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Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.
BACKGROUND - Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival.
METHODS - This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality.
RESULTS - Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P < .001) and decreased mortality (19% vs 30%, P = .03) (P value for interaction = .01).
CONCLUSIONS - In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
BACKGROUND - The Acute Dialysis Quality Initiative (ADQI) dedicated its Twelfth Consensus Conference (2013) to all aspects of fluid therapy, including the management of fluid overload (FO). The aim of the working subgroup 'Mechanical fluid removal' was to review the indications, prescription, and management of mechanical fluid removal within the broad context of fluid management of critically ill patients.
METHODS - The working group developed a list of preliminary questions and objectives and performed a modified Delphi analysis of the existing literature. Relevant studies were identified through a literature search using the MEDLINE database and bibliographies of relevant research and review articles.
RESULTS - After review of the existing literature, the group agreed the following consensus statements: (i) in critically ill patients with FO and with failure of or inadequate response to pharmacological therapy, mechanical fluid removal should be considered as a therapy to optimize fluid balance. (ii) When using mechanical fluid removal or management, targets for rate of fluid removal and net fluid removal should be based upon the overall fluid balance of the patient and also physiological variables, individualized, and reassessed frequently. (iii) More research on the role and practice of mechanical fluid removal in critically ill patients not meeting fluid balance goals (including in children) is necessary.
CONCLUSION - Mechanical fluid removal should be considered as a therapy for FO, but more research is necessary to determine its exact role and clinical application.
© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: email@example.com.
The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.
Presentation of the Nephrology Quiz and Questionnaire has become an annual "tradition" at the meetings of the American Society of Nephrology. It is a very popular session judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, with those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. Topics presented here include fluid and electrolyte disorders, transplantation, and ESRD and dialysis. Cases representing each of these categories along with single best answer questions were prepared by a panel of experts (Drs. Palmer, Hricik, and Golper, respectively). After the audience responses, the "correct" and "incorrect" answers then were briefly discussed and the results of the questionnaire were displayed. This article aims to recapitulate the session and reproduce its educational value for a larger audience-readers of the Clinical Journal of the American Society of Nephrology. Have fun.
OBJECTIVE - To assess the association of 0.9% saline use versus a calcium-free physiologically balanced crystalloid solution with major morbidity and clinical resource use after abdominal surgery.
BACKGROUND - 0.9% saline, which results in a hyperchloremic acidosis after infusion, is frequently used to replace volume losses after major surgery.
METHODS - An observational study using the Premier Perspective Comparative Database was performed to evaluate adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery. The primary outcome was major morbidity and secondary outcomes included minor complications and acidosis-related interventions. Outcomes were evaluated using multivariable logistic regression and propensity scoring models.
RESULTS - For the entire cohort, the in-hospital mortality was 5.6% in the saline group and 2.9% in the balanced group (P < 0.001). One or more major complications occurred in 33.7% of the saline group and 23% of the balanced group (P < 0.001). In the 3:1 propensity-matched sample, treatment with balanced fluid was associated with fewer complications (odds ratio 0.79; 95% confidence interval 0.66-0.97). Postoperative infection (P = 0.006), renal failure requiring dialysis (P < 0.001), blood transfusion (P < 0.001), electrolyte disturbance (P = 0.046), acidosis investigation (P < 0.001), and intervention (P = 0.02) were all more frequent in patients receiving 0.9% saline.
CONCLUSIONS - Among hospitals in the Premier Perspective Database, the use of a calcium-free balanced crystalloid for replacement of fluid losses on the day of major surgery was associated with less postoperative morbidity than 0.9% saline.
BACKGROUND - Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have beneficial effects on renal structure and function in models of diabetes and chronic kidney diseases. However, the increased incidence of weight gain and edema potentially limits their usefulness. We studied an acute minimal-change disease-like nephrotic syndrome model to assess effects of PPARγ agonist on acute podocyte injury and effects on fluid homeostasis.
METHODS - Acute podocyte injury and nephrotic syndrome were induced by puromycin aminonucleoside (PAN) injection in rats.
RESULTS - PPARγ agonist, given at the time or after, but not before PAN, reduced proteinuria, restored synaptopodin, decreased desmin and trended to improve foot process effacement. There was no significant difference in glomerular filtration, effective circulating volume, blood pressure or fractional sodium excretion. PAN-injured podocytes had decreased PPARγ, less nephrin and α-actinin-4, more apoptosis and reduced phosphorylated Akt. In PAN-injured cultured podocytes, PPARγ agonist also reversed abnormalities only when given simultaneously or after injury.
CONCLUSIONS - These results show that PPARγ agonist has protective effects on podocytes in acute nephrotic syndrome without deleterious effects on fluid homeostasis. PPARγ agonist-induced decrease in proteinuria in acute nephrotic syndrome is dependent at least partially on regulation of peroxisome proliferator-response element-sensitive gene expression such as α-actinin-4 and nephrin and the restoration of podocyte structure.
INTRODUCTION - Conservative fluid management in patients with acute lung injury (ALI) increases time alive and free from mechanical ventilation. Vascular pedicle width (VPW) is a non-invasive measurement of intravascular volume status. The VPW was studied in ALI patients to determine the correlation between VPW and intravascular pressure measurements and whether VPW could predict fluid status.
METHODS - This retrospective cohort study involved 152 patients with ALI enrolled in the Fluid and Catheter Treatment Trial (FACTT) from five NHLBI ARDS (Acute Respiratory Distress Syndrome) Network sites. VPW and central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) from the first four study days were correlated. The relationships between VPW, positive end-expiratory pressure (PEEP), cumulative fluid balance, and PAOP were also evaluated. Receiver operator characteristic (ROC) curves were used to determine the ability of VPW to detect PAOP < 8 mmHg and PAOP ≥ 18 mm Hg.
RESULTS - A total of 71 and 152 patients provided 118 and 276 paired VPW/PAOP and VPW/CVP measurements, respectively. VPW correlated with PAOP (r = 0.41; P < 0.001) and less well with CVP (r = 0.21; P = 0.001). In linear regression, VPW correlated with PAOP 1.5-fold better than cumulative fluid balance and 2.5-fold better than PEEP. VPW discriminated achievement of PAOP < 8 mm Hg (AUC = 0.73; P = 0.04) with VPW ≤67 mm demonstrating 71% sensitivity (95% CI 30 to 95%) and 68% specificity (95% CI 59 to 75%). For discriminating a hydrostatic component of the edema (that is, PAOP ≥ 18 mm Hg), VPW ≥ 72 mm demonstrated 61.4% sensitivity (95% CI 47 to 74%) and 61% specificity (49 to 71%) (area under the curve (AUC) 0.69; P = 0.001).
CONCLUSIONS - VPW correlates with PAOP better than CVP in patients with ALI. Due to its only moderate sensitivity and specificity, the ability of VPW to discriminate fluid status in patients with acute lung injury is limited and should only be considered when intravascular pressures are unavailable.
The ability to offer repetitive hemodialysis for treatment of chronic kidney failure has now reached its half-century anniversary. Although millions of patients have benefited from this life-extending procedure, current results in the United States have now stagnated with only small annual improvements in survival and continued high hospitalization rates. Recognition that this stagnation may be, at least in part, the result of inadequacies of current and prior paths utilized in dialysis treatment has led to the concept that dialysis therapy is at a crossroads and that new paths need to be articulated, explored, and applied. This article proposes some of these new paths and their rationale. Two elements of the new paths are emphasized: avoidance of indwelling catheters for vascular access and meticulous attention to control of extracellular volume and mitigation of left ventricular hypertrophy and fibrosis. It is postulated that progress in these two areas, along with continued attention to other elements embodied in the new and old paths, will unlock the stagnation in outcomes of dialysis therapy of end-stage kidney failure and allow it to realize its full potential of prolonging life and alleviating disability.