BackgroundIn this prospective study, we aimed to assess the haemodynamic changes before and after haemodialysis (HD) in cardiac healthy subjects on chronic HD by imaging methods and endocrine markers of fluid balance.MethodsMid-regional pro-atrial natriuretic peptide (MR-proANP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), vasopressin (AVP) and copeptin (CT-proAVP), metanephrines and normetanephrines, renin and aldosterone, standard transthoracic echocardiography and diameter of vena cava inferior (VCID) were performed in 20 patients with end stage renal disease (CKD5D) before and after HD and were stratified in residual excretion (RE, less or more 0.5 l) and ultrafiltration rate (UF, less or more 2 l).ResultsCopeptin was significantly higher in patients before HD. Copeptin was inversely correlated with haemodialysis treatment adequacy (KT/v), RE and UF, but was not significantly influenced by age, gender and body mass index (BMI). MR-proANP was significantly reduced by haemodialysis by 27% and was inversely correlated with KT/v, but there was a significant influence by UF, RE, age, gender and BMI. NT-proBNP was significantly higher in patients before HD and was not influenced by RE and UF. Renin, aldosterone, metanephrines and normetanephrines did not demonstrate significant differences. Echocardiographic parameters and VCID were significantly correlated with RE, UF and copeptin.ConclusionModern biomarkers will provide cardiovascular risk assessment, but elimination (UF), RE and other factors may influence the serum concentrations, e.g. in patients with renal impairment. The interpretation will be limited by altered reference ranges, and will be restricted to individual courses combined with clinical and echocardiographic data.

BackgroundAcute kidney injury (AKI) is being increasingly recognised in ageing populations. There are a paucity of data about AKI risk factors among older individuals with diabetes and infections, who are at particularly high risk of AKI. The objective of this study was to evaluate the risk factors for developing acute kidney injury (AKI) amongst older patients with diabetes and community-acquired pneumonia (CAP) in England, and whether the impact of underlying kidney function varied with age.MethodsThis was a population-based retrospective cohort study over 7 years (01/04/2004–31/3/2011) using electronic health records from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. The study population comprised individuals with diabetes aged ≥65 years with CAP. Associations between demographic, lifestyle factors, co-morbidities and medications and development of AKI within 28 days of CAP were explored in a logistic regression model.ResultsAmong 3471 patients with CAP and complete covariate data, 298 patients developed subsequent AKI. In multivariable analyses, factors found to be independently associated with AKI included: male sex (adjusted odds ratio, aOR: 1.56 95% confidence interval (CI): 1.20–2.04), hypertension (aOR1.36 95% CI 1.01–1.85), being prescribed either angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor-blockers (aOR: 1.59 95% CI: 1.19–2.13), or insulin (aOR: 2.27 95% CI: 1.27–4.05), presence of proteinuria (aOR 1.27 95% CI 0.98–1.63), and low estimated glomerular filtration rate (eGFR). The odds of AKI were more graded amongst older participants aged ≥80 years compared to those of younger age: for eGFR of ≤29 mL/min/1.73m2 (vs 60 ml/min/1.73m2) aOR: 5.51 95% CI 3.28–9.27 and for eGFR 30–59 mL/min/1.73m2 1.96 95% CI 1.30–2.96, whilst any eGFR < 60 ml/min/1.73m2 was associated with approximately 3-fold increase in the odds of AKI amongst younger individuals (p-value for interaction = 0.007).ConclusionsThe identified risk factors should help primary care and hospital providers identify high risk patients in need of urgent management including more intensive monitoring, and prevention of AKI following pneumonia.

BackgroundPatients treated with dialysis have high rates of brain infarcts, brain atrophy, and white matter disease. There are limited data regarding the presence of more subtle damage to brain white matter.MethodsIn the Cognition and Dialysis Study, we compared brain structure using diffusion tensor imaging in hemodialysis (HD) patients to individuals without known kidney disease, using tract based spatial statistics (TBSS) to compare Fractional Anisotropy (FA) and Mean Diffusivity (MD). Statistical comparison of each overlaid voxel was age controlled using a permutation based corrected p value of <0.05.ResultsThirty-four HD patients and twenty six controls (52 vs 51 years for HD vs control) had adequate magnetic resonance imaging for analysis. The HD group had fewer women (38% vs 23%) and a higher prevalence of diabetes (29% vs 8%), heart failure (29% vs 0%) and clinical stroke (15% vs 0%). Hemodialysis patients had significantly lower FA across multiple white matter fiber tracts, with fronto-temporal connections, the genu of the corpus callosum and the fornix more significantly affected than posterior regions of the brain. Similarly, HD patients had significantly higher mean diffusivity in multiple anterior brain regions. Results remained similar when those with a prior history of stroke were excluded.ConclusionsIn HD patients, there is more white matter disease in the anterior than posterior parts of the brain compared to controls without kidney disease. This pattern of injury is most similar to that seen in aging, suggesting that developing chronic kidney disease and ultimately kidney failure may result in a phenotype consistent with accelerated aging.

BackgroundAlthough hyperuricemia is common after orthotopic liver transplantation (OLT), its relationship to mortality, progressive kidney disease, or the development of end stage renal disease (ESRD) is not well-described.MethodsData from 304 patients undergoing OLT between 1996 and 2010 were used to assess the association of mean serum uric acid (UA) level in the 3-months post-OLT with mortality, doubling of creatinine, and ESRD incidence. Post-OLT survival to event outcomes according to UA level and eGFR was assessed using the Kaplan Meier method and multivariate Cox proportional hazards models.ResultsMean UA level among the 204 patients with an eGFR level ≥60 ml/min/1.73 m2 was 6.4 mg/dl compared to 7.9 mg/dl among the 100 patients with eGFR <60 (p < 0.0001). During a median of 4.6 years of follow-up, mortality rate, doubling of creatinine, and ESRD incidence were 48.9, 278.2, and 20.7 per 1000 person-years, respectively. In the first 5 years of follow-up, elevated UA was associated with mortality (Hazard Ratio, HR = 1.7; p = 0.045). However, among those with eGFR ≥ 60, UA level did not predict mortality (HR = 1.0; p = 0.95), and among those with eGFR < 60, elevated UA was a strong predictor of mortality (HR = 3.7[1.1, 12.0]; p = 0.03). UA was not associated with ESRD, but was associated with doubling of creatinine among diabetics (HR = 2.2[1.1, 4.3]; p = 0.025).ConclusionIn this post-OLT cohort, hyperuricemia independently predicted mortality, particularly among patients with eGFR < 60, and predicted doubling of creatinine among diabetics.

BackgroundIntermedin [IMD, adrenomedullin-2 (ADM-2)] attenuates renal fibrosis by inhibition of oxidative stress. However, the precise mechanisms remain unknown. Heme oxygenase-1 (HO-1), an antioxidant agent, is associated with antifibrogenic effects. ADM is known to induce HO-1. Whether IMD has any effect on HO-1 is unclear. Herein, we determined whether the antifibrotic properties of IMD are mediated by induction of HO-1.MethodsRenal fibrosis was induced by unilateral ureteral obstruction (UUO) performed on male Wistar rats. Rat proximal tubular epithelial cell line (NRK-52E) was exposed to rhTGF-β1 (10 ng/ml) to establish an in vitro model of epithelial-mesenchymal transition (EMT). IMD was over-expressed in vivo and in vitro using the vector pcDNA3.1-IMD. Zinc protoporphyrin (ZnPP) was used to block HO-1 enzymatic activity. IMD effects on HO-1 expression in the obstructed kidney of UUO rat and in TGF-β1-stimulated NRK-52E were analyzed by real-time RT-PCR, Western blotting or immunohistochemistry. HO activity in the obstructed kidney, contralateral kidney of UUO rat and NRK-52E was examined by measuring bilirubin production. Renal fibrosis was determined by Masson trichrome staining and collagen I expression. Macrophage infiltration and IL-6 expression were evaluated using immunohistochemical analysis. In vivo and in vitro EMT was assessed by measuring α-smooth muscle actin (α-SMA) and E-cadherin expression using Western blotting or immunofluorescence, respectively.ResultsHO-1 expression and HO activity were increased in IMD-treated UUO kidneys or NRK-52E. The obstructed kidneys of UUO rats demonstrated significant interstitial fibrosis on day 7 after operation. In contrast, kidneys that were treated with IMD gene transfer exhibited minimal interstitial fibrosis. The obstructed kidneys of UUO rats also had greater macrophage infiltration and IL-6 expression. IMD restrained infiltration of macrophages and expression of IL-6 in UUO kidneys. The degree of EMT was extensive in obstructed kidneys of UUO rats as indicated by decreased expression of E-cadherin and increased expression of α-SMA. In vitro studies using NRK-52E confirmed these observations. EMT was suppressed by IMD gene delivery. However, all of the above beneficial effects of IMD were eliminated by ZnPP, an inhibitor of HO enzyme activity.ConclusionThis study demonstrates that IMD attenuates renal fibrosis by induction of HO-1.

BackgroundFracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates.MethodsVolumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures.ResultsThe fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z-score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z-score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z-score.ConclusionsBone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation.Trial registrationThis study was registered at ClinicalTrials.gov with identifier NCT01344434.