitudinal study in 752 stages 2–5 CKD patients lasting 3 years and including up to seven pre-planned assessment of key biochemical measurements including K. At baseline, 203 out of 752 patients (27%) had serum K > 5.0 mM/L and 33% had acidosis (HCO
3
≤ 22 mmol/L). Among those without hyperkalemia at baseline (
n
= 549), 284 patients developed this alteration across the 3-year follow-up. The point prevalence of hyperkalemia rose from 27% (baseline) to 30% (last visit) (
P
= 0.001). In a multivariate model, hyperkalemia at baseline odds ratio (OR):7.29, 95% CI 5.65–9.41,
P
< 0.001, venous bicarbonate levels OR (1 mmol/l): 0.92, 0.89–0.96,
P
< 0.001, eGFR OR (1 ml/min/1.73m
2
): 0.98, 0.97–0.99,
P
< 0.001, use of ACE inhibitors (OR: 1.68, 1.28–2.19,
P
< 0.001) and angiotensin II antagonists (OR: 1.30, 1.01–1.68,
P
= 0.045) were related to hyperkalemia over time. Of note, venous bicarbonate levels emerged as an independent risk factor of hyperkalemia over time also in a separate analysis of patients with and without hyperkalemia at baseline. In a cohort of CKD patients including pre-planned measurements of K, 27% of patients had hyperkalemia. Metabolic acidosis and the use of drugs interfering with renin–angiotensin system were the strongest modifiable risk factors for this potentially life-threatening alteration in CKD in longitudinal analyses in the whole study cohort and in patients developing de novo hyperkalemia over time.
High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in ...dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2–4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04–1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03–1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68–4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05–2.91). High ePASP is relatively common in patients with stage 2–4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials.
Background Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is ...a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. Study Design Cross-sectional study. Setting & Participants Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. Factor Serum uric acid level, rs734553 allele, and age. Outcome Ultrasound biomarkers of atherosclerosis (intima-media thickness IMT and internal diameter) and pulse wave velocity (PWV). Results Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 ( P = 8 × 10-6 ). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (β = 0.33; P = 0.01), whereas no such relationship was found for internal diameter (β = −0.15; P = 0.3) or PWV (β = 0.10; P = 0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age–internal diameter relationships in both crude and fully adjusted (β = 0.40 P < 0.001 and β = 0.48 P = 0.003, respectively) analyses. Limitations This is a hypothesis-generating study. Conclusions Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid–lowering interventions are needed to prove this hypothesis.
ABSTRACT
Background
Metabolic acidosis accelerates chronic kidney disease (CKD) progression towards kidney failure in animal models. Clinical trials testing the effect of bicarbonate on kidney ...outcomes are underpowered and/or of suboptimal quality. On the other hand, observational studies testing the same hypothesis are generally based on bicarbonate measured at a single time point.
Methods
We studied the longitudinal relationship between repeated venous bicarbonate levels and a predefined composite renal outcome (a ≥30% estimated glomerular filtration rate reduction, dialysis or transplantation) by using group-based trajectory model (GBTM) analysis. The GBTM analysis was used to classify patients based on individual bicarbonate levels over time. The relationship between trajectory groups and renal outcomes was investigated using crude and adjusted Cox regression models. A total of 528 patients with stage 2–5 CKD were included in the analysis.
Results
The GBTM analysis identified four distinct trajectories of bicarbonate levels: low, moderate, moderate-high and high. During the follow-up period, 126 patients experienced the combined renal endpoint. The hazard rate of renal events decreased dose-dependently from the lowest to the highest bicarbonate trajectory. After adjusting for potential confounders, there was a 63% risk reduction for the composite renal endpoint for patients in the high trajectory category compared with those in the low trajectory category.
Conclusion
The study found that higher bicarbonate trajectories were associated with a lower risk of adverse renal outcomes in CKD patients. These results suggest that strategies to maintain higher bicarbonate levels may benefit patients with CKD. However, further high-quality randomised trials are needed to confirm these findings and recommend bicarbonate supplementation as a strategy to delay CKD progression.
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