Strength of the Uninvolved Limb Following Return to Activity After ACL Injury: Implications for Symmetry as a Marker of Sufficient Strength.

Background: Muscular strength deficits are common after ACL injury. While the Limb Symmetry Index (LSI), using the uninvolved limb as a reference, is widely used, negative strength adaptations may affect both limbs post-injury. It is uncertain how the strength of the uninvolved limb in those with an ACL injury compares to uninjured individuals, making it unclear whether it is appropriate as a benchmark for determining sufficient strength. Purpose: To compare the strength of key lower extremity muscles of the uninvolved limb in those with history of ACL injury (ACL-I) to the dominant limb in individuals with no history of ACL injury (control). Study Design: Cross-sectional study. Methods: A total of 5,727 military cadets were examined, with 82 females and 126 males in the ACL-I group and 2,146 females and 3,373 males in the control group. Maximum isometric strength was assessed for six muscle groups measured with a hand-held dynamometer. Separate two-way ANOVAs with limb and sex were performed for each muscle group. Results: Significant main effects for limb were observed with the uninvolved limb in the ACL-I group displaying greater strength compared to the dominant limb in the control group for the quadriceps, hamstrings, and gluteus medius, but effect sizes were small (Cohen's d <0.25). Significant main effects for sex were observed with greater male muscular strength in all six muscle groups with small to large effect sizes (Cohen's d 0.49-1.46). No limb-by-sex interactions were observed. Conclusions: There was no evidence of reduced strength in the uninvolved limb in those with a history of ACL injury compared to the dominant limb in those with no prior ACL injury. This finding suggests that, after clearance to return to activities, the uninvolved limb can be used as a standard for comparison of sufficient strength, including when using the LSI. Level of Evidence: Level 3.

Parity in bacterial communities and resistomes: Microplastic and natural organic particles in the Tyrrhenian Sea.

Petroleum-based microplastic particles (MPs) are carriers of antimicrobial resistance genes (ARGs) in aquatic environments, influencing the selection and spread of antimicrobial resistance. This research characterized MP and natural organic particle (NOP) bacterial communities and resistomes in the Tyrrhenian Sea, a region impacted by plastic pollution and climate change. MP and NOP bacterial communities were similar but different from the free-living planktonic communities. Likewise, MP and NOP ARG abundances were similar but different (higher) from the planktonic communities. MP and NOP metagenome-assembled genomes contained ARGs associated with mobile genetic elements and exhibited co-occurrence with metal resistance genes. Overall, these findings show that MPs and NOPs harbor potential pathogenic and antimicrobial resistant bacteria, which can aid in the spread of antimicrobial resistance. Further, petroleum-based MPs do not represent novel ecological niches for allochthonous bacteria; rather, they synergize with NOPs, collectively facilitating the spread of antimicrobial resistance in marine ecosystems.

Serial direct sodium removal in patients with heart failure and diuretic resistance.

AIMS: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance. METHODS AND RESULTS: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved. CONCLUSIONS: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS. CLINICAL TRIAL REGISTRATION: RED DESERT (NCT04116034), SAHARA (NCT04882358).

Jump Landing Kinematics: Establishing Normative Ranges For Male And Female Athletes.

CONTEXT: Lower extremity joint (LE) kinematics during landing tasks are important predictors of injury risk and performance outcomes in athletes. OBJECTIVE: To establish sex-related differences and normative ranges for LE kinematics during the jump-landing task in a large cohort of healthy military service academy cadets. DESIGN: Cross-Sectional Study. SETTING: US Air Force, Naval, and Military Academies. PARTICIPANTS: 5308 cadets (2062 females [38.8%]). MAIN OUTCOME MEASURE(S): Sex-related differences in LE kinematics were analyzed using independent samples t-tests. Mean differences (MD) and effect sizes (d) were reported for interpretability. Normative ranges for hip and knee joint angles were established separately for males and females at initial contact (IC) and 50% of the stance phase. RESULTS: Compared to males, moderate effect sizes (d ≥ .5) were observed for knee external rotation (negative value) where females displayed greater motion at IC and at 50% stance (MD: - 3.9˚ and -5.0˚, respectively, p < .001). The following findings were of small effect size (.2 ≥ d > .5). Females exhibited less knee and hip flexion at IC (MD: -1.8˚ and -0.5˚, respectively, p < .001) and at 50% stance (MD: -4.1˚ and -4.6˚, respectfully, p < .001). This was accompanied by females having greater knee valgus (negative value) and hip adduction at IC (MD: -2.2˚ and 1.06˚, respectively, p < .001) and at 50% stance (MD: -3.2˚ and 1.8˚, respectfully, p < .001). CONCLUSION: This study establishes normative ranges for LE kinematics during the jump-landing task in a large cohort of healthy military service academy cadets entering their first year. Sex- related differences in LE kinematics were observed, highlighting the importance of considering sex as a factor in the evaluation of lower extremity movement quality and management of injury risk.

Endovascular treatment of renal vein thrombosis in a young patient with lung transplant.

Spontaneous renal vein thrombosis is a rare entity. A 28-year-old woman with a history of a double-lung transplant was admitted with flank pain and found to have acute kidney injury. A magnetic resonance venogram demonstrated isolated left renal vein thrombosis with extension into the inferior vena cava. Initial management with therapeutic anticoagulation and hydration was unsuccessful. Thus, pharmacochemical thrombectomy was performed. A temporary suprarenal inferior vena cava filter was placed for intraoperative pulmonary prophylaxis. The patient's renal function returned to baseline and remained normal 13 months later. Early incorporation of percutaneous pharmacomechanical thrombectomy can improve renal function when medical therapy alone is unsuccessful.

Insulin Requirement and Infrainguinal Bypass Outcomes in Patients with Peripheral Arterial Disease.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for peripheral artery disease. The association of DM with major adverse limb events (MALE) after lower extremity revascularization remains controversial, as patients with diabetes are typically analyzed as a single, homogenous group. Using a large national database, this study examines the impact of insulin use and glycemic control on the outcomes following infrainguinal bypass. The hypothesis is that prevalent insulin therapy and elevated hemoglobin A1c (HbA1c) are associated with an increased risk of MALEs after infrainguinal bypass in patients with DM and could therefore be used for risk stratification. METHODS: The Vascular Quality Initiative database files for infrainguinal bypass (2007-2021) were retrospectively reviewed. Patients with DM undergoing bypass for peripheral artery disease were included. Patients on dialysis or with prior kidney transplantation were excluded. The characteristics and outcomes of patients with insulin-requiring diabetes mellitus (IRDM) were compared to those of patients not requiring insulin (noninsulin-requiring diabetes mellitus [NIRDM]) prior to the bypass procedure. RESULTS: A total of 9,686 patients with DM (56% IRDM) underwent bypass. Patients with IRDM were significantly younger than patients with NIRDM, more likely to be female (P < 0.01), African American (P < 0.01), and Hispanic (P = 0.031), and more likely to have comorbidities and be categorized into American Society of Anesthesiologist classes IV-V. They were more likely to be treated for chronic limb-threatening ischemia (P < 0.001). Patients with IRDM had significantly higher perioperative complications with no difference in perioperative mortality between the 2 groups. Beyond the perioperative period, with a mean follow-up of 427 days, patients with IRDM had significantly lower crude rates of primary patency and higher crude rates of major amputation, MALE, and mortality compared to patients with NIRDM. Regression analyses demonstrated that insulin requirement, but not HbA1c, was independently associated with a higher risk of MALE (hazard ratio = 1.17 [1.06-1.29]) and mortality (hazard ratio = 1.28 [1.16-1.43]). CONCLUSIONS: Insulin requirement, but not HbA1c, is significantly associated with MALEs and survival after infrainguinal bypass in the Vascular Quality Initiative. Stratification of patients with DM based on their prevalent insulin use prior to infrainguinal bypass surgery could improve the prediction of outcomes of peripheral arterial bypass surgery in patients with diabetes.

Circular external fixation for revision of failed tibia internal fixation.

BACKGROUND: The management of failed tibial fracture fixation remains a challenge for orthopaedic surgeons. This study investigate the utility and outcomes of circular external fixation in the management of failed internal fixation of tibial fractures. METHODS: Retrospective review of a prospectively collected database of a complex limb reconstruction unit at a major trauma centre was done during December 2022. Patients with failed internal fixation of tibial fracture who underwent revision surgery with circular external fixation frame were included. RESULTS: 20 patients with a mean age of 47.8 ± 16.5 years (range: 15-69) were included. Fourteen (70.0%) patients had failed plate and screws fixations, and the remaining six (30.0%) failed intramedullary nail fixation. The most common indication for revision surgery was development of early postoperative surgical site infection (5 patients; 25.0%). The mean duration of frame treatment was 199.5 ± 80.1 days (range = 49-364), while the mean follow-up duration following frame removal was 3.2 ± 1.8 years (range = 2-8). The overall union rate in this series was 100%; and all infected cases had complete resolution from infection. The total number of complications was 11, however, only two complications required surgical intervention. The most common complications reported were pin site infection (6; 30.0%) and limb length discrepancy of 2 cm (2; 10.0%). CONCLUSIONS: Circular external fixation is a reliable surgical option in the treatment of failed internal fixation of tibia fractures. This technique can provide limb salvage in complex infected and noninfected cases with a high union rate and minimal major complications.

In the "Plant-Based" Era, Patients With Chronic Kidney Disease Should Focus on Eating Healthy.

In the era of plant-based diets, it is important for Nephrology providers to know the evidence regarding their healthfulness in patients with chronic kidney disease (CKD). A whole food, plant-based diet, which emphasizes fresh, minimally processed or refined plant-based foods and limits animal products, has shown benefits for patients with CKD. These include reduced dietary acid load, lower bioavailability of potassium and phosphorus, increased dietary fiber intake, nutritional adequacy, and cardiovascular and mortality benefits. Potential drawbacks include the need for specific knowledge, skills, and cost involved in preparing varied, healthy, and appetizing plant-based meals, leading to lower acceptability and accessibility to certain populations. Liberalization of the standard CKD diet to include healthy, minimally processed foods such as fruits, vegetables, nuts, legumes, and whole grains is likely beneficial, though more research is needed to determine whether a plant-based-only diet is the optimal way to achieve healthier eating in patients with CKD.

Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects.

SIGNIFICANCE STATEMENT: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov ( NCT03027960 ).

Current and Developing Technologies for BP Monitoring.

PURPOSE OF REVIEW: To discuss new and emerging technologies for blood pressure measurement and monitoring, including the limitations of current blood pressure measurement techniques, hopes for new device technologies, and the current barriers impeding change in this space. RECENT FINDINGS: A number of new cuffless devices are being developed and poised to emerge on the marketplace in coming years. There are several different types of technologies and sensors currently under study. New guidelines for validation of cuffless blood pressure devices have recently been developed in anticipation of this change. The current standards for blood pressure device validation are specific to cuff-based technology and are insufficient for validating devices with cuffless-based technologies. In anticipation of a number of new cuffless technologies coming to market in the coming years, three sets of standards have been developed and published in recent years to address this gap.

Hybrid Revision of Dysfunctional Aneurysmal Arteriovenous Fistulas.

Endovascular therapy has become the first-line treatment for failing hemodialysis arteriovenous fistulas (AVFs). However, open revision remains an important modality for vascular access maintenance and the recommended approach for AVF aneurysms. This case series describes a hybrid approach for aneurysmal access revision. Three patients were referred for second opinion after failure of endovascular therapy to establish a functioning access. The medical history is briefly described to highlight the limitations of endovascular therapy and the technical advantages of the hybrid approach in these clinical scenarios.

Secondary Hypertension Overview and Workup for the Primary Care Physician.

Secondary hypertension occurs in 5% to 10% of all patients with hypertension. Given the majority of patients with hypertension will not have a secondary cause, only select patients with specific characteristics should be screened. The causes include a range of abnormalities, some are quite rare, such as pheochromocytoma, while others are much more common, such as chronic kidney disease. When considering which disorders to test for, it is important to incorporate the clinical history, family history, and prevalence of each disease. Treatment is specific to the underlying cause and includes medications, procedures, surgery, and device therapies.

Carbon dioxide angiography during peripheral vascular interventions is associated with decreased cardiac and renal complications in patients with chronic kidney disease.

OBJECTIVE: Patients with chronic kidney disease (CKD) who undergo peripheral vascular interventions (PVI) with iodinated contrast are at higher risk of post-contrast acute kidney injury (PC-AKI). Carbon dioxide (CO2) angiography can reduce iodinated contrast volume usage in this patient population, but its impact on PC-AKI has not been studied. We hypothesize that CO2 angiography is associated with a decrease in PC-AKI in patients with advanced CKD. METHODS: The Vascular Quality Initiative PVI dataset from 2010 to 2021 was reviewed. Only patients with advanced CKD (estimated glomular filtration rate <45 ml/min/1.73 m2) treated for peripheral arterial disease were included. Propensity matching and multivariate logistic regression based on demographics, comorbidities, CKD stage, and indications were used to compare the outcomes of patients treated with and without CO2. RESULTS: There were 20,706 PVIs performed in patients with advanced CKD, and only 22% utilized CO2 angiography. Compared with patients treated without CO2, patients who underwent CO2 angiography were younger and less likely to be women or White, and more likely to have poor renal function, diabetes, cardiac comorbidities, and present with tissue loss. Propensity matching yielded well-matched groups with 4472 patients in each group. The procedural details after matching demonstrated 50% reduction in the volume of contrast used (32±33 vs 65±48 mL; P < .01). PVI with CO2 angiography was associated with lower rates of PC-AKI (3.9% vs 4.8%; P = .03) and cardiac complications (2.1% vs 2.9%; P = .03) without a significant difference in technical failure or major/minor amputations. Low contrast volumes (≤50 mL for CKD3, ≤20 mL for CKD4, and ≤9 mL for CKD5) are associated with reduced risk of PC-AKI (hazard ratio, 0.59; P < .01). CONCLUSIONS: CO2 angiography reduces iodinated contrast volume usage during PVI and is associated with decreased cardiac complications and PC-AKI. CO2 angiography is underutilized and should be considered for patients with advanced CKD who require endovascular therapy.

In-Hospital Observation on Oral Diuretics After Treatment for Acute Decompensated Heart Failure: Evaluating the Utility.

BACKGROUND: Following treatment for acute decompensated heart failure, in-hospital observation on oral diuretics (OOD) is recommended, assuming it provides actionable information on discharge diuretic dosing and thus reduces readmissions. METHODS: In the Mechanisms of Diuretic Resistance (MDR) cohort, we analyzed in-hospital measures of diuretic response, provider's decisions, and diuretic response ≈30 days postdischarge. In a Yale multicenter cohort, we assessed if in-hospital OOD was associated with 30-day readmission risk. The main objective of this study was to evaluate the utility of in-hospital OOD. RESULTS: Of the 468 patients in the MDR cohort, 57% (N=265) underwent in-hospital OOD. During the OOD, weight change and net fluid balance correlated poorly with each other (r=0.36). Discharge diuretic dosing was similar between patients who had increased, stable, or decreased weight (decreased discharge dose from OOD dose in 77% versus 72% versus 70%, respectively), net fluid status (decreased discharge dose from OOD dose in 100% versus 69% versus 74%, respectively), and urine output (decreased discharge dose from OOD dose in 69% versus 79% versus 72%, respectively) during the 24-hour OOD period (P>0.27 for all). In participants returning at 30 days for formal quantification of outpatient diuretic response (n=98), outpatient and inpatient OOD natriuresis was poorly correlated (r=0.26). In the Yale multicenter cohort (n=18 454 hospitalizations), OOD occurred in 55% and was not associated with 30-day hospital readmission (hazard ratio, 0.98 [95% CI, 0.93-1.05]; P=0.51). CONCLUSIONS: In-hospital OOD did not provide actionable information on diuretic response, was not associated with outpatient dose selection, did not predict subsequent outpatient diuretic response, and was not associated with lower readmission rate. Additional research is needed to replicate these findings and understand if these resources could be better allocated elsewhere. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02546583.

Drug-Coated Balloon and Drug-Eluting Stent Safety in Patients With Femoropopliteal and Severe Chronic Kidney Disease.

Background Patients with severe-stage chronic kidney disease (CKD) were excluded from femoropopliteal disease trials evaluating drug-coated balloons (DCBs) and drug-eluting stents (DESs) versus plain balloon angioplasty (POBA) and bare metal stents (BMSs). We examined the interaction between CKD status and device type for the association with 24-month all-cause mortality and major amputation risk. Methods and Results We studied patients undergoing femoropopliteal interventions (September 2016-December 2018) from Medicare-linked VQI (Vascular Quality Initiative) registry data. We compared outcomes for: (1) early-stage CKD (stages 1-3) receiving DCB/DES, (2) early-stage CKD receiving POBA/BMS, (3) severe-stage (4 and 5) CKD receiving DCB/DES, and (4) severe-stage CKD receiving POBA/BMS. We studied 8799 patients (early-stage CKD: 94%; severe-stage: 6%). DCB/DES use was 57% versus 51% in patients with early-stage versus severe-stage CKD. Twenty-four-month mortality risk for patients with early-stage CKD receiving DCB/DES (reference) was 21% versus 28% (hazard ratio [HR], 1.47 [95% CI, 1.31-1.65]) for those receiving POBA/BMS; patients with severe-stage CKD: those receiving DCB/DES had a 49% (HR, 2.61 [95% CI, 2.06-3.31]) mortality risk versus 52% (HR, 3.64 [95% CI, 2.91-4.55]) for those receiving POBA/BMS (interaction P<0.001). Adjusted analyses attenuated these results. For severe-stage CKD, DCB/DES versus POBA/BMS mortality risk was not significant at 24 months (post hoc comparison P=0.06) but was higher for the POBA/BMS group at 18 months (post hoc P<0.05). Patients with early-stage CKD receiving DCB/DES had the lowest 24-month amputation risk (6%), followed by 11% for early-stage CKD-POBA/BMS, 15% for severe-stage CKD-DCB/DES, and 16% for severe-stage CKD-POBA/BMS (interaction P<0.001). DCB/DES versus POBA/BMS amputation rates in patients with severe-stage CKD did not differ (post hoc P=0.820). Conclusions DCB/DES versus POBA/BMS use in patients with severe-stage CKD was associated with lower mortality and no difference in amputation outcomes.

Measurement Properties of the Timed Functional Arm and Shoulder Test in Patients With Shoulder Problems.

OBJECTIVE: The purpose of this study was to determine the feasibility, reliability, validity, and responsiveness of the Timed Functional Arm and Shoulder Test (TFAST) in patients with shoulder problems. METHODS: This study was a repeated-measures clinical measurement observational cohort study. A total of 104 patients who were symptomatic participated in this study. The TFAST was collected as part of an patient's outpatient physical therapist care at 6 different sites. The test and data collection were performed at 3 time points: baseline (initial evaluation), follow-up at the patient's first return visit within 7 days of evaluation, and discharge at the patient's final visit for care. RESULTS: All participants were able to perform the TFAST at baseline, with 1 exception, and 67 participants completed data collection at all 3 time points. There were no adverse effects in any participant related to performing the TFAST. Intrarater intersession reliability, reported as ICC(2,1), was 0.91 (95% CI = 0.79-0.95). The mean difference in TFAST scores for the affected arm was 23.2 repetitions (77.4 at baseline to 100.6 at discharge). The Cohen d effect size was 1.02, and the standardized response mean was 0.95. The minimal clinically important difference was determined to be 21 repetitions. CONCLUSION: The TFAST seems to be feasible and appropriate for use in a wider population than other existing shoulder performance measures. The TFAST has demonstrated adequate reliability, validity, and responsiveness in patients with shoulder problems. Clinicians may consider using the TFAST to objectively assess patient performance. IMPACT: The TFAST may be used to expand measurement of objective shoulder performance in a wide population of patients with shoulder problems. This test may provide information beyond an patient's self-report and contribute to clinical decision-making.

Hemoconcentration of Creatinine Minimally Contributes to Changes in Creatinine during the Treatment of Decompensated Heart Failure.

Background: Worsening serum creatinine is common during treatment of acute decompensated heart failure (ADHF). A possible contributor to creatinine increase is diuresis-induced changes in volume of distribution (VD) of creatinine as total body water (TBW) contracts around a fixed mass of creatinine. Our objective was to better understand the filtration and nonfiltration factors driving change in creatinine during ADHF. Methods: Participants in the ROSE-AHF trial with baseline to 72-hour serum creatinine; net fluid output; and urinary KIM-1, NGAL, and NAG were included (n=270). Changes in VD were calculated by accounting for measured input and outputs from weight-based calculated TBW. Changes in observed creatinine (Crobserved) were compared with predicted changes in creatinine after accounting for alterations in VD and non-steady state conditions using a kinetic GFR equation (Cr72HR Kinetic). Results: When considering only change in VD, the median diuresis to elicit a ≥0.3 mg/dl rise in creatinine was -7526 ml (IQR, -5932 to -9149). After accounting for stable creatinine filtration during diuresis, a change in VD alone was insufficient to elicit a ≥0.3 mg/dl rise in creatinine. Larger estimated decreases in VD were paradoxically associated with improvement in Crobserved (r=-0.18, P=0.003). Overall, -3% of the change in eCr72HR Kinetic was attributable to the change in VD. A ≥0.3 mg/dl rise in eCr72HR Kinetic was not associated with worsening of KIM-1, NGAL, NAG, or postdischarge survival (P>0.05 for all). Conclusions: During ADHF therapy, increases in serum creatinine are driven predominantly by changes in filtration, with minimal contribution from change in VD.