Physiologic adaptations of the tubuloglomerular feedback system

The maintenance of volume homeostasis is sufficiently important to mammalian terrestrial life that a large amount of evolutionary energy has been expended in the development of multiple control systems, each involved in regulating the volume and composition of internal body fluids. The kidney, which participates in most of these systems, has evolved physiologic attributes which enhance the efficiency of volume regulation. Perhaps the most fundamental of these attributes is a close coordination between the processes of glomerular filtration and tubular reabsorption. Such coordination is required to prevent the amplification of small fluctuations in glomerular filtration rate into large fluctuations in total body salt and water content.It was first suggested by Homer Smith that reabsorption of fluid from the nephron should increase as the delivery of tubular fluid into that segment increases [1]. When applied to the proximal tubule, this principle of flow-dependent transport has come to be referred to as “glomerulotubular balance” [2, 3]. Glomerulotubular balance depends upon intrinsic properties of the proximal nephron including the affinities and densities of various solute transporters and the differential permeabilities of the nephron to various solutes and water, and upon the trans-epithelial concentration gradients of these solutes [4–6]. By definition, glomerulotubular balance describes the functional dependence of tubular reabsorption on glomerular filtration rate independently of other neuro-humoral effectors of tubular transport. However, since glomerulotubular balance is a substrate-driven process, it cannot accomplish an increment in proximal tubular reabsorption which exceeds an increment in delivered load. Therefore, in the absence of effectors other than glomerulotubular balance the volume of fluid entering the distal nephron must be a monotonically increasing function of GFR [7].How then, may the kidney avert an unintentional diuresis should the hemodynamic forces favoring glomerular filtration combine to overwhelm the reabsorptive capacity of the nephron? In 1937 Goormaghtigh suggested that the juxtaglomerular apparatus might participate in the maintenance of volume homeostasis by generating some sort of signal in response to changes in the composition of distal tubular fluid [8]. The peculiar anatomic arrangement of the nephron would facilitate transmission of this signal to the upstream glomerulus and lead to alterations in the physiologic determinants of glomerular filtration. This hypothesis has been refined over the past three decades as substantial experimental data have accrued to support the existence of an operational system of tubuloglomerular feedback (TGF) [9]. Contemporary models of the TGF system, by analogy to negative feedback-driven control systems in engineering control theory, divide the system into three component processes [10]. The first of these components is a parameter which the system is designed to regulate, in this case, the rate at which tubular fluid transits the late proximal nephron or VLP. The second component includes the macula densa and surrounding interstitium which serve to detect differences between the current value of VLP and some internal set-point, and translate this information into an output command. The third component, or effector limb, of the TGF system is constituted by the contractile glomerular mesangium and glomerular arterioles which respond to the aforementioned output command by altering nephron filtration rate (SNGFR) to keep VLP in line with the system's internal set-point. When TGF is allowed to function as a closed-loop system [7], as is the case in vivo, its presence is, by nature, undetectable. However, when late proximal flow is uncoupled from nephron filtration by artificial microperfusion of the late proximal tubule, a dependence of SNGFR on VLP can be defined [11]. This relationship is referred to as the “TGF function”, or “gain” of the TGF system [7, 10]. This TGF function specifies a continuum of points in the VLP-SNGFR plane at which the nephron may operate. The actual operating point of the system exists at the point in this plane where the TGF and glomerulotubular balance functions intersect (Fig. 1).The TGF function may vary in response to the changing needs of the organism, both with regard to volume homeostasis and renal function. The altering of TGF under conditions of pregnancy, loss of renal mass, and a variety of other pathophysiologic conditions suggests that the juxtaglomerular apparatus is involved in events pertinent not merely to volume regulation but to overall renal growth and function

A single nephron model of acute tubular injury: Role of tubuloglomerular feedback

A single nephron model of acute tubular injury: Role of tubuloglomerular feedback. A single nephron model of nephrotoxic tubular injury was established to examine the mechanism whereby acute tubular damage contributes to reductions in nephron filtration rate (SNGFR). Acute microperfusion of 0.5ng of uranyl nitrate (UN) into the early proximal tubule produced a significant reduction (16 to 30%) in SNGFR measured in both distal and proximal tubules of the same nephron and a decrease in absolute proximal reabsorption. Microperfused inulin was retained in the tubule suggesting this finding reflected a true reduction in SNGFR. Concurrent infusion of high dose furosemide (2 × 10-4M) and bumetanide (2 × 10-5M), but not low dose furosemide (2 × 10-5M), prevented the UN induced reduction in SNGFR. High dose furosemide begun after UN perfusion also prevented reduction in SNGFR. Continuous direct measurement of glomerular capillary hydrostatic pressure revealed no change. Distal intratubular Na+ and CI- concentration increased significantly after UN perfusion. Activation of tubuloglomerular feedback mechanisms best explains the reduction in glomerular ultrafiltration that is characteristic of nephrotoxic forms of tubular injury

Routine frailty assessment predicts postoperative complications in elderly patients across surgical disciplines – a retrospective observational study

BACKGROUND: Frailty is a frequent and underdiagnosed functional syndrome involving reduced physiological reserves and an increased vulnerability against stressors, with severe individual and socioeconomic consequences. A routine frailty assessment was implemented at our preoperative anaesthesia clinic to identify patients at risk. OBJECTIVE: This study examines the relationship between frailty status and the incidence of in-hospital postoperative complications in elderly surgical patients across several surgical disciplines. DESIGN: Retrospective observational analysis. SETTING: Single center, major tertiary care university hospital. Data collection took place between June 2016 and March 2017. PATIENTS: Patients 65 years old or older were evaluated for frailty using Fried's 5-point frailty assessment prior to elective non-cardiac surgery. Patients were classified into non-frail (0 criteria, reference group), pre-frail (1-2 positive criteria) and frail (3-5 positive criteria) groups. MAIN OUTCOME MEASURES: The incidence of postoperative complications was assessed until discharge from the hospital, using the roster from the National VA Surgical Quality Improvement Program. Propensity score matching and logistic regression analysis were performed. RESULTS: From 1186 elderly patients, 46.9% were classified as pre-frail (n = 556), and 11.4% as frail (n = 135). The rate of complications were significantly higher in the pre-frail (34.7%) and frail groups (47.4%), as compared to the non-frail group (27.5%). Similarly, length of stay (non-frail: 5.0 [3.0;7.0], pre-frail: 7.0 [3.0;9.0], frail 8.0 [4.5;12.0]; p < 0.001) and discharges to care facilities (non-frail:1.6%, pre-frail: 7.4%, frail: 17.8%); p < 0.001) were significantly associated with frailty status. After propensity score matching and logistic regression analysis, the risk for developing postoperative complications was approximately two-fold for pre-frail (OR 1.78; 95% CI 1.04-3.05) and frail (OR 2.08; 95% CI 1.21-3.60) patients. CONCLUSIONS: The preoperative frailty assessment of elderly patients identified pre-frail and frail subgroups to have the highest rate of postoperative complications, regardless of age, surgical discipline, and surgical risk. Significantly increased length of hospitalisation and discharges to care facilities were also observed. Implementation of routine frailty assessments appear to be an effective tool in identifying patients with increased risk. Now future studies are needed to investigate whether patients benefit from optimization of patient counselling, process planning, and risk reduction protocols based on the application of risk stratification

COVID-19 Patients Require Prolonged Extracorporeal Membrane Oxygenation Support for Survival Compared With Non-COVID-19 Patients

OBJECTIVES: To investigate the ICU survival of venovenous extracorporeal membrane oxygenation (ECMO) patients suffering from COVID-19–related acute respiratory distress syndrome (ARDS) versus ECMO patients without COVID-19 (non-COVID-19)–related ARDS. DESIGN: Preliminary analysis of data from two prospective ECMO trials and retrospective analysis of a cohort of ARDS ECMO patients. SETTING: Single-center ICU. PATIENTS: Adult ARDS ECMO patients, 16 COVID-19 versus 23 non-COVID-19 patients. Analysis of retrospective data from 346 adult ARDS ECMO patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: COVID-19 and non-COVID-19 ARDS patients did not differ with respect to preexisting disease or body mass index. ICU survival rate was 62% for COVID-19 ECMO patients and 70% for non-COVID-19 ECMO patients. COVID-19 ECMO survivors were supported with ECMO for a median of 43 days (interquartile range [IQR], 18–58 d) versus 16 days (IQR, 19–39 d; p = 0.03) for non-COVID-19 patients. The median duration of ECMO therapy for all ARDS patients between 2007 and 2018 was 15 days (IQR, 6–28 d). The subgroup of patients suffering from any viral pneumonia received ECMO support for a median of 16 days (IQR, 9–27 d), survivors of influenza pneumonia received ECMO support for 13 days (IQR, 7–25 d). CONCLUSIONS: COVID-19 patients required significant longer ECMO support compared with patients without COVID-19 to achieve successful ECMO weaning and ICU survival

The role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO

Background: Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI) in critically ill patients while the CFH-scavenger haptoglobin might play a protective role. We evaluated the association of CFH and haptoglobin with AKI in patients with an acute respiratory distress syndrome (ARDS) requiring therapy with VV ECMO. Methods: Patients with CFH and haptoglobin measurements before initiation of ECMO therapy were identified from a cohort of 1044 ARDS patients and grouped into three CFH concentration groups using a risk stratification. The primary objective was to assess the association of CFH and haptoglobin with KDIGO stage 3 AKI. Further objectives included the identification of a target haptoglobin concentration to protect from CFH-associated AKI. Measurements and main results: Two hundred seventy-three patients fulfilled the inclusion criteria. Of those, 154 patients (56.4%) had AKI at ECMO initiation. The incidence of AKI increased stepwise with increasing concentrations of CFH reaching a plateau at 15 mg/dl. Compared to patients with low [= 15 mg/dl] CFH concentrations had a three- and five-fold increased risk for AKI (adjusted odds ratio [OR] moderate vs. low, 2.69 [95% CI, 1.25-5.95], P = 0.012; and OR high vs. low, 5.47 [2.00-15.9], P = 0.001). Among patients with increased CFH concentrations, haptoglobin plasma levels were lower in patients with AKI compared to patients without AKI. A haptoglobin concentration greater than 2.7 g/l in the moderate and 2.4 g/l in the high CFH group was identified as clinical cutoff value to protect from CFH-associated AKI (sensitivity 89.5% [95% CI, 83-96] and 90.2% [80-97], respectively). Conclusions: In critically ill patients with ARDS requiring therapy with VV ECMO, an increased plasma concentration of CFH was identified as independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI and should be subject of future research

In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration

Purpose: Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. Methods: An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration ("pulsed delivery"), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5-40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. Results: Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 +/- 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. Conclusion: Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes

IMPLEmenting a clinical practice guideline for acute low back pain evidence-based manageMENT in general practice (IMPLEMENT) : cluster randomised controlled trial study protocol

Background: Evidence generated from reliable research is not frequently implemented into clinical practice. Evidence-based clinical practice guidelines are a potential vehicle to achieve this. A recent systematic review of implementation strategies of guideline dissemination concluded that there was a lack of evidence regarding effective strategies to promote the uptake of guidelines. Recommendations from this review, and other studies, have suggested the use of interventions that are theoretically based because these may be more effective than those that are not. An evidencebased clinical practice guideline for the management of acute low back pain was recently developed in Australia. This provides an opportunity to develop and test a theory-based implementation intervention for a condition which is common, has a high burden, and for which there is an evidence-practice gap in the primary care setting. Aim: This study aims to test the effectiveness of a theory-based intervention for implementing a clinical practice guideline for acute low back pain in general practice in Victoria, Australia. Specifically, our primary objectives are to establish if the intervention is effective in reducing the percentage of patients who are referred for a plain x-ray, and improving mean level of disability for patients three months post-consultation. Methods/Design: This study protocol describes the details of a cluster randomised controlled trial. Ninety-two general practices (clusters), which include at least one consenting general practitioner, will be randomised to an intervention or control arm using restricted randomisation. Patients aged 18 years or older who visit a participating practitioner for acute non-specific low back pain of less than three months duration will be eligible for inclusion. An average of twenty-five patients per general practice will be recruited, providing a total of 2,300 patient participants. General practitioners in the control arm will receive access to the guideline using the existing dissemination strategy. Practitioners in the intervention arm will be invited to participate in facilitated face-to-face workshops that have been underpinned by behavioural theory. Investigators (not involved in the delivery of the intervention), patients, outcome assessors and the study statistician will be blinded to group allocation. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN012606000098538 (date registered 14/03/2006).The trial is funded by the NHMRC by way of a Primary Health Care Project Grant (334060). JF has 50% of her time funded by the Chief Scientist Office3/2006). of the Scottish Government Health Directorate and 50% by the University of Aberdeen. PK is supported by a NHMRC Health Professional Fellowship (384366) and RB by a NHMRC Practitioner Fellowship (334010). JG holds a Canada Research Chair in Health Knowledge Transfer and Uptake. All other authors are funded by their own institutions

Induction of severe hypoxemia and low lung recruitability for the evaluation of therapeutic ventilation strategies: a translational model of combined surfactant-depletion and ventilator-induced lung injury

Background: Models of hypoxemic lung injury caused by lavage-induced pulmonary surfactant depletion are prone to prompt recovery of blood oxygenation following recruitment maneuvers and have limited translational validity. We hypothesized that addition of injurious ventilation following surfactant-depletion creates a model of the acute respiratory distress syndrome (ARDS) with persistently low recruitability and higher levels of titrated "best" positive end-expiratory pressure (PEEP) during protective ventilation. Methods: Two types of porcine lung injury were induced by lung lavage and 3 h of either protective or injurious ventilation, followed by 3 h of protective ventilation (N = 6 per group). Recruitment maneuvers (RM) and decremental PEEP trials comparing oxygenation versus dynamic compliance were performed after lavage and at 3 h intervals of ventilation. Pulmonary gas exchange function, respiratory mechanics, and ventilator-derived parameters were assessed after each RM to map the course of injury severity and recruitability. Results: Lung lavage impaired respiratory system compliance (C-rs) and produced arterial oxygen tensions (PaO2) of 84 +/- 13 and 80 +/- 15 (FIO2 = 1.0) with prompt increase after RM to 270-395 mmHg in both groups. After subsequent 3 h of either protective or injurious ventilation, PaO2/FIO2 was 104 +/- 26 vs. 154 +/- 123 and increased to 369 +/- 132 vs. 167 +/- 87 mmHg in response to RM, respectively. After additional 3 h of protective ventilation, PaO2/FIO2 was 120 +/- 15 vs. 128 +/- 37 and increased to 470 +/- 68 vs. 185 +/- 129 mmHg in response to RM, respectively. Subsequently, decremental PEEP titration revealed that C-rs peaked at 36 +/- 10 vs. 25 +/- 5 ml/cm H2O with PEEP of 12 vs. 16 cmH(2)O, and PaO2/FIO2 peaked at 563 +/- 83 vs. 334 +/- 148 mm Hg with PEEP of 16 vs. 22 cmH(2)O in the protective vs. injurious ventilation groups, respectively. The large disparity of recruitability between groups was not reflected in the C-rs nor the magnitude of mechanical power present after injurious ventilation, once protective ventilation was resumed. Conclusion: Addition of transitory injurious ventilation after lung lavage causes prolonged acute lung injury with diffuse alveolar damage and low recruitability yielding high titrated PEEP levels. Mimicking lung mechanical and functional characteristics of ARDS, this porcine model rectifies the constraints of single-hit lavage models and may enhance the translation of experimental research on mechanical ventilation strategies

Technical Aspects of Flow Cytometry-based Measurable Residual Disease Quantification in Acute Myeloid Leukemia: Experience of the European LeukemiaNet MRD Working Party

Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization