Diuretics remain the cornerstone therapy of critically ill patients with volume overload as a result of cardiac failure, acute kidney injury or aggressive fluid resuscitation. This review summarises the principles of applied renal physiology, describing the mechanisms of action, the clinical applications, and the adverse effects of commonly used diuretics during critical illness. Loop diuretics, and in particular furosemide, remain the most popular, despite evidence of any effect on mortality or, indeed, on the need for renal replacement therapy. The efficacy of loop diuretics after administration depends on three factors. Firstly, the tubular concentration of the diuretic: continuous infusion of furosemide seems to provide a higher and more stable tubular concentration of furosemide with respect to bolus injection. Secondly, the interaction with albumin both in the plasma and in the renal tubule: despite a strong physiological rationale supporting this approach, albumin supplementation in hypoalbuminaemic patients does not seem to result in a higher diuretic efficacy. Thirdly, diuretic resistance, which can be addressed by optimising loop diuretic dose and by using combination therapy with other agents, including thiazides or thiazide-like diuretics or carbonic anhydrase inhibitors. These drugs constitute a useful adjunct to overcome loop diuretic resistance. Other agents such as distal potassium-sparing diuretics and osmotic diuretics can also be considered. The latter have been used successfully in hypokalaemia, rhabdomyolysis-associated acute kidney injury or to prevent ischaemia-reperfusion injury in kidney transplantation. Finally, this review provides the basic concepts of the interplay between acid-base equilibrium and diuretic therapy.

To evaluate the predictive ability of furosemide stress test (FST), serum and urine cystatin-C in identifying progressive acute kidney injury (AKI) and the need for kidney replacement therapy (KRT).

Children aged one month to 18 y admitted in the pediatric intensive care unit (PICU) with Kidney Diseases Improving Global Outcomes (KDIGO) stage-1/2 AKI were enrolled. FST and serum and urine cystatin-C levels were performed and analyzed. The primary outcome was progression to stage-3 AKI. Secondary outcomes included comparing predictive ability of FST vs. cystatin-C for stage-3 AKI and need for KRT, adverse effects, length of hospital stay and mortality.

Of the 41 children enrolled, seven (17.07%) progressed to KDIGO stage-3 AKI. Four children were furosemide non-responders at 2 h and five at 6 h post-FST. The sensitivity, specificity and area under the receiver operating characteristic curve (AUROC) of FST at 2 h were 57.14%, 100% and 0.84 (p = 0.01), and at 6 h were 71.43%, 100% and 0.87 (p < 0.001), respectively. Urine cystatin-C was positive in 20 (48.78%) children, of which seven progressed to stage-3 AKI [sensitivity- 100%, specificity- 61.76%, AUROC- 0.91 (p = 0.003)]. Five of nine children with positive serum cystatin-C progressed to stage-3 AKI [sensitivity- 71.43%, specificity- 88.24%, AUROC- 0.75 (p = 0.08)]. All FST non-responders progressed to undergo KRT showing sensitivity and specificity of 66.67% and 100% at 2 h (AUROC- 0.87) and 85% and 100% at 6 h (AUROC- 0.89) respectively.

FST is a simple bedside tool with robust predictive value in detecting kidney impairment progression in children and can be utilized in PICU for assessing tubular dysfunction. The diagnostic accuracy of FST was comparable to that of urine and serum cystatin-C. Further studies can be done on a larger cohort for better generalizability.

The optimal time for initiating kidney replacement therapy (KRT) in acute kidney injury (AKI) has been extensively studied in recent years. In contrast, there are currently insufficient data on the best time to discontinue KRT. One diagnostic option to unmask tubular reserve and indirectly estimate the glomerular filtration rate is the furosemide stress test (FST).

We conducted a prospective, observational single-center trial. A FST was carried out in patients who developed spontaneous diuresis (SD) during ongoing KRT with a urine output of at least 400 ml in 24 h without any diuretic therapy. A positive FST was defined with urine output > 200 ml within 2 h following intravenous furosemide application. Follow-up was performed for 7 days and the need to restart KRT was assessed daily.

After 100 patients were enrolled in the trial, 98 patients were eligible for further evaluation. 76 patients were FST-positive, while 22 patients were FST-negative. Resumption of KRT within the 7-day follow-up was required in only 14.5% of the FST-positive, but 72.7% of the FST-negative patients (p < 0.001). The urine output after FST was also significantly associated with successful release from KRT (AUC 0.87; p < 0.001).

In critically ill patients with recovery of SD > 400ml/d during ongoing KRT, the FST helps to identify patients who can be successfully liberated from KRT. By detecting the tubular reserve using FST, the possibility of short-term kidney recovery after AKI can be estimated.

German Clinical Trials Registry (DRKS00030560); date of registration 18/11/2022. https://drks.de/search/de/trial/DRKS00030560 .

Acute kidney injury (AKI) has a high morbidity and mortality rate but can only be treated with supportive therapy in most cases. The diagnosis of AKI is mainly based on serum creatinine level and urine volume, which cannot detect kidney injury sensitive and timely. Therefore, new diagnostic and therapeutic molecules of AKI are being actively explored. Extracellular vesicles (EVs), secreted by almost all cells, can originate from different parts of the kidney and mediate intercellular communication between various cell types of nephrons. At present, numerous successful EV-based biomarker discoveries and treatments for AKI have been made, such as the confirmed diagnostic role of urine-derived EVs in AKI and the established therapeutic role of mesenchymal stem cell-derived EVs in AKI have been confirmed; however, these related studies lack a full discussion. In this review, we summarize the latest progression in the profound understanding of the functional role of EVs in AKI caused by various etiologies in recent years and provide new insights into EVs as viable biomarkers and therapeutic molecules for AKI patients. Furthermore, the current challenges and prospects of this research area are briefly discussed, presenting a comprehensive overview of the growing foregrounds of EVs in AKI.

Acute Kidney Injury (AKI) is a common complication after cardiac surgery affecting up to 40% leading to increased morbidity and mortality. To date, there is no specific treatment for AKI, thus, clinical research efforts are focused on preventive measures. The only pharmacological preventive intervention that has demonstrated a beneficial effect on AKI in a high-quality, double-blind, randomized controlled trial is a short perioperative infusion of a balanced mixture of amino acid solution. Amino acid infusion reduced the incidence of AKI by recruiting renal functional reserve and, therefore, increasing the glomerular filtration rate. The beneficial effect of amino acids was further confirmed for severe AKI and applied to patients with chronic kidney disease. Among non-pharmacological interventions, international guidelines on AKI suggest the implementation of a bundle of good clinical practice measures to reduce the incidence of perioperative AKI or to improve renal function whenever AKI occurs. The Kidney Disease Improving Global Outcomes (KDIGO) bundle includes the discontinuation of nephrotoxic agents, volume status and perfusion pressure assessment, renal functional hemodynamic monitoring, serum creatine, and urine output monitoring, and the avoidance of hyperglycemia and radiocontrast procedures. However, pooled data from a meta-analysis did not find a significant reduction in AKI. The aim of this review is to delineate the most appropriate evidence-based approach to prevent AKI in cardiac surgery patients.

The ability to predict progression to severe acute kidney injury (AKI) remains an unmet challenge. Contributing to the inability to predict the course of AKI is a void of understanding of the pathophysiological mechanisms of AKI. The identification of novel prognostic biomarkers could both predict patient outcomes and unravel the molecular mechanisms of AKI. We performed a multicenter retrospective observational study from a cohort of patients following cardiac surgery. We identified novel urinary prognostic biomarkers of severe AKI among subjects with early AKI. Of 2,065 proteins identified in the discovery cohort, insulin-like growth factor binding protein 1 (IGFBP-1) was the most promising. We validated IGFBP-1 as a prognostic biomarker of AKI in 213 patients. In addition, we investigated its role in the pathophysiology of AKI using a murine model of cisplatin-induced AKI (CIAKI). Urinary IGFBP-1 concentration in samples collected from patients with stage 1 AKI following cardiothoracic surgery was significantly higher in patients who progressed to severe AKI compared with patients who did not progress beyond stage 1 AKI (40.28 ng/ml vs. 2.8 ng/ml, P < 0.0001) and predicted the progression to the composite outcome (area under the curve: 0.85, P < 0.0001). IGFBP-1 knockout mice showed less renal injury, cell death, and apoptosis following CIAKI, possibly through increased activation of the insulin growth factor receptor 1. IGFBP-1 is a clinical prognostic biomarker of AKI and a direct mediator of the pathophysiology of AKI. Therapies that target the IGFBP-1 pathways may help alleviate the severity of AKI.NEW & NOTEWORTHY The ability to predict progression to severe AKI remains an unmet challenge. Early prognostic biomarkers of AKI hold promise to improve patient outcomes by early implementation of clinical therapy, as well as unravel the pathophysiological mechanisms of AKI. Here, we present a novel urinary biomarker, IGFBP-1, that predicts the progression to severe AKI following cardiac surgery. In addition, we show that IGFBP-1 mice are protected against CIAKI, suggesting a mechanistic role for IGFBP-1 in AKI.

Acute kidney injury (AKI) remains a significant challenge in critical care medicine, affecting up to 50% of intensive care unit patients with substantial mortality rates. While traditional approaches to AKI assessment rely on static measurements like serum creatinine and urine output, the furosemide stress test (FST) has emerged as a dynamic functional tool for evaluating renal tubular function and predicting AKI progression. This comprehensive review examines the historical development, physiological basis, technical aspects, and clinical applications of FST in various patient populations. Originally developed and validated in 2013, FST has demonstrated superior predictive capabilities for AKI progression and the need for renal replacement therapy compared to conventional biomarkers. The test's mechanism relies on assessing the kidney's response to a standardized furosemide challenge, providing insights into both the structural integrity and functional reserve of the renal tubular system. Standardized protocols have been established for different clinical scenarios, though implementation challenges remain, including timing considerations, patient selection, and resource requirements. FST has shown utility in critical care, post-cardiac surgery, sepsis-associated AKI, and heart failure settings. Recent developments include integration with artificial intelligence, personalized medicine approaches, and combination with novel biomarkers. While limitations exist, including contraindications and technical challenges, ongoing research continues to refine protocols and expand applications. This review highlights FST's role as a valuable prognostic tool in modern AKI management and discusses future directions, including automated monitoring systems, protocol standardization efforts, and potential applications in different patient populations.

Acute kidney injury (AKI) is a common condition in intensive care units (ICUs) and is associated with high mortality rates, particularly when kidney replacement therapy (KRT) becomes necessary. The optimal timing for initiating KRT remains a subject of ongoing debate. Emerging tools and methodologies, such as machine learning and advanced sub-phenotyping, offer promising insights into refining AKI management. Moving beyond the traditional "early" versus "delayed" paradigm and the heavy reliance on serum creatinine measurements, there is an opportunity to develop treatment strategies tailored to the unique pathophysiological and medical context of each patient. Such individualized approaches could potentially improve outcomes and transform AKI management into ICUs. However, KRT is not without risks. Hemodynamic instability poses a significant challenge, complicating the management of critically ill patients. The selection of a KRT modality-whether intermittent hemodialysis, continuous renal replacement therapy, or peritoneal dialysis-introduces additional complexities. Each modality has distinct advantages and limitations, requiring a careful, patient-specific approach to ensure optimal care. This decision-making process is further influenced by the availability of specialized equipment and trained personnel, resources that may be limited in some settings. Notably, current evidence does not demonstrate a clear survival or recovery benefit from the early initiation of dialysis. This narrative review explores the ongoing debates surrounding KRT timing and methodology, highlighting the importance of adopting patient-centric, individualized strategies to navigate the evolving landscape of AKI management.

Diuretic drugs act on electrolyte transporters in the kidney to induce diuresis and are often used in chronic kidney disease (CKD), given that nephron loss creates a deficit in the ability to excrete dietary sodium, which promotes an increase in plasma volume. This rise in plasma volume is exacerbated by CKD-induced systemic and intra-renal activation of the renin-angiotensin-aldosterone-system, which further limits urinary sodium excretion. In the absence of a compensatory decrease in systemic vascular resistance, increases in plasma volume induced by sodium retention can manifest as a rise in systemic arterial blood pressure. Management of sodium and volume overload in patients with CKD is therefore typically based on restriction of dietary sodium intake and the use of diuretic agents to enhance urinary sodium excretion. Thiazide and thiazide-type diuretics are foundational therapies for the management of hypertension, whereas loop diuretics are often needed for volume overload, which might also require combination therapies. Mineralocorticoid receptor antagonists have an important role in the management of diuretic-resistant volume overload or treatment-resistant hypertension. Additionally, diuretics can be used for the diagnosis of kidney diseases and in the management of hyperkalaemia or hypokalaemia, hyponatraemia, hypercalcaemia and hypomagnesaemia.

The role of loop diuretics in patients with acute kidney injury (AKI) is controversial. This study examined the association between the use of loop diuretics and prognosis in critically ill patients with AKI.

This study used data from the medical information mart for the intensive care IV database. Adult critically ill patients with AKI were included in the analysis. Patients were partitioned into two groups based on their use of loop diuretics in the ICU, and potentially confounding variables between the two groups were balanced using propensity score matching (PSM). We used time-dependent Cox proportional hazards regression, logistic regression, and Hodges-Lehman estimator to assess the impact of loop diuretics on all-cause mortality, renal replacement therapy (RRT) use, and the length of hospital stay, respectively.

This study included a cohort of 19,671 patients. After PSM, both groups consisted of 6200 patients. The use of loop diuretics was associated with a lower risk of in-hospital mortality (HR, 0.672; 95% CI 0.597-0.757; P < 0.001), lower in-ICU mortality (HR, 0.375; 95% CI 0.315-0.446; P < 0.001), and lower odds of in-hospital RRT (OR, 0.472; 95% CI 0.400-0.555; P < 0.001). A sensitivity analysis using the original cohort (HR, 0.624; 95% CI 0.561-0.693; P < 0.001) and weighted cohort (HR, 0.654; 95% CI 0.582-0.736; P < 0.001) also demonstrated lower in-hospital all-cause mortality.

The use of loop diuretics is associated with a substantial reduction in mortality among critically ill patients with AKI.

There is still no good method for predicting renal recovery and successful discontinuation of continuous renal replacement therapy (CRRT). This study assessed the ability of the furosemide stress test (FST) to predict successful discontinuation of CRRT.

This prospective single-center study included patients with acute kidney injury who underwent an initial attempt at discontinuation of CRRT. Successful discontinuation was defined as alive without renal replacement therapy for 7 days after discontinuation. Furosemide 1.0 mg/kg was administered intravenously within 2 h after discontinuation of CRRT. Urine output was recorded for the next 2 h. Receiver-operating characteristic curve and logistic regression analyses were performed to determine the best discriminative variable and to identify independent risk factors.

Discontinuation of CRRT was successful in 30 of 55 patients. The area under the curve for prediction of successful discontinuation was significantly greater for urine output in the 2 h following the FST (0.913) than for 24-h urine output on the previous day (0.739, P = 0.003) and urine neutrophil gelatinase-associated lipocalin (0.725, P = 0.020). A 2-h urine output of 188 mL had optimal sensitivity (0.800) and specificity (0.920). Multivariate analysis showed that 2-h urine output independently predicted successful discontinuation.

A urine output >188 mL in the first 2 h after FST predicted successful discontinuation of CRRT.

Acute kidney injury (AKI) is one of the poor prognosticating conditions in the intensive care unit (ICU). It increases mortality. Its pathophysiology involves various aspects, such as prerenal, renal, and postrenal components. Many times, it is a combination of one or more etiologies. Its management is a challenge, as no agent is approved for its prevention or treatment. It is the comprehensive treatment and timely institution of renal replacement therapy (RRT) that matter most. To understand the prognosis and outcome of patients with AKI, we conducted this observational analytical study.

It was a observational study. To analyze the effect of loop diuretics, we grouped the patients into two: one group received furosemide, and the other did not.

There was a male preponderance among AKI patients. Hypertension and diabetes were the most common comorbidities. About 44.1% of patients received diuretics. There was no significant difference among patients in the requirement for RRT or the need for vasopressors; however, the outcome of patients who received diuretics was worse.

The use of diuretics did not improve the outcome of acute kidney injury.

Acute kidney injury (AKI) is a common, heterogeneous, multifactorial condition, which is part of the overarching syndrome of acute kidney diseases and disorders. This condition's incidence highest in low-income and middle-income countries. In the short term, AKI is associated with increased mortality, an increased risk of complications, extended stays in hospital, and high health-care costs. Long-term complications include chronic kidney disease, kidney failure, cardiovascular morbidity, and an increased risk of death. Several strategies are available to prevent and treat AKI in specific clinical contexts. Otherwise, AKI care is primarily supportive, focused on treatment of the underlying cause, prevention of further injury, management of complications, and short-term renal replacement therapy in case of refractory complications. Evidence confirming that AKI subphenotyping is necessary to identify precision-oriented interventions is growing. Long-term follow-up of individuals recovered from AKI is recommended but the most effective models of care remain unclear.

Treatment of severely injured patients represents a major challenge, in part due to the unpredictable risk of major adverse events, including death. Preemptive personalized treatment aimed at preventing these events is a crucial objective of patient management; however, the currently available scoring systems provide only moderate guidance. Biomarkers from proteomics/peptidomics studies hold promise for improving the current situation, ultimately enabling precision medicine based on individual molecular profiles. To test the hypothesis that peptide biomarkers could predict patient outcomes in severely injured patients, we initiated a pilot study involving consecutive urine sampling (on days 0, 2, 5, 10, and 14) and subsequent peptidome analysis using capillary electrophoresis coupled to mass spectrometry (CE-MS) of 14 severely injured patients and two additional intensive care unit patients. The urine peptidomes of these patients were compared to those of age- and sex-matched controls. Moreover, previously established urinary peptide-based classifiers, CKD273, AKI204, and Cov50, were applied to the obtained peptidome data, and the association of the classifier's scores with a combined endpoint (death and/or kidney failure and/or respiratory insufficiency) was investigated. CE-MS peptidome analysis identified 191 significantly altered peptides in severely injured patients. A consistent increase in the abundance of peptides from A1AT, AHSG, and HBA1 was observed, while peptides derived from PIGR and UROM were consistently decreased. Most of the significant peptides (adjusted p < 0.05) were from COL1A1, and most were reduced in abundance. Two of the previously defined and validated peptidomic classifiers, CKD273 and AKI204, showed significant associations with the combined endpoint, which was not observed for the routine scores generally applied in the clinics. This prospective pilot study confirmed the hypothesis that urinary peptides provide information on patient outcomes and may guide personalized interventions in severely injured patients based on individual molecular changes. The results obtained allow the planning of a well-powered prospective trial investigating the value of urinary peptides in this context in more detail.

Furosemide stress test (FST) is a novel functional biomarker for predicting severe acute kidney injury (AKI); however, pediatric studies are limited.

Children 3 months to 18 years of age admitted to the intensive care unit (ICU) of a tertiary care hospital from Nov 2019 to July 2021 were screened and those who developed AKI stage 1 or 2 within 7 days of admission underwent FST (intravenous furosemide 1 mg/kg). Urine output was measured hourly for the next 6 h; a value > 2 ml/kg within the first 2 h was deemed furosemide responsive. Other biomarkers like plasma neutrophil gelatinase-associated lipocalin (NGAL) and proenkephalin (PENK) were also evaluated.

Of the 480 admitted patients, 51 developed AKI stage 1 or 2 within 7 days of admission and underwent FST. Nine of these patients were furosemide non-responsive. Thirteen (25.5%) patients (eight of nine from FST non-responsive group) developed stage 3 AKI within 7 days of FST, nine (17.6%) of whom (seven from non-responsive group) required kidney support therapy (KST). FST emerged as a good biomarker for predicting stage 3 AKI and need for KST with area-under-the-curve (AUC) being 0.93 ± 0.05 (95% CI 0.84-1.0) and 0.96 ± 0.03 (95% CI 0.9-1.0), respectively. FST outperformed NGAL and PENK in predicting AKI stage 3 and KST; however, the combination did not improve the diagnostic accuracy.

Furosemide stress test is a simple, inexpensive, and robust biomarker for predicting stage 3 AKI and KST need in critically ill children. Further research is required to identify the best FST cut-off in children.

This review discusses novel concepts of acute kidney injury (AKI), including subphenotyping, which may facilitate the development of target treatment strategies for specific subgroups of patients to achieve precision medicine.

AKI is a multifaceted syndrome with a major impact on morbidity and mortality. As efforts to identify treatment strategies have largely failed, it is becoming increasingly apparent that there are different subphenotypes that require different treatment strategies. Various ways of subphenotyping AKI have been investigated, including the use of novel renal biomarkers, machine learning and artificial intelligence, some of which have already been implemented in the clinical setting. Thus, novel renal biomarkers have been recommended for inclusion in new definition criteria for AKI and for the use of biomarker bundled strategies for the prevention of AKI. Computational models have been explored and require future research.

Subphenotyping of AKI may provide a new understanding of this syndrome and guide targeted treatment strategies in order to improve patient outcomes.

How to cite this article: Chatterjee R, Gupta L. The Reality of Evaluating Urine Spot Sodium and Urine Spot Sodium Creatinine Ratio in Furosemide Stress Test as a New Biomarker in Diagnosing Progressive AKI in Critically Ill. Indian J Crit Care Med 2024;28(12):1089-1090.

Acute kidney injury (AKI) is a prevalent complication in critically ill patients that affects the timing of renal replacement therapy (RRT) initiation. This study aimed to develop and validate the SACrA score for predicting non-emergent initiations (BUN ≥112 mg/dL or oliguria for >72 h) of RRT in critically ill patients.

We conducted a retrospective cohort study using data from two cohorts. The derivation cohort included patients admitted to the ICU between November 2021 and December 2023, whereas the validation cohort included patients admitted between September 2019 and October 2021. The primary outcome was non-emergent RRT initiation. The multivariate logistic regression with stepwise selection based on the Akaike information criterion finalized the model, including the variables, such as sex, albumin (Alb), creatinine (Cr), and APACHE II score (SACrA).

The derivation and validation cohorts comprised 470 and 476 patients, respectively. The SACrA score showed a strong predictive performance for non-emergent RRT initiation in both the cohorts. Cohort 1 had an ROC-AUC of 0.971, with a calibration slope of 0.982 and an intercept of 0.009, whereas cohort 2 had an ROC-AUC of 0.918, with a calibration slope of 0.988 and an intercept of 0.004.

The SACrA score is a robust tool for predicting non-emergent RRT initiation in critically ill patients using readily available clinical variables. Though additional data are needed to validate the SACrA score, our analysis suggests the tool may help clinicians make informed decisions, reduce unnecessary RRT, and thereby improve patient outcomes.

Acute kidney injury (AKI) is one of the most common complications for critically ill patients with cirrhosis, but it has remained unclear whether urine output fluctuations are associated with the risk of AKI in such patients. Thus, we explored the influence of 24-h urine-output trajectory on AKI in patients with cirrhosis through latent category trajectory modeling.

This retrospective cohort study examined patients with cirrhosis using the MIMIC-IV database. Changes in the trajectories of urine output within 24 h after admission to the intensive care unit (ICU) were categorized using latent category trajectory modeling. The outcome examined was the occurrence of AKI during ICU hospitalization. The risk of AKI in patients with different trajectory classes was explored using the cumulative incidence function (CIF) and the Fine-Gray model with the sub-distribution hazard ratio (SHR) and the 95% confidence interval (CI) as size effects.

The study included 3,562 critically ill patients with cirrhosis, of which 2,467 (69.26%) developed AKI during ICU hospitalization. The 24-h urine-output trajectories were split into five classes (Classes 1-5). The CIF curves demonstrated that patients with continuously low urine output (Class 2), a rapid decline in urine output after initially high levels (Class 3), and urine output that decreased slowly and then stabilized at a lower level (Class 4) were at higher risk for AKI than those with consistently moderate urine output (Class 1). After fully adjusting for various confounders, Classes 2, 3, and 4 were associated with a higher risk of AKI compared with Class 1, and the respective SHRs (95% CIs) were 2.56 (1.87-3.51), 1.86 (1.34-2.59), and 1.83 1.29-2.59).

The 24-h urine-output trajectory is significantly associated with the risk of AKI in critically ill patients with cirrhosis. More attention should be paid to the dynamic nature of urine-output changes over time, which may help guide early intervention and improve patients' prognoses.

This study investigated fluid removal strategies for critically ill patients with fluid overload on mechanical ventilation. Traditionally, a negative fluid balance (FB) is aimed for. However, this approach can have drawbacks. Here, we compared a new approach, namely removing fluids until patients become fluid responsive (FR) to the traditional empiric negative balance approach. Twelve patients were placed in each group (n = 24). FR assessment was performed using passive leg raising (PLR). Both groups maintained stable blood pressure and heart function during fluid management. Notably, the FR group weaned from the ventilator significantly faster than negative FB group (both for a spontaneous breathing trial (14 h vs. 36 h, p = 0.031) and extubation (26 h vs. 57 h, p = 0.007); the difference in total ventilator time wasn't statistically significant (49 h vs. 62 h, p = 0.065). Additionally, FR group avoided metabolic problems like secondary alkalosis and potential hypokalemia seen in the negative FB group. FR-guided fluid-removal in fluid overloaded mechanically ventilated patients was a feasible, safe, and maybe superior strategy in facilitating weaning and disconnection from mechanical ventilation than negative FB-driven fluid removal. FR is a safe endpoint for optimizing cardiac function and preventing adverse consequences during fluid removal.

Urine output (UO) in response to furosemide stress test (FST) can predict the progression of acute kidney injury (AKI). This study aimed to assess if changes in UO, urine spot sodium (USS), urine spot sodium creatinine ratio (USSCR) and changes in these parameters over 6 hours could differentiate between progressive and non-progressive AKI.

Fifty critically ill adults with AKI in acute kidney injury network (AKIN) stages I and II with volume overload were included in this prospective study. The FST was performed with 1 mg/kg intravenous bolus. Hourly UO, USS, USSCR, maximum USS difference (USSDMAX), and maximum USSCR difference (USSCRDMAX) were documented. Any progression of AKI was noted till day 3.

A total of 50 patients were recruited and n = 10 had progressive AKI (PAKI) and n = 40 had non-progressive AKI (NPAKI). Urine output at 1 and 2 h were significantly less in PAKI group. USS0, USS2, USS6, and USSDMAX were comparable between the groups. USSCR0 and USSCR6 were comparable between the groups whereas USSCR2 and USSCRDMAX were significantly less in PAKI group. USSDMAX did not correlate with UO1 (correlation coefficient 0.2, p = 0.16). However, USSCRDMAX showed a poor but significant correlation with UO1 (correlation coefficient 0.3, p = 0.03).

To conclude, hourly UO in the first two hours and maximum change in USSCR within 6 hours following the FST may have an important role in early differentiation of progressive AKI in critically ill patients.

Suhas P, Anand RK, Baidya DK, Dehran M. Role of Spot Urine Sodium in Furosemide Stress Test in Volume-overloaded Critically Ill Patients with Acute Kidney Injury. Indian J Crit Care Med 2024;28(12):1107-1111.

Modified furosemide responsiveness index (mFRI) is a novel biomarker for assessing diuretic response and AKI progression in patients with early AKI. However, the comparative predictive performance of mFRI and novel renal biomarkers for adverse renal outcomes remains unclear. In a single-center prospective study, we aimed to evaluate the discriminatory abilities of mFRI and other novel renal biomarkers in predicting AKI progression and prognosis in patients with initial mild and moderate AKI (KDIGO stage 1 to 2).

Patients with initial mild and moderate AKI within 48 h following cardiac surgery were included in this study. The mFRI, renal biomarkers (including serum or urinary neutrophil gelatinase-associated lipocalin [sNGAL or uNGAL], serum cystatin C, urinary N-acetyl-beta-D-glycosaminidase [uNAG], urinary albumin-to-creatinine ratio) and cytokines (TNF, IL-1β, IL-2R, IL-6, IL-8, and IL-10) were measured at AKI diagnosis. The mFRI was calculated for each patient, which was defined as 2-hour urine output divided by furosemide dose and body weight. Of 1013 included patients, 154 (15.2%) experienced AKI progression, with 59 (5.8%) progressing to stage 3 and 33 (3.3%) meeting the composite outcome of hospital mortality or receipt of renal replacement therapy (RRT). The mFRI showed non-inferiority or potential superiority to renal biomarkers and cytokines in predicting AKI progression (area under the curve [AUC] 0.80, 95% confidence interval [CI] 0.77-0.82), progression to stage 3 (AUC 0.87, 95% CI 0.85-0.89), and composite outcome of death and receipt of RRT (AUC 0.85, 95% CI 0.82-0.87). Furthermore, the combination of a functional biomarker (mFRI) and a urinary injury biomarker (uNAG or uNGAL) resulted in a significant improvement in the prediction of adverse renal outcomes than either individual biomarker (all P < 0.05). Moreover, incorporating these panels into clinical model significantly enhanced its predictive capacity for adverse renal outcomes, as demonstrated by the C index, integrated discrimination improvement, and net reclassification improvement (all P < 0.05).

As a rapid, cost-effective and easily accessible biomarker, mFRI, exhibited superior or comparable predictive capabilities for AKI progression and prognosis compared to renal biomarkers in cardiac surgical patients with mild to moderate AKI.

Clinicaltrials.gov, NCT04962412. Registered July 15, 2021, https://clinicaltrials.gov/ct2/show/NCT04962412?cond=NCT04962412&draw=2&rank=1 .

Surrogate measures of glomerular filtration rate (GFR) continue to serve as pivotal determinants of the incidence, severity, and management of acute kidney injury (AKI), as well as the primary reference point underpinning knowledge of its pathophysiology. However, several clinically important deficits in aspects of renal excretory function during AKI other than GFR decline, including acid-base regulation, electrolyte and water balance, and urinary concentrating capacity, can evade detection when diagnostic criteria are built around purely GFR-based assessments. The use of putative markers of tubular injury to detect "sub-clinical" AKI has been proposed to expand the definition and diagnostic criteria for AKI, but their diagnostic performance is curtailed by ambiguity with respect to their biological meaning and context specificity. Efforts to devise new holistic assessments of overall renal functional compromise in AKI would foster the capacity to better personalize patient care by replacing biomarker threshold-based diagnostic criteria with a shift to assessment of compromise along a pathophysiological continuum. The term AKI refers to a syndrome of sudden renal deterioration, the severity of which is classified by precise diagnostic criteria that have unquestionable utility in patient management as well as blatant limitations. Particularly, the absence of an explicit pathophysiological definition of AKI curtails further scientific development and clinical handling, entrapping the field within its present narrow GFR-based view. A refreshed approach based on a more holistic consideration of renal functional impairment in AKI as the basis for a new diagnostic concept that reaches beyond the boundaries imposed by the current GFR threshold-based classification of AKI, capturing broader aspects of pathogenesis, could enhance AKI prevention strategies and improve AKI patient outcome and prognosis.

In sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2*IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2*IGFBP-7 concentrations improves the accuracy in predicting RRT necessity.

In this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion.

32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2*IGFBP-7 decreased within 2 h from 3.26 ng2/mL2/1000 (IQR: 1.38-5.53) to 2.36 ng2/mL2/1000 (IQR: 1.61-4.87) in RRT and 1.68 ng2/mL2/1000 (IQR: 0.56-2.94) to 0.27 ng2/mL2/1000 (IQR: 0.12-0.89) and non-RRT patients, respectively. While TIMP-2*IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2*IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55-0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64-0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2*IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74-0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64-0.97), and a specificity of 0.96 (95%-CI 0.88-0.99).

The combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation.

Cardiac surgery-associated acute kidney injury (CSA-AKI) affects up to 42% of cardiac surgery patients. CSA-AKI is multifactorial, with low abdominal perfusion pressure often overlooked. Abdominal perfusion pressure is calculated as mean arterial pressure minus intra-abdominal pressure (IAP). IAH decreases cardiac output and compresses the renal vasculature and renal parenchyma. Recent studies have highlighted the frequent occurrence of IAH in cardiac surgery patients and have linked the role of low perfusion pressure to the occurrence of AKI. This review and expert opinion illustrate current evidence on the pathophysiology, diagnosis, and therapy of IAH and ACS in the context of AKI.

Background and objective Although early diuretic use and negative fluid balance (NFB) have been associated with lower mortality in mechanically ventilated patients, some patients are not tolerant to NFB. Little is known about whether urine output response after the diuretic administration predicts NFB tolerance in mechanically ventilated patients. Hence, we conducted this study to look into this. Methods This was a single-center, prospective, observational study. We included mechanically ventilated patients who were hemodynamically stable with bilateral pulmonary opacities on chest radiography and planned to be diuresed per our fluid removal protocol. In the protocol, a low dose of furosemide adjusted to each patient's estimated glomerular filtration rate (eGFR) was administered, and then we started to measure urine outputs hourly for four hours. Tolerance to NFB was defined as "absence of hypotension, fluid resuscitation and vasopressors use, and acute kidney injury during fluid removal". We investigated whether the urine output predicts the tolerance to NFB during fluid removal treatment. Results A total of 60 mechanically ventilated patients were included. Notably, 80% (48/60) of the patients were tolerant to NFB. All hourly and cumulative urine output measurements during the first four hours after the first diuretic administration were significantly higher in the NFB-tolerant group than in the non-tolerant group. Among all hourly and cumulative urine output measurements, the first four-hour cumulative urine output showed the highest area under the receiver operating characteristic curve (AUC) of 0.83 for predicting the tolerance to NFB. Multivariate logistic regression analysis adjusted for the urine output two hours before the diuretic use showed that each 100-mL increase in the first four-hour cumulative urine output was significantly associated with an increased odds ratio (OR) of the tolerance to NFB [adjusted odds ratio (aOR): 1.53; 95% CI: 1.11-2.15]. Conclusions Based on our findings, the first four-hour cumulative urine output after the first low dose of diuretic administration might help predict tolerance to NFB during fluid removal treatment in mechanically ventilated, critically ill patients.

Over the past two decades, our understanding of the impact of acute kidney injury, disorders of fluid balance, and their interplay have increased significantly. In recent years, the epidemiology and impact of fluid balance, including the pathologic state of fluid overload on outcomes has been studied extensively across multiple pediatric and neonatal populations. A detailed understating of fluid balance has become increasingly important as it is recognized as a target for intervention to continue to work to improve outcomes in these populations. In this review, we provide an update on the epidemiology and outcomes associated with fluid balance disorders and the development of fluid overload in children with acute kidney injury (AKI). This will include a detailed review of consensus definitions of fluid balance, fluid overload, and the methodologies to define them, impact of fluid balance on the diagnosis of AKI and the concept of fluid corrected serum creatinine. This review will also provide detailed descriptions of future directions and the changing paradigms around fluid balance and AKI in critical care nephrology, including the incorporation of the sequential utilization of risk stratification, novel biomarkers, and functional kidney tests (furosemide stress test) into research and ultimately clinical care. Finally, the review will conclude with novel methods currently under study to assess fluid balance and distribution (point of care ultrasound and bioimpedance).

Traditional acute kidney injury (AKI) classifications, which are centered around semi-anatomical lines, can no longer capture the complexity of AKI. By employing strategies to identify predictive and prognostic enrichment targets, experts could gain a deeper comprehension of AKI's pathophysiology, allowing for the development of treatment-specific targets and enhancing individualized care. Subphenotyping, which is enriched with AKI biomarkers, holds insights into distinct risk profiles and tailored treatment strategies that redefine AKI and contribute to improved clinical management. The utilization of biomarkers such as N-acetyl-β-D-glucosaminidase, tissue inhibitor of metalloprotease-2·insulin-like growth factor-binding protein 7, kidney injury molecule-1, and liver fatty acid-binding protein garnered significant attention as a means to predict subclinical AKI. Novel biomarkers offer promise in predicting persistent AKI, with urinary motif chemokine ligand 14 displaying significant sensitivity and specificity. Furthermore, they serve as predictive markers for weaning patients from acute dialysis and offer valuable insights into distinct AKI subgroups. The proposed management of AKI, which is encapsulated in a structured flowchart, bridges the gap between research and clinical practice. It streamlines the utilization of biomarkers and subphenotyping, promising a future in which AKI is swiftly identified and managed with unprecedented precision. Incorporating kidney biomarkers into strategies for early AKI detection and the initiation of AKI care bundles has proven to be more effective than using care bundles without these novel biomarkers. This comprehensive approach represents a significant stride toward precision medicine, enabling the identification of high-risk subphenotypes in patients with AKI.

No reliable clinical tools exist to predict acute kidney injury (AKI) progression. We aim to explore a scoring system for predicting the composite outcome of progression to severe AKI or death within seven days among early AKI patients after cardiac surgery.

In this study, we used two independent cohorts, and patients who experienced mild/moderate AKI within 48 h after cardiac surgery were enrolled. Eventually, 3188 patients from the MIMIC-IV database were used as the derivation cohort, while 499 patients from the Zhongshan cohort were used as external validation. The primary outcome was defined by the composite outcome of progression to severe AKI or death within seven days after enrollment. The variables identified by LASSO regression analysis were entered into logistic regression models and were used to construct the risk score.

The composite outcome accounted for 3.7% (n = 119) and 7.6% (n = 38) of the derivation and validation cohorts, respectively. Six predictors were assembled into a risk score (AKI-Pro score), including female, baseline eGFR, aortic surgery, modified furosemide responsiveness index (mFRI), SOFA, and AKI stage. And we stratified the risk score into four groups: low, moderate, high, and very high risk. The risk score displayed satisfied predictive discrimination and calibration in the derivation and validation cohort. The AKI-Pro score discriminated the composite outcome better than CRATE score, Cleveland score, AKICS score, Simplified renal index, and SRI risk score (all P < 0.05).

The AKI-Pro score is a new clinical tool that could assist clinicians to identify early AKI patients at high risk for AKI progression or death.

Normothermic machine perfusion (NMP) is a promising pretransplant kidney quality assessment platform, but it remains crucial to increase its diagnostic potential while ensuring minimal additional injury to the already damaged kidney. Interventions that alter tubular transport can influence renal function and injury during perfusion. This study aimed to determine whether furosemide and desmopressin affect renal function and injury during NMP.

Eighteen porcine kidneys (n = 6 per group) were subjected to 30 min of warm ischemia and 4 h of oxygenated hypothermic perfusion before being subjected to 6 h of NMP. Each organ was randomized to receive no drug, furosemide (750 mg), or desmopressin (16 μg) during NMP.

Compared with the other groups, the addition of furosemide resulted in significantly increased urine output, fractional excretion of sodium and potassium, and urea clearance during NMP. Urinary neutrophil gelatinase-associated lipocalin levels decreased significantly with furosemide supplementation compared with the other groups. The addition of desmopressin did not result in any significantly different outcome measurements compared with the control group.

This study showed that the addition of furosemide affected renal function while attenuating tubulointerstitial injury during NMP. Therefore, furosemide supplementation may provide renal protection and serve as a functional test for pretransplant kidney viability assessment during NMP.

The role of beta2-microglobulin (β2-MG) in predicting acute kidney injury (AKI) in hemophagocytic lymphohistiocytosis patients has been poorly studied. This study aimed to analyze the clinical characteristics of hemophagocytic lymphohistiocytosis patients and identify risk factors that predict AKI development.

This retrospective observational cohort study conducted at a single-center involved 938 patients diagnosed with hemophagocytic lymphohistiocytosis, who were divided into AKI  group and non-AKI group. Patient data were collected and analyzed using univariate and multivariate binary logistic regression to identify potiential risk factors associated with AKI occurrence.   RESULTS: Among the enrolled patients, 486 were male (51.9%), the median age was 37 years (interquartile range, 28.0, 52.0), 58.4% experienced AKI. Mechanical ventilation (8.0% vs. 0.8%) and vasopressor support (21.7% vs. 4.1%) occurred at significantly higher rates in the AKI group compared to the non-AKI group, with significantly higher in-hospital mortality (5.5% vs. 1.3%) and 28-day mortality (12.8% vs. 5.4%). When β2-MG was used as a continuous variable, multifactorial analysis showed that β2-MG, transplantation, and vasopressor support were independently associated with risk for the development of AKI.

The incidence of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis complicated by AKI remains high. Monitoring levels of β2-MG may provide clinicians with timely indicators of changes in renal function,  facilitating adjustments to treatment strategies.

AKI is a frequent complication of critical illness and portends poor outcome. CCL14 is a validated predictor of persistent severe AKI in critically ill patients. We examined the association of CCL14 with urine output within 48 h.

In pooled data from 2 studies of critically ill patients with KDIGO stage 2-3 AKI, CCL14 was measured by NEPHROCLEAR™ CCL14 Test on the Astute 140® Meter (low, intermediate, and high categories [1.3 and 13 ng/mL]). Average hourly urine output over 48 h, stage 3 AKI per urine output criterion on day 2, and composite of dialysis or death within 7 days were examined using multivariable mixed and logistic regression models.

Of the 497 subjects with median age of 65 (56-74) years, 49% (242/497) were on diuretics. CCL14 concentration was low in 219 (44%), intermediate in 217 (44%), and high in 61 (12%) patients. In mixed regression analysis, hourly urine output over time was different within each CCL14 risk category based on diuretic use due to significant three-way interaction (p < 0.001). In logistic regression analysis, CCL14 risk category was independently associated with low urine output on day 2 per KDIGO stage 3 (adjusted for diuretic use and baseline clinical variables), and composite of dialysis or death within 7 days (adjusted for urine output within 48 h of CCL14 measurement).

CCL14 measured in patients with moderate to severe AKI is associated with urine output trajectory within 48 h, oliguria on day 2, and dialysis within 7 days.

Congestion is the primary driver of hospital admissions in patients with heart failure and the key determinant of their outcome. Although intravenous loop diuretics remain the predominant agents used in the setting of acute heart failure, the therapeutic response is known to be variable, with a significant subset of patients discharged from the hospital with residual hypervolemia. In this context, urinary sodium excretion has gained attention both as a marker of response to loop diuretics and as a marker of prognosis that may be a useful clinical tool to guide therapy. Several decongestive strategies have been explored to improve diuretic responsiveness and removal of excess fluid. Sequential nephron blockade through combination diuretic therapy is one of the most used methods to enhance natriuresis and counter diuretic resistance. In this article, I provide an overview of the contemporary decongestive approaches and discuss the clinical data on the use of add-on diuretic therapy. I also discuss mechanical removal of excess fluid through extracorporeal ultrafiltration with a brief review of the results of landmark studies. Finally, I provide a short overview of the strategies that are currently under investigation and may prove helpful in this setting.

The impact of disorders of fluid balance, including the pathologic state of fluid overload in sick children has become increasingly apparent. With this understanding, there has been a shift from application of absolute thresholds of fluid accumulation to an appreciation of the intricacies of fluid balance, including the impact of timing, trajectory, and disease pathophysiology.

The 26th Acute Disease Quality Initiative was the first to be exclusively dedicated to pediatric and neonatal acute kidney injury (pADQI). As part of the consensus panel, a multidisciplinary working group dedicated to fluid balance, fluid accumulation, and fluid overload was created. Through a search, review, and appraisal of the literature, summative consensus statements, along with identification of knowledge gaps and recommendations for clinical practice and research were developed.

The 26th pADQI conference proposed harmonized terminology for fluid balance and for describing a pathologic state of fluid overload for clinical practice and research. Recommendations include that the terms daily fluid balance, cumulative fluid balance, and percent cumulative fluid balance be utilized to describe the fluid status of sick children. The term fluid overload is to be preserved for describing a pathologic state of positive fluid balance associated with adverse events. Several recommendations for research were proposed including focused validation of the definition of fluid balance, fluid overload, and proposed methodologic approaches and endpoints for clinical trials.

Acute kidney injury (AKI) in children is associated with increased morbidity, reduced health-related quality of life, greater resource utilization, and higher mortality. Improvements in the timeliness and precision of AKI diagnosis in children are needed. In this report, we highlight existing, novel, and on-the-horizon diagnostic and risk-stratification tools for pediatric AKI, and outline opportunities for integration into clinical practice. We also summarize pediatric-specific high-risk diagnoses and exposures for AKI, as well as the potential role of real-time risk stratification and clinical decision support to improve outcomes. Lastly, the key characteristics of important pediatric AKI phenotypes will be outlined. Throughout, we identify key knowledge gaps, which represent prioritized areas of focus for future research that will facilitate a comprehensive, timely and personalized approach to pediatric AKI diagnosis and management.

Acute kidney injury (AKI) is a common condition in hospitalized patients who often requires kidney support therapy (KST). However, predicting the need for KST in critically ill patients remains challenging. This study aimed to analyze endothelium-related biomarkers as predictors of KST need in critically ill patients with stage 2 AKI. A prospective observational study was conducted on 127 adult ICU patients with stage 2 AKI by serum creatinine only. Endothelium-related biomarkers, including vascular cell adhesion protein-1 (VCAM-1), angiopoietin (AGPT) 1 and 2, and syndecan-1, were measured. Clinical parameters and outcomes were recorded. Logistic regression models, receiver operating characteristic (ROC) curves, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used for analysis. Among the patients, 22 (17.2%) required KST within 72 h. AGPT2 and syndecan-1 levels were significantly greater in patients who progressed to the KST. Multivariate analysis revealed that AGPT2 and syndecan-1 were independently associated with the need for KST. The area under the ROC curve (AUC-ROC) for AGPT2 and syndecan-1 performed better than did the constructed clinical model in predicting KST. The combination of AGPT2 and syndecan-1 improved the discrimination capacity of predicting KST beyond that of the clinical model alone. Additionally, this combination improved the classification accuracy of the NRI and IDI. AGPT2 and syndecan-1 demonstrated predictive value for the need for KST in critically ill patients with stage 2 AKI. The combination of AGPT2 and syndecan-1 alone enhanced the predictive capacity of predicting KST beyond clinical variables alone. These findings may contribute to the early identification of patients who will benefit from KST and aid in the management of AKI in critically ill patients.

As patients with acute kidney injury (AKI) progress to a higher stage, the risk for poor outcomes dramatically rises. Early identification of patients at high risk for AKI progression remains a major challenge. This study aimed to evaluate the value of furosemide responsiveness (FR) for predicting AKI progression in patients with initial mild and moderate AKI after cardiac surgery.

We performed 2 separate exploratory analyses. The Zhongshan cohort was a single-center, prospective, observational cohort, whereas the Beth Israel Deaconess Medical Center cohort was a single-center, retrospective cohort. We calculated 2 FR parameters for each patient, namely the FR index and modified FR index, defined as 2-hour urine output divided by furosemide dose (FR index, mL/mg/2 h) and by furosemide dose and body weight (modified FR index, mL/[mg·kg]/2 h), respectively. The primary outcome was AKI progression within 7 days.

AKI progression occurred in 80 (16.0%) and 359 (11.3%) patients in the Zhongshan and Beth Israel Deaconess Medical Center cohorts, respectively. All FR parameters (considered continuously or in quartiles) were inversely associated with risk of AKI progression in both cohorts (all adjusted P < .01). The addition of FR parameters significantly improved prediction for AKI progression based on baseline clinical models involving C-index, net reclassification improvement, and integrated discrimination improvement index in both cohorts (all P < .01).

FR parameters were inversely associated with risk of AKI progression in patients with mild and moderate AKI after cardiac surgery. The addition of FR parameters significantly improved prediction for AKI progression based on baseline clinical models.