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Background: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. Aims: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. Methods: This single‐centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre‐determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. Results: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at‐risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. Conclusions: Dialysis patients are at risk of driving impairment based on self‐reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed. [ABSTRACT FROM AUTHOR]

Introduction: To determine the prevalence, severity, and change in symptoms experienced by dialysis patients following the introduction of use of a symptom-reporting questionnaire in nephrology clinic.Methods: This is an observational study of 160 prevalent dialysis patients. Palliative care Outcome Scale symptom (POS-renal) questionnaires modified for patients with end-stage kidney disease were completed at baseline and follow-up (median 3 months), with results available to nephrologists at clinic appointments.Findings: The baseline prevalence of individual symptoms ranged from 15% to 66%. The most common symptoms were lack of energy (66%) and poor mobility (58%). The median number of symptoms was 7/17 (interquartile range [IQR]: 4-10). Forty-nine percent of patients rated at least 1 symptom as severe or overwhelming. At follow-up, the median number of symptoms experienced was unchanged at 7/17 (IQR: 3-10). However, there was considerable flux in symptom severity. On average, individual symptoms that were present at baseline improved in 56% of patients and worsened in 18%; only 26% had stable symptom severity. Individual symptoms newly occurred in 8% to 20% of patients between time points, with 77% of patients experiencing at least 1 new symptom. The percent of patients rating at least 1 symptom as severe or overwhelming was reduced from 49% to 39% (P = .040).Conclusions: Use of the POS-renal questionnaire identified a high symptom burden. The presence and severity of symptoms changed dramatically over a short follow-up period, highlighting the need for regular surveillance of symptoms in the dialysis population. Routine use of a symptom questionnaire in clinic may be useful for the identification and management of symptoms in dialysis patients. [ABSTRACT FROM AUTHOR]

Enhanced tubular reabsorption of salt is important in the pathogenesis of obesityrelated hypertension, but the mechanisms remain poorly defined. To identify changes in the regulation of salt transporters in the kidney, C57BL/6 mice were fed a 40% fat diet [high-fat diet (HFD)] or a 12% fat diet (control diet) for 14 wk. Compared with control diet-fed mice, HFD-fed mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. When we examined Na+ transporter expression, Na+-K+-2Cl- cotransporter (NKCC2) was unchanged in whole kidney and reduced in the cortex, Na+-Cl- cotransporter (NCC) and α-epithelial Na+ channel (ENaC) and γ-ENaC were unchanged, and β-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of STE-20/SPS1-related prolinealanine- rich protein kinase (SPAK)/oxidative stress responsive 1 kinase (OSR1) was increased in kidneys from HFD-fed mice, and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic experiments. HFD-fed mice had reduced activating phosphorylation of AMP-activated protein kinase (AMPK) in the renal cortex. In vitro, activation of AMPK led to a reduction in phospho-SPAK/ phospho-OSR1 in AMPK+/+ murine embryonic fibroblasts (MEFs), but no effect was seen in AMPK-/- MEFs, indicating an AMPKmediated effect. Activation of the with no lysine kinase/SPAK/OSR1 pathway with low-NaCl solution invoked a greater elevation in phospho- SPAK/phospho-OSR1 in AMPK-/- MEFs than in AMPK+/+ MEFs, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto-unrecognized mediator of enhanced Na+ reabsorption in obesity and identifies a new role for AMPK in regulating the activity of SPAK/OSR1. [ABSTRACT FROM AUTHOR]

Salt reabsorption is the major energy-requiring process in the kidney, and AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism. Mice with targeted deletion of the ß1-subunit of AMPK (AMPK-ß1-/- mice) had significantly increased urinary Na+ excretion on a normal salt diet. This was associated with reduced expression of the ß-subunit of the epithelial Na+ channel (ENaC) and increased subapical tubular expression of kidney-specific Na+-K+-2Cl- cotransporter 2 (NKCC2) in the medullary thick ascending limb of Henle. AMPK-ß1-/- mice fed a salt-deficient diet were able to conserve Na+, but renin secretion increased 180% compared with control mice. Cyclooxygenase-2 mRNA also increased in the kidney cortex, indicating greater signaling through the macula densa tubular salt-sensing pathway. To determine whether the increase in renin secretion was due to a change in regulation of fatty acid metabolism by AMPK, mice with a mutation of the inhibitory AMPK phosphosite in acetyl-CoA carboxylase 1 [ACC1-knockin (KI)S79A mice] were examined. ACC1-KIS79A mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na+-Cl- cotransporter, and ENaC-ß were similar to those in control mice. When mice were placed on a salt-deficient diet, however, renin secretion and cortical expression of cyclooxygenase-2 mRNA increased significantly in ACC1-KIS79A mice compared with control mice. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1. [ABSTRACT FROM AUTHOR]

A fundamental aspect of acute renal ischemia is energy depletion, manifest as a falling level of ATP that is associated with a simultaneous rise in AMP. The energy sensor AMP-activated protein kinase (AMPK) is activated by a rising AMP-to-ATP ratio, but its role in acute renal ischemia is unknown. AMPK is activated in the ischemic heart and is reported to phosphorylate both endothelial nitric oxide synthase (eNOS) and acetyl-CoA carboxylase. To study activation of AMPK in acute renal ischemia, the renal pedicle of anesthetized Sprague-Dawley rats was cross-clamped for increasing time intervals. AMPK was strongly activated within 1 mm and remained so after 30 mm. However, despite the robust activation of AMPK, acute renal ischemia did not increase phosphorylation of the AMPK phosphorylation sites eNOS-Ser1177 or acetyl-CoA carboxylase-Ser79. Activation of AMPK in bovine aortic endothelial cells by the ATP-depleting agent antimycin A and the antidiabetic drug phenformin also did not increase phosphorylation of eNOS-Ser1177, confirming that AMPK activation and phosphorylation of eNOS are dissociated in some situations. Immunoprecipitation studies demonstrated that the dissociation between AMPK activation and phosphorylation of eNOS-Ser1177 was not due to changes in the physical associations between AMPK, eNOS, or heat shock protein 90. In conclusion, acute renal ischemia rapidly activates the energy sensor AMPK, which is known to maintain ATP reserves during energy stress. The substrates it phosphorylates, however, are different from those in other organs such as the heart. [ABSTRACT FROM AUTHOR]

A fundamental aspect of acute renal ischemia is energy depletion, manifest as a falling level of ATP that is associated with a simultaneous rise in AMP. The energy sensor AMP-activated protein kinase (AMPK) is activated by a rising AMP-to-ATP ratio, but its role in acute renal ischemia is unknown. AMPK is activated in the ischemic heart and is reported to phosphorylate both endothelial nitric oxide synthase (eNOS) and acetyl-CoA carboxylase. To study activation of AMPK in acute renal ischemia, the renal pedicle of anesthetized Sprague-Dawley rats was cross-clamped for increasing time intervals. AMPK was strongly activated within 1 mm and remained so after 30 mm. However, despite the robust activation of AMPK, acute renal ischemia did not increase phosphorylation of the AMPK phosphorylation sites eNOS-Ser1177 or acetyl-CoA carboxylase-Ser79. Activation of AMPK in bovine aortic endothelial cells by the ATP-depleting agent antimycin A and the antidiabetic drug phenformin also did not increase phosphorylation of eNOS-Ser1177, confirming that AMPK activation and phosphorylation of eNOS are dissociated in some situations. Immunoprecipitation studies demonstrated that the dissociation between AMPK activation and phosphorylation of eNOS-Ser1177 was not due to changes in the physical associations between AMPK, eNOS, or heat shock protein 90. In conclusion, acute renal ischemia rapidly activates the energy sensor AMPK, which is known to maintain ATP reserves during energy stress. The substrates it phosphorylates, however, are different from those in other organs such as the heart. [ABSTRACT FROM AUTHOR]

Aims: Acute thrombosis of hemodialysis (HD) arteriovenous access is an urgent problem for HD patients and is commonly managed by endovascular thrombolysis. Pulmonary embolism (PE) is a recognized complication of HD access thrombosis and thrombolysis but the risk and outcomes are unclear. This study aims to determine the incidence, predictors, and outcomes of PE after endovascular thrombolysis of HD arteriovenous access in patients presenting with acute thrombosis., Materials and Methods: A single-center retrospective study was performed for all adult chronic kidney disease patients undergoing arteriovenous access thrombolysis between January 1, 2012, and December 31, 2014. Investigation for PE with CT pulmonary angiography or ventilation/perfusion scintigraphy (V/Q scan) was performed as clinically directed by the managing clinicians. In cases diagnosed with PE, the pulmonary embolism severity index (PESI) was calculated., Results: A total of 48 (median age 68) patients underwent 74 thrombolysis procedures. Thrombolysis techniques were divided into pharmacological (44.6%), mechanical (17.6%), or pharmacomechanical (37.8%). Clinical success was achieved in 56/74 (75.7%) of procedures. Five episodes of thrombolysis for access thrombosis (6.8%) were associated with clinically symptomatic PE. The PESI score ranged from 51 to 127. All patients with PE were managed with 3 - 6 months of anticoagulation and recovered clinically. There were no statistically significant differences in baseline characteristics, methods of thrombolysis, or clot burden in patients that developed a PE., Conclusion: There is a clinically significant risk of symptomatic PE after arteriovenous access thrombolysis for access thrombosis in HD patients.
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Enhanced tubular reabsorption of salt is important in the pathogenesis of obesity-related hypertension, but the mechanisms remain poorly defined. To identify changes in the regulation of salt transporters in the kidney, C57BL/6 mice were fed a 40% fat diet [high-fat diet (HFD)] or a 12% fat diet (control diet) for 14 wk. Compared with control diet-fed mice, HFD-fed mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. When we examined Na(+) transporter expression, Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) was unchanged in whole kidney and reduced in the cortex, Na(+)-Cl(-) cotransporter (NCC) and α-epithelial Na(+) channel (ENaC) and γ-ENaC were unchanged, and β-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of STE-20/SPS1-related proline-alanine-rich protein kinase (SPAK)/oxidative stress responsive 1 kinase (OSR1) was increased in kidneys from HFD-fed mice, and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic experiments. HFD-fed mice had reduced activating phosphorylation of AMP-activated protein kinase (AMPK) in the renal cortex. In vitro, activation of AMPK led to a reduction in phospho-SPAK/phospho-OSR1 in AMPK(+/+) murine embryonic fibroblasts (MEFs), but no effect was seen in AMPK(-/-) MEFs, indicating an AMPK-mediated effect. Activation of the with no lysine kinase/SPAK/OSR1 pathway with low-NaCl solution invoked a greater elevation in phospho-SPAK/phospho-OSR1 in AMPK(-/-) MEFs than in AMPK(+/+) MEFs, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto-unrecognized mediator of enhanced Na(+) reabsorption in obesity and identifies a new role for AMPK in regulating the activity of SPAK/OSR1., (Copyright © 2014 the American Physiological Society.)