Intensive Care Unit–Acquired Weakness in Patients With Acute Kidney Injury: A Contemporary Review

Acute kidney injury (AKI) and intensive care unit–acquired weakness (ICU-AW) are 2 frequent complications of critical illness that, until recently, have been considered unrelated processes. The adverse impact of AKI on ICU mortality is clear, but its relationship with muscle weakness—a major source of ICU morbidity—has not been fully elucidated. Furthermore, improving ICU survival rates have refocused the field of intensive care toward improving long-term functional outcomes of ICU survivors. We begin our review with the epidemiology of AKI in the ICU and of ICU-AW, highlighting emerging data suggesting that AKI and AKI treated with kidney replacement therapy (AKI-KRT) may independently contribute to the development of ICU-AW. We then delve into human and animal data exploring the pathophysiologic mechanisms linking AKI and acute KRT to muscle wasting, including altered amino acid and protein metabolism, inflammatory signaling, and deleterious removal of micronutrients by KRT. We next discuss the currently available interventions that may mitigate the risk of ICU-AW in patients with AKI and AKI-KRT. We conclude that additional studies are needed to better characterize the epidemiologic and pathophysiologic relationship between AKI, AKI-KRT, and ICU-AW and to prospectively test interventions to improve the long-term functional status and quality of life of AKI survivors. Acute kidney injury (AKI) and intensive care unit–acquired weakness (ICU-AW) are 2 frequent complications of critical illness that, until recently, have been considered unrelated processes. The adverse impact of AKI on ICU mortality is clear, but its relationship with muscle weakness—a major source of ICU morbidity—has not been fully elucidated. Furthermore, improving ICU survival rates have refocused the field of intensive care toward improving long-term functional outcomes of ICU survivors. We begin our review with the epidemiology of AKI in the ICU and of ICU-AW, highlighting emerging data suggesting that AKI and AKI treated with kidney replacement therapy (AKI-KRT) may independently contribute to the development of ICU-AW. We then delve into human and animal data exploring the pathophysiologic mechanisms linking AKI and acute KRT to muscle wasting, including altered amino acid and protein metabolism, inflammatory signaling, and deleterious removal of micronutrients by KRT. We next discuss the currently available interventions that may mitigate the risk of ICU-AW in patients with AKI and AKI-KRT. We conclude that additional studies are needed to better characterize the epidemiologic and pathophysiologic relationship between AKI, AKI-KRT, and ICU-AW and to prospectively test interventions to improve the long-term functional status and quality of life of AKI survivors. Acute kidney injury (AKI) is a common complication of critical illness, and up to 15% of patients with AKI in the intensive care unit (ICU) receive kidney replacement therapy (KRT).1Griffin B.R. Liu K.D. Teixeira J.P. Critical care nephrology: core curriculum 2020.Am J Kidney Dis. 2020; 75: 435-452https://doi.org/10.1053/j.ajkd.2019.10.010Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Though further studies are needed, AKI and treatment with KRT may contribute to skeletal muscle dysfunction through multiple mechanisms. This article reviews the proposed pathophysiology of skeletal muscle loss and dysfunction in critical illness with a focus on patients with AKI treated by KRT (AKI-KRT). We describe preclinical and clinical data suggesting that AKI and AKI-KRT may independently contribute to ICU-acquired weakness (ICU-AW) (Fig 1), suggest interventions that may mitigate or prevent ICU-AW in AKI patients, and identify areas of uncertainty in need of future research. Despite the many unanswered questions, we propose that nephrologists should recognize AKI as risk factor for long-term functional impairment after critical illness and learn to routinely consider referring AKI survivors to physical rehabilitation. In contemporary international cohorts, the incidence of AKI ranges from 20% to >50% of all ICU admissions, with 5% to 15% of critically ill patients developing AKI-KRT.2Hoste E.A. Bagshaw S.M. Bellomo R. et al.Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.Intensive Care Med. 2015; 41: 1411-1423https://doi.org/10.1007/s00134-015-3934-7Crossref PubMed Scopus (1361) Google Scholar,3Bouchard J. Acharya A. Cerda J. et al.A prospective international multicenter study of AKI in the intensive care unit.Clin J Am Soc Nephrol. 2015; 10: 1324-1331https://doi.org/10.2215/CJN.04360514Crossref PubMed Scopus (154) Google Scholar Moreover, the rates of AKI, AKI-KRT, and AKI-related mortality have increased substantially in the last 20 years.4Wald R. McArthur E. Adhikari N.K. et al.Changing incidence and outcomes following dialysis-requiring acute kidney injury among critically ill adults: a population-based cohort study.Am J Kidney Dis. 2015; 65: 870-877https://doi.org/10.1053/j.ajkd.2014.10.017Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,5Brown J.R. Rezaee M.E. Marshall E.J. Matheny M.E. Hospital mortality in the United States following acute kidney injury.Biomed Res Int. 2016; 20164278579https://doi.org/10.1155/2016/4278579Crossref Scopus (42) Google Scholar Recently, the COVID-19 pandemic has further increased KRT use in the ICU. AKI complicates 25% to 40% of all COVID-19 admissions, and AKI-KRT develops in 20% to 45% of critically ill COVID-19 patients.6Chan L. Chaudhary K. Saha A. et al.AKI in hospitalized patients with COVID-19.J Am Soc Nephrol. 2021; 32: 151-160https://doi.org/10.1681/ASN.2020050615Crossref PubMed Scopus (323) Google Scholar AKI, especially AKI-KRT, carries a high short-term mortality of ≥50% across diverse ICU populations with or without COVID-19.1Griffin B.R. Liu K.D. Teixeira J.P. Critical care nephrology: core curriculum 2020.Am J Kidney Dis. 2020; 75: 435-452https://doi.org/10.1053/j.ajkd.2019.10.010Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,4Wald R. McArthur E. Adhikari N.K. et al.Changing incidence and outcomes following dialysis-requiring acute kidney injury among critically ill adults: a population-based cohort study.Am J Kidney Dis. 2015; 65: 870-877https://doi.org/10.1053/j.ajkd.2014.10.017Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,6Chan L. Chaudhary K. Saha A. et al.AKI in hospitalized patients with COVID-19.J Am Soc Nephrol. 2021; 32: 151-160https://doi.org/10.1681/ASN.2020050615Crossref PubMed Scopus (323) Google Scholar, 7Teixeira J.P. Ambruso S. Griffin B.R. Faubel S. Pulmonary consequences of acute kidney injury.Semin Nephrol. 2019; 39: 3-16https://doi.org/10.1016/j.semnephrol.2018.10.001Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 8Clermont G. Acker C.G. Angus D.C. Sirio C.A. Pinsky M.R. Johnson J.P. Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes.Kidney Int. 2002; 62: 986-996https://doi.org/10.1046/j.1523-1755.2002.00509.xAbstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 9Bellomo R. Cass A. et al.Investigators RRTSIntensity of continuous renal-replacement therapy in critically ill patients.N Engl J Med. 2009; 361: 1627-1638https://doi.org/10.1056/NEJMoa0902413Crossref PubMed Scopus (1085) Google Scholar, 10Palevsky P.M. Zhang J.H. et al.Network VNARFTIntensity of renal support in critically ill patients with acute kidney injury.N Engl J Med. 2008; 359: 7-20https://doi.org/10.1056/NEJMoa0802639Crossref PubMed Scopus (1328) Google Scholar Furthermore, observational studies have increasingly linked AKI to long-term impairments in functional status, including limited mobility, worsened quality of life (QoL), and muscle weakness.11Ahlstrom A. Tallgren M. Peltonen S. Rasanen P. Pettila V. Survival and quality of life of patients requiring acute renal replacement therapy.Intensive Care Med. 2005; 31: 1222-1228https://doi.org/10.1007/s00134-005-2681-6Crossref PubMed Scopus (147) Google Scholar, 12Johansen K.L. Smith M.W. Unruh M.L. et al.Predictors of health utility among 60-day survivors of acute kidney injury in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study.Clin J Am Soc Nephrol. 2010; 5: 1366-1372https://doi.org/10.2215/CJN.02570310Crossref PubMed Scopus (74) Google Scholar, 13Mayer K.P. Ortiz-Soriano V.M. Kalantar A. Lambert J. Morris P.E. Neyra J.A. Acute kidney injury contributes to worse physical and quality of life outcomes in survivors of critical illness.BMC Nephrol. 2022; 23: 137https://doi.org/10.1186/s12882-022-02749-zCrossref PubMed Scopus (2) Google Scholar Despite chronic kidney disease (CKD) being a recognized risk factor for AKI, the relationship between AKI-on-CKD and outcomes of critical illness appears to be complex, with data suggesting mortality rates are higher in AKI-on-CKD patients than in patients with neither AKI nor CKD but lower than in patients with AKI in the setting of normal baseline kidney function.14Khosla N. Soroko S.B. Chertow G.M. et al.Preexisting chronic kidney disease: a potential for improved outcomes from acute kidney injury.Clin J Am Soc Nephrol. 2009; 4: 1914-1919https://doi.org/10.2215/CJN.01690309Crossref PubMed Scopus (88) Google Scholar,15Neyra J.A. Mescia F. Li X. et al.Impact of acute kidney injury and CKD on adverse outcomes in critically ill septic patients.Kidney Int Rep. 2018; 3: 1344-1353https://doi.org/10.1016/j.ekir.2018.07.016Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar The interplay between AKI-on-CKD and long-term functional outcomes remains unknown. ICU-AW is defined as muscle weakness and wasting (atrophy) resulting from critical illness.16Latronico N. Herridge M. Hopkins R.O. et al.The ICM research agenda on intensive care unit-acquired weakness.Intensive Care Med. 2017; 43: 1270-1281https://doi.org/10.1007/s00134-017-4757-5Crossref PubMed Scopus (106) Google Scholar The reported incidence of ICU-AW ranges from 40% in systematic reviews17Appleton R.T. Kinsella J. Quasim T. The incidence of intensive care unit-acquired weakness syndromes: a systematic review.J Intensive Care Soc. 2015; 16: 126-136https://doi.org/10.1177/1751143714563016Crossref PubMed Scopus (78) Google Scholar to >80% in individual studies.18Coakley J.H. Nagendran K. Yarwood G.D. Honavar M. Hinds C.J. Patterns of neurophysiological abnormality in prolonged critical illness.Intensive Care Med. 1998; 24: 801-807https://doi.org/10.1007/s001340050669Crossref PubMed Scopus (148) Google Scholar Muscle wasting occurs early and rapidly during critical illness.19Files D.C. Sanchez M.A. Morris P.E. A conceptual framework: the early and late phases of skeletal muscle dysfunction in the acute respiratory distress syndrome.Crit Care. 2015; 19: 266https://doi.org/10.1186/s13054-015-0979-5Crossref PubMed Scopus (28) Google Scholar We and others have reported that 3% to 5% of baseline rectus femoris muscle size is lost in the first day of ICU admission, with up to 30% lost in the first 10 days.20Mayer K.P. Thompson Bastin M.L. Montgomery-Yates A.A. et al.Acute skeletal muscle wasting and dysfunction predict physical disability at hospital discharge in patients with critical illness.Crit Care. 2020; 24: 637https://doi.org/10.1186/s13054-020-03355-xCrossref PubMed Scopus (43) Google Scholar, 21Parry S.M. El-Ansary D. Cartwright M.S. et al.Ultrasonography in the intensive care setting can be used to detect changes in the quality and quantity of muscle and is related to muscle strength and function.J Crit Care. 2015; 30: 1151.e9-14https://doi.org/10.1016/j.jcrc.2015.05.024Crossref PubMed Scopus (226) Google Scholar, 22Puthucheary Z.A. Phadke R. Rawal J. et al.Qualitative ultrasound in acute critical illness muscle wasting.Crit Care Med. 2015; 43: 1603-1611https://doi.org/10.1097/ccm.0000000000001016Crossref PubMed Google Scholar, 23Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600https://doi.org/10.1001/jama.2013.278481Crossref PubMed Scopus (1077) Google Scholar Importantly, ICU-AW may persist for years and is associated with mortality, hospital readmission, long-term functional impairment, and lower QoL.24Hermans G. Van Mechelen H. Clerckx B. et al.Acute outcomes and 1-year mortality of intensive care unit-acquired weakness: a cohort study and propensity-matched analysis.Am J Respir Crit Care Med. 2014; 190: 410-420https://doi.org/10.1164/rccm.201312-2257OCCrossref PubMed Scopus (313) Google Scholar, 25Herridge M.S. Tansey C.M. Matte A. et al.Functional disability 5 years after acute respiratory distress syndrome.N Engl J Med. 2011; 364: 1293-1304https://doi.org/10.1056/NEJMoa1011802Crossref PubMed Scopus (1766) Google Scholar, 26Jolley S.E. Bunnell A.E. Hough C.L. ICU-acquired weakness.Chest. 2016; 150: 1129-1140https://doi.org/10.1016/j.chest.2016.03.045Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Traditional risk factors (Fig 2) for ICU-AW include preexisting comorbidity, high illness severity, sepsis, acute respiratory failure, prolonged immobilization, hyperglycemia, advanced age, and prolonged exposure to corticosteroids, sedatives, or paralytics.25Herridge M.S. Tansey C.M. Matte A. et al.Functional disability 5 years after acute respiratory distress syndrome.N Engl J Med. 2011; 364: 1293-1304https://doi.org/10.1056/NEJMoa1011802Crossref PubMed Scopus (1766) Google Scholar,26Jolley S.E. Bunnell A.E. Hough C.L. ICU-acquired weakness.Chest. 2016; 150: 1129-1140https://doi.org/10.1016/j.chest.2016.03.045Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Recent data suggest that ICU patients with AKI and AKI-KRT may also be at increased risk of ICU-AW. Specifically, a recent prospective multicenter cohort study of 642 intubated patients identified days on KRT as an independent risk factor for ICU-AW.27Raurell-Torreda M. Arias-Rivera S. Marti J.D. et al.Care and treatments related to intensive care unit-acquired muscle weakness: a cohort study.Aust Crit Care. 2021; 34: 435-445https://doi.org/10.1016/j.aucc.2020.12.005Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Likewise, our group analyzed a cohort of 104 ICU survivors and found that patients with stage 2 or 3 AKI had increased severity of muscle weakness, lower health-related QoL, and impaired ability to return to work or driving.13Mayer K.P. Ortiz-Soriano V.M. Kalantar A. Lambert J. Morris P.E. Neyra J.A. Acute kidney injury contributes to worse physical and quality of life outcomes in survivors of critical illness.BMC Nephrol. 2022; 23: 137https://doi.org/10.1186/s12882-022-02749-zCrossref PubMed Scopus (2) Google Scholar However, additional data are needed to further investigate the link between the risk of ICU-AW and AKI, KRT, potential confounding factors such as ICU length of stay, and overall illness severity. For this review, in concert with prior guidelines28Stevens R.D. Marshall S.A. Cornblath D.R. et al.A framework for diagnosing and classifying intensive care unit-acquired weakness.Crit Care Med. 2009; (37(10)(suppl):S299-S308)https://doi.org/10.1097/CCM.0b013e3181b6ef67Crossref Scopus (350) Google Scholar we will use the term ICU-AW as a framework that encompasses muscle atrophy, weakness, and dysfunction in ICU patients. Muscle dysfunction (ie, impaired muscle performance) due to critical illness typically results from overlapping effects of myopathy and neuropathy; however, as we will outline, the studies linking AKI and ICU-AW are overwhelmingly centered on muscle rather than nerve function. Assessment of skeletal muscle in the ICU is influenced by a patient’s ability to engage and follow simple commands and the time course and severity of their illness. With the emerging data linking AKI to ICU-AW, nephrologists practicing in the ICU should have foundational knowledge of the diagnosis and measures of ICU-AW to be able to interpret results and communicate effectively with intensivists, interprofessional team members, patients, and their care partners as part of patient-centered care (Table 1).Table 1Clinical and Research Tests to Diagnose ICU-AW or Assess Skeletal Muscle in the ICUTest or ModalityDescriptionLimitationsProviderSetting or Time FrameInterpretationMedical Research Council-sum score (MRC-ss)28Stevens R.D. Marshall S.A. Cornblath D.R. et al.A framework for diagnosing and classifying intensive care unit-acquired weakness.Crit Care Med. 2009; (37(10)(suppl):S299-S308)https://doi.org/10.1097/CCM.0b013e3181b6ef67Crossref Scopus (350) Google Scholar•Standardized manual muscle strength testing of 12 predefined bilateral muscle groups(shoulder abductors,elbow flexors,wrist extensors,hip flexors,knee extensors,foot dorsiflexors)•6-point ordinal scale (0: no contraction; 5: normal strength against full resistance) with total score of 0-60•Gold standard and clinical standard for diagnosing ICU-AW•Requires patient engagement and cognitive function•Ordinal scale may reduce sensitivity•Physical therapist•Occupational therapist•Dietician•PhysiatristaPhysiatrists are physicians specializing in physical medicine and rehabilitation.•Upon ICU awakening and repeated serially•MilestonesbPatient milestones include any change in medical or functional status that requires re-evaluation (ie, clinical decompensation or fall); ICU and hospital discharge; and 1, 3, 6, and 12 months after discharge.<48/60, with no other etiology of weakness, constitutes a diagnosis of ICU-AWHandgrip dynamometry (HGD)29Parry S.M. Berney S. Granger C.L. et al.A new two-tier strength assessment approach to the diagnosis of weakness in intensive care: an observational study.Crit Care. 2015; 19: 52https://doi.org/10.1186/s13054-015-0780-5Crossref PubMed Scopus (46) Google Scholar•Evaluates handgrip strength (concurrent strength of the elbow flexors and wrist extensors)•Standardized position recommended•Continuous outcome in kg or lb of force improves objectivity•Requires patient engagement and cognitive function•Requires equipment•Physical therapist•Occupational therapist•Dietician•PhysiatristaPhysiatrists are physicians specializing in physical medicine and rehabilitation.•Upon ICU awakening and repeated serially•MilestonesbPatient milestones include any change in medical or functional status that requires re-evaluation (ie, clinical decompensation or fall); ICU and hospital discharge; and 1, 3, 6, and 12 months after discharge.<7 kg (F) and <11 kg (M) suggests a diagnosis of ICU-AWHandheld dynamometry (HHD)110Baldwin C.E. Paratz J.D. Bersten A.D. Muscle strength assessment in critically ill patients with handheld dynamometry: an investigation of reliability, minimal detectable change, and time to peak force generation.J Crit Care. 2013; 28: 77-86https://doi.org/10.1016/j.jcrc.2012.03.001Crossref PubMed Scopus (73) Google Scholar•Evaluates strength (force generated) of a selected muscle group (eg, knee extensors)•Standardized position recommended•Continuous outcome in kg or lb of force improves objectivity•Requires patient engagement and cognitive function•Requires equipment•Physical therapist•Occupational therapist•Dietician•PhysiatristaPhysiatrists are physicians specializing in physical medicine and rehabilitation.•Rarely used in clinical practice•Commonly used in researchScore cutoffs not established for ICU-AW diagnosisMuscle ultrasound20Mayer K.P. Thompson Bastin M.L. Montgomery-Yates A.A. et al.Acute skeletal muscle wasting and dysfunction predict physical disability at hospital discharge in patients with critical illness.Crit Care. 2020; 24: 637https://doi.org/10.1186/s13054-020-03355-xCrossref PubMed Scopus (43) Google Scholar, 21Parry S.M. El-Ansary D. Cartwright M.S. et al.Ultrasonography in the intensive care setting can be used to detect changes in the quality and quantity of muscle and is related to muscle strength and function.J Crit Care. 2015; 30: 1151.e9-14https://doi.org/10.1016/j.jcrc.2015.05.024Crossref PubMed Scopus (226) Google Scholar, 22Puthucheary Z.A. Phadke R. Rawal J. et al.Qualitative ultrasound in acute critical illness muscle wasting.Crit Care Med. 2015; 43: 1603-1611https://doi.org/10.1097/ccm.0000000000001016Crossref PubMed Google Scholar, 23Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600https://doi.org/10.1001/jama.2013.278481Crossref PubMed Scopus (1077) Google Scholar,30Lambell K.J. Tierney A.C. Wang J.C. et al.Comparison of ultrasound-derived muscle thickness with computed tomography muscle cross-sectional area on admission to the intensive care unit: a pilot cross-sectional study.JPEN J Parenter Enteral Nutr. 01 2021; 45: 136-145https://doi.org/10.1002/jpen.1822Crossref PubMed Scopus (19) Google Scholar•Ultrasonography to visualize and assess respiratory and peripheral skeletal muscles•Evaluates muscle quantity: thickness, cross-sectional area, and estimated mass•Evaluates muscle composition: pennation angle, fascicle length, elastography, and EI•Requires equipment•Requires training•Heterogeneity in reported techniques, positioning, and landmarkingTrained sonographercTrained sonographer may be from any professional discipline who has received ultrasound-specific training; no current standard for muscle ultrasonography certification exists.•Variable use in clinical practice•Day 0 and repeated serially•Commonly used in research•20%-30% reduction in muscle size in first 10 d of ICU admit suggests ICU-AW•Increased EI associated with myofiber necrosis and worse patient outcomesCT or MRI30Lambell K.J. Tierney A.C. Wang J.C. et al.Comparison of ultrasound-derived muscle thickness with computed tomography muscle cross-sectional area on admission to the intensive care unit: a pilot cross-sectional study.JPEN J Parenter Enteral Nutr. 01 2021; 45: 136-145https://doi.org/10.1002/jpen.1822Crossref PubMed Scopus (19) Google Scholar•Imaging modalities with precise and accurate measures of muscle mass and composition•Cross-sectional area of psoas by CT at L3 most commonly used•Expensive•Requires significant planning in ICU for scheduling and for patient safetyRadiologist•Rarely used for muscle assessment•Typically ordered for other purpose and muscle is a secondary assessmentPsoas major muscle mass appears representative of whole-body muscle and predictive of patient outcomesEMG and evoked forces111Kennouche D. Luneau E. Lapole T. Morel J. Millet G.Y. Gondin J. Bedside voluntary and evoked forces evaluation in intensive care unit patients: a narrative review.Crit Care. 2021; 25: 157https://doi.org/10.1186/s13054-021-03567-9Crossref PubMed Scopus (4) Google Scholar•Nonvolitional measurements of motor axon depolarization (evoked force) by either electrical or magnetic stimuli•Objective measure of evoked force using an ergometer•Expensive•Requires training and equipment•Stimuli may cause discomfort•PhysiatristaPhysiatrists are physicians specializing in physical medicine and rehabilitation.•Neurologist•Physical therapist with training•Rarely used in clinical practice•Primarily used in research•Compared to healthy controls or followed longitudinally•No standardized valuesMuscle biopsy28Stevens R.D. Marshall S.A. Cornblath D.R. et al.A framework for diagnosing and classifying intensive care unit-acquired weakness.Crit Care Med. 2009; (37(10)(suppl):S299-S308)https://doi.org/10.1097/CCM.0b013e3181b6ef67Crossref Scopus (350) Google Scholar•Most commonly obtained from vastus lateralis and performed with local anesthesia•Immunohistochemical, histochemical, and biochemical examinations of tissue•Expensive•Invasive•Risk of complications•Physician or AP provider with training•Pathologist•Rarely used in clinical practice•Occasionally used in research•Interpreted by pathologists•Norms established for certain parametersAbbreviations: AP, advanced practice; AW, acquired weakness; CT, computed tomography; EI, echo intensity (a surrogate marker of muscle quality); EMG, electromyography; F, female; ICU, intensive care unit; L3, level of third lumbar vertebra; M, male; MRI, magnetic resonance imaging.a Physiatrists are physicians specializing in physical medicine and rehabilitation.b Patient milestones include any change in medical or functional status that requires re-evaluation (ie, clinical decompensation or fall); ICU and hospital discharge; and 1, 3, 6, and 12 months after discharge.c Trained sonographer may be from any professional discipline who has received ultrasound-specific training; no current standard for muscle ultrasonography certification exists. Open table in a new tab Abbreviations: AP, advanced practice; AW, acquired weakness; CT, computed tomography; EI, echo intensity (a surrogate marker of muscle quality); EMG, electromyography; F, female; ICU, intensive care unit; L3, level of third lumbar vertebra; M, male; MRI, magnetic resonance imaging. ICU-AW is diagnosed by assessing global muscle strength testing using the Medical Research Council–Sum Score (MRC-ss) in the appropriate clinical setting.26Jolley S.E. Bunnell A.E. Hough C.L. ICU-acquired weakness.Chest. 2016; 150: 1129-1140https://doi.org/10.1016/j.chest.2016.03.045Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar,28Stevens R.D. Marshall S.A. Cornblath D.R. et al.A framework for diagnosing and classifying intensive care unit-acquired weakness.Crit Care Med. 2009; (37(10)(suppl):S299-S308)https://doi.org/10.1097/CCM.0b013e3181b6ef67Crossref Scopus (350) Google Scholar MRC-ss grades volitional strength in 12 predefined peripheral muscle groups (bilateral shoulder abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, and foot dorsiflexors). Handgrip dynamometry measures grip strength and has been proposed as a valid and reliable screening tool for ICU-AW, but like MRC-ss it requires patient participation.29Parry S.M. Berney S. Granger C.L. et al.A new two-tier strength assessment approach to the diagnosis of weakness in intensive care: an observational study.Crit Care. 2015; 19: 52https://doi.org/10.1186/s13054-015-0780-5Crossref PubMed Scopus (46) Google Scholar Imaging permits muscle assessment in patients who are unable to follow commands, potentially leading to earlier detection of ICU-AW. Computed tomography (CT) can quantify muscle size and quality but is rarely performed clinically for this purpose. Muscle ultrasound has similarly been proposed as a diagnostic tool to assess muscle size and quality and has been demonstrated in ICU patients to correlate well with CT-derived measures30Lambell K.J. Tierney A.C. Wang J.C. et al.Comparison of ultrasound-derived muscle thickness with computed tomography muscle cross-sectional area on admission to the intensive care unit: a pilot cross-sectional study.JPEN J Parenter Enteral Nutr. 01 2021; 45: 136-145https://doi.org/10.1002/jpen.1822Crossref PubMed Scopus (19) Google Scholar and immunohistochemical analysis of muscle biopsy specimens.22Puthucheary Z.A. Phadke R. Rawal J. et al.Qualitative ultrasound in acute critical illness muscle wasting.Crit Care Med. 2015; 43: 1603-1611https://doi.org/10.1097/ccm.0000000000001016Crossref PubMed Google Scholar,23Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600https://doi.org/10.1001/jama.2013.278481Crossref PubMed Scopus (1077) Google Scholar However, whether ultrasound reliably predicts patient-relevant outcomes including ICU-AW requires further study. Electromyography (EMG), nerve conduction velocity studies (NCV), and muscle biopsy may be useful to diagnose ICU-AW but are relatively costly and invasive techniques typically reserved for complex neuromuscular disorders and research. Ultimately, imaging, EMG/NCV, and muscle biopsy are diagnostic adjuncts to strength testing by trained providers using MRC-ss; despite its limitations, strength testing remains the gold standard and most practical method to diagnose ICU-AW. Multiple mechanisms have been proposed for ICU-AW (Fig 1). Critical illness is associated with a significant inflammatory response, which has been demonstrated in experimental studies to alter mitochondrial, myofibrillar, and collagen protein homeostasis and to trigger myofibrillary oxidative stress.19Files D.C. Sanchez M.A. Morris P.E. A conceptual framework: the early and late phases of skeletal muscle dysfunction in the acute respiratory distress syndrome.Crit Care. 2015; 19: 266https://doi.org/10.1186/s13054-015-0979-5Crossref PubMed Scopus (28) Google Scholar Additional animal, space flight, and human research has shown that disuse or immobility lead to muscle atrophy through mechanical silencing—the process of inducing myosin loss and atrophy through the removal or reduction of internal (ie, muscle contraction) or external (ie, loading or weight-bearing) stimuli.31Llano-Diez M. Renaud G. Andersson M. et al.Mechanisms underlying ICU muscle wasting and effects of passive mechanical loading.Crit Care. 2012; 16: R209https://doi.org/10.1186/cc11841Crossref PubMed Scopus (87) Google Scholar Patients requiring mechanical ventilation with deep sedation are therefore at the greatest risk of muscle dysfunction. We propose that AKI and AKI-KRT may independently contribute to ICU-AW. Though muscle wasting in CKD, including in kidney failure, has been studied for decades,32Coles G.A. Body composition in chronic renal failure.Q J Med. 1972; 41: 25-47PubMed Google Scholar,33Solagna F. Tezze C. Lindenmeyer M.T. et al.Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs.J Clin Invest. 2021; 131e135821https://doi.org/10.1172/JCI135821Crossref PubMed Scopus (15) Google Scholar less is known about muscle wasting i