Search

Background Endothelin A receptor antagonists (ETARA) slow chronic kidney disease (CKD) progression but their use is limited due to fluid retention and associated clinical risks. Sodium glucose cotransporter 2 inhibitors (SGLT2i) cause osmotic diuresis and improve clinical outcomes in CKD and heart failure. We hypothesized that co-administration of the SGLT2i dapagliflozin with the ETARA zibotentan would mitigate the fluid retention risk using hematocrit (Hct) and bodyweight as proxies for fluid retention. Methods Experiments were performed in 4% salt fed WKY rats. First, we determined the effect of zibotentan (30, 100 or 300 mg/kg/day) on Hct and bodyweight. Second, we assessed the effect of zibotentan (30 or 100 mg/kg/day) alone or in combination with dapagliflozin (3 mg/kg/day) on Hct and bodyweight. Results Hct at day 7 was lower in zibotentan versus vehicle groups (zibotentan 30 mg/kg/day 43% (standard error [SE] 1), 100 mg/kg/day, 42% (1); and 300 mg/kg/day 42% (1); versus vehicle 46% (1); p Conclusions Combining ETARA with SGLT2i prevents ETARA induced fluid retention, supporting clinical studies to assess the efficacy and safety of combining zibotentan and dapagliflozin in individuals with CKD.

Background Estimation of influenza disease burden is necessary to monitor the impact of intervention programmes. This study aims to estimate the attributable fraction of respiratory and circulatory disease due to influenza among Australian adults 50–64 and ≥65 years of age. Methods A semi‐parametric generalised‐additive model was used to estimate annual and average rate of influenza‐attributable hospitalisation and death per 100,000 population under the principal diagnosis of influenza/pneumonia, respiratory, circulatory and myocardial infarction (MI) from 2001 through 2017. Results Over the study period, seasonal influenza accounted for an estimated annual average respiratory hospitalisation rate of 78.9 (95%CI: 76.3, 81.4) and 287.5 (95%CI: 279.8, 295.3) per 100,000 population in adults aged 50–64 and ≥65 years, respectively. The corresponding respiratory mortality rates were 0.9 (95%CI: 0.7, 1.2) and 18.2 (95%CI: 16.9, 19.4) per 100,000 population. The 2017 season had the highest influenza‐attributable respiratory hospitalisations in both age groups, and respiratory complications were estimated approximately 2.5 times higher than the average annual estimate in adults aged ≥65 years in 2017. For mortality, on average, influenza attributed 1,080 circulatory and 361 MI deaths in adults aged ≥65 years per year. Influenza accounted for 1% and 2.8% of total MI deaths in adults aged 50–64 and ≥65 years, respectively. Conclusion Rates of cardiorespiratory morbidity and mortality were high in older adults, whilst the younger age group contributed a lower disease burden. Extension of influenza vaccination programme beyond the targeted population could be an alternative strategy to reduce the burden of influenza.

Supplemental Digital Content is available in the text., GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ′5538. In male wild-type mice, intravenous AZ′5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ′5538 had no effect on blood pressure or renal hemodynamics in Gpr81−/− mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ′5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81−/− mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

Chronic ACTH exposure is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2 weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P Ki67, Ccna2, Ccnb2 and Tk1 expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1a and Cdkn1c, which are known to be active in hypertrophied cells, were increased >4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were downregulated and apoptotic cells (Tunel staining) were fewer (P

In the kidney, purinergic (P2) receptor‐mediated ATP signaling has been shown to be an important local regulator of epithelial sodium transport. Appropriate sodium regulation is crucial for blood pressure (BP) control and disturbances in sodium balance can lead to hypo‐ or hypertension. Links have already been established between P2 receptor signaling and the development of hypertension, attributed mainly to vascular and/or inflammatory effects. A transgenic mouse model with deletion of the P2X4 receptor (P2X4−/−) is known to have hypertension, which is thought to reflect endothelial dysfunction and impaired nitric oxide (NO) release. However, renal function in this model has not been characterized; moreover, studies in vitro have shown that the P2X4 receptor can regulate renal epithelial Na+ channel (ENaC) activity. Therefore, in the present study we investigated renal function and sodium handling in P2X4−/− mice, focusing on ENaC‐mediated Na+ reabsorption. We confirmed an elevated BP in P2X4−/− mice compared with wild‐type mice, but found that ENaC‐mediated Na+ reabsorption is no different from wild‐type and does not contribute to the raised BP observed in the knockout. However, when P2X4−/− mice were placed on a low sodium diet, BP normalized. Plasma aldosterone concentration tended to increase according to sodium restriction status in both genotypes; in contrast to wild‐types, P2X4−/− mice did not show an increase in functional ENaC activity. Thus, although the increased BP in P2X4−/− mice has been attributed to endothelial dysfunction and impaired NO release, there is also a sodium‐sensitive component.

Chronic activation of the renin-angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia, and inflammation. Despite similar hypertension, an injurious response to excess angiotensin II is greater in F344 than in Lewis rats; the latter displaying renoprotection. Here we studied whether p2rx7, encoding the P2X7 receptor (P2X7R), is a candidate gene for the differential susceptibility to vascular dysfunction under high angiotensin II tone. A 14-day infusion of angiotensin II into F344 rats increased blood pressure by about 15 mm Hg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by half, and the corticomedullary oxygenation gradient disrupted. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the slope. Sodium excretion was increased sixfold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in angiotensin II-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Thus, activation of P2X7R induces microvascular dysfunction and regional hypoxia when angiotensin II is elevated and these effects may contribute to progression of renal injury induced by chronic angiotensin II.

The regulation of extracellular fluid volume is a key component of blood pressure homeostasis. Long-term blood pressure is stabilized by the acute pressure natriuresis response by which changes in renal perfusion pressure evoke corresponding changes in renal sodium excretion. A wealth of experimental evidence suggests that a defect in the pressure natriuresis response contributes to the development and maintenance of hypertension. The mechanisms underlying the relationship between renal perfusion pressure and sodium excretion are incompletely understood. Increased blood flow through the vasa recta increases renal interstitial hydrostatic pressure, thereby reducing the driving force for transepithelial sodium reabsorption. Paracrine signalling also contributes to the overall natriuretic response by inhibiting tubular sodium reabsorption in several nephron segments. In this brief review, we discuss the role of purinergic signalling in the renal control of blood pressure. ATP is released from renal tubule and vascular cells in response to increased flow and can activate P2 receptor subtypes expressed in both epithelial and vascular endothelial/smooth muscle cells. In concert, these effects integrate the vascular and tubular responses to increased perfusion pressure and targeting P2 receptors, particularly P2X7, may prove beneficial for treatment of hypertension.

Oxygenation defects may contribute to renal disease progression, but the chronology of events is difficult to define in vivo without recourse to invasive methodologies. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) provides an attractive alternative, but the R2* signal is physiologically complex. Postacquisition data analysis often relies on manual selection of region(s) of interest. This approach excludes from analysis significant quantities of biological information and is subject to selection bias. We present a semiautomated, anatomically unbiased approach to compartmentalize voxels into two quantitatively related clusters. In control F344 rats, low R2* clustering was located predominantly within the cortex and higher R2* clustering within the medulla (70.96 ± 1.48 vs. 79.00 ± 1.50; 3 scans per rat; n = 6; P < 0.01) consistent anatomically with a cortico-medullary oxygen gradient. An intravenous bolus of acetylcholine caused a transient reduction of the R2* signal in both clustered segments ( P < 0.01). This was nitric oxide dependent and temporally distinct from the hemodynamic effects of acetylcholine. Rats were then chronically infused with angiotensin II (60 ng/min) and rescanned 3 days later. Clustering demonstrated a disruption of the cortico-medullary gradient, producing less distinctly segmented mean R2* clusters (71.30 ± 2.00 vs. 72.48 ± 1.27; n = 6; NS). The acetylcholine-induced attenuation of the R2* signal was abolished by chronic angiotensin II infusion, consistent with reduced nitric oxide bioavailability. This global map of oxygenation, defined by clustering individual voxels on the basis of quantitative nearness, might be more robust in defining deficits in renal oxygenation than the absolute magnitude of R2* in small, manually selected regions of interest defined exclusively by anatomical nearness.

Nucleotides are key subunits for nucleic acids and provide energy for intracellular metabolism. They can also be released from cells to act physiologically as extracellular messengers or pathologically as danger signals. Extracellular nucleotides stimulate membrane receptors in the P2 and P1 family. P2X are ATP-activated cation channels; P2Y and P1 are G-protein coupled receptors activated by ATP, ADP, UTP and UDP or adenosine, respectively. Renal P2 receptors influence both vascular contractility and tubular function. Renal cells also express ectonucleotidases that rapidly hydrolyze extracellular nucleotides. These enzymes integrate this multi-receptor purinergic-signaling complex by determining the nucleotide milieu, as well as titrating receptor activation. Purinergic signaling also regulates immune cell function by modulating the synthesis and release of various cytokines such as IL1-β and IL-18 as part of inflammasome activation. Abnormal or excessive stimulation of this intricate paracrine system can be pro- or anti-inflammatory, and is also linked to necrosis and apoptosis. Kidney tissue injury causes a localized increase in ATP concentration, and sustained activation of P2 receptors can lead to renal glomerular, tubularand vascular cell damage. Purinergic receptors also regulate the activity and proliferation of fibroblasts, promoting both inflammation and fibrosis in chronic disease. In this short review we summarize some of the recent findings related to purinergic signaling in the kidney. We focus predominantly on the P2X7 receptor, discussing why antagonists have so far disappointed in clinical trials and how advances in our understanding of purinergic signaling might help to reposition these compounds as potential treatments for renal disease.

Exosomes are vesicles released following fusion of endosomes with the plasma membrane. Urine contains exosomes that are released from the entire length of the nephron and change in composition with kidney disease. Exosomes can shuttle information between non-renal cells via transfer of protein and RNA. In this study murine kidney collecting duct (mCCDC11) cells were used to demonstrate that exosomes can act as a signalling mechanism between cells. First, the release of exosomes by mCCDC11 cells was confirmed by multiple approaches. Following isopynic centrifugation, exosomal proteins flotillin-1 and TSG101 were identified in fractions consistent with exosomes. Electron microscopy demonstrated structures consistent in size and shape with exosomes. Exposure of mCCDC11 cells to the synthetic vasopressin analogue, desmopressin, did not affect exosomal flotillin-1 or TSG101 but increased aquaporin 2 (AQP2) in a dose- and time-dependent manner that was highly correlated with cellular AQP2 (exosomal AQP2 vs. cellular AQP2, Pearson correlation coefficient r = 0.93). To test whether the ratio of exosomal AQP2/flotillin-1 is under physiological control in vivo, rats were treated with desmopressin. The ratio of AQP2/flotillin-1 in the urinary exosome was significantly increased. Inter-cellular signalling by exosomes was demonstrated: exosomes from desmopressin-treated cells stimulated both AQP2 expression and water transport in untreated mCCDc11 cells (water flow across cells: control exosome treatment 52.8 ± 11 μl cm(-2); AQP2-containing exosomes 77.4 ± 4 μl cm(-2), P = 0.05, n = 4). In summary, the amount of AQP2 in exosomes released from collecting duct cells is physiologically regulated and exosomal AQP2 closely reflects cellular expression. Exosomes can transfer functional AQP2 between cells and this represents a novel physiological mechanism for cell-to-cell communication within the kidney.

Reduced glomerular filtration, hypertension and renal microvascular injury are hallmarks of chronic kidney disease, which has a global prevalence of ~10%. We have shown previously shown that the Fischer (F344) rat has lower GFR than the Lewis rat, and is more susceptible to renal injury induced by hypertension. In the early stages this injury is limited to the pre-glomerular vasculature. We hypothesized that poor renal hemodynamic function and vulnerability to vascular injury are causally linked and genetically determined. In the present study, normotensive F344 rats had a blunted pressure diuresis relationship, compared with Lewis rats. A kidney microarray was the interrogated using the Endeavour enrichment tool to rank candidate genes for impaired blood pressure control. Two novel candidate genes, P2rx7 and P2rx4, were identified, having a 7- and 3- fold increased expression in F344 rats. Immunohistochemistry localized P2X4 and P2X7 receptor expression to the endothelium of the pre-glomerular vasculature. Expression of both receptors was also found in the renal tubule; however there was no difference in expression profile between strains. Brilliant Blue G (BBG), a relatively selective P2X7 antagonist suitable for use in vivo, was administered to both rat strains. In Lewis rats, BBG had no effect on blood pressure, but increased renal vascular resistance, consistent with inhibition of some basal vasodilatory tone. In F344 rats BBG caused a significant reduction in blood pressure and a decrease in renal vascular resistance, suggesting that P2X7 receptor activation may enhance vasoconstrictor tone in this rat strain. BBG also caused reduced the pressure diuresis threshold in F344 rats, but did not alter its slope. These preliminary findings suggest a physiological and potential pathophysiological role for P2X7 in controlling renal and/or systemic vascular function, which could in turn affect susceptibility to hypertension-related kidney damage.

Enhanced surveillance for invasive pneumococcal disease (IPD) was conducted in all Australian states and territories in 2007 and 2008 with comprehensive comparative data available since 2002. There were 1,477 cases of IPD notified to the National Notifiable Diseases Surveillance System in Australia in 2007; a notification rate of 7.0 cases per 100,000 population. In 2008 there were 1,628 cases; a notification rate of 7.6 cases per 100,000 population. The overall rate of IPD in Indigenous Australians was almost 6 times the rate in non-Indigenous Australians in 2007 and almost 5 times in 2008. By 2008, the 4th year of a funded universal infant 7-valent pneumococcal conjugate vaccine (7vPCV) program in Australia with a 3+0 schedule, vaccine serotype IPD notification rates in those identified as non-Indigenous decreased in all age groups compared with 2002 levels, most significantly by 96% in children aged less than 5 years. However, rates of disease in non-vaccine serotypes increased by 168% in children aged less than 5 years, including a four-fold increase in the number of cases due to serotype 19A. For the Aboriginal and Torres Strait Islander population, national pre-vaccination data are not available, as the vaccine program was funded for this group from 2001. From 2002 to 2008, the proportion of disease due to 7vPCV serotypes in children aged less than 5 years decreased by 77%, while disease due to non-7vPCV serotypes increased by 76%. In Indigenous adults (≥50 years), rates of 23vPPV serotypes increased by 92%. There were 120 deaths attributed to IPD in 2007 and 113 in 2008, although it should be noted that deaths may be under-reported. The number of invasive pneumococcal isolates with reduced penicillin susceptibility remains low and reduced susceptibility to third-generation cephalosporins is rare.

The Australian National Serosurveillance Program (ANSP) was established in 1997 to provide national estimates of population immunity to vaccine preventable diseases and inform immunisation policy in Australia. The 1st round tested opportunistically collected sera from pathology laboratories across Australia, a 2nd round was carried out in 2002, and a 3rd round of testing is currently ongoing using sera from 2007-08. This is the 1st systematic evaluation of the ANSP since its inception. Existing information and outputs from the ANSP were reviewed and used in conjunction with data collected from a survey of the program operators to evaluate the overall utility of the ANSP and the following system attributes; acceptability, stability, simplicity, flexibility, data quality, sensitivity, representativeness and timeliness. So far the ANSP has generated 26 peer-reviewed publications and provided useful data that have influenced and provided an evidence base for immunisation policy in Australia; for example informing mathematical models, which identified the need for the young adult measles-mumps-rubella immunisation campaign. However, difficulties have been encountered with obtaining enough samples for testing in the 3rd round currently being undertaken. This is a concern that has the potential to undermine the representativeness and stability of the system, and other methods of sample collection must be investigated. Serological surveillance is an important component of any comprehensive system for monitoring population immunity to vaccine preventable diseases and evaluating the effectiveness of immunisation programs. However, an effective ongoing program requires strong support to ensure it remains sustainable in an era when laboratory based population health research for the public good is becoming increasingly challenging.

Low levels of reporting indigenous status to the Australian Childhood Immunisation Register (ACIR) in the past have resulted in reduced confidence in vaccination coverage data for Aboriginal and Torres Straight Islander children. This study shows that the reporting of indigenous status has improved from 42% of the estimated national cohort of Indigenous children aged 12 to 14 months in 2002 to 95% in 2005. Over that period diphtheria-tetanus-pertussis (DTP) vaccination coverage estimates for Indigenous children increased slightly from 86.0% to 86.9%. Data by state and territory or remoteness are also presented. ACIR vaccination coverage estimates for Indigenous children can now be used with confidence for program planning at the national and jurisdictional level.

In 2005, 60 diseases and conditions were nationally notifiable in Australia. States and territories reported a total of 125,461 cases of communicable diseases to the National Notifiable Diseases Surveillance System: an increase of 10% on the number of notifications in 2004. In 2005, the most frequently notified diseases were sexually transmissible infections (51,557 notifications, 41% of total notifications), gastrointestinal diseases (29,422 notifications, 23%) and bloodborne diseases (19,278 notifications, 15%). There were 17,753 notifications of vaccine preventable diseases; 4,935 notifications of vectorborne diseases; 1,826 notification of other bacterial infections (legionellosis, leprosy, meningococcal infections and tuberculosis) and 687 notifications of zoonotic diseases.

In 2004, 60 diseases and conditions were nationally notifiable in Australia. States and Territories reported a total of 110,929 cases of communicable diseases to the National Notifiable Diseases Surveillance System (NNDSS): an increase of 4 per cent on the number of notifications in 2003. In 2004, the most frequently notified diseases were sexually transmissible infections (46,762 cases; 42% of total notifications), gastrointestinal diseases (25,247 cases; 23% of total notifications) and bloodborne diseases (19,191 cases; 17% of total notifications). There were 13,206 notifications of vaccine preventable diseases, 6,000 notifications of vectorborne diseases, 1,799 notifications of other bacterial infections (includes, legionellosis, leprosy, meningococcal infections and tuberculosis) and 877 notifications of zoonotic diseases.

Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.