Higher Plasma Creatinine Research Articles

Higher Plasma Creatinine Is Associated with an Increased Risk of Death in Patients with Non-Metastatic Rectal but Not Colon Cancer: Results from an International Cohort Consortium.

Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates AbsoluteIDQ p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I-III) colon (n = 394) or rectal cancer (n = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23-1.72, pFDR = 0.03; but not colon cancer: pFDR = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.

One-year rehospitalisation and mortality after acute heart failure hospitalisation: a competing risk analysis

ObjectiveTo identify factors that independently predict the risk of rehospitalisation and death after acute heart failure (AHF) hospital discharge in a real-world setting, considering death without rehospitalisation as a competing...

The Diagnostic and Prognostic Value of Plasma Galectin 3 in HFrEF Related to the Etiology of Heart Failure.

Aim: The aim of present study is to evaluate the diagnostic and prognostic value of plasma galectin 3 (Gal-3) for HF originating from different causes.Methods: We investigated the plasma levels and expression of Gal-3 in cardiac tissues in two transgenic (TG) strains of mice with cardiomyocyte-restricted overexpression of either β2- adrenergic receptor (β2- AR TG) or Mammalian sterile 20-like kinase 1 (Mst1-TG) in the present study. Additionally, 166 patients suffering from heart failure with reduced ejection fraction (HFrEF) in two hospitals within the Shaanxi province were examined in this study. All these patients were treated according to the Chinese HF guidelines of 2014; subsequently, they were followed up for 50 months, and we analyzed the prediction value of baseline Gal-3 to endpoints in these patients.Results: Gal-3 was localized in the cytoplasm and nucleus of cardiomyocytes, often formed aggregates in Mst1-TG mice. Extracellular Gal-3 staining was uncommon in Mst1-TG hearts. However, in β2-AR TG mice, although Gal-3 was also expressed in myocardial cells, it was more highly expressed in interstitial cells (e.g., fibroblasts and macrophages). Plasma Gal-3 was comparable between nTG and Mst1-TG mice. However, plasma Gal-3 was higher in β2-AR TG mice than in nTG mice. In the cohort of HFrEF patients, the median plasma Gal-3 concentration was 158.42 pg/mL. All participants were divided into two groups according to Gal-3 levels. Patients with Gal-3 concentrations above the median were older, and had lower plasma hemoglobin, but higher plasma creatinine, tissue inhibitor of metalloproteinases 1 (TIMP-1), left ventricular end systolic diameter (LVESD), left ventricular end-systolic volumes (LVESV) and end-diastolic, as well as left ventricular end-diastolic volumes (LVEDV). Spearman correlation analysis revealed that Gal-3 was positively correlated with TIMP-1 (r = 0.396, P < 0.001), LVESV (r = 0.181, P = 0.020) and LVEDV (r = 0.190, P = 0.015). The 50-month clinical follow-up revealed 43 deaths, 97 unplanned re-hospitalizations, and 111 composite endpoint events. Cox analysis demonstrated that although Gal-3 did not provide any prognostic value in either total-HF subjects or coronary-heart-disease (CHD) patients, it did provide prognostic value in non-CHD patients.Conclusion: Although plasma Gal-3 is associated with TIMP-1 and echocardiographic parameters, the diagnostic and prognostic value of Gal-3 in HFrEF is determined by the etiology of HF.

Predicting heart failure events in patients with coronary heart disease and impaired glucose tolerance: Insights from the Acarbose Cardiovascular Evaluation (ACE) trial

AimsHeart failure is a fatal complication of type 2 diabetes but little is known about its incidence in people with impaired glucose tolerance (IGT). We used Acarbose Cardiovascular Evaluation (ACE) trial data to identify predictors of hospitalisation for heart failure (hHF) or cardiovascular (CV) death in patients with coronary heart disease (CHD) and IGT randomised to acarbose or placebo. MethodsIndependent hHF/CV death risk factors were determined using Cox proportional hazards models, with participants censored at first hHF event, CV death, or end of follow-up. ResultsDuring median 5-year follow-up, the composite outcome of hHF/CV death occurred in 393 (6.0%) participants. Significant hHF/CV death multivariate predictors were higher age and plasma creatinine, and prior heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF) and stroke. Acarbose, compared with placebo, did not reduce hHF/CV death (hazard ratio [HR] 0.89, 95% CI 0.64–1.24, P = 0.48) or hHF (HR 0.90, 95% CI 0.74–1.10, P = 0.32). ConclusionsPatients with CHD and IGT at greater risk of hHF/CV death were older with higher plasma creatinine, prior HF, MI, AF or stroke. Addition of acarbose to optimised CV therapy to reduce post-prandial glucose excursions did not reduce the risk of hHF/CV death or hHF. Clinical Trial RegistrationClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513.

Plasticity of gut and metabolic limitations of Deoni calves in comparison to crossbred calves on a high plane of nutrition.

Plasticity of the digestive system is important for the development and productivity of cows. The objective of the study was to measure the plasticity of the gut in 10 each of Holstein Friesian (HF)-crossbred (Bos taurus; X) and indigenous (Bos indicus, e.g. Deoni breed; D) calves randomly distributed to recommended plane (RN) or 25% higher plane (HN) of nutrition. Body weight (BW) change during a 6-month period in indigenous calve irrespective of the plane of nutrition was 35 kg. Dry matter intake (DMI) in Deoni calves was reduced on a high plane of nutrition but not in HF-crossbred (X) calves. DMI in XHN was 7% more than that in XRN. Compared to crossbred, energy intake, metabolism and energy efficiency of indigenous calves were poor. Significantly higher plasma glucose, triglycerides, cholesterol, AST, ALT and creatinine in DRN or DHN than in XRN or XHN indicated metabolic limitations in indigenous calves. Higher triglycerides and AST, ALT and AST/ALT ratio in indigenous calves may be due to poor insulin sensitivity and hyperlipidaemia. Higher triglycerides in serum may also one of the reasons for the reduced DMI in DHN. Serum creatinine (P < 0.05) in XHN or DHN was higher due to increased crude protein (CP) consumption. The study concluded poor plasticity of the digestive system in indigenous calves on a higher plane of nutrition compared to crossbred calves. Indigenous calves suffer metabolic disturbances like hyperglycaemia, hyperlipidaemia and increased creatinine level because of digestive limitation and slower muscle growth.

P0069MICRO RNA 155, 210, 494, 29B AND 34A EXPRESSION PROFILE IN PREECLAMPSIA AND NORMAL PREGNANCIES

Abstract Background and Aims Preeclampsia (PE) is a complex disorder that is characterized by hypertension and proteinuria after the 20th week of pregnancy, and it causes most neonatal morbidity and perinatal mortality. Despite many efforts, the knowledge acquired regarding its pathogenesis and pathophysiology does not allow us to treat it efficiently. It is not possible to arrest its progressive nature, and the available therapies are limited to symptomatic treatment. MicroRNAs (miRNAs) are small non-coding RNAs of approximately 19–23 nucleotides that can bind to the 3’ untranslated region of target mRNAs resulting in the degradation and translation inhibition of the mRNA, thereby regulating gene expression at the post-transcriptional level. Many studies have confirmed deregulated miRNA in pregnant patients with PE, and the function and mechanism of these differentially expressed miRNA are gradually being revealed. Method Sample collection Among the patients in the maternity ward, Department of Obstetrics and Gynecology. pregnant women who carried fetuses from 26 to 40 weeks of gestation were selected for study. Plasma samples were obtained from a total of 90 women in two groups; 48 being preeclamptic and 42 being healthy pregnancies, forming the control group. None of these subjects had undergone an invasive procedure. A volume of 5 mL maternal venous blood was drawn and collected in an ethylenediamine tetraacetic acid (EDTA) tube. The blood samples were centrifuged initially at 1200 g for 10 min and a second time at 10,000 g for 10 min, and 500 mL from the supernatant layer were used. The supernatant layer of the plasma was taken to Department of Molecular Biology and Genetics, Molecular Diagnosis Laboratory for storage at -80°C until the time of study. Total RNA extraction Total RNA was isolated from plasma using Trizol (Invitrogen, Carlsbad, CA) following the manufacturer protocol. Total RNA was analyzed using the commercially available Bioanalyzer Agilent RNA 6000 picoassay. MicroRNA isolation from maternal plasma MicroRNAs were obtained with the High-Specificity miRNA QRT-PCR detection kit (Stratagene-an Agilent Technologies Company, USA-Canada) according to manufacturer recommendations. Micro RNAs were subjected to a polyadenylation reaction as previously described. Next, using an oligo dT primer harboring a consensus sequence, reverse transcription was performed using an Affinity Script RT/RNase Block Enzyme mixture (Stratagene). miRNA was anayzed using the Bioanalyzer 2100- Agilent Small RNA assay. QRT-PCR platform The cDNA was amplified by real-time PCR. The real-time PCR analysis was performed on a Stratagene Mx3005P. This reaction contained a microRNA-specific forward primer, a TaqMan probe complementary to the 3ꞌ of the specific microRNA sequence, as well as part of the polyA adaptor sequence, and a universal reverse primer complementary to the consensus 3ꞌ sequence of the oligodT tail. Results were recorded in clinic sheets and were analyzed using SPss version 22. Results G1 consist of 48 and G2 42 pts. There were no differences in two group in respect to age (mean age was 28± 9.5 and 27± 5.23 in G1 and G2 respectively). Micro RNA155, 210 and 494 were significantly higher in plasma of G1 (Pv 0.001, 0.0001, 0.005 respectively). Micro RNA 29b was significantly lower in G1 (Pv 003). And there was no difference between two groups in respect to Micro RNA 34a (Pv 0.09). And also PE patients with higher plasma creatinine have more plasma level of Micro RNA155 and 210. There was a significant correlation between Micro RNA 494 and anemia in PE patients Conclusion In this study we showed that Micro RNA155, 210 and 494 increased and Micro RNA 29b decreased in PE and after clarifying by further studies may use as a predictor in clinical practice.

Longitudinal study of kidney water management in patients diagnosed with idiopathic hypercalciuria in childhood

IntroductionThere is much debate about whether idiopathic hypercalciuria (IH) affects kidney water management. For the first time in the literature, we carried out a longitudinal study of kidney water management (KWM) in patients diagnosed with IH in childhood and followed-up until adulthood (mean follow-up 17.7±1.4 years). MethodsTwenty-nine patients (7 M, 22 F) over the age of 24 years (mean 28.2±2.9 years, range: 24.1–35.9) who were diagnosed with IH in childhood (mean 7.6±3.2 years, range: 1–14) were included. Maximum urine osmolality (UO) and/or urine volume adjusted for 100ml of glomerular filtration rate (V/GFR) in both age groups (pediatric and adult) were determined. Moreover, whenever possible, in both age groups plasma creatinine levels, plasma sodium levels, uric acid levels, the citrate/creatinine ratio and the calcium/citrate ratio were recorded and a renal and bladder ultrasound was performed. ResultsIn the pediatric age group, KWM was altered in 9/29 cases (31%) (4 with reduced maximum UO and 5 with elevated V/GFR). In adulthood, KWM was found to be affected in 7/29 cases (24.1%) (6 with reduced UO and one with elevated V/GFR). Compared to the pediatric age group, adult patients had lower V/GFR, calcium/creatinine and citrate/creatinine values, as well as higher plasma creatinine, uric acid and calcium/citrate. There were no differences in the maximum UO in both age groups. However, UO in adulthood was significantly lower in subjects who had renal colic compared to those who did not (p=.04). ConclusionsKWM was affected in approximately one third of patients with IH, which persisted 20 years after diagnosis. We think that these results may be due to adherence to the recommended protective diet and to the pharmacological treatment administered at the diagnosis of IH during childhood.

Estudio longitudinal del manejo renal del agua en pacientes diagnosticados de hipercalciuria idiopática en la infancia

IntroductionThere is much debate about whether idiopathic hypercalciuria (IH) affects kidney water management. For the first time in the literature, we carried out a longitudinal study of kidney water management (KWM) in patients diagnosed with IH in childhood and followed-up until adulthood (mean follow-up 17.7±1.4 years). MethodsTwenty-nine patients (7 M, 22 F) over the age of 24 years (mean 28.2±2.9 years, range: 24.1-35.9) who were diagnosed with IH in childhood (mean 7.6±3.2 years, range: 1-14) were included. Maximum urine osmolality (UO) and/or urine volume adjusted for 100ml of glomerular filtration rate (V/GFR) in both age groups (paediatric and adult) were determined. Moreover, whenever possible, in both age groups plasma creatinine levels, plasma sodium levels, uric acid levels, the citrate/creatinine ratio and the calcium/citrate ratio were recorded and a renal and bladder ultrasound was performed. ResultsIn the paediatric age group, KWM was altered in 9/29 cases (31%) (4 with reduced maximum UO and 5 with elevated V/GFR). In adulthood, KWM was found to be affected in 7/29 cases (24.1%) (6 with reduced UO and one with elevated V/GFR). Compared to the paediatric age group, adult patients had lower V/GFR, calcium/creatinine and citrate/creatinine values, as well as higher plasma creatinine, uric acid and calcium/citrate. There were no differences in the maximum UO in both age groups. However, UO in adulthood was significantly lower in subjects who had renal colic compared to those who did not (P=.04). ConclusionsKWM was affected in approximately one third of patients with IH, which persisted 20 years after diagnosis. We think that these results may be due to adherence to the recommended protective diet and to the pharmacological treatment administered at the diagnosis of IH during childhood.

1479-P: Predictors of Incident Hospitalization for Heart Failure in the ACE Trial Population

Background and Aims: Heart failure (HF) is a deadly complication of type 2 diabetes but little is known about its incidence in patients with coronary heart disease (CHD) and impaired glucose tolerance (IGT). We used Acarbose Cardiovascular Evaluation (ACE) trial data to identify baseline variables predictive of incident hospitalization for HF (hHF) or HF-death during median 5.0 years follow-up in this Chinese population with CHD and IGT. Methods: Independent predictors of hHF/HF-death were determined using a Cox proportional hazards model. Patients were censored at first hHF event, HF-death or end of follow-up. The 16 variables tested included age, gender, BMI, smoking, plasma creatinine, prior cardiovascular events, fasting and 2-hour postload glucose and HbA1c. Those with a univariate hHF association (P&amp;lt;0.10) were considered for inclusion in the model, with P values &amp;lt;0.05 required for retention in the multivariable model. Results: Of the 6522 ACE participants, 6278 had no prior HF. They were mean (SD) 64.2 (8.0) years old, BMI 25.4 (3.1) kg/m2 and 73% were male. Of these, 111 (1.8%) had ≥1 episode of adjudicated hHF. Significant independent hHF/HF-death predictors were age, plasma creatinine, prior myocardial infarction (MI) and prior atrial fibrillation (AF) (Table). Conclusion: In Chinese patients with CHD and IGT, those at higher risk of hHF/HF-death were older with higher plasma creatinine values, prior MI and prior AF. Disclosure C.A.B. Scott: None. J.J. McMurray: Other Relationship; Self; AbbVie Inc., Amgen Inc., AstraZeneca, Bayer AG, Bayer AG, Bristol-Myers Squibb Company, DalCor Pharmaceuticals, GlaxoSmithKline plc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Theracos, Inc., Vifor Pharma. L. Rydén: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Bayer AG. Other Relationship; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Y. Sun: None. M. Tendera: Consultant; Self; Bayer AG, Servier. R.L. Coleman: None. R.R. Holman: Advisory Panel; Self; Bayer AG, Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp &amp; Dohme Corp. Other Relationship; Self; AstraZeneca, Bayer AG, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.

Tacrolimus overexposure in kidney transplant recipients during the first post-operative week: caution is required in older patients.

In liver transplantation, tacrolimus trough concentrations (Cmin) above 20 ng/mL during the first days led to worse outcome at 1 year but data in the kidney transplant (KT) era are scarce. The aim of this study was to evaluate the impact of tacrolimus overexposure during the first week post-transplantation on the kidney function (KF) of KT recipients. In this retrospective study, 105 KT recipients were attributed to overexposure group (OG) or normal group according to their Cmin during the first week of treatment. KF was evaluated by comparing the rate of delayed graft function (DGF) and by collecting plasma creatinine from day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 and at 1 year. Risk factors for developing DGF were also investigated using a multivariate model. DGF was more frequent in OG (43% of patients; P = 0.027) which has higher plasma creatinine on day 7, 14, and 21. OG patients were older with more extended criteria donor's grafts. In the multivariate analysis, only cold ischemia time (CIT) remained associated with DGF (OR = 1.003), while TAC overexposure did not reach significance (P = 0.06; OR = 3.9). In this study, we confirmed the predominant role of CIT as a risk factor for the onset of DGF in kidney transplantation. 43% of KT recipients were overexposed with more DGF, especially older patients.

Abstract 122: Deletion of Gstm1 Results in Poor Survival and Exaggerated Kidney Injury Associated With Increased Oxidative Stress and Apoptosis in a Mouse Model of Chronic Kidney Disease

In humans, a common deletion variant of the GSTM1 gene, the GSTM1(0) null allele, results in decreased GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. We reported that GSTM1(0) is associated with increased risks of chronic kidney disease (CKD) progression and death in the African Americans Study of Kidney Disease. To establish a causal relationship between GSTM1 deficiency and CKD progression, we deleted Gstm1 in the mouse, and determined its effect in the sub-total nephrectomy (Nx) model of CKD. After the 8 th week after Nx, 4 out of 8 Gstm1 knockout (KO) mice began to die, whereas wild-type (WT) mice had 100% survival by the study endpoint at 13 th week. Remaining KO mice had significantly higher plasma creatinine (p &lt; 0.05), suggestive of lower GFR. Due to early mortality in KO mice after the 8th week after Nx, we phenotyped mice at the 8 th week (n=6 each). KO mice had significantly higher 1) mean systolic blood pressure (by radiotelemetry): KO 157.2 ± 5, WT 141.1 ± 2.4 mmHg, 2) urine albumin/creatinine ratio (μg/mg): KO 748.4 ± 187.9, WT 235.1 ± 24.6, and 3) renal superoxide (O2·-) levels (counts/min/mg dry tissue): KO 249.7 ± 63; WT 74.5 ± 14.7; P ≤ 0.02. Hydrogen peroxide levels were not different. Renal mRNA levels of the superoxide dismutase isoforms SOD1, SOD2, and SOD3 were significantly lower in KO mice (KO 7.78 ± 0.047, 0.446 ± 0.062, 0.18 ± 0.03; WT 10.64 ± 0.43, 2.432 ± 0.386, 1.188 ± 0.124, respectively, P ≤ 0.003. Total kidney pathology score (KO 18.7 ± 1.5; WT 8 ± 0.6; P &lt;0.0001) showed that KO mice had worse kidney injury, with severe glomerulosclerosis, proteinaceous casts, and chronic inflammation. Both glomerular surface area (SA)/total non-infarcted kidney area (KO 3.347 ± 0.301; WT 2.286 ± 0.268; P = 0.02) and mesangial SA/glomerular SA (KO 35.62 ± 2.219; WT 23.6 ± 2.569; P = 0.005) were significantly increased in KO mice. GSTM1 has also been shown to suppress ASK1 - the apoptosis signal-regulating kinase 1 that induces apoptosis via activation of caspase-3. Consistent with activated ASK1 pathway, KO mice had significantly higher renal TUNEL staining and caspase-3 protein levels (KO 3.594 ± 0.327; WT 2.511 ± 0.208; P = 0.01). In conclusion, in CKD, loss of GSTM1 leads to deleterious outcome associated with increased O2·- levels and apoptosis.

The prevalence of hyperuricemia in Xinjiang Kazaks in Fuhaii

to investigate the prevalence of hyperuricemia (HUA) in Kazak population in Fuhai county, Xinjiang Aletai area. A randomized cross-sectional cluster sampling was performed in Kazaks in Fuhai. A total of 2 006 inhabitants were investigated by household survey. The questionnaires were completed for general performance, past illness history and family history. Height, weight, body mass index (BMI) and blood pressure were measured and recorded. Fasting blood samples were collected for serum uric acid and other biochemical tests. (1) Finally a total of 1 921 Kazaks were enrolled.The serum uric acid level in Kazaks in Fuhai was (234.11 ± 82.56) μmol/L, which was higher in males (287.48 ± 80.27) μmol/L than that in females (201.03 ± 64.74) μmol/L (P<0.001). In HUA group, serum uric acid level also had significant difference between men and women [(498.93 ± 130.24) μmol/L vs (471.20 ± 167.71) μmol/L; P = 0.044]. (2) the prevalence of HUA in Kazak general population was 2.97% (57/1 921). After standardization according to the natural population survey in 2000, the standardized rate in general group was 3.34%, in which the prevalence in males (4.76%, standardized rate was 4.64%) was higher than that in females (1.85%, standardized rate was 1.88%) (P<0.001). There was no gout found in 1 921 Kazaks in Fuhan when the study was taken. (3) Cohorts of different dietary habit ( who preferred vegetable or meat or both of them) who had drunk alcohol had higher prevalence of HUA than those with vegetarian diet without alcohol group (7.69%, 5.66% and 5.62% vs 0.78%; all P<0.05). The cohort who preferred animal food with alcohol had higher prevalence of HUA than those who preferred both vegetable and meat without alcohol (5.66% vs 5.62%; P = 0.009). (4) In men, those who had stable career, higher degree of education, regular income, had higher HUA prevalence than other cohorts. (5) people with HUA had higher plasma TC, TG, LDL, urea nitrogen and creatinine levels, higher blood pressure and higher BMI. The prevalence of HUA was lower in Kazaks in Fuhai than that in other areas in China. Males were more susceptible to HUA. diet, occupation, educational background and economic status may partly affect the prevalence of HUA in Kazaks in Fuhai.

Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial.

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17% by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29% (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.

Transferred allogenic S1P3 deficient dendritic cells (DCs) interact with recipient splenocytes to prevent kidney ischemic-reperfusion injury (IRI) (IRC5P.459)

Abstract The plasticity of DCs permits phenotypic modulation ex-vivo by gene expression or pharmacological agents. Sphingosine-1-phosphate (S1P), a sphingolipid is the natural ligand for S1Pr1-5s. We tested the ability of S1P3-/-(3KO) DC to suppress kidney IRI. BMDCs from B6 WT (B6DC) or 3KOB6DC were adoptively transferred into (-&amp;gt;) Balb/c 1d/7d prior to IRI. Naïve Balb (noDC) had higher plasma creatinine (PCr; mg/dl) compared to sham (1.2±0.17;0.2±0.004,p≤0.01). 3KOB6DCs-&amp;gt;Balb/c were protected from IRI (PCr:0.3±0.07,p≤0.01). 3KOB6DCs-&amp;gt;Balb/c had higher Treg and less CD4 cells compared to naïve or B6DC mice in spleen. The protection afforded by 3KOB6DCs-&amp;gt;Balb/c mice required the recipient mouse to have a spleen; Tregs, CD11c+ DC and T/B cells; Splnx Balb, use of Rag1-/- mice or depletion of recipient Tregs (PC61) or DCs (CD11c-DTR) rendered adoptively transferred 3KODCs ineffective. PKH-26 labeled DCs from WT or 3KO-&amp;gt;Balb/c were located in the marginal zone (MZ) of recipient spleen with close proximity to Tregs. WT and 3KO mice injected with latex beads to demonstrate clearance efficiency showed disruption of MZ in 3KO. Adoptive transfer of 3KOB6DCs prior to IRI attenuates injury through interaction with splenocytes, recipient DCs resulting in induction of Tregs through possible disruption of MZ macs. We conclude that genetically induced deficiency or pharmacological blockade of allogenic S1P3DCs could serve as a useful therapeutic approach to IRI or DGF associated with Transplant.

Genetic variation in the renin–angiotensin–aldosterone system is associated with cardiovascular risk factors and early mortality in established coronary heart disease

This study examined renin-angiotensin-aldosterone (RAAS) system gene variants for associations with cardiovascular risk factors and outcomes in coronary heart disease. Coronary disease patients (n=1186) were genotyped for 21 single-nucleotide polymorphisms (SNPs) within angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin-II type-1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Associations with all-cause mortality and cardiovascular readmissions were assessed over a median of 3.0 years. The AGT M235T 'T' allele was associated with a younger age of clinical coronary disease onset (P=0.006), and the AGT rs2478545 minor allele was associated with lower circulating natriuretic peptides (P=0.0001-P=0.001) and E/E(1) (P=0.018). Minor alleles of AGT SNPs rs1926723 and rs11122576 were associated with more frequent history of renal disease (P0.04) and type-2 diabetes (P0.02), higher body mass index (P0.02) and greater mortality (P0.007). AGT rs11568054 minor allele carriers had more frequent history of renal disease (P=0.04) and higher plasma creatinine (P=0.033). AGT rs6687360 minor allele carriers exhibited worse survival (P=0.02). ACE rs4267385 was associated with older clinical coronary disease onset (P=0.008) and hypertension (P=0.013) onset, increased plasma creatinine (P=0.01), yet greater mortality (P=0.044). Less history of hypertension was observed with the AGTR1 rs12685977 minor allele (P=0.039). Genetic variation within the RAAS was associated with cardiovascular risk factors and accordingly poorer survival.

OC-068 Albumin is central in mediating the cardio-renal dysfunction of cirrhosis: a study in analbuminaemic rats

IntroductionAlbumin is a multifunctional protein which is reduced in concentration and function in liver disease. Albumin infusion prevents and improves renal dysfunction in patients with advanced liver failure but the...

577 ALBUMIN IS CENTRAL IN MEDIATING THE CARDIO-RENAL DYSFUNCTION OF CIRRHOSIS: A STUDY IN ANALBUMINAEMIC RATS

Introduction Albumin is a multifunctional protein which is reduced in concentration and function in liver disease. Albumin infusion prevents and improves renal dysfunction in patients with advanced liver failure but the mechanisms of its beneficial properties are unclear. We hypothesised that albumin is central in the maintenance of cardio-renal function in cirrhosis and albumin impairment worsens outcome. In order to answer this question we investigated analbuminaemic rats, characterised by lack of albumin but with normal protein concentration, following induction of cirrhosis with bile duct ligation (BDL). Methods Male Sprague-Dawley (SD) and Nagase analbuminaemic (NAR) rats were studied 6 weeks after BDL or sham surgery (n=6 sham-SD, 8 sham-NAR, 7 SD-BDL, 7 NAR-BDL). Rats underwent systemic mean arterial pressure (MAP) and portal pressure (PP) assessment under terminal anaesthesia. Plasma and urine were collected for measurements of renal function and protein profile. Plasma renin activity (PRA) was measured as a marker of cardio-renal dysfunction. Urinary neopterin, a marker of macrophage activation was assessed. Results NARs showed plasma total protein concentration similar to SD despite lack of albumin before (72±15 vs 82±8) and after BDL (67±7 vs 75±22). After BDL both groups of animals showed histological evidence of severe liver damage, though the NARs showed a significantly worse systemic haemodynamics with lower MAP (p=0.01), evidence of renal dysfunction indicated by higher plasma creatinine and higher PRA (p Conclusion A lack of albumin was associated with a raised PRA and a marked deterioration in systemic haemodynamics and renal function after liver injury (BDL), despite normal total plasma protein concentration. This worsened outcome in the absence of albumin strongly supports the central role of albumin in maintenance of cardio-renal function in liver failure and may indicate that albumin plays a crucial role in moderating inflammation. Competing interests None declared.

Associations between the use of metformin, sulphonylureas, or diet alone and cardiovascular outcomes in 6005 people with type 2 diabetes in the FIELD study

Aims We aimed to determine the associations between metformin or sulphonylurea monotherapy at study entry into the FIELD diabetes trial and (1) metabolic risk factors, (2) risk of a first major cardiovascular (CVD) outcome, and (3) the effect of each therapy on the risk-modifying effect of fenofibrate. Methods Patients receiving metformin or sulphonylureas without insulin therapy were compared for the relative risk of CVD outcomes, adjusted for differences in baseline characteristics likely to affect risk. Results Metformin-treated patients were likely to be younger, female, or obese. Metformin was associated with higher levels of lipids (other than LDL-C) and homocysteine ( P < 0.001). Sulphonylurea-treated patients had a longer history of diabetes and more CVD and microvascular disease. Sulphonylurea treatment was associated with higher plasma creatinine and lower plasma HDL-C ( P < 0.001). The risks of all CVD outcomes were higher for those on sulphonylureas than diet alone, but were nonsignificant after adjustment for the duration and intensity of diabetes and severity of risk factors. Metformin and sulphonylureas did not significantly influence the benefits of fenofibrate on CVD outcomes. Conclusions Apparent differences in the risk of CVD outcomes associated with oral hypoglycemics therapy were largely abolished by adjustment for diabetes and CVD risk factors.

Determinants of the hyperdynamic circulation and central hypovolaemia in cirrhosis

BackgroundPatients with advanced cirrhosis often develop a hyperdynamic circulation with central hypovolaemia. The events that initiate the systemic haemodynamic abnormalities and the coupling of these factors to splanchnic haemodynamics are...

Canine dilated cardiomyopathy: a retrospective study of prognostic findings in 367 clinical cases

To review the association between clinical signs and diagnostic findings and the survival time of dogs with dilated cardiomyopathy (DCM), and any influence of treatment prescribed. A retrospective observational study of 367 dogs with DCM. Survival times until death or euthanasia for cardiac reasons were analysed using the Kaplan-Meier method plus univariate and multivariate Cox proportional hazards models. Two-tailed P values less than 0.05 were considered statistically significant. In the multivariate model, left ventricular diameter (LVDs)-index (P=0.0067), presence of pulmonary oedema on radiography (P=0.043), presence of ventricular premature complexes (VPCs) (P=0.0012), higher plasma creatinine (P=0.0002), lower plasma protein (P=0.029) and great Dane breed (P=0.0003) were negatively associated with survival. Most dogs were treated with angiotensin-converting enzyme inhibitors (93%) or furosemide (86%), and many received digoxin (50%) and/or pimobendan (30%). Thirteen dogs were lost to follow-up. No conclusions could be made in this study on the association between use of drugs and survival. The LVDs-index was the single best variable for assessing the prognosis in this group of dogs with DCM. Other variables that were negatively associated with survival were presence of pulmonary oedema on radiography, presence of VPCs, higher plasma creatinine, lower plasma protein and great Dane breed.